Headaches
Eva Vlčková, Martin Pail
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Introduction to neurology
Neurology is the branch of medicine concerned with the study and treatment of disorders of the nervous
system.
Major neurological disorders include:
⎯ Cerebrovascular disease, such as stroke
⎯ Headache disorders
⎯ Seizure disorders, such as epilepsy
⎯ Autoimmune diseases of the central and peripheral nervous system, such as multiple sclerosis
(demyelinating diseases), Guillain-Barre syndrome,...
⎯ Infections of the brain, spinal cord and peripheral nervous system, such as meningitis,
encephalitis, myelitis, radiculoneuritis
⎯ Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and syndromes,
amyotrophic lateral sclerosis, etc.
⎯ Neuromuscular disorders (myopathies, peripheral neuropathies, neuromuscular junction
disorders).
⎯ Degenerative spine diseases and their complications
⎯ Traumatic lesions of the brain, spinal cord and peripheral nerves
⎯ Sleep disorders
⎯ Tumours
From an aetiological point of view, disorders of the nervous system can be divided into two basic groups:
genetic (congenital) and acquired lesions. The latter group includes a wide range of causes: vascular
disorders, infections, autoimmune diseases, traumatic lesions, compressive disorders or degenerative
diseases.
In addition, lesions of the nervous system can be divided into two types: structural and functional.
Structural lesions include trauma, stroke, tumour, inflammation, compression and many others. From a
functional point of view, the nervous system can be affected by metabolic dysregulation, e.g. hypo-,
hyperglycaemia; hypo-, hypernatremia; hypo-, hypercalcemia; hypo-, hypermagnesemia; hypoxia;
hyperammonemia; ion and channel and synaptic abnormalities, ... Some diseases involve both of the
above-mentioned components. If the cause of the disease is not known, this possibility is called
idiopathic disease.
From another point of view, the nervous system can be damaged at a certain level to such an extent
that some (or even all) of its function is lost (for example, paresis or loss of speech or language due to
stroke). The second group of symptoms is called irritative. This term refers to a set of symptoms that
are typically associated with increased neuronal excitability or abnormal electrical activity in the nervous
system. These symptoms often arise from a part of the nervous system experiencing irritability or
hyperexcitability (e.g. rhythmic motor activity during an epileptic seizure or neuropathic pain and
paresthesia in painful mono- or polyneuropathies).
The clinical manifestation of the disease depends on whether the whole nervous system is affected or
only part of it. In the latter case, only part of the nervous system is not functioning properly (For more
details, see the section on focal and non-focal neurological deficits below.) In this situation, the first step
is to determine whether the central or peripheral nervous system is affected (see below). In addition, by
looking at the distribution of symptoms and signs, neurologists can usually identify the specific part of
the nervous system that is affected in a particular patient. Knowledge of the basic anatomical principles
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of the organization of the nervous system is therefore essential for making a correct diagnosis and for
understanding neurology in general.
1. Nervous system
The nervous system is a highly complex and sophisticated system of the body that regulates and coordinates
its actions and sensory information through the transmission of signals to and from different
parts of the body. It has two main parts:
- The central nervous system (CNS): the brain and the spinal cord. The brain can be divided into the
infratentorial area (brainstem and cerebellum) and the supratentorial area (cortex, thalamus, basal
ganglia and white matter of the hemispheres).
- The peripheral nervous system (PNS) consists mainly of nerves, which are closed bundles of long
fibres or axons that connect the CNS to every other part of the body. This system also includes neural
elements called "sensory receptors" in the eyes, ears, skin, etc. The PNS is divided into two separate
subsystems, the somatic (motor and somatosensory) and autonomic (sympathetic and
parasympathetic). The autonomic nervous system is involuntary. Nerves that come from the brain are
called cranial nerves, while those that come from the spinal cord are called spinal nerves. Several
PNS levels can be distinguished: neuromuscular junction, peripheral nerve (motor-sensitive-mixed),
plexus, spinal roots, peripheral (lower) motor neuron, pseudounipolar neuron.
At a cellular level, the nervous system is defined by the presence of a specific type of nerve cell called
a neuron. Neurons have unique structures that allow them to send signals quickly and precisely to other
cells. They send these signals in electrochemical form along thin fibres called axons, which cause
chemicals called neurotransmitters (glutamate, GABA, acetylcholine,...) to be released at junctions
called synapses. A cell that receives a synaptic signal from a neuron can be excited, inhibited or
otherwise modulated. The connections between neurons can form neural pathways, neural circuits and
larger networks that generate an organism's perception of the external environment and determine its
behaviour. In addition to neurons, the nervous system contains other specialised cells called glial cells,
which provide structural and metabolic support.
Fig. 1 Scheme of synaptic junction (nerve to nerve)
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1.1 Signs and symptoms of nervous system disorders
In general, neurological deficits can be divided into focal and non-focal. A focal neurological deficit is
caused by a lesion (ischemia, hemorrhage, tumor infiltration or compression, etc.) of a specific part of
the peripheral or central nervous system, i.e. a specific area of the brain or spinal cord or a peripheral
nerve The lesion therefore only affects the function of the relevant part of the nervous system. The
clinical manifestation depends on what specific functions are localized in the affected area (i.e.
what pathways pass through it or what centers are located there). The most common clinical
manifestations are motor (paresis, repetitive focal movements during an epileptic seizure), sensory
(hypoesthesia, paresthesia), or affect speech or language functions. Olfaction, vision, hearing and
vestibular dysfunctions are also considered focal neurological deficits.
Typical examples of the focal neurological deficits are global aphasia and right-sided hemiparesis in leftsided
middle cerebral artery ischaemia, or paresthesias of the fingers I-IV and the palm of the right hand
in a patient with compression of the median nerve in the wrist, i.e. right-sided carpal tunnel syndrome.
