The lecture has been given on Oct. 30th & Nov. 6th, 2010 by Dr. Rasool.

1. DISORDERS OF THE
NEUROMUSCULAR JUNCTION
MYASTHENIA GRAVIS

2. Myasthenia Gravis

4. Definition:
• Progressive fatiguable weakness, particularly
of the ocular, neck, facial & bulbar muscles.

5. Aetiology / pathology:
• Most commonly caused by autoantibodies to Ach receptors in
the post-junctional membrane of NMJ.
• These antibodies block neuromuscular transmission & initiate a
complement-mediated inflammatory response which reduces
the number of Ach receptors & damages the end plate.
• A minority have other auto Abs to other epitopes, sp to a
muscle-specific kinase (MuSK) .
• 15% (mainly late onset) have a thymoma&the majority of the
remainder have thymic follicular hyperplasia.
• Increased incidence of other autoimmune diseases &it is linked
with certain HLA haplotypes.
• Penicillamine causes an Ab-mediated myasthenic syndrome &
aminoglycosides /ciprofloxacin exacerbate it &all avoided.

7. Clinical features
• Usually presents between 15-50 years.
• Women affected > men in younger ages &reverse at older ages.
• It has relapsing / remitting course, esp during the early years.
• The cardinal symptom is abnormal fatiguable weakness of the
muscles (different from a sensation of muscle fatigue);
movement is initially strong but rapidly weakens.
• Worsening towards the end of the day or following exercise is
characteristic.
• There are no sensory signs or signs of CNS involvement,
although weakness of the oculomotor muscles may mimic a
central eye movement disorder.
• The first symptoms are usually intermittent ptosis or diplopia,
but weakness of chewing, swallowing, speaking or limb
movement also occurs.

8. Clinical features
• Any limb muscle may be affected, most commonly those of the
shoulder girdle; unable to undertake tasks above shoulder level,
as combing the hair, without frequent rests.
• Respiratory muscles may be involved& respiratory failure is a
not uncommon cause of death & may be the first presentation,
in which case the diagnosis is difficult if not thought of.
• Aspiration may occur if the cough is ineffectual.
• Sudden weakness from a cholinergic or myasthenic crisis may
require ventilatory support.

9. Investigations
• Tensilon test: IV short-acting anticholinesterase, edrophonium
bromide, is a valuable diagnostic aid; 2 mg initially, with a
further 8 mg given half a minute later if there are no
undesirable side-effects. Improvement in muscle power occurs
within 30 seconds & usually persists for 2-3 minutes.
• Ice pack test: is simple & less risky than tensilon test with
improvement in ptosis in 2 mins.
• EMG with repetitive stimulation may show the characteristic
decremental response.
• Anti-acetylcholine receptor antibody (AChRA) is found in >
80%, < in purely ocular myasthenia (50%).
• Anti-MuSK antibodies are found especially in AChRA-negative
patients with prominent bulbar involvement.
• Positive anti-skeletal muscle antibodies suggest the presence of
thymoma, but all patients should have a thoracic CT to exclude
this condition, which may not be visible on plain X-ray.
• Screening for other autoimmune disorders, particularly thyroid
disease, is important.

10. Investigations

11. Management
• The principles of treatment are:
• 1.Maximise the activity of acetylcholine at remaining receptors
in the neuromuscular junctions
• 2.Limit or abolish the immunological attack on motor end
plates.

12. Management: 1.Ach estrase inhibs
• The duration of action of acetylcholine is greatly prolonged by
inhibiting its hydrolysing enzyme, acetylcholinesterase.
• The most commonly used anticholinesterase drug is
pyridostigmine, orally 30-120 mg, usually 6-hourly.
• Muscarinic side-effects, including diarrhoea/ colic, controlled
by propantheline (15 mg as required).
• Over-dosage of anticholinesterases may cause a cholinergic
crisis due to depolarisation block of motor end plates, with
muscle fasciculation, paralysis, pallor, sweating, excessive
salivation & small pupils, distinguished from severe weakness
due to exacerbation of myasthenia (myasthenic crisis) by the
clinical features & if necessary, by the injection of a small dose
of edrophonium.

13. Management: 2.IMMUNOLOGICAL Trt
• Thymectomy
• in early stages leads to a much better overall prognosis, whether
a thymoma is present or not.
• Should be performed as soon as feasible in any antibody-positive
patient < 45 years with symptoms not confined to extraocular
muscles, unless the disease established for > 7 years.
• Plasma exchange
• Removing antibody from the blood may produce marked
improvement but, usually brief, so normally reserved for myasthenic
crisis or for pre-operative preparation
• IV immunoglobulin
• An alternative to plasma exchange in severe myasthenia
• Corticosteroid treatment
• Improvement is commonly preceded by marked exacerbation of
myasthenic symptoms So should be initiated in hospital
• It is usually necessary to continue treatment for months or years,
often resulting in adverse effects
• Other immunosuppressant treatment
• Azathioprine 2.5 mg/kg can reduce the dosage of steroids necessary
& may allow steroids to be withdrawn.
• The effect on clinical disease is often delayed for several months

14. Prognosis
• Variable.
• Remissions sometimes occur spontaneously.
• When myasthenia is confined to the eye muscles, the prognosis
is excellent & disability slight.
• Young female patients with generalised disease have high
remission rates after thymectomy, whilst older patients are less
likely to have a remission despite treatment.
• Rapid progression of the disease > 5 years after its onset is
uncommon.

