1
Pediatric epileptology
Habilitation thesis
(Collection of published scholarly works with commentary)
Pavlína Danhofer, M.D., Ph.D.
Department of Pediatric Neurology, Faculty of Medicine,
Masaryk University, University Hospital Brno
Brno 2022
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I hereby declare that I wrote this habilitation thesis on my own, using the relevant resources
listed in the references.
………….........................
Signature
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Commentary:
Pediatric epileptology is a very important branch of pediatric neurology. The classification of the
epilepsies has changed significantly in recent years, pointing to experience we know from clinical
practice: Is Rolandic epilepsy benign, indeed? Do idiopathic epilepsies always have a good prognosis?
Is it only epileptiform discharges in the EEG that interfere with the neurodevelopment of a child with
epilepsy? There are still many questions; advances in diagnostics, especially genetic, answer some of
them. The genetics of epilepsies have made tremendous progress and elucidated the cause of epilepsy
in many of our patients. It ended a very exhausting and stressing diagnostic oddyssey and relieved many
patients and their families. It also showed us a new path that is a huge challenge for pediatric
epileptologists and a promising outlook for the future - precision medicine strategy. Treating not only
the symptoms of epilepsy, but also its cause sounds like the music of the future and we believe it will
become more and more real.
The author's work is divided into several parts, which are interwoven with her own scientific results and
observations.
The first part deals with the classification of seizure types and epilepsies.
The second part focuses on the description of important epileptic syndromes and outlines the proposal
of the forthcoming ILAE Classification of Epileptic Syndromes.
The last part is focused on the genetic causes of epilepsy and concludes the work on linking genetics
and phenotype to "new genetic epileptic syndromes" with the possibility of applying precision medicine
strategy.
Where relevant, chapters are accompanied by commentaries introducing the topic of each publication,
describing the current state of knowledge and how the author has contributed to knowledge in this field.
The work is based on research activities at the authors’ workplaces, the Department of Pediatric
Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno.
The work is concluded with a collection of author´s published scholarly works with commentary.
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Content:
ACKNOWLEDGMENTS: ....................................................................................................................................6
ABBREVIATIONS: ...............................................................................................................................................7
1 INTRODUCTION AND BACKGROUND ...............................................................................................12
1.1 INCIDENCE AND PREVALENCE OF EPILEPSY: ..........................................................................................12
1.2 EPILEPTIC SEIZURE.................................................................................................................................12
1.2.1 Focal epileptic seizures ....................................................................................................................13
1.2.2 Generalised epileptic seizures..........................................................................................................15
1.2.3 Provoked vs. unprovoked seizures....................................................................................................17
1.3 EPILEPSY................................................................................................................................................22
1.4 EPILEPTIC SYNDROMES..........................................................................................................................25
1.4.1 Epilepsy syndromes of neonatal and infantile period ......................................................................27
1.4.2 Epilepsy syndromes of childhood period..........................................................................................40
1.4.3 Epilepsy syndromes of adolescence..................................................................................................48
1.5 THE NEW ILAE PROPOSAL FOR THE CLASSIFICATION OF EPILEPTIC SYNDROMES ..................................54
1.5.1 ILAE Classification & Definition of epilepsy syndromes in the neonate and infant: Position statement
by the ILAE Task Force on nosology and definitions....................................................................................54
1.5.2 ILAE Classification and definition of epilepsy syndromes with onset in childhood: Position paper by
the ILAE Task Force on nosology and definitions.........................................................................................55
1.5.3 ILAE Classification and definition of epilepsy syndromes with onset at a variable age: Position
statement by the ILAE Task Force on nosology and definitions – Fig. 28....................................................57
1.5.4 ILAE Definition of the Idiopathic generalized epilepsy syndromes: Position statement by the ILAE
Task Force on nosology and definitions........................................................................................................57
1.6 ETIOLOGY ..............................................................................................................................................59
1.6.1 Structural etiology............................................................................................................................59
1.6.2 Genetic etiology................................................................................................................................59
1.6.3 Infectious etiology.............................................................................................................................66
1.6.4 Metabolic etiology ............................................................................................................................66
1.6.5 Immune etiology ...............................................................................................................................66
1.7 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHIES .........................................................................67
1.8 PRECISION MEDICINE STRATEGY:...........................................................................................................70
1.9 CONCLUSION: ........................................................................................................................................72
1.10 REFERENCES:.........................................................................................................................................73
2 ANNEXES - COLLECTION OF AUTHOR´S PUBLISHED SCHOLARLY WORKS WITH
COMMENTARY..................................................................................................................................................84
2.1 ANNEX 1:...............................................................................................................................................84
2.2 ANNEX 2:...............................................................................................................................................96
2.3 ANNEX 3:..............................................................................................................................................102
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2.4 ANNEX 4...............................................................................................................................................110
2.5 ANNEX 5...............................................................................................................................................117
2.6 ANNEX 6...............................................................................................................................................122
2.7 ANNEX 7...............................................................................................................................................128
2.8 ANNEX 8...............................................................................................................................................134
2.9 ANNEX 9...............................................................................................................................................139
2.10 ANNEX 10:............................................................................................................................................143
2.11 ANNEX 11:............................................................................................................................................149
2.12 ANNEX 12.............................................................................................................................................156
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Acknowledgments:
I would like to thank ass. prof. Hana Ošlejšková M.D., Ph.D. who tought me the pediatric
epileptology and who guided me throughout my clinical research projects. I also want to thank
all my clinical collaborators from the Center for Epilepsy Brno - Department of Pediatric
Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno and 1st
Department of Neurology, Faculty of Medicine, Masaryk University and St. Anne Hospital
Brno. I would like to particularly mention prof. Ivan Rektor M.D., Ph.D., prof. Milan Brázdil
M.D., Ph.D., prof. Robert Kuba, M.D., Ph.D., Ondřej Horák M.D., Michal Ryzí M.D., Ph.D.
and Senad Kolář M.D. Finally, many thanks to my whole family for their support especially
during the period of two maternity leaves.
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Abbreviations:
ACE – angiotensin converting enzyme
ACTH – adrenocorticotropin hormone
ADHD – Attention deficit hyperactivity disorder
ALDH7A1 - aldehyde Dehydrogenase 7 Family Member A1
ALG13 - UDP-N-Acetylglucosaminyltransferase Subunit
ARX - aristaless-related homeobox
ASS – acute symptomatic seizure
BDZ - benzodiazepine
BRD2 - bromodomain containing 2
CACNA1A - calcium voltage-gated channel subunit alpha1 A
CACNB4 - voltage-dependent L-type calcium channel subunit beta-4
CAE – childhood absence epilepsy
CBZ - carbamazepine
CDKL5 - cyclin-dependent kinase-like 5
CHD2 - chromodomain DNA helicase protein 2
CLB - clobazame
CLCN2 - chloride voltage-gated channel 2
CLZ - clobazame
CNS – central nervous system
CNV – copy number variant
COE-G – childhood occipital epilepsy - Gastaut
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CSF – cerebrospinal fluid
CSWS – cerebral salt wasting syndrome
CTS – centrotemporal spike
DBS – deep brain stimulation
DEE – developmental and epileptic encephalopathy
DNET – dysembryoplastic neuroepithelial tumor
DNM1 - Dynamin 1
DS – Dravet syndrome
DSAP – Dystonia severity action plan
EFMR – epilepsy related to females with mental retardation
EEG - electoencephalogrphy
EFHC1- EF-hand domain containing 1
ELP4 – elongator protein 4
EMG - electromyography
ERBB4 - Erb-B2 receptor tyrosine kinase 4
ESES – electrical status epilepticus in sleep
ESM - ethosuximide
FBM - felbamate
FBTCS – focal to bilateral tonic-clonic seizure
FOXG1 - forkhead box G1
GABRA1 - gamma-aminobutyric acid type A receptor subunit alpha1
GABRB2 - gamma-aminobutyric acid type A receptor subunit beta2
GABRB3 - gamma-aminobutyric acid type A receptor subunit beta3
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GABRG2 - gamma-aminobutyric acid type A receptor subunit gamma2
GEE – genetic generalized epilepsy
GLUT1 – glucose transporter 1
GNAO1 – G-protein subunit alpha O1
GPi-DBS – globus pallidus internus – deep brain stimulation
GPR56 – G-protein-coupled receptor
GRIN2A - glutamate ionotropic receptor NMDA type subunit 2A
GTCS – generalized tonic-clonic seizure
ICK - intestinal cell kinase
ICU – intensive care unit
IGE – idiopathic generalized epilepsy
ILAE – Intenrational League Against Epilepsy
IQ – intelligence quocient
IS – infantile spasms
JAE – Juvenile absence epilepsy
JME – Juvenile myoclonic epilepsy
KCNA2 - potassium voltage-gated channel subfamily A member 2
KCNB1 - potassium voltage-gated channel subfamily B member 2
KCNQ2 - potassium voltage-gated channel subfamily Q member 2
KCNQ3 - potassium voltage-gated channel subfamily Q member 3
LCM - lacosamide
LGG – low-grade glioma
LGS – Lennox-Gastaut syndrome
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MAE – Myoclonic-atonic epilepsy
MAG12 - membrane associated guanylate kinase
MEI – Myoclonic epilepsy in infancy
MRI – magnetic resonance imaging
mTOR - mammalian target of rapamycin
MTS – mesiotemporal sclerosis
NGS – next-generation sequencing
NREM – non-rapid eye movement
OXC - oxcarbazepine
PB - phenobarbital
PER - perampanel
PHT - phenytoin
PRES – Posterior reversible encephalopathy snydrome
PRRT2 - proline-rich transmembrane protein 2
RFN - rufinamide
S-B – suppresion-burst
SCB – sodium-channel blockers
SCN1A - sodium voltage-gated channel alpha subunit 1
SCN1B - sodium voltage-gated channel beta subunit 1
SCN2A - sodium voltage-gated channel alpha subunit 2
SCN8A - sodium voltage-gated channel alpha subunit 8
SI – spike index
SIADH - syndrome of inappropriate antidiuretic hormone
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SIK1 - saltiInducible kinase 1
SLC2A1 - solute carrier family 2 member 1
SLC25A22 - solute carrier family 52 member 22
SLC4A22 - solute carrier family 4 member 22
SMEI – Severe myoclonic epilepsy of infancy
SPTAN1 - spectrin alpha, non-erythrocytic 1
SSRI - selective serotonin reuptake inhibitors
STM - sulthiame
STXBP1 - syntaxin-binding protein 1
SWA – slow-wave activity
TPM - topiramate
TSC1 – tuberous sclerosis complex 1
TSC2 - tuberous sclerosis complex 2
VNS – vagal nerve stimulation
WES – whole-exome sequencing
WGS – whole-genome sequencing
WS – West syndrome
ZDHHC9 - zinc finger DHHC-type palmitoyltransferase 9
ZNS - zonisamide
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1 Introduction and background
1.1 Incidence and prevalence of epilepsy:
Epilepsy is one of the most common chronic neurological diseases in children. The incidence
of epilepsy in childhood is highest in the first year of age, estimated at 144 / 100,000 in children
aged 0-1 years and 58 / 100,000 in children aged 1-10 years (1). The cumulative incidence (total
proportion of children with epilepsy aged 0-10 years) is reported to be 0.66% (1). Graphically,
the results are shown in Fig. 1. A systematic review and meta-analysis of 222 international
studies on epilepsy incidence and prevalence reported a point prevalence of epilepsy of 6.38
per 1,000 persons (95% CI 5.57-7.30), a pooled lifetime prevalence of 7.6 per 1,000 and an
incidence rate of 61.44 per 100,000 patients / year (95% CI 50.75 - 74.38) (2).
Fig. 1: Incidence of epilepsy in children in the first 10 years of age (1).
1.2 Epileptic seizure
In 2005, the International League Against Epilepsy (ILAE) formulated a conceptual definition
of seizures and epilepsy. According to this definition, an epileptic seizure is defined as a
transient occurrence of symptoms resulting from abnormal excessive or synchronous (epileptic)
neuronal activity in the brain (3). According to the new 2017 ILAE Classification of seizure
types (4), seizures are divided into focal, generalized and seizures of unknown origin - all these
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groups are further divided into the category of motor seizures, or seizures without motor
manifestations (see Fig. 2).
Fig. 2: ILAE 2017 Classification of seizure types (4)
1.2.1 Focal epileptic seizures
In focal seizures, the initial clinical manifestations and / or EEG changes suggest the onset in
part of one cerebral hemisphere. Localization can be very discrete or widely distributed. Focal
seizures can begin in subcortical structures. For each type of seizure, the ictal onset is given and
unchanged, and there are preferential propagation patterns that can extend into the contralateral
hemisphere (5). A state of awareness can be classified for focal seizures. An aware seizure
means that the affected person is aware of himself / herself and the environment throughout the
course of the course, even though he is, for example, immobile or aphasic. A seizure with
impaired awareness means that consciousness is not maintained during the seizure. Focal
seizures, with or without impaired awareness, are further subdivided into motor or non-motor.
Furthermore, the individual groups are specified, as shown schematically in Fig. 2. The
assignment of a certain term is decided by the first predominant symptom or manifestation of
the seizure (5).
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Focal motor seizures: are characterized by the dominance of motor manifestations. For some,
these are unnatural movements and body positions different from physiological movements for
their unnatural speed, chronology or posture (focal clonic, myoclonic, tonic, etc.). In other
seizures, it is a complex motor activity similar to physiological movement patterns, but which
occurs in an inadequate situation (eg automatisms).
Focal motor seizures with automatisms are characterized by the presence of unconscious
movements - licking lips, clapping, swallowing, scratching, playing with clothes or a blanket,
etc.
Focal atonic seizures are manifested by a short (250ms-1s) and sudden loss or decrease in
muscle tone of the head, body, jaws and limbs without previous myoclonic or tonic
manifestations.
Hyperkinetic seizures are characterized by marked physical agitation or the occurrence of
movements resembling pedaling a bicycle.
Cognitive seizures express a disorder of speech or other cognitive functions or, conversely,
describe positive symptoms reported by a patient, such as déjà vu, hallucinations, illusions, or
feelings of distorted perception.
Emotional seizures express subjectively reported anxiety, fear, joy, or other emotions as the
predominant symptom reported at the onset of the seizure, but also the situation around the
observed emotional expression in a patient without subjectively reported emotions.
In a seizure with behavioral arrest, the disappearance of the patient's activity is the
predominant symptom (5).
The 2010 ILAE Revision of the classification (6) and the 2017 ILAE Classification of seizure
types (4) also include epileptic spasms; first in the group of seizures of unknown origin (6),
then according to the new classification either in the group of focal seizures, generalized or with
unknown origin (4). Their correct classification requires detailed analysis of the video-EEG
recording. Because epileptic spasms may continue beyond the age of infancy or even occur de
novo outside this age, it is no longer recommended to use the term infantile spasms as before.
If a focal seizure spreads to both hemispheres and a tonic-clonic seizure develops, the term
"focal to bilateral tonic-clonic seizure - FBTCS" is used (4).
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1.2.2 Generalised epileptic seizures
Generalized seizures are characterized by the fact that the first clinical changes indicate the
involvement of both hemispheres (EEG patterns are bilateral from the beginning). They are also
divided into motor seizures or non-motor seizures (= absences). Generalized seizure
manifestations can be asymmetric, which sometimes makes it difficult to distinguish them from
focal seizures.
1.2.2.1 Generalised motor seizures
Tonic-clonic (GTCS): are characterised by bilateral symmetrical tonic contraction, then
bilateral clonic contractions of somatic muscles usually associated with autonomic phenomena.
Examples of GTCSs in children include most febrile seizures and GTCSs in idiopathic
(=genetic) eplepsies (IGEs, GGEs), such as juvenile myoclonic epilepsy (JME). Focal
epilepsies can manifest with focal seizures evolving to bilateral tonic-clonic seizures (FBTCS).
Investigations of symptoms and precipitating factors immediately before the onset of a GTCS
is a crucial part of the history taking, with significant diagnostic and management implications.
Ictal EEG: Rhythm at ≥ 10 cycles/s decreasing in frequency and increasing in amplitude during
tonic phase. Interrupted by slow waves during clonic phase.
Clonic: manifest by bilateral rhythmic clonic convulsions only. Each clonic event lasts ˂100ms
at a rate of 1-5Hz. They should be distinguished from myoclonic seizures; clonic seizures are
rhythmic at 1-5Hz, whereas myoclonic seizures are singular or irregular recurrent events.
Ictal EEG: each clonic convulsion corresponds to a generalised discharge of spike and multiple
spikes or, more rarely, a mixture of rapid rhythms and slow waves.
Tonic: convulsive attacks of sustained muscular contractions only, without clonic component.
They are of longer duration than myoclonic jerks and spasms (>2 – 10s).
Ictal EEG: low-voltage, fast activity or a fast rhythm 9-10 cycles/s, decreasing in frequency and
increasing in amplitude.
Myoclonic: myoclonus is termed epileptic when it occurs in combination with cortical
epileptiform discharges. Another possible definition is that myoclonus is epileptic when
generated in the cortex, and non-epileptic, when generated in subcortical structures.
Panayitopoulos proposes the following definition: epileptic myoclonus is a transient (˂100 ms)
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involuntary single or multiple muscle jerk due to abnormal excessive synchronous neuronal
activity in the brain (7). Myoclonic seizures are briefer than tonic seizures and epileptic spasms.
Ictal EEG: polyspike and wave or sometimes spike and wave or sharp and slow wave.
Atonic: a sudden loss or diminution of muscle tone without an apparent preceding myoclonic
or tonic event, lasting approximately 1 or 2 s, involving the head, trunk, jaw or limb
musculature.
Ictal EEG: polyspikes and wave or flattening or low-voltage fast activity.
Epileptic spasms: seizures that can be generalised, focal, or of unclear onset. Epileptic spasms
are sudden and brief bilateral tonic contractions of the axial and proximal limb muscles with
abrupt onset and termination. They usually last for around 1 s and thus they are of longer
duration than myoclonic jerks but of shorter duration than tonic seizures. The most common
and characteristic form of epileptic spasm is with West syndrome (WS) but epileptic spasm
may also occur in older children with epileptic encephalopathies. They are usually symmetrical
and may involve widespread muscle groups or only the neck, abdomen or shoulders.
Lateralising features may occur. Subtle spasms may occur as episodes of facial grimacing or
isolated eye movements. The end of the attack is often followed by a cry or laughter. Epileptic
spasms usually occur in clusters, often on awakening (7).
Ictal EEG: is heterogenous; a high amplitude, biphasic, slow wave or spike and wave activity
may occur.
The new ILAE 2017 Classification of seizure types also recognizes the inclusion of seizure
combinations: myoclonic-atonic and myoclonic-tonic-clonic as new types (4).
1.2.2.2 Generalized non-motor seizures
Typical absence seizures: generalized epileptic seizures of abrupt onset and abrupt
termination, clinically manifesting as impairment of consciousness often associated with other
concomitant symptoms, such as myoclonia, automatisms or autonomic distrubances. In 90% of
patients, they are precipitated by hyperventilation. Other specific modes of precipitation include
photic, pattern, video games and thinking.
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Ictal EEG: generalized spike-slow wave discharges of 3 – 4 Hz. Typical absence seizures are
present in childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE), mild can be
seen in juvenile myoclonic epilepsy (JME) (7).
Atypical absence seizures: clinical symptoms of mild-to-severe impairment of consciousness,
often significant changes in tone with hypotonia and atonia, mild tonic or autonomic alterations.
Their duration ranges from 5-10s to minutes. Atypical absence seizures occur in the context of
severe epileptic encephalopathies, typically in Lennox-Gastaut syndrome (LGS), myoclonicatonic
epilepsy (MAE) etc.
Ictal EEG: slows generalised spike-wave discharegs (˂2.5Hz). These are hererogenous, often
assymetrical.
Absences with eyelid myoclonias could be placed in a group of generalized seizures with
motor manifestations. Because eyelid myoclonias are the most prominent clinical feature of
these seizures, they are placed in the category of absences.
1.2.3 Provoked vs. unprovoked seizures
Seizures can be divided into unprovoked, occurring in the absence of precipitating factors and
provoked – acute symptomatic seizures (ASSs) as explained below.
At this point, it is important to highlight the issue of reflex seizures, which by definition are
ranked among the unprovoked. These are, for example, seizures that occur in response to photo
stimuli and are therefore provoked. However, because there is a clear trend to respond to these
stimuli with repeated seizures, there is an abnormal permanent predisposition to them, and
therefore the occurence of reflex seizures meets the conceptual definition of epilepsy (7).
Provoked seizures - acute symptomatic seizures (ASSs) occur in close temporal connection
with the ongoing CNS structural, toxic, metabolic or inflammatory insult. ASSs have higher
early mortality, which depends on their cause. However, they have lower risk of further
unprovoked seizures and the development of epilepsy (4).
The causes of ASSs are for example as follows (8):
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Hypoglycaemia
In hypoglycemia, we can often see focal seizures that may divert our attention to the search for
the structural cause of the seizures. In the case of the development of any ASS, it is necessary
to consider the possibility of hypoglycemia.
Hypocalcaemia
The level of ionized calcium is crucial, which depends on the blood pH and decreases during
alkalosis (binding to albumin). Therefore, we must be careful with the correction of metabolic
acidosis in patients with limit values of ionized calcium.
Hypomagnesaemia
Diarrhea, insufficient income, malabsorption are the main causes of this condition.
Hyponatremia
Hyponatremia can occur in cardiac or renal edema or iatrogenically in hyperhydration. It can
also have intracranial causes after head injuries or neurosurgical procedures - the syndrome of
inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt wasting syndrome
(CSWS), the mechanism of which is inadequate renal sodium loss accompanied by
hypovolemia. CSWS increases the production of brain natriuretic peptide, leading to increased
sodium excretion and renal loss of sodium and water. This produces a large volume of diluted
urine and reduces the extracellular volume of water. In SIADH, fluid retention and dilution
hyponatremia occur, so the volume of the extracellular fluid is normal, hypervolemia develops,
and highly concentrated urine is formed with a small volume. The cause may be an injury,
infection, stroke, drugs (tricyclic antidepressants, carbamazepine, ACE inhibitors, vincristine,
etc.). Hyponatremia leads to the development of cerebral edema. With hyponatremia below 125
mmol/l, gastrointestinal symptoms (nausea, vomiting) appear, and when sodium falls below
120 mmol/l, mild cognitive dysfunction is added. More severe encephalopathy with ASSs,
delirium and coma occurs when sodium drops below 120 mmol/l.
Cerebral hypoxia and anoxia
This condition can occur for a number of reasons - heart and circulation failure in myocardial
infarction, arrhythmia, bleeding, septic shock, etc. In diffuse hypoxia, the hippocampus and
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cerebellum are affected first, then the cerebral cortex, the most resistant is the brainstem. Shortterm
hypoxia can lead to the development of syncope, which can also be convulsive, then it
acts as an epileptic seizure.
Drug causes
The combination of tramadol with SSRIs, for example, or some chemotherapeutics, which we
often encounter in pediatric oncology patients (methotrexate, ifosfamide), has a proconvulsant
effect.
Withdrawal syndrome
After the withdrawal of barbiturates, opiates or benzodiazepines, especially after a rapid action.
Brain tumor
Supratentorial tumors in children are less common, and even in this location the risk of
developing seizures is relatively low compared to adult patients. Epileptic seizure as an initial
symptom has been described in 15% of children with supratentorial tumor localization (8). Only
1% of children after the first epileptic seizure were diagnosed with a brain tumor as the
underlying cause. Brain tumors in children occur predominantly in the posterior fossa, their
growth is rapid and they are highly malignant. Such tumors often have symptoms other than
seizures, based on their location and the extent of brain tissue involvement. ASSs in these
tumors are caused mainly by decompensation of intracranial pressure, which is caused by rapid
tumor growth and collateral edema. In contrast, slow-growing tumors such as dysembryoplastic
neuroepithelial tumor (DNET) or low-grade gliomas (LGGs) are associated with a risk of
seizures and the development of epilepsy. DNET is often associated with a malformation of
cortical development and epileptogenicity is ensured by cortical dysplasia in its surroundings.
Epileptic seizures in these children can be the first manifestation of the disease. Children are
treated for epilepsy and can be candidates for epileptosurgery.
Stroke
In general, stroke is rare in children. ASSs in this condition occur in 4.2-6.1% of cases. Most
of them take place within 24 hours after the onset of clinical symptoms (9). They are slightly
more common in hemmorhagic stroke. In cerebral venous thrombosis, ASS occurs in up to 40%
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of cases (8). It is necessary to perform brain MRI with venography in these pateints and
carefully search for cerebral venous thrombosis.
CNS infections
As ASSs are concerned, brain abscesses are especially important. As many as a quarter of
patients with a brain abscess manifest with ASS (8).
Posterior Reversible Encephalopathy Syndrome (PRES)
As mentioned above, ASSs also occur, for example, in PRES syndrome, which is a clinicoradiological
syndrome. This is defined as transient cerebral vasogenic edema, which occurs
preferentially in the posterior cerebral circulation. It is clinically characterized by headaches,
seizures, impaired consciousness, visual and other focal neurological symptoms (10). The
radiological finding of vasogenic edema in the posterior cerebral circulation is characteristic,
but other areas may also be affected, especially the basal ganglia, brainstem and white matter
(Fig. 3). The pathophysiology of the syndrome is unclear. Arterial hypertension and endothelial
dysfunction, which lead to a blood-brain barrier disorder and the development of vasogenic
brain tissue edema, are thought to occur (10). Moderate to severe hypertension can be traced in
up to 75% of patients (11). In pediatrics, this syndrome is most commonly encountered in
oncology patients, especially in children with hematological malignancies during the protocol
treatment.
The author studied PRES in children treated at the Department of Pediatric Oncology of the
Faculty of Medicine, Masaryk University and University Hospital Brno in the years 2008-2018
and evaluated a group of 21 patients with this diagnosis (12). ASSs were identified in 17 of 21
patients (80.9%), 4 of 21 patients (19.0%) had seizures even after the acute period, and epilepsy
was present in 2 of 21 children (9.5%) at one-year follow-up. Interestingly, both of these
patients had glial changes on the brain MRI. These two patients were discussed from the point
of pathophysiology. Were there other factors in addition to vasogenic edema at PRES onset?
Vasogenic edema should be reversible and possibly other factors that worsened the patients´
prognosis were involved. The key finding was that PRES is mainly reversible with a good
prognosis and seizures in this syndrome are mostly acute symptomatic (12).
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Fig. 3: MRI at PRES onset showing FLAIR (a,b) and T2-weightened (c,d) subcortical
hyperintensities in occipital regions with right predominance.
Images from the archive of the Department of Pediatric Radiology, Faculty of Medicine, Masaryk University,
University Hospital Brno.
Annex 1
c
a
)
b
a
)
d
a
)
a
a
)
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1.3 Epilepsy
Epilepsy was defined in 2005 as a disorder of the brain characterized by an enduring
predisposition to generate epileptic seizures, and by the neurobiologic, cognitive,
psychological, and social consequences of this condition. The definition of epilepsy requires
the occurrence of at least one epileptic seizure (3). In 2014, the ILAE newly proposed an
amendment to the conceptual definition of epilepsy for practical clinical needs (13):
Epilepsy is a disease of the brain defined by any of the following conditions:
1. At least two unprovoked (or reflex) seizures occurring >24 h apart
2. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general
recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years
3. Diagnosis of an epilepsy syndrome
Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy
syndrome but are now past the applicable age or those who have remained seizure-free for the
last 10 years, with no antiseizure medication for the last 5 years (13).
Epilepsy is a very heterogeneous group of diseases and their correct classification, including
the determination of etiology, has a major impact on treatment and prognosis (3). The current
ILAE 2017 Classification of the epilepsies is multi-level and, where possible, should be set at
all three levels (14). See Fig. 4.
The first level is the seizure type classification, as discussed in the previous chapter.
Classifications of seizure type and epilepsy also take into account the results of examinations
such as EEG and imaging methods, along with others to reveal the etiology of epilepsy.
The second level is the determination of the type of epilepsy - see the 2014 definition of epilepsy
(13). Thus, we distinguish between focal and generalized epilepsy; since 2017, two new groups
have been added: combined generalized and focal epilepsy and epilepsy of an unknown origin
(14).
A patient with generalized epilepsy typically has generalized discharges of spike and wave
complexes in the EEG. These patients may have different types of generalized seizures:
absence, myoclonic, atonic, tonic, tonic-clonic, etc. The diagnosis is conditioned by a typical
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clinical manifestation and EEG findings. Caution should be exercised if the patient has a history
of generalized tonic-clonic seizures and a negative EEG. The diagnosis may be supported by,
for example, the occurrence of myoclonic jerks or a relevant family history (14).
Fig. 4: 2017 ILAE Classification of the epilepsies (14)
Focal epilepsy can be unifocal or multifocal, or seizures affect one hemisphere, as described in
detail in the previous chapter. In the EEG, we typically find focal epileptiform discharges and
the diagnosis can be based on a clinical picture supported by the EEG finding.
A new group of combined generalized and focal epilepsy, where one patient may experience
both focal and generalized seizures, is essential especially for epileptic encephalopathies.
Typically this type of epilepsy can be found in Lennox-Gastaut syndrome or Dravet syndrome
(14).
Epilepsy of an unknown type indicates a situation where the patient has epilepsy, but we are
unable to determine whether it is focal or generalized because there is a lack of information
about the type of seizures. Likewise, the EEG does not provide enough information or is not
available at all.
The third level is the determination of epileptic syndrome, as discussed below.
24
There are several major changes in the new classification of epilepsy compared to the 1989
ILAE Classification (15):
Idiopathic generalized epilepsy (IGE): this is a very well-defined and widely used term for a
group of diseases that include Childhood absence epilepsy (CAE), Juvenile absence apilepsy
(JAE), Juvenile myoclonic epilepsy (JME), and Generalized tonic-clonic seizures alone. The
last group used to be called GTCS on awakening. The circadian rhythm dependence is not
always present, thus the syndrome´s name has been changed. Recently, the name of these
epileptic syndromes has been changed to Genetic generalized epilepsy (GGE). This name has
been supported by clinical research on the inheritance of these syndromes in twin and familial
studies. This does not mean that a pathogenic sequence variant or genetic cause in general
explains the etiology of the disease in patients with GGE. Therefore, it is still possible to use
both IGE and GGE terms (14).
The term "idiopathic" has also been used to indicate that it is a highly pharmacoresponsive
syndrome, often remitting in age and essentially "benign." Concomitant cognitive and
behavioral changes in patients with these epileptic syndromes have often not been reported (14).
The author studied a group of 46 patients with JAE followed up at the Center for Epilepsy Brno
in the years 2006-2011 (16) and found that almost half of the patients had a high level of drug
resistance with ongoing seizures. On average, patients in this cohort took 4-6 antiseizure drugs.
This is an example of an epileptic syndrome generally considered to be a syndrome with a very
good prognosis, but the results did not support this claim.
Annex 2
A similar question also arose in the group of „benign focal epilepsies“, where Rolandic eplepsy
(Self-limited epilepsy with centrotemporal spikes) is a typical example. This syndrome was
considered as benign for a long time, as the name suggested (formerly Benign childhood
epilepsy with centrotemporal spikes – BCECTS). The truth is that most patients with this
syndrome have a very good prognosis, but the accompanying cognitive and behavioral changes
in these children cannot be neglected, and this syndrome is typically associated with Attention
Deficit Hyperactivity Disorder (ADHD) (17–19). Even before the announcement of the new
ILAE 2017 Classification of the epilepsies in 2017 (14), the author prepared her dissertation on
25
the topic "The influence of EEG-detected nocturnal centrotemporal discharges on the
expression of on core symptoms of ADHD in children with BCECTS" (20). The work evaluated
32 children aged 6-11 years treated at the Department of Pediatric Neurology, Faculty of
Medicine, Masaryk University and University Hospital Brno, with a diagnosis of Rolandic
epilepsy. ADHD was diagnosed in 65.8% of them. Patients with greater activation of
epileptiform discharges in sleep also had a higher rate of attention deficit and impulsivity. The
influence of nocturnal epileptiform discharges on the development of cognitive functions in the
critical period of development of neuropsychological functions was extensively discussed in
the work.
The ILAE 2017 Classification of the epilepsies leaves the labeling of "benign focal epilepsies"
as benign. The renaming this group to "self-limited focal epilepsies" is somewhat more
appropriate, reflects their age and does not emphasize the benign course, which may not always
be a condition. Other self-limited focal childhood epilepsy is Panayitopoulos syndrome and
Self-limited focal occipital epilepsy of Gastaut. Self-limited epilepsis of the frontal lobe,
temporal lobe or parietal lobe have been described with beginning in adolescence or even in
adulthood (14).
Annex 3
1.4 Epileptic syndromes
An epileptic syndrome is a condition characterized by epileptic seizures in which a consistent
cluster of clinical, EEG and investigative features has specific etiological, management and
prognostic implications. An epileptic syndrome may have one or more etiologies. When a single
etiology is associated with a consistent epilepsy phenotype, the etiology, for example a genetic
or structural lesion, may best define the syndrome rather than a single clinical feature or
eponym. The definition would allow hippocampal sclerosis with focal seizures, hypothalamic
hamartoma with gelastic seizures, and CDKL5 developmental and epileptic encephalopathy to
all be classified as epileptic syndrome (21).
26
Neonatal
benign familial and non-familial neonatal seizures (BFNS, BNFNS)
early myoclonic encephalopathy (EME)
early infantile epileptic encephalopathy (EIEE)
Infantile
Infantile spasms syndrome (West syndrome - WS)
Lennox-Gastaut syndrome (LGS)
epilepsy of infancy with migrating focal seizures
myoclonic-atonic epilepsy (MAE)
myoclonic epilepsy in infancy (MEI)
Dravet syndrome (previously severe myoclonic epilepsy in infancy SMEI)
febrile seizures +
Childhood
childhood absence epilepsy (CAE)
Epilepsy with myoclonic absences (EMA)
self-limited focal epilepsy with centrotemporal spikes – Rolandic epilepsy
Panayitopoulos syndrome (PS)
Childhood occipital epilepsy of Gastaut (COE-G)
Encephalopathy related to status epilepticus during slow sleep (ESES) incl. Landau-Kleffner
syndrome (LKS)
Adolescence
juvenile absence epilepsy (JAE)
epilepsy with absences with eyelid myoclonia
juvenile myoclonic epilepsy (JME)
generalised tonic-clonic seizures only
Others
Rasmussen syndrome
new-onset refractory status epilepticus/ febrile infection related epilepsy syndrome
(NORSE/FIRES)
photosensitive epilepsy
reading epilepsy
progressive myoclonic epilepsy (PME)
frontal lobe epilepsy (FLE)
temporal lobe epilepsy (TLE) mesiotemproal limbic epilepsy syndrome (MTLE)
parietal lobe epilepsy
occipital lobe epilepsy
hemiplegia/hemiconvulsions syndrome (HHS)
Tab. 1: Epileptic syndromes divided by age at onset; frequently used in pediatric neurology
practice (taken from (21)).
27
A number of epileptic syndromes are currently described, but their formal classification has not
yet been issued by the ILAE.
Tab.1 summarizes the overview of the most important and most common age-related epileptic
syndromes used in pediatric neurological practice.
The next part will be devoted to selected clinically important age-related epileptic syndromes
– adopted and modified from (7) and (21):
All EEG graphs are from the archive of the Department of Pediatric Neurology, Faculty of
Medicine, Masaryk University, University Hospital Brno.
1.4.1 Epilepsy syndromes of neonatal and infantile period
1.4.1.1 Benign familial and non-familial neonatal seizures
Patients have typically neonatal onset of seizures, usually on the second or third day of life, and
spontaneous remission by 6 months of age. Seizures are focal with different motor
manifestations, mainly clonic, never tonic. They are often lateralised, starting on one side then
affecting the other side.
EEG findings: interictal EEG is normal, discontinuous with focal or multifocal abnormalities
or with theta pointu alternant pattern. The ictal pattern is characterised by a generalized
flattening of the background activity followed by focal or bilateral spikes or slow waves lasting
as long as the clinical manifestation.
Etiology: The linkage studies led to the identification of mutations in the voltage-gated
potassium channel genes KCNQ2 and KCNQ3 (22, 23). Spectrum of phenotypes associated
with KCNQ2 and KCNQ3 mutations and gene variants have been also associated to different
epileptic phenotypes, from self-limited to drug-resistant epilepsy associated with
developmental delay. More recently the phenotype of KCNQ2-related developmental and
epileptic encephalopathy has been distinguished into two clinical phenotypes due to the
different impact of the mutation on the channel functionality (gain or loss of function) (24).
Variants that cause the loss of function cause the neonatal onset epileptic encephalopathy, while
variants that cause a gain of function of the potassium channel cause a developmental and
epileptic encephalopathy (DEE) with an infantile onset with epileptic spasms followed by drug-
28
resistant focal epilepsy and the occurence of non-epileptic myoclonus during the first months
of life (24).
Treatment: This type of epilepsy syndrome is characterised by good prognosis, seizures are
self-limited independently from the treatment. Nevertheless, seizures may be difficult to control
in the neonatal period, then we use PB or BDZ. Currently, the use of sodium-channel blocker,
such as CBZ and PHT, is preffered (21).
1.4.1.2 Early severe neonatal and infantile epilepsies - Early myoclonic encephalopathy
(EME) and Ohtahara syndrome - Early infantile epileptic encephalopathy
(EIEE)
ILAE described two age-dependent electroclinical syndromes characterised by encephalopathy
which occur in the neonatal period (6): Early myoclonic encephalopathy (EME) and Ohtahara
syndrome, also known as Early infantile epileptic encephalopathy (EIEE). Each of these
syndromes are characterised by a specific clinical seizure type, clinical signs of encephalopathy
and a suppression-burst (S-B) pattern on the EEG (Fig. 5 and 6). Detailed comparison between
EME and EIEE is shown in Tab. 2.
Etiology: Two etiologic factors in EME received the most attention: genetic disorders or inborn
errors of metabolism. Kojima et al. (25) recently summarized reported genetic causes of EME
to include involvement of KCNQ2, ERBB4, SIK1, SLC4A22, and GABRB2. The most
commonly reported inborn error of metabolism connected wth EME is nonketotic
hyperglycinemia (26). Other reported metabolic disorders include hyerglycinemia, D-glyceric
acidemia, methylmalonic acidemia, hyperammonemia, and propionic acidemia (21).
Although genetic factors have been most recently extensively investigated in EIEE, structural
brain abnormalities still represent the most important etiologic factor in EIEE, making detailed
neuroimaging critical component of the evaluation of these infants (21). Several authors
reported cases of EIEE associated with mitochondrial chain deficiency (27,28). In a recent
review, Pearl et al. (29) listed genes which have been associated with EIEE: CDKL5,
SLC25A22, STXBP1, KCNQ2 and SCN2A.
Treatment: Due to the high degree of farmacoresistance, therapy is usually unsuccessful. If
infants survive, transition to West syndrome is possible.
29
EME EIEE
predominant seizure type erratic myoclonus tonic spasms
other possible seizure type
generalized myoclonus,
focal seizures, tonic
spasms (late)
focal seizures, generalized
myoclonus (rare), no erratic
myoclonus
neurological examination abnormal, hypotonia
abnormal, lateralized in case of
brain structural abnormalities
EEG features
S-B with short
paroxysmal bursts and
longer period of
suppression, S-B
enhanced in sleep
S-B with longer periods of bursts
and shorter periods of suppression
evolution West syndrome
West syndrom or EEG and epilepsy
improvement
etiology
metabolic disorders;
genetic
CNS structural abnormalities;
genetic
prognosis
early death or
progressive deterioration
of survivors
mental retardation, severe
neurological impairment, variable
epilepsy outcome
Tab. 2: Clinical features of EME vs. EIEE (21)
Fig. 5: Early myoclonic encephalopathy: Suppression-bursts EEG pattern with myoclonic
jerks associated to the bursts in a neonate with non-ketotic hyperglycinemia.
30
Fig. 6: Early infantile epileptic encephalopathy (Ohtahara syndrome): Suppression-bursts
EEG pattern with left-sided accentation in a 3-month-old child with extensive malformation of
the cortical development (focal cortical dysplasia) predominantly in the left temporo-parietal
region.
1.4.1.3 Infantile spasms syndrome (IS; West syndrome)
The development of this syndrome is most common in the first year of age, around 3 to 4 months
of age, then it is called West syndrome. The syndrome is characterized by the occurence of
epileptic spasms and hypsarhytmia on EEG (Fig. 7-11) frequently associated with modification
of behavior or cognitive decline.
Etiology: Etiology of IS is classified as structural, genetic, infectious, metabolic, immune, or
unknown (4). Genetic etiology represents about 25% of IS (30). Several chromosomal
abnormalities have been reported in about a fourth of spasms of genetic etiology and the most
frequent are trisomy 21, XXY, 17p13.3 microdeletion, and 1p36 del (31,32). Moreover,
mutations in X-linked genes have been described such as CDKL5, particularly in female, and
ARX, usually in male patients (33). Other gene mutation (SCN1A, MAG12, CACNA1A) have
also been reported (34). IS can also be the first manifestation of tuberous sclerosis with mutation
in TSC1 or TSC2 gene. In about 20% of IS, the underlying cause is unknown (21).
31
Fig. 7: West syndrome: High-amplitude slow waves intermingled with spikes with
asynchronous occurence – the EEG pattern of hypsarrhythmia in a 5-month-old child with West
syndrome of unknown etiology.
Fig.8: West syndrome: Ictal pattern of epileptic spasms in a 4-month-old child with CACNA1Arelated
DEE. The ictal pattern is an asynchronous high amplitude diffuse slow wave.
Treatment: Hormonal treatment (ACTH or corticosteroids) and vigabatrin (VGB) are now
considered as two standard first line therapies. Earlier the diagnosis and earlier the treatment,
32
better the developmental outcome (35). Conventional antiseizure medication is less efficient
than standard therapy, VPA, TPM, or ZNS are frequently used.
Fig. 9: West syndrome: Left-sided hemihypsarrhythmia in an 8-month-old girl with severe
perinatal hypoxic-ischemic encephalopathy.
Fig. 10: West syndrome: Ictal pattern of epileptic spasms in an 8-month-old girl with severe
hypoxic-ischemic perinatal encephalpathy. Hemihypsarrhythmia is interrupted by a high
amplitude asynchronous slow wave in the lefte hemisphere.
33
Fig. 11: Perinatal hypoxic-ischemic encephalopathy with West syndrome: Brain MRI in a
girl with severe hypoxic-ischemic perinatal encephalopathy. T2W axial in 2,5months of age (on
the left) and T2W axial in 8 months of age.
Images from the archive of the Department of Pediatric Radiology, Faculty of Medicine, Masaryk University,
University Hospital Brno.
1.4.1.4 Dravet syndrome (DS; previously Severe Myoclonic Epilepsy in Infancy - SMEI)
Dravet syndrome was first described in 1978 by Professor Charlotte Dravet in France (36). The
development of epileptic seizures typically begins in infancy with a peak around 5 months in
still normally developing children. The incidence is reported as 1:30,000 children (7), boys are
more often affected in a 2: 1 ratio (7). The following types of seizures occur: generalized tonicclonic
seizures (or often lateralized alternating seizures), myoclonic seizures, atypical absences
and focal seizures with impaired awareness. Status epilepticus is very common, especially in
the initial period, mainly in febrile seizures.
The clinical course of DS can be divided in three stages: a "febrile phase", in the first year of
life, then a "catastrophic phase", of variable duration, and a "sequel phase" (21).
Etiology: In accordance with the ILAE 2017 Classification of the epilepsies, DS ranks
etiologically among epilepsies on a genetic basis. The vast majority of patients carry a mutation
in the sodium channel alpha1 subunit gene (SCN1A gene), this mutation occurs in 70-80% of
patients (37). There is a reduction in the excitability of GABAergic interneurons in the
34
neocortex and hippocampus (38), which results in a reduction in discharges in these inhibitory
interneurons. This will increase the excitability in the neural network and development SCN1ADEE.
There is a certain variability in these patients in the clinical picture, we speak of DSspectrum
(37).
Approximately 5% of patients carry a mutation in the PCDH19 gene with X-linked inheritance
(39). It is a gene encoding protocadherin 19, the function of which has not yet been fully
elucidated, but its involvement in neural networks is thought to be involved. The mutation
causes Epilepsy limited to females with mental retardation (EFMR). A characteristic feature
here is a lower incidence of epileptic states and myoclonic seizures rarely occur. In 45% of
patients, mental retardation is only mild, autistic features are common. Mutations in the
GABARG2 (40) and SCN1B (41) genes have rarely been identified.
Treatment: Therapeutic options are relatively rich, but their effect is limited by high drug
resistance. The drugs of first choice are VPA and BDZ (42), especially CLB. Stiripentol (STP)
is indicated if these do not work. STP is classified as an orphan-drug in DS therapy and is
approved as adjunctive therapy to VPA + CLB. DS therapy has been approved in Europe since
2007. Other therapeutic options are TPM (43) and LEV (effective mainly for myoclonic
seizures (44)), which can be used as adjunctive drugs. LTG, CBZ, VGB and high doses of PB
may worsen seizures and should be avoided. Last but not least, it is necessary to mention the
ketogenic diet, which has a relatively high effectiveness in the treatment of DS in comparison
with other epileptic encephalopathies (45). Vagal nerve stimulation (VNS) also shows
favorable results in DS therapy (46).
1.4.1.5 Myoclonic epilepsies in infancy and early childhood
1.4.1.5.1 Myoclonic epilepsy in infancy (MEI)
MEI is characterized by brief and generalized myoclonic seizures without other seizure types,
in the first three years of life in cognitively normal infants.
The age of onset is usually between 4 months and 3 years, myoclonic seizures are initially often
rare, involving the upper limb and the head. Later, their frequency increases up to several times
a day.
Etiology: the genetic contribution to MEI is unclear.
35
Treatment: VPA can lead to seizure freedom in 82.9% of patients and is considered as the first
choice treatment (47). If myoclonic seizures are not completely controlled by VPA, other
options can be chosen: CLB, CLZ, ESM, LTG (7).
1.4.1.5.2 Epilepsy with myoclonic-atonic seizures (MAE)
MAE is a childhood nonlesional generalized epilepsy with multiple seizure types, including
myoclonic-atonic seizures, absence, atonic, GTCS, and tonic seizures, and with onset between
7 months and 6 years of age.
Myoclonic-atonic seizures are characterized by brief, massive or axial, symmetrical jerks,
involving the neck, shoulders, arms and legs, often resulting in head nodding, abduction of arms
and flexion of the legs at the knees. Each jerk is immediately followed by an abrupt loss of
muscle tone that contributes causing the drop to the floor. Falls in MAE can also result from
purely myoclonic or atonic seizures. The EEG of myoclonic-atonic seizure shows bursts of
spike/polyspike and wave complexes at 2 to 4 Hz (Fig. 12 and 13). EMG recordings show that
the myoclonic potential is usually followed by an EMG silence lasting up to 500ms. The
interictal EEG can be normal at onset. Bursts of 3Hz spike-waves may occur without apparent
clinical manifestations and may be activated by sleep. The most suggestive finding is the 4 to
7 Hz theta rhythm with parietal predominance and the occipital 4-Hz rhythm which is constantly
blocked by eye opening (21).
Etiology: Genetic factors play an important role, dominant mutations have been demonstrated
in the SLC2A1 (GLUT1-deficit) (48), SCN2A (49), GABRB3 (50), and SPTAN1 genes (51).
Treatment: Treatment of myoclonic seizures is primarily with VPA, ESM and BDZ. LTG can
be effective especially in associated GTCSs. Other drugs, such as LEV, TPM and STM can be
effective. The ketogenic diet can be very effective. If a mutation on SCL2A1 has been found,
then the ketogenic diet should be used as the first-line treatment and maintained even with
seizure freedom (21).
36
Fig.12: Myoclonic-atonic epilepsy: Ictal recording in a 3-year-old boy with myoclonic-atonic
epilepsy. A myoclonic jerk is correlated with a brief and diffuse spike and wave discharge. Preictal
baskground aktivity is normal. .
Fig.13: Myoclonic-atonic epilepsy. Sleep EEG in a 3-year-old boy with MAE of unknown
etiology. Generalized polyspike wave complexes in NREM II sleep.
1.4.1.6 Lennox-Gastaut syndrome (LGS)
The LGS remains one of the most severe epileptic encephalopathies with high seizure
frequency, progressive cognitive impairment and drug resistence. In the 2017 ILAE
37
Classification of the epilepsies, LGS is classified in the new group of combined generalized
and focal epilepsies, because patients have both focal and generalized seizures (14). The typical
LGS is desribed according to the following symptomatic triad:
1) EEG abnormalities: bursts of diffuse slow spike-wave during wakefullness (Fig. 14) and
bursts of fast rhythmic waves and slow polyspikes and above all generalized fast
rhythms at about 10 Hz during sleep (Fig. 15)
2) Epileptic seizures: axial tonic (Fig. 16), atonic (Fig. 17), atypical absence (Fig. 18)
3) Slowing of intellectual growth and associated personality disorders
Etiology: Several common etiologies of LGS have been described: perinatal hypoxic
encephalopathy, cerebrovascular disorders or cerebromeningeal infections. LGS is also caused
by malformations of cortical development or chromosomal disorders. In tuberous sclerosis, the
LGS can occur with or without previous WS (52). Exome studies or case reports of patients
with LGS have shown the role of other gene mutations such as GABRB3, ALG13, SCN8A,
STXBP1, DNM1, FOXG1, CHD2 (53–55).
Fig. 14: Lennox-Gastaut syndrome: Interictal EEG in a 15-year-old patient with LennoxGastaut
syndrome of unknown etiology. Bifrontal bursts of slow spike-waves.
38
Fig. 15: Lennox-Gastaut syndrome: Interictal sleep EEG in a 15-year-old patient with LennoxGastaut
syndrome of unknown etiology. Generalized 12-Hz rhythmic activity with anterior
dominance.
Fig. 16: Lennox-Gastaut syndrome: Ictal EEG in a patient with Lennox-Gastaut syndrome of
unknown etiology. Tonic axorhizomelic seizure with an initially high-amplitude complex,
followed by low-voltage activity with fast rhythms.The discharge ends with slow delta waves
with anterior dominance.
39
Fig. 17: Lennox-Gastaut syndrome: Ictal EEG in a 15-year-old patient with Lennox-Gastaut
syndrome of unknown etiology. Atonic seizure with ictal EEG correlate of brief generalized
3Hz spike/polyspike and slow wave complex. Atonic seizure is associated with the slow wave.
Fig. 18: Lennox-Gastaut syndrome: Ictal EEG in a 15-year-old patient with Lennox-Gastaut
syndrome of unknown etiology. Atypical absence seizure with ictal correlate of fluctuating
generalized slow (1,5-2,5Hz) spike and wave complexes.
Treatment: The LGS is one of the most pharmacoresistant epileptic syndromes. It is currently
acknowledged that antiepileptic drug polytherapy is the most appropriate treatment due to the
40
severity of this type of epilepsy and to the wide range of seizure types with varying reaction to
the different molecules. VPA is the first line treatment for LGS and especially in combination
with LTG (56). VPA can also be combined with TPM, CLB, felbamate (FBM), LEV,
rufinamide (RFN), ZNS. Two antiseizure drugs have special status as "orphan drugs" in the
LGS: FBM and RFN. VNS can be very effective in patients with LGS with more than 50%
responders in this group of patients. VNS can also improve cognitive skills, alertness, behavior,
and sometimes intellectual ability and mood control (57). Another possibility of palliative
surgical treatment in patients with LGS is corpus callosotomy. Callosotomy has been discussed
in a large number of publications and clinical improvement was observed in 50 to 90% of
subjects with more than 50% decrease in seizure frequency. It is particuarly effective in
reducing falls during atonic and tonic seizures (58). Deep brain stimulation of the centromedian
nucleus of the thalamus has brought favorable results in LGS subjects (59).
1.4.2 Epilepsy syndromes of childhood period
1.4.2.1 Self-limited focal epilepsies in childhood
Self-limited focal epilepsies affect 25% of children with non-febrile seizures. They comprise
three identifiable electroclinical syndromes recognized by the ILAE: Rolandic epilepsy,
Panayitopoulos syndrome (PS) and the idiopathic childhood occipital epilepsy of Gastaut
(ICOE-G) including the idiopathic photosensitive occipital lobe epilepsy.
1.4.2.1.1 Rolandic epilepsy (self-limited epilepsy with centro-temporal spikes)
Children develop infrequent focal seizures consisting of unilateral facial sensorimotor
symptoms, oropharyngolaryngeal manifestations, speech arrest, and hypersalivation (7).
Rolandic seizures are usually brief lasting for 1-3 minutes. 75% of seizures occur during NREM
sleep, mainly at sleep onest or just before awakening.
EEG: Centrotemporal spikes (CTSs) are the hallmark of this epileptic syndrome. They are
mainly localised in the C3 and C4 electrodes. CTSs are often bilateral activated by drowsiness
and NREM sleep (Fig. 19).
41
Fig.19: Self-limited epilepsy with centrotemporal spikes: Left-sided centrotemporal spike and
wave complexes in a 6-year-old child with Rolandic epilepsy, ictal onset of a typical rolandic
focal motor seizure in the second part of the graph in the same region.
CTSs and their impact on the neuropsychological profile of patients: Although Rolandic
epilepsy used to be described as a "benign" epilepsy syndrome, many studies have revealed that
a significant number of patients have some degree of neuropsychological impairment. Despite
a favourable seizure outcome and normal intelligence, children with Rolandic epilepsy often
have difficulties in various domains of neuropsychological functioning, such as behaviour (60),
language (61,62), cognition (18,61,63), attention (17,19), and memory (19), which may lead
to learning difficulties (62,64). A prominent comorbidity in children with Rolandic epilepsy is
attention-deficit/hyperactivity disorder (ADHD) (17–19). The prevalence of ADHD in the
general population is 3% to 7% (65); it is 31% in children with this type of epileptic syndrome
(18).
Despite studies demonstrating the genetic basis of Rolandic epilepsy, the development of
symptoms of this epilepsy syndrome and typical EEG discharges are age related and time
limited. The prerequisite is thus the existence of a developmental window during which
permissive factors appear that cause changes in the processes of the aging of affected brain
areas. This developmental window is associated with cortical functional activity that can be
42
defined on the basis of regional cerebral blood flow (66) and local metabolic changes (67,68).
At birth, the regional cortical cerebral blood flow is lower than in adults. After birth, it increases
up to 5-6 years of age to values which are about 50-85% higher than in adults. It then decreases
again and reaches adult values between 5-19 years (69). The time required to reach adult values
varies depending on the area of the cortex. The shortest is in the primary cortex and the longest
in associate cortical areas. The metabolic profile measured by glucose utilization is almost
identical: low at birth, rising to 4 years of age when the child’s brain consumes up to twice as
much glucose as an adult, and then decreasing and reaching adult values at the age of 16-18.
These changes correlate with an initial overproduction and subsequent elimination of excessive
neurons, synapses, and dendrites, which can be seen in the developing brain (69). Early
development of epilepsy can have long-term effects on the developing brain. The vulnerability
of the developing brain emerges from impaired developmental processes such as
synaptogenesis, dendritic branching, neural migration, and differentiation, rather than from
neuronal death, which dominates in the case of development of seizures in adults when the brain
is already matured (70). For this reason, it is possible to see more global autistic regression with
more severe speech deficits in children with early development of ESES than in children with
LKS with relatively later development where isolated speech regression is observed. Very
different impacts of epilepsy can therefore be expected depending on the degree of the brain
maturity when epilepsy becomes active. In a study (20), the author demonstrated that children
with earlier seizure onset had lower IQs. In other neuropsychological testing, she found
statistically significantly higher attention deficit and impulsivity in children with earlier onset
of seizures. The results are supported by another study of 25 children with Rolandic epilepsy
that proved that the early onset of seizures leads to worse results in neuropsychological testing
of cognitive functions (71). Another study of 33 children with Rolandic epilepsy demonstrated
that the patients with an average epilepsy onset at around 8 years were at higher risk of
neuropsychological problems (64). In self-limited focal epilepsies, Rolandic epilepsy included,
sleep increases the frequency of epileptiform discharges and the discharges remain high during
the first phase of NREM sleep. During REM sleep, the frequency decreases; this decrease can
also be observed in other NREM sleep cycles (64). The atypical development of Rolandic
epilepsy to "Rolandic epilepsy plus" conditions shows that ongoing nocturnal epileptiform
activity causes neuropsychological deficit and the level of severity depends on the rate of awake
and sleep pathology (72). Night epileptiform discharges intervening during brain development
may lead to the impaired development of neural networks involved in various neurocognitive
functions. If these sleep discharges last for a certain time, they can lead to extensive
43
synaptogenesis with excess growth of the axons that ensure contact with the target cells. This
interferes with the process of branching of neuronal processes, thus maintaining connections
that should be eliminated. The affected neural network replaces the normal functional neuronal
network at the cortical level and frequent epileptiform discharges encourage it to further growth
so that it cannot be recovered (73). Slow wave activity (SWA) is the fundamental characteristic
of NREM sleep on scalp EEG. Its neural correlate is the slow oscillation of membrane potentials
of cortical neurons between depolarization and hyperpolarization. If these oscillations are
synchronized and the majority of cortical neurons in a certain area are affected, they are
detectable as slow waves on scalp EEG. The local increase in SWA during NREM sleep and
the decrease in other phases of sleep is important for the plasticity of learning processes and
synaptic homeostasis (74,75). The normal reduction of SWA during sleep is absent in patients
with ESES. The interference of epileptiform discharges with normal sleep SWA may explain
the cognitive deterioration in these patients (75).