The nature, distribution and severity of the clinical symptoms and signs may thus indicate which area of
the brain or nervous system is affected.
Knowledge of at least the most important neural pathways and centres is therefore a key condition for
the diagnosis of neurological diseases. Knowledge of at least the major nerve tracts and centres is
therefore essential for the diagnosis of neurological diseases. The basic anatomical principles are
reviewed below.
In contrast, non-focal deficits are NOT specific to a particular area of the brain. They can include
confusion, headaches, cognitive impairment or emotional problems. It's usually not possible to identify
the specific area of the brain or nervous system that is affected in patients with this type of clinical
presentation.
The following are the most common signs and symptoms of a nervous system disorders.
However, each person may experience the symptoms in a different way. In addition, each neurological
condition presents with only some of these symptoms, often in typical and largely disease-specific
combinations called 'syndromes'.
Symptoms may include:
⎯ Weakness or loss of muscle strength
⎯ Muscle wasting
⎯ Loss of sensation (numbness) or tingling
⎯ Headaches
⎯ Visual field loss
⎯ Double vision
⎯ Language impairment (expression or comprehension)
⎯ Slurred speech
⎯ Altered consciousness or awareness
⎯ Memory loss, confusion
⎯ Impaired mental ability
⎯ Lack of coordination
⎯ Dizziness or loss of balance
⎯ Muscle rigidity, hypokinesia, and bradykinesia
⎯ Tremors, hyperkinesias
⎯ Seizures
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⎯ Back pain that radiates into the leg or the arm
1.2 Upper and lower motor neuron
Voluntary movement is controlled by a motor nervous system. The body of the first (upper)
motoneuron is located in the cerebral cortex. Nerve cell impulses (or action potentials) leave the
motor cortex via the axons of the upper motoneurons, which cross (decussate) at the junction of the
medulla oblongata and the spinal cord. The axons then enter the spinal cord as part of the corticospinal
tracts. The corticobulbar pathway then carries impulses from the motor cortex to the nuclei of the cranial
nerves in the brainstem. In this case, the pathway crosses just short of the nucleus. Second (lower)
motor neurons then carry impulses from the ventral horns of the spinal cord or the nuclei of the
cranial nerves to the skeletal muscles. If a lesion occurs in the upper motor neuron (and it does not
matter whether it is the body or the axon), we are talking about a central lesion. The manifestation of
the affected function will be contralateral to the lesion. Similarly, a lesion of the lower motor neurons is
called a peripheral lesion. The manifestation of the affected function is ipsilateral to the lesion. The
manifestation of a motor neuron lesion is paresis (some movement is possible) or plegia (no
movement).
Fig.2 Upper and lower motor neuron
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Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
Fig. 3 The topographical representation of the homunculus - sensory and motor cortex
1.3 Somatosensory system
The somatosensory system is a complex system of sensory neurons and pathways that respond to
changes at the surface or inside of the body. The axons (as afferent nerve fibres) of sensory neurons
connect to or respond to different receptor cells (mechanoreceptors, thermoreceptors, chemoreceptors
and nociceptors,...). Sensory receptors are found throughout the body, including the skin, epithelial
tissues, muscles, bones and joints, internal organs and the cardiovascular system. The first-order
neurons are the pseudounipolar cells whose cell bodies are located in the dorsal root ganglion of the
spinal nerve, or in the trigeminal ganglion, or in the ganglia of other sensory cranial nerves. These
neurons are connected to the receptor and transmit the signal to the spinal cord. The somatosensory
system consists of two basic neural pathways.
1. Neurons that carry information about deep sensations (vibration and proprioception, i.e. the
sensation of position, direction and changes in speed of movement). When these neurons enter the
spinal cord, they rise in the ipsilateral spinal column in the medulla oblongata of the brainstem, where
they switch to second-order neurons and cross over. They then continue to the thalamus and primary
somatosensory cortex. This pathway is called the spino-bulbo-thalamo-cortical pathway (dorsal
column, spinobulbar pathway).
2. Neurons that carry information about superficial sensations - temperature and pain - cross in the
spinal cord near their entry point and the rest of the pathway goes along the contralateral part of the
spinal cord and the brainstem in the thalamus and later on to the primary somatosensory cortex. This
pathway is called the spinothalamic (or spino-thalamo-cortical) pathway.
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Fig.4 The somatosensory system – spinobulbar pathway
Fig.5 The somatosensory system – spinothalamic pathway
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The superficial tactile sensation (touch) is transmitted in both pathways.
As can be seen from the pictures information, the two tracts cross each other in their course. Therefore,
lesions localized above the crossing point lead to contralateral clinical manifestations (i.e., contralateral
hemihypoesthesia for the corresponding modalities). Second-order neurons have their cell bodies
either in the spinal cord (spinothalamic pathway) or in the brainstem (spinobulbar pathway). Third-order
neurons are located in the thalamus and terminate in the postcentral gyrus of the parietal cortex,
specifically in the primary somatosensory cortex or related areas. The most common clinical symptoms
caused by lesions of the somatosensory system are hypoesthesia or anesthesia (for some or even all
modalities) (so-called negative symptoms) or paresthesia and neuropathic pain (positive symptoms).
Some patients experience a combination of these two types of symptoms.
1.4 Cranial nerves
The olfactory nerves (I) and the optic nerves (II) arise from the cerebrum, while the remaining ten pairs
of cranial nerves arise from the brainstem, the lower part of the brain. The cranial nerves provide motor,
sensory and autonomic supply mainly to the structures within the head and neck. The sensory supply
includes both 'general' sensations such as temperature and touch, and 'special' senses such as taste,
visual perception, smell, balance and hearing.
