Dr.Mohammad Shaikhani

DISORDERS OF THE NEUROMUSCULAR JUNCTION

MYASTHENIA GRAVIS

Definition:• Progressive fatigable weakness, particularly

of the ocular, neck, facial & bulbar muscles.

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), an agrin receptor involved in the regulation /maintenance of the Ach receptors.

• 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.

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 fatigable 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.

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.

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.

Investigations

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.

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.

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

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.

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

Differences between MG & Myasthenic (Eaton-Lamberts) syndrome:

MS MG

1.Autoimmune immunological attack on presynaptic membrane limiting the release of ACH.2.Mosrly 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 +

atzathioprine can control immuologocal attack.

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. 

 

   

  

Disease of muscles:MYOPATHIESMYOPATHIES

  

Heriditary DYSTROPHIC MYOPATHIESHeriditary DYSTROPHIC MYOPATHIESeg. Duchenne’s muscular dystrophyeg. Duchenne’s muscular dystrophy

CONGENITAL MYOPATHIESCONGENITAL MYOPATHIESfloppy infantfloppy infant

METABOLIC MYOPATHIESMETABOLIC MYOPATHIESINFLAMMATORY MYOPATHISINFLAMMATORY MYOPATHIS

eg. polymyositiseg. polymyositisTOXIC MYOPATHIESTOXIC MYOPATHIES

eg. alcoholeg. alcohol

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.

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.

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

Proximal myotonic myopathy (PROMM; DM2)

AD; chr 3q Adult Proximal, esp thigh, sometimes muscle hypertrophy

As for DM1 but cognition not affected, Muscle pain

Duchenne XL; deletd dystrophin gene 1st 5ys Proximal/ limb girdle Pseudohypertrophy of calvesCardiomyopathy,

Gower sign +ve:patient climbs thigh by hand to stand

Becker XL; deled dystrophin gene LC/EA Proximal/limb girdle Pseudohypertrophy of calvesCardiomyopathy

Gower +ve.

Disease of muscles: MUSCULAR

DYSTROPHIES

  

Limb girdle AD (type 1)AR (type 2)different chromosomes

Childhood/early adult

Limb girdle Some have calf hypertrophySome have cardiac conduction abnormalities

Facioscapulohumeral (FSH)

AD; chromosome 4q 7-30 ys Face/ upper limb girdle Pain in shoulder girdle common

Oculopharyngeal

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 earlyCardiac involvement leads to sudden death

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.

1.Myasthenia gravis can be associated with:A. Presynaptic antibodies.B. Thymoma.C. Thymic hyperplasia.D. Skeletal muscle antibodies.E. Other autoimmune diseases.

2.M2yasthenia gravis &Thymic hyperplasia:A. Most cases have the disorder.B. Chest X Ray is indicated in every cases.C. Thymic surgery is indicated in every case.D. Thymic hyperplasia makes prognosis worse.E. Thymic hyperplasia occur in elderly patients.

3.Thymoma with myasthenia gravis:A. Makes prognosis worse.B. Occurs in elderly.C. Associated with skeletal muscle antibodies.D. More common than Thymic hyperplasia.E. Makes the disease more severe.

4.Diagnosis of myasthenia gravis can be supported by:A. Positive tensilon test.B. Ice on Eyes test.C. Number counting test.D. Ach antibodies.E. Anti skeletal muscle antibodies.

5. The following suggest cholinergic crisis rather than myasthenic crisis:A. Sweating.B. Salivation.C. Severe Paralysis.D. Pallor.E. Respiratory failure.

Myasthenia Gravis