In the author´s study (20), the results of detailed neuropsychological testing showed that the
occurrence of discharges in total NREM sleep led to higher attention deficit and impulsivity in
patients, but without proven statistical significance. The influence of epileptiform discharges in
children with centrotemporal EEG pathology was examined in several studies (63,64,71). These
studies found a significant negative impact of epileptiform discharge activation in patients with
Rolandic epilepsy on their neuropsychological profiles.
Annex 3
Etiology: Rolandic epilepsy is genetically determined but the genetic factors are complex. The
first clue to the epileptic cause of Rolandic epilepsy has led to pathogenic variants in the ELP4
gene (76), but other variants also appear in other locations: KCNQ2, KCNQ3 (77), GRIN2A
(78), GABRG2 (79) or ZDHHC9 (80). Still, recent studies have yielded genetic and phenotypic
heterogeneties supporting polygenic and complex inheritance pattern.
Treatment: In general, patients with infrequent, mild or nocturnal seizures may not need the
antiseizure medication. STM, VPA or LEV can be used in specific cases. Sometimes we
observe aggravation after CBZ or LTG administration (21).
44
1.4.2.1.2 Panayitopoulos syndrome
It is a common childhood-related idiopathic benign susceptibility to autonomic seizures and
autonomic status epilepticus. Seizures comprise an unusual constelation of autonomic, mainly
emetic symptoms, behavioral changes, unilateral deviation of the eyes etc. Autonomic status
epilepticus can be observed.
EEG: Interictal EEG shows great variability in functional focal spikes at various electrode
locations. Spikes are usually of high amplitude similar to CTSs. Two-thirds of patients have at
least one EEG with occipital localisation of spikes (Fig. 20), the other one third never show
occipital spikes.
Etiology: PS can be genetically determined although conventional genetic influences may be
less important.
Fig. 20: Panayitopoulos syndrome: Interictal EEG in a 7-year-old girl with Panayitopoulos
syndrome: frequent spike and wave complexes in temporo-occipital regions with right sided
amplitude dominance.
45
Treatment: Prophylactic treatment with antiseizure mediacation is not reccomended, there is no
increased risk of subsequent epilepsy or neurological deficit. Prophylaxis can be desired in
multiple seizure reccurences. Most authors prefer CBZ or VPA. LEV can be used succesfully.
1.4.2.1.3 Childhood occipital epilepsy of Gastaut (COE-G)
Sizures are occipital and primarily manifest with elementary visual hallucinations, blindness or
both. Postictal headache indistinguishable from migraine headache occurs in half of the
patients.
EEG: The interictal EEG shows mostly occipital epileptiform discharges, which are usually
bilateral and synchronous. They are activated in both occipital regions by the elimination of
fixation and central vision.
Treatment: Patients often suffer from frequent seizures, and prophylactic treatment with CBZ
is likely to be mandatory.
1.4.2.2 Encephalopathy related to status epilepticus during slow sleep (ESES) including
Landau-Kleffner syndrome
The first description of subclinical status epilepticus induced by sleep in children dates back to
1971 (81). In 1978 Kellerman et al. first documented that patients with acquired epileptic
aphasia or Landau-Kleffner syndrome (LKS) had an extreme activation of spike and wave
discharges during slow sleep consistent with ESES (82). Actually, LKS is now considered a
clinical variant of a subtype of ESES (83) (Fig. 22).
ESES syndrome is typically characterized by: focal and generalized seizures (clonic, tonicclonic,
absences), neurological deterioration, involving cognitive, behavioral and motor
domains, typical EEG finding of electrical status epilepticus during sleep, defined as the
appearance at sleep onset of a pattern of diffuse spike-and-waves occuring in up to 85% of slow
sleep (Fig. 21).
46
Etiology: ESES is often seen in patients with important perinatal insults, hydrocephalus,
malformations of cortical development and structural etiology in general. ESES has been
observed, as a rare unfavorable evolution, in children with self-limited focal epilepsies (7).
Genetic factors are difficult to define. A recent review has provided an overview of all genetic
etiologies which have been reported to be associated with ESES spectrum. The conclusion was
that SCN2A, KCNQ2, KCNB1, KCNA2 and GRIN2A contributed to the etiology of many
patients with ESES (84).
Fig. 21: Encephalopathy related to status epilepticus during slow sleep: Continuous diffuse
spike and waves activities during NREM sleep in a 5-year-old boy with ESES syndrome.
Treatment: Therapeutic options must intend not only to reduce epileptic seizures but above all
to "treat" the ESES responsible for the encephalopathy. BDZ, VPA, ESM, CBZ, PHT are the
drugs most commonly used to treat the seizures. Taking into account the relationship between
the occurence of ESES and the neuropsychological deterioration, a rapid aggressive therapy of
ESES is mandatory. Treatment options include variety of antiseizure medications,
immunosupressant treatments or surgical approach. Chronic oral treatment with CLB, CLZ
associated with VPA or ESM seems to be effective. In drug-resistant cases, steroid treatment
has been proposed (85). Intravenous immunoglobulins were also reported as succesful in some
47
cases (86). Limited evidence is available in favour of ketogenic diet, however there are some
succesfully treated patients reported (87).
Fig. 22: Landau-Kleffner syndrome: Continuous diffuse spike and waves activities during
NREM sleep with right temporal dominance.
1.4.2.3 Childhood absence epilepsy (CAE)
CAE is a genetic generalized epilepsy or idiopathic generlized epilepsy defined as follows:
occurs in children of school age (age at onset between 4-10 years, peak manifestation age 6-7
years), with a strong genetic predisposition in otherwise normal children. It is characterized by
very frequent typical absences with abrupt and severe impairment of consciousness.
Automatism are frequent but have no significance in the diagnosis.
EEG: ictal discharges of generalized high-amplitude spike and slow wave complexes. They are
rhythmic at around 3 Hz. Their duration varies from 4-20 seconds. Normal background activity
(Fig. 23).
48
Fig.23: Childhood absence epilepsy: Ictal EEG in a 5-year–old boy with CAE. Abrupt onset of
generalized 3Hz SWC during hyperventilation.
Treatment: ESM, VPA or LTG alone or in combination. Gradual withdrawal of medication is
reccomended in patients with CAE who have been seizure-free for 1-2 years and have a
normalized EEG.
1.4.3 Epilepsy syndromes of adolescence
1.4.3.1 Juvenile absence epilepsy (JAE)
JAE is an idiopathic (genetic) generalized epilepsy characterized by genetic predisposition, an
average age at onset around puberty, no evidence of neurological or intellectual deficit. Seizures
are typical absences, longer and less frequent than i CAE, GTCSs in 80% and sporadic
myoclonic jerks in 20%.
EEG: the interictal EEG shows a normal background and ictal EEG shows generalized
symmetric spike-waves or polyspike-waves with frontal accentuation. The frequency is usually
faster than 3 Hz (3.5-4Hz) (Fig. 24).
49
Fig. 24: Juvenile absence epilepsy: Ictal EEG in a 9-year-old boy with JAE. Initial generalized
PSWC discharge followed by 3.5-4Hz diffuse SWC activity.
Etiology: The etiology of JAE is a subject primarily of a genetic research. The research results
have shown that genetic mutations for voltage-gated sodium channels (CACNB4 gene) (88,89)
and potassium channels (CLCN2 gene) (88) are involved. Different mutations were found in
genes for GABA receptors (ligand ion channels), specifically in the GABRA1 gene (90).
Treatment and prognosis: Approximately 80% of cases become seizure-free with ESM and
VPA, but the rate of relapse after drug discontinuation is probably close to 100% (91). As
author already mentioned above, the study with 46 patients who met criteria for the diagnosis
of JAE was performed in the Center for epilepsy Brno between 2006-2011 (16).
According to the type of seizure control during the five-year observational period (OP) and at
the end of the OP, following outcome groups were defined:
1. Completely seizure free
2. Only absence seizures
3. Only GTCSs with a frequency 1 seizure per year
4. Only GTCSs with a frequency >1 seizure per year
5. Both GTCS and absence seizures; GTCSs with a frequency 1 seizure per year
50
6. Both GTCS and absence seizures; GTCSs with frequency >1seizure per year
The average patient age at the time of the first clinical manifestation was 12.9±5.6 years (ranged
from 3 to 28 years). In 30 of the 46 patients (65.2%) the first clinical manifestation of JAE were
absences, in 15 patients (32.6%) GTCS, and in 1 patient (2.2%) absence status epilepticus. In
43 patients (93.5%), at least one GTCS occurred in the course of the disease. At the end of the
OP, 7 of the 46 patients (15.2%) had been seizure free during the whole OP (Group 1). In the
same period, 8 patients (17.4%) had only absences (Group 2). Other types of predefined
outcomes are presented in Fig. 25. In total, 31 patients (67.4%) experienced at least 1 GTCS
during the OP. The assessment of antiseizure medication revealed that the number of drugs used
in the history varied from 1 to 10 with an average of 3.8± 2.3 antiseizure drugs (Tab. 3). The
most commonly used ASM in the series was LTG (25 patients; 12 in monotherapy and 13 in
combined therapy), followed by VPA (20 patients; 5 in monotherapy and 15 in combined
therapy) and LEV (11 patients; all in combined therapy). Other ASM used both in monotherapy
and in combinations are noted in Tab. 3.
Fig. 25: Number of patients in different groups according to the rate of seizure control at the
end of the OP (pts: patients)
51
Tab. 3: AED treatment in the whole cohort of patients with JAE
There are some studies that indicate that the outcome of patients with JAE is not favorable as a
rule. Wirell et al. (92) studied the prognostic factors of initial pharmacotherapy failure.
According to the study results, only 3 of the 11 children with JAE (27.3%) were seizure free
after the drug initiation (mostly VPA). There were 7 out of 46 patients (15.2%) seizure free
(Group 1) during the OP in this study. These patients did not achieve seizure freedom after
administration of 1 AED as we would expect. They tried 1–3 AEDs and only 5 of them (10.9%)
stayed on 1 AED during the whole OP. Compared to the literature, Tovia et al. (93) presented
nine of the 17 patients (52.9%) who were responsive for the first AED, but only 6 patients
(35.3%) stayed seizure free on mono- therapy during the follow-up period. These results show
that even in the group of patient who were seizure free, the seizure freedom was not achieved
in the simple way and does not have to be permanent. They showed that the occurrence of
GTCS predicted a worse prognosis (93). Only 37.5% of the patients in that study who
experienced GTCSs were seizure free during the follow-up period, compared with 55.5% of
patients without GTCSs. Similar results were observed by Trinka et al. (94) where the
proportion of seizure free patients in the follow-up period who experienced GTCSs was 35%
compared to 78% of the patients with only absence seizures. In this study, there was also a
strong correlation between the mean follow-up duration and outcome, indicating a lower
proportion of seizure-free patients with longer follow up periods. From this point of view, the
occurrence of GTCSs during the course of the disease seems to be another important prognostic
factor for the long-term outcome in patients with JAE. The author´s retrospective analysis of
patients with JAE indicates that more than half of the patients with this epileptic syndrome
show problems with seizure management and often require more AEDs to reach partial or total
seizure freedom.
52
Annex 2
1.4.3.2 Epilepsy with myoclonic absences (EMA)
This epileptic syndrome is characterized by a specific seizure type: a myoclonic absence. Loss
of contact and impairment of consciousness are of variable intensity, less pronounced than in
CAE. The myoclonias are felt as a very disturbing experience. The duraton ranges from 10 to
60 seconds. In one third of patients, MA are the only seizure type observed throughout the
evolution. GTCS were observed in 45% of cases.
EEG: the ictal EEG consists of rhythmic spike-wave discharges at 3 Hz that are bilateral,
synchronous and symmetric. SW complexes are intermixed with polyspikes. Normal
background activity.
Treamtent: Myoclonic absences can be completely controlled by VPA or ESM or in
combination – in case GTCSs do not occur.
1.4.3.3 Juvenile myoclonic epilepsy (JME)
JME appears around adolescence and is characterized by seizures with bilateral, single or
repetitive, arrhythmic, irregular myoclonic jerks, predominantly in the arms. Jerks may cause
some patients to fall. No disturbance of consciousness is noticeable. Often, there are GTCSs
and, less often, absences. The seizures usually occur shortly after awakening and are often
precipitated by sleep deprivation.
EEG: Interictal and ictal EEGs have rapid, generalized, often irregular spike-waves and
polyspike-waves, there is no close phase correlation between EEG spikes and clinical jerks.
Frequently, the patients are photosensitive (Fig. 26).
53
Fig. 26: Juvenile myoclonic epilepsy in a 16-year-old girl. Generalized polyspike wave
discharges during photostimulation with clinical correlate of myoclonic jerks. Normal
background activity.
Etiology: Family history is positive in one third of patients (95). Three genes have been
identified in the etiology of JME: GABRA1 (96), EFHC1 (97) and ICK (98). Other
susceptibility genes include: BRD2 (99) and 15q13.3 microdeletions (100). From a genetic
point of wiev, JME appears highly heterogenous (21).
Treatment: Counseling of lifestyle is essential: avoiding of sleep deprivation, excessive alcohol
intake and visual stimuli when patients are photosensitive.
Antiseizure medication is reccomended in almost all patients. LTG and LEV are considered as
the first-line drugs, still we have to be careful with LTG for its potential to aggravate myoclonic
jerks, which may occur after a long delay (21). TPM and ZNS can be considered second-line
drugs, perampanel (PER) is promising. VPA was also prooved very effective, but it is no longer
recommended for its side effects in the first-line therapy.
Prognosis: JME cannot be considered a truly benign conditon, although it may remit, at least
partially, with age. Some patients are pharmacoresistant. A logical therapeutic attitude is to
maintain treatment in most patients beyond early adulthood.
54
1.5 The new ILAE proposal for the classification of epileptic syndromes
In 2021, ILAE members presented four papers dealing with definitions of age-related epileptic
syndromes. The ILAE acceptance process requires feedback and comments from individual
members. These comments will be reviewed by the working group before the document is
finalized and published. So far, the draft of this document can be viewed at:
https://www.ilae.org/guidelines/definition-and-classification/proposed-classification-and-
definition-of-epilepsy-syndromes.
The works are divided into 4 groups - the first deals with epileptic syndromes of neonatal and
infant age, the second deals with epileptic syndromes in childhood, the third deals with epileptic
syndromes of variable age at onset and the fourth with idiopathic generalized epilepsy.
1.5.1 ILAE Classification & Definition of epilepsy syndromes in the neonate and infant:
Position statement by the ILAE Task Force on nosology and definitions
Syndromes are broadly divided into Self-limited epilepsies (where there is likely to be
spontaneous remission) and Developmental and epileptic encephalopathies (disorders where
there is developmental impairment related to both the underlying etiology independent of
epileptiform activity and the epileptic encephalopathy). Etiology-specific epilepsy syndromes
are due to specific genetic, structural, metabolic, immune or infectious etiologies, and have
consistent electroclinical features, management and prognostic implications. Most etiology
specific syndromes that begin in the neonatal or infantile period are DEEs. See Fig. 27.
55
Fig. 27: ILAE Classification & Definition of Epilepsy Syndromes in the Neonate and Infant:
Position Statement by the ILAE Task Force on Nosology and Definitions
https://www.ilae.org/guidelines/definition-and-classification/proposed-classification-and-
definition-of-epilepsy-syndromes/proposed-classification-syndromes-in-neonates-and-infants
1.5.2 ILAE Classification and definition of epilepsy syndromes with onset in childhood:
Position paper by the ILAE Task Force on nosology and definitions
Here, too, based on the ILAE 2017 Classification of the epilepsies, the names of some
syndromes were updated using terms directly describing the semiology of seizures. Epileptic
syndromes beginning in childhood were divided into three groups:
1. Self-limited focal epilepsy, comprising four syndromes: Self-limited epilepsy with
centrotemporal spikes, Self-limited epilepsy with autonomic seizures, Childhood occipital
visual epilepsy and Photosensitive occipital lobe epilepsy;
56
2. Generalized epilepsy involving four syndromes: Myoclonic-atonic epilepsy, Childhood
absence epilepsy, Epilepsy with myoclonic absences and Epilepsy with eyelid myoclonia;
3. Developmental and epileptic encephalopathies comprising four syndromes: Lennox-Gastaut
syndrome, developmental and/or epileptic encephalopathy with spike-wave activation in sleep,
Hemiconvulsion-hemiplegia epilepsy and FIRES (Febrile infection related epilepsy syndrome).
For each syndrome, typical seizures, EEG findings, phenotypic specifics, and findings of other
key examinations are defined. These syndromes are summarized in Tab. 4.
Tab. 4: ILAE Classification and Definition of Epilepsy Syndromes with Onset in Childhood:
Position Paper by the ILAE Task Force on Nosology and Definitions
https://www.ilae.org/guidelines/definition-and-classification/proposed-classification-and-
definition-of-epilepsy-syndromes/proposed-classification-syndromes-in-children/proposed-
classification-syndromes-in-children
57
1.5.3 ILAE Classification and definition of epilepsy syndromes with onset at a variable
age: Position statement by the ILAE Task Force on nosology and definitions – Fig.
28.
Fig. 28: The epilepsy syndromes that begin in adolescents, adults and at a variable age
https://www.ilae.org/guidelines/definition-and-classification/proposed-classification-and-
definition-of-epilepsy-syndromes/proposed-classification-syndromes-with-onset-at-variable-
ages
1.5.4 ILAE Definition of the Idiopathic generalized epilepsy syndromes: Position
statement by the ILAE Task Force on nosology and definitions
The IGEs are a specific subgroup of Genetic Generalized Epilepsies, comprised solely of CAE,
JAE, JME and GTCA. In addition to the IGEs, Genetic Generalized Epilepsies include:
1. individuals with generalized seizure types and generalized 2.5-5.5 spike-wave discharge on
EEG who do not meet criteria for a specific syndrome
2. syndromes which have genetic overlap with the IGE syndromes but may also, at times, be
associated with DEEs, such as Myoclonic-atonic epilepsy, Epilepsy with myoclonic absences
58
and Epilepsy with eyelid myoclonia; other syndromes such as Myoclonic epilepsy in infancy
are more consistent with a generalized epilepsy which may have a developmental
encephalopathy (ie. intellectual disability). Additionally, certain cases of GEFS+, with only
generalized seizure types could be classified as GGEs, but individuals with GEFS+ and focal
seizures would not be included. The triangles denote individuals with generalized epilepsies
and developmental delay/intellectual disability (dark blue) and those with DEEs (light blue).
The distinction between these two groups is that patients with DEEs have developmental
slowing or regression with frequent epileptiform activity on EEG and/or frequent seizures. See
Fig. 29.
Fig. 29: ILAE Definition of the Idiopathic generalized epilepsy syndromes: Position statement
by the ILAE Task Force on nosology and definitions
https://www.ilae.org/guidelines/definition-and-classification/proposed-classification-and-
definition-of-epilepsy-syndromes/proposed-classification-idiopathic-generalized-epilepsies
59
1.6 Etiology
The creation of a new classification of the epilepsies has been more than desirable for a long
time, especially in terms of fast scientific development (not only) in the field of epileptology.
New possibilities for neuroimaging, the revolutionary development of genetics with the
domestication of new genetic methods such as next-generation sequencing (NGS panels,
whole-exome sequencing (WES), etc.), discoveries in molecular biology and a number of other
factors have shown that the ILAE 1989 Classification of the epilepsies is not sufficient.
In the ILAE 2017 Classification of the epilepsies, there is a parallel division of epilepsy
according to etiology into six groups: structural, genetic, infectious, metabolic, immune and of
unknown etiology (Fig. 3). There is no hierarchy in this division and the classification of a
patient into a given group depends on different circumstances. For example, a patient with
tuberous sclerosis may be included in the structural group if epileptosurgery is crucial for
further treatment of this patient, or in the genetic group, which in turn is important in terms of
genetic counseling and/or new therapeutic options such as in the case of mTOR inhibitors (14).
1.6.1 Structural etiology
The concept behind a structural etiology is that a structural abnormality has a substantially
increased risk of being associated with epilepsy based on appropriately designed studies (14).
Structural etiologies may be acquired such as stroke, trauma, infection, or genetic such as many
malformations of cortical development. Identification of a subtle structural lesion requires
appropriate MRI studies using specific epilepsy protocols (101). There are well recognised
associations within the epilepsies with a structural etiology (eg. temporal lobe seizures with
hippocampal sclerosis, gelastic seizures with hypothalamic hamartoma, Rasmussen syndrome
and hemiconvulsion-hemiplegia epilepsy) (14).
Another interesting point is that the underlying basis for a structural abnormality may be genetic
or acquired or both. For example, polymicrogyria may be secondary to mutations in genes such
as GPR56, or acquired secondary to intrauterine cytomegalovirus infection (102).
1.6.2 Genetic etiology
The concept of a genetic epilepsy is that it directly results from a known or presumed genetic
mutation in which seizures are a core symptom of the disorder.
60
Firstly, the genetic etiology of epilepsy can be presumed on the basis of positive family history
of an autosomal dominant disorder. For example, in Benign familial neonatal seizures, most
families have mutations of one of the pottasium channel genes, KCNQ2 or KCNQ3 (103).
Genetic etiology can also be suggested by clinical research in populations with the same
syndrome, such as JME (14).
If the epilepsy syndrome is accompanied by dysmorphic features, cognitive regression and
autism-like features, one can start looking for structural variants like copy number variants
(CNVs), deletion/duplication by array comparative genomic hybridisation (CGH-array). In
single gene epileptic disorders, a specific gene may be targeted (eg. tuberous sclerosis complex
TSC1, TSC2) or a panel of multiple genes associated with a specific phenotype in a so-called
panel that can target hundreds of genes (21).
Next generation sequencing (NGS) is currently experiencing a great boom in the diagnosis of
epilepsy; NGS is revolutionary especially in terms of the possibility of simultaneously
examining many genes. Combining NGS with CNV analysis (exon-level deletion/duplication
analysis) makes it possible to detect most disease-causing variants in epilepsy genes in a single
test. NGS testing includes not only specific gene panels, but a methodology that can encompass
the entire exome (whole exome sequencing, WES) or genome (whole genome sequencing,
WGS), methods that have the potential to further increase the yield of genetic testing in patients
with epilepsy. Geneticists interpret and report detected sequence variants on the basis of
currently valid recommendations according to the American College of Medical Genetics and
Genomics (ACMG) (104). Thus, each sequence variant is included in the group of pathogenic
(P), likely pathogenic (LP), benign (B), likely benign (LB), or with uncertain significance
(VUS). The thorough genotypic-phenotypic correlation and interpretation of genetic results
from the neurological-epileptological point of view, taking into account other anamnestic data,
is an integral and crucial part of the process of interpreting the result of NGS; it importantly
increases the diagnostic yield of NGS examination. Knowing the genetic cause of epilepsy in a
patient opens new horizons in terms of understanding the pathophysiology of the epileptological
process, and it also creates a space for the study of pharmacological models of antiepileptic
drugs. The definition of precision medicine thus takes on real proportions in some patients with
epilepsy.
61
NGS of multiple disease-related genes is an effective tool for diagnosing the cause of epilepsy
(105–108). This finding is particularly true for early onset epileptic encephalopathy, which has
been reported to have a higher proportion of monogenic causes than other epilepsies (109).
The author performed a single-centre retrospective study with total of 175 patients (95 males
and 80 females) aged 0-19 years. They were examined between 2015 and 2020 using an NGS
epilepsy gene panel (255 genes). The results show a 26.28% yield of NGS epilepsy gene panel
with 255 genes associated with epilepsy (110). The yield of different multigene panels varies
from 18% to 48%, depending on the results of various studies (111). The individual panels
differ in the number and proportion of individual genes; after careful examination, it is clear
that there is no direct relationship between the number of genes in the NGS epilepsy gene panel
and its yield. It is evident that only a few genes are still repeated in the results, and the SCN1A,
KCNQ2, CDKL5, SCN2A, and STXBP1 genes are most often represented in positive cases
(111). Thus, the diagnostic yield of the NGS panel appears to be determined by the number of
commonly mutated genes included in the panel rather than the total number of genes in the
panel (112). It is worth mentioning the comparison of the yield of the NGS epilepsy gene panel
and examinations using WES or WGS technique. The largest meta-analysis from 2021 shows
that the yield of the NGS panel was on average 24%; WES was 27.2%, i.e. slightly higher. A
smaller meta-analysis showed the yield of WES analysis was 31% (113). The truth is that
accurate quantification of the positive results of WES analysis is very difficult given that WES
is very often tested in patients with negative results using the NGS epilepsy gene panel
technique. If WES is performed independently of the NGS multiple gene panel, its yield may
be significantly higher (19% vs. 37%) (106).
Consistent with the world literature (112,114) is the fact that the age at epilepsy manifestation
in positive patients is lower. The mean age of epilepsy manifestation in the author´s group was
around 2.5 years; in the children who tested positive it was 1.5 years and in the children with a
negative result it was almost 3.5 years. It is also worth noting that cohorts with patients with
early onset epilepsy encephalopathies, i.e. children at neonatal age (0-3 months), show a higher
yield of NGS panel. Costain et al. even showed a panel yield in children under 12 months of
72% (106), higher yields in newborns (37.1%) were also shown in the study by Ko et al. (114).
These results are in line with the author´s observation, in which the yield in the group of children
under 3 months was 38.46%. These observations are logical and are based on the fact that severe
developmental and epileptic encephalopathies manifest in the neonatal period and a serious
clinical picture often requires prompt diagnosis leading to the detection of the cause and the
62
introduction of possible specific therapy in indicated cases. Therefore, these children receive a
genetic diagnosis much earlier. For these reasons, genetic diagnosis using new multi-gene
sequencing techniques is recommended as a standard diagnostic tool for children with neonatal
DEE (108,115). Making an early molecular diagnosis can also end the genetic odyssey, enable
recurrence risk counselling, guide participation in gene-specific clinical trials, and provide
families with the opportunity to interact with support groups or advocate for research (105).
Oates et al. showed that early genetic diagnosis in children with DEE can reduce costs up to
70% compared to its failure (116). The argument based on the high cost of genetic testing
therefore seems unfounded.
Few studies have emphasized the precise systematic and standardized procedure in interpreting
the results of the NGS panel (107,114). Accurate interpretation of NGS panel results includes
several key areas:
1. population data and database review
2. computational data, allelic data, and literature review
3. clinical review and family study
4. consensus multidisciplinary discussions (107).
The results of this work show that the multidisciplinary approach led to a definitive diagnosis
in some patients with novel not previously described variants and increased the diagnostic yield
of NGS analysis from 30 to 46 patients, which is by 53.33%. This is very important from a
clinical point of view.
Annex 4
The author has dealt with the genetics and clinical spectrum of Dravet syndrome since the
introduction of its diagnostics at the Department of Pediatric Neurology, Faculty of Medicine,
Masaryk University and University Hospital Brno in 2011 into clinical practice. Diagnostics is
performed in the Center of Molecular Biology and Gene Therapy, Faculty of Medicine,
Masaryk University and University Hospital Brno. Its implementation into practice has brought
new insights into the genetics of epilepsy. In up to 80% of cases, patients with Dravet syndrome
have a pathogenic variant in the SCN1A gene (37). Interestingly, this pathogenic variant can
63
lead to very variable clinical expression, from genetic epilepsy with febrile seizures plus (GEFS
+) to Dravet syndrome with a very severe clinical course. In her works, the author studied case
series of patients with DS (117,118), wrote a review concerning the clinical course of Dravet
syndrome in childhood (119) and adulthood (120).
The author and her team studied the structure of the SCN1A channel in relation to individual
pathogenic sequence variants and phenotypic expression (121). This study included 6 patients
with pathogenic sequence variant in SCN1A gene, 3 males and 3 females. Clinical
characteristics of all patients are summarized in Tab. 5. In 3 patients (50%), a milder clinical
phenotype was observed, which was mainly associated with the occurrence of recurrent febrile
convulsions or GTCSs. Neurological examination was normal. In 2/3 of patients, the genetic
analysis showed a positive family history for an identical pathogenic sequence variant. In both
patients, the carrier was the father. The parents also had a very mild course of the disease.
However, the DS phenotype was observed in 50% of patients. Status epilepticus was reported
in 66% of these patients. All of them suffered from various seizure types (myoclonic, GTCS,
absence, focal motor seizures). In 2/3 of patients with this severe phenotype, there was an
alteration of the neurological status and pathogenic sequence variants were all de novo. Based
on the knowledge of the particular sequence variant, these were localized into a particular
region of the alpha one subunit of the sodium channel (Fig. 30). The authors report the
correlation of the clinical course of the disease and the localization of the pathogenic sequence
variant in the SCN1A gene. Missense mutations located in the pore region or in the region of
the voltage sensor predict so-called „loss of function“, or „partial loss of function“, ie severe
functional impairment (LOF, p-LOF). Mutations located in the terminal region or in the region
of the D-linkers, which are remote from the pore region, cause rather milder phenotype (121).
Missense mutations in other regions cause heterogeneous manifestations. However, for a more
accurate analysis of a specific degree of functional damage, it is necessary to perform a
functional analysis.
64
Fig. 30: Localisation of pathogenic sequence variants in the α-1-subunit of the SCN1A channel.
Patients´ pathogenic sequence variants marked 1-6 (121).
Sex
Year
of
birth
Age at
epilepsy
onset
(months)
Seizure
provocation
Seizure
type
Status
epilepticus
Neurological
status
Family
history
of
epilepsy
Type of
mutation
Fenotype
1. F 1999 16 +
Febrile
seizure,
focal
myoclonus,
GTCS
0
Attention
deficit,
learning
disability,
memory
deficit
0 missense SMEI
2. M 2015 16 +
Febrile
seizure
0 normal
+
(father)
missense GEFS+
3. M 2017 4 +
Febrile
seizure
+ normal 0 missense SMEI
4. M 1986 36 +
Febrile
seizure
GTCS
0 normal 0 missense GEFS+
5. F 2018 15 +
Febrile
seizure
0 normal
+
(father)
missense GEFS+
6. M 2020 4 +
Myoclonus,
GTCS
+
hypotonie
centr. typu,
mikroccefalie,
invertované
bradavky
0 missense SMEI
Tab. 5: Clinical characteristics of patient with DS included in the study, patients 1-6 (121).
Annex 5, 6, 7, 8
The phenotypic expression of a given pathogenic sequence variant is dependent on many factors
in its expression. As noted above, localization of the product of the mutation near a significant
portion of the channel leads to a more severe phenotype than localization at sites less important
65
for channel function, and this is certainly logical. The next point of view is whether the product
of the mutated gene has a so-called "gain of function" or "loss of function". An illustrative case
is in the GNAO1 gene. Mutations in GNAO1 were first reported in patients with Ohtahara
syndrome and early infantile epileptic encephalopathy 17 (EIEE17) (122,123). But the clinical
course can be very different and patients with GNAO1 patogenic variant can present with
movement disorder. GNAO1 (guanine nucleotide-binding protein 1) encodes the α-subunit of
a heterotrimeric guanine nucleotide-binding protein (Gαo) which is the most abundant
membrane protein in the mammalian central nervous system (124). The author reported a case
of a 12-year-old boy with GNAO1 mutation who presented with severe biballistic
symptomatology with dystonic features (DSAP 3) and required emergency deep brain
stimulation (DBS) to avoid life-threatening symptoms (125). The boy was first examined at the
Department of Pediatric Neurology at the age of 2 years. At the age of 12 years, the patient
deteriorated after respiratory infection and worsening of extrapyramidal symptomatology with
dominating biballism and dystonic features developed with the threat of status dystonicus. He
experienced almost continuous generalized ballistic movements combined with dystonic
postures, which were very painful and limited his normal activity, feeding, or sleep (DSAP 3).
The patient was hospitalized in the ICU with the necessity of muscle relaxation. Taking into
consideration the seriousness of this condition, DBS of bilateral globus pallidus internus (DBSGPi)
was performed. The sedative medication was gradually tapered off over the next 14 days
and his condition rapidly improved to DSAP 1. Half a year after DBS, motor functions returned
to the condition before the brittle biballism-dystonia developed. Whole exome sequencing
(WES) identified a heterozygous missense variant in GNAO1 gene c.625 C>T; p. (Arg209Cys)
previously described in the study by Koy et al. (2018) (126) and considered as pathogenic. The
mutation was absent in the patient’s parents and considered as de novo.
When pre-status dystonicus persists despite orally active anti-dystonia drugs and unsuccessful
weaning from sedative or anesthetic agents, intrathecal baclofen or deep brain stimulation
should be considered (124). Several case reports and one small series have been published in
which DBS was effective in patients with a GNAO1 mutation (123,126) . DBS may be effective
due to its general effects in modulating aberrant synchronization in the basal ganglia-thalamocortical
loops. The effect of DBS in our patient was very fast, with the improvement to DSAP
1 in 14 days. The patient tolerated the stimulation very well; however, only 3 months after
initiation he developed generalized epileptic seizure. It is uncertain whether this occurred as a
result of DBS (potentially triggered by tapering off the medication during the switching on and
66
adjusting the DBS parameters) or was merely a coincidence in a patient with a history of
epilepsy. In any case, stimulation should be increased cautiously and mildly in patients with
epilepsy. After the introduction of LEV, no further seizures occurred. In patients with GNAO1
mutation and severe dystonia, GPi-DBS could be a treatment option with life-saving potential.
Annex 9
1.6.3 Infectious etiology
The concept of an infectious etiology is that it directly results from a known infection in which
seizures are a core symptom of the disorder. It is the most common etiology of epilepsy and
accoridng to specific regions can be caused by neurocysticercosis, tuberculosis, HIV, malaria,
toxoplasmosis and congenital infections such as Zika virus or cytomegalovirus (14).
1.6.4 Metabolic etiology
Metabolic causes refer to a well delineated metabolic defect with manifestations or biochemical
changes throughout the body such as porfyria, uremia, amino-acidopathies or pyridoxine
dependent seizures. In many cases, metabolic disorders will have a genetic defect. The
identification of specific metabolic causes of epilepsy is extremely important due to the
imlications for specific therapies and potential prevention of intellectual impairement.
1.6.5 Immune etiology
A range of immune epilepsies has been recently recognised with characteristic presentations in
both adults and children (127). Diagnosis of these autoimmune encephalopathides is rapidly
increasing, particularly with greater access to antibody testing. The most common are antiNMDA
receptor encephalitis and anti-LG1 encephalitis.
67
1.2.1 Unknown etiology
There remain many patients with epilepsy for whom the cause is not known.
1.7 Developmental and epileptic encephalopathies
This section is dedicated to a relatively new entity that is of immense importance from the point
of view of pediatric epileptology.
The term "epileptic encephalopathy" was redefined in the Berg et al. 2010 report (6) as where
the epileptic acitvity itself contributes to severe cognitive and behavioral impairments above
and beyond what might be expected from the underlying pathology alone. In an epileptic
encephalopathy, the abundant epileptiform activity interferes with development resulting in
cognitive slowing and often regression, and sometimes associated with psychiatric and
behavioral consequences. A key component of the concept is that amelioration of the
epileptiform activity may have the potential to improve the developmental consequences of the
disorder.
The influence of epileptiform discharges on development and cognitive functions is evident not
only in severe epileptic encephalopathies, but also in the so-called "benign" syndromes, as the
author explains in the previous part of the work dealing with Rolandic epilepsy.
Many of the genetic epileptic encephalopathies also have developmental consequences arising
directly from the effect of the genetic mutation, in addition to the effect of the frequent epileptic
activity on development. A well-known example is Dravet syndrome, in which developmental
slowing occurs between one and two years of age, at a time when epileptiform activity on EEG
is typically not yet frequent. This suggests a developmental component in addition to an
epileptic component with both occuring secondary to the underlying sodium channel subunit
gene (SCN1A) mutation. Another example is in KCNQ2 encephalopathy or STXBP1
encephalopathy where the epilepsy settle down relatively early in the child´s history but the
developmental consequences may remain profound. These reasons lead to the concept of
"developmental and epileptic encephalopathy" where both aspects are involved (14).
68
Common epileptic syndromes such as Ohtahara syndrome, West syndrome, Lennox-Gastaut
syndrome, etc. are wll known and described. They are clearly defined, clinically and
electrographically, and we can see these patients in everyday practice. In the light of the
development of novel genetic techniques, we went much further, to the level of individual genes
and gene sequence variants, so we clarified the etiology in number of patients with these
epileptic syndromes and began to notice gentle nuances in the clinical and EEG manifestation.
Then, we can find that Ohtahara syndrome may have slightly different specifics in patients with
KCNQ2 mutation than in patients with SCN2A mutation, and we arrive at the concept of
SCN2A-related or KCNQ2-related developmental and epileptic encephalopathies. We can
specify the disease at the genetic level and thus differentiate subtle phenotypic variations in the
spectrum of clinical manifestation. In cases, where a genetic variant of mayor effect is
identified, the term "developmental and epileptic encephalopathy" may be subsumed by using
the name of the underlying condition (for example STXBP1-related DEE) (14).
An example can be a group of 6 patients with a pathogenic sequence variant in the SCN2A
gene, who have been diagnosed and treated at the Department of Pediatric Neurology, Faculty
of Medicine, Masaryk University, University Hospital Brno. A detailed description is shown in
Tab. 6. This case serie was presented by the author at the 54th Czech-Slovak Pediatric
Neurology Conference in 2021 (128).
69
Tab. 6: Clinical characteristics of a case serie of patients with SCN2A-related DEE (128).
pathogenic
variant
origin protein
domain
age at
seizure
onset
(months)
time to
genetic
diagnosi
s
(months)
epilepsy
syndrome
neurological
examination
MRI anti-seizure
medication
1 SCN2A
(NM_001040
143.1):
c.2642T>C
p.(Leu881Pr
o)
de novo Transmem
brane
helical
domain
4 9 WS→F mikrocephaly,
quadruparetic
cerebral palsy with
central hypotonia and
extrapyramidal
symptomatology,
severe impairment of
psychomotor
development
negati
ve
VGB, ACTH,
CLB, LEV,
PHT, ZNS,
RFN
2 SCN2A
(NM_001040
143)
c.4633A>G
p.Met1545V
al
de novo Transmem
brane
helical
domain
neonatal 23 EME→ne
ar-WS
mikrocephaly,
quadruparetic
cerebral palsy with
central hypotonia and
extrapyramidal
symptomatology,
severe impairment of
psychomotor
development
negati
ve
B6,VPA, PB,
LEV, BRV
3 SCN2A
(NM_001040
143)
c.416T>C
p.Ile139Thr
- nová
de novo Transmem
brane
helical
domain
neonatal 8 EIEE→W
S
mikrocephaly,
quadruparetic
cerebral palsy with
central hypotonia and
extrapyramidal
symptomatology,
severe impairment of
psychomotor
development
negati
ve
B6, PB, LEV,
CLZ, PHT,
TPM, CLZ
4 SCN2A
(NM_001040
143)
c.788C>T
p.Ala263Val
de novo Transmem
brane
helical
domain
neonatal 120 EME→F mikrocephaly,
quadruparetic
cerebral palsy with
central hypotonia and
extrapyramidal
symptomatology,
severe impairment of
psychomotor
development
cereb
ellar
atrop
hy
PHT, VGB,
CLZ, PB,
CLB
5 SCN2A
NM_001040
143.1
c.5626C>T
p.(Arg1876*
) - nová
de novo Variant
causing
premature
translation
terminatio
n
8 7 EME→ne
ar-WS
mikrocephaly,
quadruparetic
cerebral palsy with
central hypotonia and
extrapyramidal
symptomatology,
severe impairment of
psychomotor
development
negati
ve
PB, LEV,
VPA, CLB
6 SCN2A
NM_001040
143.1
c.3973G>A
p.(Val1325Il
e)
matern
al
Cytoplas
mic
domain
4 9 F developmental
dysphasia, ASD
negat. LEV, VPA
70
Results show that common features of SCN2A-related DEE in this group are:
1) early manifestation of seizures - most often during the first year of life (maximum in the
neonatal period)
2) combination of seizures and electroclinical correlation leading to the classification of
the epileptic syndrome as EME / EIEE / WS, but with certain atypia
3) severe neurological deficit with a predominant central hypotonia with quadruparetic
syndrome and extrapyramidal symptoms, severe psychomotor retardation
4) the effect of PHT in patients with neonatal seizures
5) a sequence variant located in the cytoplasmic domain may cause a milder phenotype
than a variant located in the transmembrane domain
For SCN2A-related DEE, two groups can be distinguished (49):
1) DEE with onset before 3 months of age, mutations with "gain-of-function" effect, with
very good PHT (HD) effect, another possibly effective antiseizure drugs are CBZ, OXC,
LCM, ZNS.
2) DEE with onset after 3 months of age, mutations with "loss-of-function" effect, where
PHT is not effective or even worsens seizures, possible effect of LEV, BDZ, VPA.
And other examples of DEEs could follow and undoubtedly will with knowledge and
identification of other pathogenic sequence variants in various genes.
1.8 Precision medicine strategy:
Genetic diagnosis of monogenic epilepsies presents great challenges. Knowledge of the
pathophysiological mechanisms of the epileptic process could make it possible to use the
principles of precision medicine and optimize the patient’s therapeutic regime. For example,
some drugs are more effective than others in some genetic epilepsy syndromes, i.e. sodium
channel blockers (SCBs) in KCNQ2- and PRRT2-related seizures (129,130). Some antiseizure
medication can worsen the seizure activity, as observed in SCBs in SCN1A-related epilepsies
(131). Some antiseizure drugs can lead to fatal liver failure, as observed in patients with POLGassociated
epilepsy receiving VPA (132). In the author´s study with 175 patients who
underwent genetic testing with NGS panel of 155 genes, 46 patients had pathogenic sequence
71
variant causing the epilepsy (110). In 13 of these 46 patients (28.26%) the therapeutic regimen
was modified. This was effective in reducing seizures by at least 50% in 9 of them (69.23%).
Due to the size of the cohort, these are only case observations, and will be discussed in details
below. Eighteen of these patients underwent targeted therapies. Eight of the patients carried a
SCN1A variant, which was the most frequent sequence variant detected in our cohort. In most
patients, the phenotype of Dravet’s syndrome was presumed before targeted molecular genetic
diagnosis, so a combination of VPA, CLB, and STP was used. None of these patients were
treated with SCBs at the time of diagnosis. Several studies proved that there is an improvement
not only in seizure frequency after SCBs are tapered off but also in cognitive performance,
language skills, and general well-being.(133). One of the SCN1A positive patients importantly
improved on TPM and another on STP.
In one patient, a ketogenic diet led to a 70% seizure reduction. Six patients with SCN2A-related
DEE were diagnosed. PHT was administered in four of them: in one patient with a clinical
manifestation of DEE at 4 months of age, PHT was ineffective; in three patients with a clinical
manifestation in neonatal age, SCB therapy had a very good effect, with more than 50% seizure
reduction which is in accordance with the principles of "gain of function" and "loss of function"
model as published by Wolff et al. (49).
Two patients carried a SLC2A1 variant (GLUT1-deficiency) and were administered ketogenic
diet. One of them improved promptly and became seizure-free. In the second patient, ketogenic
diet was without significant effect. The sequence variant identified in this patient was located
in exon 9 of the SLC2A1 gene, a site where causal mutations in patients with GLUT1deficiency
syndrome are often found, as has been well documented (134). Thus, the sequence
variant was marked as pathogenic, and a biochemical correlate of the disease with a
pathological absolute concentration of glucose in cerebrospinal fluid (CSF) and ratio of glucose
concentration in CSF and serum was also confirmed. The patient’s phenotype was not in
conflict with the diagnosis of GLUT1-deficiency syndrome. Molecular diagnosis of the disease
was made with a latency of almost 6 years from the manifestation of epilepsy, so ketogenic diet
was introduced late, which may be related to its lower effectiveness (135). The ketogenic diet
in patient was also less tolerant and it was not possible to increase the energy intake to provide
sufficient energy for the CNS cells due to the fact that he did not tolerate the higher fat intake
and he vomited. The poorer response to diet was relatively accented by the fact that the patient
was also diagnosed with bilateral MTS on brain MRI, which, the authors assume, developed
72
secondarily after prolonged seizure activity and could continue to maintain the epileptogenic
process regardless of the primary cause of epilepsy. One patient was diagnosed with pyridoxindependent
epilepsy and carried an ALDH7A1 variant; he became seizure-free after vitamin B6
was administered. One was diagnosed with CACNA1A variant, severely aggravated after
ethosuximide (ESM) administration. The worsening of seizures after a calcium blocker can be
explained by the fact that the given variant is either of a loss-of-function or gain-of-function
nature, which we were not able to determine for the given patient. It is documented that gainof-function
and loss-of-function CACNA1A mutations are associated with similarly severe
DEEs and that functional validation is required to clarify the underlying molecular mechanisms
and to guide therapies (136). Here we can only state that such a negative response to ESM is
evidence that the patient’s sequence variant is pathogenic.
1.9 Conclusion:
We are currently able to diagnose some epilepsies down to the level of individual pathogenic
sequence variants. We have therefore come to understand the genetic cause of epilepsy in some
cases. The possibilities of development of new molecules dedicated to treatment of epilepsy
and future perspectives of gene therapy emerge and open up new research and treatment
horizons.
73
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84
2 Annexes - Collection of author´s published scholarly works with
commentary
2.1 Annex 1:
Danhofer P, Tomečková M, Černá D, Zapletalová D, Horák O, Aulická Š, Juříková L,
Doamnský J, Kovalčíková P, Pavlík T, Štěrba J, Ošlejšková H. Prognostic factors and seizure
outcome in posterior reversible encephalopathy syndrome (PRES) in children with
hematological malignancies and bone marrow failure: A retrospective monocentric study.
Seizure. 2019 Nov;72:1–10. doi: 10.1016/j.seizure.2019.08.007.
Summary:
Purpose: The aim of this study was to evaluate seizure outcome in children with hematological
malignancies and PRES and to identify prognostic factors that could help manage the syndrome.
Method: We retrospectively reviewed the report data of 21 patients diagnosed with
hematological malignancy or aplastic anemia and PRES between 2008 and 2018. Basic
demographic data, oncology treatment, presymptomatic hypertension before PRES
manifestation, neurological status, seizure type, and EEG and MRI findings at PRES onset and
at the one-year follow-up visit were studied. Patients who developed remote symptomatic
seizures or epilepsy were identified.
Results: We included 21 children (11 females and 10 males) in the study. Sixteen patients
(76.2%) were diagnosed with ALL and the rest individually with AML, CML, T-lymphoma,
Burkitt lymphoma, and severe aplastic anemia. Presymptomatic hypertension (PSH) was
evaluated in 19 patients and was present in 18 (94.7%). The duration was 9 h and more in 16
patients (88.8%); the severity was grade II in 12 patients (66.7%). Seizures as the initial
symptom of PRES were present in 17 patients (80.9%). Four patients (19.0%) were assessed
with remote symptomatic seizures. Two of them (9.5%) had ongoing seizures at the one-year
follow-up visit and were diagnosed with epilepsy. The presence of gliosis on follow-up MRI
indicated worse outcome with development of epilepsy (without statistical significance).
85
Conclusions: PRES syndrome has an overall good prognosis and the evolution to epilepsy is
rare. The severity and duration of PSH or seizure severity and EEG findings at PRES onsetwere
not associated with worse neurological outcomes in this study.
Contents lists available at ScienceDirect
Seizure: European Journal of Epilepsy
journal homepage: www.elsevier.com/locate/seizure
Prognostic factors and seizure outcome in posterior reversible
encephalopathy syndrome (PRES) in children with hematological
malignancies and bone marrow failure: A retrospective monocentric study
Pavlína Danhofera,⁎
, Michaela Tomečkováa
, Dáša Černáb
, Danica Zapletalováb
, Ondřej Horáka
,
Štefánia Aulickáa
, Lenka Juříkováa
, Jiří Domanskýb
, Petra Kovalčíkovác
, Tomáš Pavlíkc
,
Jaroslav Štěrbab
, Hana Ošlejškováa
a
Epilepsy Center Brno, Department of Child Neurology, University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
b
Pediatric Oncology Department, University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
c
Institute of Biostatistics and Analysis, Faculty of Medicine, Masaryk University, Brno, Czech Republic
A R T I C L E I N F O
Keywords:
PRES
Children
Oncology
Seizure
MRI
Prognosis
A B S T R A C T
Purpose: The aim of this study was to evaluate seizure outcome in children with hematological malignancies and
PRES and to identify prognostic factors that could help manage the syndrome.
Method: We retrospectively reviewed the report data of 21 patients diagnosed with hematological malignancy or
aplastic anemia and PRES between 2008 and 2018. Basic demographic data, oncology treatment, presymptomatic
hypertension before PRES manifestation, neurological status, seizure type, and EEG and MRI findings at
PRES onset and at the one-year follow-up visit were studied. Patients who developed remote symptomatic
seizures or epilepsy were identified.
Results: We included 21 children (11 females and 10 males) in the study. Sixteen patients (76.2%) were diagnosed
with ALL and the rest individually with AML, CML, T-lymphoma, Burkitt lymphoma, and severe aplastic
anemia. Presymptomatic hypertension (PSH) was evaluated in 19 patients and was present in 18 (94.7%). The
duration was 9 h and more in 16 patients (88.8%); the severity was grade II in 12 patients (66.7%). Seizures as
the initial symptom of PRES were present in 17 patients (80.9%). Four patients (19.0%) were assessed with
remote symptomatic seizures. Two of them (9.5%) had ongoing seizures at the one-year follow-up visit and were
diagnosed with epilepsy. The presence of gliosis on follow-up MRI indicated worse outcome with development of
epilepsy (without statistical significance).
Conclusions: PRES syndrome has an overall good prognosis and the evolution to epilepsy is rare. The severity and
duration of PSH or seizure severity and EEG findings at PRES onsetwere not associated with worse neurological
outcomes in this study.
1. Introduction
Posterior reversible encephalopathy syndrome (PRES), as defined
by Hinchey et al., is a phenomenon of transient cerebral vasogenic
edema occurring preferentially in posterior circulation [1]. Clinically,
PRES is characterized by headaches, seizures, reduced consciousness,
and visual and other focal neurological symptoms [2,3]. PRES is a
clinicoradiological syndrome; a characteristic radiologic finding is vasogenic
edema in the bilateral parietal-occipital lobes, which might be
related to the lower concentrations of sympathetic innervation of the
posterior intracranial arteries in comparison with other cerebral
regions, resulting in lower autoregulatory capacity in these vessels [4].
However, other cerebral areas can be involved, and focal areas of PRES
vasogenic edema may also be seen in the basal ganglia, brainstem, and
deep white matter [5]. Systemic lupus erythematosus, sickle cell disease,
sepsis, use of cytotoxic medications (for malignancy or immune
suppression), renal failure, and organ transplantation are some of the
conditions that have been associated with PRES [6,7]. There is still
controversy concerning the pathophysiologic mechanisms of the syndrome;
however, the mechanism that produces vasogenic edema (arterial
hypertension and endothelial dysfunction) seems to be associated
with loss of integrity of the blood-brain barrier [8]. Moderate-to-severe
https://doi.org/10.1016/j.seizure.2019.08.007
Received 19 May 2019; Received in revised form 10 July 2019; Accepted 14 August 2019
⁎
Corresponding author.
E-mail address: pavlina.cahova@seznam.cz (P. Danhofer).
Seizure: European Journal of Epilepsy 72 (2019) 1–10
1059-1311/ © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
T
hypertension is seen in approximately 75% of patients with PRES [9].
There are many detailed studies regarding the clinical and radiologic
aspects of PRES in adults or children. However, the data regarding
electroencephalographic changes and seizure outcome are very
limited. Furthermore, few studies have yet focused on the very specific
group of high-risk pediatric patients: children with hematopoietic or
lymphoid tissue tumors or bone marrow failure.
The aim of this study was to retrospectively evaluate neurological
status and EEG and MRI findings in children with hematological malignancies
or bone marrow failure and PRES. The neurological outcome
beyond the acute phase and the development of remote symptomatic
seizures (RSS) in these patients was evaluated.
The secondary aim was to correlate these data with the severity and
duration of presymptomatic hypertension (PSH) in this group of patients.
Arterial hypertension is considered to be an important pathophysiological
mechanism of PRES and can be influenced in order to
achieve more favorable outcomes in these patients.
2. Material and methods
We retrospectively analyzed 24 patients diagnosed with PRES from
2008 to 2018 at the University Hospital Brno, Czech Republic, from the
hospital database. All patients were diagnosed with malignancy or bone
marrow failure and treated at the Pediatric Oncology Department,
University Hospital Brno, according to appropriate protocols.
The inclusion criteria were: 1) acute clinical symptoms of PRES –
alteration of consciousness, encephalopathy, seizures, headache, and
visual disturbances and/or other focal neurological deficit; 2) PRES on
MRI as diagnosed by a neuroradiologist; and 3) clinical agreement by
treating physicians whose reports also were relied upon to determine
the etiology.
We collected and analyzed clinical, radiographic, and encephalographic
data from the institutional database.
Demographic data were analyzed: sex, age at the manifestation of
malignancy, and PRES.
Each patient’s clinical manifestation and causal factors were identified:
oncological diagnosis, protocol treatment, and phase of treatment
with medication in the last 4 weeks. We retrospectively evaluated
PSH. Every patient admitted for hospitalization was measured by BP
cuff in 3 -h intervals; if hypertension was present, the measurements
were taken in 1-h intervals. We evaluated the severity and duration of
the PSH prior to PRES clinical manifestation. The blood pressure was
classified as normal, prehypertension, hypertension grade I, and hypertension
grade II according to the age- and height-related standardized
percentile graphs for pediatric populations. All patients were
hospitalized at the time of PRES manifestation for various reasons
(protocol treatment, febrile neutropenia, infection, etc.) so the collection
of arterial pressure measurements were complete from the beginning
of the PSH. Patients for whom the data were incomplete, e.g. PSH
onset after admission with hypertension, were excluded from the ana-
lysis.
Neurological examination was established by the institutional neurologist
at PRES manifestation – up to 3 h from the manifestation and
then every 3 months, or more often if needed. We evaluated the neurological
status at PRES manifestation and after one year of follow-up
care.
Neurological status was classified as follows: 1 – normal; 2 – focal
deficit without loss of consciousness; 3 – qualitative disturbance of
consciousness (hypoactive or hyperactive delirium: confusion, disorientation,
memory disturbance, illusions, or hallucinations); 4 –
quantitative disturbance of consciousness – somnolence; 5 – quantitative
disturbance of consciousness – sopor; 6 – quantitative disturbance
of consciousness – coma.
The interpretation of EEGs was established by epileptologists from
the Department of Child Neurology, University Hospital Brno. EEG
were recorded digitally using a standard 10–20 system with standard
20-minute recordings with or without activations. All patients had EEG
at PRES manifestation or in the first 12 h and then follow-up EEG every
3 months, or more often if needed. We evaluated the EEG at PRES
manifestation and after one year of follow-up care.
EEGs were classified as follows: 1 – normal; 2 – focal slowing; 3 –
diffuse slowing; 4 – focal epileptiform discharges; 5 – generalized epileptiform
activity; 6 – LPDs.
Epileptic seizures were classified as follows according to the 2017
ILAE classification: 1 – no seizures; 2 – focal – aware; 3 – focal – impaired
awareness; 4 – focal to bilateral tonic-clonic seizure (FBTCS); 5 –
generalized tonic clonic seizure (GTCS); 6 – non-convulsive status
epilepticus (NCSE); 7 – convulsive status epilepticus (CSE).
Acute symptomatic seizures were defined as seizures occurring in
direct association with the PRES syndrome and/or within 6 weeks of its
termination. Seizures that occurred later in the course of the oncological
disease but still in possible association with PRES syndrome and
with no other identified cause were defined as remote symptomatic seizures
(RSS). We arbitrarily determined one year from the manifestation of
PRES as the borderline for another assessment: the one-year follow-up
visit.