Fig.6 The cortico-bulbar motor pathway, the position of motor nuclei of cranial nerves
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Fig.7 Examples of cranial nerve functions
1.5 Functions of individual brain lobes/neocortex
The functional specialisation of individual parts of the neocortex has been taught in detail in
neuroanatomy. The most important information is summarised in the following tables and figures.
Frontal Lobe
• Frontal Lobe
• Body Movement
• Personality
• Reasoning, concentration, judgement
• Executive function (planning, organising, problem solving)
• Emotional control centre and reactions, impulse control
• Social interactions
• Memory (mainly short-term)
• Language - Expression (dominant hemisphere)
• Smell
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Fig.8 Functional Areas of the Cerebral Cortex
Parietal Lobe
• Receives and processes sensory input from the body and skin
(somatosensory information)
• Integrates sensory information between different modalities
• Body awareness
Temporal Lobe
• Hearing
• Language - understanding (dominant hemisphere)
• Recognising faces
• Meaning and emotion
• Memory (mainly long term)
• Smell
Occipital Lobe
• Visual perception
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1.6 Basal ganglia
The term "basal ganglia" (BG) refers to a group of subcortical nuclei that are primarily responsible for
motor control. Disruption of the basal ganglia network is the basis of several movement disorders.
Important functions of the BG are posture, regulation of muscle tone and coordination of voluntary and
automatic movements. The basal ganglia are involved in the generation of movement programmes, the
initiation and timing of movements, the adaptation of movements to external conditions, as well as other
functions such as motor learning, executive functions and behaviour, emotionality and mental
integration. Manifestations of basal ganglia damage include rigidity, hypo- and bradykinesia, tremor,
dystonia, chorea, etc.
1.7 Cerebellum
The physiological functions of the cerebellum are the regulation of muscle tone,
balance and movement co-ordination (course and goal of movement, positioning
of body segments, recruitment of muscle groups during movement). Clinical
manifestation is ipsilateral, i.e. the affected part of the body is on the same side
as the affected hemisphere of the cerebellum.
1.8 Blood supply to the brain
The brain receives blood from two sources: the
internal carotid arteries, which arise from the common
carotid arteries, and the vertebral arteries. The internal
carotid arteries branch to form two major cerebral
arteries, the anterior cerebral artery, and the middle
cerebral artery. These two arteries together supply the
major part of the anterior and middle cerebral
hemispheres.
The two vertebral arteries join together at the base of
the skull to form the basilar artery, which supplies the
brainstem. At the level of the midbrain, the basilar
artery bifurcates to form the two posterior cerebral
arteries, which supply the posterior cerebral
hemispheres.
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Fig.9 Blood supply to the brain – territories
2 Headache
2.1 Basic terms
Headache: Pain located in the head, above the orbitomeatal line and/or nuchal ridge.
Facial pain: Pain below the orbitomeatal line, anterior to the auricles, and above the neck.
Cervical pain: Pain in the nuchal region (dorsal aspect of the upper neck, including the region of insertion
of neck muscles on the cranium).
Attack of headache: Headache that builds up, remains (at a certain level for minutes, hours or days),
then wanes until it has resolved completely.
Duration of attack: Time from onset until termination of an attack of pain.
Frequency of attacks: The rate of occurrence of attacks of headache per time period (commonly one
month).
New headache: Any phenotype of headache from which the patient was not previously suffering.
Headache diagnosis: Diagnostic criteria for the particular type of headache must be met in an individual
patient to obtain a specific headache diagnosis. The basic classification of headaches is based on
pathophysiology, as primary or secondary (with different types, subtypes or subforms). Patients with
different headache phenotypes should receive more than one diagnosis (remember that patients with
migraine or tension-type headache may have any type of secondary headache, which should be
considered especially if the clinical presentation of the headache is different from previous episodes
experienced by the patient).
Primary headache: Headache or headache disorder that is not caused by or attributed to another
disorder. The potentially causative disorder must be excluded, the headache phenotype must fulfil the
requirements described in the criteria for this diagnosis and a minimum number of attacks (usually five)
must be experienced.
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Secondary headache: Headache or headache disorder caused by another underlying disorder. A
secondary headache is attributed to the causative disorder, although it may have clinical characteristics
similar to some types of primary headache.
In general, the most important tools for distinguishing between headache types are the patient's history
and the clinical neurological examination. The former provides information about the quality and
intensity of the headache, the mode of onset, the time course (including the presence of
exacerbations/remissions or continuous increase in pain intensity), the presence of associated
symptoms like nausea and vomiting, photophobia (intolerance of bright light), phonophobia (intolerance
of intense sounds), and factors that relieve or aggravate the pain. The latter focuses on identifying the
presence of any focal neurological deficits.
2.2 Headache classification (examples of types or subtypes are
provided in brackets)
2.2.1 Primary headaches
1. Migraine (e.g. migraine with aura, migraine without aura)
2. Tension-type headache
3. Trigeminal autonomic cephalalgias (e.g. cluster headache)
4. Other primary headache disorders (e.g. primary exercise headache, primary headache associated
with sexual activity)
2.2.2 Secondary headaches
(It is not necessary to know this classification in detail - rather, it is here to give an idea of the basic
spectrum of causes for the development of secondary headaches)
5. Headache attributed to trauma or injury to the head and/or neck (e.g. acute headache attributed to
traumatic injury to the head or whiplash, persistent post-traumatic headache)
6. Headache attributed to cranial and/or cervical vascular disorder (e.g. acute headache attributed to
non-traumatic subarachnoid haemorrhage, headache or facial or neck pain attributed to cervical carotid
or vertebral artery dissection, headache attributed to cerebral venous thrombosis, headache attributed
to reversible cerebral vasoconstriction syndrome, headache attributed to giant cell arteritis)
7. Headache attributed to non-vascular intracranial disorder (e.g. headache attributed to intracranial
neoplasia, headache attributed to idiopathic intracranial hypertension)
8. Headache attributed to a substance or its withdrawal (e.g. medication-overuse headache, alcoholinduced
headache)
9. Headache attributed to infection (e.g. headache attributed to intracranial infection, headache
attributed to systemic viral infection)
10. Headache attributed to disorder of homoeostasis (e.g. headache attributed to arterial hypertension
[systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥120 mmHg is required; headache
remits after normalization of blood pressure])
11. Headache or facial pain attributed to disorder of the cranium, neck, eyes, ears, nose, sinuses,
teeth, mouth or other facial or cervical structure
12. Headache attributed to psychiatric disorder
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2.3 Red flags for severe secondary headaches
In the case of a new or unexpected headache, the differential diagnosis includes a number of serious
secondary headaches that are important to recognize and require urgent investigations, including CT
and CT angiography (both arterial and venous phases) of the head and/or CSF examination.
