Myasthenia gravis

HISTORY, DEFINITION, EPIDEMIOLOGY, ETIOLOGY, PATHOLOGY, PATHOPHYSIOLOGY, CLINICAL FEATURES, GENERAL CLASSIFICATION, CLINICAL CLASSIFICATION - MGFA, INVESTIGATION, DIFFERENTIAL DIAGNOSIS, MEDICAL MANAGEMENT

1. MYASTHENIA GRAVIS MRS. M. PRADEEPA MPT (NEURO) VICE PRINCIPAL PPG COLLEGE OF PHYSIOTHERAPY COIMBATORE, TAMILNADU, INDIA

2. INTRODUCTION Myasthenia gravis is a disorder of neuromuscular transmission This condition is a consequence of an autoimmune destruction / auto antibodies formation against NICOTINIC POSTSYNAPTIC RECEPTORS FOR ACETYLCHOLINE at the neuromuscular junction of skeletal muscles.

3. History First recognised by Oxford physician Thomas Willis in 1672. The first modern description - Samuel Wilks , a London physician in 1877 - described bulbar and peripheral muscular weakness without any CNS pathology. The first full descriptions of Myasthenia gravis were by the German physicians Wilhelm Erb in 1879 and Samuel Goldflam in 1893  The term "Myasthenia gravis pseudo- paralytica " was proposed in 1895 by Jolly, a German physician In 1901, Carl Weigert , a German pathologist (1845–1904), first described a myasthenic patient with a thymic mass

4. Medical history Mary Walker treated a person with MG with  physostigmine  in 1934. In 1937, Blalock established the removal of thymus as a treatment for MG. Simpson and Nastuck suggested the autoimmune etiology of MG in 1959–1960 depending on several observations . In the 1970s, prednisolone , azathioprine , and, later, plasma exchange were established as treatments for MG.

5. Definition Myasthenia gravis (MG) is a relatively rare acquired, autoimmune disorder caused by an antibody-mediated blockade of neuromuscular transmission resulting in skeletal muscle weakness. The word is from the Greek " mys " "muscle" and " astheneia " "weakness", and the Latin "gravis" "serious". It is a type-II hypersensitivity immune response.

6. Anatomy

7. Epidemiology The worldwide prevalence of MG is 100–200 per million population, affecting more than 700,000 people all over the world Bimodal distribution with a female predominance in the 2 nd  to 3 rd  decade of life and male predominance in the 6 th  to 8 th   decades Female-to-male ratio for incidence is 3:2 in people below the age of 30 and 1:1.5 in people more than 50 years of age.  Life-threatening MG crises occur approximately in 15–20% of patients, typically within the first 2 years of diagnosis 

8. ETIOLOGY MG is idiopathic in most patients Thymic abnormalities are 75% have thymic disease, 85% have thymic hyperplasia, 10–15% have thymoma . Extrathymic tumors may include small cell lung cancer and Hodgkin disease.   Hyperthyroidism is present in 3–8% of patients with MG and has a particular association with ocular MG . Genetic predisposition linked to human leukocyte antigen complex Risk factors - positive personal or family history of autoimmune disease like rheumatoid arthritis, HLA-B8, DR3, and women being less than 40 and men more than 60 years of age.

9. Classification Congenital myasthenia gravis: a genetic defect Ocular myasthenia gravis Generalized myasthenia gravis Transient neonatal myasthenia gravis: Infants born to mothers with myasthenia gravis may develop symptoms of the disease about 48 hours after birth . Symptoms can include impaired sucking and swallowing, a weak cry, and respiratory insufficiency. The symptoms typically disappear within days or weeks . Juvenile myasthenia gravis: symptoms begin before the onset of puberty

10. Pathology Changes are found in the THYMUS gland and in muscle. The main function of the thymus is to affect the production of T-cell lymphocytes, which participate in immune responses. The gland is most active during the induction of normal immune responses in the neonatal period and attains its largest size at puberty after which it involutes. In myasthenia gravis: 20% - involuted gland, 70% - show hyperplasia with lymphoid follicles demonstrating germinal centres, 10% thymoma , and encapsulate tumour of lymphoid and epithelial cells which may be locally invasive but rarely metastases . The thymus gland may give wrong instructions to immune cells

11. The disorder occurs when the immune system malfunctions and generates antibodies  Antibodies bind to the receptor sites in post synaptic area resulting in their destruction These antibodies are referred to as acetylcholine receptor antibodies ( AChR antibodies 80 – 90% ) AChR antibodies in MG attack a normal human protein, the nicotinic acetylcholine receptor, or a related protein called  MuSK 5- 7%  a muscle-specific kinase . Other less frequent antibodies are found against  LRP4,  Agrin  and  titin  proteins

12. Pathophysiology ↓ ↓ ↓ Ach was released normally AchR antibodies binding in the postsynaptic membrane Results in destruction and reduction in the number of available Ach receptors on the muscle end plate membrane (binding site for Ach ) An inconsistent generation of muscular action potentials manifesting as muscle weakness

13. Pathophysiology In patients without antibodies against AChRs , a muscle-specific tyrosine kinase ( MuSK ), an agrin -dependent protein on muscle membrane, has been found to be the antigenic target. These autoantibodies are T-cell dependent and there is interesting differential involvement of muscle groups, especially the extraocular muscles.

14. Clinical features Fatigable weakness, involving specific susceptible groups of muscles, is the clinical hallmark of MG. This weakness usually fluctuates from hour to hour, day to day, worsens with activity, and improves on rest The demonstration of fatiguing is important in reaching diagnosis and in monitoring the response to treatment: Look upwards - Ptosis becomes apparent and the eye drifts to neutral position Look left – ptosis becomes apparent and a dysconjugate drift develops Fatiguing of other bulbar muscles may be demonstrated by: blowing out cheeks against pressure. counting as far as possible in one breath, etc.