2.1. Statistics
Categorical variables were summarized using absolute and relative
frequencies. To summarize the continuous characteristics, mean, standard
deviation (SD), median, minimum and maximum were used.
Testing was carried out using Fisher’s exact test. A value of p < 0.05
was considered statistically significant.
3. Results
3.1. Basic data
We identified 24 patients out of 1627 (1.4%) diagnosed with PRES
and treated at the Pediatric Oncology Department at the University
Hospital Brno between 2008 and 2018. Three patients were lost to
follow-up care; they died due to the complications of treatment of
malignancy. Therefore, 21 patients (11 females and 10 males) with
PRES syndrome were included in the study. All patients had been diagnosed
with malignancies; one patient was diagnosed with bone
marrow failure. The average patient age at presentation was 6.6 ± 4.0
years (ranged from 2 to 16 years). Sixteen out of 21 patients (76.2%)
were diagnosed with acute lymphoblastic leukemia (ALL), one patient
(4.8%) had a diagnosis of acute myeloid leukemia (AML), one patient
(4.8%) was diagnosed with chronic myeloid leukemia (CML), two patients
(9.4%) were diagnosed with non-Hodgkin lymphoma (NHL - Tlymphoma
and Burkitt lymphoma), and one patient (4.8%) was treated
for severe aplastic anemia (Table 1). The incidence of PRES for each
diagnosis for 10 years (2008–2018) can be expressed as follows: 16 out
of 174 patients with ALL (9.2%), one out of 33 patients with AML
(3.0%), one out of 15 patients with CML (6.6%), two out of 74 patients
with NHL (2.7%), and one out of 9 patients with severe aplastic anemia
(11.0%).
The time from the diagnosis of malignancy to the manifestation of
PRES was 4.4 ± 4.9 months (ranged from 0.1 to 19.7 months). All
patients received some form of chemotherapy according to the appropriate
treatment protocol. The most common drugs used at the onset of
PRES were intrathecal methotrexate (N = 18; 85.7%), corticosteroids
(N = 16; 76.2%), L-asparaginase (N = 15; 71.4%), vincristine (N = 14;
66.7%), doxorubicin (N = 13; 61.9%), and cytarabine (N = 9; 42.9%);
fewer than five patients used other drugs. In accordance with the
treatment protocol, all patients were using polytherapy; see Table 1 and
Table 3. Intrathecal methotrexate is used at the child oncology clinic in
the treatment of hematological malignancies, and it is known for possible
neurotoxicity. PRES syndrome developed in 18 patients out of 248
(7.2%) treated with intrathecal methotrexate between 2008 and 2018.
P. Danhofer, et al. Seizure: European Journal of Epilepsy 72 (2019) 1–10
2
PSH was assessed in 19 patients; data from 2 patients were incomplete.
Only 1 patient out of 19 (5.3%) had normal blood pressure in
the presymptomatic period and prehypertension at PRES manifestation;
this patient was not included in the statistical evaluation. Two patients
out of 18 (11.2%) had 6 -h long PSH, 8 patients out of 18 (44.4%) had
9 -h long PSH, and another 8 patients out of 18 (44.4%) had more than
9 -h long PSH with 18 h as maximum.
The PSH severity was as follows: 1 patient out of 19 (5.3%) had
normal pressure, 6 patients out of 18 (33.3%) had hypertension grade I,
and 12 patients out of 18 (66.7%) had hypertension grade II. Factors
involved in the pathogenesis of PRES (oncological diagnosis and
treatment and PSH) are summarized in Table 1.
We compared the number of antihypertensives used to achieve
normotension and the duration of antihypertensive therapy in non-RSS
patients and RSS patients. In the first group, 236 ± 1.33 antihypertensive
drugs (ranged from 1 to 5 drugs) were used for 2.14 ± 2.88 months
(ranged from 0 to 12 months). In the second group, 3.75 ± 0.83 antihypertensive
drugs (ranged from 3 to 5 drugs) were used for
4.25 ± 4.49 months (ranged from 1 to 12 months). Although higher
values in the second group are obvious, results in such a small sample
size are not statistically significant.
3.2. Clinical-radiological diagnosis of PRES
The PRES clinical manifestations were as follows: seizures with or
without disturbance in consciousness, in 17 patients out of 21 (80.9%);
quantitative or qualitative disturbance of consciousness without seizures,
in 4 patients out of 21 (19.0%); headache, in 4 patients out of 21
(19.0%); and visual disturbances, in 3 patients out of 21 (14.3%).
Headache and visual disturbances were not the first symptoms of PRES
reported by the patient but they were often immediately described after
seizure or restoration of consciousness. Patients who reported headache
as one of the first symptoms of PRES were 8.50 ± 4.50 years of age
(ranged from 5 to 16 years). Visual disturbances at PRES onset were
reported at 8.33 ± 1.36 years of age (ranged from 7 to 10 years). This is
in accordance with the fact that small children often have difficulty
describing their symptoms, so these symptoms could have been
overlooked.
The neurological examination at PRES onset was normal in 4 patients
out of 21 (19.0%); 1 patient out of 21 (4.8%) had only focal
deficit without disturbance of consciousness; 8 patients out of 21
(38.1%) had qualitative disturbance of consciousness; 1 patient out of
21 (4.8%) had somnolence; 4 patients out of 21 (19.0%) were in sopor;
and 3 patients out of 21 (14.3%) were in coma state; see Table 2.
In the non-RSS group, the neurological status normalized in
4.75 ± 8.82 days (ranged from 1 to 28 days). In the RSS group of patients,
the neurological status normalised in 69.25 ± 105.81 days
(ranged from 1 to 252 days); see Table 2.
All patients underwent a structural examination of the brain, either
CT or MRI. Two patients out of 21 patients had only a CT scan, with
hypodense lesions in the posterior regions correlating with the image of
vasogenic edema; 19 patients out of 21 had MRI scans in correlation
with the radiologic diagnosis of PRES; 15 patients out of 21 (71.4%)
had lesions typically in the parieto-occipital region; 2 patients out of 21
(9.5%) had pathology in the parieto-occipital region, but also with
frontal involvement; 4 patients out of 21 (19.1%) had severe diffuse
involvement in bilateral fronto-temporo-parieto-occipital regions, including
the cerebellum or brainstem in 2 of them; see Table 2. Followup
MRI was performed in all patients after 43.1 ± 29.6 days (ranged
from 12 to 90 days): 19 patients out of 21 (90.5%) had normal followup
MRI; 2 patients out of 21 (9.5%) had persisting gliosis in the parietooccipital
region on MRI at the one-year follow-up visit (Table 2,
Figs. 1–4).
3.3. Seizures at PRES manifestation and RSS
Seventeen patients out of 21 (80.9%) had seizures as the clinical
manifestation of PRES (Table 2). Focal seizures were described in one
patient out of 17 (5.9%); focal seizures with impaired awareness in 5
patients out of 17 (29.4%); focal seizures with evolution to tonic-clonic
seizure in 1 patient out of 17 (5.9%); generalized tonic-clonic seizures
were described in 4 patients out of 17 (23.6%); nonconvulsive status
epilepticus in 3 patients out of 17 (17.6%); and convulsive status epilepticus
also in 3 patients out of 17 (17.6%).
Four patients out of 21 (19%) were assessed as having RSS; 2 of
them (9.5%) had ongoing seizures at the one-year follow-up visit.
Antiepileptic drugs (AEDs) used in the management of acute
symptomatic seizures at PRES onset and chronic AEDs are presented in
Table 3. All patients with RSS took levetiracetam (LEV) at the one-year
follow-up visit. Three patients out of 17 (17.6%) from the non-RSS
group were also on AEDs at the one-year follow-up visit (see Table 3).
GBP was used in the treatment of neuropatic pain. All AEDs in these
patients were tapered off in the course of the second year after PRES
onset. We have to take into consideration that this fact could possibly
mask the development of RSS in these patients during the one-year
follow-up period. However, these patients arbitrarily met the study
inclusion criteria, so they were included in the non-RSS group of pa-
tients.
3.4. EEG findings (Table 2)
All patients had EEG recorded directly at PRES manifestation or
within no more than 12 h (24/7 EEG availability is provided). Followup
EEG were performed every 3 months in all patients, or often if
needed.
Normal EEG at PRES manifestation was described in 4 patients out
of 21 (19.0%); focal or regional slowing was present 9 patients out of 21
(42.8%); and diffuse slowing was present in 2 patients out of 21 (9.6%).
Three patients out of 21 (14.3%) had focal epileptiform discharges on
EEG, and 3 patients out of 21 (14.3%) had LPDs on EEG.
Localization of focal slow waves or epileptiform discharges on EEG
was predominantly in the parieto-occipital region (for details, see
Table 2).
Table 1
Factors involved in the pathogenesis of PRES.
Factors involved in the pathogenesis of PRES
oncological diagnosis: 21 patients
ALL 16 76.2%
AML 1 4.8%
CML 1 4.8%
T-lymfoma 1 9.4%
Burkitt lymfoma 1
severe aplastic anemia 1 4.8%
blood pressure: 19 patients
normotension 1 5.3% not included in the evaluation of PSH
presymptomatic hypertension: 18 patients
hypertension grade I 6 33.3%
hypertension grade II 12 66.7%
duration (hours)
6 2 11.2%
9 8 44.4%
12 6 33.4%
15 1 5.5%
18 1 5.5%
protocol treatment at the PRES onset and /or 4 weeks before
methotrexat 18 85.7%
corticosteroids 16 76.2%
L-asparaginase 15 71.4%
vincristine 14 66.7%
doxorubicine 13 61.9%
cytarabine 9 42.9%
puri-nethol 6 28.6%
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Table2
ClinicalcharacteristicsandEEGandMRIfindingsofpatientswithPRES.
acutePRESonset
Patient
No.
oncological
diagnosis
treatmentprotocolageatoncological
diagnosis(years)
PRESonset-from
oncological
diagnosis(months)
neurological
examination
seizuretypeEEGlocalisationonEEGMRIdurationofPSH
(hours)
1T-ALLALL-IC20021710311normalPObilat.0
2praeB-ALLALL-ICBFM200281652slowingPObilat.PObilat.9
3cALLALL-ICBFM200262152slowingObilat.PObilat.(CT)9
4praeB-ALLALL-ICBFM200271131normalFright,Oleft6
5ALLALL-ICBFM2002410532slowingObilat.PObilat.(CT)NA
6cALLAIEOP-BFMALL2009211332slowingTPOrightPObilat.NA
7cALLAIEOP-BFMALL200942366LPDsPTrightFTPObilat.,cerebellum15
8praeB-ALLALL-ICBFM200230511normalPObilat.9
9T-ALLAEIOP-BFMALL200961652slowingObilat.Obilat.12
10cALLALL-ICBFM2002161312slowingObilat.Obilat.9
11AMLAMLBFM201252313diffuseslowingFTPObilat.,brainstem9
12preB-ALLALL-ICBFM200272476LPDsPOrightPObilat.12
13cALLAIEOP-BFMALL200947364SWCTPOleftPObilat.6
14cALLAIEOPBFMALL200937541normalFPbilat.9
15NHLAIEOP-BFMALL200975532slowingTOleftPObilat.18
16AAEWOGSAA201051364SWCFTPOright,
maxF
PObilat.12
17BLINTBNHL201081172slowingrightPPright12
patientswithremotesymptomaticseizures
1praeB-ALLAIEOP-BFMALL2009138122slowingPObilat.FTPObilat.12
2CMLCMLpaed20061019353diffuseslowingFPObilat.9
3cALLAIEOP-BFMALL200971236LPDsTOrightObilat.12
4praeB-ALLAIEOPBFMALL200931664SWCTOrightFTPObilat.
cerebellum
9
acutePRESonsetrestorationafteracutestateone-yearfollow-upvisit
Patient
No.
severityofPSH
(grade)
neurological
examination(days)
EEG(days)durationofanti-HT
therapy(months)
neurological
examination
EEGAEDsMRItimetofollow-up
MRI(days)
1normal1NANA110normal12
22110110normal12
32110110normal60
421NA3110normal60
5NA13NA110normal14
6NA128NA110normal60
7228NA1213LEVnormal60
82NANA1110normal14
92332110normal14
10111111GBP+VPAnormal14
1123283110normal90
122190111GBPnormal14
1311901110normal21
1411NA3110normal60
1523901110normal28
16228NA1120normal14
1711901110normal90
patientswithremotesymptomaticseizures
1213111LEVnormal28
(continuedonnextpage)
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4
In the non-RSS group, EEG was normalized in 38.64 ± 39.96 days
(ranged from 1 to 90 days), in the RSS group, EEG was normalised in
32.67 ± 40.55 days (ranged from 3 to 90 days); see Table 2.
At the one-year follow-up visit, 18 patients out of 21 (85.7%) had
normal EEG; 2 patients out of 21 (9.5%) had focal slowing; and 1 patient
out of 21 (4.8%) had diffuse slowing on EEG. No epileptiform
discharges were recorded.
3.5. Findings in patients with RSS
Four patients out of 21 (19%) were assessed as having with RSS. The
small sample size prevents a statistically significant analysis, but it is
possible to describe these patients’ important characteristics. There
were 3 girls and 1 boy in this group, ages 13, 10, 7, and 3 years respectively
at the PRES onset. Three of them were diagnosed with ALL
and one had CML. PSH took 9 h in 2 patients and 12 h in 2 patients; PSH
was grade I in 2 patients and grade II in two patients. The seizure type
at PRES onset was different in each patient: focal aware, GTCS, focal
with impaired awareness, or NCSE. Acute EEG findings were different
in each patient as well: focal slowing, diffuse slowing, LPDs, or focal
epileptiform discharges. All patients started treatment with levetiracetam
at a dose of 40–50 mg/kg/day after acute symptomatic seizures.
The first patient had two focal aware RSS 3 months after PRES
onset, leading to an increase in the dose of levetiracetam to 60 mg/kg/
day. Acute MRI showed diffuse lesions in the fronto-temporo-parietooccipital
region correlating with edema. Control MRI was normal after
one month. The patient was seizure free at the one-year follow-up visit
with normal neurological examination and EEG, still taking levetir-
acetam.
The second patient had one RSS with headache and visual illusion
+ns 9 months after PRES onset, while tapering off levetiracetam. Acute
MRI correlated with PRES syndrome with fronto-parieto-occipital lesions.
A follow-up MRI 3 months later was normal. The patient was
seizure-free at the one-year follow-up visit with normal neurological
examination and EEG; the patient was still taking levetiracetam.
The third patient had repeated seizures, continuing at one-year
follow-up visit. The patient described positive visual symptoms and
headache while fully aware. The dose of levetiracetam was increased to
60 mg/kg/day and the seizures reduced in frequency (1/month). The
patient and his parents preferred not to change medications; the seizures
did not disturb him. The patient had occipital lesions on acute
MRI with right-sided predominance; gliosis in the same region persisted
on MRI at the one-year follow-up visit (Figs. 1 and 2). Neurological
examination was normal after one year, with focal slowing on EEG
(occipital right).
The fourth patient had focal aware repeated seizures, continuing at
the one-year follow-up visit. The dose of levetiracetam was increased
with partial effect, eslicarbazepine was added at the one-year follow-up
visit with effect and the patient became seizure-free. Acute MRI was
with diffuse cortico-subcortical fronto-temporo-parieto-occipital findings
and with cerebellum involvment; these lesions persisted with occipital
predominance as gliosis on MRI at the one-year follow-up visit
(Figs. 3 and 4). Neurological examination and EEG was normal after
one year.
3.6. Statistics
Statistical analysis did not reveal a statistically significant difference
between sex or age at PRES onset (patients younger than 6 years vs. 6
years and older) in terms of duration and severity of PSH, clinical
manifestation, seizure type, or EEG findings at PRES onset and at the
one-year follow-up visit and the occurrence of RSS.
Statistical analysis also did not reveal a statistically significant difference
between the group of patients with PSH grade I and those with
grade II in terms of neurological status, seizure type, or EEG findings at
PRES onset and at the one-year follow-up visit and the occurrence of
Table2(continued)
acutePRESonsetrestorationafteracutestateone-yearfollow-upvisit
Patient
No.
severityofPSH
(grade)
neurological
examination(days)
EEG(days)durationofanti-HT
therapy(months)
neurological
examination
EEGAEDsMRItimetofollow-up
MRI(days)
21331211LEVnormal60
3121NA212LEVObilat.gliosis90
4225290211LEVPObilat.gliosis90
Neurologicalexamination:1–normal;2–focaldeficitwithoutlossofconsciousness;3–qualitativedisturbanceofconsciousness(hypoactiveorhyperactivedelirium:confusion,disorientation,memorydisturbance,
illusionsorhallucinations);4–quantitativedisturbanceofconsciousness–somnolence;5–quantitativedisturbanceofconsciousness–sopor;6–quantitativedisturbanceofconsciousness–coma.Seizuretype:1–no
seizures;2–focal–aware;3–focal–impairedawareness;4–focaltobilateraltonic-clonicseizure(FBTCS);5–generalizedtonicclonicseizure(GTCS);6–non-convulsivestatusepilepticus(NCSE);7–convulsivestatus
epilepticus(CSE).EEG:1–normal;2–focalslowing;3–diffuseslowing;4–focalepileptiformdischarges;5–generalizedepileptiformactivity;6–LPDs.
Oncologicaldiagnosis:ALL–acutelymphoblasticleukemia,AML–acutemyeloidleukemia,NHL-Non-Hodgkinlymphoma,AA–aplasticanemia,BL–Burkittlymphoma,CML–chronicmyeloidleukemia;localization
onEEGandMRI:F-frontal,P-parietal,T-temporal,O-occipital;anti-HT-antihyperensive,AEDs–antiepilepticdrugs:LEV–levetiracetam;GBP–gabapentine;VPA–valproate.
P. Danhofer, et al. Seizure: European Journal of Epilepsy 72 (2019) 1–10
5
Table3
Characteristicsofoncological,antihypertensiveandantiepileptictreatment.
PatientNo.oncologicaldiagnosistreatmentprotocoloncologicaltreatment6weeksbeforeand/oratPRESmanifestationantihypertensivetreatmentNo.ofanti-HT
drugs
acuteAEDsi.v.chronicAEDs
1T-ALLALL-ICBFM2002corticosteroids,i.th.MTX,cytarabin,cyclophosphamide,mercaptopurine,
vincritsine,doxorubicin,asparaginase
NANA00
2praeB-ALLALL-ICBFM2002corticosteroids,i.th.MTX,vincritsine,doxorubicin,asparaginasefurosemide1DZP0
3cALLALL-ICBFM2002corticosteroids,i.th.MTX,vincritsine,doxorubicin,cyclophosphamideenalapril1DZP0
4praeB-ALLALL-ICBFM2002corticosteroids,i.th.MTX,vincritsine,doxorubicin,asparaginasecaptopril,isradipine200
5ALLALL-ICBFM2002corticosteroids,i.th.MTX,cytarabin,cyclophosphamide,mercaptopurine,
vincritsine,doxorubicin,asparaginase
NANADZP0
6cALLAIEOP-BFMALL
2009
corticosteroids,i.th.MTX,cytarabin,cyclophosphamide,mercaptopurine,
asparaginase
NANADZP0
7cALLAIEOP-BFMALL
2009
i.th.MTX,cytarabin,cyclophosphamide,mercaptopurineenalapril1DZP,LEVLEV
8praeB-ALLALL-ICBFM2002corticosteroidsfurosemide100
9T-ALLAEIOP-BFMALL
2009
corticosteroids,i.th.MTX,vincritsine,doxorubicin,asparaginaseenalapril,furosemide,propranolol,esmolol4DZP,LEV0
10cALLALL-ICBFM2002corticosteroids,i.th.MTX,cytarabin,cyclophosphamide,mercaptopurine,
vincritsine,doxorubicin,asparaginase
captopril,furosemide2DZP,VPAGBP,VPA
11AMLAMLBFM2012i.th.MTX,i.th.cytarabin,i.th.prednisone,cytarabin,etoposiddihydralazine,furosemide,clonidine,enalapril,
amlodipine
500
12preB-ALLALL-ICBFM2002corticosteroids,i.th.MTX,vincritsine,doxorubicin,asparaginasecaptopril,isradipine2DZP,CLZGBP
13cALLAIEOP-BFMALL
2009
corticosteroids,i.th.MTX,vincritsine,doxorubicin,asparaginasedihydralazine,furosemide,enalapril3DZP,PB,LEV0
14cALLAIEOPBFMALL
2009
i.th.MTX,cytarabine,thioguanine,cyklophosphamide,asparaginaseenalapril1DZP,LEV0
15NHLAIEOP-BFMALL
2009
i.th.MTX,vincristine,asparaginasedihydralazine,clonidine,enalapril,metoprolol4LEV,VPA0
16AAEWOGSAA2010Atgam,cyclosporineA,corticosteroidsdihydralazine,furosemide,clonidine,enalapril,
amlodipine
5LEV0
17BLINTBNHL2010corticosteroids,i.th.andi.v.MTX,i.th.cytarabin,cyclophosphamide,
vincritsine,doxorubicin,rituximab
enalapril1LEV0
patientswithremotesymptomaticseizures
1praeB-ALLAIEOP-BFMALL
2009
corticosteroids,i.th.MTX,cytarabin,cyclophosphamide,mercaptopurine,
vincritsine,doxorubicin,erwinase
clonidine,metipranolol,enalapril3CLZ,LEVLEV
2CMLCMLpaed2006Atgam,melphalan,cyclophosphamide,thiotepa,fludarabinedihydralazine,lercanidipine,perindopril,
metoprolol,captopril
5CLZ,LEVLEV
3cALLAIEOP-BFMALL
2009
corticosteroids,i.th.MTX,vincritsine,doxorubicin,asparaginasedihydralazine,enalapril,furosemide3CLZ,LEVLEV
4praeB-ALLAIEOPBFMALL
2009
corticosteroids,i.th.MTX,vincritsine,doxorubicin,asparaginasedihydralazine,clonidine,enalapril,propranolol4DZP,LEVLEV
Oncologicaldiagnosis:ALL–acutelymphoblasticleukemia,AML–acutemyeloidleukemia,NHL-Non-Hodgkinlymphoma,AA–aplasticanemia,BL–Burkittlymphoma,CML–chronicmyeloidleukemia.
MTX–methotrexate,i.th.–intrathecal,AEDs–antiepileptiocdrugs,anti-HT–antihypertensive,DZP-diazepame,CLZ–clonazepame,PB-phenobarbital,GBP–gabapentine,VPA–valproate,LEV–levetiracetame.
P. Danhofer, et al. Seizure: European Journal of Epilepsy 72 (2019) 1–10
6
RSS. Neither were there statistically significant differences between the
group of patients with PSH of duration ≤9 h and >9 h in terms of
neurological status, seizure type, or EEG findings at PRES onset and at
the one-year follow-up visit and the occurrence of RSS.
We tested the relationship between the seizure type and EEG or MRI
findings at PRES onset and the occurrence of RSS. There was not a
statistically significant difference between these variables.
4. Discussion
4.1. Pathophysiology of PRES in children with malignancy or bone marrow
failure
PRES is a possible complication in children undergoing chemotherapy
[6,10]. The overall incidence of PRES in child malignancies
Fig. 1. Patient No. 3 from RSS group: MRI at PRES onset showing FLAIR (a,b) and T2-weighted (c,d) subcortical hyperintensities in occipital regions with right
predominance.
Fig. 2. Patient No. 3 from RSS group: follow-up MRI showing T1-weighted (a) hypointensities and T2- weighted hyperintensities in occipital regions with right
predominance correlating to gliosis.
Fig. 3. Patient No. 4 from RSS group: MRI at PRES onset showing FLAIR (a,b) and T2-weighted (c,d) diffuse supratentorial cortical-subcortical hyperintensities with
occipital predominance.
P. Danhofer, et al. Seizure: European Journal of Epilepsy 72 (2019) 1–10
7
in our series is 1.4%, which makes this diagnosis very rare. According to
the literature, it affects mainly patients with ALL (55%), and less frequently
patients with AML (9%), which is also due to the different incidence
of these diagnoses [11]. There are also reports of PRES associated
with Langerhans histiocytosis, Hodgkin’s lymphoma, nonHodgkin’s
lymphoma [12], and aplastic anemia [13]. In our series, the
majority of patients in the study had ALL (76.2%) individual patients
were also diagnosed with AML, CML, lymphoma, or severe aplastic
anemia.
Corticosteroid treatment, L-asparaginase, cyclosporin A, and intrathecal
methotrexate are suggested to have an important role in the
development of PRES [6,14]. In total, 85.7% of patients were treated
with intrathecal methotrexate, 76.2% of patients with corticosteroids,
and 71.4% of patients with L-asparaginase. Intrathecal methotrexate is
known for its neurotoxicity, and case reports with acute polyradiculoneuropathy
[15], acute myelopathy [16] or MTX-induced
stroke-like neurotoxicity [17] after intrathecal methotrexate administration
have been published. Recent studies with animal models indicate
possible late cognitive deficits induced by methotrexate [18,19].
In our study, PRES syndrome developed in 7.2% of patients with malignancy
treated with intrathecal methotrexate over a 10-year period. It
has been hypothesized that endotheliotoxic effects of both immunosuppressive
as well as cytostatic drugs may lead to blood-brain
barrier disturbances as well as to the impairment of cerebral vascular
autoregulation [20] with the development of brain vasogenic edema. In
addition, corticosteroids may play an indirect role in the development
of PRES due to the higher risk of steroid-related hypertension [11].
Hypertension is considered to be another key risk factor of PRES.
Severe hypertension leads to failed autoregulation and subsequent hyperperfusion,
again with the development of vasogenic edema [21].
Hypertension is often seen in children with PRES (100% according to
Morris [12]; 68% according to Kim [6]. We observed hypertension in
all patients except one (94.7%) and the hypertension was severe: grade
II in the majority of patients. The duration of PSH was 9 h or longer in
almost all patients. The clinical manifestation of PRES was observed
most often between 9 and 12 h of the PSH.
The effect of PSH on PRES severity was studied in 65 patients with
PRES by Lee et al. [22]. The brain lesion distribution degree, or lesion
scoring point (LSP) on MRI was numerically calculated and compared
with presymptomatic blood pressure. The LSP was significantly correlated
with pre-MAP (mean arterial pressure before the clinical manifestation
of PRES). The authors concluded that patients with PRES who
have relatively higher blood pressure in the presymptomatic period
could have worse degrees of impaired cerebral autoregulation and are
more likely to have wider lesion distributions than patients with lower
blood pressure. A possible limitation is that only the distribution of
edematous lesions was studied (number of brain regions affected),
which does not necessarily correlate with their severity. In our study,
we examined the relationship between PSH and neurological outcomes
in children with PRES: neurological status, type of seizures, and EEG at
PRES onset and at the one-year follow-up visit. We did not find any
statistically significant relationship.
We can conclude that hypertension is not the only causative factor
in the pathogenesis of PRES, especially in this specific group of patients
with hematological malignancies, in whom it is necessary to consider
the endothelial dysfunction caused by the cytotoxic and immunosuppressive
drugs used. It is also necessary to highlight the hypertensive
effect of corticosteroids used in most patients. However,
targeted and prompt blood pressure control can be crucial in the
management of PRES and should not be underestimated in the context
of the multifactorial etiology of this syndrome.
4.2. Seizure outcome in patients with PRES
Many studies describe the clinical and radiological features of PRES
in adults and in children. However, studies concerning the electroencephalographic
findings and seizure occurrence and prognosis are
rare and are mostly designed for the adult population.
Seizures are significantly more frequent in pediatric PRES patients
as an initial PRES-related symptom than in adults [11,20]. Experimental
data suggest that exposure to calcineurin inhibitors causes more
severe neurotoxicity at a young age due to an increased permeability of
the immature blood-brain barrier, allowing PRES-mediating circulating
substances to act on the brain [5,23]. These factors might contribute to
the high incidence of seizures observed in pediatric PRES, possibly
sharing pathophysiological similarities with pediatric febrile seizures, a
common pediatric condition that might also be partially triggered by
fever-associated circulating proinflammatory cytokines [24].
Fig. 4. Patient No. 4 from RSS group: follow-up MRI showing T1-weighted (a) hypointensities and T2- weighted hyperintensities in parietooccipital regions with right
predominance correlating to postischemic lesions and gliosis.
P. Danhofer, et al. Seizure: European Journal of Epilepsy 72 (2019) 1–10
8
Seizure occurrence in patients with PRES suggests that this syndrome
is not just a subcortical pathology. Cortical irritation resulting
from the adjacent vasogenic edema that follows disruption of the blood
brain barrier is the most probable implicating factor [9].
Seventeen patients out of 21 (80.9%) had seizures as the clinical
manifestation of PRES. Almost half of the patients had severe seizure
manifestation at PRES onset: GTCS was observed in 4 patients out of 17
(23.6%), NCSE was observed in 3 patients out of 17 (17.6%), as was
convulsive SE. Only one patient of this group – the patient with NCSE –
developed RSS.
EEG patterns are not well described, but common patterns are reported
and include diffuse and focal (mostly posterior) slowing with or
without epileptiform discharges [9,10,25] as we found in our series.
Lateralized periodic discharges (LPDs) are not commonly associated
with PRES [11,13,26] but when they occur, they are associated with a
worse prognosis and the development of ongoing seizures or epilepsy
[26]. In our study, 3 patients out of 21 (14.3%) had LPDs on acute EEG;
only one of them developed RSS.
The results from our study showed that neither the severity of seizure
type at PRES onset nor the severity of acute EEG findings are associated
with worse neurological prognosis in patients with PRES syndrome.
But we have to take into consideration relatively small number
of patients in the study.
RSS or the development of epilepsy after PRES syndrome is rare.
Recurrent seizures were observed in 4 adult patients out of 46 (8.7%); 3
of those patients had atypical PRES pattern on MRI (involvement of the
basal ganglia, thalamus, corpus callosum, and periventricular white
matter, in addition to typical lesions) [27]. Sha et al. published a series
of 75 adult patients with PRES: 4 of them (5.3%) developed RSS, 2
patients (2.6%) developed epilepsy with seizures occurring more than
one year after the PRES [25]. An interesting Swedish study of 52
children with ALL and PRES syndrome was recently published. According
to this study, 7 patients out of 52 (13.4%) had epilepsy after
PRES and the same number of patients had neurocognitive difficulties
as a consequence of ALL diagnosis and treatment [28]. In our study,
almost one fifth of patients (19%) had RSS beyond the acute phase of
PRES syndrome. Statistical analysis in such a small cohort is not strong
enough to trace common factors provoking RSS after PRES syndrome. If
this group of patients is studied more closely, it emerges that patients
with persisting gliosis on MRI had ongoing seizures at the one-year
follow-up visit. According to the definition of epilepsy (ILAE 2017),
these 2 patients can be classified as having epilepsy (9.5%). It seems
that a persisting structural lesion on MRI is important prognostically. In
a study by Sha et al. in which 4 patients out of 75 developed RSS, two
patients had post-ischemic lesions on MRI, one patient had focal
atrophy, and one patient had normal MRI at the follow-up visit [25]. To
date, the correlations between imaging findings and seizure outcome
have been poorly described [25,29]. Yamamoto et al. (2015) studied a
group of 40 children with PRES; 10% developed focal epilepsy [30].
The same study examined cytotoxic edema on MRI, represented by ADC
reduction, which can lead to irreversible cerebral damage; vasogenic
edema is likely to be reversible. Almost half of the studied patients had
focal gliosis or atrophy on follow-up MRI; this finding was associated
with ADC reduction during the acute period. Three of four patients with
focal epilepsy had gliosis or atrophy on follow-up MRI. The study
concluded that cytotoxic edema with ADC reduction during the acute
period and subsequent focal lesions could lead to epileptogenic focus.
Recently, atypical neuroimaging findings such as cytotoxic edema, infarction,
hemorrhage, contrast enhancement, and a non-reversible
clinical course including subsequent epilepsy, have been highlighted
[29,31,32]. The pathogenesis of cytotoxic edema in PRES syndrome is
not clear. A comparative study of 19 pediatric versus 100 adult patients
with PRES proved ADC reduction was statistically significant in children
as compared to adults [33]. Further studies are needed to clarify
the cause of persistent lesions on MRI and their relationship to PRES
syndrome, its neurological outcome, and possible epileptogenesis.
4.3. Study limitations
The results of this study have to be assessed in the context of the
following facts. The study is retrospective and the cohort is not large;
we included 21 patients in the study. Comparing the data with the
literature, this is one of few studies assessing EEG and MRI findings and
seizure outcome in children with PRES. Other studies are designed for
the adult population. Literature concerning clinico-radiologic findings
in children with PRES often describe small series: 7 patients [11], 5
patients [14], 19 patients [15], and 8 patients [16]. Nevertheless, the
number of patients in this study limits the statistical analysis. MRI data
are inconsistent. We have CT scans in the acute phase of only two patients
and MRI was performed on various machines with different
protocols between 2008 and 2018 (0.2 T, 1 T, and 1.5 T). For these
reasons, the MRI data cannot be studied more precisely (the extent of
lesions, ADC maps, etc.).
5. Conclusion
PRES is a rare complication in the treatment of children with hematological
malignancies and bone marrow failure. It is considered to
be a reversible condition, but RSS or epilepsy can develop. Persisting
structural lesions on follow-up MRI can be associated with a worse
prognosis, but further studies are needed to explain the pathophysiology
of these MRI changes and their epileptogenesis. The severity
and duration of PSH does not correlate with the neurological and seizure
outcomes, but the study nevertheless encourages the prompt and
targeted treatment of hypertension in patients with PRES.
Declaration of Competing Interest
None of the authors has any conflict of interest to disclose. We
confirm that we have read the Journal’s position on issues involved in
ethical publication and affirm that this report is consistent with those
guidelines.
Acknowledgments
This work was supported by funds from the Faculty of Medicine of
the University of Masaryk to junior researcher Pavlína Danhofer, M.D.,
Ph.D. and Štefánia Aulická M.D., Ph.D. (2726 – IRP 2018- ROZV/24/
LF/18).
Thanks to Anne Johnson for grammatical assistance.
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96
2.2 Annex 2:
Danhofer P, Brázdil M, Ošlejšková H, Kuba R. Long-term seizure outcome in patients with
juvenile absence epilepsy; a retrospective study in a tertiary referral center. Seizure. 2014
Jun;23(6):443–7. doi: 10.1016/j.seizure.2014.03.002.
Summary:
Purpose: The study aim was to evaluate pharmacotherapy effects and long-term seizure
outcomes in patients with juvenile absence epilepsy (JAE) during a five-year follow-up period.
The secondary aim was to identify factors from patient history and determine their influence on
seizure control.
Method: We retrospectively studied 46 patients with JAE in the period between 2006 and 2011.
The age at seizure onset, onset seizure type, family history of epilepsy, status epilepticus in
history, medication history, and the rate of seizure control were studied.
Results: There were 30 females (65.2%) and 16 males (34.8%) in the study. The mean age at
seizure onset was 12.9±5.6 years (ranged from 3 to 28 years). In 30 patients (65.2%), seizure
onset was with absences, in 15 patients (32.6%) with generalized tonic-clonic seizure (GTCS),
and in 1 patient (2.2%) with absence status. In 43 patients (93.5%), GTCS occurred in the course
of the disease. Family history for epilepsy was positive in 10 patients (21.7%). In the five-year
follow-up period, seizure freedom (Group 1) was achieved in 7 patients (15.2%). In total, 22
patients (47.8%) were classified into the groups involving very poor seizure control and
antiepileptic drug resistance (Groups 5 and 6). The mean number of antiepileptic drugs (AEDs)
used in the course of the disease in appropriate therapeutic doses was 3.8±2.3 (1-10 AEDs).
Conclusion: The study results show that almost half of JAE patients have poor seizure control
with a high rate of pharmacoresistance. The outcome of JAE can be very uncertain.
Author's personal copy
Long-term seizure outcome in patients with juvenile absence epilepsy;
a retrospective study in a tertiary referral center
Pavlı´na Danhofer a,
*, Milan Bra´zdil b,c
, Hana Osˇlejsˇkova´ a
, Robert Kuba a,b,c
a
Epilepsy Center Brno, Department of Child Neurology, University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
b
Epilepsy Center Brno, First Department of Neurology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
c
Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
1. Introduction
According to ILAE Epilepsy Classification (1989),1
juvenile
absence epilepsy (JAE) is classified among the age-related
idiopathic generalized epilepsies in adolescence. The proposed
ILAE Epilepsy Classification revision2
gives preference to the terms
‘‘genetic’’ or ‘‘unknown’’ instead of ‘‘idiopathic’’. The presumably
genetic cause and specific mutation in most patients with JAE is
still unknown. JAE is characterized by typical absence seizures, a
long-life prevalence of GTCS for 80–83% of patients,3,4
and sporadic
myoclonic jerks are observed in 20% of patients. The seizure onset
is typically between 9 and 13 years of age. GTCS and myoclonic
seizures often occur 1–10 years after the absence seizure onset.4
No sex predominance has been observed among the patients with
JAE.4
The incidence of JAE is not precisely known. JAE patients
account for approximately 2–3% of patients with adult epilepsy in
general, and about 8–10% of patients with idiopathic generalized
epilepsy (IGE).4
The etiology of JAE is a subject primarily of genetic
research. The research results have shown that genetic mutations
for voltage-gated sodium channels (CACNB4 gene)5,6
and potassium
channels (CLCN2 gene)5
are involved. Different mutations were
found in genes for GABA receptors (ligand ion channels),
specifically in the GABRA1 gene.7
The aim of this retrospective study is to evaluate the effects of
pharmacotherapy and the long-term seizure outcome in patients
with JAE in a tertiary referral center. To our knowledge, there is
insufficient information concerning the long-term outcome of
Seizure 23 (2014) 443–447
A R T I C L E I N F O
Article history:
Received 21 October 2013
Received in revised form 28 February 2014
Accepted 4 March 2014
Keywords:
Epilepsy
Juvenile absence epilepsy
JAE
Therapy
Outcome
Seizure control
A B S T R A C T
Purpose: The study aim was to evaluate pharmacotherapy effects and long-term seizure outcomes in
patients with juvenile absence epilepsy (JAE) during a five-year follow-up period. The secondary aim was
to identify factors from patient history and determine their influence on seizure control.
Method: We retrospectively studied 46 patients with JAE in the period between 2006 and 2011. The age
at seizure onset, onset seizure type, family history of epilepsy, status epilepticus in history, medication
history, and the rate of seizure control were studied.
Results: There were 30 females (65.2%) and 16 males (34.8%) in the study. The mean age at seizure onset
was 12.9 Æ 5.6 years (ranged from 3 to 28 years). In 30 patients (65.2%), seizure onset was with absences, in
15 patients (32.6%) with generalized tonic-clonic seizure (GTCS), and in 1 patient (2.2%) with absence status.
In 43 patients (93.5%), GTCS occurred in the course of the disease. Family history for epilepsy was positive in
10 patients (21.7%). In the five-year follow-up period, seizure freedom (Group 1) was achieved in 7 patients
(15.2%). In total, 22 patients (47.8%) were classified into the groups involving very poor seizure control and
antiepileptic drug resistance (Groups 5 and 6). The mean number of antiepileptic drugs (AEDs) used in the
course of the disease in appropriate therapeutic doses was 3.8 Æ 2.3 (1–10 AEDs).
Conclusion: The study results show that almost half of JAE patients have poor seizure control with a high
rate of pharmacoresistance. The outcome of JAE can be very uncertain.
ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Abbreviations: ESM, ethosuximide; GTCS, generalized tonic-clonic seizure; IGE,
idiopathic generalized epilepsy; ILAE, International League Against Epilepsy; JAE,
juvenile absence epilepsy; LEV, levetiracetam; LTG, lamotrigine; MRI, magnetic
resonance imaging; PRM, primidone; PSWC, polyspike-wave complex; SE, status
epilepticus; SWC, spike-wave complex; TPM, topiramate; VPA, valproic acid; ZNS,
zonisamide.
* Corresponding author at: Brno Epilepsy Center, First Department of Neurology,
St. Anne’s University Hospital and Faculty of Medicine, Masaryk University,
Pekarˇska´ 53, 656 91 Brno, Czech Republic. Tel.: +420 543 182 658;
fax: +420 543 182 624.
E-mail addresses: pavlina.cahova@seznam.cz (P. Danhofer),
mbrazd@med.muni.cz (M. Bra´zdil), hoslej@fnbrno.cz (H. Osˇlejsˇkova´),
robert.kuba@fnusa.cz (R. Kuba).
Contents lists available at ScienceDirect
Seizure
journal homepage: www.elsevier.com/locate/yseiz
http://dx.doi.org/10.1016/j.seizure.2014.03.002
1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Author's personal copy
patients with JAE. Another aim of this study is to identify selected
case history data (age at seizure onset, type of seizure at onset,
family history) and determine their influence on the rate of seizure
control.
2. Methods
We retrospectively evaluated the long-term seizure outcome in
patients with JAE who had been referred to the Epilepsy Center
Brno. We included only patients who had been observed and
clinically managed in the center for at least five years (specifically
in the period between 2006 and 2011). This period was described
as the observational period (OP).
All patients met the criteria of JAE according to the ILAE 1989
Classification1
i.e. clinical (age at seizure onset, normal psychomotor
development, presence of absence seizures, GTCS or nondominant
myoclonic jerks) and electroencephalographic (normal
background activity, ictal pattern of bilateral, symmetric, and
synchronous discharge of regular 3–4 Hz spike wave discharges).
All patients underwent a 1.5 T MRI scan, which excluded patients
with potentially epileptogenic lesions.
We retrospectively evaluated the patient age at seizure onset,
seizure type, family history of epilepsy, status epilepticus in the
patient history, and history of medication, including the number of
AEDs and AED treatment during the OP. The rate of seizure control
was evaluated at the end of the five-year OP. The data concerning
the types of seizures and their frequency were based on interviews
with the patients and their caregivers. All of the patients were
regularly followed up during the whole OP for clinical purposes.
Patients from whom we could not obtain complete data or who
were assessed irregularly were excluded from the study.
According to the type of seizure control during the five-year OP
and at the end of the OP, we defined the following outcome groups:
1. Completely seizure free
2. Only absence seizures
3. Only GTCSs with a frequency 1 seizure per year
4. Only GTCSs with a frequency >1 seizure per year
5. Both GTCS and absence seizures; GTCSs with a frequency 1
seizure per year
6. Both GTCS and absence seizures; GTCSs with frequency >1
seizure per year
Since the data regarding the absence seizures were based on
interviews with patients and their caregivers, without video EEG
verification, we did not precisely evaluate the frequency of this
type of seizure.
2.1. Statistics
We used the Mann–Whitney U-Test to analyze the possible
differences among patients who were or were not completely
seizure free during the whole OP in terms of their age, age at
epilepsy onset, and epilepsy duration. A chi-square test was used
to evaluate the possible differences among patients who were or
were not completely seizure free during the whole OP in terms of
the positive/negative family history and type of the seizure as a
first manifestation of JAE (i.e. absences or GTCS). A value of p < 0.05
was considered statistically significant.
3. Results
We studied a group of 46 patients (30 females and 16 males)
who met the criteria for JAE according to the ILAE 1989
Classification1
and had been observed for at least 5 years. The
patient age ranged from 19 to 49 years with an average age of
31.2 Æ 8 years. There were 10 out of 46 patients (21.7%) with a positive
family history for epilepsy in our cohort. Because the evaluation was
retrospective, we were only able to obtain exact and specific data
concerning the type of epilepsy in each patients’ relative from 4 of the
10 patients. IGE (not more specified) was present in 2 patients’
relatives, 1 patient had a brother with febrile convulsions, and 1 patient
had a child with benign neonatal convulsions. Precise data concerning
the family history from other patients were not available.
Fig. 1. Number of patients in different groups according to the rate of seizure control at the end of the OP (pts: patients).
P. Danhofer et al. / Seizure 23 (2014) 443–447444
Author's personal copy
The average patient age at the time of the first clinical
manifestation was 12.9 Æ 5.6 years (ranged from 3 to 28 years). In
30 of the 46 patients (65.2%) the first clinical manifestation of JAE
were absences, in 15 patients (32.6%) GTCS, and in 1 patient (2.2%)
absence status epilepticus. In 43 patients (93.5%), at least one GTCS
occurred in the course of the disease.
At the end of the OP, 7 of the 46 patients (15.2%) had been
seizure free during the whole OP (Group 1). In the same period,
8 patients (17.4%) had only absences (Group 2). Other types of
predefined outcomes are presented in Fig. 1. In total, 31 patients
(67.4%) experienced at least 1 GTCS during the OP.
The assessment of AED treatment revealed that the number of
AEDs used in the history varied from 1 to 10 with an average of
3.8 Æ 2.3 AEDs. Only 8 of the 46 patients (17.4%) had just 1 AED,
19 patients (41.3%) had 3 or fewer AEDs, and 27 patients (58.7%) had
4 or more AEDs.
At the end of the OP, 20 of the 46 patients (43.5%) had been
treated by monotherapy, 20 patients (43.5%) used a combination of
2 AEDs concurrently, 3 patients (6.5%) used a combination of
3 AEDs, and 3 patients (6.5%) used a combination of 4 AEDs.
Patients from Group 1 (i.e. seizure-free patients during the
whole OP) were seizure free on 1 AED in 5 cases (71.4%) and on 2
AEDs in 2 cases (28.6%). In these patients, seizure freedom was
achieved by the use of 1 to 3 AEDs: 1 patient tried 1 AED, 4 patients
2 AEDs, and 2 patients 3 AEDs. Finally, 3 patients remains seizurefree
on monotherapy of LTG, 2 patients on monotherapy of VPA, 1
patient on the combination of VPA + LTG and 1 patient on the
combination of LTG + ESM.
The most commonly used AED in our series was lamotrigine (25
patients; 12 in monotherapy and 13 in combined therapy),
followed by valproic acid (20 patients; 5 in monotherapy and
15 in combined therapy) and levetiracetam (11 patients; all in
combined therapy). Other AEDs used both in monotherapy and in
combinations are noted in Table 1.
Statistical analysis did not reveal a statistically significant
difference between the group of patients who were completely
seizure free during the whole OP (Group 1) and the patients who
were not (Groups 2–6) in terms of their age (p = 0.736), age at
epilepsy onset (p = 0.747), epilepsy duration (p = 0.666), positive/
negative family history (p = 0.557), or the type of seizure that was
the first manifestation of JAE (0.854).
4. Discussion
Patients fulfilling the criteria for JAE according to the ILAE 1989
Classification1
were enrolled in the study. The sub-classification of
absence epilepsies in CAE and JAE is still a source of some
controversy. We tried to exclude patients with CAE in terms of the
seizure onset (younger than 10 years) and the dominant type of
seizures (less often associated with other seizure types – GTCS and
myoclonic seizures). Patients with EEG characterized by polyspike
wave and wave complexes and dominant myoclonic seizures,
which fit the diagnosis of JME, were also excluded from the study
even if they started with absences as a dominant seizure type at the
onset. Patients overlapping the boundaries between all the
syndromes, and who thus could not be assigned to one or another
group without effort and uncertainty, were excluded from the
study.
To our knowledge, there are not many studies concerning the
pharmacotherapy and long-term treatment outcome in patients
with JAE. This could be due to the relatively low prevalence of this
syndrome and the general opinion that JAE is classified as a
syndrome with a good prognosis and therapy responsiveness.
Literature data provide inconsistent results concerning the
long-term prognosis of patients with JAE. For example, Tovia et al.8
published a study of 17 patients with JAE with an average followup
period of 6.05 years (2–12 years). In the course of the follow-up
period, 8 of the 17 patients (43.7%) were seizure free. The average
disease duration was 6.93 years (1–13 years). The average patient
age when the remission of absences was observed was 15.75 years.
Eight of the 17 patients (47%) had GTCS in the course of the disease.
Trinka et al.9
published a study of 64 patients with JAE with an
average follow-up period of 25.8 years (3–69 years). Of the 64
patients, 40 patients (62%) were seizure free during the follow-up
for 2 or more years. Generally, seizure freedom can be achieved
with antiepileptic medication in 62–84% of all patients with
JAE.4,9,10
There are some studies that indicate that the outcome of
patients with JAE is not favorable as a rule. Wirell et al.11
studied
the prognostic factors of initial pharmacotherapy failure.
According to the study results, only 3 of the 11 children with
JAE (27.3%) were seizure free after the drug initiation (mostly
VPA).
There were 7 out of 46 patients (15.2%) seizure free (Group 1)
during the OP in this study. These patients did not achieve seizure
freedom after administration of 1 AED as we would expect. They
tried 1–3 AEDs and only 5 of them (10.9%) stayed on 1 AED during
the whole OP. Compared to the literature, Tovia et al.8
presented
nine of the 17 patients (52.9%) who were responsive for the first
AED, but only 6 patients (35.3%) stayed seizure free on monotherapy
during the follow-up period. These results show that even
in the group of patient who were seizure free, the seizure freedom
was not achieved in the simple way and does not have to be
permanent.
Table 1
AED treatment in the whole cohort of patients with JAE.
Treatment type AEDs No. of pts. Total no. of pts.
Monotherapy LTG 12 20
VPA 5
ETS 2
CBZ 1
Combination of 2 AEDs VPA + LTG 5 20
VPA + LEV 4
LTG + LEV 3
TPM + ZNS 2
TPM + LTG 2
LTG + ZNS; LTG + ESM; CBZ + PRM; VPA + TPM Each 1
Combination of 3 AEDs VPA + PRM + LEV; VPA + LEV + ZNS; LEV + LTG + ZNS Each 1 3
Combination of 4 AEDs VPA + LEV + CBZ + CLN; VPA + LTG + PRM + CLN;
VPA + LTG + LEV + CLN
Each 1 3
No.: number; pts.: patients.
P. Danhofer et al. / Seizure 23 (2014) 443–447 445
Author's personal copy
Tovia et al.8
showed that the occurrence of GTCS predicted a
worse prognosis. Only 37.5% of the patients in that study who
experienced GTCSs were seizure free during the follow-up period,
compared with 55.5% of patients without GTCSs. Similar results
were observed by Trinka et al.9
where the proportion of seizure
free patients in the follow-up period who experienced GTCSs was
35% compared to 78% of the patients with only absence seizures. In
this study, there was also a strong correlation between the mean
follow-up duration and outcome, indicating a lower proportion of
seizure-free patients with longer follow up periods. From this
point of view, the occurrence of GTCSs during the course of the
disease seems to be another important prognostic factor for the
long-term outcome in patients with JAE. In our study, only 8.7% of
the patients did not experience GTCS during the course of the
disease; therefore, we were unable to perform this type of
analysis.
The AEDs of choice in the JAE therapy are VPA and LTG. VPA is
the second medication choice for young women. Efficacy was
also proved in ETS, LEV, TPM, and ZNS. VPA is an efficient
treatment for all types of seizures in patients with JAE in 70–
80% of patients, LTG in 50–60% of patients.4,12
If VPA deals with
only partial seizure control, add-on LTG (GTCS) or ETS (absence
seizures) can be beneficial.13
LEV can be efficient in GTCS and
myoclonic seizures, and its efficacy in absence seizures was
also recently proved.14–16
The first AED in JAE therapy can be
efficient in 60% of cases, especially in patients on VPA in
monotherapy or in patients with isolated absence seizures.
With monotherapy failure, the prognosis becomes less favorable
and the rate of pharmacoresistance increases.11
The
results of this study concerning pharmacological treatment
show that patients used an average of almost 4 AEDs during the
course of the disease, and that 58.7% of patients tried more than
4 AEDs during the course of the disease from the seizure onset.
At the end of the follow up period, all of the patients were on
AED treatment: 43.5% were on monotherapy, 43.5% used a
combination of 2 AEDs, 6.5% used a combination of 3 or 4 AEDs.
LTG was studied in the paper published by Gericke et al.13
who
observed 12 patients with JAE on add-on therapy with
lamotrigine. The average follow-up was 25.5 months. Ten of
the 12 patients (83.3%) became seizure free on lamotrigine; in 2
of the 12 patients (16.6%) there was a seizure reduction of more
than 50% during the follow-up period.
Trinka et al. published a study of patients with CAE, JAE and
patients that could not be clearly defined as either CAE or JAE,
and were therefore called ‘‘the overlap group’’. The follow-up
period was 25.8 years (range 3–69). 61 of the 81 patients (75%)
with nonpyknoleptic absences (JAE and ‘‘overlap group’’) were
on AEDs at the last follow-up visit. Of the 61 patients, 42
patients (69%) were on VPA monotherapy; 11 patients (18%)
were treated with VPA in combination with other AEDs (LTG,
ETS, PRM, TPM).
Our retrospective analysis of patients with JAE indicates that
more than half of the patients with this epileptic syndrome show
problems with seizure management and often require more AEDs
to reach partial or total seizure freedom. Although we did not
reveal a statistically significant difference between the groups of
patients who were completely seizure free during the whole OP
and the patients who were not in terms of different variables, we
noticed that these patients became seizure free using less number
of AEDs. The number of studied patients did not allow us to
evaluate this difference statistically.
The results of this study have to be assessed in the context of
several facts:
 The study involves patients observed at a specialized center for
epilepsy. These are patients sent from outpatient clinics due to
their difficult seizure management. The prognosis of these
patients is considered to be more grave.
 The study is retrospective. We were able to precisely assess the
frequency of GTCS, because their clinical manifestation is
noticeable. With absence seizures, patients do not often take
them into consideration and it is difficult to count them exactly,
so we did not assess their frequency. Thus, we did not distinguish
between patients with rare absence seizures and daily absence
seizures. This could be quite misleading in the context of
assessing clinical manifestation.
 The assessment of patients was strictly set between 2006 and
2011. In this period of time, every patient presented in a different
phase of the disease.
5. Conclusion
The prognosis of patients with JAE is often unfavorable, and the
rate of pharmacoresistance can be quite important. To better
understand the course of the disease and its prognosis, more
studies are needed. We emphasize the need for studies with
longer follow-up periods that assess the rate of seizure management
and the cognitive and behavioral changes in patients with
JAE.
Conflicts of interest
None of the authors has any conflict of interest to disclose.
We confirm that we have read the Journal’s position on issues
involved in ethical publication and affirm that this report is
consistent with those guidelines.
Acknowledgments
This work was supported by the project ‘‘CEITEC – Central
European Institute of Technology’’ (CZ.1.05/1.1.00/02.0068) from
the European Regional Development Fund.
Thanks to Anne Johnson for grammatical assistance.
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Clinical experience with levetiracetam in idiopathic generalised epilepsy
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102
2.3 Annex 3:
Danhofer P, Pejčochová J, Dušek L, Rektor I, Ošlejšková H. The influence of EEG-detected
nocturnal centrotemporal discharges on the expression of core symptoms of ADHD in
children with benign childhood epilepsy with centrotemporal spikes (BCECTS): A
prospective study in a tertiary referral center. Epilepsy Behav EB. 2018 Feb;79:75–81. doi:
10.1016/j.yebeh.2017.11.007.
Summary:
Benign childhood epilepsy with centrotemporal spikes (BCECTS) is the most frequent benign
focal epilepsy in childhood. Although it is described as a benign epilepsy syndrome, many
studies have revealed that a significant number of patients have some degree of
neuropsychological impairment. Thirty-two patients with BCECTS aged 6-11years were
included in the study. All patients (without any antiepileptic or psychiatric medication)
underwent all-night EEG monitoring and complex neuropsychological testing to diagnose the
presence of core symptoms of attention-deficit/hyperactivity disorder (ADHD). The spike index
(number of spikes per minute) on awake and asleep EEG, age at seizure onset, family history
of epilepsy, and perinatal risks were correlated with the results of neuropsychological testing.
Of the 32 patients, 21 patients (65.6%) fulfilled the criteria for ADHD diagnosis. Children who
were younger at epilepsy onset demonstrated lower IQ and higher attention deficit (P=0.004)
and higher impulsivity (P=0.016). The occurence of epileptiform discharges on nocturnal EEG
was positively related to higher attention deficit and higher impulsivity. The findings are
discussed in terms of how interictal discharges in the centrotemporal region during sleep affect
the development of cognitive functions in children during critical epochs of neuropsychological
development.