15. OTHER MYASTHENIC SYNDROMES
• Other conditions present with muscle weakness due to impaired
transmission across NMJ.
• The most common is the Lambert-Eaton myasthenic syndrome
(LEMS), in which transmitter release is impaired, often in
association with antibodies to pre-junctional voltage-gated
calcium channels.
• Patients may have autonomic dysfunction (& dry mouth) in
addition to muscle weakness, but the cardinal clinical sign is
absence of tendon reflexes, which can return immediately after
sustained contraction of the relevant muscle.
• The condition is associated with underlying malignancy in a
high percentage of cases& investigation must be directed
towards detecting such a cause.
• The condition is diagnosed electrophysiologically by the
presence of post-tetanic potentiation of motor response to nerve
stimulation at a frequency of 20-50/s.
• Treatment is with 3,4-diaminopyridine

16. Differences between MG & Myasthenic
(Eaton-Lamberts) syndrome:
MS MG
1.Autoimmune immunological attack on presynaptic
membrane limiting the release of ACH.
2.Mostly paraneoplastic : in 2/3 of cases due to oat cell
Ca. of the lungs > 40 ys . of age & 1/3 non neoplastic
occuring at any age.
3.Realative sparing of extra ocular & bulbar muscles.
4.Autonomic dysfunction occur in 50% of cases.
5.EMG shows decreases amplitude of contraction with
single nerve stimulation
, but repetitive stimulation at frequencies > 10htz
produces normal amplitude.
6. Treatment: ACH estrase inhibitors has
minimal effect. Paraneoplastic type needs
management of underlying cancer with
guanidine & diaminopyridine having some
benefits. For nonneoplastic type steroids +
azathioprine can control immunological attacks.
1.Postsynaptic ACH receptors Abs.
2.All autoimmune type 3.
3.Common .
4.Not present,
5.Just contrary to that.
6.Good response to ACH estrase inhibitors.

17. Disease of muscles:MYOPATHIESMYOPATHIES
 Heriditary DYSTROPHIC MYOPATHIESHeriditary DYSTROPHIC MYOPATHIES
eg. Duchenne’s muscular dystrophyeg. Duchenne’s muscular dystrophy
CONGENITAL MYOPATHIESCONGENITAL MYOPATHIES
floppy infantfloppy infant
METABOLICMETABOLIC
MYOPATHIES(hypokalemia,hyperkalemia,hypocalcemia,hyperMYOPATHIES(hypokalemia,hyperkalemia,hypocalcemia,hyper
calcemia.) also (hypothyroid,hyperthyroid,Cushings, Addisons)calcemia.) also (hypothyroid,hyperthyroid,Cushings, Addisons)
INFLAMMATORY MYOPATHISINFLAMMATORY MYOPATHIS
eg. polymyositiseg. polymyositis
TOXIC MYOPATHIESTOXIC MYOPATHIES
eg.eg.
Alcohol,thiazide,zidovudine,carbinoxolone,statins,glucocorticAlcohol,thiazide,zidovudine,carbinoxolone,statins,glucocortic
oids.oids.

18. Disease of muscles: MUSCULAR DYSTROPHIES
A group of inherited disorders characterised by progressive
degeneration of muscles, sometimes with heart muscle or conducting
tissue& other parts of the nervous system.
 Clinically:
Wasting weakness are usually symmetrical, there is no
fasciculation& no sensory loss& tendon reflexes are preserved until
a late stage, except in myotonic dystrophy.
 Investigations
 Confirmed by specific molecular genetic testing, supplemented
with EMG& muscle biopsy if necessary.
Creatine kinase is markedly elevated in Duchenne type, but is
normal or only moderately elevated in the other dystrophies.
Screening for an associated cardiac abns (cardiomyopathy or
dysrhythmia) is important.

19. Disease of muscles: MUSCULAR DYSTROPHIES
Management:
 There is no specific therapy for these conditions, but
physiotherapy & occupational therapy help patients cope with their
disability.
Treatment of associated cardiac failure or arrhythmia (with
pacemaker insertion if necessary) may be required.
 Management of respiratory complications (including nocturnal
hypoventilation) can improve quality of life.
Genetic counselling is important.

20. Disease of muscles: MUSCULAR DYSTROPHIES
Type Genetics onset Muscles affected Other features
Myotonic
dystrophy
(DM1)
AD; triplet repeat chr19q Any Face (ptosis),
sternomastoids,
distal limb,
generalised later
Myotonia, cognitive dulling,
cardiac conduction
abnormalities, lens
opacities, frontal balding,
hypogonadism
Duchenne XL; deletd dystrophin gene 1st 5ys Proximal/ limb girdle Pseudohypertrophy of calves
Cardiomyopathy,
Gower sign +ve:patient climbs
thigh by hand to stand
Becker XL; deled dystrophin gene Early&
lat
Proximal/limb girdle Pseudohypertrophy of calves
Cardiomyopathy
Gower +ve.

