Josef Bednařík
Department of Neurology, University Hospital Brno and
Faculty of Medicine, Masaryk University Brno
3.5.2020
Disorders of neuromuscular transmission: myasthenia gravis
and Lambert-Eaton myasthenic syndrome
NEUROLOGIC DISEASES THOUGHT TO BE AUTOIMMUNE
Type or site of dysfunction Disease
Neuromuscular junction Myasthenia gravis;
Lambert Eaton myasthenic syndrome
Neuropathies/Neuronopathies AIDP;
CIDP;
Mononeuritis multiplex (vasculitis);
Neuropathies with various antibodies:
gangliosides
sulfatides
MAG;
Neuropathies with dysproteinemias;
Sensory neuropathy: with Sjogren´s syndrome
paraneoplastic;
Isaac´s syndrome;
Motor neuron disease?
Myopathies Polymyositis;
Dermatomyositis;
Inclusion body myositis
Demyelinating Diseases Multiple sclerosis;
Optic neuritis;
Transverse myelitis;
Acute disseminated encephalomyelitis
Paraneoplastic syndromes Cerebellar degeneration;
Limbic encephalitis;
Opsoclonus-myoclonus;
Plasmocytoma-myeloma neuropathy;
POEMS syndrome;
Others listed above
Retroviral related HTLV associated myelopathy (HAM, TSP);
HIV associated neuropathy, myelopathy, etc.
MYASTHENIA GRAVIS: EPIDEMIOLOGY
 Estimates of the annual incidence of myasthenia gravis per million
population vary from a low of 2 to 5 to a high of 10.4. Estimates of
prevalence vary from 25 to 125 per million.
 The ratio of female to male patients is 6:4. The disease presents at any
age. The female incidence peaks in the third decade and the male
incidence in the sixth or seventh decade of life. The mean age of onset is
28 years in females and 42 years in males
MYASTHENIA GRAVIS: ETIOLOGY AND PATHOGENESIS
 Antibodies to ACh receptor protein have been found to be present in
approximately 85 % of patients with generalized myasthenia and in 60
percent of those with ocular myasthenia. The level of receptor
antibodies in serum does not correlate precisely with the severity of the
myasthenia; the absence of measurable Ab in 15 % of patients remains
unexplained. What is not known is what stimulates the production of
these antibodies and where they are formed.
 Autoantibodies directed against acetylcholine receptors decrease the
number of available receptors by at least three mechanisms: (1) by
accelerating the degradation of acetylcholinreceptors; (2) by blocking
the receptors´ active sites; (3) by acting with complement, damaging
the acetylcholine receptors and their junctional surface membrane.
MYASTHENIA GRAVIS: ETIOLOGY AND PATHOGENESIS
Further auto-antibodies:
 Antibodies against striated muscles - titin, ryanodin receptor, aktinin; MG:
in 30%; > 60 years: in 55%, MG + thymoma: in 75%; more severe weakness,
myopathic changes in EMG
 Antibodies against MuSK (tyrozin kinase receptor in muscles): younger MG
patients, in 30-70% AChRAb negative cases; worse therapeutic response
MYASTHENIA GRAVIS AND
NEUROMUSCULAR TRANSMISSION
MYASTHENIA GRAVIS AND THYMUS
 The complex relation of the thymus to MG - the frequent association between
MG and either thymic hyperplasia or thymoma (10% of MG cases), and the greatly
increased chance of permanent remission or improvement following thymectomy
- suggests that this organ may play an important part in both the origin and the
maintenance of the autoimmune process.
MYASTHENIA GRAVIS: CLINICAL MANIFESTATION
The most important clinical feature of MG is weakness, that exhibits
several striking characteristics:
 fluctuating nature (increase at the end of the day);
 fatiguability (weakening during activity and quick restoration after
rest);
 distribution (particularly muscles innervated by motor nuclei of the
brainstem are involved, i.e., ocular, masticatory, facial, deglutitional, and
lingual);
 dramatic improvement in strength following the administration of
anticholinesterase drugs.
MYASTHENIA GRAVIS: CLINICAL MANIFESTATION 2
MYASTHENIA GRAVIS: CLINICAL MANIFESTATION 2
MYASTHENIA GRAVIS: CLINICAL MANIFESTATION 2
MYASTHENIA GRAVIS: CLINICAL MANIFESTATION
GORELICK SIGN
MYASTHENIA GRAVIS: CLINICAL MANIFESTATION
SEMAN’S SIGN (MYASTHENIC DYPHONIA AND DYSARTRIA
MYASTHENIA GRAVIS: CLINICAL MANIFESTATION 2
 The onset is usually insidious, but there are instances of fairly rapid development,
sometimes initiated by an emotional upset or infection.
 Symptoms may first appear during pregnancy or the puerperium, or in the response to
drugs used during anesthesia.
 Ocular palsies and ptosis are present in 90 % of cases. Normal pupillary responses to
light and accommodation in the face of weakness of extraocular muscles and
orbicularis oculi are virtually diagnostic of MG.