The influence of EEG-detected nocturnal centrotemporal discharges on
the expression of core symptoms of ADHD in children with benign
childhood epilepsy with centrotemporal spikes (BCECTS): A prospective
study in a tertiary referral center
Pavlína Danhofer a,
⁎, Jana Pejčochová a
, Ladislav Dušek b
, Ivan Rektor c,d
, Hana Ošlejšková a
a
Brno Epilepsy Center, Department of Pediatric Neurology, University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
b
Institute of Biostatistics and Analysis, Faculty of Medicine, Masaryk University, Brno, Czech Republic
c
Brno Epilepsy Center, First Department of Neurology, St. Anne's University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
d
Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
a b s t r a c ta r t i c l e i n f o
Article history:
Received 18 September 2017
Revised 2 November 2017
Accepted 5 November 2017
Available online 15 December 2017
Benign childhood epilepsy with centrotemporal spikes (BCECTS) is the most frequent benign focal epilepsy in
childhood. Although it is described as a benign epilepsy syndrome, many studies have revealed that a significant
number of patients have some degree of neuropsychological impairment.
Thirty-two patients with BCECTS aged 6–11 years were included in the study. All patients (without any antiepileptic
or psychiatric medication) underwent all-night EEG monitoring and complex neuropsychological testing
to diagnose the presence of core symptoms of attention-deficit/hyperactivity disorder (ADHD).
The spike index (number of spikes per minute) on awake and asleep EEG, age at seizure onset, family history of
epilepsy, and perinatal risks were correlated with the results of neuropsychological testing.
Of the 32 patients, 21 patients (65.6%) fulfilled the criteria for ADHD diagnosis. Children who were
younger at epilepsy onset demonstrated lower IQ and higher attention deficit (P = 0.004) and higher impulsivity
(P = 0.016). The occurence of epileptiform discharges on nocturnal EEG was positively related to higher
attention deficit and higher impulsivity.
The findings are discussed in terms of how interictal discharges in the centrotemporal region during sleep affect
the development of cognitive functions in children during critical epochs of neuropsychological development.
© 2017 Elsevier Inc. All rights reserved.
Keywords:
Benign childhood epilepsy with centrotemporal
spikes
BCECTS
ADHD
Attention deficit
Impulsivity
Hyperactivity
1. Introduction
Benign childhood epilepsy with centrotemporal spikes (BCECTS) is
the most frequent benign focal epilepsy in childhood and represents
around 15% to 25% of epilepsy syndromes in children below 15 years
of age [1,2]. The age at onset is between 4 and 10 years in 90% of the
patients, and the median age at onset is around 7 years. The BCECTS is
seen more frequently in males than females, with a ratio of 3:2 [2].
Seizures are clearly related to sleep in 80% to 90% of the patients, but
in 10% of the patients, the seizures occur only in waking states [2].
Seizure frequency is usually low; around 10% of cases present only
one seizure. The seizures are characterized by hemifacial motor signs,
with speech arrest usually preceded by somatosensory signs; seizures
often involve the limbs ipsilateral to the involved facial side [2]. Electroencephalogram
(EEG) in BCECTS typically reveals specific epileptiform
foci characterized by a wide, biphasic spike–wave complex localized
in a centrotemporal region, with a normal background [3]. Epileptiform
discharges amplify during nonrapid eye movement (NREM) sleep by a
factor of two to five times without disturbing sleep organization [1].
Although BCECTS is described as a benign epilepsy syndrome, many
studies have revealed that a significant number of patients have some
degree of neuropsychological impairment. Despite a favorable seizure
outcome and normal intelligence, children with BCECTS often have
difficulties in various domains of neuropsychological functioning, such
as behavior [4–7], language [8–11], cognition [6,12–16], attention [11,
17–20], and memory [11,21], which may lead to learning difficulties
[9,22,23]. A prominent comorbidity in children with BCECTS is
attention-deficit/hyperactivity disorder (ADHD) [11,15,17–20,24–26].
The prevalence of ADHD in the general population is 3% to 7% [27]; it
is 31% in children with BCECTS [15].
Some studies have tried to identify the factors responsible for the development
of neuropsychological impairment and especially ADHD
Epilepsy & Behavior 79 (2018) 75–81
⁎ Corresponding author at: Brno Epilepsy Center, Department of Pediatric Neurology,
University Hospital and Faculty of Medicine, Masaryk University, Brno, Černopolní 9,
613 00 Brno, Czech Republic.
E-mail addresses: pavlina.cahova@seznam.cz (P. Danhofer), page.och@seznam.cz
(J. Pejčochová), dusek@iba.muni.cz (L. Dušek), ivan.rektor@fnusa.cz (I. Rektor),
hoslej@fnbrno.cz (H. Ošlejšková).
https://doi.org/10.1016/j.yebeh.2017.11.007
1525-5050/© 2017 Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
Epilepsy & Behavior
journal homepage: www.elsevier.com/locate/yebeh
symptomatology in children with BCECTS. Age at seizure onset, epilepsy
duration, impact of AED treatment, etc., have been evaluated, as having
the impact of epileptiform discharges, their lateralization, and mainly
their sleep activation [19,22,28]. The atypical evolutions of BCECTS –
to ‘BCECTS plus conditions’ such as Landau–Kleffner syndrome, to
electrical status epilepticus in slow wave sleep, or to atypical forms of
BCECTS which can be present in 1% to 7% of patients [1] – prove that
ongoing nocturnal interictal epileptiform activity can influence
neuropsychological deficits in children and the severity can depend on
the sleep activation of EEG discharges [15].
The aim of our study was to quantify the prevalence of ADHD in
children with BCECTS and to analyze the effect of nocturnal epileptiform
discharge activation on the development of executive functions and
ADHD symptomatology in children with BCECTS. We discuss hypotheses
of how sleep disruption interferes with the complexity of specific
neuronal networks.
2. Methods
2.1. Participants
This prospective single center study included 52 consecutive
children diagnosed with BCECTS at the Brno Epilepsy Center, Department
of Pediatric Neurology of the University Hospital Brno between
2008 and 2016. All patients were admitted to the hospital directly
after the first epileptic seizure. None of the patients had been diagnosed
with ADHD before the manifestation of the first seizure.
Inclusion criteria were the following: a) aged 6–11 years; b) diagnosis
of BCECTS made by a board-certified pediatric neurologist based on
International League Against Epilepsy (ILAE) criteria [29]; and
c) normal neurological examination.
The following exclusion criteria were applied: a) any neurological or
psychiatric medication 6 months prior to the diagnosis or during EEG
and neuropsychological testing; b) any structural brain magnetic resonance
imaging abnormality that could exclude the diagnosis of BCECTS;
c) any accompanying neurological disorder; and d) mental retardation
(intelligence quotient (IQ) less than 70).
In total, 32 patients of the initial 52 were enrolled in the study; 20
patients were excluded because of improper age, a lack of asleep EEG
needed for the evaluation, or incomplete neuropsychological testing.
2.2. EEG
Applying the international 10-20 system, awake and asleep EEG
recordings were performed for all patients. Electroencephalogram
recordings were obtained before the initiation of antiepileptic drug
(AED) or psychiatric treatment. At least 30 min of awake EEG recording
consisted of routine activation procedures including eye closing and
opening, photic stimulation, and hyperventilation. Asleep EEG was
performed as an all-night EEG lasting 6 to 8 h. In BCECTS, the frequency
of epileptiform discharges is known to increase upon falling asleep and
during the first NREM phase of sleep. To eliminate the impact of this
observation resulting in a false higher activation of the epileptiform
discharges, we evaluated the asleep EEG throughout the whole night.
The number of interictal epileptiform discharges in the centrotemporal
region was manually counted during the whole awake EEG
and in ten randomly chosen 20-minute epochs in NREM I–II and
NREM III. Patients were divided into three groups according to the
laterality of spikes on EEG (left, right, and bilateral).
The spike index (SI) (number of spikes per minute) was calculated
during wakefulness, NREM I–II, NREM III, and total NREM sleep. The
rate of occurrence of epileptiform discharges on EEG was evaluated by
SI differently in the awake and asleep states. An SI lower than 10 was
assessed as low occurrence during wakefulness; an SI higher than 10
was assessed as high occurrence. The border for this assessment during
the different sleep phases was 30, with SI under 30 assessed as low
occurence and SI above 30 as high occurence.
2.3. Neuropsychology
Czech versions of standardized neuropsychological batteries were
applied to assess the core symptoms of ADHD (attention deficit, hyperactivity,
and impulsivity) (Table 1). All neuropsychological testings were
performed by a certified child psychologist. The assessment of patients
according to the core symptoms of ADHD was established on the basis
of a study by McGrew [30].
All patients were AED and psychiatric drug naive at the testing. The
Wechsler Intelligence Scale for Children III (WISC III) and its subtests
were used for assessing IQ in order to exclude patients with mental retardation
(IQ less than 70). The WISC III subtests for Coding, Symbol Search,
Letter Number Sequencing, and Labyrinths were used for assessing attention
deficit; impulsivity was also evaluated using Labyrinths. A scaled
score of 8 or lower (1 standard deviation below the mean) was taken as
indicative of attention impairment. The Number Sequencing Test was applied
for evaluating attention deficit. A sten score of 4 or less (1 standard
deviation below the mean) was taken as indicative of attention deficit.
The Trail Making Test was similarly applied for impulsivity. The results
of these tests were not directly used to diagnose ADHD or to assess
ADHD severity.
The Conners' Parent Rating Scale (CPRS) and the Test Observation
Form were used to examine the core symptoms of ADHD. According to
the results, subjects were divided into two groups: with ADHD and without
ADHD. The T-score border was 60; higher values led to a diagnosis of
ADHD.
2.4. Procedures
The patients were admitted to the department after the first seizure.
Once the diagnosis of BCECTS has been established, they underwent allnight
EEG recording and complete neuropsychological testing. Both
examinations were performed within 2–5 days, and all patients were
AED and psychiatric drug naïve at the testing.
Age at seizure onset, sex, handedness, family history of epilepsy, and
perinatal risks were assessed.
2.5. Statistical analysis
Standard summary statistics were used to express primary data,
absolute and relative frequencies for categorical and binary data, arithmetic
mean supplied with standard deviation, and median supplied
with minimum–maximum range for continuous data.
The statistical significance of the differences among the groups of
patients in continuous variables was tested by the nonparametric
Mann–Whitney or Kruskal–Wallis test. Robust rank methods were
used because assumptions of normality could not be fulfilled in the
primary distribution of values.
The degree of relationship between continuous variables was
described by Spearman's rank correlation coefficient and its statistical
significance.
Analysis was performed in SPSS software 24.0.0.0 (IBM Corporation,
2015).
3. Results
3.1. Baseline data (Table 2)
We studied a group of 32 patients (17 males and 15 females). All patients
met the BCECTS criteria according to the 1989 ILAE Classification.
The average patient age at seizure onset was 7.5 ± 1.4 years;
median: 8.0 years (6.0; 11.0).
76 P. Danhofer et al. / Epilepsy & Behavior 79 (2018) 75–81
Of the 32 patients, 2 patients (6.3%) were left handed; and 30
(93.7%) were right handed. Three patients had a positive family history
for epilepsy (9.4%); the type of epilepsy was not specified. Perinatal risks
were present in 17 patients (53.1%): prolonged delivery with asphyxia
and oxygen therapy in 8 patients, neonatal icterus with phototherapy
in 5 patients, preeclampsia in 2 patients, gestation diabetes in 1 patient,
and placenta abruption with preterm delivery (in the 32nd week of
gestation) in 1 patient.
3.2. EEG profile (Table 2)
Electroencephalogram investigation revealed that of the 32 patients,
10 patients (31.3%) had left localized centrotemporal epileptiform
activity, 6 patients (18.8%) had right localized centrotemporal epileptiform
activity on EEG, and 16 patients (49.9%) had bilateral epileptiform
activity. The average SI in the awake state was 11.0 ± 10.2 with a
median of 7.4 (0.0; 38,7); in NREM I–II, 35.9 ± 17.2 with a median of
29.4 (7.5; 77.0); in NREM III, 28.2 ± 14.3 with a median of 23.2 (5.7;
55.8); and in total NREM sleep, the average SI was 32.4 ± 15.4 with a
median of 27.2 (6.6; 66.4). Low occurrence of SI in the awake state
was present in 18 patients (56.3%), and high occurrence of SI was
present in 14 patients (43.7%). Low occurence of SI in NREM I–II was
observed in 17 patients (53.1%), and high occurence of SI in NREM I–II
was observed in 15 patients (46.9%). Low occurence of SI in NREM III
was observed in 17 patients (53.1%), and high occurence of SI in
NREM III was observed in 15 patients (46.9%). Low occurence in total
NREM was observed in 18 patients (56.3%), and high occurence of SI
in total NREM was present in 14 patients (43.7%).
3.3. ADHD profile
The criteria for the diagnosis of ADHD were fulfilled in 21 of the 32
patients (65.6%) according to Conners' Parent Rating Scale (CRPS) and
Test Observation Form (TOF) results, with the highest average T-score
of 72.7. Thus, all patients with ADHD had mild symptomatology.
3.4. Correlations
First, clinical characteristics and EEG findings were compared
between patients with ADHD and those without ADHD according to
the CRPS and TOF results (Table 3). Statistical analysis did not reveal a
statistical difference between the group of patients with ADHD and
those without ADHD in terms of their sex, family history of epilepsy,
perinatal risks, age at seizure onset, awake and sleep SI occurrence,
and laterality of centrotemporal epileptiform discharges on EEG.
Second, we correlated the results of detailed neuropsychological tests
(Table 1) with similar clinical and EEG characteristics as in the first step
described above (sex, family history of epilepsy, perinatal risks, age at
seizure onset and SI on EEG in wakefulness, NREM I–II, NREM III, and
total NREM – Table 4). Overall, children demonstrated average intellect
with IQt 101.5, consistent with a normal distribution. There was a relationship
between IQ (IQt, IQv, IQp) and the age at seizure onset: the
lower the age at seizure onset, the lower the IQ, but this relationship
was not statistically significant (P = 0.091 for IQp, P = 0.106 for IQt,
and P = 0.127 for IQv). Children with a family history of epilepsy had
lower IQs than the other group, but there was no statistical significance
in this relationship. The correlation between IQ and SI in the awake
state showed a negative trend in IQt (P = 0.017) and IQp (P = 0.026).
Some other associations were found in other neuropsychological
testings. Girls showed higher attention deficit in TOF, with statistical
significance (P = 0.030). The lower the age at seizure onset, the
lower the scores in subtests of WISC III for attention deficit (Symbol
Search P = 0.004) and in the Trail Making Test (P = 0.016), demonstrating
higher attention deficit and impulsivity in these children.
Relationship between SI on EEG and results of neuropsychological
testing indicated negative trends in Coding and in the Trail Making
Test, which can be interpreted as higher rates of attention deficit and impulsivity
in patients with higher SI in the awake state and in total NREM;
however, this was without exact statistical significance (P value ranged
from 0.165 to 0.186). There was also a positive trend between TOF results
in all three domains and SI in NREM I–II and NREM III, again without
statistical significance (P value ranged from 0.112 to 0.370). There was
Table 1
Neuropsychological test list according to the core symptoms of ADHD assessed.
Neuropsychological test Subtest Assessing Evaluation
Wechsler Intelligence Scale for
Children III (WISC III)
Total IQ (IQt) Intelligence Standard scores
Verbal IQ (IQv) Intelligence Standard scores
Performance IQ (IQp) Intelligence Standard scores
Coding Attention deficit Scaled scores
Symbol Search Attention deficit Scaled scores
Letter Number Sequencing Attention deficit Scaled scores
Labyrinths Attention deficit, impulsivity Scaled scores
Number Sequencing Test Attention deficit Sten M1 — time in the first half
M2 — time in the second half
M — total time
Trail Making Test Impulsivity Sten
Conners' Parent Rating Scale
(CPRS)
Oppositional (Op) T scores
Inattention/cognitive problems (In) Attention deficit T scores
Hyperactivity (Hy) Hyperactivity T scores
Test Observation Form (TOF) Inattention (In) Attention deficit T scores
Hyperactivity–impulsivity (H–I) Hyperactivity, impulsivity T scores
Summing index according to DSM (AD/HP) Attention deficit, hyperactivity, impulsivity T scores
Table 2
Clinical and EEG characteristics of patients.
Clinical characteristics
Sex Males 17 (56.2%)
Females 15 (43.8%)
Age at seizure onset (years) 7.5 (1.4); 8.0 (6.0; 11.0)
6–8 years, n (%) 26 (81.2%)
9–11 years, n (%) 6 (18.8%)
Laterality Left 3 (9.4%)
Right 29 (90.6%)
Family history of epilepsy Yes 3 (9.4%)
No 29 (90.6%)
Perinatal risks Yes 17 (53.1%)
No 15 (46.9%)
EEG characteristics
Spike index
Wakefulness 11.0 (10.2); 7.4 (0.0; 38.7)
NREM I–II 35.9 (17.2); 29.4 (7.5; 77.0)
NREM III 28.2 (14.3); 23.2 (5.7; 55.8)
Total NREM 32.4 (15.3); 27.2 (6.6; 66.4)
Laterality of EEG discharges Left 10 (31.3%)
Right 6 (18.8%)
Bilateral 16 (49.9%)
77P. Danhofer et al. / Epilepsy & Behavior 79 (2018) 75–81
no statistical significance in the correlation between neuropsychological
testing and perinatal risks.
4. Discussion
4.1. The incidence of ADHD in patients with BCECTS
In this study, 65.6% of the patients with BCECTS had ADHD. This is
much higher than the prevalence of ADHD in healthy school children
(5–10%) [3–5] or in children with epilepsy (30–40%) [31–34]. Similar
results can be found in a study by Kim et al. who diagnosed ADHD in
64.9% of 74 children with BCECTS [26]. The diagnosis of ADHD in our
study was based on the results of CRPS and TOF. Conners parent rating
scale is a questionnaire based on parental observation. We found that
these results were much lower than the results of TOF, which is a questionnaire
completed by a psychologist. We assume that parents try to
downplay the ADHD symptomatology in their children who already
have a diagnosis of epilepsy; thus, the number of patients and ADHD
could be even higher. This could also be a reason why all of the children
with ADHD in our study had only mild symptomatology of ADHD according
to these results. Still, these numbers are very high in comparison
with the epilepsy population and raise questions about a common
pathophysiology of ADHD and BCECTS. The pathophysiology of cognitive
dysfunction in patients with BCECTS is a subject for further research.
In general, two hypotheses are discussed. The first hypothesis
assumes that the presence of rolandic epileptiform discharges and especially
their sleep activation in patients with BCECTS are responsible for
the development of cognitive dysfunction in these patients [28]. The
second hypothesis supposes that the cognitive dysfunction and epileptiform
discharges are a phenomenon with a common genetic basis [9,
35]. We can conclude that the genetic basis affects the brain maturation
and this leads to the development of epilepsy. Electroencephalogram
discharges can then worsen this cognitive deficit [36].
4.2. The role of family history of epilepsy
Of the 32 patients, 3 had a family history of epilepsy. All of them
were diagnosed with ADHD, and they had lower IQs, but without
statistical significance. The type of epilepsy syndrome in these families
was not identified. Recent studies have attempted to determine the candidate
genes in the pathogenesis of BCECTS—chromosome 15q14,
Table 3
Comparison of clinical and EEG characteristics between patients with ADHD and without
ADHD.
All patients With
ADHD
Without
ADHD
P
n = 32 n = 21 n = 11
Males, n (%) 17 13 4 0.266
Females, n (%) 15 8 7
Family history of epilepsy, n (%) 3 3 0 0.539
Perinatal risks, n (%) 17 9 8 0.198
Age at seizure onset (years)
6–8 years, n (%) 26 15 11 0.683
9–11 years, n (%) 6 5 1
Spike index
Wakefulness SI b 10/min 12 (66.7%) 6 (33.3%) 1.000
SI ≥ 10/min 9 (64.3%) 5 (35.7%)
NREM I–II SI b 30/min 10 (58.8%) 7 (41.2%) 0.472
SI ≥ 30/min 11 (73.3%) 4 (26.7%)
NREM III SI b 30/min 10 (58.8%) 7 (41.2%) 0.449
SI ≥ 30/min 9 (75.0%) 3 (25.0%)
NREM total SI b 30/min 11 (61.1%) 7 (38.9%) 0.712
SI ≥ 30/min 10 (71.4%) 4 (28.6%)
Laterality of EEG discharges (n)
Left 10 7 3 0.999
Right 6 4 2
Bilateral 16 11 5
Table4
CorrelationbetweenvaluesofSI(wakefulness,NREMI–II,NREMIII,totalNREM)andresultsofneuropsychologicaltesting.1
Spearman'scorrelationcoefficientanditsstatisticalsignificance.
Corrrelation1
IQtIQvIQpCodSSLNSLabM1M2MABCPRS-OpCPRS-InCPRS-HyTOF-InTOF-H–ITOF-A–D
Wakefulness−0.419−0.211−0.393−0.355−0.238−0.148−0.148−0.153−0.284−0.260.129−0.3370.150−0.152−0.2180.0640.0040.082
P′=0.017P′=0.246P′=0.026P′=0.046P′=0.190P′=0.420P′=0.418P′=0.486P′=0.190P′=0.231P′=0.611P′=0.172P′=0.414P′=0.407P′=0.230P′=0.726P′=0.983P′=0.657
NREMI–II−0.219−0.152−0.113−0.196−0.1580.026−0.038−0.033−0.024−0.073−0.066−0.1820.0350.0910.0810.1890.2830.287
P′=0.228P′=0.407P′=0.537P′=0.282P′=0.387P′=0.887P′=0.836P′=0.881P′=0.914P′=0.741P′=0.794P′=0.470P′=0.851P′=0.620P′=0.661P′=0.299P′=0.117P′=0.112
NREMIII−0.126−0.04−0.029−0.252−0.085−0.08−0.0220.0380.0660.016−0.21−0.1730.1940.130.0560.2830.1860.173
P′=0.516P′=0.836P′=0.883P′=0.186P′=0.660P′=0.679P′=0.908P′=0.869P′=0.775P′=0.946P′=0.436P′=0.523P′=0.313P′=0.501P′=0.774P′=0.168P′=0.334P′=0.370
TotalNREM−0.184−0.114−0.094−0.252−0.168−0.033−0.020−0.028−0.007−0.058−0.144−0.1690.0450.0490.0220.1390.2070.202
P′=0.313P′=0.534P′=0.609P′=0.165P′=0.359P′=0.859P′=0.913P′=0.901P′=0.976P′=0.793P′=0.568P′=0.503P′=0.805P′=0.789P′=0.904P′=0.450P′=0.255P′=0.267
IQt–IQtotal;IQv–IQverbal;IQp–IQperformance;Cod–Coding;SS–SymbolSearch;LNS–LetterNumberSequencing;Lab–Labyrinths;M1–NumberSequencingTestM1;M2–NumberSequencingTestM2;M–NumberSequencingTestM;A–Trail
MakingTestA;B–TrailMakingTestB;CPRSOp–CPRSOppositional;CPRSIn–CPRSInattention;CPRSHy–CPRSHyperactivity;TOFIn–TOFInattention;TOFH–I–TOFHyperactivityImpulsivity;TOFA–D–TOFAttentionDeficit.
Bolddataindicatesstatisticalsignificance.
78 P. Danhofer et al. / Epilepsy & Behavior 79 (2018) 75–81
where the gene for acetylcholine receptor subunit is located [37];
chromosome 11p13; and several polymorphic markers in the gene for
Elongator Protein Complex 4 (ELP4) [38]. Elongator protein regulates
the growth of cortical projection neurons. A noncoding mutation in
the ELP4 gene interferes with brain development and maturation and
increases seizure susceptibility. Another factor is Brain-Derived Neurotrophic
Factor (BDNF), for which the gene is also located on chromosome
11p13, close to ELP4 [39]. This factor is very important in
synaptic plasticity and neurotransmission. Its location, so close to
ELP4, indicates a possible role of this gene in the etiology of BCECTS.
4.3. The role of perinatal risks
The number of patients with perinatal risks was relatively high in
this study. All perinatal risks were included in the study, even those
with moderate expression, which may not have a clear effect on the
development of cognitive dysfunction in the study subjects. It is difficult
to determine to what extent the proportion of cognitive dysfunction is
the result of perinatal insult.The possible genetic basis for the development
of ADHD should also be considered.
4.4. The role of age at seizure onset
Despite studies demonstrating the genetic basis of BCECTS, the
development of symptoms of this epilepsy syndrome and typical EEG
discharges are age-related and time-limited. The prerequisite is thus
the existence of a developmental window during which permissive
factors appear that cause changes in the processes of the aging of affected
brain areas. This developmental window is associated with cortical
functional activity that can be defined on the basis of regional cerebral
blood flow [40,41] and local metabolic changes [42,43]. At birth, the
regional cortical cerebral blood flow is lower than in adults. After
birth, it increases up to 5–6 years of age to values which are about 50–
85% higher than in adults. It then decreases again and reaches adult
values between 5 and 19 years [2]. The time required to reach adult
values varies depending on the area of the cortex. The shortest is in
the primary cortex and the longest in associate cortical areas. The
metabolic profile measured by glucose utilization is almost identical:
low at birth, rising to 4 years of age when the child's brain consumes
up to twice as much glucose as an adult, and then decreasing and
reaching adult values at the age of 16–18 years. These changes correlate
with an initial overproduction and subsequent elimination of excessive
neurons, synapses, and dendrites, which can be seen in the developing
brain [2]. Early development of epilepsy can have long-term effects on
the developing brain. The vulnerability of the developing brain emerges
from impaired developmental processes such as synaptogenesis,
dendritic branching, neural migration, and differentiation, rather than
from neuronal death, which dominates in the case of development of
seizures in adults when the brain is already matured [44]. For this
reason, it is possible to see more global autistic regression with more
severe speech deficits in children with early development of Continual
Spike and Waves in Sleep Syndrome (CSWS) than in children with Landau-Kleffner
Syndrome (LKS) with relatively later development where
isolated speech regression is observed [45]. Very different impacts of epilepsy
can therefore be expected depending on the degree of the brain
maturity when epilepsy becomes active. In our study, we demonstrated
that children with earlier seizure onset had lower Intelligence Quotient
(IQs). In other neuropsychological testings, we found statistically significantly
higher attention deficit and impulsivity in children with earlier
onset of seizures. Our results are supported by another study of 25 children
with rolandic epilepsy that proved that the early onset of seizures
leads to worse results in neuropsychological testing of cognitive
functions [28]. Another study of 33 children with BCECTS spectrum
demonstrated that the patients with an average epilepsy onset at
around 8 years were at higher risk of neuropsychological problems [22].
4.5. The role of lateralization in EEG epileptiform discharges
The impairment of cognitive functions in children with BCECTS may
be caused by interictal paroxysmal EEG activity, which can lead to transient
cognitive deficit, or it can be a consequence of the chronic effect of
epileptiform discharges, resulting in cortical inhibition of the area and
leading to delayed or incomplete maturation [18]. Cognitive functions
are most vulnerable when the hemispheric lateralization of its neural
correlates is affected by the epileptic focus. Therefore, in children with
left lateralization of the epileptiform activity, speech difficulties are observed
[46,47]; right lateralization of the EEG focus can be associated
with spatial orientation deficit [48].
The influence of the side of epileptiform activity on EEG in children
with BCECTS is very controversial. It is known that the shift of the
centrotemporal spikes from one side to another can be observed in
patients with BCECTS during the disease. In 86 children with epilepsy
with somatosensory-evoked potentials (a kind of functional correlate of
rolandic discharges), the localization was parietal in 42% of cases,
centrotemporal in 32% of cases, and both parietal and centrotemporal in
26% of cases [49]. Parietal localization was dominant in younger ages
(around 3–8 years), centrotemporal localization was dominant in children
at the ages of 6–11 years, and the simultaneous occurrence in both
areas was observed in a transitional age group of 6–8 years and probably
represents the transition between these localization patterns [49].
In our study, we did not find any association between the lateralization
of EEG epileptiform discharges and ADHD diagnosis and the results
of detailed neuropsychological testing.
Taking into account the age-dependent focus localization, the shift of
the focus from one side to another, and its bilateralization in sleep, it is
very difficult to determine an influence of the lateralization of the focal
epileptiform activity on cognitive functions in patients with BCECTS.
4.6. The role of nocturnal epileptiform discharges and SI
In benign focal epilepsies, BCECTS included, sleep increases the
frequency of epileptiform discharges, and the discharges remain high
during the first phase of NREM sleep. During REM sleep, the frequency
decreases; this decrease can also be observed in other NREM sleep
cycles [22]. The atypical development of BCECTS to ‘BCECTS plus’
conditions shows that ongoing nocturnal epileptiform activity causes
neuropsychological deficit and the level of severity depends on the
rate of awake and sleep pathology [50]. Night epileptiform discharges
intervening during brain development may lead to the impaired
development of neural networks involved in various neurocognitive
functions. If these sleep discharges last for a certain time, they can
lead to extensive synaptogenesis with excess growth of the axons that
ensure contact with the target cells. This interferes with the process of
branching of neuronal processes, thus maintaining connections that
should be eliminated. The affected neural network replaces the normal
functional neuronal network at the cortical level and frequent epileptiform
discharges encourage it to further growth so that it cannot be
recovered [51].
Slow wave activity (SWA) is the fundamental characteristic of NREM
sleep on scalp EEG. Its neural correlate is the slow oscillation of
membrane potentials of cortical neurons between depolarization and
hyperpolarization. If these oscillations are synchronized and the majority
of cortical neurons in a certain area are affected, they are detectable
as slow waves on scalp EEG. The local increase in SWA during NREM
sleep and the decrease in other phases of sleep are important for the
plasticity of learning processes and synaptic homeostasis [52,53].
The normal reduction of SWA during sleep is absent in patients with
electrical status epilepticus during slow wave sleep. The interference of
epileptiform discharges with normal sleep SWA may explain the cognitive
deterioration in these patients [53].
In our study, we performed an extensive battery of neuropsychological
testing in order to identify the rate of ADHD core symptoms in
79P. Danhofer et al. / Epilepsy & Behavior 79 (2018) 75–81
children with BCECTS during nocturnal EEG testing. We performed allnight
EEG recordings to eliminate the impact of the high activation of discharges
during drowsiness and the first sleep cycle; we also studied the
discharges during the slow stages of NREM sleep (NREM III) in which
the interference of epileptiform discharges with SWA in relation to cognitive
dysfunction is important. We did not find any relation between
the diagnosis of ADHD and SI occurence in any sleep stages. This could
be explained by the fact that the division of patients into the two groups
with ADHD and without ADHD was very approximate, and even the
ADHD patients had mild symptomatology of the disorder. The results of
detailed neuropsychological testing show that the occurrence of discharges
in total NREM sleep leads to higher attention deficit and impulsivity
in patients, but without proven statistical significance. Sleep SI is
also positively related to the TOF results, which is a test that affects all
core symptoms of ADHD, again without exact statistical significance.
The influence of temporal epileptiform discharges in children with
centrotemporal EEG pathology was examined in several studies. Filippini
et al. [50] conducted an extensive study of 33 children with BCECTS in
which they prospectively evaluated an overnight sleep EEG recording
with a two-year follow-up period. Patients were divided into 3 groups
according to the frequency of nocturnal epileptiform discharges: Group
1A—less than 50% of sleep; Group 1B—50–85% of sleep; and Group
2—more than 85% of sleep. Half of the patients in Group 1A had a
neuropsychological deficit by the end of the follow-up period, especially
in short-term verbal memory, visuo-spatial orientation, and learning
difficulties such as dyslexia and dysorthography. This deficit was more
pronounced in patients with early-onset epilepsy (under the age of
5 years). All of the patients in Group 2 had persistent neuropsychological
deficits, especially in the verbal area, and all patients had specific learning
disabilities.
Kim et al. [26] published a study in 2014 that evaluated asleep EEG in
71 patients with BCECTS. They found that patients with a high SI (more
than 40/min) had deficits in visual selective attention.
Baglietto et al. [28] studied nine children with centrotemporal
discharges on EEG, who were seizure free for at least 2 months. All the
children were on valproate monotherapy, and they had SI higher than
10/min confirmed on two EEG spaced 6 months apart. Electroencephalogram
controls were performed every 3 months until the SI dropped to
5/min. Neuropsychological tests were performed at baseline (T0) and
after a decrease of SI on sleep EEG (T1). At T0, patients showed normal
IQs, but lower than the control group, and they had neuropsychological
deficits in short-term memory, attention, and cognitive flexibility. At the
end of the follow-up period (T1), there was a significant improvement
in IQ scores and in other neuropsychological tests, and patient performance
did not differ from that of controls.
All of these studies found a significant negative impact of epileptiform
discharge activation in patients with BCECTS on their neuropsychological
profiles.
The limitation of this study is the number of patients. It was a very
limited group of closely selected patients. All of the patients were
examined without any neurological or psychiatric medication, and
they all completed all-night video-EEG monitoring and fairly extensive
neuropsychological examinations. The patients were selected for a
long period of time, 6 years, in a tertiary referral epilepsy center. In
the global literature, other studies have investigated 9 [28] or 33 [50]
patients; a larger study group was published with 74 patients [26].
Given the sizes of previous studies, this study group is not that small.
Conflict of interest
The authors indicated no potential conflict of interest.
Ethics in publishing report
We confirm that we have read the Journal's position on issues involved
in ethical publication and affirm that this report is consistent
with those guidelines. We confirm that the research was approved by
the Ethical Committee of the Institution and informed consent was obtained
from the patients' guardians.
Acknowledgment
Thanks to Anne Johnson for grammatical assistance.
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81P. Danhofer et al. / Epilepsy & Behavior 79 (2018) 75–81
110
2.4 Annex 4
Horák O*, Burešová M*, Kolář S*, Španělová K, Jeřábková B, Kolář S, Česká K, Réblová K,
Zídková J, Fajkusová L, Ošlejšková H, Danofer P. Next-generation sequencing in children
with epilepsy: The importance of precise genotype-phenotype correlation. Epilepsy Behav
2022; 19; 128:108564. doi: 10.1016/j.yebeh.2022.108564.
Summary:
Aim: New methods in molecular genetics, including next-generation sequencing (NGS), are
powerful tools in diagnosing the cause of epilepsy. The primary goal of this study was to use a
multidisciplinary approach to determine the yield of NGS epilepsy gene panels and the
importance of genotype-phenotype correlations. The secondary goal was to evaluate the
application of precision medicine in selected patients.
Methods: This single-centre retrospective study included a total of 175 patients (95 males and
80 females) aged 0-19 years. They were examined between 2015 and 2020 using an NGS
epilepsy gene panel (255 genes). A bioinformatic analysis was performed including copy
number variation identification.
Results: Out of 175 patients, 89 (50.86%) experienced developmental and epileptic
encephalopathy (DEE), 45 (25.71%) were classified with generalized epilepsy (GE), and 41
(23.43%) had focal epilepsy (FE). Described pathogenic variants or novel variants with clear
pathogenic impact were identified in 30 out of 175 patients (17.14%). Genotype-phenotype
correlations and parental DNA analysis were performed, and genetic diagnosis was confirmed
on the basis of the results in another 16 out of 175 patients (9.14%). The diagnostic yield of our
study was 46 out of 175 patients (26.28%).
Interpretation: We emphasize a complex genotype-phenotype correlation and a
multidisciplinary approach in evaluating the results of the NGS epilepsy gene panel, which
enables the most accurate genetic diagnosis and correct interpretation of results
Next-generation sequencing in children with epilepsy: The importance
of precise genotype–phenotype correlation
Ondrˇej Horák a,1
, Martina Burešová b,1
, Senad Kolárˇ a,1
, Klára Španeˇlová a
, Barbora Jerˇábková b
,
Renata Gaillyová c
, Katarína Cˇeská a
, Kamila Réblová b
, Jana Šoukalová c
, Jana Zídková b
,
Lenka Fajkusová b
, Hana Ošlejšková a
, Ivan Rektor d,e
, Pavlína Danhofer a,⇑
a
Department of Pediatric Neurology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Centre, Czech Republic
b
Centre of Molecular Biology and Genetics, Internal Haematology and Oncology Clinic, Masaryk University and University Hospital Brno, Czech Republic
c
Institute of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and University Hospital Brno, Czech Republic
d
Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
e
Brno Epilepsy Center, First Department of Neurology, St. Anne’s University Hospital and Medical Faculty of Masaryk University, Brno, Czech Republic
a r t i c l e i n f o
Article history:
Received 8 November 2021
Revised 5 January 2022
Accepted 5 January 2022
Keywords:
Epilepsy
Genetic testing
Children
Next-generation sequencing
Precise medicine
a b s t r a c t
Aim: The primary goal was to determine the yield of next-generation sequencing (NGS) epilepsy gene
panels used for epilepsy etiology diagnosing using a multidisciplinary approach and to demonstrate
the importance of genotype–phenotype correlations. The secondary goal was to evaluate the application
of precision medicine in selected patients.
Methods: This single-center retrospective study included a total of 175 patients (95 males and 80
females) aged 0–19 years. They were examined between 2015 and 2020 using an NGS epilepsy gene
panel (270 genes). A bioinformatic analysis was performed including copy number variation identification.
Thorough genotype–phenotype correlation was performed.
Results: Out of 175 patients, described pathogenic variants or novel variants with clear pathogenic
impact were identified in 30 patients (17.14%). Genotype–phenotype correlations and parental DNA analysis
were performed, and genetic diagnosis was confirmed on the basis of the results in another 16 out of
175 patients (9.14%). The diagnostic yield of our study increased from 30 to 46 patients (by 53.33%) by the
precise genotype–phenotype correlation.
Interpretation: We emphasize a complex genotype–phenotype correlation and a multidisciplinary
approach in evaluating the results of the NGS epilepsy gene panel, which enables the most accurate
genetic diagnosis and correct interpretation of results.
Ó 2022 Elsevier Inc. All rights reserved.
1. Introduction
Epilepsy affects 0.5% to 1% of children and is the most frequent
chronic neurologic condition in childhood [1]. The underlying etiology
is unknown in 40–50% of cases of epilepsy, although it has
been estimated that approximately 30% of epilepsy is genetic [2].
Clinical genetic diagnosis methods have become popular in
recent years and include various technologies and strategies. Next
generation sequencing (NGS) is revolutionary especially in terms of
the possibility of simultaneously examining many genes. NGS testing
includes not only specific gene panels, but a methodology that
can encompass the entire exome (whole exome sequencing, WES)
or genome (whole genome sequencing, WGS), methods that have
the potential to further increase the yield of genetic testing in
patients with epilepsy. The yield of NGS epilepsy gene panels
ranges from 20 to 40% depending on the sample investigated [3–
5]. Geneticists interpret and report detected sequence variants on
the basis of currently valid recommendations according to the
American College of Medical Genetics and Genomics (ACMG) [6].
Thus, each sequence variant is included in the group of pathogenic
(P), likely pathogenic (LP), benign (B), likely benign (LB), or with
uncertain significance (VUS). The thorough genotypic–phenotypic
correlation and interpretation of genetic results from the
neurological-epileptological point of view, taking into account
other anamnestic data, are an integral and crucial part of the pro-
https://doi.org/10.1016/j.yebeh.2022.108564
1525-5050/Ó 2022 Elsevier Inc. All rights reserved.
⇑ Corresponding author at: Department of Pediatric Neurology, Faculty of
Medicine, Masaryk University and University Hospital Brno, Brno Epilepsy Centre,
Cˇernopolní 9, 613 00 Brno, Czech Republic.
E-mail address: Danhofer.pavlina@fnbrno.cz (P. Danhofer).
1
These authors contributed equally to the paper as first authors.
Epilepsy & Behavior 128 (2022) 108564
Contents lists available at ScienceDirect
Epilepsy & Behavior
journal homepage: www.elsevier.com/locate/yebeh
cess of interpreting the result of NGS; it importantly increases the
diagnostic yield of NGS examination.
Knowing the genetic cause of epilepsy in a patient opens new
horizons in terms of understanding the pathophysiology of the
epileptological process, and it also creates a space for the study
of pharmacological models of antiepileptic drugs. The definition
of precision medicine thus takes on real proportions in some
patients with epilepsy.
We present our single-center experience of using targeted
gene-panel sequencing to diagnose the genetic etiology of epilepsy
in children and we focus on the precise multidisciplinary genotype–phenotype
correlation of each patient in order to maximize
the yield of this examination method.
2. Methods
This retrospective study included 175 unrelated patients aged 0
to 19 at the time of genetic testing. All patients were examined
using an NGS epilepsy gene panel including 270 genes. A detailed
list is attached to the work as supplementary data, table 2. All
patients were examined between 2015 and 2020 at the Department
of Pediatric Neurology of the Faculty of Medicine, Masaryk
University and University Hospital Brno, Czech Republic, and were
diagnosed with epilepsy. Informed consent for genetic testing was
obtained from all the patients/parents undergoing testing. The
study was approved by the Ethics Board of the Faculty of Medicine
of Masaryk University and University Hospital Brno.
Medical records were retrospectively studied in all patients and
the following characteristics were monitored: sex, age at epilepsy
onset, time to genetic testing, family history of epilepsy, perinatal
risks, and type of epilepsy: epileptic encephalopathy (EE), generalized
epilepsy (GE), or focal epilepsy (FE). If possible, epilepsy was
further specified according to the ILAE classification of epilepsies
[7]. We also studied the neurological status in patients, associated
psychiatric comorbidities, findings on brain magnetic resonance
imaging (MRI, 1.5T), and changes in clinical management in relation
to the sequence variant in the group of genetically positive
patients. With regard to the efficacy of the therapeutic regimens,
we considered the changes in clinical management as effective if
they contributed to a more than 50% decrease in the seizure frequency
from the baseline.
Detection of single nucleotide variants (SNV) and copy number
variants by the targeted gene sequencing were performed at the
Center of Molecular Biology and Genetics, Masaryk University
and University Hospital Brno, Czech Republic.
2.1. Targeted gene sequencing
A custom-designed solution-based capture method (Roche
NimbleGen) was used to capture exons with adjacent intron
regions of the 270 genes known to be associated with epilepsy
and epileptic syndromes. Sequencing of the captured regions was
performed using next-generation sequencing on the NextSeq 550
System (Illumina). The individual DNA sequence reads were
aligned to the published human genome reference (HG19/GRCh37)
and variants were called using the software Sequence Pilot (JSI
Medical Systems) or the CLC Genomics Workbench (QIAGEN).
Large gene deletions/duplications were identified by CNV analysis
by the software CLC Genomics Workbench. In case of large gene
deletion/duplication identification, this was verified by Multiple
Ligation-dependent Probe Amplification (SALSA MLPA Probemix
P348 ATP1A2-CACNA1A-PRRT2, SALSA MLPA Probemix P395
MEF2C-FOXG1, SALSA MLPA Probemix P137 SCN1A; MRC Holland).
Identified sequence variants were interpreted using the standards
and guidelines from the joint consensus recommendation of the
American College of Medical Genetics and Genomics (ACMG) and
the Association of Molecular Pathology (AMP) published in 2015
[6]. Using these criteria, genetic variants were divided into five categories:
pathogenic (P), likely pathogenic (LP), benign (B), likely
benign (LB), and variants of uncertain significance (VUS). The segregation
of P/LP variants and VUS in a patient’s family was assessed
by Sanger sequencing. The last step in variant interpretation
involved the analysis of all possible P/LP variants and VUS by the
patient’s pediatric neurologist or epileptologist. If the variant was
evaluated as VUS, but the patient’s phenotype was highly suspected
of its pathogenicity, parental analysis was performed, and
the variant could have been reclassified. This was a complex process
where several factors, often overlapping, had to be evaluated
to complete the diagnosis and reclassification of the variant to P/
LP. The clinicians performed an in-depth review of each patient’s
phenotype and gave an opinion from their point of view. Each case
was further reviewed and discussed in a consensus meeting that
included the participation of the molecular and medical geneticists
and clinicians. Genotype–phenotype correlation and parental DNA
analysis were an integral part of the NGS diagnostic process in
accordance with currently valid recommendations [6].
2.2. Statistics
Categorical variables were summarized using absolute and relative
frequencies. To summarize the continuous characteristics,
mean, standard deviation (SD), median, minimum, and maximum
were used, see Table 1.
Testing was carried out using the Mann–Whitney U test and
Fisher’s exact test. A value of p < 0:05 was considered statistically
significant.
3. Results
A total of 175 patients (95 males and 80 females) aged 0 to
19 years were included in the study. All patients had been diagnosed
with epilepsy and underwent genetic testing with the NGS
epilepsy gene panel between 2015 and 2020.
Dividing patients into categories by type of epilepsy, 89 out of
175 patients (50.86%) experienced developmental and epileptic
encephalopathy (DEE), 45 (25.71%) were classified with generalized
epilepsy (GE), and 41 (23.43%) had focal epilepsy (FE). We further
classified the cohort of patients in more detail into specific
epileptic syndromes according to the ILAE classification of epileptic
syndromes, where possible [7].
The mean patient age at epilepsy onset was
33.05 ± 40.07 months (ranged from 0 to 215 months). Time from
the epilepsy manifestation to genetic testing was
46.7 ± 52.5 months (ranged from 0 to 215 months). In 61 out of
175 patients (35.88%), a positive family history of epilepsy was
identified; in 81 patients (46.29%), important perinatal risks were
recorded in the medical history; and 71 out of the 166 patients
tested (42.77%) had pathology on brain MRI (9 patients did not
have an MRI examination). See Table 1 for more details concerning
the basic characteristics.
3.1. NGS testing
The described pathogenic variants were identified in 25
patients; other 5 patients carried novel variants, but can be classified
as pathogenic because the creation of a premature termination
codon in genes where variants of this type occur is a known disease
mechanism. Genotype–phenotype correlations and parental DNA
analysis confirmed the association of the identified variants and
patient diseases. Sixteen patients (marked in Table 2) carried novel
Ondrˇej Horák, M. Burešová, S. Kolárˇ et al. Epilepsy & Behavior 128 (2022) 108564
2
missense variants, which were classified as P/LP after genotype–
phenotype correlations and parental DNA analysis. The diagnostic
yield of our study was 46 out of 175 patients (26.28%).
P/LP sequence variants were detected in 27 genes; 17 genes are
associated with autosomal dominant inheritance - SCN1A (8
patients), SCN2A (6 patients), PRRT2 (4 patients), CACNA1A (2
patients), KCNT1 (2 patients), SLC2A1 (2 patients), TSC2 (2 patients),
and ASXL3, GABRA1, GABRG2, GNAO1, HCN, KCNQ2, MEF2C, SCN5A,
SCN8A, SLC6A1, STXBP1 (each 1 patient); 4 genes with autosomal
recessive inheritance – ALDH7A1, POLG, SZT2, and WWOX (each 1
patient); and 5 genes had X-linked inheritance – MECP2, NEXMIF,
PCDH19, SMC1A, and WDR45 (each 1 patient). In total, 48 different
types of P/LP sequencing variants were identified (44 small-scale
variants and 4 large gene deletions); 23 of these variants were
novel and not previously described in the literature, 18 of these
are missense variants; detailed characteristics of patients with
newly described missense genetic abnormalities are shown in
Table 2.
Detailed characteristics of patients with newly described
genetic abnormalities are clearly shown in Table 2.
3.2. Comparison of genetically positive and negative cases
When the 46 patients with positive genetic findings were compared
to the 129 patients who showed negative findings in the NGS
epilepsy gene panel, the age at seizure onset was significantly earlier
(p ¼ 0:0004) in positive cases, and the proportion of patients
with DEE was significantly larger (p ¼ 0:0001) and with FE was significantly
smaller (p ¼ 0:1571). Other characteristics were not statistically
significant (Table 3). The diagnostic yield was higher in
patients with seizure onset during the neonatal period (0–
3 months of age), with 38.46% (10 out of 26) of patients proven
Table 1
Basic statistical data of cohort. DEE = developmental epileptic encephalopathy, GE = generalised epilepsy, FE = focal epilepsy.
Category Subcategory Mean/Abs. value (relative) Min – max SD Median
Sex Male n = 95 (54.29%) – – –
Female n = 80 (45.71%) – – –
Type of epilepsy DEE n = 89 (50.86%) – – –
GE n = 45 (25.71%) – – –
FE n = 41 (23.43%) – – –
Age at epilepsy onset (months) 33.05 0 – 215 40.07 18.00
Time from epilepsy onset to genetic diagnosis (months) 47.14 0 – 264 53.83 29.00
Contributing factors MRI pathology n = 71 (42.77%) – – –
Family history n = 61 (35.88%) – – –
Perinatal risks n = 81 (46.29%) – – –
Table 2
Detailed characteristics of patients with newly described genetic abnormalities. These patients carry novel missense variants, which were classified as P/LP after genotype–
phenotype correlations and parental DNA analysis. Variant status was determined according to the occurrence in Human Gene Mutation Database. The reference sequences can
be found in supplementary information. M = male, F = female, AD = autosomal dominant, AR = autosomal recessive, XD = x-linked dominant, NA = not available/applicable,
Y = yes, N = no, DEE = developmental epileptic encephalopathy, GE = generalised epilepsy, FE = focal epilepsy, DS = Dravet syndrome, GEFS+ = genetic epilepsy with febrile
seizures plus, EOEE = early-onset epileptic encephalopathy, WS = West syndrome, , FIRES = Febrile Infection-Related Epilepsy Syndrome, NORSE = New-Onset Refractory Status
Epilepticus, LGS = Lennox–Gastaut syndrome.
Patient
No.
Sex Pathogenic/Likely pathogenic
variant
Variant
status
Inheritance Origin Age at
onset
(months)
Time to
diagnosis
(months)
Family
history
Type of
epilepsy
Epileptic
syndrome
1 M SCN1A: c.251A > C p.(Tyr84Ser) new AD de novo 4 10 N DEE DS
3 F SCN1A: c.383 + 3A > G p.? new AD de novo 6 1 N DEE DS
8 F SCN2A: c.416 T > C p.(Ile139Thr) new AD de novo 0 1 N DEE EOEE
11 M SCN2A: c.3973G > A p.
(Val1325Ile)
new AD maternal 4 3 mother DEE EOEE
17 M KCNT1: c.2815 T > C p.
(Ser939Pro)
new AD de novo 31 2 N EE FIRES/
NORSE
19 M SLC2A1: c.1199G > C p.
(Arg400Pro)
new AD de novo 62 71 father FE FE
24 M GABRA1: c.911 T > G p.
(Leu304Arg)
new AD de novo 8 179 N DEE LGS
26 M GNAO1: c.133G > A p.(Gly45Arg) new AD de novo 0 0 N DEE EOEE/WS
27 F HCN1: c.838C > G p.(Gln280Glu) new AD maternal 24 37 mother GE GEFS+
30 F PCDH19: c.787A > C p.
(Ser263Arg)
new XD NA 42 57 N DEE NA
31 F POLG: c.1399G > A p.
(Ala467Thr); POLG: c.3604A > T
p.(Asn1202Tyr)
described;
new
AR maternal,
paternal
54 1 brother DEE NA
33 F SCN5A: c.5153 T > G p.
(Leu1718Arg)
new AD de novo 7 0 N DEE WS
34 F SCN8A: c.1243G > A, p.
(Glu415Lys)
new AD de novo 11 168 mother DEE LGS
35 F SLC6A1: c.739C > A p.
(Pro247Thr)
new AD NA 36 122 N DEE LGS
38 M SZT2: c.1769 + 1G > C p.?; SZT2:
c.8435C > T p.(Ser2812Phe)
new; new AR paternal/maternal 97 74 grandfather FE FE
39 F WWOX: c.321C > G p.(Tyr107*);
WWOX: c.845C > A p.
(Pro282Gln)
new; new AR maternal/
paternal
0 7 N DEE EOEE/WS
Ondrˇej Horák, M. Burešová, S. Kolárˇ et al. Epilepsy & Behavior 128 (2022) 108564
3
to have a causative mutation. Nevertheless, this was not statistically
significant when compared to the patients whose seizures
began after 3 months of age; they show a diagnostic yield of
24.16% (p ¼ 0:1487).
3.3. Precision medicine implications
In 13 of 46 patients (28.26%) the therapeutic regimen was modified
(Table 4). This was effective in reducing seizures by at least
50% in 9 of them (69.23%). Due to the size of the cohort, these
are only case observations, and will be discussed in detail in the
discussion section. Table 4 summarizes precision medicine applications
in these 13 patients.
4. Discussion
4.1. Diagnostic yield of NGS epilepsy gene panel
Previous studies have shown that NGS of multiple diseaserelated
genes is an effective tool for diagnosing the cause of epilepsy
[8–11]. This finding is particularly true for early-onset epileptic
encephalopathy, which has been reported to have a higher
proportion of monogenic causes than other epilepsies [3].
The results of our retrospective study show a 26.28% yield of
NGS epilepsy gene panel with 270 genes associated with epilepsy.
The yield of different multigene panels varies from 20% to 40%,
depending on the results of various studies [12]. The individual
panels differ in the number and proportion of individual genes;
after careful examination, it is clear that there is no direct relationship
between the number of genes in the NGS epilepsy gene panel
and its yield. It is evident that only a few genes are still repeated in
the results, and the SCN1A, KCNQ2, SCN2A, and STXBP1 genes are
most often represented in positive cases [12]. Thus, the diagnostic
yield of the NGS panel appears to be determined by the number of
commonly mutated genes included in the panel rather than the
total number of genes in the panel [13].
Consistent with the world literature is the fact that the age at
epilepsy manifestation in positive patients is lower [9,11]. The
mean age of epilepsy manifestation in our group was around
2.5 years; in the children who tested positive it was 1.5 years
and in the children with a negative result it was almost 3.5 years.
It is also worth noting that cohorts with patients with early-onset
epilepsy encephalopathies, i.e. children at neonatal age (0–
3 months), show a higher yield of NGS panel. Costain et al. [9] even
showed a panel yield in children under 12 months of 72%, higher
yields in newborns (37.1%) were also shown in the study by Ko
et al. [14]. These results are in line with our observation, in which
the yield in the group of children under 3 months was 38.46%.
These observations are logical and are based on the fact that severe
developmental and epileptic encephalopathies manifest in the
neonatal period and a serious clinical picture often requires
prompt diagnosis leading to the detection of the cause and the
introduction of possible specific therapy in indicated cases. Therefore,
these children receive a genetic diagnosis much earlier. For
these reasons, genetic diagnosis using multi-gene sequencing techniques
is recommended as a standard diagnostic tool for children
with neonatal DEE [11,15]. Making an early molecular diagnosis
can also end the genetic odyssey, enable recurrence risk counseling,
guide participation in gene-specific clinical trials, and provide
families with the opportunity to interact with support groups or
advocate for research [8]. Oates et al. showed that early genetic
diagnosis in children with DEE can reduce costs up to 70% compared
to its failure or even over 85% in case of diagnosis of Dravet
syndrome [16,17]. The argument based on the high cost of genetic
testing therefore seems unfounded.
Few studies have emphasized the precise systematic and standardized
procedure in interpreting the results of the NGS panel
[10,14]. Accurate interpretation of NGS panel results includes several
key areas: (1) population data and database review; (2) computational
data, allelic data, and literature review; (3) clinical
Table 3
Statistical comparison of genetically positive and negative cases. S = statistically significant (p < 0:05), NS = not statistically significant.
Category Group Mean/Abs. value (relative) SD Median p-value S/NS
Number of patients Pos. n = 46 (26.29%) – – – –
Neg. n = 129 (73.71%) – – – –
Age of epilepsy manifestation (months) Pos. 17.96 22.28 8.00 – –
Neg. 38.43 43.35 24.00 – –
Pos. vs. Neg. – – – p ¼ 0:0004 S
Time to diagnosis (months) Pos. 51.02 66.82 11.50 – –
Neg. 45.75 48.05 30.00 – –
Pos. vs. Neg. – – – p ¼ 0:3742 NS
Type of epilepsy – DEE Pos. n = 35 (76.09%) – – – –
Neg. n = 54 (41.86%) – – – –
Pos. vs. Neg. – – – p ¼ 0:0001 S
Type of epilepsy – GE Pos. n = 4 (8.7%) – – – –
Neg. n = 41 (31.78%) – – – –
Pos. vs. Neg. – – – p ¼ 0:0016 S
Type of epilepsy – FE Pos. n = 7 (15.21%) – – – –
Neg. n = 34 (26.36%) – – – –
Pos. vs. Neg. – – – p ¼ 0:1571 NS
MRI pathology Pos. n = 17 (39.53%) – – – –
Neg. n = 54 (43.90%) – – – –
Pos. vs. Neg. – – – p ¼ 0:7209 NS
Family history Pos. n = 11 (23.91%) – – – –
Neg. n = 51 (39.53%) – – – –
Pos. vs. Neg. – – – p ¼ 0:0725 NS
Perinatal risks Pos. n = 22 (47.82%) – – – –
Neg. n = 60 (46.51%) – – – –
Pos. vs. Neg. – – – p ¼ 1:0000 NS
Diagnostic yield (0–3 months vs. 4 months and older) 0–3 M n = 10 (38.46%) – – – –
4 M + n = 36 (24.16%) – – – –
0–3 M vs. 4+ – – – p ¼ 0:1487 NS
Ondrˇej Horák, M. Burešová, S. Kolárˇ et al. Epilepsy & Behavior 128 (2022) 108564
4
review and family study; and (4) consensus multidisciplinary discussions
[10]. At our workplace, we work closely with a team of
molecular and medical geneticists and consult the interim results
during the NGS gene panel testing. The results of this work show
that the multidisciplinary approach led to a definitive diagnosis
in some patients with novel not previously described variants
and increased the diagnostic yield of NGS analysis from 30 to 46
patients, which is by 53.33% (yield increased from 17.14% to
26.28%). This is very important from a clinical point of view.