21. Disease of muscles: MUSCULAR
DYSTROPHIES
Limb girdle AD (type 1)
AR (type 2)
different chromosomes
Childho
od/early
adult
Limb girdle Some have calf
hypertrophy
Some have cardiac
conduction
abnormalities
Facioscapul
ohumeral
(FSH)
AD; chromosome 4q 7-30 ys Face/ upper limb girdle Pain in shoulder
girdle common
Oculophary
ngeal
AD/AR recessive; chromosome 14q 30-50
years
Ptosis, external
ophthalmoplegia,
dysphagia, tongue
weakness
Mild lower limb
weakness
Emery-
Dreifuss
XLR; mutations in emerin gene 4-5
years
Humero-peroneal,
proximal limb girdle later
Contractures early
Cardiac
involvement leads
to sudden death

22. Disease of muscles: MUSCULAR
DYSTROPHIES
Prognosis:
Patients with Duchenne dystrophy used to die within 10 years of
diagnosis, but with improved general care they are now living into
the third decade.
The lifespan in limb girdle & facioscapulohumeral dystrophies is
normal.
In myotonic dystrophy, there is considerable phenotypic variation
& the prognosis is very variable, limited by cardiac & respiratory
complications.

23. Spinal muscular atrophiesSpinal muscular atrophies
These rare genetic disorders of motorThese rare genetic disorders of motor
neurones give rise to slowly progressive,neurones give rise to slowly progressive,
usually symmetrical, muscle wasting andusually symmetrical, muscle wasting and
weakness. An acute infantile typeweakness. An acute infantile type
(Werdnig-Hoffmann disease), a chronic(Werdnig-Hoffmann disease), a chronic
childhood type (Kugelberg-Welanderchildhood type (Kugelberg-Welander
disease) and adult forms are recognized.disease) and adult forms are recognized.
Clinically these conditions may beClinically these conditions may be
confused with muscular dystrophies ,confused with muscular dystrophies ,
hereditary neuropathies or MND.hereditary neuropathies or MND.

24. Recklinghausen's disease)Recklinghausen's disease)
This is characterized by multiple skinThis is characterized by multiple skin
neurofibromas and pigmentation.neurofibromas and pigmentation.
The neurofibromas arise from theThe neurofibromas arise from the
neurilemmal sheath. One new caseneurilemmal sheath. One new case
occurs in every 4000 live births. Theoccurs in every 4000 live births. The
mode of inheritance is autosomalmode of inheritance is autosomal
dominant with complete penetrance.dominant with complete penetrance.

25. ClinicallyClinically
neurofibromatosis is divided into type 1neurofibromatosis is divided into type 1
(peripheral >70%) and type 2 (central). The(peripheral >70%) and type 2 (central). The
abnormal gene for NF1 is on chromosome 17abnormal gene for NF1 is on chromosome 17
(q11.2) and for NF2 on chromosome 22 (q12.2)(q11.2) and for NF2 on chromosome 22 (q12.2)
.The main application for these genetic markers.The main application for these genetic markers
are potential antenatal diagnosis andare potential antenatal diagnosis and
counselling. A wide variety of abnormalitiescounselling. A wide variety of abnormalities
occur. Peripheral (NF1) Skin neurofibromasoccur. Peripheral (NF1) Skin neurofibromas
present as subcutaneous, soft, sometimespresent as subcutaneous, soft, sometimes
pedunculated, tumours. They increase inpedunculated, tumours. They increase in
numbers throughout life. Multiple café-au-laitnumbers throughout life. Multiple café-au-lait
patches are presentpatches are present

26. Central (NF2)Central (NF2)
The abnormal protein (merlin orThe abnormal protein (merlin or
schwannomin) is a cytoskeletal protein.schwannomin) is a cytoskeletal protein.
Many neural tumours occur:Many neural tumours occur:
meningiomameningioma
acoustic neuromaacoustic neuroma
glioma (including optic nerve glioma)glioma (including optic nerve glioma)
plexiform neuroma (massive cutaneousplexiform neuroma (massive cutaneous
overgrowth)overgrowth)
cutaneous neurofibroma.cutaneous neurofibroma.
Rarely, the benign tumours undergoRarely, the benign tumours undergo
sarcomatous change.sarcomatous change.

27. Associated abnormalitiesAssociated abnormalities
ScoliosisScoliosis
Orbital haemangiomaOrbital haemangioma
Local gigantism of a limbLocal gigantism of a limb
Phaeochromocytoma and ganglioneuromaPhaeochromocytoma and ganglioneuroma
Renal artery stenosisRenal artery stenosis
Pulmonary fibrosisPulmonary fibrosis
Obstructive cardiomyopathyObstructive cardiomyopathy
Fibrous dysplasia of bone.Fibrous dysplasia of bone.