 In generalized MG the proximal muscles are more affected than distal ones.
 Tendon reflexes are not altered, muscle atrophies are absent, sensitivity is normal.
 The peak age of onset in women is between 20 and 30 years, while the male incidence
peaks in the sixth of seventh decade.
MYASTHENIA GRAVIS: CLINICAL CLASSIFICATION
Osserman´s classification:
1. Ocular myasthenia
2. A. Mild generalized myasthenia with slow progression; no crises; drug
responsive
B. Moderate generalized myasthenia: severe skeletal and bulbar involvement,
but no crises; drug response less then satisfactory
3. Acute fulminating myasthenia; rapid progression of severe symptoms with
respiratory crises and poor drug response; high incidence of thymoma; high
mortality
4. Late severe myasthenia, same as (3), but progression over two years from
class 1 to 2.
MYASTHENIA GRAVIS: PATHOGENETIC CLASSIFICATION
Pathogenetic classification:
1.Early onset MG (up to 40 years of age); female preponderance; thymus
hyperplasia; association with HLA-B8 and D/DR 3;
2.Late onset MG (over 40 years of age); male preponderance, thymus
atrophy
3.MG associated with thymoma (about 10%)
4.Ocular MG
5.MG with no detectable AChR Ab
MYASTHENIA GRAVIS: DIAGNOSIS
 Typical clinical symptoms and signs
 Positive pharmacological tests (acetylocholinesterase inhibitors Edrophonium or
Neostigmin improve the muscle strength);
 Electrophysiological tests showing disturbance of neuromuscular transmission of
postsynaptic type: repetitive stimulation, single fiber EMG);
 Measurement of ACh receptor antibodies in blood
REPETITIVE STIMULATION OF MOTOR NERVES
MYASTHENIA GRAVIS: DIAGNOSIS - JITTER
Normal jitter Abnormal jitter
MYASTHENIA GRAVIS: DIAGNOSIS - JITTER
MYASTHENIA GRAVIS: DIAGNOSIS - JITTER
MYASTHENIA GRAVIS: THERAPY
1. Anticholinesterase drugs (inhibitors of acetylcholin-esterase): neostigmine
(Syntostigmin, Prostigmin), pyridostigmin (Mestinon, Kalymin) symptomatically
counteract myasthenic weakness;
2. Thymectomy are recommended in all patients with generalized MG responding poorly to
anticholiesterase medication, especially in patients up to 40 years of age, and in all
patients with thymoma; the remission occurs usually within 3 years after thymectomy;
3. Corticosteroids are proper treatment for moderately severe myasthenic patients, in
whom a remission has not been induced by thymectomy;
SIDE EFFECTS OF
CORTICOSTEROI
DS AND THEIR
PREVENTION
Side effect Prevention Monitoring
Generalized obesity; abnormal fat
distribution with moon facies, buffalo
hump, and thinning of extremities
Diet (caloric restriction) Checking body weight
Impaired glucose tolerance or diabetes
mellitus
Diet (low carbohydrate) Checking blood
glucose
Sodium retention; edemas;
hypertension
Diet (low salt) Checking natremia, BP
Hypokalemia Supplementation (up to 40
mEq daily)
Checking kalemia
Adrenal suppression Alternate-day regimen Double any low
maintenance dosis
during acute periods
of stress
Growth retardation in children
Irregular menses
Osteoporosis; vertebral compression
fractures
Supplementation of calcium (1
g daily), vitamin D (50.000 u.
once a week), and gonadal
hormones, esp. in
postmenopausal women and
long-term steroid therapy
Monitoring 24-hr
urinary calcium and
serum 25-OH vitamin
levels
Lipolytic action resulting in hyperlipidemia;
rarely fat emboli in the
femoral head and aseptic necrosis of
the hip; epidural lipomatosis resulting
in spinal cord compression
Steroid myopathy Diet: high protein
intake;
isometric training
programme
Steroid psychosis
Behavioral and affective changes
(nervousness, irritability, moodiness,
insomnia, depression
Pseudotumor cerebri
Peptic ulcer ??? Antacids or H2 receptor
antagonists
Skin changes (acne, striae, facial
hirsutism, ekchymoses)
Impaired wound healing
Posterior subscapular cataract Regular
ophthalmologic exam
Glaucoma Regular
ophthalmologic exam
Herpes zoster and other opportunistic
infections
MYASTHENIA GRAVIS: THERAPY 2
4. Azathioprine is proper treatment for the same patients as corticosteroids; it has later
beginning of the effect, but less side effects than corticosteroids; it is better for longterm
treatment;
5. Mycophenolate mophetil, cyclosporin: immunosupressants
6. Plasmapheresis (or Immunoadsorption) may be lifesaving during crisis; it is also useful
before and after thymectomy and at the start of immunosupressive therapy; its effect
is, however, temporary
7. Intravenous intravenous human immunoglobulin
8. Rituximab (a humanized monoclonal antibody to CD20) and Eculizumab (C5 inhibition
by monoclonal antiboty)
LAMBERT-EATON MYASTHENIC SYNDROME: HISTORY AND PATHOGENESIS
 History
 In 1957 Drs. Lambert and Eaton described a myasthenic syndrome
associated with malignant tumors.