Unfortunately, we failed to identify causal mutations in approximately
2/3 of patients. This result is consistent with the results of
many studies dealing with NGS techniques. It is clear that other
genetic mechanisms come into play, such as epigenetics or somatic
mutations.
It is also worth mentioning the comparison of the yield of NGS
epilepsy gene panel and examination using WES or WGS technique.
The largest meta-analysis from 2021 shows that the yield
of the NGS panel is on average 24% compared to WES, which is
27.2%, i.e., slightly higher, as well as a smaller meta-analysis shows
the yield of WES analysis 31% [18]. The truth is that accurate quantification
of positive results of WES analysis is very difficult given
that WES is very often tested in patients who are negative using
the NGS epilepsy gene panel technique. If WES is performed independently
of the NGS multiple gene panel, its yield may be significantly
higher (19% vs. 37%) [9].
4.2. Precision medicine strategy
Genetic diagnosis of monogenic epilepsy presents great challenges.
Knowledge of the pathophysiological mechanisms of the
epileptic process could make it possible to use the principles of
precision medicine and optimize the patient’s therapeutic regime.
For example, some AEDs are more effective than others in some
genetic epilepsy syndromes, i.e., sodium channel blockers (SCBs)
in KCNQ2- and PRRT2-related seizures [19,20]. Some AEDs can worsen
the seizure activity, as observed in SCBs in SCN1A-related
epilepsies [21]. Some AEDs can lead to fatal liver failure, as
observed in patients with POLG-associated epilepsy receiving valproic
acid (VPA) [22]. In our cohort, more than half of the patients
had ‘‘actionable” genes with immediate treatment implications.
Eighteen of these patients underwent targeted therapies.
Eight of the patients carried a SCN1A variant, which was the
most frequent sequence variant detected in our cohort. In most
patients, the phenotype of Dravet’s syndrome was presumed
before targeted molecular genetic diagnosis, so a combination of
VPA, clobazam (CLB), and stiripentol (STP) was used. None of these
patients were treated with SCBs at the time of diagnosis. Several
studies proved that there is an improvement not only in seizure
frequency after SCBs are tapered off but also in cognitive performance,
language skills, and general well-being [23]. One of the
SCN1A positive patients importantly improved on TPM and another
on STP. In one patient, a ketogenic diet (KD) led to a 70% seizure
reduction.
We diagnosed six patients with SCN2A-related epileptic
encephalopathy. Phenytoin (PHT) was administered in four of
them and led to important seizure reduction in three patients.
Wolff et al. [24] reported that SCN2A mutations cause two distinct
phenotypes: early-infantile onset (up to 3 months of age) and
infantile/childhood onset (more than 3 months of age) encephalopathies.
The early infantile form was associated with gain-offunction
mutations, and therefore showed good response to
sodium channel blockers, while the later onset form was associated
with the loss-of-function variants and SCBs were rarely effective
and sometimes worsened the seizures [24]. These observations
are consistent with our experience: in one patient with a clinical
manifestation of DEE at 4 months of age, PHT was ineffective; in
three patients with a clinical manifestation in neonatal age, SCB
therapy had a very good effect, with more than 50% seizure
reduction.
Two patients carried a SLC2A1 variant (Glut1-deficiency) and
were administered KD. One of them improved promptly and
became seizure free. In the second patient, KD was without significant
effect. The sequence variant identified in this patient was
located in exon 9 of the SLC2A1 gene, a site where causal mutations
in patients with Glut1-deficiency syndrome are often found, as has
been well documented [25]. Thus, the sequence variant was
marked as pathogenic, and a biochemical correlate of the disease
with a pathological absolute concentration of glucose in cerebrospinal
fluid (CSF) and ratio of glucose concentration in CSF
and serum was also confirmed. The patient’s phenotype was not
in conflict with the diagnosis of Glut1-deficiency syndrome. Molecular
diagnosis of the disease was made with a latency of almost
6 years from the manifestation of epilepsy, so KD was introduced
late, which may be related to its lower effectiveness [26]. The KD
patient was also less tolerant, and it was not possible to increase
the energy intake to provide sufficient energy for the CNS cells
Table 4
Precision medicine applications in 13 patients with P/LP variants. M = male, F = female, AD = autosomal dominant, NA = not available/applicable, Y = yes, N = no, DEE = developmental
epileptic encephalopathy, FE = focal epilepsy, DS = Dravet syndrome, EOEE = early-onset epileptic encephalopathy, TPM = topiramate, KD = ketogenic diet,
STP = stiripentol, PHT = phenytoin, ESM = ethosuximide, B6 = vitamin B6.
Patient
No.
Sex Pathogenic/Likely
pathogenic gene variant
Variant
status
Inheritance Origin Type of
epilepsy
Epileptic
syndrome
Precision medicine (reduction of seizures more
than 50%)
1 M SCN1A new AD de novo DEE DS N (TPM)
2 F SCN1A new AD NA DEE DS Y (KD)
3 F SCN1A new AD de novo DEE DS Y (STP)
8 F SCN2A new AD de novo DEE EOEE Y (PHT)
9 M SCN2A described AD de novo DEE EOEE NA (PHT with very good effect before the
genetic diagnosis; administered at 2 months of
age)
12 F SCN2A described AD de novo DEE EOEE Y (PHT)
14 M CACNA1A described AD de novo DEE EOEE N (ESM with important aggravation of seizures)
16 F KCNT1 described AD de novo DEE EOEE Y (KD)
18 F SLC2A1 described AD de novo DEE NA Y (KD)
19 M SLC2A1 new AD de novo FE FE N (KD)
23 M ALDH7A1, ALDH7A1 described;
described
AR maternal/paternal DEE DS Y (B6)
25 F GABRG2 described AD de novo DEE MAE Y (KD)
43 F SCN1A; deletion of the
entire gene /CNV
analysis/
NA AD de novo DEE DS Y (STP)
Ondrˇej Horák, M. Burešová, S. Kolárˇ et al. Epilepsy & Behavior 128 (2022) 108564
5
due to the fact that he did not tolerate the higher fat intake and he
vomited. The poorer response to diet was relatively accented by
the fact that the patient was also diagnosed with bilateral MTS
on brain MRI, which, we assume, developed secondarily after prolonged
seizure activity, and could continue to maintain the epileptogenic
process regardless of the primary cause of epilepsy.
5. Conclusion
Our results support the introduction of the NGS epilepsy gene
panel into the diagnostic algorithm, especially in children with
DEE. Early diagnosis is desirable not only in terms of completing
the demanding diagnostic process, but also in terms of introducing
targeted therapy. In the interpretation of genetic examination
results, we appeal for a very complex genotypic–phenotypic correlation
and a multidisciplinary approach that will enable the most
accurate genetic diagnosis and the correct interpretation of the
results.
Declaration of competing interest
None of the authors has any conflict of interest to disclose. We
confirm that we have read the Journal’s position on the issues
involved in ethical publication and affirm that this report is consistent
with those guidelines.
Acknowledgements
This work was supported by funds from the Faculty of Medicine of
Masaryk University, Czech republic to junior researcher (Pavlína
Danhofer, M.D., Ph.D., ROZV/28/LF/2020).
This study was supported by the project of the Ministry of
Health of the Czech Republic (FNB RVO 65269705).
Thanks to Anne Johnson for grammatical assistance.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.yebeh.2022.108564.
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117
2.5 Annex 5
Danhofer P, Horák O, Fajkusová L, Pavloušková J, Ošlejšková H. Syndrom Dravetové:
těžká myoklonická epilepsie v časném dětství – kazuistiky. Cesk Slov Neurol N 2014;
7/110(2): 243-6.
Summary:
Dravet syndrome (DS) is classified as a rare progressive epileptic encephalopathy. Seizure
onset is in the first year of life in thus far normally developing children. Typically,
prolonged generalised convulsive seizures occur. Subsequently, other types of seizures are
seen, accompanied by deterioration of psychomotor development. At present, detection of
a specific mutation may confirm the clinical syndrome. 70–80% of patients have mutation
in SCN1A gene, 5% in PCDH19 gene. Rarely, mutations in the GABARG2 gene
and SCN1B gene are detected. Early diagnosis of DS is very important from the
therapeutical point of view. Two case reports of patients with typical clinical course of DS
and genetically detected mutation in SCN1A gene are presented
Cesk Slov Neurol N 2014; 77/110(2): 243–246 243
KAZUISTIKA CASE REPORT
Syndrom Dravetové: těžká myoklonická
epilepsie v časném dětství – kazuistiky
Dravet Syndrome: Severe Myoclonic Epilepsy in Infancy –
Case Reports
Souhrn
Syndrom Dravetové se řadí mezi vzácné progresivní epileptické encefalopatie. Klinická
manifestace je v prvním roce života u dosud normálně se vyvíjejících kojenců. Typicky začíná
febrilními protrahovanými konvulzivními záchvaty, později se objevují i jiné typy
záchvatů a dochází k psychomotorické deterioraci. Diagnóza se dá stanovit na podkladě
klinického obrazu, v současnosti je možné u převážné většiny pacientů i potvrzení
genetické. U 70–80 % pacientů nalézáme mutaci v genu SCN1A, u 5 % je detekována
mutace v PCDH19 genu, vzácně pak v GABARG2 a SCN1B genu. Časná diagnostika
pacientů je velmi žádoucí vzhledem k terapeutickým specifikům nemoci. Jsou prezentovány
kazuistiky dvou pacientů s typickým průběhem DS a geneticky potvrzenou mutací
v SCN1A genu.
Abstract
Dravet syndrome (DS) is classified as a rare progressive epileptic encephalopathy. Seizure
onset is in the first year of life in thus far normally developing children. Typically, prolonged
generalised convulsive seizures occur. Subsequently, other types of seizures are seen, accompanied
by deterioration of psychomotor development. At present, detection of a specific
mutation may confirm the clinical syndrome. 70–80% of patients have mutation in SCN1A
gene, 5% in PCDH19 gene. Rarely, mutations in the GABARG2 gene and SCN1B gene are
detected. Early diagnosis of DS is very important from the therapeutical point of view. Two
case reports of patients with typical clinical course of DS and genetically detected mutation
in SCN1A gene are presented.
Autoři deklarují, že v souvislosti s předmětem
studie nemají žádné komerční zájmy.
The authors declare they have no potential
conflicts of interest concerning drugs, products,
or services used in the study.
Redakční rada potvrzuje, že rukopis
práce splnil ICMJE kritéria pro publikace
zasílané do biomedicínských časopisů.
The Editorial Board declares that the manuscript
met the ICMJE “uniform requirements”
for biomedical papers.
P. Danhofer1
, O. Horák1
,
L. Fajkusová2
, J. Pavloušková2
,
H. Ošlejšková1
LF MU a FN Brno:
1
Klinika dětské neurologie, Centrum
pro epilepsie Brno
2
Centrum molekulární biologie
a genové terapie Interní hematoonkologické
kliniky

MUDr. Pavlína Danhofer
Klinika dětské neurologie
LF MU a FN Brno
Centrum pro epilepsie Brno
Černopolní 9
613 00 Brno
e-mail:
pavlina.cahova@seznam.cz
Přijato k recenzi: 5. 7. 2013
Přijato do tisku: 24. 10. 2013
Klíčová slova
Dravetové syndrom – myoklonická epilepsie
– epilepsie – terapie
Key words
Dravet syndrome – myoclonic epilepsy –
epilepsy – therapy
244
SYNDROM DRAVETOVÉ: TĚŽKÁ MYOKLONICKÁ EPILEPSIE V ČASNÉM DĚTSTVÍ – KAZUISTIKY
Cesk Slov Neurol N 2014; 77/110(2): 243–246
Úvod
Syndrom Dravetové (DS), těžká myoklonická
epilepsie v časném dětství, se řadí
mezi vzácné progresivní epileptické encefalopatie
[1]. Diagnostika a syndromologické
zařazení se dá provést na podkladě
klinického obrazu, v současné době
je možné diagnózu potvrdit i geneticky.
Cílem této publikace je upozornit na
včasné rozpoznání pacientů s DS. Pacienti
s podezřením na DS by měli být co nejdříve
odesláni do specializovaných center
ke genetické diagnostice a specifické
terapii. Včasná diagnostika DS a jeho intenzivní
léčba může vést k redukci protrahovaných
epileptických záchvatů, které se
nepřímo mohou spolupodílet na míře psychomotorické
retardace u pacientů s DS.
Kazuistika 1
U první pacientky, aktuálně 2,5leté, se záchvaty
objevily ve čtyřech měsících věku.
V rodinné anamnéze bez pozoruhodností,
v graviditě bez komplikací, perinatální průběh
bez rizik s normální poporodní adaptací.
Motorický vývoj byl lehce disharmonický
s dobrým efektem rehabilitace dle
Vojty. Ve čtyřech měsících věku se objevil
první afebrilní protrahovaný pravostranný
hemikonvulzivní záchvat. V témže
měsíci pak 50minutový epileptický status
s levostrannými křečemi při febrilním infektu.
Provedená vyšetření (MR mozku,
odběr mozkomíšního moku, EEG a odběr
krve a moči k vyšetření dědičných poruch
metabolizmu) byla negativní. Byla
zahájena terapie fenobarbitalem v dávce
4,5mg/kg/den. V dalším průběhu ale záchvaty
trvaly s frekvencí několika paroxyzmů
za měsíc. Objevovaly se konvulzivní
záchvaty se střídavou lateralizací, často vázány
na febrilní infekt, pacientka byla velmi
citlivá i na teplé počasí, v létě se stav výrazně
zhoršil, délka záchvatů byla od 5 do
40 min. Vzhledem k závažnosti a délce trvání
záchvatů byla pacientka opakovaně
hospitalizována na jednotce intenzivní
péče, opakovaně vyžadovala i hospitalizaci
na ARO s nutností intubace. Od devíti měsíců
věku se začaly objevovat i protrahované
záchvaty charakteru areaktivity s celkovou
hypotonií a deviací hlavy a bulbů
(stranově střídavě, převážně ale doprava) –
záchvaty hypomotorické s verzivní složkou.
Tyto záchvaty byly přítomny s frekvencí několika
za měsíc. V EEG se objevilo zpomalení
a dezorganizace základní aktivity do
pásma delta, ojediněle i ostré vlny pod F4.
V dalším průběhu byly nasazeny postupně
valproát, levetiracetam a klonazepam,
vždy jen s přechodným efektem a vymizením
záchvatů na několik měsíců. Ve dvou
letech věku byla přímou DNA analýzou potvrzena
mutace c.408C>A, p.(Cys136*)
v genu SCN1A v heterozygotní formě.
Identifikovaná mutace nebyla v literatuře
ani databázi HGMD (Human Gene Mutation
Database, http://www.hgmd.cf.ac.
uk/ac/index.php) popsána. Byla provedena
detekce mutace u rodičů a dle předpokladu
bylo zjištěno, že se jedná o mutaci
de novo. Postupně byla zahájena redukce
fenobarbitalu a levetiracetamu, pacientka
poté zůstala na kombinaci valproát a klonazepam,
který byl zaměněn za klobazam.
Ve dvou letech věku bylo zahájeno nasazování
stiripentolu v dávce 50mg/kg/den
s parciálním efektem. Došlo ke snížení frekvence
záchvatů generalizovaných konvulzivních
na cca jeden za měsíc, především
ale byly výrazně kratší v trvání maximálně
do 3 min, záchvaty hypomotorické dále rodiče
nereferovali. Ve 2,5 letech věku se objevil
nový typ záchvatů, atypické absence
s EEG korelátem generalizovaných komplexů
hrot vlna o frekvenci 3,5 Hz s počátkem
temporálně vpravo. V EEG se nově
objevila interiktální epileptiformní patologie
vpravo temporoparietálně. Nyní pacientka
zahajuje ketogenní dietu. Aktuálně
ve 2,5 letech věku je v objektivním neurologickém
nálezu lehká centrální hypotonie,
pacientka již sama obchází kolem
nábytku, jemná motorika je lehce nedokonalá.
Psychický vývoj je disharmonický,
odpovídá 12–15 měsícům věku. Dominuje
slabší schopnost komunikace a řečového
vývoje s atypiemi v sociálním chování
(menší zastoupení reciprocity), vývoj však
jak po motorické, tak i psychické stránce
pozvolna pokračuje.
Kazuistika 2
Druhý pacient je čtyřletý chlapec. V rodinné
anamnéze bez pozoruhodností,
těhotenství probíhalo bez komplikací,
porod byl spontánní v termínu bez perinatálních
komplikací s normální poporodní
adaptací. Až do klinické manifestace epileptických
záchvatů byl psychomotorický
vývoj normální. Záchvaty se objevily
v sedmi měsících věku s konstantní vazbou
na febrilní infekty. Klinicky se jednalo
o konvulzivní záchvaty se střídavou
lateralizací v trvání obvykle do 5 min, nejdelší
záchvat byl 10minutový. Frekvence
záchvatů byla jeden za měsíc. Pacient byl
opakovaně hospitalizován v okresní nemocnici,
kde bylo provedeno CT mozku
a MR mozku s normálním nálezem,
vstupní EEG negativní. Dále byl proveden
odběr séra a moči na vyšetření dědičných
poruch metabolizmu s negativním
nálezem. V krevním obraze zjištěna
lehká hypochromní anémie, na kardiologii
inkompletní blok pravého Tawarova
raménka. Vzhledem k četnosti záchvatů
byl nasazen valproát, poté přidán klonazepam.
I přes dvojkombinaci léků se záchvaty
objevovaly dále s frekvencí 1–2 za
měsíc, vždy s vazbou na febrilní infekt.
Ke stávající dvojkombinaci léků byl přidán
levetiracetam a pacient byl odeslán k vyšetření
na Kliniku dětské neurologie LF MU
a FN Brno, kde byla zahájena dispenzarizace.
V dalším období, ve věku od 13 měsíců
do dvou let byl chlapec klinicky kompenzován.
Poté se objevily záchvaty opět,
s četnější frekvencí a nově i bez vazby na
horečku. Trvají záchvaty charakteru generalizovaných
nebo stranově střídajících lateralizovaných
křečí v délce do 5 min, dále
se objevuje nový typ záchvatů bez křečí
s areaktivitou a oroalimentárními automatizmy
v trvání do 10 min. Záchvaty se
objevují s frekvencí 1–2 za měsíc. V EEG
zachycen opakovaně negativní nález, od
tří let věku se vyskytují ojedinělé ostré vlny
v bifrontální lokalizaci s pravostrannou
převahou. Vzhledem k neúčinnosti stávající
medikace byla zahájena redukce levetiracetamu,
aktuálně je chlapec na dvojkombinaci
valproátu s klobazamem, který
byl nasazen výměnou za klonazepam,
a nasazuje se stiripentol.
Ve 2,5 letech věku byla přímou DNA
analýzou u pacienta prokázána mutace
c.1989delT, p.(Phe663Phefs*9) v genu
SCN1A v heterozygotní formě. Identifikovaná
mutace nebyla v literatuře ani databázi
HGMD popsána. V objektivním neurologickém
nálezu lze sledovat centrální
hypotonii s bederní hyperlordózou, je
schopen samostatné chůze s valgózním
postavením kolen a bérců. V psychologickém
profilu dominuje hyperaktivita a porucha
koncentrace, slabší sociální kontakt
při zachovalé dovednosti jeho navázání.
Intelekt celkově v pásmu normy rozkolísaný
především pro slabou koncentraci.
Diskuze
Syndrom Dravetové byl poprvé popsán
v roce 1978 profesorkou Charlotte Dra-
SYNDROM DRAVETOVÉ: TĚŽKÁ MYOKLONICKÁ EPILEPSIE V ČASNÉM DĚTSTVÍ – KAZUISTIKY
Cesk Slov Neurol N 2014; 77/110(2): 243–246 245
vet ve Francii [2]. Dle ILAE klasifikace epileptických
syndromů z roku 1989 se řadí
mezi epilepsie a epileptické syndromy nezařaditelné
jako ložiskové či generalizované
[3]. Dle revize této klasifikace z roku
2010 patří mezi elektroklinické syndromy
časného dětství [4].
V souladu s ILAE revizí epileptických
syndromů 2010 se syndrom Dravetové
z etiologického hlediska řadí mezi epilepsie
na genetickém podkladě. Převážná
část pacientů jsou nositelé mutace v genu
pro alfa1 podjednotku sodíkového kanálu
(gen SCN1A), tato mutace se vyskytuje
u 70–80 % pacientů [5]. Dochází zde ke
snížení excitability GABAergních interneuronů
v neokortexu a hipokampu [6], což
má za následek snížení výbojů v těchto inhibičních
interneuronech. Dojde tak ke
zvýšení excitability v neuronální síti a rozvoji
SCN1A epileptické encefalopatie.
Mutace v SCN1A genu jsou odpovědné
za rozvoj velmi variabilního fenotypového
vyjádření, tzv. GEFS+ spektra.
Na „benigním“ konci spektra se vyskytují
pacienti se syndromem GEFS+ (febrilní
záchvaty + afebrilní generalizované
tonicko-klonické záchvaty), na druhém
konci spektra se nachází DS. Mutace u pacientů
s DS jsou ve 40 % tzv. truncating
mutace, které způsobují předčasný vznik
terminačního kodonu, čímž vedou k předčasnému
ukončení translace, a nebo
v dalších 40 % případů se jedná o tzv. missense
mutace [7]. Za rozvoj GEFS+ je odpovědná
spíše missense mutace v genu
SCN1A, nicméně genotypová-fenotypová
korelace není konzistentní. Předpokládá
se, že pokud se missense mutace nachází
v pór formující oblasti SCN1A genu, rozvine
se DS, pokud je mutace mimo tuto
oblast, fenotypově se rozvine spíše GEFS+
syndrom [7].
Genetika DS je ještě komplexnější.
Vzácně byly identifikovány u pacientů s DS
i mutace v genu GABARG2 [8] a SCN1B [9].
Zhruba 5 % pacientů nese mutaci
v genu PCDH19 s X-vázanou dědičností
[10]. Jedná se o gen kódující protocadherin
19, jehož funkce nebyla dosud
plně objasněna, ale předpokládá se
jeho zapojení v neuronálních sítích. Mutace
způsobuje epilepsii limitovanou na
ženy s mentální retardací (Epilepsy limited
to Females with Mental Retardation,
EFMR). Charakteristickým rysem je zde
menší výskyt epileptických statů a jen
zřídka se objevují myoklonické záchvaty.
U 45 % pacientů je mentální retardace
jen mírného stupně, časté jsou autistické
rysy.
U pacienta s typickým fenotypem DS dochází
k rozvoji epileptických záchvatů v kojeneckém
věku s vrcholem kolem 5. měsíce
u dosud normálně se vyvíjejících dětí.
Incidence je udávána 1 : 30 000 dětí [1],
častěji jsou postiženi chlapci v poměru
2 : 1. Objevují se tyto typy záchvatů: generalizované
klonicko-tonické záchvaty
(resp. často lateralizované stranově střídající),
myoklonické záchvaty, atypické
absence a fokální záchvaty s poruchou
vědomí. Velmi častý je výskyt status epilepticus,
především v počátečním období,
a to převážně u febrilních záchvatů.
Tab. 1 ukazuje příznaky, kdy je třeba myslet
na možnost DS (tzv. red flags).
V klinickém obraze pacientů s DS existuje
jistá variabilita, mluvíme o DS-spektru
(tab. 2) [5].
V současné době je v České republice genetické
potvrzení DS možné provést v Brně
a v Praze, a to na úrovni vyšetření SCN1A
genu. V Brně vyšetření provádí Centrum
molekulární biologie a genové terapie Interní
hematoonkologické kliniky LF MU
a FN Brno (kontakt: RNDr. Lenka Fajkusová,
CSc., lfajkusova@fnbrno.cz). V Praze se lze
obrátit na Ústav biologie a lékařské genetiky
2. LF UK a FN v Motole (kontakt: RNDr.
Petra Hedvičáková, petra.hedvicakova@lfmotol.cuni.cz).
V případě podezření na DS
je vhodné provést genetickou konzultaci
na výše uvedených pracovištích.
Vyšetření vzácnějších mutací DS probíhá
na celoevropské úrovni pod záštitou
projektu EuroEPINOMICS, a to v programu
RES (genetics of Rare Epilepsy
Syndromes). Pro zájemce odkazujeme na
stránku http://www.euroepinomics.org/.
Terapeutické možnosti jsou poměrně bohaté,
jejich efekt je však limitován vysokou
farmakorezistencí pacientů. Lékem první
volby jsou valproát a benzodiazepiny [11],
především klobazam. Při neefektu těchto
je indikován stiripentol. Stiripentol (Diacomit)
je řazen mezi orphan-drug v terapii DS
a je schválen jako přídatná terapie k valproátu
+ klobazamu. V terapii DS je v Evropě
schválen od roku 2007. Dosud byly
realizovány dvě randomizované placebem
kontrolované studie, které sledují efekt stiripentolu
jako přídatné terapie ke kombinaci
VPA + CLB. Za tímto účelem byla
zformována studijní skupina STICLO (STIripentol
CLObazame study group) ve Francii
a Itálii. Výsledky francouzské skupiny
byly publikovány Catherine Chiron et al
v roce 2000 [12]. Výsledky italské skupiny
publikovány dosud nebyly, jsou však zahrnuty
v metaanalýze [13]. Výsledky ukázaly
71 % [13], resp. 67 % [12] respondérů
ve srovnání s placebem 5 % [13], resp.
9 % [12]. Další terapeutickou možností
jsou topiramat [14] a levetiracetam (účinný
především na myoklonické záchvaty [15]),
které lze využít jako přídatné léky. Lamotrigin,
karbamazepin, vigabatrin a vysoké
dávky fenobarbitalu mohou záchvaty zhoršovat
a je vhodné se jim v léčbě vyhnout.
Tab. 1. Příznaky a klinické nálezy upozorňující na diagnózu DS a další průběh
onemocnění.
Příznaky a klinické nálezy upozorňující
na diagnózu DS (tzv. red flags)
Další průběh DS
manifestace v kojeneckém věku
normální objektivní neurologický nález centrální hypotonie, ataxie
normální psychomotorický vývoj v době
manifestace
rozvoj psychomotorické
retardace
protrahované konvulzivní epileptické záchvaty
(často SE), často lateralizované
rozvoj dalších typů záchvatů –
atypické absence, myoklonické
záchvaty, fokální záchvaty
febrilní záchvaty, provokace v horkém počasí
normální iniciální EEG
dezorganizace základní aktivity,
multifokální výboje hrotů a komplexů
hrot/pomalá vlna, fotosenzitivita
v průběhu onemocnění
normální nález na MR mozku možný rozvoj atrofie mozku
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V neposlední řadě je nutno uvést i ketogenní
dietu, která má v terapii DS relativně
vysokou účinnost ve srovnání s jinými epileptickými
encefalopatiemi [16]. Příznivé
výsledky ukazuje v terapii DS i implantace
vagového stimulátoru [17].
Prezentované kazuistiky představují geneticky
potvrzené případy DS s prokázanou
mutací v genu SCN1A. Klinický průběh
onemocnění je zde poměrně typický.
Zavádějící může být fakt, že se u pacientů
dosud nevyskytly myoklonické záchvaty,
které má syndrom Dravetové – jako těžká
myoklonická epilepsie v časném dětství –
přímo v názvu. Myoklonické záchvaty se
však vyskytovat vůbec nemusí [1] nebo
často se objevují až po několika letech
od klinické manifestace onemocnění.
Název tak může být zavádějící. Již v roce
1994 Aicardi navrhoval pro DS název
„těžká polymorfní epilepsie v časném dětství“,
který však v klasifikačním systému
epileptických syndromů etablován nebyl.
U 70–80 % pacientů se syndrom geneticky
potvrdit podařit nemusí. Je třeba
však myslet na to, že DS lze diagnostikovat
již na podkladě klinického obrazu a diagnostika
genetická je pouze potvrzující.
Diagnóza již na základě klinického vyjádření
je zásadní, poněvadž umožní nasměrovat
terapii správným směrem, vyvarovat
se potenciálně zhoršujících léků
a zvolit naopak ty, které by mohly mít
efekt na redukci záchvatů. Zásadní je především
časná diagnostika syndromu. Stiripentol
se ukázal efektivní v redukci především
konvulzivních záchvatů, jež mohou
být v počátečním stadiu protrahované až
charakteru epileptických statů. Právě ty se
velkou měrou spolupodílí na rozvoji neurokognitivního
deficitu pacientů a regresu
v psychomotorickém vývoji [11].
Pojmenování nemoci je důležité i pro rodiče
pacienta. Ukončí extenzivní a často
stresující došetřování příčiny epilepsie,
umožní s rodiči mluvit o prognóze, vysvětlit
jim možné komplikace a soustředit se více
na komplexní péči zahrnující psychologa,
logopeda, ortopeda, rehabilitaci a další
formy podpůrné terapie, které mohou
celkový stav dítěte a jeho psychomotorický
vývoj povzbudit. Důležité informace
mohou rodiče i odborníci získat na stránkách
http://www.dravetfoundation.org/.
Závěr
Syndrom Dravetové se řadí mezi prognosticky
závažné epilepsie manifestující se
v časném dětství. Časná a správná diagnostika
je zásadní pro další terapii, která
u DS představuje určitá specifika. V současné
době je možná i diagnostika genetická,
jež u většiny pacientů prokáže mutaci
a pro diagnózu DS je potvrzující.
Literatura
1. Panayiotopoulos CP. A clinical guide to Epileptic
syndromes and their treatment. 2nd ed. London:
Springer Healthcare Ltd 2002: 283–287.
2. Dravet C. Les épilepsies graves del’enfant. Vie Med
1978; 8: 543–548.
3. Commission on Classification and the Terminology
of the International League Against Epilepsy. Proposal
for revised classification of epilepsies and epileptic
syndromes. Epilepsia 1989; 30(4): 389–399.
4.BergAT,BerkovicSF,BrodieMJ,BuchhlaterJ,CrossHJ,
Van Emde Boas W et al. Revised terminology and concepts
for organisation of seizures and epilepsies: report
of the ILAE Commission on Classification and Terminology,
2005–2009. Epilepsia 2010; 51(4): 676–685.
5. Marini C, Scheffer IE, Nabbout R, Suls A, de Jonghe P,
Zara F et al. The genetics of Dravet syndrome. Epilepsia
2011; 52 (Suppl 2): 24–29.
6.YuFH,MantegazzaM,WestenbroekRE,RobbinsCA,
Klaume F, Burton KA et al. Reduced sodium current
in GABAergic interneurons in a mouse model of severe
epilepsy in infancy. Nat Neurosci 2006; 9(9):
1142–1149.
7. Dravet C, Guerrini R. Dravet syndrome. Topics in
Epilepsy series. Vol. 3. London: John Libbey Eurotext
2011: 51–61.
8.HarkinLA,BowserDN,DibbensLM,SinghR,PhillipsF,
Wallace RH et al. Truncation of the GABA/A-receptor
gamma2 subunit in a family with generalized epilepsy
with febrile seizures plus. Am J Hum Genet 2002;
70(2): 530–536.
9. Patino GA, Claes LR, Lopez-Santiago LF, Slat EA,
Dondeti RS, Chen C et al. A functional null mutation
of SCN1B in a patient with Dravet syndrome. J Neurosci
2009; 29(34): 10764–10778.
10. Depienne C, Bouteiller D, Keren B, Cheuret E,
Poirier K, Trouillard O et al. Sporadic infantile epiletic
encephalopathy caused by mutation in PCDH19 resembles
Dravet syndrome but mainly affects females.
PLoS Genet 2009; 5: e1000381.
11. Chiron C. Current therapeutic procedures in Dravet
syndrome. Dev Med Child Neurol 2011; 53 (Suppl
2): 16–18.
12. Chiron C, Marchand MC, Tran A. STICLO study
group. Stiripentol in severe myoclonic epilepsy
in infancy: a randomised placebo-controlled syndrome-dedicated
trial. Lancet 2000; 356(9242):
1638–1642.
13. Kassaï B, Chiron C, Augier S, Cucherat M, Rey E,
Gueyffier F et al. Severe myoclonic epilepsy in infancy:
a systematic review and a meta-analysis
of individual patient data. Epilepsia 2008; 49(2):
343–348.
14. Coppola G, Capovilla G, Montagnini A, Romeo A,
Spanò M, Tortorella G et al. Topiramate as add-on
drug in severe myoclonic epilepsy in infancy: an Italian
multicenter open trial. Epilepsy Res 2002; 49(1):
45–48.
15. Striano P, Coppola G, Pezzella M, Ciampa C,
Specchio N, Ragona F et al. An open-label trial of levetiracetam
in severe myoclonic epilepsy in infancy.
Neurology 2007; 69(3): 250–254.
16. Caraballo RH. Nonpharmacologic treatments of
Dravet syndrome: focus on ketogenic diet. Epilepsia
2011; 52 (Suppl 2): 79–82.
17. Zamponi N, Passamonti C, Cappanera S, Petrelli C.
Clinical course of young patients with Dravet syndrome
after vagal nerve stimulation. Eur J Paediatr
Neurol 2011; 15(1): 8–14.
Tab. 2. Klinické spektrum syndrom Dravetové – DS spektrum [5].
Název Anglický název
Typ epileptických
záchvatů
Nevyskytující
se záchvaty
Psychomotorický
vývoj
Těžká myoklonická epilepsie
v časném dětství
Severe Myoclonic Epilepsy of
Infancy (SMEI)
GTCS, absence,
fokální a myoklinické
záchvaty
psychomotorická deteriorace
v různé míře
Hraniční těžká myoklonická
epilepsie v časném dětství
Borderline Severe Myoclonic
Epilepsy of infancy (SMEB)
GTCS, absence,
fokální záchvaty
myoklonické
záchvaty
psychomotorická deteriorace
v různé míře
Rezistentní dětská epilepsie
s generalizovanými tonicko-klonickými
záchvaty
Intractable Childhood Epilepsy
with Generalised Tonic-Clonic
seizures (ICEGTC)
GTCS
myoklonické záchvaty,
absence
a fokální záchvaty
významná a časná
psychomotorická
deteriorace
Těžká multifokální epilepsie
v časném dětství
Severe Infantile MultiFocal
Epilepsy (SIMFE)
multifokální
záchvaty
myoklonické záchvaty
a nebo absence
psychomotorická deteriorace
v různé míře
GTCS – generalizovaný tonicko-klonický záchvat.
122
2.6 Annex 6
Česká K, Aulická Š, Danhofer P, Horák O, Fajkusová L, Pouchlá S, Ošlejšková H. Syndróm
Dravetovej s mutáciou v SCN1A géne, genetické aspekty a klinické skúsenosti. Cesk Slov
Neurol N 2018; 81(1): 55-9.doi: 10.14735/amcsnn201855.
Summary:
Aims: We present retrospective analysis of the set of 11 patient group with SCN1A
gene (sodium voltage-gated channel alpha subunit 1) positive Dravet syndrome (DS). Patients
were examined with suspected DS from 2010 to February 2017. The aim of the study was to
analyse epidemiological and clinical data and to assess the efficacy of drug therapy and MRI
and EEG findings.
Material and methods: In the study the analysis of medical records of patients with SCN1A
mutation positive DS and its statistic evaluation was used. We monitored development of
disease, gender, types of epileptic seizures and their association with age of patient, findings
on EEG and MRI, drug ef- fect. We also evaluated the neurological and behavioral-mental
status of patients.
Results: In group of 11 patients, there were 7 women (63.6%) and 4 men (36.4%). Average
age by manifestation of seizures was 6.5 months. All of the patients have mutation in SCN1A
gene. The most frequent seizures were generalized tonic-clonic (81.8%). On the other hand
the least occurring seizures were myoclonic seizures – only 2 from 11 (18.2%). Average time
from development of symptomatology to correct diagnosis was by 116 months. In patients
born before 2010 it was only 19 months.
Conclusion: DS is from prognostic point of view serious type of epilepsy. Since 2010, 52
samples of DS suspected patients were investigated. Eleven proven causal mutations represent
21% of samples. Early diagnostics of disease and correct management is crucial for further
course of disease and has major impact on mental status and predicted prognosis
Cesk Slov Neurol N 2018; 81/114(1): 55–59 55
ORIGINAL PAPER PŮVODNÍ PRÁCE
doi: 10.14735/amcsnn201855
Syndróm Dravetovej s mutáciou v SCN1A géne,
genetické aspekty a klinické skúsenosti
SCN1A mutation positive Dravet syndrome,
genetic aspects and clinical experiences
Súhrn
Ciele: Prezentujeme retrospektívnu analýzu súboru 11 pacientov s Dravetovej syndrómom (DS)
s preukázanou mutáciou v SCN1A géne (sodium voltage-gated channel alpha subunit 1 – alfa1
podjednotka sodíkového kanálu). Pacienti boli vyšetrení s podozrením na DS od roku 2010 do
februára 2017. Cieľom práce bola analýza epidemiologických a klinických nálezov, ako aj
hodnotenie efektivity medikamentóznej terapie a nálezov na MR mozgu a EEG.Materiálametodika:
Zvolenou metódou bola analýza údajov a nálezov v zdravotníckej dokumentácií pacientov s DS
s preukázanou mutáciou v SCN1A géne a jeho následné štatistické zhodnotenie. Sledovali sme
rozvoj ochorenia, pohlavie, typy záchvatových prejavov a ich vekovú väzbu, nálezy na EEG a MR,
efekt medikamentóznej terapie. Taktiež sme sa venovali hodnoteniu neurologického nálezu
a behaviorálne-mentálneho statusu pacientov. Výsledky: V súbore 11 pacientov početne prevládajú
ženy nad mužmi – 7 žien (63,6 %), 4 muži (36,4 %). Priemerný vek pri manifestácií záchvatov je
6,5 mesiaca. Všetci pacienti majú preukázanú mutáciu v SCN1A géne. Najčastejším typom
záchvatov v skupine boli generalizované tonicko-klonické (81,8 %), naopak najmenej sa vyskytujú
myoklonické záchvaty (2/11; tj. 18,2 %). Priemerný čas od rozvoja symptomatológie k stanoveniu
správnej diagnózy bol u pacientov narodených pred rokom 2010 priemerne 116 mesiacov.
U pacientov narodených po roku 2010 tento poklesol na 19 mesiacov. Záver: Dravetovej syndróm sa
radí medzi prognosticky závažné epilepsie. Od roku 2010 sme vyšetrili celkom 52 vzoriek pacientov
s podozrením na DS. Preukázaných 11 kauzálnych mutácií predstavuje 21% záchyt. Včasná diagnostika
ochorenia a správny management je zásadný pre ďalší priebeh ochorenia a má veľký
vplyv na mentálny status pacienta a predpokladanú prognózu.
Abstract
Aims: We present retrospective analysis of the set of 11 patient group with SCN1A gene (sodium
voltage-gated channel alpha subunit 1) positive Dravet syndrome (DS). Patients were examined
with suspected DS from 2010 to February 2017. The aim of the study was to analyse epidemiological
and clinical data and to assess the efficacy of drug therapy and MRI and EEG findings. Material and
methods: In the study the analysis of medical records of patients with SCN1A mutation positive
DS and its statistic evaluation was used. We monitored development of disease, gender, types
of epileptic seizures and their association with age of patient, findings on EEG and MRI, drug effect.
We also evaluated the neurological and behavioral-mental status of patients. Results: In group
of 11 patients, there were 7 women (63.6%) and 4 men (36.4%). Average age by manifestation
of seizures was 6.5 months. All of the patients have mutation in SCN1A gene. The most frequent
seizures were generalized tonic-clonic (81.8%). On the other hand the least occurring seizures were
myoclonic seizures – only 2 from 11 (18.2%). Average time from development of symptomatology
to correct diagnosis was by 116 months. In patients born before 2010 it was only 19 months.
Conclusion: DS is from prognostic point of view serious type of epilepsy. Since 2010, 52 samples
of DS suspected patients were investigated. Eleven proven causal mutations represent 21% of
samples. Early diagnostics of disease and correct management is crucial for further course of
disease and has major impact on mental status and predicted prognosis.
Tento projekt bol podporený grantem LF MU ROZV/25/LF/2017.
Autoři deklarují, že v souvislosti s předmětem
studie nemají žádné komerční zájmy.
The authors declare they have no potential
conflictsofinterestconcerningdrugs,products,or
services used in the study.
Redakční rada potvrzuje, že rukopis práce
splnil ICMJE kritéria pro publikace zasílané
do biomedicínských časopisů.
The Editorial Board declares that the manuscript
met the ICMJE “uniform requirements” for
biomedical papers.
K. Česká1
, Š. Aulická1
, P. Danhofer1
,
O. Horák1
, L. Fajkusová2
,
S. Pouchlá2
, H. Ošlejšková1
1
Klinika dětské neurologie LF MU
a FN Brno, Centrum vysoce specializované
péče pro farmakorezistentní
epilepsie MZ ČR
2
Centrum molekulární biologie
a genové léčby, Interní hematoonkologická
klinika LF MU a FN Brno

MUDr. Katarína Česká
Klinika dětské neurologie LF MU
a FN Brno, Centrum vysoce
specializované péče pro farmakorezistentní
epilepsie MZ ČR
Černopolní 9
613 00 Brno
e-mail: ceska.katarina@fnbrno.cz
Prijaté k recenzii: 13. 7. 2017
Prijaté do tlače: 15. 11. 2017
Kľúčové slová
Dravetovej syndróm – SCN1A gén – genetická
diagnostika – manifestácia – farmakorezistencia
– antiepileptická medikácia
Key words
Dravet syndrome – SCN1A gene – genetic
diagnostic – manifestation – pharmacoresistency
– antiepileptic drugs
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SYNDRÓM DRAVETOVEJ S MUTÁCIOU V SCN1A GÉNE, GENETICKÉ ASPEKTY A KLINICKÉ SKÚSENOSTI
Cesk Slov Neurol N 2018; 81/114(1): 55–59
Úvod
Dravetovej syndróm sa klinicky manifestuje
v priebehu 1. roku života. Podľa doporučení
Medzinárodnej ligy proti epilepsii (The International
League Against Epilepsy; ILAE) pre
klasifikáciu epileptických záchvatov a epilepsií
z roku 2017 sa z etiologického hľadiska radí DS
medzi epilepsie s genetickým podkladom [1].
Klinickým prejavom sú recidivujúce febrilné
protrahované záchvaty, až dĺžky status
epilepticus (konvulzívne alebo hemikonvulzívne,
stranovo alternujúce). Neskôr dochádza
k rozvoju aj iných typov záchvatov (myoklonické
záchvaty, atypické absencie, fokálne
paroxyzmy). Syndróm Dravetovej vedie postupne
k deteriorácií psychomotorického
vývoja až k rozvoji mentálnej retardácie
rôzneho stupňa [1,2]. Bližšia klinická charakteristika
ochorenia, ako aj priebeh ochorenia
v detstve a dospelosti je možné ďalej študovať
v rôznych literárnych zdrojoch v tuzemskej
aj zahraničnej literatúre [1–4].
Asi 70–80 % pacientov nesie abnormalitu
v géne pre alfa1 podjednotku sodíkového
kanálu – SCN1A. Celkom 5 % pacientov má
mutáciu v géne pre PCDH19 (gén pre proteín
zvaný protokadherín 19), asociácia je preukázaná
aj s GABRG2 (gene coding gamma 2 subunit
GABA receptor) a génom SCN1B (sodium
voltage-gated channel beta subunit 1).
Prvé spojenie mutácie SCN1A génu a DS bolo
definované v roku 2001 [1].
V článku prezentujeme vlastný súbor
11 pacientov s DS.
Materiál a metodika
V našej práci sme hodnotili súbor 11 pacientov
s preukázanou mutáciou v géne SCN1A sledovaných
a diagnostikovaných na Klinice dětské
neurologie FN Brno v spolupráci s Centrem
molekulární biologie a genové terapie Interní
hematoonkologické kliniky FN Brno. Od roku
2010, kedy bola diagnostika zavedená, sme
vyšetrili celkom 52 vzoriek pacientov s podozrením
na DS. Preukázaných 11 kauzálnych
mutácií predstavuje 21% záchyt. Percentuálny
výsledok záchytnosti ochorenia nedokážeme
plausibilne vysvetliť. U dvoch pacientov s fenotypom
DS nebola preukázaná kauzálna
mutácia v SCN1A géne, a neboli preto zahrnutí
do aktuálne hodnoteného súboru. Etiologické
došetrovanie u týchto pacientov bolo rozšírené
o ďalšie genetické vyšetrovanie (aktuálne
gén, GABRG2 a PCDH19 u probanda ženského
pohlavia), ktoré neprinieslo pozitívne výsledky.
Konkrétne výsledky genetického vyšetrenia
a charakteristika súboru v tab. 1.
Metódou hodnotenia bola retrospektívna
analýza demografických a klinických údajov
dostupných zo zdravotníckej dokumentácie
Kliniky dětské neurologie FN Brno.
V súbore pacientov sme zisťovali tieto
charakteristiky:
• pohlavie
• rodinná a osobná anamnéza
• vek pri vzniku ochorenia
• konkrétny typ záchvatov a vek pacientov
pri ich manifestácii
• provokácia epileptických paroxysmov
• neurologický a behaviorálne-mentálny
status pacienta
• elektroencefalografické charakteristiky pred
rozvojom ochorenia a v jeho priebehu
• nálezy na MR mozgu
• efektivita medikamentóznej antiepileptickej
terapie.
Výsledky
Pacienti v hodnotenej skupine sú narodení
od roku 1999 do roku 2015. Vyhodnocovanie
klinických údajov a priebehu ochorenia prebiehalo
do februára roku 2017. Ďalší klinický
priebeh konkrétnych subjektov nie je zahrnutý
do predkladaného prehľadu.
Rodinná anamnéza febrilných záchvatov
alebo epilepsie je pozitívna u 3 pacientov
(27 %). V dvoch prípadoch sa jedná o opakované
epizódy febrilných kŕčov. Genetické
vyšetrenie bolo u jedného z týchto rodičov
negatívne na mutáciu v SCN1A géne a v druhom
prípade nebolo v čase prípravy publikácie
ošetrujúcim lekárom indikované.
V poslednom prípade došlo k rozvoju záchvatových
prejavov zodpovedajúcich fenotypu
DS. Etiologické potvrdenie, resp. vyvrátenie
diagnózy u tohto rodiča nie je možné
zo sociálnych dôvodov (dieťa v starostlivosti
náhradného rodiča, bez kontaktu s biologickou
matkou). U 3 pacientov (27 %) boli
prítomne prenatálne a perinatálne riziká –
prematurita, intenzívna antiepileptická terapia
matky počas gravidity.
Manifestácia klinickej symptomatológie
v súbore je od veku 116 mesiacov. Priemerne
voveku6,5mesiaca.Najčastejšímtypomparoxyzmu
v úvode boli febrilné hemikonvulzívne
záchvaty (rozvoj priemerne vo veku 6,5 me-
siaca;u6pacientov,tj.54,5%).Voveku3–9mesiacov
(priemer 6 mesiacov; u 8 pacientov)
sa manifestujú prolongované záchvatové
prejavy (trvajúce viac ako 10 minút). V priemernom
veku 7,4 mesiaca sa rozvinul u našich
pacientov ďalší typ záchvatov, a to generalizované
tonicko-klonické, resp. klonické
záchvaty. Tieto boli pozorované u 9 pacientov
(81,2 %). Manifestácia status epilepticus bola
priemerne v 17 mesiacoch (7; 63,6 %). U 100 %
pacientov sa jednalo o konvulzívne epileptické
staty. Myoklonické záchvaty sa rozvinuli
u 2 pacientov (18,2 %), priemerne vo veku
32,5 mesiaca. Len u 4 pacientov sme zaznamenali
výskyt atypických absencií, a to v priemernom
veku 36 mesiacov. Pri 9 pacientoch
(81,2 %) bola anamnesticky jasná provokácia
záchvatov. U 7 (63,6 %) išlo o zvýšenú telesnú
teplotu, u 1 (9,1 %) o teplú vodu (externá expozícia
pri kúpeli a saune) a časovú súvislosť
s očkovaním a následnými subfebríliami.
U 2 pacientov (18,2 %) jasná provokácia po retrospektívnej
analýze anamnézy preukázaná
nebola.
V objektívnom neurologickom náleze dominujú
predovšetkým poruchy tonusu v zmysle
centrálnej hypotónie, a to u 5 pacientov
(45,5 %), mikrocefália u 2 (18,2 %), ataxia, neistá
Tab. 1. Prehľad konkrétnych mutácií.
Pacient č.
Vek začiatku epilepsie (v
mesiacoch)
Pohlavie Uloženie mutácie v SCN1A géne
1 4 žena c.408C>A, p.Cys136*
2 8 muž c.1989delT/-, p.Pro663Profs*9
3 6 muž c.3521C>G, p.Thr1174Ser
4 5 muž c.942G>A/-, p.Trp314*
5 9 žena c.3521C>G, p.Thr1174Ser
6 4 žena c.1086C>T/-, p.Tyr362*
7 10 žena c.4135G>T, p.Val1379Leu
8 8 muž c.140delA/-
9 3 žena c.3429+1G>A/-
10 16 žena c.2837G>A, p.Arg946His
11 1 žena c.4889T>G
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Cesk Slov Neurol N 2018; 81/114(1): 55–59 57
chôdza, motorická dyspraxia u 2 pacientov
(18,2 %). Len u jednej pacientky je pozitívny
ložiskový neurologický nález v zmysle hemiparézy
(9,1 %). Pri hodnotení behaviorálne-mentálnych
schopností sa v našom súbore
vyskytujú známky Attention Deficit Hyperactivity
Disorder (ADHD), a to u 4 subjektov
(36,4 %), zníženie intelektu rôznej miery
u 7 (63,6 %), dyslália u 5 (45,5 %). Vo väčšine
prípadov rozvoj neurologickej symptomatológie
a kognitívnej deteriorácie pozorujeme
až v batolivom období. Známky
poruchy autistického spektra sa vyvinuli
v priebehu ochorenia u 2 pacientov (18,2 %)
a boli zaznamenané po 3. roku života.
Pri vyhodnocované EEG sme dospeli k záverom,
že len 2 pacienti (18,2 %) mali iniciálne
abnormitu v EEG. V priebehu ochorenia
došlo k záchytu abnormít na EEG
u väčšiny pacientov – 8 (72,7 %). U 7 bola
zachytená abnormita v základnej aktivite,
u 5 pacientov sme zaznamenali výskyt hrotov.
Komplexy hrot-vlna boli zachytené len
v izolovanom prípade.
Abnormity na MR mozgu boli zaznamenané
u 6 pacientov (54,5 %). Tieto boli charakteru
meziotemporálnej sklerózy (záchyt
vo veku 15 rokov), miernej atrofie mozgu
(záchyt už v kojeneckom veku), ľahkej redukcie
objemu mozočku, rozšírenia vonkajších
likvorových priestorov (záchyt v predškolskom
veku), cisterna magna permagna,
u jednej pacientky jednostranná periventrikulárna
leukomalácia (PVL). Záchyt posledných
dvoch nálezov na MR bol zaznamenaný
v skorom kojeneckom období.
Priemerný počet použitých antiepileptík
(AEDs) (v našom súbore je 6. Ako efektívne,
resp. parciálne efektívne boli vyhodnotené
nasledujúce: valproát u 6 z 8 pacientov
(75 %), topiramát u 6/7 (85,7 %), klobazam
u 5/6 (83,3 %), clonazepam bol použitý
u 5 pacientov a u 100 % mal parciálny efekt.
Levetiracetam u 3/7 (42,8 %), zonisamid
u 3 (100 %). Vigabatrin a primidon boli použité
len izolovane a bez efektu na záchvaty.
Stiripentol ako add-on terapia do kombinácie
valproát + klobazam bol použitý s parciálnym
efektom u 8 pacientov. Lamotrigin
bol použitý u 4 pacientov a u 100 % z nich
viedol k zhoršeniu početnosti záchvatov. Fenobarbital
v per os forme zhoršil záchvaty čo
do početnosti u 1/3 pacientov (33,3 %).
Stiripentol ako „orphan drug“ (liek-sirota
– liek určený pre liečbu vzácnych ochorení)
bol použitý celkom u 8 pacientov. Priemerný
vek pri jeho nasadení u pacientov na
klinice dětské neurologie bol 3 roky a 9 mesiacov.
Viditeľný efekt stiripentolu je pozorovaný
predovšetkým pri redukcii počtu epileptických
statov. V sledovanom súbore sa
jednalo o 100% redukciu (počet epileptických
statov u pacientov medikujúcich stiripentol
pred jeho nasadením bol 20, po
nasadení 0). Taktiež táto liečba dosahuje
výrazné zníženie počtu prolongovaných
záchvatov. Celkový počet prolongovaných
záchvatov bol pred zavedením tejto liečby
26, po zavedení len 5, tj. došlo k poklesu
ich výskytu o 80,8 %. Stiripentol vo zvolenej
kombinácií AEDs však nedosiahol valné
zníženie počtu kratších epileptických záchvatov.
Nežiadúce účinky boli pozorované
u polovice pacientov, s rôznou mierou závažnosti.
U 25 % sa jednalo o agresívne správanie,
v rovnakej miere pozorujeme poruchy
spánku (insomnia/hypersomnia). Celkom
12,5 % pacientov trpelo únavou a známkami
Tab. 2. Charakteristika epileptických záchvatov (n = 11).
Typ záchvatu
Priemerný vek
(mesiace)
Počet
pacientov (%)
1. záchvat 6,5 11 (100 %)
prolongované záchvaty (> 10 min) 6 8 (72,7 %)
hemikonvulzívne záchvaty 6,5 6 (54,5 %)
generalizované tonicko-klonické/klonické záchvaty 7,4 9 (81,8 %)
status epilepticus 17 7 (63,6 %)
moklonické záchvaty 32,5 2 (18,2 %)
atypické absencie 36 4 (36,4 %)
n – počet pacientov v súbore
Tab. 3. Fenotypové charakteristiky (n = 11).
Charakteristika Počet pacientov (%)
pozitívna rodinná anamnéza 3 (27,3 %)
pozitívna osobná anamnéza 3 (27,3 %)
provokácia I. paroxysmu:
zvýšená teplota 7 (63,6 %)
teplá voda 1 (9,1 %)
očkovanie 1 (9,1 %)
bez jasnej provokácie 2 (18,2 %)
abnormálne EEG v úvode ochorenia 2 (18,2 %)
abnormálne EEG v priebehu ochorenia 8 (72,7 %)
abnormity na MR mozgu 6 (54,5 %)
autistické prejavy 2 (18,2 %)
ataxia 2 (18,2 %)
centrálna hypotónia 5 (45,5 %)
ložiskový neurologický nález 1 (9,09 %)
problémy so správaním (hyperaktivita, porucha pozornosti) 4 (36,4 %)
oneskorený psychomotorický vývoj 5 (45,5 %)
dyslália 5 (45,5 %)
zníženie intelektu 7 (63,6 %)
mikrocefália 2 (18,2 %)
n – počet pacientov v súbore
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Cesk Slov Neurol N 2018; 81/114(1): 55–59
hyperaktivity. Nežiadúce účinky pre svoju závažnosť
priamo viedli k vysadeniu stiripentolu
len u jednej pacientky (predovšetkým
sa jednalo o výraznú agresivitu, koproláliu,
závažné poruchy spánku). U ďalšej pacientky
došlo k úprave dávkovania, s klinickým efektom,
bez nutnosti vysadenia. Podrobne sú
spracované výsledky uvedené v tab. 2–5.
Diskusia
V hodnotenom súbore pozorujeme miernu
štatistickú prevahu výskytu DS u žien –
7 žien (63,6 %), 4 muži (36,4 %). Gendrové
rozdelenie podľa svetovej literatúry sa pohybuje
v pomere 1 : 2 (žena : muž) [1,2]. Nekorešpondujúce
rozdelenie na základe pohlavia
prisudzujeme malému počtu pacientov
v sledovanom súbore.