The following red flags in the history or on examination may suggest secondary headache:
⎯ Headache that is new in an individual patient (especially in a patient older than 50 years or in a
prepubertal child, in a patient with a history of cancer, HIV infection, immunodeficiency, or recent
head trauma) (may indicate meningitis, space-occupying lesions, stroke and many others).
⎯ Thunderclap headache (severe headache with abrupt or 'explosive' onset) (may indicate
subarachnoid hemorrhage).
⎯ Progressive headache that worsens over weeks or longer, usually worse when lying down (may
indicate intracranial space-occupying lesion).
⎯ Headache associated with focal neurological signs, including headache with "atypical aura" (no
history of migraine with aura, lasting >1 hour, or including motor weakness) (may be symptoms of
transient ischemic attack or stroke).
⎯ Otherwise unexplained fever associated with headache (may indicate meningitis).
2.4 Basic principles of primary headaches treatment
Every headache requires an appropriate initial evaluation, i.e. assessment of the headache
phenotype by history and clinical neurological examination, combined with neuroimaging in appropriate
cases. Primary headache is usually a lifelong condition (at least in adult patients) and many patients
with primary headache need only acute (symptomatic) treatment. Simple, common analgesics
(paracetamol, non-steroidal anti-inflammatory drugs) should be taken in adequate doses early in the
attack, combined with antiemetics in patients with nausea or vomiting. Opioids should be avoided.
Specific symptomatic therapies are available for certain types of primary pain (e.g. triptans for migraine).
Any patient with frequent or prolonged primary headache should be offered prophylaxis in addition to
acute medication. Prophylactic treatment for 3-6 months in migraine and tension-type headache
requires slow titration (starting with a low dose and increasing every 1-2 weeks) to reduce the risk of
intolerance. It is better to avoid prophylaxis during pregnancy and lactation, as several drugs are
contraindicated. If prophylactic treatment fails or is contraindicated, biological therapies based on
anti-CGRP drugs should be considered in migraine patients.
2.5 The most important types of primary headache
2.5.1 Migraine
Migraine is the most disabling headache disorder, having a large negative socioeconomic impact due
to temporary disability and loss of productivity during migraine attacks. The prevalence of migraine in
the general population is 12% to 16%. In prepubertal children, the prevalence is around 3-7%, with no
difference between girls and boys. From puberty onwards, the prevalence of migraine increases, and
females are more affected than males by a ratio of 3:1. The pathophysiology of migraine attacks involves
the vasoactive neuropeptide CGRP (calcitonin gene-related peptide). There are two main types of
migraine: migraine without aura and migraine with aura.
Migraine without aura is a clinical syndrome characterized by attacks lasting 4-72 hours. Typical
characteristics of the headache include:
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⎯ Unilateral location
⎯ Pulsating quality
⎯ Moderate or severe intensity
⎯ Association with nausea, photophobia, and phonophobia
⎯ Aggravation by routine physical activity
A minority of migraineurs (about 20%) experience migraine aura, which may present as:
⎯ Visual disturbances (scotoma, colored or black-and-white zigzag lines)
⎯ Sensory disturbances (usually unilateral arm and/or face paresthesias)
⎯ Speech or language disturbances
⎯ Motor symptoms (weakness)
The temporal course of the aura is characterized by the gradual development of symptoms (over more
than 5 minutes), with each symptom's duration not exceeding 60 minutes. Aura symptoms are
completely and spontaneously reversible and are usually, but not always, accompanied or followed by
headache (with or without migraine characteristics). The following table summarizes treatment options
for patients with migraine:
Acute treatment (NSAID or common analgesics and antimemetics)
Oral: ibuprofen, diclofenac, metamizol
Rectal administration of indomethacin
Intravenous infusion therapy containing sodium salicyliate + metoclopramide + Mg2SO4 in normal
saline solution (many alternatives are available)
Acute treatment (triptans) (contraindicated in pregnancy; should be avoided in people with:
uncontrolled hypertension; coronary heart disease, cerebrovascular disease or peripheral vascular
disease; multiple risk factors for coronary or cerebrovascular disease)
sumatriptan (oral or nasal spray or subcutaneous injection), eletriptan or zolmitriptan
Prophylactic treatment (conventional drugs for daily oral medication)
topiramate (contraindicated in pregnancy)
amitriptyline
metoprolol or bisoprolol (ECG monitoring recommended)
cinarizine
sodium valproate (avoid in women of childbearing potential, contraindicated in pregnancy)
Prophylactic treatment – Biologic therapies (anti-CGRP monoclonal antibodies, subcutaneous
administration monthly or quarterly)
erenumab
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fremanezumab
galcanezumab
2.5.2 Tension-type Headache (TTH)
Tension-type headache is the most common type of headache, with a lifetime prevalence in the general
population ranging from 30% to 78% (depending on the study). It is usually characterized by:
⎯ Infrequent episodes of headache
⎯ Typically bilateral headache
⎯ A pressing or tightening quality
⎯ Mild to moderate intensity
⎯ Headache episodes lasting from minutes to days
⎯ Pain not aggravated by routine physical activity
⎯ Not associated with nausea
⎯ Mostly without photophobia or phonophobia (although mild photophobia or phonophobia may be
present).