15. Clinical features Group of muscle Clinical features Ocular muscle Fluctuating ptosis and/or diplopia Bulbar muscle Dysarthria, painless dysphagia , dysphonia , and masticatory weakness, The tongue occasionally shows the characteristic triple grooved appearance with two lateral and one central furrow. Facial muscle Facial weakness, inability to close eye firmly, drooling of saliva, expressionless appearance. On smiling, buccinator weakness produces a characteristic smile Myasthenic snarl. Axial muscular Weakness of neck muscles - lolling of the head Limb muscle Weakness involving the arms more than legs, hyperactive limb reflexes , fatigue on repeated testing. Muscle wasting - 15% of cases Respiratory muscle Labor breathing, orthopnea , dyspnea , and respiratory failure – Myasthe nic crisis

16. MYASTHENIC SNARL PTOSIS

17. Clinical classification - MGFA Class Clinical description Class 1 Any eye muscle weakness, possible ptosis , all other muscles’ strength is normal Class 2 2a 2b Mild weakness of other muscles; may have eye muscle weakness of any severity Predominantly limb or axial muscles weakness or both Predominantly oropharyngeal or respiratory muscle weakness or both Class 3 3a 3b Moderate weakness of other muscles; may have eye muscle weakness of any severity Predominantly limb or axial muscle weakness or both Predominantly oropharyngeal or respiratory muscle weakness or both Class 4 4a 4b Severe weakness of other muscles; may have eye muscle weakness of any severity Predominantly limb or axial muscle weakness or both Predominantly oropharyngeal or respiratory muscle weakness or both; use of feeding tube without intubation Class 5 Intubation needed to maintain airway

18. Differential diagnosis Chronic fatigue syndrome Progressive ophthalmoplegia , e.g. mitochondrial myopathy , oculopharyngeal dystrophy. Multiple sclerosis – diplopia , dysarthria and fatigue with a relapsing and remitting course. Lambert-Eaton myasthenic syndrome: It is a rare presynaptic disorder of neuromuscular transmission in which quantal release of acetylcholine ( ACh ) is impaired, causing a unique set of clinical characteristics, which include proximal muscle weakness, depressed tendon reflexes, post tetanic potentiation , and autonomic changes.  

19. Investigation Pharmcological : Anticholinesterase drugs are used to confirm diagnosis. Tensilon test: ( edrophonium ) – short action, 2–4 minutes, given i.v . 2–10 mg slowly, with atropine pretreatment to counter muscarinic side effects (nausea and bradycardia – resuscitation facilities need to be available). This is positive when clear improvement in weakness occurs on objective testing. A control injection of saline and blinded observer can be useful. The Tensilon test may be negative in ocular myasthenia and give a false positive in the Lambert-Eaton

20. Serological investigation Acetylcholine receptor antibodies (anti- AchR ) are detected in 90% of patients and are virtually specific to this disease. In ocular myasthenia, only 60% show antibodies. Anti- Muscle specific Kinase (anti-MUSK) antibodies are found in a proportion of anti- AchR negative patients. Other antibodies e.g. microsomal , colloid, rheumatoid factor, gastric parietal cell antibody – are occasionally found, reflecting the overlap with other autoimmune disorders. Anti striated muscle antibodies are found in 30% of all patients and in 90% of those with thymoma .

21. Electrophysiological investigation Reduction of the amplitude of the compound muscle action potential evoked by repetitive supramaximal nerve stimulation – ‘the decrementing response’. Various rates of stimulation; even as low as 3/second may produce a decrementing response. Single fibre electromyography – measure of ‘Jitter’ – the time interval variability of action potentials from two single muscle fibres of the same motor unit – is a more sensitive index of neuromuscular function and is increased (95% of mild cases are abnormal).

22. Imaging test Chest X ray will show a large mediastinal mass but will not exclude a small thymoma . CT of chest should be performed in all newly diagnosed cases.

23. Treatment In severely ill patients, the first priority is to protect respiration by intubation and, if necessary, ventilation. Anticholinesterase drugs – Inhibit cholinesterase, the enzyme responsible for the breakdown of acetylcholine, allowing enhanced receptor stimulation. Edrophonium – Intravenous Neostigmine – Intravenous, intramuscular, oral Pyridostigmine – Oral A muscarinic inhibitor, atropine, may be required to counter side effects Atropine may mask early warning symptoms of the potential life-threatening state.

24. Steriods : Prednisone 60 mg/day is initially used. Deterioration may briefly occur before improvement Immunosuppressants other than steroids Azathioprine and cyclosporine are considered in patients who do not respond to steroids or who require an unacceptably high steroid maintenance dose.

25. Thymectomy There are two indications for this: When thymoma is present When myasthenia is generalised and benefits of surgery outweigh risks. Trans- sternal is preferred to supra- sternal approach giving better chance of total clearance. Within 5 yrs of surgery 70% of patients are in remission.

26. Plasmapheresis Plasma filtration removes antibodies and other circulating factors and has short term benefit (4–6 weeks). A plasma volume of 1.5–2 litres is exchanged 3–5 times over a 6–8 day period. Immunoglobulin (IVIG) May be used in place of plasmapheresis at a dose of 400 mg per kg intravenously daily for 5 days. Mechanism may act by blocking ACh receptors. A positive response (75% of patients) lasts for 2–3 months.