Manifestácia ochorenia bola v sledovanom
súbore v priemere 6,5 mesiaca
(od 1. mesiaca po 16. mesiac). Najčastejších
typom záchvatov v dobe manifestácie
ochorenia sú prolongované záchvaty trvajúce
viac ako 10 minút (8; tj. 72,7 %). V porovnaní
s údajmi z veľkých multicentrických
štúdií oba údaje korelujú (Brunklaus et al
uvádzajú rozvoj prvého záchvatu okolo 6.
mesiaca a výskyt prolongovaných záchvatov
okolo 7. mesiaca) [5,6]. Hemikonvulzívne
záchvaty sa v našom súbore vyskytujú u 6,
tj. 54,5 %, s priemerným rozvojom vo veku
6,5 mesiaca. Identické výsledky uvádzajú aj
Brunklaus et al (72 % pacientov rozvinie hemikonvulzívne
záchvaty vo veku okolo 7 mesiacov).
Badateľný rozdiel v porovnaní s multicentrickými
štúdiami je viditeľný v počte
pacientov s myoklonickými záchvatmi a manifestácií
atypických absencií. Brunklaus et al
pozorujú výskyt myoklonií u 69 % pacientov
a atypických absencií u 51 % subjektov [5].
V našom súbore hovoríme o 18,2 % a 36,4 %.
Rozdiel v údajoch v porovnaní s publikovanými
údajmi súvisí pravdepodobne s počtom
pacientov v našom súbore. Významný
je aj fakt, že myoklonické záchvaty sa často
objavujú až po niekoľkých rokoch od klinickej
manifestácie ochorenia, alebo sa vyskytovať
vôbec nemusia [7].
Analýza vybraných klinických parametrov
ukazuje, že väčšina záchvatov je provokovaná
zvýšenou telesnou teplotou, a to
u 7 (63,6 % pacientov). V práci Bayat et al
sa febrílie ukazujú ako provokačný faktor
u 30 % pacientov. Najčastejším provokačným
faktorom v spomínanej práci bolo vyhodnotené
očkovanie (40 % pacientov) [6].
V našom súbore bolo očkovanie v časovej
súvislosti s rozvojom symptomatológie príčinou
len u 1 pacienta (9,1 %).
Pri hodnotení neurologického nálezu sme
preukázali manifestáciu neurologickej symptomatológie
až po 3. roku života. Najčastejšie
sme diagnostikovali centrálny hypotonický
syndróm (5; čo predstavuje 45,5 %). Ataxiu
sme zaznamenali u 2 subjektov (18,2 %). Percentuálne
zastúpenie je v zhode s údajmi zo
svetovej literatúry [5,6]. Známky autistického
spektra sme zaznamenali u 2 (18,2 %). V porovnaní
s prácou Brunklausa et al je tento
údaj výrazne nižší (46 %). Prevalencia autizmu
u pacientov s DS sa v rôznych prácach
líši (Bayat et al uvádzajú len 12% prevalenciu
autizmu) [5,6]. Predpokladáme niekoľko
príčin nižšieho zastúpenia porúch autistického
spektra v našom súbore. Významne
sa podieľa nízky počet pacientov v súbore,
ale aj relatívne väčší podiel pacientov mladších
ako 3 roky. Porucha aktivity a pozornosti
sa v našom súbore vyskytuje u 4 pacientov
(36,4 %). Tento údaj korešponduje s nálezmi
z multicentrických štúdií [5,6]. U jedného
pacienta (9,1 %) v neurologickom náleze
dominuje centrálna hemiparéza na
podklade PVL. Ložiskový neurologický nález
je netypický pre pacientov s DS. Toto súvisí
so závažnými perinatálnymi komplikáciami
a ovplyvňuje fenotyp.
Abnormity na MR mozgu boli identifikované
u 6 pacientov (54,5 %). Tento údaj je
podstatne vyšší ako v práci Brunklausa et al
a nedokážeme ho plauzibilne interpretovať.
Brunklaus et al zaznamenali v EEG fotosenzitivitu
u 33 % pacientov [5]. V našom súbore
sme nezaznamenali zmeny v EEG pri fotostimulácií
u žiadneho z pacientov.
V terapii DS sa ukázali ako parciálne efektívne
valproát, topiramát, klobazam, klonazepam,
stiripentol, levetiracetam, zonisamid.
Ako nevhodné sa v našom súbore preukázalo
použitie lamotriginu a fenobarbitalu.
Viedlo k zhoršeniu frekvencie záchvatových
prejavov,atopredovšetkýmpripoužitílamotriginu
(100 % pacientov). Fenobarbital bol
použitý celkom u 4 pacientov. Traja pacienti
medikovali fenobarbital v rámci dlhodobej
medikácie. Pri 1 pacientovi bol použitý
ako liečba epileptického statu. V perorálnej
forme viedol k zhoršeniu záchvatov len
u 1 pacienta (33,3 %), v intravenóznej forme
nedošlo k zastaveniu epileptického statu. Vigabatrín
a primidon neovplyvnili záchvatové
prejavy žiadnym spôsobom.
Lamotrigín, karbamazepín, fenytoín sú nevhodné
pri terapií DS. Ďalej je kontraindikoTab.
4. Farmakologická odpoveď u pacientov s DS (n = 11).
Medikácia s parciálnym efektom Podiel pacientov s odpoveďou (%)
valproát 6/8 (75 %)
topiramát 6/7 (85,7 %)
clobazam 5/6 (83,3 %)
clonazepam 5/5 (100 %)
levetiracetam 3/7 (42,8 %)
stiripentol 4/4 (100 %)
zonisamid 3/3 (100 %)
Medikácia zhoršujúca klinický priebeh Podiel pacientov s odpoveďou (%)
lamotrigin 4/4 (100 %)
fenobarbital 1/3 (33,3 %)
n – počet pacientov v súbore
Tab. 5. Interiktálne EEG (n = 11)
Abnormita ZA (áno/nie) Výskyt hrotov (áno/nie) Výskyt SWC (áno/nie)
7/4 5/6 1/10
n – počet pacientov v súbore; ZA – základná aktivita v EEG; SWC – komplex hrot-vlna (spike
wave complex)
proLékaře.cz | 23.1.2022
SYNDRÓM DRAVETOVEJ S MUTÁCIOU V SCN1A GÉNE, GENETICKÉ ASPEKTY A KLINICKÉ SKÚSENOSTI
Cesk Slov Neurol N 2018; 81/114(1): 55–59 59
vané použitie vigabatrínu a neodporúčajú sa
vysoké dávky fenobarbitalu [1,5,6]. Blokátory
sodíkových kanálov, ako aj ďalšie neodporúčané
AEDs boli použité vo všetkých prípadoch
pred znalosťou diagnózy.
Štúdia autorov z Japonska popisuje 10%
úmrtnosť pacientov s DS [8]. V našom súbore
neevidujeme žiadne úmrtie. Vedúcim
dôvodom úmrtia u DS je náhla smrť u epileptikov
(sudden unexpected death in epilepsy;
SUDEP). Nasledujú úmrtie pri epileptickom
statuse, úmrtie pri nehode [9].
Etiologická súvislosť vyššieho percenta
SUDEP u pacientov s DS súvisí s mutáciami
v génoch pre sodíkové kanály. Princípom je
patologická regulácia v sinoatriálnom uzle
autonómnym nervovým systémom (prevaha
sympatika nad parasympatikom), čo
následne môže viesť k život ohrozujúcim srdcovým
arytmiám [10].
Ďalším parametrom, ktorý sme v našom
súbore hodnotili, bol priemerný čas od rozvoja
klinickej symptomatológie k stanoveniu
diagnózy. Pacienti narodení pred rokom
2010 priemerne dospeli k správnej diagnóze
až po 116 mesiacoch trvania ochorenia.
U pacientov narodených po roku
2010 je to priemerne 19 mesiacov, čo predstavuje
významné skrátenie doby trvania
diagnostického procesu. Diagnostika mutácie
v SCN1A géne je dostupná od roku 2010.
Retrospektívne vyhľadávanie vhodných kandidátov
je náročné a na túto eventualitu sa
v mnohých prípadoch nemyslí. Diagnostika
DS je aktuálne bežne dostupná, čo umožňuje
urýchliť diagnostický proces a zvýšiť záchyt
pacientov v skoršom veku.
Analyzovaný súbor pacientov má v 100 %
prípadov preukázanú mutáciu v géne pre
SCN1A. V súčasnej dobe je identifikovaných
viac ako 600 mutácií asociovaných s DS a tieto
sú náhodne distribuované v priebehu celého
SCN1A génu. Mutácie génov pre iónové kanály
hrajú významnú úlohu v etiopatogenéze,
preto hovoríme o kanálopatiách [11–13].
V prípade, že sa mutácia v danom géne
nepreukáže a naďalej trvá podozrenie na DS,
je potrebné rozšíriť genetickú diagnostiku.
Mutácia PCDH19 (chromozóm Xq22) bola
objavená u jednotky epilepsia a mentálna
retardácia viazaná na ženy (EFMR). EFMR je
X- viazaná choroba. Klinická manifestácia je
u heterozygotných pacientok. Hemizygotní
muži sú nepostihnutí. Mutácia tohto génu
pri DS je len v 5 %. Dôležité je pozorovanie
častej familiárnej väzby [12]. Klinicky priebeh
je miernejší v porovnaní s DS spôsobeným
mutáciou v SCN1A géne. Začína v neskoršom
veku – medián 9,5 mesiacov, myoklonické záchvaty
a status epilepticus sú zriedkavé. Psychomotorická
retardácia je u 45 % pacientov
len ľahkého stupňa a častý je výskyt autistických
rysov. U malého počtu pacientov
s DS bola identifikovaná mutácia v géne pre
gama2 podjednotku GABAa receptoru –
GABRG2 [1,2].
Záver
DS sa radí medzi epilepsie s genetickým podkladom.
Na diagnózu je nutné pomýšľať v prípade
výskytu opakovaných, prolongovaných
febrilných záchvatov. Genetické testovanie
prináša pre pacienta množstvo benefitov.
Predovšetkým sa jedná o výber vhodného
a nevhodného antiepileptika, odbremenenie
od zbytočných testov a procedúr, predpoklad
prognózy. Nesporný význam je aj
v správnom managemente pacienta a zabezpečenie
komplexného multioborového
prístupu vrátane zaradenia pravidelných kardiologických
kontrol [14], logopédie, rehabilitácie
a podobne. Svoj význam má genetické
testovanie aj na prenatálnej úrovni v rámci
invitro fertilizácie [13]. Cieľom liečby DS je zníženie
frekvencie záchvatov a záchvatmi indukovaných
zranení, limitácia rozvoja mentálneho
defektu, psychosociálnych problémov,
zníženie rizika SUDEP [14,15].
Dané fakty sme potvrdili aj v našom súbore.
U pacientov zo sledovaného súboru
narodených pred rokom 2010 je celkový
vývoj ochorenia menej priaznivý a má výrazný
dopad na mentálny status, náročnosť
ošetrovateľskej starostlivosti a budúceho života
pacienta a rodiny.
Literatúra
1. Danhofer P, Horák O, Fajkusová L et al. Syndrom
Dravetové: těžká myoklonická epilepsie v časném
dětství – kazuistiky. Cesk Slov Neurol N 2014; 77/110(2):
243–246.
2. Danhofer P, Horák O, Fajkusová L et al. Syndrom Dravetové:
těžká myoklonická epilepsie v časném dětství. Neurol
praxi 2015; 16(1): 38–40.
3. Aulická S, Horák O, Brunová K et al. Syndrom Dravetové
v pediatrické praxi. Pediatr praxi 2017; 18(2): 100–102.
4. Danhofer P, Brunová K, Ošlejšková H. Syndrom Dravetové
(těžká infantilní myoklonická epilepsie): charakteristiky
onemocnění v dospělém věku. Neurol praxi 2017;
18(2): 113–116.
5. Brunklaus A, Ellis R, Reavey E et al. Prognostic, clinical
and demographic features in SCN1A utation – positive
Dravet syndrome. Brain 2012; 135(Pt 8): 2329–2336.
doi: 10.1093/brain/aws151.
6. Bayat A, Hjalgrim H, Moller R. The incidence of SCN1A-related
Dravet syndrome in Denmark is 1:22 000: a population-based
study from 2004 to 2009. Epilepsia 2015;
56(4): e36–e39. doi: 10.1111/epi.12927.
7. Panayiotopoulos CP. A clinical guide to Epileptic syndromes
and their treatment. 2nd
ed. London: Springer
Healthcare Ltd 2002: 283–287.
8. Sillanpää M, Shinnar S. Long-term mortality in childhood
– onset epilepsy. N Eng J Med 2010; 363(26):
2522–2529. doi: 10.1056/NEJMoa0911610.
9. Shmuely S, Sisodiya SM, Gunning WB et al. Mortality
in Dravet syndrome: a review. Epilepsy Behav 2016;
64(Pt A): 69–74. doi: 10.1016/j.yebeh.2016.09.007.
10. Delogu AB, Spinelli A, Battaglia D et al. Electrical
and autonomic cardiac function in patients with Dravet
syndrome. Epilepsia 2011; 52 (Suppl 2): 55–58. doi:
10.1111/j.1528-1167.2011.03003.x.
11. Brunklaus A, Zuberi SM. Dravet syndrom – from epileptic
encephalopathy to channelopathy. Epilepsia 2014;
55(7): 979–984. doi: 10.1111/epi.12652.
12. Meisler MH, Kearney JA. Sodium channel mutations
in epilepsy and other neurological disorders. J Clin Invest
2005; 115(8): 2010–2017. doi: 10.1172/JCI25466.
13. Yu FH, Catterall WA. Overview of the voltage-gated
channel family. Genome Biol 2003; 4(3): 207.
14. Bagnall RD, Crompton DE, Semsarian CH. Genetic
basis of sudden unexpected death in epilepsy.
Front J Neurol 2017; 8: 348. doi:10.3389/fneur.2017.00348.
15. Wirrell EC. Treatment of Dravet syndrome. Can J Neurol
Sci 2016; 43 (Suppl 3): 13–18. doi: 10.1017/cjn.2016.
249.
proLékaře.cz | 23.1.2022
128
2.7 Annex 7
Danhofer P, Horák O, Fajkusová L, Pavloušková L, Ošlejšková H. Syndrom Dravetové:
těžká myoklonická epilepsie v časném dětství. Neurol praxi 2015; 16(1): 38-42.
Summary:
Dravet syndrome is classified as a rare progressive epileptic encephalopathy. Seizure onset
starts in the first year of life in so far normal developped children. Generalised or lateralized
clonic-tonic seizures, often prolonged and during the febrile infect can be observed. Later on,
we can see other types of seizures accompanied by deterioration of psychomotor development.
In present, the genetic basis of this syndrom with mutations in SCN1A gene can be detected in
70–80 % of patients. 5 % of patients have mutation in PCDH19 gene, rarely the mutations in
GABARG2 and SCN1B genes can be detected. Beneficial effect in the therapy of DS is
observed in valproic acid, clobazame and as add-on therapy stiripentol. Topiramat,
levetiracetam and ketogenic diet can also bring a positive effect in the seizure reduction. Early
diagnostics of DS is very important from the therapeutical point of view.
38
Neurologie pro praxi | 2015; 16(1) | www.neurologiepropraxi.cz
Přehledové články
Úvod
SyndromDravetové, těžkámyoklonickáepilepsie
v časném dětství, se řadí mezi vzácné progresivní
epileptické encefalopatie (Panayiotopoulos,
2010). Klinická manifestace začíná v prvním roce
života u dosud normálně se vyvíjejících dětí.
Recidivující protrahované febrilní konvulzivní
a hemikonvulzivní záchvaty s pozdějším vývojem
jiných typů záchvatů vedou k postupné deterioraci
psychomotorického vývoje a rozvoji mentální
retardace různého stupně (Panayiotopoulos,
2010).Epilepsiejefarmakorezistentní,některéléky
mohou záchvaty zhoršovat, jiné naopak mohou
jejich výskyt redukovat. Především stiripentol je
schopen redukovat výskyt a délku trvání protra-
hovanýchfebrilníchkonvulzivníchzáchvatů,které
jsou spojeny s mírou psychomotorické retardace
(Chiron et Dulac, 2011). Časná diagnostika a vhodná
léčebná strategie je tedy žádoucí. Vzhledem
k dostupnostigenetickédiagnostikyjev současné
doběsyndromologickézařazenípacientůmožno
genetickypotvrdita na tutojednotkubymělobýt
pomýšleno.
Klasifikace
SyndromDravetové– těžkámyoklonickáepi-
lepsiev časnémdětství(SevereMyoclonicEpilepsy
in Infancy – SMEI) byl popsán poprvé v roce 1978
profesorkou Charlotte Dravet ve Francii (Dravet,
1978).DleILAEklasifikaceepileptickýchsyndromů
z roku 1989 se řadí mezi epilepsie a epileptické
syndromy nezařaditelné jako ložiskové či generalizované
(ILAE, 1989). Dle revize této klasifikace
z roku2010se řadímezielektro-klinickésyndromy
časného dětství (Berg et al., 2010).
Etiologie a patofyziologie
V souladu s ILAE revizí epileptických syndromů
2010 se syndrom Dravetové z etiologického
hlediska řadí mezi epilepsie s genetickým podkladem.
70–80% pacientů je nositelem mutace
v genu pro α-1 podjednotku sodíkového kanálu
– SCN1A genu (Marini et al., 2011). Jedná se buď
o truncating mutace, které způsobují předčasný
vznik terminačního kodonu, čímž vedou
k předčasnému ukončení translace (40%) nebo
o missense mutace (40%). Zhruba 5% ženských
pacientů nese mutaci PCDH19 (Dapienne et
al., 2009) a byly identifikovány i vzácné mutace
v genu GABARG2 (Harkin et al., 2002) a SCN1B
(Patino et al., 2009). U 20% pacientů je etiologie
syndromu neznámá. Předpokládá se její genetický
podklad, mutaci se však nepodaří prokázat.
U pacientů s mutacemi v SCN1A genu existuje
jistá fenotypová variabilita, lze mluvit o DSspektru
(Harkin et al., 2007; Marini et al., 2011).
Kromě klasického klinického obrazu syndromu
Dravetové (SMEI) sem lze zařadit i tyto jednotky:
hraniční těžká myoklonická epilepsie v časném
dětství (Borderline severe myoclonic
epilepsy of infancy – SMEB) – zde v klinickém
obraze chybí myoklonické záchvaty nebo
generalizovaná epileptiformní aktivity charakteru
hrot-vlna v EEG (Harkin et al., 2007),
rezistentní dětská epilepsie s  generalizovanými
tonicko-klonickými záchvaty
(Intractable childhood epilepsy with generalised
tonic-clonic seizures – ICEGTC) –
psychomotorický vývoj se zpomaluje především
v druhém roce života a míra psychomotorické
retardace je významná; ve srovná-
ní DS zde chybí jiné typy záchvatů, jako jsou
myoklonické záchvaty, absence a fokální
záchvaty (Fujiwara et al., 2003),
těžká multifokální epilepsie v časném dětství
(Severe infantile multifocal epilepsy – SIMFE)
– zde se objevuje časný výskyt multifokálních
záchvatů, zpomalení psychomotorického
vývoje a multifokální epileptiformní aktivity
v EEG; epilepsie má spíše obraz fokálních
záchvatů, myoklonické záchvaty anebo abSyndrom
Dravetové: těžká myoklonická
epilepsie v časném dětství
MUDr. Pavlína Danhofer1
, MUDr. Ondřej Horák1
, RNDr. Lenka Fajkusová, CSc.2
, Mgr. Jana Pavloušková2
,
doc. MUDr. Hana Ošlejšková, Ph.D.1
1
Klinika dětské neurologie LF MU a FN Brno, Centrum pro epilepsie, Brno
2
Centrum molekulární biologie a genové terapie Interní hematoonkologické kliniky LF MU a FN, Brno
Syndrom Dravetové se řadí mezi vzácné progresivní epileptické encefalopatie. Klinická manifestace začíná v prvním roce života u dosud
normálně se vyvíjejících dětí. Objevují se generalizované nebo lateralizované klonické záchvaty, často protrahované a vázané na febrilní
infekty. Později se objevují i jiné formy záchvatů doprovázené deteriorací psychomotorického vývoje. V současné době je možné genetické
potvrzení mutace v SCN1A genu u 70–80% pacientů. V 5% případů se jedná o mutaci v genu PCDH19, vzácně pak jsou prokázány i mutace
v GABARG2 a SCN1B genu. V terapii se uplatňuje především valproát a klobazam, jako přídatná terapie stiripentol. Dále pak topiramat,
levetiracetam, ketogenní dieta. Časná diagnostika a zařazení tohoto epileptického syndromu jsou z terapeutického hlediska velmi důležité.
Klíčová slova: Dravetové syndrom, myoklonická epilepsie, epilepsie, terapie.
Dravet syndrome: severe myoclonic epilepsy in infancy.
Dravet syndrome is classified as a rare progressive epileptic encephalopathy. Seizure onset starts in the first year of life in so far normal
developped children. Generalised or lateralized clonic-tonic seizures, often prolonged and during the febrile infect can be observed.
Later on, we can see other types of seizures accompanied by deterioration of psychomotor development. In present, the genetic basis
of this syndrom with mutations in SCN1A gene can be detected in 70–80% of patients. 5% of patients have mutation in PCDH19 gene,
rarely the mutations in GABARG2 and SCN1B genes can be detected. Beneficial effect in the therapy of DS is observed in valproic acid,
clobazame and as add-on therapy stiripentol. Topiramat, levetiracetam and ketogenic diet can also bring a positive effect in the seizure
reduction. Early diagnostics of DS is very important from the therapeutical point of view.
Key words: Dravet syndrome, myoclonic epilepsy, epilepsy, therapy.
Neurol. praxi 2015; 16(1): 38–42
39
www.neurologiepropraxi.cz | 2015; 16(1) | Neurologie pro praxi
Přehledové články
sence chybí nebo jsou jen vzácné, nevyskytují
se zde ani generalizované epileptiformní
výboje v EEG (Harkin et al, 2007).
Patofyziologická podstata mutace v genu
pro sodíkový kanál přepokládá snížení excitability
GABAergních interneuronů v neokortexu
a hipokampu (Yu et al., 2006), což má za následek
snížení výbojů v těchto inhibičních interneuronech.
Dojde tak ke zvýšení excitability v neuronální
síti a rozvoji epileptické encefalopatie.
Klinický obraz
Klinická manifestace začíná již v prvním roce
života s vrcholem kolem 5. měsíce u dosud
normálně se vyvíjejících kojenců. Incidence je
udávána 1:30 000 dětí (Panayiotopoulos, 2010),
častěji jsou postiženi chlapci v poměru 2:1.
Typickým klinickým projevem jsou tyto typy
záchvatů: časné infantilní febrilní klonické křeče,
myoklonické záchvaty, atypické absence a fokální
záchvaty s poruchou vědomí. Míra vyjádření
jednotlivých typů záchvatů je různá, některý
z uvedených typů záchvatů být přítomen nemusí.
Častý je výskyt epileptických statů, tonické
záchvaty jsou jen výjimečné. Klinický průběh
lze rozdělit do tří stadií (Panayiotopoulos, 2010):
1) Pre-seizmické stadium
Trvá 2 týdny až 6 měsíců a je charakteristické
pro výskyt febrilních klonických záchvatů, často
unilaterálních, stranově se střídajících. Záchvaty
jsou delšího trvání, často protrahované až ve formě
epileptických statů. U tří čtvrtin pacientů
jsou záchvaty provokované zvýšenou teplotou
(infekce, očkování, horká vana).
2) Seizmické stadium
Objevují se další typy záchvatů uvedené výše
a neurokognitivní deteriorace. Deteriorace
psychomotorického vývoje se objevuje mezi
2.–6. rokem života, je vyjádřena v různé míře,
ale často je těžšího stupně. Dále pak již zůstává
stabilní. V neurologickém nálezu se objevují
nejčastěji ataxie, centrální hypotonie a pozitivní
pyramidové iritační jevy.
3) Post-seizmické stadium
Toto stadium je již stabilizované, záchvaty
mohou odeznívat, zůstává však v závažném
stupni vyjádřena mentální deteriorace.
Za zmínku stojí i klinický obraz pacientů s mutací
v PCDH19 genu. Jedná se o mutaci kódující
protocadherin 19 (Dapienne et al., 2009), jehož
funkce není úplně jasná, ale předpokládá se jeho
zapojení v neuronálních sítích. Klinicky tato
mutace způsobuje epilepsii limitovanou na ženy
s mentální retardací (Epilepsy limited to females
with mental retardation – EFMR) (Dapienne et al.,
2009). Velmi připomíná syndrom Dravetové, ale
začíná zpravidla později, kolem 9,5 měsíce věku,
je zde menší výskyt protrahovaných záchvatů
a záchvatů charakteru epileptických statů. Jen
zřídka se vyskytují myoklonické záchvaty. Důležité
je, že u 45% pacientů je mentální retardace jen
mírného stupně, časté jsou autistické rysy. A jak již
z názvu vyplývá, postižení je limitováno na dívky,
jedná se o X vázanou dědičnost.
Diagnostika
Z diagnostického hlediska je důležitý negativní
nález na MRI mozku, u některých pacientů
se ale vyskytuje lehká mozková nebo mozečková
atrofie. Vyšetření dědičných poruch metabolizmu
je v normě. Zásadní je pak genetické
potvrzení dané mutace.
V EEG je zpočátku normální nález, u 20%
pacientů lze nalézt generalizovanou fotoparo-
xyzmálníodpověď(Panayiotopoulos,2010).V průběhu
roku se stává EEG u 2/3 pacientů hrubě
abnormní. Dochází ke zpomalení a desorganizaci
základní aktivity. Objevují se krátké, asymetrické
výboje vícečetných hrotů/hrotů-pomalých
vln a různé multifokální a fokální abnormity.
Patologie v EEG je často aktivována ve spánku.
Fotoparoxyzmální odpověď lze nalézt u 40%
pacientů(Panayiotopoulos,2010). Iktálnínálezpak
odpovídá jednotlivým typům záchvatů.
Jak bylo uvedeno výše, DS se manifestuje
nejčastěji febrilními záchvaty v prvním roce života
u dosud normálně se vyvíjejících dětí. Z tohoto
hlediska je na počátku obtížné jej odlišit od febrilních
křečí. Vzhledem k tomu, že terapie DS nese
jistá specifika a časná intenzivní léčba je žádoucí,
je nutné na DS myslet co nejdříve a z tohoto důvodu
byl vyvinut screeningový test rizikových
faktorů (Hattori et al., 2008). Pokud je součet rizikových
faktorů v tomto testu ≥ 6 (tabulka 1), je
doporučeno provést analýzu SCN1A genu.
Vyšetření SCN1A genu v ČR lze provést v Brně
a v Praze. V Brně vyšetření provádí Centrum molekulární
biologie a genové terapie Interní hematoonkologické
kliniky LF MU a FN Brno (kontakt:
RNDr. Lenka Fajkusová, CSc., lfajkusova@fnbrno.
cz). V Praze se lze obrátit na Ústav biologie a lékařské
genetiky 2. LF UK a FN Motol (kontakt:
RNDr. Petra Hedvičáková, petra.hedvicakova@
lfmotol.cuni.cz). V případě podezření na DS je
vhodné provést genetickou konzultaci na výše
uvedených pracovištích a po domluvě s genetikem
indikovat vyšetření SCN1A genu.
Prognóza
Prognóza u DS je velmi závažná, mentální
retardace je vyjádřena v různé míře, méně než
10% pacientů si vytvoří a uchová komunikační
schopnosti (Panayiotopoulos, 2010). Závažné
je i vyšší riziko náhlé smrti (SUDEP), a to u 15%
pacientů (Panayiotopoulos, 2010) ve srovnání
s 5% v ostatní populaci pacientů s epilepsií.
DS v dospělosti
Další vývoj ukazuje souhrnně práce prezentována
v roce 2006 na 7. evropském epileptologickém
kongresu profesorkou Ch. Dravet
na souboru 24 dospělých pacientů s DS ve věku
18–46 let (Dravet et al., 2006; Nikanorova et al.,
2009). U všech pacientů byl přítomen mentální
deficit, od lehkého po těžký stupeň. Řeč byla
převážně pomalá, bez větné struktury s přítomnou
dysartrií, u některých pacientů se řečové
funkce nevyvinuly vůbec. V objektivním neurologickém
nálezu byl často přítomen myoklonus,
ataxie, neobratnost v jemné i hrubé motorice,
významné jsou i skeletální deformity (kyfoskolióza,
ploché nohy, kladívkové prsty), pacienti byli
často schopni chůze. V dospělém věku dominují
noční generalizované tonicko-klonické záchvaty,
často stále vázané na febrilie. Jiné typy záchvatů
(myoklonické záchvaty a absence) jsou jen ojedinělé.
Na MRI mozku lze nalézt mozkovou atrofii
(významněji byla popsána u pacientů užívajících
vysoké dávky fenobarbitalu) a hipokampální
sklerózu. Pět pacientů ze souboru (20%) zemřelo
náhlou smrtí – SUDEP.
Terapie (viz tabulka 2 a 3)
Antiepileptika indikována v terapii DS
Terapeutické možnosti u DS jsou omezené.
Jedná se o vysoce farmakorezistentní epilepsii.
Lékem první volby jsou VPA a benzodiazepiny
(CLB, CZP), často je ale jejich efekt nedostatečný
(Chiron, 2011).
Dalším lékem, jenž lze využít v terapii DS
je TPM. Ve dvou retrospektivních studiích byl
Tabulka 1. Screeningový test rizikových faktorů
DS (převzato z Hattori et al., 2008)
rizikový faktor počet
bodů
klinická manifestace epilepsie
v ≤ 7 měsících věku
2
celkový počet záchvatů ≥ 5 3
lateralizované záchvaty – hemikonvulzivní 3
fokální záchvaty 1
myoklonické záchvaty 1
protrahované záchvaty 3
záchvaty indukované horkou vodou 2
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Neurologie pro praxi | 2015; 16(1) | www.neurologiepropraxi.cz
Přehledové články
TPM nasazen jako přídatná terapie u pacientů
s DS. U 56 % pacientů došlo k redukci záchvatů
o více jak 50 % a 16,7 % pacientů bylo bez
záchvatů (Coppola et al., 2002; Nieto-Barrera
et al., 2000).
Další možností v terapii DS může být LEV.
Výsledky studií jsou zde však rozporuplné. Byla
prokázána jeho účinnost v prospektivní add-on
studii, a to především na generalizované tonicko-klonické
záchvaty (64% respondérů) a myoklonické
záchvaty (62% respondérů) (Striano et
al., 2007). Naproti tomu Chhun et al. publikovali
v roce 2011 výsledky prospektivní studie, kde
byl LEV užit jako přídatný lék v terapii DS u 9
pacientů. Jen jeden z nich (11%) byl klasifikován
jako respondér ve 3 a 6 měsících léčby.
Příznivé výsledky ukazují studie s využitím
bromidu v terapii DS. U 32 dětí s DS byl využit
jako přídatná terapie, zde dokonce 81% pacientů
byli označeni jako respondéři po 3 měsících
léčby (47% po jednom roce léčby). Poměrně
vysoké však bylo procento nežádoucích reakcí
(56%), v 16% byla léčba z tohoto důvodu ukončena
(Lotte et al., 2012). Tanabe et al. publikovali
v roce 2008 retrospektivní studii se souborem
99 dětí s DS odpovídajících na bromid jako lék
v prevenci epileptického statu.
Stiripentol (Diacomit), orphan-drug v terapii
DS je schválen jako přídatná terapie k VPA+CLB.
V terapii DS je v Evropě schválen od roku 2007.
STP není strukturálně podobný jinému dosud
užívanému antiepileptiku. V in vitro studiích
byl u něj zjištěn GABAergní efekt. Působí jako
přímý allosterický modulátor GABA-A receptorů
především přes vývojovou alfa-3 podjednotku.
(Fischer, 2009). U lidí inhibuje také cytochromoxidázový
systém P450 v  játrech, což vede
ke zvýšení koncentrací jiných antiepileptik, které
jsou touto cestou metabolizovány. Tato farmakokinetická
interakce je významná především
u CLB, a to přes CYP 2C19 (Giraud et al., 2006).
Dosud byly realizovány 2 randomizované placebem
kontrolované studie, které sledují efekt STP
jako přídatné terapie ke kombinaci VPA+CLB.
Za tímto účelem byla zformována studijní skupina
STICLO (STICLO Study Group) ve Francii
a Itálii. Výsledky francouzské skupiny byly publikovány
Catherine Chiron v roce 2000. Výsledky
italské skupiny publikovány dosud nebyly, jsou
však zahrnuty v metaanalýze (Kassai et al., 2008).
Výsledky ukázaly 71% (Kassai et al., 2008) resp.
67% (Chiron et al, 2000) respondérů ve srovnání
s placebem 5% (Kassai et al., 2008) resp.
9% (Chiron et al., 2000). Japonská studie (Inoue
et al., 2009) ukázala, že STP může být efektivní
i v jiné kombinaci než s VPA+CLB. Přinesl efekt
u 61% pacientů i na terapii CZP, PB, bromidem
a ZNS. STP je schopen především redukovat
délku protrahovaných záchvatů. Vzhledem k tomu,
že právě frekvence a délka těchto záchvatů
v prvním roce života je dávána do souvislosti
s mírou následné psychomotorické retardace,
je vhodné zahájit léčbu STP co nejdříve a snažit
se tak tyto záchvaty co nejvíce redukovat.
(Chiron, 2011; Chiron et Dulac, 2011)
Po nasazení STP dojde ke zvýšení hladin VPA
a CLB. Tato skutečnost je zodpovědná za nejčastější
nežádoucí účinky STP (ospalost, zpomalení
mentálních funkcí, ataxie, diplopie, nechutenství,
snížení hmotnosti, nauzea, bolesti břicha, asymptomatickáneutropenie).Protojepo
jehonasazení
často nutné snížit dávky VPA na 20mg/kg/den
a CLB na 0,5mg/kg/den (Chiron et Dulac, 2011).
Antiepileptika nevhodná v terapii DS
Při výběru nejvhodnějšího antiepileptika je
nutno myslet na existenci léků, které epilepsii
u pacientů s DS mohou zhoršovat. Jedná se především
o LTG, CBZ, VGB a vysoké dávky PB. Těmto
je třeba se v terapii DS vyvarovat. Ve studii 21
pacientů s DS bylo zhoršení záchvatů v souvisTabulka
2. Přehled studií prokazujících efekt farmakoterapie a nefarmakologických možností u DS
lék autor design studie počet pacientů výsledky indikace v terapii DS
topiramat Coppola et al., 2002;
Nieto-Barrera et al., 2000
retrospektivní add-on 18 56% repondérů, 3 bez záchvatů příznivý efekt
bromid Lotte et al., 2000 prospektivní observační
add-on
32 81% respondérů po 3 měsících,
47% po 1 roce
příznivý efekt
Tanabe et al., 2008 retrospektivní 99 41,7% úspěšný v prevenci rozvoje SE příznivý efekt
levetiracetam Striano et al., 2007 prospektivní add-on 28 64% respondérů (GTCS), 62% respondérů
(myoklonické záchvaty)
příznivý efekt
Chhun et al., 2011 prospektivní add-on 9 11%respondérůve3a6měsícíhléčby příznivý efekt
stiripentol
(add-on k VPA+CLB)
STICLO Study Group Francie
a Itálie - Chiron et al.,
2000; Kassai et al., 2008
prospektivní randomizované
placebem kontrolované
studie
příznivý efekt
Francie 41 71% respondérů (vs. 5% placebo),
45% bez záchvatů
Itálie 23 66,7% repondérů (vs. 9 = placebo),
27% bez záchvatů
lamotrigine Guerrini et al., 1998 retrospektivní 21 80% pacientů zhoršeno kontraindikován
karbamazepin Thanh et al., 2002 retrospektivní 46 61% pacientů zhoršeno kontraindikován
vigabatrin Thanh et al., 2002 retrospektivní 46 64% pacientů zhoršeno kontraindikován
rufinamid Mueller et al., 2011 retrospektivní 20 20% respondérů, 30% zhoršeno rozporuplné výsledky –
není indikován
fenobarbital – vysoké
dávky intravenózně
Chipaux et al., 2010 retrospektivní atrofie mozku na MRI a zhoršení
neurologického nálezu
rozporuplné výsledky –
vysoké dávky a i.v. aplikace
kontraindikovány
ketogenní dieta Caraballo et al., 2011 prospektivní observační 24/ hodnoceno
16 pacientů po
24 měsících léčby
12,5% bez záchvatů, u 62,5% pacientů
redukce záchvatů o 75%, u 25%
redukce záchvatů o více než 50%
příznivý efekt
VNS Zamponi et al., 2011 prospektivní observační 8 50% respondérů, zlepšení kontaktu
a komunikačních schopností
příznivý efekt
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www.neurologiepropraxi.cz | 2015; 16(1) | Neurologie pro praxi
Přehledové články
losti s LTG pozorováno u téměř 80% pacientů,
a to jak zhoršení GTCS (40%), tak myoklonických
záchvatů (33%) (Guerrini et al., 1998). Zhoršení záchvatů
bylo pozorováno ve studii se 46 pacienty
u 61% pacientů na CBZ a 64% pacientů na VGB
(Thanhetal.,2002). U pacientů,kteříužívalivysoké
dávky intravenózního PB v terapii konvulzivních
epileptických statů, byla zjištěna souvislost s mozkovou
atrofií a zhoršením neurologického nálezu.
(Chipaux et al., 2010). Mueller et al. publikovali
v roce 2011 studii 20 dětí s DS užívajících RFM.
20% pacientů bylo klasifikováno jako respondéři,
ve 30% došlo ke zhoršení záchvatových projevů.
RFM není doporučen v terapii DS.
Další, nefarmakologické
možnosti v terapii DS
Vhodnou léčebnou volbu představuje také
ketogenní dieta, která má právě u syndromu
Dravetové(i ve srovnánís jinýmiepileptickýmisyn-
dromy)relativněvysokouúčinnost.Caraballo(2011)
publikoval soubor 24 pacientů se syndromem
Dravetové,z nichž16(66,5%)setrvalona ketogenní
dietě déle než 24 měsíců – 2 pacienti (12,5%) byli
zcela bez záchvatů, 10 pacientů (62,5%) dosáhlo
většíněž75%a zbývající4pacienti(25%)většínež
50%redukcizáchvatů.KDbyprotomělabýtzvažovánajižpo
selhání3až 4antiepileptik,a nikolivpo-
nechávánajakoposledníléčebnámožnost.Zatím
je stále preferována klasická KD s poměrem 4:1 s/
bezúvodníhohladovění,zkoušíse i Modifikovaná
Atkinsonovadieta,jejížúčinnostjevšakještě třeba
ověřit na větších studiích.
Příznivé výsledky ukazuje v terapii DS i implantace
vagového stimulátoru. Zamponi et
al. v roce 2011 publikovali výsledky stimulace
bloudivého nervu u 8 pacientů s DS (průměrný
věk 10,28 let, rozmezí 5–25 let). Po jednom roce
stimulace bylo u 4 pacientů (50%) pozorováno
snížení frekvence záchvatů o 50–79%, u jednoho
pacienta méně než 50% a u 3 pacientů nedošlo
ke změně ve frekvenci záchvatů. Poukazují,
že i u pacientů, u kterých nedošlo k výrazné redukci
záchvatů, bylo zjištěno zlepšení v kontaktu
a komunikačních schopnostech.
Závěr
Syndrom Dravetové se řadí mezi prognosticky
závažné epilepsie manifestující se v časném
dětství. Diagnózu DS lze stanovit již na základě
klinického obrazu. Na možnost DS je nutné myslet
v těchto případech:
rozvoj epilepsie u dosud normálně se vyvíjejících
kojenců,
generalizované resp. lateralizované tonicko-klonické
záchvaty,
protrahovanýprůběhzáchvatů,opakovanéSE,
především febrilní záchvaty,
iniciálně normální EEG,
v dalším průběhu rozvoj myoklonických zá-
chvatů,atypickýchabsencí,fokálníchzáchvatů,
rozvoj psychomotorické deteriorace.
Potvrzení klinické diagnózy je možné i geneticky,
zhruba ve 20% případů DS je však genetika
negativní. V terapii se jako lék volby uplatňuje
VPA v kombinaci s CLB, jako přídatná terapie
se užívá STP. STP je schopen redukovat výskyt
protrahovaných generalizovaných tonicko-klonických
záchvatů, které jsou dávány do souvislosti
s rozvojem psychomotorické retardace.
Rychlá syndromologická diagnostika a nasazení
adekvátní terapie je tedy žádoucí.
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Tabulka 3. Terapeutický algoritmus u DS
VPA
VPA + CLB
VPA + CLB + STP
další terapeutické možnosti:
TPM
LEV, ZNS, bromid
ketogenní dieta
CBZ, LTG, VGB, vysoké dávky i.v. PB
Co nejdříve
k dosažení redukce
protrahovaných
záchvatů
Kontraindikovány
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Přehledové články
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Von Stuelpnagel C, Kluger G. Low long-term efficacy and tolerability
of add-on rufinamide in patients with Dravet syndrome.
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del Portal LR. Topiramate in the treatment of severe ymoclonic
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25. Nikanorova M, Genton P, Sabers A. Long-term evolution
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26. Panayiotopoulos CP. A clinical guide to Epileptic syndromes
and their treatment. 2nd ed. Springer Healthcare
Ltd.; 2010: 283–287.
27. Patino GA, Claes LR, Lopez-Santiago LF, Slat EA,
Dondeti RS, Chen C, O´Malley HA, Gray CB, Miyazaki H,
Nukina N, Oyama F, De Jonghe P, Isom LL. A functional null
mutation of SCN1B in a patient with Dravet syndrome. J Neurosci
2009; 29: 10764–10778.
28. Striano P, Coppola G, Pezella M, Ciampa C, Specchio N,
Ragona F, Mancardi MM, Gennaro E, Beccaria F, Capovilla G,
Rasmini P, Besana D, Coppola G, Elia M, Granata T, Vecchi M,
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29. Tanabe T, Awaya Y, Matsuishi T. Management and prophylaxis
against status epilepticus in children with severe
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30. Thanh TN, Chiron C, Dellatolas F. Efficacité et tolerance
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Arch Pediatr 2002; 9: 1120–1127.
31. Yu FH, Mantegazza M, Westenbroek RE, Robbins CA,
Klaume F, Burton KA, Spain WJ, McKnight GS, Scheuer T,
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32. Zamponi N, Passamonti C, Cappanera S, Petrelli C. Clinical
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nerve stimulation. Eur J Paediatr Neurol 2011; 15 (1): 8–14.
Článek doručen redakci: 23. 5. 2013
Článek přijat k publikaci: 11. 8. 2013
MUDr. Pavlína Danhofer
KlinikadětskéneurologieLFMUaFNBrno
Centrum pro epilepsie Brno
Černopolní 9, 613 00 Brno
pavlina.cahova@seznam.cz
134
2.8 Annex 8
Danhofer P, Brunová K, Ošlejšková H. Syndrom Dravetové (těžká infantilní myoklonická
epilepsie): charakteristiky onemocnění v dospělém věku. Neurol praxi 2017; 18 (2):
113-6.
Summary:
Dravet syndrome (DS) is ranked among severe epileptic syndromes with occurence in the first
year of life in normal children. It can be diagnosed according to the clinical course, genetics
can be very helpful by assessing the mutation in SCN1A gene, which is responsible for 70–80
% of cases with DS. Other mutations were identified more rarely (SCN2A, SCN3A, SCN7A,
SCN8A a SCN9A, GABARG2, SCN1B and PCDH19). Dravet syndrom in adulthood is
characterised by cognitive and behavioral changes in patients with various rate of mental
retardation, language deficit and cerebellar symptomatic. The course of epilepsy is milder, the
rate of seizure freedom is still low. Patients often suffer from nocturnal partial complex
seizures with secondary generalisation, often with frontal origin. Present possibilities
of genetic confirmation of DS are very important from the therapeutical point of view.
This allows to improve the prognosis of the disease and the quality of life of patients with DS.
www.neurologiepropraxi.cz  /  Neurol. praxi 2017; 18(2): 113–116  /  NEUROLOGIE PRO PRAXI 113
PŘEHLEDOVÉ ČLÁNKY
Syndrom Dravetové (těžká infantilní myoklonická epilepsie): charakteristiky onemocnění v dospělém věku
Syndrom Dravetové (těžká infantilní
myoklonická epilepsie): charakteristiky
onemocnění v dospělém věku
MUDr. Pavlína Danhofer, MUDr. Katarína Brunová, doc. MUDr. Hana Ošlejšková, Ph.D.
Klinika dětské neurologie LF MU a FN Brno, Centrum pro epilepsie Brno
Dravetové syndrom se řadí mezi závažné epileptické syndromy s rozvojem v kojeneckém věku u dosud zdravých dětí. Diagnózu
lze stanovit na podkladě klinického obrazu, v současné době lze využít i genetického stanovení mutace v SCN1A genu, která
je zodpovědná za 70–80 % případů a diagnózu tak potvrzuje. Vzácněji byly identifikovány u pacientů s DS i mutace v dalších
genech (SCN2A, SCN3A, SCN7A, SCN8A a SCN9A, GABARG2, SCN1B a PCDH19). DS se v dospělém věku vyznačuje především
kognitivními a behaviorálními změnami u pacientů s různou mírou mentální retardace, závažné jsou řečové poruchy a mozečková
symptomatika. Epilepsie je již mírnější, plné kompenzace však dosáhne malé procento pacientů. Dominují noční záchvaty
parciální komplexní se sekundární generalizací často s frontálním počátkem. Současné možnosti genetické diagnostiky DS
jsou velmi důležité z hlediska zahájení časné a správné léčby, která umožní zlepšit prognózu, a tím i kvalitu života pacientů
s tímto onemocněním.
Klíčová slova: dravetové syndrom, myoklonická epilepsie, dospělost, terapie.
Dravet syndrome (severe myoclonic epilepsy of infancy – SMEI): characteristics of adulthood
Dravet syndrome (DS) is ranked among severe epileptic syndromes with occurence in the first year of life in normal children. It
can be diagnosed according to the clinical course, genetics can be very helpful by assessing the mutation in SCN1A gene, which
is responsible for 70–80 % of cases with DS. Other mutations were identified more rarely (SCN2A, SCN3A, SCN7A, SCN8A a SCN9A,
GABARG2, SCN1B and PCDH19). Dravet syndrom in adulthood is characterised by cognitive and behavioral changes in patients
with various rate of mental retardation, language deficit and cerebellar symptomatic. The course of epilepsy is milder, the rate
of seizure freedom is still low. Patients often suffer from nocturnal partial complex seizures with secondary generalisation, often
with frontal origin. Present possibilities of genetic confirmation of DS are very important from the therapeutical point of view.
This allows to improve the prognosis of the disease and the quality of life of patients with DS.
Key words: dravet syndrome, myoclonic epilepsy, adulthood, therapy.
Úvod
Dravetové syndrom (DS) byl poprvé popsán
v roce 1978 profesorkou Charlottou Dravetovou
ve Francii (Dravet, 1978). Dle ILAE klasifikace epileptických
syndromů z roku 1989 se řadí mezi
epilepsie a epileptické syndromy nezařaditelné
jako ložiskové či generalizované (ILAE, 1989).
Dle revize této klasifikace z roku 2010 mezi elektroklinické
syndromy časného dětství (Berg et
al., 2010). V souladu s ILAE revizí epileptických
syndromů 2010 se z etiologického hlediska zařazuje
mezi epilepsie na genetickém podkladě.
Patofyziologické aspekty
a genetika u pacientů s DS
Převážná část pacientů jsou nositelé mutace
v genu pro alfa1 podjednotku sodíkového kanálu
(gen SCN1A), tato mutace se vyskytuje u 70–80 %
pacientů (Marini et al., 2011). Dochází zde ke snížení
excitability GABAergních interneuronů v neokortexu
a hipokampu (Yu et al, 2006), čímž dojde
ke zvýšení excitability v neuronální síti a rozvoji
SCN1A epileptické encefalopatie. Snížení exprese
napětově řízených sodíkových kanálů typu 1.1
v Purkyňovýchbuňkáchvedoucík abnormálnímu
influxu sodíku má za následek ataxii na zkoumaných
zvířecích modelech (Yu et al., 2006).
KORESPONDENČNÍ ADRESA AUTORA: MUDr. Pavlína Danhofer, pavlina.cahova@seznam.cz
Klinika dětské neurologie LF MU a FN Brno, Centrum pro epilepsie Brno
Černopolní 9, 613 00 Brno
Cit. zkr: Neurol. praxi 2017; 18(2): 113–116
Článek přijat redakcí: 1. 8. 2016
Článek přijat k publikaci: 1. 12. 2016
NEUROLOGIE PRO PRAXI  /  Neurol. praxi 2017; 18(2): 113–116  /  www.neurologiepropraxi.cz114
PŘEHLEDOVÉ ČLÁNKY
Syndrom Dravetové (těžká infantilní myoklonická epilepsie): charakteristiky onemocnění v dospělém věku
Mutace v SCN1A genu jsou odpovědné za
rozvoj velmi variabilního fenotypového vyjádření,
tzv. GEFS+ (Generalized epilepsy and febrile
seizures plus – generalizovaná epilepsie s febrilními
záchvaty plus) spektra. Na „benigním“ konci
spektra se vyskytují pacienti se syndromem
GEFS+, na druhém konci spektra se nachází
pacienti s DS. Mutace u pacientů s DS jsou ve
40 % tzv. truncating mutace, které způsobují
předčasný vznik terminačního kodonu, čímž vedou
k předčasnému ukončení translace a nebo
v dalších 40 % případů se jedná o tzv. missense
mutace (mutace měnící smysl – způsobují
změnu jedné báze za druhou). Většina mutací
vzniká de novo, v 5–10 % případů se setkáváme
s familiárním výskytem onemocnění v rámci rodin
s GEFS+ s autosomálně dominantním typem
dědičnosti. V těchto případech je pozorováno, že
pokud je v důsledku missense mutace postižen
transmembránový segment proteinu, vzniká
fenotyp DS. Pokud je postižení mimo tento důležitý
segment, vzniká spíše epilepsie z druhého
konce GEFS+ spektra (Dravet et Guerrini, 2011).
Přítomnost fenotypové variability v rámci jedné
rodiny lze zčásti vysvětlit mozaicizmem v SCN1A
genu (Guerrini, 2012). Příčina je však pravděpodobně
komplexní, uplatňuje se jak genetické
pozadí, tzv. modifikující geny, tak vliv prostředí.
SCN1A negativní pacienti mohou mít mutaci
přesahujícíuloženíSCN1Agenu.Z tohotohlediska
jsou významné sousedící geny pro jiné části alfa
podjednotky napěťově řízeného sodíkového kanálu
jako SCN2A, SCN3A, SCN7A, SCN8A a SCN9A.
Tím dochází ke zvýšení variability fenotypového
vyjádření onemocnění v rámci GEFS+ spektra
(Marini et al., 2011). Vzácně byly identifikovány
u pacientů s DS i mutace v genu GABARG2
(Harkin et al., 2002) a SCN1B (Patino et al., 2009).
Zhruba 5 % pacientů s fenotypovým vyjádřením
DS, i když s určitými odlišnostmi, nese
mutaci v genu PCDH19 s X-vázanou dědičností
(Depienne et al., 2009). Postižené jsou heterozygotní
ženy, hemizygotní muži jsou zdraví. Jedná
se o gen kódující protocadherin 19, jehož funkce
nebyla dosud plně objasněna, ale předpokládá
se jeho zapojení v neuronálních sítích. Mutace
způsobuje Epilepsii limitovanou na ženy s mentální
retardací (Epilepsy limited to females with
mental retardation – EFMR). Charakteristickým
rysem je zde pozdější začátek onemocnění,
menší výskyt epileptických statů a jen zřídka se
objevují myoklonické záchvaty. U 45 % pacientů
je mentální retardace jen mírného stupně, časté
jsou autistické rysy.
V současné době je v České republice
genetické vyšetření možné provést v Brně
a v Praze. Jedná se o vyšetření celého panelu
mutací u pacientů s fenotypovým vyjádřením
GEFS+ spektra a DS. V Brně vyšetření provádí
Centrum molekulární biologie a genové terapie
Interní hematoonkologické kliniky LF MU
a FN Brno (kontakt: RNDr. Lenka Fajkusová, CSc.,
lfajkusova@fnbrno.cz). V Praze se lze obrátit
na Ústav biologie a lékařské genetiky 2. LF UK
a FN Motol (kontakt: RNDr. Petra Hedvičáková,
petra.hedvicakova@lfmotol.cuni.cz). V případě
podezření na toto onemocnění je vhodné provést
genetickou konzultaci na výše uvedených
pracovištích.
Pro zájemce o podrobnější informace
o genetice DS autoři odkazují na připravovaný
článek „Genetické aspekty Dravetové
syndromu“, který bude v brzké době publikován
v České neurologii a neurochirurgii
kolektivem autorů z Kliniky dětské neurologie
LF MU a FN Brno.
Klinický obraz a terapie DS
v dětském věku
V klinickém obraze dochází k rozvoji epileptických
záchvatů v kojeneckém věku s vrcholem
kolem 5. měsíce u dosud normálně se
vyvíjejících dětí. Incidence je dle nejnovějších
údajů udávána 1:22 000 (výskyt DS v dánské populaci
– Bayat et al., 2015), častěji jsou postiženi
chlapci v poměru 2:1 (Panayiotopoulos, 2002).
Objevují se tyto typy záchvatů: generalizované
tonicko-klonické záchvaty (resp. často lateralizované
stranově střídající), myoklonické záchvaty,
atypické absence a fokální záchvaty s poruchou
vědomí. Velmi častý je výskyt status epilepticus
(SE), především v počátečním období, a to převážně
u febrilních záchvatů. V klinickém obraze
existuje určitá variabilita, mluvíme o DS-spektru,
kam se řadí Borderline severe myoclonic epilepsy
in infancy (SMEB), kde se nesetkáváme
s myoklonickými záchvaty, Intractable child
epilepsy with generalised tonic-clonic seizures
(ICEGTC), kde se vyskytují převážně jen GTCS
a Severe infantile multifocal epilepsy (SIMFE),
kde dominují multifokální záchvaty.
V terapii DS jsou lékem volby valproát a benzodiazepiny
(Chiron, 2011), především klobazam.
Při jejich nedostatečném efektu je indikován
stiripentol. Stiripentol (Diacomit) je řazen mezi
orphan-drug v terapii DS a je schválen jako přídatná
terapie k valproátu+klobazamu. V terapii
DS je v Evropě schválen od roku 2007. Dosud
byly realizovány dvě randomizované placebem
kontrolované studie, které sledují efekt stiripentolu
jako přídatné terapie ke kombinaci VPA+CLB.
Výsledky ukázaly 71 % (Kassai et al., 2008) resp.
67 % (Chiron et al., 2000) respondérů ve srovnání
s placebem. Zásadním poznatkem je, že stiripentol
má nejvyšší efekt především na generalizovaTab.
1.  Charakteristika pacientů s DS v dětském věku a dospělosti
DS v dětském věku DS v dospělém věku
Typy záchvatů iniciálně: febrilní/afebrilní SE hemiklonický nebo generalizovaný generalizované tonicko-klonické záchvaty resp. parciální komplexní
záchvaty s nebo bez sekundární generalizace, často s frontálním počátkem
dále (1–4 roky): myoklonické záchvaty, atypické absence
a fokální záchvaty
vazba na noční spánek
Provokace záchvatů vysoká teplota, horká vana, infekce, očkování, emoce provokace vysokou teplotou již mírnější, ale trvá
EEG zpočátku normální nález, u 20  % pacientů fotoparoxyzmální
odpověď; v dalším roce zpomalení a desorganizace základní
aktivity, výboje vícečetných hrotů/hrotů – pomalých vln a různé
multifokální a fokální abnormity
zpomalení a desorganizace základní aktivity, multifokální heterogenní
abnormity, výrazná redukce až vymizení fotoparoxyzmální odpovědi
MRI normální nebo lehká mozková nebo mozečková atrofie normální nebo lehká mozková nebo mozečková atrofie
Objektivní
neurologický nález
iniciálně normální mozečková symptomatika – ataxie, dysartrie, intenční tremor;
pyramidová symptomatika nebo extrapyramidové jevy, ortopedické
obtíže – skolióza, kyfoskolióza, plochonoží nebo kladívkovité prsty
Neuropsychologické
vyšetření
iniciálně normální PMV, od 2. roku zpomalení či zástava vývoje lehká až těžká mentální retardace, behaviorální a kognitivní poruchy,
řečové dysfunkce, autistické rysy
www.neurologiepropraxi.cz   /  Neurol. praxi 2017; 18(2): 113–116  /  NEUROLOGIE PRO PRAXI 115
PŘEHLEDOVÉ ČLÁNKY
Syndrom Dravetové (těžká infantilní myoklonická epilepsie): charakteristiky onemocnění v dospělém věku
né tonicko-klonické záchvaty, které jsou v časném
dětství zodpovědné za dramatický obraz této
epileptické encefalopatie a nepřímo tak vedou
k rozvoji mentální retardace u pacientů s DS, nasadit
stiripentol je vhodné tedy co nejdříve.