The following table summarizes treatment options for patients with tension-type headache:
Acute treatment (NSAID or common analgesics, over-the-counter drugs)
Oral: ibuprofen, diclofenac, metamizol, paracetamol
Rectal administration of indomethacin
Prophylactic treatment
amitriptyline
mirtazapine
venlafaxine
2.5.3 Cluster Headache (CH)
Cluster headache is characterized by brief attacks of very severe unilateral orbital and/or supraorbital
pain associated with ipsilateral cranial autonomic symptoms, including:
⎯ Conjunctival injection
⎯ Lacrimation
⎯ Nasal congestion
⎯ Rhinorrhea
⎯ Forehead and facial sweating
⎯ Miosis
⎯ Ptosis
⎯ Eyelid edema
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These headache attacks usually last between 15 and 180 minutes and occur from once every other day
to eight times a day, often at night. The attacks are somehow clustered into so-called cluster periods,
which usually last several weeks with monthly or yearly breaks. The following table summarizes
treatment options for patients with cluster headaches:
Acute treatment
sumatriptan
oxygen inhalation
Prophylactic treatment
verapamil
topiramate
lithium carbonate
2.6 The most important types of secondary headaches
As mentioned above (in Section 2.2), there is a wide range of diseases or conditions that may present
with secondary headache. The most important clinical entities (which may even be life-threatening or
cause significant and long-lasting disability) are the following:
2.6.1 Acute cerebrovascular diseases (Stroke)
Acute cerebrovascular diseases, commonly known as strokes, rank among the leading causes of
hospital admissions. The incidence of these conditions varies across regions, with the Czech Republic
reporting an annual incidence of approximately 241 per 100,000 people and a prevalence of 700 per
100,000, where nearly one-third of affected individuals face severe disability.
Strokes are categorized into three primary types based on their origin and characteristics:
⎯ acute ischemic stroke (80-87%): This prevalent type occurs due to the sudden blockage or
narrowing of a blood vessel in the brain, leading to a significant reduction or complete cessation
of blood flow to specific brain regions. Common causes include large artery atherosclerosis
(embolus or thrombosis), small vessel occlusion, cardioembolism (often linked to atrial
fibrillation), and hypercoagulability conditions like antiphospholipid antibody syndrome or
polycythemia vera.
⎯ acute intracerebral hemorrhage (10-15%): This type arises from the localized accumulation of
blood within the brain parenchyma or ventricular system, not associated with trauma. It typically
results from the rupture of a blood vessel within the brain.
⎯ acute subarachnoid hemorrhage (3-5%): In this less common form of stroke, bleeding occurs
into the subarachnoid space, predominantly due to the rupture of an aneurysm. See the separate
section below for more details on this type of stroke.
All of these conditions share a common prominent clinical feature—an abrupt onset of symptoms
and signs that develop within seconds or a few minutes.
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⎯ In the case of acute ischemic stroke and acute intracerebral hemorrhage, focal neurological
deficits are the major clinical symptoms, such as hemiparesis, hemihypesthesia, aphasia or
dysarthria, hemianopia, and occasionally others. These deficits arise due to impaired function in
specific brain regions caused by hypoperfusion or blood extravasation. While headaches may
occur, they are usually not the primary clinical presentation.
⎯ On the other hand, acute subarachnoid hemorrhage is characterized by a prominent headache,
which may be accompanied by focal neurological deficits in some cases.
Additionally, the term transient ischemic attack (TIA) refers to a specific type of acute ischemic stroke
characterized by a transient episode of neurological dysfunction resulting from focal brain, spinal cord,
or retinal ischemia. Importantly, neuroimaging does not show evidence of acute infarction in TIA cases.
Major risk factors for ischemic stroke:
⎯ Cardiovascular diseases, including arterial hypertension, myocardial infarction, atrial fibrillation,
and left atrial enlargement.
⎯ Metabolic factors, such as high cholesterol, diabetes, and obesity.
⎯ Lifestyle factors, like smoking, heavy alcohol use, and drug abuse.
⎯ Carotid artery stenosis.
⎯ History of transient ischemic attack (TIA).
⎯ Dietary factors, including increased sodium intake and consumption of processed foods, with
lower intake of fruits, vegetables, fish, and whole grains.
⎯ Poor physical function.
⎯ Demographic factors, such as age, sex, race, and lower income.
⎯ Genetic factors.
⎯ Sleep apnea.
⎯ Hormone replacement therapy and oral contraceptives (ethinylestradiol).
Major risk factors for intracerebral hemorrhage:
⎯ Arterial hypertension.
⎯ Bleeding disorders.
⎯ Use of anticoagulant treatment.
⎯ Presence of abnormal vascular structures, such as aneurysms, arteriovenous malformations, and
abnormal vascularization in tumors.
⎯ Demographic factors, smoking, and alcohol or drug abuse also contribute to the risk of
hemorrhagic stroke.
In the management of acute stroke, time plays a critical role, and treatment must be administered as
swiftly as possible. Precisely determining the time of symptom onset is essential when assessing
eligibility for thrombolytic therapy, endovascular therapy, or other emergency interventions. This is
typically defined as the moment the patient was last asymptomatic and at their neurological baseline or
when they were "last known well."