 Epidemiology
 3% of SCLC develop LEMS; annual incidence is 5/per million in SCLC
related LEMS;
 It most often occurred in men over 40 (male/female ratio 2:1)
LAMBERT-EATON MYASTHENIC SYNDROME: PATHOGENESIS
 LEMS is a rare condition in which weakness results from a presynaptic abnormality
of acetylcholine (Ach) release at the neuromuscular junction
 It was first described in association with lung cancer and was initially considered to
be a paraneoplastic syndrome. Recent developments demonstrate that LEMS
results from an autoimmune attack directed against the voltage-gated calcium
channels (VGCC) on the presynaptic motor nerve terminal
 Approximately 70% of patients have small cell carcinoma of the lung (mostly small
cell lung cancer) with the remaining patients having underlying autoimmune
diseases. In most cases the syndrome predates the discovery of the tumor.
 A few patients have an overlapping syndrome with both MG and Lambert-Eaton
myasthenic syndrome as shown by the fact that they have antibodies not only to
anticholine receptor but also to voltage-gated P/Q - type calcium channels
indicating presynaptic abnormality.
LAMBERT-EATON MYASTHENIC SYNDROME: CLINICAL SIGNS AND SYMPTOMS
 Weakness is the predominant symptom and the proximal muscles of the lower
extremities are predominantly involved, with less involved proximal upper
extremities, and to a much lesser extent the cranial musculature. About 50% of
these patients have partial bilateral ptosis. Sometimes neck weakness is found.
Bulbar and facial weakness are rare however
 Tendon reflexes are reduced or absent
 While some develop fatigue, it is not as clear cut as the fatigue observed in AM.
Strengh may improve after exercise and then weaken as activity is sustained
 The patients also complain of peculiar leg pains and paresthesias; the weak
muscles may ache and are occasionally tender
 Autonomic nervous system is affected producing impotence and dry mouth and
much less often other autonomic phenomenon
LAMBERT-EATON MYASTHENIC SYNDROME: DIAGNOSIS
Clinical diagnosis: The disease should be suspected in any patient complaining of
proximal weakness. Several clinical tests have been developed: One is to have the
patient grip the examiner's hand as hard as he can. The examiner feels an increase
in strength over several seconds. In addition the knee jerk amplitude is noted to be
augmented after a vigorous contraction of the quadriceps lasting 10-20 seconds.
LAMBERT-EATON MYASTHENIC SYNDROME: DIAGNOSIS 2
Electrophysiological tests:
 Standard EMG: low amplitude motor revoked responses on EMG with normal
nerve conduction studies and normal findings on needle EMG examination.
 Repetitive stimulation of motor nerves: decrement of both amplitude and
area of CMAP at frequencies between 1 to 5 Hz; increment (>100%) of CMAP
amplitude at frequencies from 20 to 50 Hz
 Single fiber EMG: abnormal jitter and blockings
 The defect is generalized and repetitive stimulation studies or SFEMG can be
done on almost any muscle
Serological tests: detection of autoantibodies against voltage-gated
P/Q - type calcium channels
LAMBERT-EATON MYASTHENIC SYNDROME: DIAGNOSIS 2
Repetitive stimulation of
motor nerves: increment
LAMBERT-EATON MYASTHENIC SYNDROME: THERAPY
 Extensive search for underlying malignancy  cancer therapy
 Cholinesterase inhibitors
 Guanidine hydrochloride or 3,4-diaminopyridine
 Immunosupression (corticosteroids, azathioprine)
 Plasma exchange
 Intravenous human immunoglobulin
AUTOIMMUNE ETIOPATHOGENESIS OF MYASTHENIA GRAVIS AND LAMBERTEATON
MYASTHENIC SYNDROME
 Myasthenia gravis (MG) and the Lambert-Eaton myasthenic syndrome
(LEMS) are each a distinct pathophysiological entity, but nevertheless
have striking similarities.
 Both are organ-specific autoimmune disorders that are mediated by
IgG autoantibodies interacting with cation channel proteins in plasma
membranes of the neuromuscular synapse.
AUTOIMMUNE ETIOPATHOGENESIS OF MYASTHENIA GRAVIS AND LAMBERTEATON
MYASTHENIC SYNDROME 2
 The principal autoantigens that are the respective targets of these highly
specific immunoglobulins are extracellular segments of
1) the nicotinic acetylcholine receptor (AChR), which is the Na+/K+ channel in the
muscle's postsynaptic membrane that is opened by acetylcholine, and
2) the motor nerve terminal's voltage-sensitive Ca channel that is opened by the
action potential.
 Both disorders are significantly associated with an intrathoracic neoplasm,
epithelial thymoma in MG and primary lung carcinoma, usually small cell
type, in LEMS.