Další terapeutickou možností jsou topiramat
a levetiracetam (účinný především na myoklonické
záchvaty), které lze využít jako přídatné
léky. Z patofyziologie DS vyplývá, že inhibitory
napětově řízených kanálů (fenytoin, lamotrigine,
karbamazepin a vysoké dávky fenobarbitalu)
mohou záchvaty zhoršovat a je žádoucí se jich
v léčbě vyvarovat. V neposlední řadě je nutno
zmínit i ketogenní dietu, která má v terapii DS
relativně vysokou účinnost ve srovnání s jinými
epileptickými encefalopatiemi (Caraballo, 2011).
Příznivé výsledky ukazuje v terapii DS i implantace
vagového stimulátoru (Zamponi et al., 2011).
DS v dospělém věku
Existuje jen limitovaný počet studií, které se
zabývají klinickým obrazem a dalšími charakteristikami
DS u dospělých pacientů. Je to dáno
především tím, že tento syndrom je řazen mezi
vzácná onemocnění a pacientů tedy obecně
není mnoho. Dalším důvodem může být to, že
je znám teprve z konce 70. let minulého století,
možnosti genetické diagnostiky DS jsou ještě
mnohem mladší a u řady dospělých pacientů
je tedy stále poddiagnostikován a jsou vedeni
často jako pacienti s farmakorezistentní epilepsií
a mentální retardací, blíže nezařazení.
Níže jsou shrnuty výsledky studií, které se
zabývají popisem klinického obrazu u pacientů
s DS v dospělém věku (tab. 1). V souhrnu se autoři
těchto studií shodují v tom, že záchvaty a především
SE v raném dětském věku a dále frekventní
epileptiformní výboje v EEG jsou považovány
za hlavní příčinu kognitivních a behaviorálních
změn u pacientů s DS v dětském a dospělém
věku (Dravet et al., 2005). Dnes víme mnohem
více o patofyziologii tohoto onemocnění a pacienty
jsme schopni časně diagnostikovat. Jak
záchvaty, tak EEG abnormity jsou potencionálně
léčitelné a jejich kontrola může zlepšit outcome
u pacientů s DS (Scheffer et al., 2009).
Epilepsie u dospělých
pacientů s DS
Epileptickézáchvatyjsouu dospělýchpacientů
s DS méně časté a mírnější. Plné kompenzace
však dosahuje malé procento pacientů – 16,1 %
(Akiyamaetal.,2010),8,3 %(Gentonetal.,2011),0 %
(Jansen et al., 2006). Míra kompenzace záchvatů
souvisí nepřímou úměrou s četností a závažností
epileptických statů v dětství a s četností výskytu
epileptiformních grafoelementů v EEG během
dalšího vývoje (Akiyama et al., 2010). Citlivost na
zvýšenou teplotu přetrvává i v dospělém věku,
ale její dopad na frekvenci a závažnost epileptických
záchvatů je menší (Genton et al., 2011).
V klinickém obraze dominují generalizované
konvulzivní záchvaty a často jsou jediným typem
záchvatů u těchto pacientů (Dravet et al., 2009;
Jansen et al., 2006). 35 pacientů ze 40 (87,5 %)
anamnesticky popisovali generalizované konvulzivní
záchvaty, jejich typické záchvaty však byly
zachyceny na iktálním EEG jako parciální záchvaty
často s frontálním počátkem a s nebo bez sekundární
generalizace (Akiyama et al., 2010). Typický
je výskyt záchvatů s vazbou na noční spánek
(Genton et al., 2011; Dravet et al., 2009). Další typy
záchvatů, jako jsou myoklonické záchvaty, atypické
absence nebo komplexní parciální záchvaty,
jsou v dospělém věku málo časté (Genton et al.,
2011). Pokud se vyskytují, tak spíše v nakupení
před rozvojem GTCS (Dravet et al., 2009). Se SE
se u dospělých pacientů setkáváme méně často.
Akiyama et al. ukazují dramatický pokles výskytu
SE, kdy po 10. roce již žádný zaznamenán nebyl
(Akiyama et al., 2010). V dospělém věku se však
vyskytovat mohou, jak je patrné ze studie 24 pacientů
s DS, kde byl SE zaznamenán u 3 z nich,
a to ve věku 24, 26 a 28 let (Genton et al., 2011).
Pacienti, kteří trpí myoklonickými záchvaty nebo
atypickými absencemi, mohou mít nonkonvulzivní
SE v rámci nakupení těchto záchvatů.
Změny v EEG se s věkem také mění, stále
dominují ale výboje multifokální a jsou velmi
heterogenní, jak v interiktálním, tak iktálním obraze.
Fotosenzitivita již v dospělém věku není tak
výrazná, má tendenci vymizet před dosažením
20. roku (Genton et al., 2011).
Objektivní neurologický nález
u dospělých pacientů s DS
Motorické abnormity v neurologickém nálezu
jsou časté. Nejčastěji se vyskytuje mozečková
symptomatika jako ataxie, dysartrie a intenční
tremor, tento obraz je patrný u 30 % pacientů
(Genton et al., 2011) resp. 28,5 % pacientů (Jansen
et al., 2006). Méně často lze nalézt pyramidovou
symptomatiku nebo extrapyramidové jevy (16 %
resp. 12,5 % – Genton et al., 2011). U části pacientů
s DS se v druhé dekádě života začíná rozvíjet
progresivní porucha chůze – tzv. „crouch gait“
(crouch = krčit se). Typicky zde nacházíme ortopedické
abnormity, jako je zvýšená anteverze
krčku stehenních kostí, vnejší torze holenních
kostí a pedes valgi. Tyto změny mají výrazný negativní
dopad na schopnost samostatné chůze
u pacientů s DS (Rodda et al., 2012). Velmi časté
jsou další ortopedické obtíže jako skolióza, kyfoskolióza,
plochonoží nebo kladívkovité prsty.
Začínají se rozvíjet v dětském věku a zhoršují
se v adolescenci i přes intenzivní fyzioterapii
(Genton et al., 2011).
Neuropsychologický profil
u dospělých pacientů s DS
Obecně lze konstatovat, že velká míra pacientů
prokazuje deficit v jedné nebo několika sférách
neuropsychologického vyšetření. Mentální
retardace se vyskytuje od lehké po těžkou formu
(Genton et al., 2011). V australské studii byla prokázána
lehká mentální retardace u 5 z 11 pacientů
(45,5 %) a těžká u 6 z 11 pacientů (54,5 %)
(Jansen et al., 2006). Berkvens et al. prokazují
těžkou nebo hlubokou mentální retardaci u 9
pacientů ze 13 (69,2 %) (Berkvens et al., 2015).
Závažný je deficit v oblasti řečových funkcí.
Ve studii 21 dospělých pacientů s DS byl závažný
řečový deficit prokázán u 14 z nich (66,6 %),
z toho 3 (14,3 %) nemluvili vůbec a slabé komunikační
schopnosti mělo 7 (33,3 %) z nich (Genton
et al., 2011). V další studii s 31 dospělými pacienty
byl závažný řečový deficit prokázán u 30
(96,7 %) pacientů. Sedm (22,6 %) jich nemluvilo
vůbec, 23 (74,2%) z nich mělo slabé komunikační
schopnosti a jen jeden (3,3 %) pacient měl jen
lehký řečový deficit, u tohoto však dominovaly
psychotické projevy (Akiyama et al., 2010).
Zatímco v dětském věku jsou u pacientů s DS
významně zastoupeny behaviorální poruchy, jako
je hyperaktivita, porucha pozornosti, impulzivita,
opoziční chování nebo emoční labilita, v dospělém
věku již tyto projevy tak výrazné nejsou
(Berkvens et al., 2015). Behaviorální poruchy lze
vystopovat ještě v adolescentním věku, jak prokazuje
studie u 20 adolescentů s DS, kde u všech
tyto problémy diagnostikovány byly (Olivieri et al.,
2016). Poruchy autistického spektra byly popsány
u osmidospělýchpacientůz 13(61,5 %),automutilační
tendence u čtyř pacientů ze 13 (30,8 %) a behaviorální
poruchy u žádného z nich (Berkvens
et al., 2015). Lze říci, že v dospělém věku dominují
NEUROLOGIE PRO PRAXI  /  Neurol. praxi 2017; 18(2): 113–116  /  www.neurologiepropraxi.cz116
PŘEHLEDOVÉ ČLÁNKY
Syndrom Dravetové (těžká infantilní myoklonická epilepsie): charakteristiky onemocnění v dospělém věku
poruchy autistického spektra, které však jsou také
patrny již v dětském věku. Zajímavým rysem
je, že pacienti s DS často prokazují nedostatek
sociální odtažitosti a bývají nadměrně familiární
k cizím osobám, jejich socializační schopnosti
jsou výrazně lépe vyvinuty, než jak jsou popsány
u poruch autistického spektra. Často tak ani jako
autisté klasifikováni nejsou (Berkvens et al., 2015).
Závislost na okolí je konstantním rysem
u dospělých pacientů, a to v 85,7–96,7% případů
(Genton et al., 2011; Jansen et al., 2006; Akiyama
et al., 2010).
Terapie dospělých pacientů s DS
V současné době je jen málo studií, které se
zabývají terapií DS v dospělém věku. Uplatňují
se obecné terapeutické principy léčby jednotlivých
typů záchvatů podle toho, které v klinickém
obraze dominují a využívají se obdobná
terapeutická schémata identická pro léčbu DS
v dětském věku. Lékem volby jsou tedy valproát
a benzodiazepiny, pokud je jejich efekt nedostatečný,
lze přidat stiripentol, případně topiramát,
levetiracetam nebo zonisamid. Je třeba se vyvarovat
blokátorů napěťově řízených kanálů, jak bylo
uvedeno v části o terapii DS v dětském věku.
Ohledně efektu stiripentolu v dospělém
věku byla publikována studie 13 dospělých pacientů
s DS. V průběhu 36měsíčního sledovacího
období byla zaznamenána redukce záchvatů
o více než 50 % u tří pacientů (23,1 %), zhoršení
záchvatů u tří pacientů (23,1 %) a beze změny
zůstali tři pacienti (23,1 %). Nežádoucí reakce
referovalo sedm pacientů (53,8 %), nejčastěji se
jednalo o nechutenství, ztrátu hmotnosti a únavu.
Tři z těchto pacientů STP pro nežádoucí reakce
vysadili. Studie ukazuje nižší účinnost STP
a obdobnou snášenlivost ve srovnání s dětskými
pacienty (Balestrini et al., 2016).
Mortalita u dospělých
pacientů s DS
DS je asociován se zvýšenou mírou úmrtnosti
a úmrtí se může vyskytnout v jakémkoliv
věku, častěji však během dětství (Genton et al.,
2011). Průměrný věk úmrtí pacientů je 11 let
(15,9 % pacientů ze souboru) (Dravet et al., 2009)
resp. 65 měsíců (14,3 % pacientů ze souboru)
(Oguni et al., 2001). Nejčastější příčinou úmrtí je
SE u malých dětí, u starších dětí a dospělých pacientů
pak SUDEP (Sudden Unexpected Death in
EPilepsy – Náhlé neočekávané úmrtí u pacientů
s epilepsií).
Závěr
Pro diagnostiku DS v dospělém věku je zásadní
především důkladná anamnéza z období
manifestace záchvatů, klinický obraz těchto
pacientů v dospělém věku je sice popsán,
ale nevykazuje typické rysy, na základě kterých
bychom pacienty mohli diagnostikovat.
Definitivní diagnóza je však pro pacienty důležitá,
ukončí často náročné vyšetřování a umožní
se zaměřit na specifika léčby a zlepšit tak kvalitu
života pacientů s tímto závažným onemoc-
něním.
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139
2.9 Annex 9
Danhofer P, Zech M, Bálintová Z, Baláž M, Jech R, Ošlejšková H. Brittle Biballism-Dystonia
in a Pediatric Patient with GNAO1 Mutation Managed Using Pallidal Deep Brain
Stimulation. Mov Disord Clin Pract. 2021;8(1):153–5. doi: 10.1002/mdc3.13118.
Summary:
In this work, the author presents a case report of a patient with a pathogenic variant in the
GNAO1 gene, in which the movement disorder dominated in the clinical manifestation. The
patient was kept under a diagnosis of dyskinetic cerebral palsy with epilepsy for a long time,
until the cause of his condition was clarified by genetic examination. During the respiratory
infection, there was a significant deterioration of the clinical condition up to the image of brittle
dystonia. The patient was implanted with DBS with excellent effect. The author discusses the
possible effect of DBS in these patients.
Brittle Biballism-Dystonia in a Pediatric
Patient with GNAO1 Mutation Managed
Using Pallidal Deep Brain Stimulation
Pavlína Danhofer, PhD,1,
* Michael Zech, PhD,2,3
Zdenka Bálintová,1
Marek Baláž, PhD,4
Robert Jech, PhD,5
and Hana Ošlejšková, PhD1
Early onset movement disorders are a clinically and genetically
heterogenous group of disorders. Mutations in GNAO1 were
first reported in patients with Ohtahara syndrome and early
infantile epileptic encephalopathy 17 (EIEE17).1,2
GNAO1 (guanine
nucleotide-binding protein 1) encodes the α-subunit of a
heterotrimeric guanine nucleotide-binding protein (Gαo) which
is the most abundant membrane protein in the mammalian central
nervous system.3
The early recognition of worsening extrapyramidal
symptoms may facilitate intervention or prevent
progression to status dystonicus.4
A dystonia severity and action
plan (DSAP, grades 1–5) can be very useful in assessing the threat
of status dystonicus.4
We report a case of a 12-year-old boy with GNAO1 mutation
who presented with severe biballistic symptomatology with
dystonic features (DSAP 3) and required emergency deep brain
stimulation (DBS) to avoid life-threatening symptoms. The boy
was first examined at the Department of Pediatric Neurology at
the age of 2 years. The clinical course is summarized in Table 1.
At the age of 12 years, the patient deteriorated after respiratory
infection and worsening of extrapyramidal symptomatology with
dominating biballism and dystonic features developed with the
threat of status dystonicus (Video S1). He experienced almost
continuous generalized ballistic movements combined with dystonic
postures, which were very painful and limited his normal
activity, feeding, or sleep (DSAP 3). The patient was hospitalized
in the ICU with the necessity of muscle relaxation. The course
of treatment is summarized in Table 1. Taking into consideration
the seriousness of this condition, DBS of bilateral globus pallidus
internus (DBS-GPi) was performed. The sedative medication
was gradually tapered off over the next 14 days and his condition
rapidly improved to DSAP 1 (Video S2). Half a year after DBS,
motor functions returned to the condition before the brittle
biballism-dystonia developed. Whole exome sequencing (WES)
identified a heterozygous missense variant in GNAO1 gene
c.625 C > T; p. (Arg209Cys) previously described in the study
by Koy et al. (2018)5
and considered as pathogenic. The mutation
was absent in the patient’s parents and considered as
de novo.
When pre-status dystonicus persists despite orally active antidystonia
drugs and unsuccessful weaning from sedative or anesthetic
agents, intrathecal baclofen or deep brain stimulation
should be considered.4
Several case reports and one small series
have been published in which DBS was effective in patients with
a GNAO1 mutation.3,5
DBS may be effective due to its general
effects in modulating aberrant synchronization in the basal
ganglia-thalamo-cortical loops. The effect of DBS in our patient
was very fast, with the improvement to DSAP 1 in 14 days. The
patient tolerated the stimulation very well; however, only
3 months after initiation he developed generalized epileptic seizure.
It is uncertain whether this occurred as a result of DBS
(potentially triggered by tapering off the medication during the
switching on and adjusting the DBS parameters) or was merely a
coincidence in a patient with a history of epilepsy. In any case,
stimulation should be increased cautiously and mildly in patients
with epilepsy. After the introduction of levetiracetam, no further
seizures occurred.
In patients with GNAO1 mutation and severe dystonia, GPiDBS
could be a treatment option with life-saving potential.
Acknowledgments
Many thanks to Ass. Prof. Jan Chrastina, Ph.D. (Faculty of Medicine
of Masaryk University Brno, University Hospital of
St. Anne, Czech Republic) for DBS implantation. Thanks to
Anne Johnson for grammatical assistance.
1
Department of Child Neurology, Faculty of Medicine of Masaryk University Brno, University Hospital Brno, Brno, Czech Republic; 2
Institute of Neurogenomics,
Helmholtz Zentrum München, Munich, Germany; 3
Institut für Humangenetik, Technische Universität München, Munich, Germany; 4
1st
Department of Neurology,
Faculty of Medicine of Masaryk University Brno, University Hospital of St. Anne, Brno, Czech Republic; 5
Department of Neurology, Charles University, 1st Faculty of
Medicine and General, University Hospital in Prague, Prague, Czech Republic
*Correspondence to: Dr. Pavlína Danhofer, Department of Pediatric Neurology, Faculty of Medicine of Masaryk University Brno, University Hospital
Brno, Cˇernopolní 9, 613 00 Brno, Czech Republic; E-mail: pavlina.cahova@seznam.cz
Keywords: dystonia, biballism, epilepsy, neurosurgery, next-generation sequencing.
Received 13 July 2020; revised 20 October 2020; accepted 27 October 2020.
Published online 28 December 2020 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mdc3.13118
MOVEMENT DISORDERS CLINICAL PRACTICE 2021; 8(1): 153–155. doi: 10.1002/mdc3.13118
153
© 2020 International Parkinson and Movement Disorder Society
LETTERS: GENOTYPE AND PHENOTYPE
CLINICAL PRACTICE
Author Roles
1. Research Project: A. Conception, B. Organization,
C. Execution;
2. Statistical Analysis: A. Design, B. Execution, C. Review
and Critique;
3. Manuscript Preparation: A. Writing of the first draft,
B. Review and Critique;
PD: 1A, 1B, 1C, 2A, 2B, 3A
MZ: 1C, 2C, 3B
ZB: 1A, 2B, 2C, 3B
MB: 1C, 2B, 3B
RJ: 1C, 2C, 3B
HO: 1C, 2C, 3B
Disclosures
Ethical Compliance Statement: The study was approved by
the Ethical Committee of the institutions concerned and both
parents and the patient agreed with the publication after receiving
all information relevant to the study. We confirm that we have
read the Journal’s position on issues involved in ethical publication
and affirm that this work is consistent with those guidelines.
TABLE 1 Clinical course and therapy
Age Clinical characteristics
Neurological and
psychological
examination Therapy Effect Note
3 months episodes of apnoe and
cyanosis - gastroesophageal
reflux
normal none spontaneous
remission
2 years epilepsy - generalised
tonic–clonic seizures
(GTCSs)
valproic acid seizure
freedom
discontinuation at the
age of 10
severe central
hypotonia,
developmental
delay, speech delay
physiotherapy,
speech therapy
3 years generalised
spasticity with
persistent axial
hypotonia, dystonic
postures,
developmental delay,
speech delay
physiotherapy,
speech therapy
5 years severe dystonic storm
after thiethylperazin
(DSAP 4)
i.v. continuous
clonazepam
partial with
sedation
i.v. continuous
midazolam
partial with
sedation
baclofen p.o. good effect
12 years brittle biballism-dystonia
(DSAP 3) after respiratory
infection
i.v. continuous
clonazepam
partial with
sedation
i.v. continuous
midazolam
partial with
sedation
i.v. pulses of
phenobarbital
partial with
sedation
i.v. pulses of
propofol
very good
effect
used with precaution
for the risk of
propofol infusion
syndrome
tetrabenazine p.o. worsened
i.v. tiapride no effect
i.v. valproic acid no effect
gabapentin p.o. no effect
GPi-DBSa
very good
effect
initial stimulation:
0.5 V/130 Hz/90usec
actual
parametres:
3.2 V/130 Hz/120usec
12 years -
3 months
after DBS
GTCS levetiracetam seizure
freedom
a
GPi-DBS electrodes position: contacts 0 and 9, with distal contacts of electrodes on the right side: 1.6 mm anteriorly, 3.1 mm caudally and 18.1 mm
laterally from mid-commisural point. On the left side: 2.6 mm anteriorly, 3.7 mm caudally and 19.8 mm laterally from mid-commisural point.
154 MOVEMENT DISORDERS CLINICAL PRACTICE 2021; 8(1): 153–155. doi: 10.1002/mdc3.13118
LETTERS: GENOTYPE AND PHENOTYPE THE EFFECT OF DBS IN A PATIENT WITH GNAO1 MUTATION
Funding Sources and Conflict of Interest: PD: This work
was supported by funds from the Faculty of Medicine of the
University of Masaryk to junior researcher Pavlína Danhofer,
M.D., Ph.D. (2744 - IRP 2019-ROZV/23/LF3/19). MZ was
supported by an internal research program at Helmholtz
Zentrum München, Munich, Germany (Physician Scientists for
Groundbreaking Projects). RJ: This project was also supported
by the Czech Ministry of Education under the frame of EJP
RD, the European Joint Programme on Rare Diseases (EJP RD
COFUND-EJP N
825,575) and by the Czech Ministry of
Health - AZV grant NV19-04-00233. None of the authors has
any conflict of interest to disclose. We confirm that we have read
the Journal’s position on issues involved in ethical publication
and affirm that this report is consistent with those guidelines.
Other authors declare that there are no additional disclosures to
report.
Financial Disclosures for the previous 12 months: All
authors declare that there are no disclosures to report. ■
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encephalopathy. Am J Hum Genet 2013;93:496–505.
2. Ananth AL, Robichaux-Viehoever A, Kim YM, et al. Clinical course of
six children with GNAO1 mutations causing severe and distinctive movement
disorder. Pediatr Neurol 2016;59:81–84.
3. Waak M, Mohammad SS, Coman D, et al. GNAO1-related movement
disorder with life-threatening exacerbations: movement phenomenology
and response to DBS. J Neurol Neurosurg Psychiatry 2018;89:221–222.
4. Allen NM, Lin J-P, Lynch T, King MD. Status dystonicus: a practice
guide. Dev Med Child Neurol 2014;56:105–112.
5. Koy A, Cirak S, Gonzalez V, et al. Deep brain stimulation is effective in
pediatric patients with GNAO1 associated severe hyperkinesia. J Neurol Sci
2018;391:31–39.
Video 2. Clinical condition of the patient 2 months after DBS
implantation. He is able to climb independently on all fours. Motor
skills and coordination of movements are improved.
Video 1. Clinical condition before DBS implantation. Deterioration
into the picture of brittle biballism-dystonia and impending status
dystonicus. Almost continuous biballistic movements with dystonic
postures that impede normal movement, they are painful and
exhaust the patient.
MOVEMENT DISORDERS CLINICAL PRACTICE 2021; 8(1): 153–155. doi: 10.1002/mdc3.13118 155
DANHOFER P. ET AL. LETTERS: GENOTYPE AND PHENOTYPE
143
2.10 Annex 10:
Česká K, Aulická Š, Horák D, Danhofer P, Říha P, Mareček R, Šenkyřík J, Rektor I, Brázdil
M, Ošlejšková H. Autosomal dominant temporal lobe epilepsy associated with
heterozygous reelin mutation: 3 T brain MRI study with advanced neuroimaging
methods. Epilepsy Behav Case Reports 2019; 11: 39-42. doi: 10.1016/j.ebcr.2018.10.003
This publication provides more information on the genetics of epilepsy. Authors present a
patient with MR-negative focal temporal lobe epilepsy. Only genetic examination using the
NGS panel clarified the etiology. Genetics plays an important role in the diagnosis of epilepsy
and may end further investigations within the epileptosurgery program.
Summary:
Purpose: Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy
syndrome characterized by focal seizures with dominant auditory symptomatology. We present
a case report of an 18-year-old patient with acute onset of seizures associated with epilepsy.
Based on the clinical course of the disease and the results of the investigation, the diagnosis of
ADLTE with a proven mutation in the RELN gene, which is considered causative, was
subsequently confirmed. The aim of this study was to use 3 Tesla (3 T) magnetic resonance
imaging (MRI) and advanced neuroimaging methods in a patient with a confirmed diagnosis of
ADTLE.
Methods: 3 T MRI brain scan and advanced neuroimaging methods were used in the standard
protocols to analyzse voxel-based MRI, cortical thickness, and functional connectivity.
Results: Morphometric MRI analysis (blurred grey-white matter junctions, voxel-based
morphometry, and cortical thickness analysis) did not provide any informative results. The
functional connectivity analysis revealed higher local synchrony in the patient in the left
temporal (middle temporal gyrus), left frontal (supplementary motor area, superior frontal
gyrus), and left parietal (gyrus angularis, gyrus supramarginalis) regions and the cingulate
(middle cingulate gyrus) as compared to healthy controls.
Conclusions: Evidence of multiple areas of functional connectivity supports the theory of
epileptogenic networks in ADTLE. Further studies are needed to elucidate this theory.
144
The following two papers are important mainly in terms of epilepsy and comorbidities. In her
dissertation, the author dealt with the incidence of ADHD in patients with Rolandic epilepsy
and prepared a review on co-occurence of ADHD and epilepsy (Annex 12). As already
mentioned in the text, the new ILAE 2017 Classification of epilepsies takes this aspect into
account in children with „benign“ focal epilepsies. The term „benign“ is replaced by the term
„self-limited“.
Autistic symptoms are often observed in children with epilepsy, and Autism Spectrum Disorder
(ASD) is a significant comorbidity associated with epilepsy in children. The author prepared a
review on this topic (Annex 12).
Case Report
Autosomal dominant temporal lobe epilepsy associated with
heterozygous reelin mutation: 3 T brain MRI study with advanced
neuroimaging methods
Katarína Česká a,1
, Štefánia Aulická a,
⁎,1
, Ondřej Horák a
, Pavlína Danhofer a
, Pavel Říha b
, Radek Mareček b
,
Jan Šenkyřík c
, Ivan Rektor b,d
, Milan Brázdil b,d
, Hana Ošlejšková a
a
Brno Epilepsy Centre, Department of Paediatric Neurology, University Hospital, Masaryk University, Brno, Czech Republic
b
Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
c
Department of Paediatric Radiology, University Hospital Masaryk University Brno, Czech Republic
d
Brno Epilepsy Centre, First Department of Neurology, St. Anne's University Hospital, Masaryk University, Brno, Czech Republic
a b s t r a c ta r t i c l e i n f o
Article history:
Received 25 August 2018
Received in revised form 24 October 2018
Accepted 25 October 2018
Available online 1 November 2018
Purpose: Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy syndrome characterized
by focal seizures with dominant auditory symptomatology. We present a case report of an 18-year-old patient with
acute onset of seizures associated with epilepsy. Based on the clinical course of the disease and the results of the
investigation, the diagnosis of ADLTE with a proven mutation in the RELN gene, which is considered causative,
was subsequently confirmed. The aim of this study was to use 3 Tesla (3 T) magnetic resonance imaging (MRI)
and advanced neuroimaging methods in a patient with a confirmed diagnosis of ADTLE.
Methods: 3 T MRI brain scan and advanced neuroimaging methods were used in the standard protocols to analyzse
voxel-based MRI, cortical thickness, and functional connectivity.
Results: Morphometric MRI analysis (blurred grey-white matter junctions, voxel-based morphometry, and cortical
thickness analysis) did not provide any informative results. The functional connectivity analysis revealed higher
local synchrony in the patient in the left temporal (middle temporal gyrus), left frontal (supplementary motor
area, superior frontal gyrus), and left parietal (gyrus angularis, gyrus supramarginalis) regions and the cingulate
(middle cingulate gyrus) as compared to healthy controls.
Conclusions: Evidence of multiple areas of functional connectivity supports the theory of epileptogenic networks in
ADTLE. Further studies are needed to elucidate this theory.
© 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords:
Autosomal dominant temporal lobe epilepsy
RELN gene
3 Tesla brain MRI
Functional connectivity
Epileptogenic networks
1. Introduction
Autosomal dominant lateral temporal epilepsy (ADLTE), also known
as autosomal dominant partial epilepsy with auditory features
(ADPEAF), is a genetic focal epilepsy syndrome. It is characterized by
focal seizures with or without a loss of consciousness, inconstantly
with secondary generalization. Focal seizures are mainly characterized
by auditory symptoms. Auditory auras are the most common symptom,
and occur in isolation or precede some kind of receptive aphasia. Other
symptoms following the auditory phenomena include vertigo,
paroxysmal headache, déjà-vu, and epigastric discomfort [2]. Sensory
symptomatology (e.g., visual, olfactory) and autonomic motor symptomatology
are less common. Neurological findings and the mental status
of patients are normal. The manifestation of the syndrome occurs
between the ages of four and 50 years, with the maximal occurrence
in the adolescent period [3]. Structural examinations of the brain (CT,
MRI) at standard resolutions most often return normal findings. Routine
and sleep electroencephalography (EEG) may be normal, but findings of
focal/slow wave abnormality in the temporal areas are not uncommon,
occurring in approximately 20% of patients [2,3]. The disease heredity is
autosomal dominant with varying penetration (about 70%) [1]. The diagnosis
is based on personal and family history, seizure semiology,
and normal MRI brain scan. Approximately 33% of patients show a pathogenic
variant in the LGI1 gene [2]. In a smaller percentage of ADLTE
cases, mutation in the reelin (RELN) gene is shown in heterozygous
Epilepsy & Behavior Case Reports 11 (2019) 39–42
Abbreviations: ADLTE, Autosomal dominant lateral temporal epilepsy; ADPEAF,
Autosomal dominant partial epilepsy with auditory features; LGI1, Leucine-rich, glioma
inactivated 1; RELN, Reelin; MRI, Magnetic resonance imaging; CT, Computer
tomography; EEG, Electroencephalography; CBZ, Carbamazepine; CLB, Clobazam; 3 T,
three Tesla; 1.5 T, one Tesla; TLE, Temporal Lobe Epilepsy; HDEEG, high density restingstate
EEG; GMC, grey matter concentration; GMV, grey matter volume; WMC, white matter
concentration; WMV, white matter volume; LS, Local synchrony.
⁎ Corresponding author at: Brno Epilepsy Centre, Department of Paediatric Neurology,
University Hospital, Medical School of Masaryk University, Brno, Czech Republic.
E-mail address: stefania.aulicka@gmail.com (Š. Aulická).
1
These authors contributed equally to this work.
Contents lists available at ScienceDirect
Epilepsy & Behavior Case Reports
journal homepage: www.elsevier.com/locate/ebcr
https://doi.org/10.1016/j.ebcr.2018.10.003
2213-3232/© 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
form [2]. The RELN gene is primarily expressed in brain tissue. The protein
product of the RELN gene is called reelin. Reelin regulates the correct
formation of laminated structures during embryonic development
and postnatally modulates dendritic growth and synaptic plasticity
[2]. Homozygous variants of the RELN mutation cause lissencephaly
with cerebellar hypoplasia, severe neuronal migration defects, delayed
cognitive development, and epileptic seizures [5]. Heterozygous mutation
of the RELN mutation can cause small changes in the cortex corresponding
to neuronal migration disorders [2]. The prognosis of the
disease is benign and, in most cases, there is a very good response to
treatment with properly selected anti-seizure drugs (valproate, phenytoin,
and carbamazepine are recommended).
2. Case report
We present a case report of an 18-year-old man who was admitted to
the Department of Pediatric Neurology of the University Hospital Brno in
2017. According to his personal history, he was born in the 32nd week of
gestation (the reason is unknown) and his psychomotor development
was normal. The family history showed no neurological disease or epilepsy.
At the age of 17, the patient suddenly began to experience epileptic
seizures without clear provocation. The clinical manifestation was dominated
by focal auditory seizures, without the loss of consciousness. The
seizures (auras) were described as a short-term loss of hearing and simultaneous
sensations of warmth lasting up to 30 s. The auras consistently
progressed into focal seizures with right-handed facial-brachial motor
symptomatology. Focal to bilateral tonic-clonic seizures occurred inconsistently.
The seizures were daily, and the frequency at initial onset was
very high. The auditory and vegetative auras occurred several times a
day and convulsive seizures following auras occurred five to six times
per week. On admission, the patient was already being treated with
valproic acid monotherapy at a total dose of 1500mg per day with a suitable
serum concentration. This medication had no significant effect. A CT
and MRI (1.5 T) scan, performed at another institution, were described as
normal. A routine EEG showed a non-specific finding of theta activity in
the left fronto-centro-temporal region. The patient was admitted to our
department urgently after a generalized tonic–clonic seizure. A complete
neurological examination and routine laboratory tests as well as EEG
returned normal findings. Due to the clinical course of the disease and
the seizure semiology, a genetic examination with high suspicion for
ADLTE (a requirement for the LGI1 gene and the RELN gene) was performed.
For therapeutic purposes, the patient was switched from
valproate to carbamazepine (CBZ), at a total dose of 600 mg per day,
with a partial effect on seizures (there was a reduction in seizure intensity,
not a reduction in frequency). Clobazam (CLB) was added to the carbamazepine
at a dose of 40 mg per day, with a pronounced effect on
seizures: convulsive seizures disappeared and auditory seizures decreased
to 20%. Overall, the patient's quality of life improved, as reported
by the patient and his family.
The causal mutation in the RELN gene (c.877GNA p. (Asp293Asn)) in
the heterozygous state was confirmed. Despite the patient's negative
family history, an investigation of the patient's parents' DNA was recommended.
An identical mutation was found in the patient's mother
through genetic testing. The patient's mother's EEG was normal and further
treatment of the mother was not pursued.
3. Methods
The magnetic resonance data was acquired on a 3 T Siemens Prisma
machine. The protocol contained: T1 MPRAGE, T2 FLAIR, T1 MP2RAGE;
T2 TSE; T2 FLASH; T1 TIR; T2 TIRM; T1 TIR; T2 TIRM; and T2 TSE
sequences.
The high density resting-state EEG (HDEEG) data was acquired using
the GES 400 amplifier (Electrical Geodesics, Inc.) with a 256-channel
EEG cap. The subject was instructed to sit still with closed eyes during
20 min of recordings.
4. Image analysis
4.1. Morphometry
The T1 MPRAGE and T2 FLAIR images were preprocessed using the
SPM12 and CAT12 toolbox (http://dbm.neuro.uni-jena.de/cat/index.
html) running under MATLAB (Mathworks, Inc.). We obtained images
showing the spatial distribution of the local grey matter volume/
concentration (GMV/GMC). The resulting GMV and GMC images
were voxel-wise compared to a set of GMV/GMC images and white
matter volume/concentration (WMV/WMC) images acquired with the
same MR protocol and resulting from the same preprocessing process
applied to data from healthy subjects (HC) (N = 48). The data were intensity
normalized by estimating the total intracranial volume to correct
for bias introduced by variability in head size [6]. The GMC and
WMC images were used to localize abnormalities in grey/white matter
junctions [7]. The patient's junction image was compared with the HC
using a two-sample T-test with age and gender as nuisance covariates.
The CAT12 output contains an estimate of cortical thickness [13],
which makes it possible to localize abnormalities in grey matter with
higher sensitivity than VBM. The patient data were compared to HC
data in the same way as junctions and GMC/GMV images.
4.2. Functional connectivity
The HDEEG data were segmented into 1 s epochs. We select 300
epochs with clean EEG. The sensor-space data from 256 channels
were projected using sLORETA into the source space using Cartool [9].
Using the Corrected Imaginary Coherence metric, we estimated the spatial
distribution of local synchrony (LS) in source-space. The increased
local synchrony was shown to be a potential marker of epileptogenicity
[10]. We compared the patient's LS image with LS images from 26
healthy controls using a two-sample T-test.
5. Results
5.1. MRI findings
Brain 3 T MRI was used with our patient. We found discrete changes
(subtle cortical thickness in T2-weighted sequences and very mild decrease
of signal intensity in T1-weighted sequences) in the left superior
temporal gyrus on 3 T MRI. Subtle cortical dysplasia in this site was.
Consequently, advanced neuroimaging methods (voxel-based 3D MRI
analysis, cortical thickness analysis, and functional connectivity) were
used. Morphometric MRI analysis (blurred grey-white matter junctions,
voxel-based morphometry, and cortical thickness analysis) did not provide
any informative results. The functional connectivity analysis revealed
higher local synchrony in the left temporal (middle temporal
gyrus), left frontal (supplementary motor area, superior frontal gyrus),
left parietal (gyrus angularis, gyrus supramarginalis) region and the cingulate
(middle cingulate gyrus) gyrus of the patient as compared to
healthy controls (See Fig. 1 and Table 1).
6. Discussion
We present a case of an 18-year-old patient with an acute manifestation
of severe epileptic seizures that had a significant impact on the
quality of life of the patient and his family. The age at seizure onset, clinical
course of the disease, seizure semiology and the results of the
paraclinical examinations indicated possible ADLTE. The diagnosis was
supported by genetic testing, which revealed a heterozygous mutation
in the RELN gene. In 30–50% of cases, ADLTE is caused by a mutation
in the LGI1 gene; around 17% of patients carry a mutation in the RELN
gene [2,3]. Nearly 50% of patients are not tested for causal mutation.
Due to the similar clinical course of the disease in both mutations, it is
recommended to test for both genes for ADLTE in suspected patients
40 K. Česká et al. / Epilepsy & Behavior Case Reports 11 (2019) 39–42
[2]. To our knowledge, seven families have thus far been identified with
a proven mutation in the RELN gene [1,2]. Dazza et al. reported that the
dominant type of focal auditory seizures is present in 71% of patients.
However, these seizures occur mostly at a low frequency (weekly or
yearly). Seizure freedom was achieved with the first antiepileptic drug
in 63% of patients; 31% of patients continued to experience sporadic auditory
auras on established antiepileptic therapy. Tonic–clonic seizures
disappeared in all studied patients [1]. The patient in this case report
was not seizure free even after trying several anti-seizure drugs. He continued
to experience sporadic auditory auras. However, the quality of
life of the patient and the whole family has improved. As a significant
success of therapy, the patient reports that the seizure frequency has
decreased to 20%, and the tonic–clonic seizures have disappeared on
the combination of CBZ and CLB. The patient's EEG was abnormal only
at the onset of the disease. Dazza et al. observed routine and/or sleep
EEG revealing epileptiform abnormality or deceleration in 12 patients
out of a total of 15 (80%); 20% of those patients had normal EEG or
non-specific abnormalities [1]. The family history of some individuals
with ADLTE may appear negative due to the early unrelated death of a
parent, later manifestations of epilepsy (perhaps manifested in the
50th year of life), or reduced penetration. Approximately 33% of patients
with a pathogenic variant of the gene remain asymptomatic [3]. If the
genetic examination in the proband parents is negative, there are two
explanations for the result: germinal mosaicism in the parents or de
novo mutation in the proband. The possibility of de novo mutation in
this type of epilepsy is assumed to be less than 1% [3].
The homozygous form of mutation in the RELN gene can cause serious
brain damage, such as lissencephaly and cerebellar hypoplasia, as
well as severe neuronal migration disorders. It can thus be assumed
that in the heterozygous form of mutation, small changes in the cortex
corresponding to neuronal migration disorders may result [2]. These
subtle changes cannot be detected on commonly available low resolution
MRI devices. Brain 3 T MRI and advanced neuroimaging methods
(voxel-based MRI analysis, cortical thickness analysis, and functional
connectivity) were used with our patient. The 3 T MRI findings in the
left superior temporal gyrus were felt to be insignificant . Advanced
neuroimaging methods including morphometric MRI analysis (blurred
grey-white matter junctions, voxel-based morphometry, and cortical
thickness analysis) did not provide any informative results. The functional
connectivity analysis revealed higher local synchrony in the left
temporal, left frontal, and left parietal regions and the cingulate when
the patient was compared to healthy controls (see Fig. 1 and Table 1).
The evaluation of brain networks using functional connectivity fMRI
is a relatively new technique that has been used successfully to identify
brain networks in several conditions, including autism, depression, and
schizophrenia [11]. Evidence of multiple areas of functional connectivity
confirms the theory of epileptogenic networks in ADTLE. Connectivity
abnormalities have potential for clinical relevance and correlation.
They may assist with diagnosis, they may provide insights into neurologic
deficits associated with TLE, and they may benefit invasive treatments
through a more accurate understanding of the functional
anatomy of TLE [11]. The epileptogenic network concept is a key factor
in identifying the anatomic distribution of the epileptogenic process,
which is particularly important in the context of epilepsy surgery [12].
Ethical publication statement
We confirm that we have read the Journal's position on issues involved
in ethical publication and affirm that this report is consistent
with those guidelines.
Disclosure
None of the authors has any conflict of interest to disclose.
Acknowledgments
This project was supported by Masaryk University, Faculty of
Medicine [grant number ROZV/25/LF/2017] and by project 17-32292A
of the Czech Health Research Council. We acknowledge the core facility
MAFIL of CEITEC, supported by the Czech-BioImaging large RI project
(LM2015062 funded by MEYS CR), for their support with obtaining
the scientific data presented in this paper. We thank Anne Johnson for
English language assistance.
References
[1] Dazzo E, Fanciulli M, Serioli E, Minervini G, Pulitano P, Binelli S, et al. Heterozygous
reelin mutations cause autosomaldominant lateral temporal epilepsy. Am J Hum
Genet 2015;96(6):992–1000.
[2] Michelucci R, Pulitano P, Di Bonaventura C, Binelli S, Luisi C, Pasini E, et al. The clinical
phenotype of autosomal dominant lateral temporal lobe epilepsy related to
reelin mutations. Epilepsy Behav 2017;68:103–7.
[3] Ottman Ruth. Autosomal dominant partial epilepsy with auditory features. 2007
April 20. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews®
Fig. 1. The regions showing increased local synchrony in the patient as compared to HC
(N = 26; p b 0.001).
Table 1
The regions that show increased local synchrony in the patient as compared to the HC
(N = 26; p b 0.001). The underlined regions are depicted in Fig. 1.
Region # voxels Z-valuea
Coordinatea
[mm]
L SMA 19 7.02 −6 18 72
L supramarginal g 14 6.12 −66 −30 30
L angular g 40 5.84 −48 −66 42
L middle temporal g 13 5.31 −66 −48 −6
L middle cingulate g 31 5.26 −6 12 36
R superior frontal g 5 4.29 24 36 54
a
Cluster maximum; L — left; g — gyrus; SMA — supplementary motor area; voxel
size = (6 × 6 × 6) mm3
.
41K. Česká et al. / Epilepsy & Behavior Case Reports 11 (2019) 39–42
[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017 Available
from: https://www.ncbi.nlm.nih.gov/books/NBK1537/.
[5] Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, et al. Autosomal
recessive lissencephaly with cerebellar hypoplasia is associated with human
RELN mutations. Nat Genet 2000;26:93.
[6] Ashburner J, Friston KJ. Voxel-based morphometry—the methods. Neuroimage
2000;11:805–21. https://doi.org/10.1006/nimg.2000.05.
[7] Huppertz HJ, Grimm C, Fauser S, Kassubek J, Mader I, Hochmuth A, et al. Enhanced
visualization of blurred gray-white matter junctions in focal cortical dysplasia by
voxel-based 3D MRI analysis. Epilepsy Res 2005;67:35–50.
[9] Michel CM, Koenig T, Brandeis D, Gianotti LRR, Wackermann J. Electrical neuroimaging.
Cambridge University Press; 2009.
[10] Schevon CA, Cappell J, Emerson R, Isler J, Grieve P, Goodman R, et al. Cortical abnormalities
in epilepsy revealed by local EEG synchrony. Neuroimage 2007;35:140–8.
[11] Haneef Z, Lenartowicz A, Yeh HJ, Levin HS, Engel Jr J, Stern JM. Functional connectivity
of hippocampal networks in temporal lobe epilepsy. Epilepsia 2014;55(1):
137–45. https://doi.org/10.1111/epi.12476.
[12] Bartolomei F, Lagarde S, Wendling F, McGonigal A, Jirsa V, Guye M, et al. Defining epileptogenic
networks: contribution of SEEG and signal analysis. Epilepsia 2017;58
(7):1131–47. https://doi.org/10.1111/epi.13791.
[13] Dahnke R, Yotter RA, Gaser C. Cortical thickness and central surface estimation.
Neuroimage 2013;65(15):336–48 http://dbm.neuro.uni-jena.de/cat/index.html.
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149
2.11 Annex 11:
Cahová P, Pejčochová J, Ošlejšková H. Hyperkinetická porucha/ „Attention Deficit
Hyperactivity Disorder“ u dětských pacientů s epilepsií. Cesk Slov Neurol N 2011;
74/107(2): 157-162.
Summary:
Hyperkinetic disorder, also known as attention deficit hyperactivity disorder (HKD/ADHD),
is a neurodevelopmental disorder characterised by an age-related and inappropriate rate
of hyperactivity with impulsivity together with an inability to remain focused on tasks or
activi- ties. HKP/ADHD incidence in children with epilepsy is estimated to be as high as
30%–40%. Several studies show that in children with ADHD the presence of
epileptiform discharges can be found in 6%–51% of cases. The hypothesis that the
comorbid incidence of epilepsy and ADHD may be merely coincidental is not accepted.
Cognitive and behavioural changes in patients with epilepsy used to be explained as the
consequences of recurrent seizures, the influence of antiepileptic medication and the
substantial substrate of epilepsy. However, in the majority of ADHD and epilepsy children,
the onset of ADHD symptomatology precedes the onset of clinical seizures. The onset of
spontaneous seizures arises out of a complex process of epileptogenesis that involves a
cascade of transcriptional changes involving the processes of plasticity, apoptosis and
neurogenesis. All of these changes may influence the behavioural and cognitive profile
before seizure onset. The pathophysiology of ADHD is explained by disturbances in the
prefrontal-thalamo-striato-cortical neuronal circuits. It is the frontal lobe that is important to
the understanding of the common neurobiological substrate of ADHD and epilepsy.
Cesk Slov Ne urol N 2011; 74/ 107(2): 157–162 157
PŘEHLEDNÝ REFERÁT
Hyperkinetická porucha/
„Attention Deficit Hyperactivity Disorder“
u dětských pacientů s epilepsií
Hyperkinetic Disorder/Attention Deficit Hyperactivity Disorder
in Children with Epilepsy
Souhrn
Hyperkinetická porucha/„Attention deficit hyperactivity disorder“ (HKP/ADHD) se řadí mezi
neurovývojové poruchy. Je charakterizována věku nepřiměřenou mírou nepozornosti, impulzivity
a hyperaktivity. HKP/ADHD je jednou z relativně častých komorbidit u dětí s epilepsií.
Symptomy této poruchy se u dětí s epilepsií vyskytují až ve 30–40 % případů. Výsledky studií
ukazují, že u dětí s HKP/ADHD lze nalézt epileptiformní grafoelementy v EEG v 6–51 % případů.
Co se týká komorbidního výskytu HKP/ADHD, nelze se spokojit s hypotézou pouhé
náhodné koincidence. Kognitivní a behaviorální změny u pacientů s epilepsií byly dříve vysvětlovány
následky opakovaných záchvatů a vlivy antiepileptické medikace. Naopak u řady
pacientů symptomatika HKP/ADHD předchází časově rozvoji záchvatů. Nástup záchvatů je
výsledkem komplexního procesu epileptogeneze, který zahrnuje řetězec transkripčních změn
zasahujících na úrovni plasticity, apoptózy a neurogeneze. Všechny tyto změny mohou ovlivňovat
behaviorální a kognitivní profil ještě před rozvojem klinických záchvatů. Patofyziologie
HKP/ADHD je vysvětlována poruchou na úrovni prefronto-thalamo-striato-kortikálních neuronálních
okruhů. A právě frontální lalok je důležitý pro pochopení společného neurobiologického
substrátu HKP/ADHD a epilepsie.
Abstract
Hyperkinetic disorder, also known as attention deficit hyperactivity disorder (HKD/ADHD),
is a neurodevelopmental disorder characterised by an age-related and inappropriate rate of
hyperactivity with impulsivity together with an inability to remain focused on tasks or activities.
HKP/ADHD incidence in children with epilepsy is estimated to be as high as 30%–40%.
Several studies show that in children with ADHD the presence of epileptiform discharges
can be found in 6%–51% of cases. The hypothesis that the comorbid incidence of epilepsy
and ADHD may be merely coincidental is not accepted. Cognitive and behavioural changes
in patients with epilepsy used to be explained as the consequences of recurrent seizures, the
influence of antiepileptic medication and the substantial substrate of epilepsy. However, in
the majority of ADHD and epilepsy children, the onset of ADHD symptomatology precedes
the onset of clinical seizures. The onset of spontaneous seizures arises out of a complex
process of epileptogenesis that involves a cascade of transcriptional changes involving the
processes of plasticity, apoptosis and neurogenesis. All of these changes may influence the
behavioural and cognitive profile before seizure onset. The pathophysiology of ADHD is
explained by disturbances in the prefrontal-thalamo-striato-cortical neuronal circuits. It is the
frontal lobe that is important to the understanding of the common neurobiological substrate
of ADHD and epilepsy.
P. Cahová, J. Pejčochová,
H. Ošlejšková
Klinika dětské neurologie
LF MU a FN Brno
*	
MUDr. Pavlína Cahová
Klinika dětské neurologie
LF MU a FN Brno
Černopolní 9
613 00 Brno
e-mail: pavlina.cahova@seznam.cz
Přijato k recenzi: 17. 9. 2010
Přijato do tisku: 5. 10. 2010
Klíčová slova
hyperkinetická porucha – ADHD –
epilepsie – epilepsie frontálního laloku –
dětské absence – BERS
Key words
hyperkinetic disorder – ADHD –
epilepsy – frontal lobe epilepsy –
childhood absence epilepsy – BECTS
158
Hyperkinetická porucha Attention Deficit Hyperactivity Disorder (HKP/ADHD) u dětských pacientů s epilepsií
Cesk Slov Ne urol N 2011; 74/ 107(2): 157–162
Úvod
Hyperkinetická porucha/Attention Deficit
Hyperactivity Disorder (HKP/ADHD)
se řadí mezi neurovývojové poruchy. Je
charakterizována věku nepřiměřenou
mírou nepozornosti, impulzivity a hyperaktivity.
Postihuje děti již od raného věku
a ve 40–50 % [1] přechází do dospělého
věku. HKP/ADHD je jedna z častých komorbidit
u dětí s epilepsií. Komorbidní výskyt
obou těchto diagnóz není jasně vysvětlen.
Vzhledem k  jejich četnosti se
nelze spokojit s hypotézou náhodné koincidence.
Patofyziologicky lze předpokládat
genetickou poruchu na úrovni vyzrávání
CNS vedoucí jak k epileptiformní
aktivitě v EEG, tak ke kognitivním a behaviorálním
změnám [2]. Výskyt HKP/ADHD
u pacientů s epilepsií nesmí být opomíjen.
HKP/ADHD významně snižuje kvalitu
života těchto pacientů a negativně ovlivňuje
úroveň jejich dosažených školních
výsledků a dovedností.
Autoři textu se snaží blíže vysvětlit patofyziologické
souvislosti koincidenčního
výskytu HKP/ADHD a epilepsie, dále se zaměřují
na epileptické syndromy, které bývají
nejčastěji spojeny s HKP/ADHD.
Diagnostická kritéria HKP/ADHD
Diagnostická kritéria hyperkinetické poruchy
vychází z MKN-10 [3], kde jsou rozlišovány
dva subtypy: porucha pozornosti
a hyperaktivita (F90.0) a hyperkinetická
porucha chování (F90.1) (tab.1, 2). Pro
diagnózu je nutné, aby byly přítomny
všechny jádrové příznaky, a to porucha
pozornosti, hyperaktivita a  impulzivita.
Porucha se musí manifestovat před sedmým
rokem věku a  musí trvat alespoň
šest měsíců. Pokud se k jádrovým příznakům
hyperkinetické poruchy přidají i poruchy
chování (agresivita, kriminální činy,
sociální nepřizpůsobivost atd.), mluvíme
o hyperkinetické poruše chování (F90.1),
která vyžaduje odlišný terapeutický algoritmus
a z pohledu sociální adaptace je
závažnější.
V současnosti hojně používaný termín
ADHD (Attention Deficit Hyperactivity Disorder)
vychází z amerických diagnostických
manuálů. Ve svých diagnostických
kritériích využívá jiné členění subtypů
a  v  tomto směru je diagnostika ADHD
o něco méně „přísná“ ve srovnání s HKP.
DSM-IV [4] definuje ADHD odlišně a rozlišuje
tři subtypy: ADHD s převládající poruchou
pozornosti (ADHD Inattentive type),
ADHD s převládající hyperaktivitou a impulzivitou
(ADHD Hyperactivity/Impulsivity
type) a ADHD smíšený typ (ADHD Combined
type) (tab. 1–3). Zásadní rozdíl oproti
klasifikaci dle MKN-10 je, že pro diagnostiku
není nutná přítomnost všech jádrových
příznaků. Podmínkou diagnózy je
nutnost výskytu některých jádrových příznaků
již před sedmým rokem věku, některé
příznaky se objevují na dvou či více
místech (např. doma či ve škole) a musí
být zohledňován i aspekt sociální. DSM-IV
klasifikace ADHD se oproti MKN-10 klasifikaci
HKP liší i tím, že nezahrnuje poruchy
chování jako součást ADHD, neexistuje
tedy analogie diagnózy F90.1 jako
v MKN-10 klasifikaci a pacienti s ADHD
a  poruchami chování jsou vedeni pod
dvojí diagnózou. Právě odlišnosti v tomto
členění jsou příčinou vyšší incidence ADHD
Tab. 1. Diagnostická kritéria HKP (MKN-10) vs ADHD (DSM-IV).
Diagnostická kritéria HKP dle MKN-10 Diagnostická kritéria ADHD dle DSM-IV
symptomy poruchy pozornosti: • kritéria A1: 6 nebo více příznaků trvajících minimálně 6 měsíců
• alespoň 6 příznaků po dobu 6 měsíců porucha pozornosti:
obtížná koncentrace pozornosti nepozornost při školních úkolech, opomíjení detailů, chyby z nepozornosti
neposlouchá neudrží pozornost při hře
nedokončuje úkoly neposlouchá během rozhovoru
vyhýbá se úkolům vyžadujícíh mentální úsilí neposlouchá instrukce, není schopno dokončit úkol
nepořádný, desorganizovaný organizační problémy
ztrácí věci nesnáší úkoly vyžadující mentální úsilí, vyhýbá se jim
roztržitý ztrácí věci
zapomnětlivý dá se snadno rozptýlit vnějšími podněty
často zapomnětlivost
symptomy hyperaktivity: • kritéria A2: 6 nebo více příznaků hyperaktivity-impulzivity trvajících minimálně
6 měsíců, nepřiměřených vývojovému stupni
Hyperaktivita:
• alespoň 3 příznaky po dobu 6 měsíců
neposedí, vrtí se neklid rukou, nohou, vrtí se na židli
pobíhá kolem vstává ve třídě, když má sedět
vyrušuje, je hlučný, obtížně zachovává klid často pobíhá v nevhodných situacích
v neustálém pohybu neumí si hrát tiše
excesivně mnohomluvný trvale příliš vysoká motorická aktivita
symptomy impulzivity: nadměrně mnohomluvný
• alespoň 1 příznak po dobu 6 měsíců Impulzivita:
nezdrženlivě mnohomluvný často vyhrkne odpověď na otázky, které ještě nebyly dokončeny
vyhrkne odpověď bez přemýšlení často není schopno čekat ve frontě nebo až přijde na řadu ve hře či komunikaci
nedokáže čekat často přerušuje ostatní nebo se jim vnucuje
přerušuje ostatní často příliš mluví bez ohledu na sociální zábrany
Hyperkinetická porucha Attention Deficit Hyperactivity Disorder (HKP/ADHD) u dětských pacientů s epilepsií
Cesk Slov Ne urol N 2011; 74/ 107(2): 157–162 159
ve Spojených státech amerických a způsobují
jisté rozpaky a nepřesnosti při srovnávání
výsledků našich studií s výsledky studií
designovaných dle kritérií DSM-IV.
Autoři se dále soustředí na výskyt a klinické
rysy epilepsie bez ohledu na využití
klasifikačního schématu HKP, resp.
ADHD. Proto je termín HKP/ADHD používán
současně. V citacích je terminologie
zachována dle záměru autora původní
práce.
Epidemiologie současného
výskytu HKP/ADHD a epilepsie
Již v  roce 1955 publikoval Ounsted [5]
práci, kde dává do souvislosti výskyt poruchy
pozornosti jako součásti hyperkinetické
poruchy a epilepsie. S dalším rozvojem
pohledu a klasifikačních schémat
ADHD se objevily další práce [6,7], jež využívají
u pacientů s ADHD klasifikačního
schématu DSM-IV a zjišťují signifikantně
vyšší výskyt ADHD v této skupině pacientů
s  nejpočetnějším zastoupením subtypu
s poruchou pozornosti.