The primary diagnostic tool used in acute stroke patients (besides history and clinical neurological
examination) is a noncontrast CT scan. It serves multiple purposes, including diagnosing stroke, ruling
out intracranial hemorrhage (which is an absolute contraindication to thrombolytic therapy), and is the
preferred method for diagnosing subarachnoid hemorrhage. For potential candidates for mechanical
thrombectomy for ischemic stroke, additional imaging techniques like CT angiography, CT perfusion,
diffusion-weighted MRI, or MRI perfusion may be used to determine eligibility.
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Furthermore, certain blood tests (such as blood glucose, serum electrolytes, renal function tests, blood
count, and coagulation profile) and an electrocardiogram (ECG), along with other relevant tests when
necessary, are highly relevant in the evaluation process.
Prompt evaluation and initial management of stroke patients are crucial to enable timely
intervention, which can help preserve neurological function and reduce mortality. Patients should be
admitted to the stroke unit or intensive care unit. Thrombolytic therapy (using a fibrinolytic agent
called alteplase, also known as tissue plasminogen activator (tPA)) is recommended for patients with
ischaemic stroke and a measurable neurological deficit within 4.5 hours of stroke onset (this interval
may be extended based on CT perfusion scan according to specific criteria), provided there are no
contraindications. Endovascular therapy, particularly mechanical thrombectomy with a stent retriever,
is also an option for achieving reperfusion in adults with functionally disabling acute ischemic stroke
within 6-24 hours after stroke onset, depending on imaging studies.
Moreover, several measures should be taken to optimize the patient's internal environment,
including blood pressure control, blood glucose management, fluid and electrolyte balance, fever
reduction, and treatment of any infectious complications. Early physical therapy is also essential.
In addition, the implementation of strategies to address underlying risk factors and prevent future
strokes, such as lifestyle changes, elimination (or reduction) of cerebrovascular risk factors (if
applicable) and medication management (e.g. acetylsalicylic acid, possibly in combination with
clopidogrel, or oral anticoagulants in specific cases) is referred to as secondary stroke prevention.
For hemorrhagic stroke, managing high blood pressure and discontinuing
anticoagulant/antithrombotic therapy are critical. In specific cases, surgical evacuation of the
hematoma may be considered. Similar to ischemic stroke patients, optimizing the internal environment
and early physical therapy are important steps in the management process.
2.6.1.1 Subarachnoid Hemorrhage (SAH)
Subarachnoid hemorrhage (SAH) is a serious type of stroke that occurs in approximately 8-10 patients
per 100,000 per year. It is most frequently caused by the rupture of aneurysms of the vessels lying in
the subarachnoid space (70-75%). Other causes, such as rupture of arteriovenous malformation (AVM)
or so-called perimesencephalic SAH (presumed to be caused by the rupture of small intracranial veins),
are much less frequent (the former representing up to 5% of SAH, and the latter about 20%).
The most prominent clinical symptom is a severe headache. Its onset is usually instantaneous (often
described as a 'blow to the head'), and patients often describe it as 'the worst they have ever
experienced.' Nausea, vomiting, photophobia, and phonophobia commonly occur, and objective signs
of meningeal irritation (neck stiffness, Kernig's sign) develop after 3–12 hours.
Other clinical symptoms depend on the extent of the bleed. In major SAH, a transient or prolonged loss
of consciousness or epileptic seizure may immediately follow. If the ruptured aneurysm or AVM is
located on the small vessel embedded within the brain tissue, a focal hematoma develops and leads to
focal signs depending on the location of the hematoma, e.g., limb weakness or aphasia. Similar focal
symptoms and signs may develop due to focal ischemia, which may occur in the territory supplied by
the ruptured vessel, but this occurrence is less common among SAH patients.
The CT scan is the investigation of choice and should be performed as soon as possible after the
headache onset. It confirms the diagnosis of SAH in 95% of patients (if within 48 hours of the bleed). In
patients with a negative CT scan despite a highly suspicious medical history, cerebrospinal fluid (CSF)
examination from the lumbar puncture should be performed more than 6-12 hours from onset. SAH
could be confirmed by the presence of so-called hemoglobin degradation products (bilirubin,
oxyhemoglobin, methemoglobin) detected on spectrophotometry. These products indicate an 'older
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bleed,' i.e., more than 6 hours. Fresh blood is not significant since it may be artificial from the puncture
procedure. In patients with confirmed SAH (either by CT or by spectrophotometry), acute angiography
is a very important next diagnostic step (mostly CTAG, alternatively digital subtraction angiography or
MRAG could be used), which shows the aneurysms or AVM.
Intracranial aneurysms are found in about 2% of the population
(autopsy-based data). In patients below 40 years, they are more frequent
in men, while in older age, more prevalent in female patients.
They are usually saccular.
Their size varies from a few millimeters to several centimeters and is
mostly located in the vessel bifurcation of the circle of Willis.
SAH from a ruptured aneurysm carries a high initial mortality risk, which
gradually declines with time. Of those who survive the initial bleed,
rebleeding and cerebral infarction are the major causes of death.
The most important complications of SAH are mainly intracranial and include:
⎯ Rebleeding: In untreated aneurysms, approximately 30% of patients would rebleed within the
first 28 days; of these, 70% die. The clinical picture of rebleeding is that of SAH, but the effects
are usually more severe than the initial bleed. Repeated CT scans help to disclose rebleeding.