Dle výsledků různých studií jsou symptomy
HKP/ADHD přítomny u 30–40 %
pacientů s epilepsií [7–9]. Dle Salpekara
et al [10] se dokonce ADHD řadí mezi nejčastější
psychiatrickou komorbiditu u pacientů
s epilepsií. U pacientů s HKP/ADHD
lze nalézt epileptiformní aktivitu v  EEG
v  6–53 % [11–13]. Prediktivní hodnota
epileptiformní EEG abnormality ve vztahu
k následnému rozvoji klinických záchvatů
u pacientů s ADHD je 14 % [11].
Neurobiologické aspekty
v patogenezi HKP/ADHD
a epilepsie
V současné době je pro pochopení patofyziologie
HKP/ADHD přijímána hypotéza
prefronto-striato-thalamo-kortikálního
okruhu. Z  pohledu exekutivních funkcí
rozlišujeme v neuroanatamicko-fyziologickém
pojetí v zapojení frontálního laloku
s oblastí bazálních ganglií tři okruhy [14]:
•	dorzolaterální okruh (dorzolaterální
prefrontální kortex – nucleus caudatus
dorsolateralis – globus pallidum lat.
dorsomedialis – thalamus ventralis anterior
a mediodorsalis), jehož poškození
vede k  rozvoji dorzolaterálního syndromu
(postižení exekutivních kognitivních
funkcí s projevy mentální a motorické
perseverace, poruchy provádění
komplexních cílených činností, motorického
programování, snížená plynulost
řeči, poruchy řešení problému, poruchy
paměti a učení).
•	orbitofrontální okruh (laterální orbitální
kortex – nucleus caudatus ventromedialis
– globus pallidum med.
dorsomedialis – thalamus ventralis anterior
a  mediodorsalis), jehož poškození
vede k rozvoji prefrontálního syndromu
s emoční labilitou a desinhibicí
v chování.
•	přední cingulátový (mediofrontální)
okruh (přední cingulum – nucleus
accumbens – globus pallidum rostrolateralis
– thalamus mediodorsalis),
jehož poškození vede k rozvoji apatie
až akinetického mutizmu.
Právě poruchy neurotransmise vyskytující
se v zapojení prefronto-stirato-thalamo-kortikálního
okruhu hrají významnou
roli v etiopatogenezi HKP/ADHD. V roce
1970 byla vyslovena Kortenskym katecholaminová
hypotéza hyperaktivity. Noradrenalin
a dopamin se ukázaly hlavními
neurotransmitery uplatňujícími se v patogenezi
HKP/ADHD. Tato hypotéza byla
upevňována výsledky celé řady studií využívajících
funkční zobrazení CNS a podpořena
také efektem dopaminergních
a noradrenergních psychofarmak v terapii
HKP/ADHD. Výsledky zobrazovacích
a  funkčních studií poukazují na hypofunkční
katecholaminovou projekci z oblasti
bazálních ganglií do prefrontálního
kortexu. V neurotransmiterové oblasti se
tato dysfunkce projevuje jako relativní
hypo­aktivita kortikálního dopaminového
systému s relativní hyperaktivitou striatálního
dopaminu. Jedinci s HKP/ADHD mají
hypoaktivitu kortikálního dopaminového
systému (nižší tonický dopamin) a hyperaktivitu
striatálního dopaminu (zvýšený fyzický
dopamin).
Prefrontální oblasti a funkce s těmito
oblastmi asociované, jako je kontrola pozornosti
či impulzivity, nedozrávají dříve
než v období rané dospělosti [15]. Tento
fakt je zásadní pro pochopení neurovývojového
aspektu HKP/ADHD. HKP/ADHD
jako porucha nastupuje před sedmým
rokem věku, první známky lze pozorovat
již v kojeneckém období. Průběh HKP/
/ADHD mění svůj klinický obraz i  tíži
vyjád­ření současně se zráním mozku jedince.
U poloviny případů HKP/ADHD dochází
ke spontánnímu ústupu kolem 12.
roku věku. Ve 40–60 % případů však porucha
přetrvává do dospělosti [16].
Tato „čistá forma“ HKP/ADHD se nezabývá
aspekty EEG či výskytu klinicky manifestních
epileptických záchvatů. Prevalence
HKP/ADHD v  dětské populaci
je 3–7 % [17], a jak bylo uvedeno výše,
u  30–40 % pacientů s  epilepsií je pozorována
symptomatika HKP/ADHD.
Vzhledem k této četnosti komorbidního
výskytu HKP/ADHD a epilepsie by bylo odvážné
považovat jejich současný výskyt za
pouhou náhodnou koincidenci. Jaký je ale
Tab. 2. Klasifikace HKP (MKN-10) vs ADHD (DSM-IV).
Hyperkinetická porucha (MKN-10)
Attention Deficit Hyperactivity
Disorder – ADHD (DSM-IV)
Porucha pozornosti a hyperaktivita (F90.0)
ADHD typ s převahou poruchy
pozornosti
ADHD typ hyperaktivně-impulzivní
ADHD typ smíšený
Hyperkinetická porucha chování (F90.1) ADHD typ nespecifický
ADHD v časné remisi
Tab. 3. Klasifikace ADHD
(DSM-IV) dle diagnostických
kritérií.
Subtypy ADHD (DSM-IV)
ADHD typ s  převahou poruchy
pozornosti
kritéria A1 alespoň 6 měsíců
ADHD typ hyperaktivně impulzivní
kritéria A2 alepsoň 6 měsíců
ADHD typ kombinovaný
kritéria A1 a A2 alespoň 6 měsíců
ADHD typ nespecifický
prominentí symptomy nepozornosti,
hyperaktivity-impulzivity, které však nesplňují
kritéria ADHD
ADHD v časné remisi
současné symptomy již nesplňují
všechna kritéria
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Hyperkinetická porucha Attention Deficit Hyperactivity Disorder (HKP/ADHD) u dětských pacientů s epilepsií
Cesk Slov Ne urol N 2011; 74/ 107(2): 157–162
vztah mezi symptomy HKP/ADHD a epilepsií,
zůstává otázkou.
Epileptická aktivita, která se vyskytuje
v kortikálních oblastech funkčně asociovaných
s exekutivními funkcemi, může zapříčiňovat
rozvoj symptomů HKP/ADHD.
Pokud nastupuje v kritickém vývojovém
stadiu CNS, může interferovat se zráním
mozku a  poškozovat vyvíjející se
kortikální sítě [18]. Tuto hypotézu podporují
i výsledky studií, které hodnotí lokalizaci
EEG patologie u pacientů s HKP/
/ADHD. Silvestri et al [13] prokazují u pacientů
s ADHD výskyt epileptiformní aktivity
v EEG nejčetněji v centrotemporální
oblasti (28,2 %), dále frontálně (12,5 %),
zastoupena je i lokalizace fokusu v oblasti
okcipitální (9,3 %) a generalizoavné
výboje byly zastoupeny 2,3 %. Na Klinice
dětské neurologie FN Brno bylo retrospektivně
hodnoceno 135 pacientů ve
věku 6–18 let s HKP a s výskytem či bez
výskytu komorbidní epilepsie. U 60 z nich
byla zachycena specifická epileptická aktivita
v EEG. V této skupině byl nejčetnější
výskyt generalizovaných výbojů u 18 pacientů
(30 %), dále u 17 pacientů (28 %)
frontálně, u osmi pacientů (13 %) centrotemporálně,
u 16 pacientů (27 %) temporálně
a u jednoho pacienta (2 %) okcipitálně
[19]. Vysvětlení, proč lze u pacientů
s HKP/ADHD nalézt fokální epileptiformní
grafoelementy i  v  jiných oblastech než
temporálních či okcipitálních, může být
složitější. Lze předpokládat, že šíření epileptické
aktivity ovlivňuje komplexnější
neuronální okruhy a ty jsou schopny zahrnout
i oblast frontálního laloku, event.
lze přijmout i hypotézu, že určitá část komorbidních
epilepsií s HKP/ADHD může
být opravdu koincidencí.
Druhou otázkou zůstává, jaký je vztah
manifestní epilepsie a  HKP/ADHD symptomatiky.
Dlouhou dobu byly kognitivní
a behaviorální změny typické pro klinický
obraz HKP/ADHD u pacientů s epilepsií
připisovány především následkům opakovaných
epileptických záchvatů, vlivu antiepileptické
medikace či podstatě epilepsie
jako onemocnění samotného [20,21].
Proti těmto tvrzením byl podán důkaz, že
antiepileptika nejsou hlavní příčinou kognitivních
a behaviorálních změn u pacientů
s epilepsií [22] a že délka klinicky
vyjádřené epilepsie či doba vzniku prvního
záchvatu neovlivňuje obraz ADHD [23].
Symptomy ADHD předcházejí klinickou
manifestaci epilepsie až u 82 % dětí [8].
Existují neurovývojové abnormality, jež
předcházejí rozvoj záchvatů a mají vztah
k vývoji ADHD a asociovaných komorbi-
dit [8]. Cortez et al předložili důkaz, že nástup
spontánních epileptických záchvatů
je výsledkem komplexního procesu epileptogeneze,
jež zahrnuje kaskádu transkripčních
změn odstartovanou interakcí
genetických faktorů a faktorů prostředí.
Tyto transkripční změny zasahují do procesů
plasticity, apoptózy a neurogeneze.
Tyto všechny mohou ovlivnit kognitivní
a  behaviorální změny již před vlastním
rozvojem klinických záchvatů [24].
Z výše uvedeného vyplývá, že klinická
manifestace symptomů HKP/ADHD je častěji
vázána s epileptickými syndromy asociovanými
s frontálním lalokem. Jedná se
především o  epilepsii frontálního laloku
(FLE) a benigní epilepsii s centrotemporálními
hroty (BERS, BECTS). Další významnou
skupinou jsou idiopatické generalizované
epilepsie (IGE). Zde se předpokládá
patofyziologický podíl abnormálních thalamo-kortikálních
okruhů, které aktivují
patologické oscilační rytmy a generují generalizované
epileptiformní EEG výboje.
Předpokládá se propojení thalamu s kortikálními
oblastmi (thalamokortikální okruhy)
právě v oblasti frontálního laloku [25].
V poslední době se objevuje celá řada
studií, jež předpokládají patofyzio­logický
podíl mozečku v  rozvoji HKP/ADHD.
U dětí s ADHD byl zjištěn signifikantně
menší objem mozečkových hemisfér [26]
a snížený objem vermis cerebella [27,28].
Podíl mozečku na patofyziologii ADHD
je nesporný a ukazuje se, že mozeček je
silně zapojen do kognitivních a afektivních
procesů [29–31]. Jak ve skupině pacientů
s ADHD, tak ve skupině pacientů
s  ADHD a  epilepsií byla zjištěna nižší
frakční anizotropie (FA) (pomocí difuzní
MR) v oblasti pravého středního mozečkového
pedunklu, tedy oblasti která je
funkčně zapojena do kortiko-ponto-cerebelárního
okruhu [32]. Tento deficit
může vést k  defektní transmisi signálu
z pre­frontálních oblastí do mozečku, vedoucí
k symptomatice ADHD. Protože ve
skupině ADHD i ADHD/epilepsie byla zjištěna
nižší FA v identických oblastech mozečku,
lze předpokládat, že podíl mozečku
na patofyziologii ADHD je u obou
skupin pacientů stejný. Výsledky této studie
ukazují, že podíl mozečku na procesu
epileptogeneze u pacientů s ADHD prokázán
nebyl.
Epileptické syndromy
asociované s HKP/ADHD
Epilepsie frontálního laloku (FLE)
Prefrontální oblasti hrají klíčovou úlohu
v  neuronálních okruzích zodpovědných
za exekutivní funkce a chování. Epileptiformní
výboje lokalizované v oblasti frontálního
laloku mohou interferovat s vývojem
těchto funkčních okruhů [33].
Ve studii 16 pacientů s epilepsií frontálního
laloku ve věku 8–16 let byl prokázán
kognitivní a behaviorální deficit kvalitativně
srovnatelný s FLE u dospělých.
Děti s FLE vykazovaly obtíže v otázkách
motorické koordinace, plánování komplexních
motorických úkolů, ve vizuo-prostorové
organizaci, tenacitě pozornosti,
inhibici odpovědi, plánování a schopnosti
řešit úkoly [34]. Prevost et al [35] prokazují
symptomy ADHD u 14 dětských pacientů
s FLE v souboru 21 dětí. Významným
faktem je, že celá řada pacientů
s nonlezionální FLE může vykazovat poruchy
v těchto oblastech a u těchto pacientů
kontrola záchvatů nezaručí i zlepšení
v oblasti symptomů ADHD [35].
Idiopatické generalizované
epilepsie – dětské absence (CAE)
Dětské absence se řadí mezi benigní dětské
epileptické syndromy, míra spontánní
remise je vysoká. Z hlediska neurokognitivního
a behaviorálního je CAE prognosticky
závažnější. U dětí s absencemi jsou
pozorovány potíže v pozornosti verbální
i vizuální, zejména ve složce vytrvalosti
[36–38]. Caplan et al [39] prokázali v souboru
69 dětí s CAE výskyt lehkého kognitivního
deficitu v 25 %, poruch řeči v 43 %
a 61 % pacientů splnilo diagnostická kritéria
dle DSM-IV pro ADHD či úzkostnou
poruchu. Symptomy těchto poruch
byly v korelaci s délkou trvání a frekvencí
absencí. Jen malá část pacientů s ADHD
či úzkostnou poruchou měla adekvátní
psychiatrickou terapii. Nejčastější subtyp
ADHD u dětí s CAE je ADHD – subtyp
s poruchou pozornosti [7,39]. Kognitivní
a behaviorální změny jsou závažnější
u pacientů s nástupem CAE před čtvrtým
rokem věku [38].
Epilepsie s centrotemporálními
hroty („rolandické epilepsie“)
Skupina epilepsií s  centrotemporálními
hroty je zvolena čistě topograficky, nevychází
z  aktuálně platné ILAE klasifikace
epileptických syndromů. Zahrnuje
Hyperkinetická porucha Attention Deficit Hyperactivity Disorder (HKP/ADHD) u dětských pacientů s epilepsií
Cesk Slov Ne urol N 2011; 74/ 107(2): 157–162 161
pacienty s epileptickými syndromy či pacienty
s  EEG patologií, pro něž je společná
lokalizace EEG patologie v oblasti
cen­trotemporální (rolandické). U těchto
pacientů bývá často vyjádřen kognitivní
deficit a  behaviorální změny [40–45].
Výskyt centrotemporálních hrotů v EEG
u  pacientů s  HKP/ADHD je popisován
v 3,7–5,6 % případů [40]. Jejich epileptogenicita
je nízká, 2–10 % nositelů této
patologie vyvine klinické záchvaty [43].
Kromě pacientů s „náhodným nálezem“
EEG patologie v centrotemporální oblasti,
která se nemanifestuje klinicky epileptickými
záchvaty, je nutno uvést i pacienty
s epileptickými syndromy, pro které je lokalizace
v  rolandické oblasti typická až
pato­gnomická. Hroty v centrotemporální
oblastinacházímeu pacientůs benignídětskou
epilepsií s rolandickými hroty (BERS/
/BECTS), která je v ILAE klasifikaci řazena
do skupiny fokálních, idiopatických věkově
vázaných epilepsií. Další významnou
skupinou jsou pacienti s atypickou
benigní parciální epilepsií (Pseudo-Lennox
syndromem), která dosud v ILAE klasifikaci
své místo nemá. A v neposlední
řadě je třeba uvést pacienty s Landau-Kleffner
syndromem (dle ILAE klasifikace
epileptických syndromů je řazen do skupiny
epilepsií nezařazených – fokálních či
generalizovaných), se syndromem fragilního
chromozomu X a Rettovým syndromem,
kde lze v EEG patologii lokalizovat
do centro­temporální oblasti [43].
Benigní dětská epilepsie
s rolandickými hroty (BERS/
/BECTS)
Benigní epilepsie s rolandickými hroty se
řadí mezi nejčastější epileptické syndromy
v dětském věku. Podle International Classification
of Epilepsies and Epileptic Syndromes
(Commission on Classification
and terminology of the ILAE 1989)
[46] je BERS řazena mezi věkově vázané
epileptické syndromy manifestující se
mezi 3–13 lety věku dítěte s normálním
psycho­motorickým vývojem. Považuje se
díky dobré prognóze za benigní epilepsii,
je dobře kontrolovatelná antiepileptickou
medikací a  spontánně remituje
v adolescenci.
U pacientů s BERS je ADHD diagnostikováno
signifikantně dříve než u pacientů
bez centrotemporálních hrotů, vykazují
více vyjádřenou hyperaktivně-impuzivní
symptomatiku. Předpokládá se, že centrotemporální
EEG patologie může nejasným
mechanizmem snižovat práh citlivosti,
způsobovat tak časnější nástup
a těžší průběh ADHD. U pacientů s BERS
je také zjištěn signifikantní deficit pozornosti.
Důležité je, že míra poruchy pozornosti
není závislá na frekvencí epileptiformních
výbojů v  bdělém stavu či
četnosti záchvatů [42,44]. Naopak lateralizační
aspekt může být významný a právě
lokalizace centrotemporálních hrotů pravostranně
či bilaterálně je častěji spojena
s poruchou pozornosti [42]. Předpokládá
se funkční dysbalance mezi hemisférami
způsobená epileptiformními výboji. Lateralizační
aspekty je však nutno brát obezřetně,
poněvadž právě u pacientů s BERS
je často pozorována alterace fokusu
z jedné hemisféry na druhou.
Aktivace epileptiformní aktivity v EEG ve
spánku a její možná sekundární generalizace
u pacientů s BERS může významně
ovlivňovat kognitivní deficit a vizuálně-percepční
schopnosti. Je zodpovědná za signifikantně
nižší celkový inteligenční skór dle
WISC-III testu, slabší vizuomotorickou koordinaci,
nonverbální krátkodobou paměť
a  udržení pozornosti [45]. Snížení frekvence
epileptiformní aktivity ve spánku,
ať již spontánně, či po nasazení antiepileptické
medikace, může zlepšit neuropsychologický
profil pacientů s BERS, a to
dokonce do takové míry, že je poté srovnatelný
s kontrolní skupinou [45].
Spánkové epileptické syndromy
Spánek může být významným aktivátorem
epileptiformních grafoelementů
v EEG. Právě aktivace specifické patologie
u pacientů s BERS může být spoluzodpovědná
za kognitivní deficit a behaviorální
změny, jak bylo již uvedeno v předchozím
odstavci. Frekventní epileptiformní
výboje ve spánku, které lze zaznamenat
např. u pacientů s CSWS (se syndromem
s kontinuálními komplexy hrot-vlna v synchronním
spánku) mohou narušovat neurální
okruhy a zasahovat do procesů učení
a kognitivních funkcí [46]. Další významnou
skupinou jsou pacienti s noční epilepsií
frontálního laloku (NFLE). Ta vychází
z orbitofrontálních a mediálních oblastí
frontálního laloku a je často asociována
s ADHD [47].
Nelze opomenout ani fakt, že spánková
EEG patologie a noční epileptické
záchvaty snižují kvalitu spánku, oddalují
nástup první REM fáze a vedou k defragmentaci
spánku [48]. Tyto faktory bezesporu
vedou k  denní ospalosti, jež se
může především u dětí manifestovat paradoxně
hyperaktivitou a také poruchou
pozornosti.
Závěr
U pacientů s epilepsií se nezřídka setkáváme
se symptomy hyperkinetické poruchy/ADHD.
Není dosud jednoznačně
vysvětleno, jaké jsou společné patofyziologické
mechanizmy. Současné znalosti
a výsledky výzkumů nás vedou k pochopení
prefronto-striato-thalamo-kortikálních
okruhů jako možných příčinných mechanizmů
a řada epileptických syndromů
s frontálním lalokem spojených tuto hypotézu
podporuje. Jaký je podíl epilepsie
či EEG patologie na klinickém vyjádření
a prognóze HKP/ADHD, je v současné
době předmětem zájmu mnoha studií.
Právě pochopení komplexnosti těchto patofyziologických
spojitostí nám umožní
správně diagnostikovat a  vést terapii,
která může být pro pacienta s HKP/ADHD
a epilepsií zásadní a v nemalé míře se podílí
na socioekonomických aspektech
těchto komorbidních diagnóz.
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156
2.12 Annex 12
Danhofer P, Horák O, Aulická Š, Česká K, Pejčochová J, Fajkusová L, Ošlejšková H.
Genetické a neurobio logické aspekty komorbidního výskytu poruch autistického
spektra a epilepsie. Cesk Slov Neurol N 2019; 82(2): 148-54. doi: 10.14735/
amcsnn2019148.
Summary:
Autism spectrum disorder (ASD) is ranked among neurodevelopmental and neuropsychiatric
disorders with clinical onset in childhood. In recent years, this disorder has come to the
forefront of scientific interest, mainly due to increasing prevalence of up to 1/68 in 2014.
The genetic causes of the disorder and the pathophysiological mechanisms that might be
involved in the development of ASD are revealed. Comorbid occurrence with epilepsy is
quite common, in up to 46% of cases. This article summarizes the current knowledge in this
field with a focus on the hypothesis of excitatory-inhibitory imbalance. Some genetic
causes of ASD and current diagnostic options are also discussed. The pathophysiology of
the co-morbidity of ASD and epilepsy is discussed in terms of possible therapeutic
interventions.
148 Cesk Slov Neurol N 2019; 82/115(2): 148–154
PŘEHLEDNÝ REFERÁT REVIEW ARTICLE
doi: 10.14735/amcsnn2019148
Genetické a neurobiologické aspekty
komorbidního výskytu poruch autistického
spektra a epilepsie
Genetic and neurobiological aspects
of comorbid occurence of autism spectrum
disorder and epilepsy
Souhrn
Poruchy autistického spektra (PAS) se řadí mezi neurovývojové a neuropsychiatrické poruchy
s klinickou manifestací v dětském věku. V posledních letech se tato porucha dostává do popředí
vědeckého zájmu, a to především z důvodu narůstající prevalence až na 1/68 v roce 2014. Odhalují
se genetické příčiny poruchy a patofyziologické mechanizmy, které by se na rozvoji PAS mohly
podílet. Komorbidní výskyt s epilepsií je poměrně častý, a to až ve 46 % případů. Práce shrnuje
dosavadní poznatky v této oblasti se zaměřením na hypotézu excitačně-inhibiční nerovnováhy.
Jsou probrány i některé genetické příčiny PAS a současné možnosti diagnostiky. Patofyziologie
komorbidního výskytu PAS a epilepsie je diskutována z pohledu možných terapeutických
intervencí.
Abstract
Autism spectrum disorder (ASD) is ranked among neurodevelopmental and neuropsychiatric
disorders with clinical onset in childhood. In recent years, this disorder has come to the forefront of
scientific interest, mainly due to increasing prevalence of up to 1/68 in 2014. The genetic causes of
the disorder and the pathophysiological mechanisms that might be involved in the development
of ASD are revealed. Comorbid occurrence with epilepsy is quite common, in up to 46% of cases.
This article summarizes the current knowledge in this field with a focus on the hypothesis of
excitatory-inhibitory imbalance. Some genetic causes of ASD and current diagnostic options are
also discussed. The pathophysiology of the co-morbidity of ASD and epilepsy is discussed in terms
of possible therapeutic interventions.
Tento projekt a publikace byly podpořeny z fondu Lékařské fakulty Masarykovy univerzity pro
juniorského výzkumníka MUDr. Pavlínu Danhofer, Ph.D. a MUDr. Štefánii Aulickou, Ph.D. (č. projektu:
2726 - IRP 2018-ROZV/24/LF/18).
Autoři deklarují, že v souvislosti s předmětem
studie nemají žádné komerční zájmy.
The authors declare they have no potential
conflictsofinterestconcerningdrugs,products,or
services used in the study.
Redakční rada potvrzuje, že rukopis práce
splnil ICMJE kritéria pro publikace zasílané
do biomedicínských časopisů.
The Editorial Board declares that the manuscript
met the ICMJE “uniform requirements” for
biomedical papers.
P. Danhofer1
, O. Horák1
,
Š. Aulická1
, K. Česká1
,
J. Pejčochová1
, L. Fajkusová2
,
H. Ošlejšková1
1
Klinika dětské neurologie LF MU
a FN Brno, Centrum pro epilepsie Brno
2
Centrum molekulární biologie
a genové terapie Interní hematoonkologické
kliniky LF MU a FN Brno

MUDr. Pavlína Danhofer, Ph.D.
Klinika dětské neurologie LF MU
a FN Brno
Černopolní 9
613 00 Brno
e-mail: pavlina.cahova@seznam.cz
Přijato k recenzi: 11. 10. 2018
Přijato do tisku: 14. 1. 2019
Klíčová slova
autizmus – epilepsie – poruchy autistického
spektra – genetika – PAS
Key words
autism – epilepsy – autism spectrum disorder
– genetics – ASD
Poruchy autistického spektra
Poruchy autistického spektra (PAS) se řadí
mezi neurovývojové a neuropsychiatrické
poruchy s klinickou manifestací v dětském
věku charakterizované potížemi v sociální interakci
a komunikaci, omezenými zájmy a repetitivními
prvky v chování. Příznaky přetrvávají
celoživotně a děti s PAS proto po
18. roce věku přecházejí do péče lékařů pro
dospělép acienty.
Častěji se PAS vyskytují u mužů v poměru
4 : 1. Odhadovaná prevalence PAS v populaci
se zvýšila z 1/476–1/323 v 90. letech 20. století
[1,2] na 1/68 v roce 2014 [3]. Takový značný
nárůst prevalence může být dán zčásti zvýšenou
informovaností a povědomím populace
o této poruše, zčásti i změnami v diagnostických
postupech. Svůj podíl mohou
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mít i faktory ze strany matky a faktory prostředí.
Infekce plodu v prenatálním období
může negativně zasáhnout do vývoje imunoregulačních
mechanizmů [4], podstatný
vliv je přikládán febriliím [5]. Dále jsou studovány
např. zvýšená koncentrace toxických
látek v ovzduší [6] a vliv těžkých kovů, kde výsledky
jsou kontroverzní [7,8].
V oblasti klasifikace PAS byla během posledních
let provedena celá řada změn. Autizmus
lze dělit na vysokofunkční a nízkofunkční
(na podkladě kognitivního profilu),
autizmus s regresí nebo bez ní (s ohledem
na vývojové aspekty), syndromický nebo
nesyndromický aj. U nesyndromického autizmu
je PAS primární diagnózou a není
součástí komplexní poruchy, která je charakterizována
vývojovými abnormitami a malformacemi.
Naproti tomu u syndromického
(atypického) autizmu je znám genetický syndrom,
v rámci něhož část pacientů vykazuje
PAS (např. Angelmanův syndrom, syndrom
fragilního chromozomu X, Rettův syndrom).
ProklinickéúčelyvycházejívČRdiagnostická
kritéria PAS z mezinárodní klasifikace nemocí
MKN-10. Zde se autizmus řadí mezi pervazivní
neurovývojové poruchy (F84.0–F84.9). Praktičtější
je, a to především z pohledu možnosti
srovnání pacientů se soubory publikovanými
ve světovém písemnictví, využití klasifikace
DSM (diagnostický a statistický manuál). Tato
klasifikace nemocí zařadila PAS do svého obsahu
ve svém třetím vydání a od té doby prošla
celou řadou změn. Kritéria PAS v DSM-III [9]
vycházela z původních Kannerových případů
[10] a byla poměrně přísná. DSM-IV [11]
poté spektrum autizmu rozšířilo o případy
méně závažně (pervazivní vývojové poruchy
jinak nespecifikované [PDD-NOS] a Aspergerův
syndrom). Poslední revize DSM-V z roku
2013 [12] kombinuje všechny podskupiny do
jedné diagnózy poruch autistického spektra.
PAS se již nedělí do jednotlivých subkategorií,
ale diferencují se pouze varianty autizmu [12].
Současným zlatým standardem v dia-
gnosticeautizmujepodrobnápsychologicko-psychiatrická
anamnéza a testování alespoň
dvěma škálami – celosvětově uznávaným nástrojem
je The Autism Diagnostic Interview –
Revised (ADI-R) a The Autism Diagnostic Observation
Schedule (ADOS). Testování musí
provádět specialista na PAS. ADI-R je velmi podrobná
dotazníková škála založená na strukturovaném
pohovoru s rodiči. ADOS je standardizovaný
diagnostický test, který skóruje na
základě přímé observace dítěte a zohledňuje
i jeho vývojový stupeň a věk. Je doporučován
jako vhodný standardizovaný diagnostický
observační nástroj. Vyšetřující nabízí dítěti interaktivní
aktivity, které jsou navrženy tak, aby
bylo možno hodnotit sociální interakci a komunikaci
i repetitivní prvky v chování, jež jsou
podkladem diagnostiky PAS [13].
Na Klinice dětské neurologie LF MU a FN
Brno byla v roce 2007 provedena retrospektivní
studie 204 dětí s PAS s cílem zjistit, zda
je diagnóza stanovena časně nebo dochází
ke zpoždění v diagnostickém procesu. Závěrem
této studie bylo, že diagnostika autizmu
je často provedena pozdě, a tím je znemožněno
zahájení časných edukačních, behaviorálních
a léčebných intervencí [14]. Zvýšené
povědomí o PAS, lepší informovanost široké
veřejnosti a formování týmů specialistů, kteří
se zabývají diagnostikou této poruchy, přináší
v tomto ohledu slibné výsledky a v současné
době lze konstatovat, že u většiny pacientů je
diagnostika PAS dokončena před dosažením
5. roku věku [15].
Epilepsie u pacientů s PAS
Komorbidní výskyt autizmu a epilepsie byl
znám již od doby, kdy byl autizmus poprvé popsán
Leo Kannerem v roce 1943 [10]. Je všeobecně
známo, že u pacientů s autizmem je
výskyt epilepsie vyšší než v běžné populaci.
Prevalence však kolísá v poměrně širokém rozmezí
– 2 [16] až 46 % [17]. Na Klinice dětské
neurologie LF MU a FN Brno bylo hodnoceno
205 dětí s PAS ve vztahu ke komorbidnímu výskytu
epilepsie nebo epileptiformní aktivity
v EEG. PAS byly spojeny s epileptickými záchvaty
ve 40 % případů a s epileptiformní aktivitou
v EEG bez manifestních záchvatů ve 20 %
případů. Nejvyšší výskyt epilepsie byl ve skupině
dětí s dětským autizmem (66 %) a atypickým
autizmem (30,1 %). Nejnižší výskyt byl
zjištěn u dětí s Aspergerovým syndromem
(3,9 %) [18]. Výsledky studií jsou značně nekonzistentní
[16,17]. Je to dáno především opakovanými
změnami v klasifikačních schématech
a různými diagnostickými postupy. Velký
podíl nese i spektrum vyšetřovaných pacientů.
Obecně lze říci, že soubory z terciárních center
soustřeďující „komplikovanější“ pacienty
(tj. často farmakorezistentní s četnějšími komorbiditami)
vykazují vyšší výskyt komorbidního
výskytu PAS a epilepsie ve srovnání se
soubory „běžných“ pacientů s PAS dispenzarizovaných
v sektorovém ambulantním provozu.
Faktory diskutované v souvislosti
s výskytem epilepsie u pacientů s PAS
Deficit intelektu
Přítomnost intelektového deficitu u PAS
(tj. IQ < 70) je běžně asociována se zvýšenou
mírou výskytu komorbidní epilepsie. Metaanalýza
z roku 2008, která studovala data
z publikovaných studií z let 1963–2006, ukazuje
prevalenci epilepsie u dětí s PAS mladších
12 let 21,4 % v případě přítomného intelektového
deficitu ve srovnání s 8 % u dětí
bez deficitu v intelektu [19]. Další metaanalýza
– z roku 2012, která zahrnula jen studie,
kde follow-up byl delší než 12 měsíců, ukázala
prevalenci 23,7, resp. 1,8 % [20]. Silná
asociace mezi intelektovým deficitem a epilepsií
u dětí s PAS vysvětluje nižší výskyt epilepsie
u pacientů s Aspergerovým syndromem,
kde je intelekt normální.
Pohlaví
Existuje zvýšené riziko epilepsie u dívek
s PAS ve srovnání s chlapci [21].
Etiologie onemocnění
Výskyt epilepsie u pacientů s nesyndromickým
neboli idiopatickým autizmem je nižší
než u pacientů se syndromickým (atypickým)
autizmem. Například dle výsledků jedné studie
20 % u nesyndromické formy ve srovnání
s 33 % u syndromických PAS [22]. I přesto je
ale i u pacientů s idiopatickou formou PAS výskyt
epilepsie vyšší než v běžné populaci. Syndromické
formy PAS spojené s epilepsií jsou
popsány např. u Rettova syndromu, Rett-like
syndromů (mutace v genu pro methyl CpG
binding protein 2 [MECP2], mutace v genu
pro cyclin-dependent kinase-like 5 [CDKL5]),
Angelmanova syndromu (mutace v genu pro
ubiquitin-protein ligázu E3A [UBE3A]), tuberózní
sklerózy (mutace v genu pro tuberous
sclerosis complex [TSC] 1 a TSC2), neurofibromatózy
typu I (mutace v genu pro neurofibromin
1 [NF1]), Dravetova syndromu (mutace
v genu pro sodium voltage-gated channel
alpha subunit 1 [SCN1A]), tedy syndromů, se
kterými se v praxi setkáváme nejčastěji.
Vývojový regres
Vývojový regres je definován jako ztráta již
dříve naučených dovedností. Odhaduje se,
že zhruba 30 % pacientů s PAS prochází vývojovým
regresem, který se typicky objevuje
mezi 18. a 24. měsícem věku [23]. Výskyt
epilepsie a/nebo epileptiformní patologie
v EEG je považován za rizikový faktor pro přítomnost
vývojového regresu [23,24].
Vliv epilepsie a/nebo epileptiformní
aktivity v EEG na rozvoj PAS
Předpokládá se, že epileptiformní abnormita
se může spolupodílet na rozvoji neuropsychologického
deficitu u pacientů s PAS.
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Studie 77 dětí s PAS prokázala, že epileptiformní
výboje v EEG jsou signifikantně více
spojeny s abnormálním vývojem v 1. roce
života [24]. Například u Rettova syndromu,
syndromu fragilního X, Angelmanova syndromu
nebo Prader-Williho syndromu lze
současně nalézt jak patologii v EEG, tak i příznaky
PAS. Je však nutné brát v úvahu, že nejsme
schopni přesně vystopovat, kdy se epileptiformní
aktivita v EEG u daného pacienta
objevila poprvé. Je ovšem možné, že epileptiformní
výboje v EEG, které se objeví v kritickém
období vývoje, jsou částečně odpovědné
za rozvoj autistických symptomů [25]
nebo se mohou asociovat s autistickým regresem
u těchto dětí [24].
Epileptiformní výboje mohou mít negativní
dopad na senzorické, paměťové a vyšší
kognitivní funkce, a to především pokud se
vyskytují ve spánku, který je považován za
klíčový v procesech učení a paměti. Toto
je patrno zvláště u pacientů s Landau-Kleffnerovým
syndromem, kde se ve spánku
setkáváme s kontinuálními výboji v EEG.
Pacienti mají těžký kognitivní deficit a často
i PAS [26]. Potlačení výbojů antiepileptickou
medikací však nepřináší vždy jednoznačný
a předvídatelný efekt [27].
Vidíme tedy, že epileptiformní výboje
v EEG mají dopad na kognitivní funkce
pacienta, ale potlačení výbojů nevede
k předpokládanému zlepšení neuropsychologického
profilu. V takovém případě je
nutné zvažovat i jiné faktory, které se dostávají
do hry, jak je probíráno dále v textu.
Zvířecí modely ukazují, že pokud je epilepsie
provokována epileptickým statem
(status epilepticus; SE), lze pozorovat rozvoj
aseptického zánětu, objevují se poruchy buněčného
metabolizmu a poruchy na úrovni
iontových kanálů a receptorů. Rozvíjí se poruchy
vedení vzruchu, tvoří se aberantní
neuronální sítě. Nakonec může dojít až
k apoptóze buněk. Zároveň jsou poškozeny
neuronální okruhy citlivé na rozvoj dalších
záchvatů a nejsou schopny udržet normální
kognitivní funkce [28]. Pravda je, že samotný
SE se často objevuje jako důsledek zánětu,
infekce nebo traumatu. Pak je obtížné rozlišit,
jaký je podíl samotného etiologického
procesu a jak se v rozvoji kognitivního deficitu
uplatňuje následný SE. Potlačení záchvatů
však vede jen k minimálnímu zlepšení
kognitivního profilu pacientů. Proto je
možné, že samotná příčina epilepsie může
vést přímo k poškození neuropsychologických
funkcí autistických pacientů [25] více
než další epileptický proces.
Etiopatogeneze komorbidního
výskytu epilepsie a PAS
Genetické aspekty v patogenezi
komorbidního výskytu epilepsie
a PAS
Studie s dvojčaty ukazují, že dědičnost PAS
je zhruba 85–92 % [29,30]. I v případě, že se
nepodaří identifikovat mutaci odpovědnou
za rozvoj PAS, je riziko pro další potomky
vyšší [31]. V etiopatogenezi PAS se předpokládá
role jak vzácných, tak běžných variant
genů. S pokrokem na poli molekulárně-genetických
technologií (jako jsou chromozomální
microarray technologie nebo celoexomové
sekvenování – whole exome
sequencing) bylo identifikováno více než
800 chromozomálních lokusů a genů, které
by mohly být asociovány s PAS, což poukazuje
na vysoce heterogenní genetickou architektoniku
této poruchy [3]. Geny a jejich
příslušné proteiny se uplatňují v celé řadě
biologických procesů, např. remodelaci
chromatinu, regulaci genové transkripce,
buněčném růstu a proliferaci a v neuronálně
specifických procesech, jako jsou např. synaptická
organizace a aktivita, dendritická
morfologie a axonogeneze [3].
Přehlednou databází genů asociovaných
s PAS je Simons Foundation Autism Research
Initiative (SFARI) gene [32]. Databáze
podává informace o hladině významnosti
dané mutace na podkladě výsledků zvířecích
a humánních studií. Všechny geny, pro
které existuje hladina úrovně důkazu v diagnostice
PAS, jsou skórovány v databázi: 1 –
vysoce důvěryhodný a 2 – silný kandidátní
gen. Je jich 51 (aktuální počet v roce 2018)
a jsou uvedeny souhrnně v tab. 1.
Co se týká komorbidního výskytu PAS
a epilepsie, riziko rozvoje epilepsie u dětí
s PAS je 12,8 %, u jejich sourozenců 2,3 %, což
je 2× vyšší riziko než v běžné populaci. Genetické
pozadí se tedy týká nejen PAS, ale i epilepsie
v rodinách s mnohočetným výskytem
autizmu [33,34]. Vztah mezi PAS a epilepsií
zůstává nejasný; může zde být kauzální
vztah mezi těmito dvěma poruchami (především
v případě epileptických encefalopatií
či syndromického autizmu) nebo jsou
obě výsledkem stejného neuropatofyziologického
procesu. V každém případě se předpokládá,
že na rozvoj PAS a epilepsie mají
vliv nejen dědičné, ale i další faktory [25], jak
bude detailněji probráno dále.
Imunitní faktory v patogenezi
komorbidního výskytu epilepsie a PAS
Zánětlivé procesy v CNS hrají poměrně významnou
roli ve společné patogenezi epilepsie
a PAS. Jejich dopadem mohou být
Tab. 1. Přehled genů se skóre 1 a 2 z databáze genů asociovaných s autismem SFARI
gene: „1“ – vysoce důvěryhodný a „2“ – silný kandidátní gen.
Gen Chromozom Název genu Skóre
ADNP 20q13.13 activity-dependent neuroprotector homeobox 1
ANK2 4q25-q26 ankyrin 2, neuronal 1
ARID1B 6q25.3 adenin thymin rich interactive domain 1B (SWI1-like) 1
ASH1L 18q12.1 Ash1 (absent, small, or homeotic)-like (Drosophila) 1
ASXL3 18q12.1 additional sex combs like 3 (Drosophila) 1
CACNA1H 16p13.3 calcium channel, voltage-dependent, alpha 1H subunit 2
CACNA2D3 3p21.1-p14.3
calcium channel, voltage-dependent,
alpha 2/delta subunit 3
2
CHD8 14q11.2 chromodomain helicase DNA binding protein 8 1
CNTN4 3p26.3-p26.2 contactin 4 2
CTNND2 5p15.2 catenin (cadherin-associated protein), delta 2 2
CUL3 2q36.2 cullin 3 1
DSCAM 21q22.2 Down syndrome cell adhesion molecule 1
DYRK1A 21q22.13
dual-specificity tyrosine-(Y)-phosphorylation
regulated kinase 1A
1
GABRB3 15q12 gamma-aminobutyric acid (GABA) A receptor, beta 3 2
GIGYF2 2q37.1
growth factor receptor-bound protein 10 (GRB10) interacting
glycine-tyrosine-phenylalanine domain protein 2
2
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změny indukované mediátory zánětu v excitačních
neuronálních sítích.
U komorbidního výskytu PAS a epilepsie
nacházíme zvýšení HMBG-1 (high mobility
group box protein 1), klíčové zánětlivé
molekuly, která aktivuje signální cestu
přes interleukin (IL)-1 a IL-1ß. U pacientů
s PAS toto zvýšení koreluje s postižením
v sociální interakci [35]. Stejně tak zvýšení
exprese HMBG-1 bylo detekováno v hipokampu
pacientů s epilepsií temporálního laloku
(TLE) [36] a dětí s febrilními křečemi [37].
Poznatky opět ukazují na aktivaci IL-1 signální
kaskády vedoucí k zánětlivé reakci se
zvýšenou excitabilitou v neuronálních sítích.
Ukazuje se, že antagonisté HMBG-1 jsou
v preklinických studiích účinné v kontrole
záchvatů [36].
U pacientů s PAS bylo detekováno zvýšení
Th1 prozánětlivých cytokinů (např. IL-6,
tumor necrosis factor α [TNF-α] a interferon
γ [IFN-γ]), hladina protizánětlivých Th2 cytokinů
(např. IL-4, IL-5, IL-10) zůstává nezměněna.
U pacientů tím dochází ke zvýšení
poměru Th1/Th2 (T-helper lymphocytes 1/T-helper
lymphocytes 2). Periferní lymfocyty
u pacientů s PAS vykazují 2× vyšší hladiny
prozánětlivých cytokinů ve srovnání s kontrolami.
Pokud byl TNF-α vyšetřen u všech nepostižených
sourozenců pacientů s PAS, byla
zjištěna opět signifikantně vyšší hladina této
molekuly, což svědčí pro určitý podíl genetiky
v nastavení zánětlivých signálních kaskád
[38]. Stejně tak byla zjištěna elevace prozánětlivých
cytokinů (TNF-α, IL-1β a IL-6)
u pacientů s TLE. Tyto cytokiny mají in vivo
i in vitro prokázaný prokonvulzivní efekt [39].
Dalšími společnými patofyziologickými
vodítky mezi PAS a epilepsií mohou být
porucha integrity hematoencefalické bariéry
(HEB), mikrogliální aktivace a zánět indukovaný
stresem. Mastocyty lokalizované
v hypotalamu mohou být aktivovány stresem,
jak bylo pozorováno u pacientů s PAS,
a mohou vést k poruše HEB. Aktivace mastocytů
vede ke spuštění prozánětlivých kaskád
(např. exprese IL-6, vaskulárního endoteliálního
růstového faktoru – vascular endothelial
growth factor [VEGF]), které mají dopad
na úrovni tight junctions HEB, což způsobuje
poruchu její integrity [40]. Porucha integrity
HEB byla zjištěna i na modelech chronické
epilepsie, kde je opět důsledkem aktivace
prozánětlivých signálních kaskád [41].
Společným důsledkem aktivace zánětlivého
procesu u pacientů s PAS a epilepsií je
zvýšení excitability mozku a progrese klinického
vyjádření obou syndromů. Následkem
Tab. 1 – pokračování. Přehled genů se skóre 1 a 2 z databáze genů asociovaných
s autismem SFARI gene: „1“ – vysoce důvěryhodný a „2“ – silný kandidátní gen.
Gen Chromozom Název genu Skóre
GRIN2B 12p13.1 glutamate receptor, inotropic, N-methyl D-apartate 2B 1
GRIP1 12q14.3 glutamate receptor interacting protein 1 2
ILF2 1q21.3 interleukin enhancer binding factor 2Â 2
INTS6 13q14.3 integrator complex subunit 6 2
IRF2BPL 14q24.3 interferon regulatory factor 2 binding protein-like 2
KAT2B 3p24.3 lysine (K) acetyltransferase 2BÂ 2
KATNAL2 18q21.1 katanin p60 subunit A-like 2 1
KDM5B 1q32.1 lysine (K)-specific demethylase 5B 2
KMT2C 7q36.1 lysine (K)-specific methyltransferase 2CÂ 2
KMT5B 11q13.2 lysine methyltransferase 5B 1
MED13L 12q24.21 mediator complex subunit 13-like 2
MET 7q31.2
met proto-oncogene (hepatocyte growth factor
receptor)
2
MSNP1AS 5p14.1 moesin pseudogene 1, antisense 2
MYT1L 2p25.3 myelin transcription factor 1-like 1
NAA15 4q31.1 N(alpha)-acetyltransferase 15, NatA auxiliary subunit 1
NCKAP1 2q32.1
non-catalytic region of tyrosine kinase adaptor-associated
protein 1
1
NLGN3 Xq13.1 neuroligin 3 2
NRXN1 2p16.3 neurexin 1 2
POGZ 1q21.3 pogo transposable element with zinc finger domain 1
PTEN 10q23.31
phosphatase and tensin homolog (mutated in multiple
advanced cancers 1)
1
RANBP17 5q35.1 ras-related nuclear binding protein 17 2
RELN 7q22.1 reelin 1
RIMS1 6q13 regulating synaptic membrane exocytosis 1 2
SCN2A 2q24.3 sodium channel, voltage-gated, type II, alpha subunit 1
SCN9A 2q24.3 sodium voltage-gated channel alpha subunit 9 2
SETD5 3p25.3
Su(var)3-9, enhancer-of-zeste and trithorax (SET)
domain containing 5
1
SHANK2 11q13.3-q13.4 Src homology 3 and multiple ankyrin repeat domains 2 2
SHANK3 22q13.33
Src homology 3 and multiple ankyrin repeat
domains 3
1
SLC6A1 3p25.3
solute carrier family 6 (neurotransmitter transporter),
member 1
2
SPAST 2p22.3 spastin 2
SYNGAP1 6p21.32
synaptic Ras guanosin tri phosphate (GTP)ase activating
protein 1
1
TBR1 2q24.2 T-box, brain, 1 1
TNRC6B 22q13.1 trinucleotide repeat containing 6B 2
TRIP12 2q36.3 thyroid hormone receptor interactor 12 1
USP7 16p13.2 ubiquitin specific peptidase 7 (herpes virus-associated) 2
WDFY3 4q21.23
tryptophan-aspartic acid repeat and FYVE domain
containing 3
2
FYVE – Fab 1 (yeast orthologue of PIKfyve), YOTB, Vac 1 (vesicle transport protein), and EEA1
SFARI – Simons Foundation Autism Research Initiative
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zvýšení excitability v mozkových neuronálních
okruzích nastane porucha excitačně-inhibiční
(E/I) rovnováhy, která představuje
velmi křehké ekvilibrium mezi excitačními
a inhibičními vlivy mozku. Dochází pak k nekontrolovatelným
neuronálním výbojům
a rozvoji záchvatů, jak bude blíže vysvětleno
v další kapitole [25]. U pacientů s PAS a epilepsií
byla v post mortem studiích zjištěna
astroglióza, odpovědná za poruchu zpětného
vychytávání glutamátu, což vede ke
zvýšení jeho extracelulárních hladin a zvýšení
excitability. Aktivace mikroglie (opět
pozorována u obou procesů) zvýšení glutamátu
ještě podporuje. Stejný efekt má aktivace
IL-6, která stimuluje tvorbu excitačních
synapsí [42].
Hypotéza společného
patofyziologického mechanizmu
komorbidní epilepsie a PAS
Shrnutím výše uvedených pozorování a výsledků
lze předpokládat, že autizmus a epilepsie
mohou mít alespoň v některých případech
společný neurobiologický podklad.
Jak bylo uvedeno v úvodu, existují syndromy,
pro které je společný výskyt těchto
dvou diagnóz typický. Právě v těchto případech
je patrné a všeobecně přijímané, že jak
PAS, tak epilepsie mohou mít společnou genetickou
příčinu, která postihuje synaptické
funkce a vývoj mozku. Jedna z nejrozšířenějších
hypotéz, která popisuje komorbidní výskyt
PAS a epilepsie, předpokládá, že neurovývojový
defekt různého původu (např.
genetického, metabolického, imunitního
nebo působením faktorů vnějšího prostředí)
vede ke změně struktury excitačních a inhibičních
okruhů, což má za následek rozvoj
perzistující E/I nerovnováhy [42]. Tento vztah
ilustruje obr. 1 [43].
Podkladem hypotézy E/I rovnováhy je
předpoklad, že normální mozkové funkce
závisí na dokonalé rovnováze mezi excitačními
a inhibičními vstupy do klíčových mozkových
buněk. Pokud je přítomna nadměrná
excitace nebo nedostatečná inhibice, dojde
k hyperexcitabilitě neuronální sítě a rozvoji záchvatů.
U celé řady epileptických syndromů
může být za rozvoj záchvatů odpovědná nedostatečná
inhibice, např. alterace receptorů
pro gama aminomáselnou kyselinu (GABA)
nebo funkce interneuronů. Může také dojít
k nadměrné excitaci např. na úrovni excitačních
receptorů nebo excitačních neuronálních
okruhů. V souladu s teorií E/I rovnováhy
je i princip terapie antiepileptiky, který
známe z běžné neurologické praxe: použití
GABAergních agonistů ke zvýšení inhibice
nebo snižování excitačních vlivů blokátory
sodíkových nebo vápníkových kanálů.
V oblasti rozvoje PAS je hypotéza excitačně-inhibiční
rovnováhy přijímána již více
než 10 let. Pokud E/I nerovnováha vede
k rozvoji záchvatů, pak samotná přítomnost
záchvatů může indikovat rozvoj E/I nerovnováhy
i u pacientů s PAS [25]. Ztráta inhibice
cestou alterace GABAergní transmise, dysfunkce
interneuronů nebo abnormální migrace
byla dokumentována i u pacientů s PAS.
Bylo zjištěno snížení hladin GABA v kortikálních
oblastech mozku u těchto pacientů [44]
a snížení GABAA
receptorů v oblasti frontálního
kortexu [45]. Post mortem studie ukazují
redukci parvalbuminových interneuronů
v mediálním prefrontálním kortexu [46].
E/I nerovnováha může být vysvětlením v pa-
togeneziiuceléřadygenetickýchsyndromů,
které spojují epilepsii a PAS – mutace v genu
pro SCN1A, mutace v genu pro podjednotku
epsilon-1 glutamátového receptoru
(GRIN2A) nebo mutace v genu pro phosphatase
and tensin homolog (PTEN) [25].
Logickým důsledkem této hypotézy je
úvaha, že antiepileptika by mohla zlepšit
kognitivně-behaviorální komorbidity u autistických
pacientů. Zvířecí modely nabízí
velmi slibné výsledky, např. u SCN1A +/myší
bylo prokázáno zlepšení sociálních
a paměťových funkcí po léčbě klonazepamem
[47]. Bohužel antiepileptika v případě
podání pacientům s autizmem tento efekt
nevykazují [48,49]. Naše zkušenosti ukazují,
že podání klonazepamu pacientům se syndromem
Dravetové nevede ke zlepšení kognitivních
a behaviorálních funkcí (vlastní
nepublikované pozorování).
Z předchozího vyplývá, že problematika
autistických projevů u pacientů s epilepsií nebude
jen důsledkem samotné epilepsie nebo
E/I nerovnováhy. Do hry vstupují další faktory.
E/I rovnováhu nelze chápat jako statické ekvilibrium.
Dokonce i v klidovém stavu jsou mozkové
struktury aktivní a informace v mozku
jsou zpracovávány prostřednictvím specifických
rytmů. Právě tyto mozkové rytmy jsou
schopny koordinovat neuronální výboje,
a tak je umožněn přenos informací. Základní
roli v uvedených procesech hraje GABAergní
inervace. GABAergní inhibice vytváří rytmickou
aktivitu oscilací a „rytmické ticho“ neuronů
během oscilací způsobuje okno, ve kteObr.
1. Schematické znázornění patofyziologického modelu komorbidního výskytu poruch
autistického spektra a epilepsie – hypotéza excitačně-inhibični nerovnováhy. Převzato
a modifikováno z [43].
GABA – gama aminomáselná kyselina
Fig. 1. Schematic representation of the pathophysiological model of the comorbid
occurence of autism spectrum disorder and epilepsy – hypothesis of excitatory-inhibitory
dysbalance. Taken and modified from [43].
GABA – gamma-aminobutyric acid
imunologické
a metabolické
faktory
mozek
genetické
faktory
GABAergní
a glutamátergní
dysfunkce
• snížení inhibice
• zvýšení excitace
• excitačně-inhibični nerovnováha
• změna mozkových rytmů a koordinace
oscilací v neuronálních sítích
• alterace sociálního chování a kognitivní
poruchy
• rozvoj epileptických záchvatů
faktory
prostředí
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Cesk Slov Neurol N 2019; 82/115(2): 148–154 153
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Antagonisté glutamátového receptoru
Předpokládá se jejich efekt na snížení hyperexcitability
u pacientů s PAS a komorbidní
epilepsií a byla provedena celá řada studií
u pacientů s PAS a syndromem fragilního X.
Výsledky jsou opět nekonzistentní a rozporuplné.
Antagonista N-metyl-D-aspartát receptoru
memantin ukázal pozitivní efekt na
myších modelech [59] a dokonce i v klinické
studii u pacientů s autizmem [60].
Mammalian Target of Rapamycin
(mTOR) inhibitory
Zapojení mTOR inhibitorů je klíčové v regulaci
řady buněčných procesů – růstu, proliferaci
a translaci proteinů. Komponenty mTOR
signální cesty v mozku jsou lokalizovány na
synapsích, kde kontrolují synaptogenezi.
mTOR inhibitor rapamycin je schopen zlepšit
neurobehaviorální deficit u myší s PAS [61].
Probíhají klinické studie s mTOR inhibitory
u pacientů s tuberózní sklerózou a refrakterní
epilepsií, kde měly pozitivní vliv na redukci
záchvatů, jak ukazuji výsledky III. fáze
klinické studie [62].
Závěr
Komorbidní výskyt PAS a epilepsie není
zřejmě pouhou koincidencí, ale jedná se
o velmi komplexní a vícesubstrátový proces.
Porozumění patofyziologickému substrátu
tohoto komorbidního výskytu je stěžejní
nejen pro pochopení procesů probíhajících
v mozku u pacientů, ale může být zásadní
i z pohledu možných terapeutických intervencí.
Hypotéza porušené E/I rovnováhy
nabízí hned několik cílových molekul v léčebných
možnostech těchto onemocnění
(GABA agonisté, neurosteroidy, antagonisté
glutamátových receptorů, mTOR inhibitory
a další). Výsledky na zvířecích modelech jsou
slibné. Jejich aplikace na člověka ale musí
projít ještě složitou cestou, která je vzhledem
k závažnosti těchto diagnóz a limitovaným
terapeutickým možnostem velkou výzvou
v celosvětovém vědeckém měřítku.
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Pochopení patofyziologického substrátu komorbidního
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Hypotéza porušené E/I rovnováhy
nabízí hned několik cílových molekul v léčebných
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GABA agonisté
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Ukazuje se, že STX209 může zlepšit symptomatiku
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jako např. riluzol, tiagabin, vigabatrin, zlepšení
symptomatiky PAS je rozporuplné
a nepřesvědčivé [56].
Neurosteroidy
Řadí se mezi pozitivní modulátory GABAA
receptorů. Příkladem je syntetický derivát
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ganaxolon. Ukázal se efektivní
v redukci záchvatů na myších modelech
epileptických spazmů [57] a chování u myší
s PAS [58]. Výzkum ganaxolonu se nachází
ve fázi II u pacientů s refrakterní epilepsií
a u pacientů s PAS a syndromem fragilního X.
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proLékaře.cz | 23.1.2022