⎯ Cerebral ischemia/infarction: Cerebral ischemia/infarction may occur as an immediate and
direct result of the hemorrhage, but more often develops 4–12 days after the onset due to
vasospasms, i.e., arterial narrowings on angiography, which occur in up to 60% of patients after
SAH and can be either focal or diffuse. Approximately 25% of patients develop clinical evidence
of delayed ischemia/infarction. Vasospasms are caused by various vasoconstrictive substances
released from the vessel wall or from the blood clot, appearing in the CSF after SAH, e.g.,
serotonin, prostaglandin, oxyhemoglobin, endothelin-1. Furthermore, endothelial dysfunction and
the increased influx of calcium ions into the smooth muscle cells of the blood vessel walls
contribute to their development. Vasospasms, together with hypovolemia and low blood pressure,
contribute to the development of hypoperfusion in particular parts of the brain (or even diffuse
brain hypoperfusion) and can lead to focal brain deficits (hemiparesis, aphasia, etc.) as well as
non-focal deficits (increase in headache, decreased level of consciousness, etc.). All SAH
patients are provided with nimodipine (calcium-channel blocker) for the prevention of
vasospasms, and prevention of hypovolemia and blood pressure management are applied.
Regular monitoring of vasospasms with transcranial ultrasound examination should be
performed, and CT + CT angiography should be used in symptomatic patients to confirm
vasospasms and reveal the extent of ischemic changes. Endovascular treatments using
vasodilator substances are used in patients with symptomatic ischemia due to vasospasms.
⎯ Hydrocephalus: Affects about 20% of SAH patients, usually in the first few days after SAH, due
to the impairment of cerebrospinal fluid drainage. This might be caused either by blood clot within
the ventricular system (which causes obstructive hydrocephalus) or by the clot within the basal
cisterns and obstruction of the arachnoid villi, which may cause communicating hydrocephalus.
Headache and impaired consciousness level represent the most prominent symptoms, followed
by gait impairment, incontinence, and/or cognitive decline. The diagnosis is confirmed by CT, and
treatment is neurosurgical.
⎯ Epileptic seizures.
Furthermore, many extracranial complications may develop in SAH patients, e.g., myocardial
infarction, cardiac arrhythmias, pulmonary edema, or gastric hemorrhage (stress ulcers).
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The SAH treatment is based on strict bed rest with mild elevation of the upper part of the body,
analgesics, and antiemetics, and prevention or treatment of complications. As a prevention of
rebleeding, both surgical (clipping of the aneurysm neck) and endovascular (coil embolization of
the aneurysm sac) techniques are used for aneurysm repair and should be performed within 48 hours
of the bleed. Prevention and management of vasospasms/cerebral ischemia and hydrocephalus are
mentioned above.
2.6.2 Neuroinfections
Neuroinfections refer to infections that involve the central nervous system (CNS), including the brain
and spinal cord, and their coverings (meninges). Considering the anatomical structures affected, they
can be divided into:
⎯ meningitis (i.e., affecting meninges and sometimes cranial or spinal nerves that emerge from the
central nervous system through meninges as its coverings),
⎯ encephalitis (affecting the brain tissue and causing focal neurological deficits),
⎯ myelitis (spinal cord infections),
⎯ meningoencephalitis or meningoencephalomyelitis (combining more options).
They can be caused by various pathogens, such as:
⎯ bacteria (e.g., Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis,
Borrelia burgdorferi),
⎯ viruses (e.g., herpesviruses, tick-borne encephalitis virus),
⎯ fungi,
⎯ and parasites.
The agents may invade the subarachnoid space or nervous tissue directly by spreading from
contiguous structures, e.g., inner ears, sinuses, and fractures, or by intravascular invasion
(bacteremia).
The clinical presentation of neuro-infections varies widely, making them challenging to diagnose and
treat. Common symptoms include fever, headache, neck stiffness, nausea, vomiting, photophobia, and
phonophobia as signs and symptoms of meningeal syndrome. Patients with encephalitis, myelitis, or
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impairment of cranial or spinal nerves also develop focal neurological deficits. Altered mental status, or
seizures are also frequent.
To diagnose neuroinfections, a thorough patient history, physical examination, and neurological
assessment are important. Lumbar puncture (spinal tap) is a crucial diagnostic procedure to analyze
cerebrospinal fluid (CSF) for signs of infection, such as increased white blood cells, elevated protein
levels, and decreased glucose concentration. Blood tests (C-reactive protein, procalcitonin,
leukocytosis), imaging studies like CT scans and MRI, and specific pathogen tests (e.g., antibodies,
PCR) aid in identifying the causative agent.
Treatment of neuroinfections depends on the underlying pathogen. Bacterial infections usually require
prompt and aggressive antibiotic therapy. The same applies to some viral infections (e.g., herpetic
ones), where antivirals are provided for treatment, while other viral infections are managed
symptomatically since no specific antiviral medication is available. In most cases, supportive care, such
as antipyretics, anticonvulsants, and corticosteroids, is necessary to manage symptoms and
reduce inflammation. Empirical treatment is often initiated while awaiting specific test results, and
adjustments are made once the causative agent is identified.
Prompt recognition and management of neuroinfections are vital to prevent serious complications like
brain damage, neurological deficits, or even death since the clinical course of some neuroinfections is
extremely rapid (fulminant).
2.6.3 Intracranial Mass Lesions presenting with Intracranial Hypertension
Intracranial mass lesions, such as tumors, constitute a significant category of neurological disorders that
can present with headaches due to intracranial hypertension. These conditions involve abnormal
tissue growth within the confined space of the skull, resulting in increased pressure inside the
cranial cavity. Intracranial hypertension is a critical medical condition characterized by elevated pressure
exerted on the brain and its surrounding structures, which can lead to potentially life-threatening
consequences if left untreated.
The most common types of intracranial mass lesions include primary brain tumors arising from the
brain tissue itself (gliomas, glioblastomas) or its coverings (meningiomas) and secondary tumors that
have spread from other parts of the body (metastatic tumors). Additionally, several other clinical
conditions, such as obstructive hydrocephalus or chronic subdural hemorrhages, represent a growing
mass in the intracranial space and may present with similar clinical pictures. Clinical manifestations of
intracranial hypertension often include:
⎯ severe headaches that gradually increase within days, weeks or even months, and worsen when
lying down and decrease in the standing position,
⎯ nausea, vomiting,
⎯ altered mental status,
⎯ focal neurological deficits, and seizures, depending on the lesion's location and size.
Furthermore, patients usually exhibit bradycardia (low heart rate), irregular respirations, and arterial
hypertension with a significant difference between systolic and diastolic blood pressure, collectively
known as Cushing's triad.
Diagnosing intracranial mass lesions and associated intracranial hypertension requires a
comprehensive approach, including a detailed patient history, thorough physical examination,
fundoscopy (ophthalmoscopy, where the prominence of optic papillae correlates with increased
intracranial pressure), and imaging techniques, such as magnetic resonance imaging (MRI) and
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computed tomography (CT) scans. Early recognition of these conditions is crucial, as prompt
intervention can help prevent severe complications and improve patient outcomes.
Treatment strategies for intracranial mass lesions vary depending on the type, location, and extent of
the lesion. They may involve surgical resection, radiation therapy or chemotherapy in certain types of
tumors, or a combination of these approaches. Additionally, managing intracranial hypertension often
involves approaches to reduce brain swelling and control elevated intracranial pressure, which can
include medications (corticoids, mannitol), and sometimes drainage of cerebrospinal fluid.
2.6.4 Intracranial hypotension
Intracranial hypotension, also known as low intracranial pressure (ICP), is a medical condition
characterized by abnormally low pressure within the cranial cavity. This condition typically occurs when
cerebrospinal fluid (CSF) leaks from the subarachnoid space, often as a complication of a spinal
tap (lumbar puncture) or, rarely, after traumatic events.
Common symptoms of intracranial hypotension include:
⎯ positional headaches (worsening when upright and improving when lying down: Please note
that this is opposite to intracranial hypertension!)
⎯ nausea, vomiting,
⎯ possibly dizziness.
Diagnosing intracranial hypotension involves a combination of patient history and physical
examination, sometimes complemented by imaging studies such as magnetic resonance imaging
(MRI) or computed tomography (CT) scans. Treatment approaches may include conservative
management with bed rest, hydration, and pain relief, or, in some cases, specific surgical or local
interventions to repair the CSF leak.
References
⎯ https://commons.wikimedia.org/wiki/File:SynapseSchematic_lines.svg, author Thomas
Splettstoesser (www.scistyle.com)
⎯ https://www.getbodysmart.com/nervous-system
⎯ https://i.dailymail.co.uk/i/pix/2012/04/15/article-2130124-129C97C8000005DC-813_634x443.jpg
⎯ Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, Elkind MS, George
MG, Hamdan AD, Higashida RT, Hoh BL, Janis LS, Kase CS, Kleindorfer DO, Lee JM, Moseley
ME, Peterson ED, Turan TN, Valderrama AL, Vinters HV; American Heart Association Stroke
Council, Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular
Radiology and Intervention; Council on Cardiovascular and Stroke Nursing; Council on
Epidemiology and Prevention; Council on Peripheral Vascular Disease; Council on Nutrition,
Physical Activity and Metabolism. An updated definition of stroke for the 21st century: a
statement for healthcare professionals from the American Heart Association/American Stroke
Association. Stroke. 2013 Jul;44(7):2064-89. doi: 10.1161/STR.0b013e318296aeca. Epub 2013
May 7. Erratum in: Stroke. 2019 Aug;50(8):e239
⎯ Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of
clinically identifiable subtypes of cerebral infarction. Lancet. 1991 Jun 22;337(8756):1521-6. doi:
10.1016/0140-6736(91)93206-o.
⎯ Chandra A, Stone CR, Du X, et al. The cerebral circulation and cerebrovascular disease III:
Stroke. Brain Circ. 2017 Apr-Jun;3(2):66-77full-text
⎯ Yew KS, Cheng EM. Diagnosis of acute stroke. Am Fam Physician. 2015 Apr 15;91(8):528-36
Headaches
23
⎯ Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lancet. 2008 May 10;371(9624):1612-23
⎯ DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. Record
No. T922863, Epidemiology, Etiology, and Pathogenesis of Stroke. Available
from https://www.dynamed.com/topics/dmp~AN~T922863.
⎯ DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. Record No. T143427, Stroke
(Acute Management) Available from https://www.dynamed.com/topics/dmp~AN~T143427.
⎯ European principles of management of common headache disorders in primary care TJ Steiner ,
K Paemeleire , R Jensen , D Valade , L Savi , MJA Lainez , H-C Diener , P Martelletti and EGM
Couturier on behalf of the European Headache Federation and Lifting The Burden: The Global
Campaign to Reduce the Burden of Headache Worldwide
⎯ https://epomedicine.com/medical-students/circle-willis-forebrain-blood-supply/
⎯ Headache Classification Committee of the International Headache Society (IHS) The
International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38: 1-211. doi:
10.1177/0333102417738202.
⎯ Steiner TJ, Jensen R, Katsarava Z, Linde M, MacGregor EA, Osipova V, Paemeleire K, Olesen J,
Peters M, Martelletti P. Aids to management of headache disorders in primary care (2nd edition) :
on behalf of the European Headache Federation and Lifting The Burden: the Global Campaign
against Headache. J Headache Pain 2019; 20: 57. doi: 10.1186/s10194-018-0899-2.
⎯ Vetvik KG, MacGregor EA. Sex differences in the epidemiology, clinical features, and
pathophysiology of migraine. Lancet Neurol 2017; 16: 76-87.
⎯ Buture A, Ahmed F, Dikomitis L, et al. Systematic literature review on the delays in the diagnosis
and misdiagnosis of cluster headache. Neurol Sci 2019; 40: 25–39.
⎯ https://www.iasp-pain.org/Advocacy/GYAP2016Detail.aspx?ItemNumber=5573