Myasthenia Gravis

1. Weekly clinical seminar Neurology team By Chidimma A Onwurah Myasthenia Gravis

2. Outline • Introduction • Epidemiology • Aetiology • Pathophysiology • Clinical features • Investigations • Differentials • Management • MG in pregnancy • Complications • Prognosis • Conclusion

3. Introduction • Myasthenia gravis - relatively rare acquired autoimmune disorder • Antibodies are formed against nicotinic acetylcholine (ACh) postsynaptic receptors at the neuromuscular junction (NMJ) of skeletal muscles • Treatment now available for MG is highly effective, although a specific cure has remained elusive.

4. Epidemiology • Estimated annual US incidence – 2/1,000,000. Prevalence - 0.5 to 14.2/100,000 people. • This has risen over the past 2 decades - increased lifespan of patients with MG & earlier diagnosis • 15-20% of patients will experience a myasthenic crisis. 3/4ths of these patients experience their first crisis within 2 years • The female-to-male ratio - 3:2, with a female predominance in younger adults (aged 20-30 years) and a slight male predominance in older adults >50 years • Onset of MG at a young age is slightly more common in Asians than in other races

5. Ocular MG - male preponderance • Prevalence in United Kingdom - 15 cases per 100,000 population. • Ojini FI et al in LUTH (1995-2000): peak age incidence - third decade, male:female ratio 1.7 to 1. Commonest presentations - ptosis (85.1% ), diplopia (37% ), limb weakness (37% ) • Bakari AG et al (ABUTH) in a 10 year retrospective study (2002) - only 4 patients were identified from the hospitals records

6. OnyekweluFA et al in UNTH (1992-2004): median age at presentation - 29 years (20 to 42 y). Male:female ratio of 1:2.7. Overall mortality rate = 27.3%.

8. Aetiology • Unknown but the thymus plays a role • IgG antibodies develop against AChR in the NMJ (muscle). Reason - unknown • Half of patients who are seronegative for anti AChR may be seropositive for anti MuSK • Anti MuSK +ve are mostly females with bulbar and respiratory involvement.

9. Females & px with HLA-B8, HLA-DRw3, and HLA-DQw2 are associated with autoimmune disease & family history of autoimmune disorder (minus the strictly ocular variant) • Thymic abnormalities are common: thymichyperplasia, and thymoma. • Myoid cells within the thymus may serve as a source of autoantigen antibody formation • Other MG associations - small cell lung cancer and Hodgkin disease. • Hyperthyroidism is associated with ocular MG. • Infants born to myasthenic mothers can develop a transient myasthenia-like syndrome

10. Drug causes of MG • These can induce true myasthenia, with elevated anti-AChR antibody titers in most cases. Weakness is mild, full recovery is achieved weeks to months after stopping the drug • D-Penicillamine • Nitrofurantoin - linked to ocular MG • Interferon alfa, beta • Chloroquine • Trimethadione • Statins • Riluzole

11. Drugs that exacerbate MG: • Antibiotics (eg, aminoglycosides, polymyxins, ciprofloxacin, erythromycin, and ampicillin) • Beta-blockers (eg, propranolol, timolol, oxprenolol) • Lithium • Magnesium • Procainamide • Verapamil • Quinidine • Prednisone • Anticholinergics (eg, trihexyphenidyl) • Neuromuscular blocking agents (eg, vecuronium and curare) • Botulinum toxin

12. Pathophysiology • Normally - Decreasing Ach stores in presynapticneurone with each impulse (presynaptic rundown). • In MG, AChRs at the muscle endplate and flattening of the postsynaptic folds. • Consequently, even with normal amounts of Ach, fewer endplate potentials are produced, and they may fall below the threshold value for generation of an action potential. • The end result is inefficient neuromuscular transmission

14. Inefficient neuromuscular transmission + presynaptic rundown = progressive in muscle fibers being activated by successive nerve fiber impulses. • Patients become symptomatic when number of AChRs is reduced to approximately 30% of normal. • The cholinergic receptors of smooth and cardiac muscle have a different antigenicity and are not affected by the disease.

15. Binding of AChR antibodies to AChR results in impairment of neuromuscular transmission by: • Cross-linking 2 adjacent AChRs, thus accelerating internalization and degradation • Causing complement-mediated destruction of junctional folds of the postsynaptic membrane • Blocking the binding of ACh to AChR

17. Clinical features • The initial complaint is a specific muscle weakness rather than generalized muscle weakness. • The severity of the weakness typically fluctuates over hours being least severe in the morning and worse as the day progresses; it is increased by exertion and alleviated by rest. • The degree of weakness also varies over the course of weeks or months, with exacerbations and remissions. • Remissions are rarely complete or permanent

18. Cranial muscles, lids and extraocular muscles, are involved early in the course of MG; diplopia and ptosis are common initial complaints. • Facial weakness "snarling" expression when the patient attempts to smile. • Weakness in chewing is most noticeable after prolonged effort. • Nasal speech from weakness of the palate, or a dysarthric "mushy" speech quality from tongue weakness. • Palatal, tongue, pharyngeal weakness Difficulty in swallowing and nasal regurgitation or aspiration.

19. In most patients, the weakness becomes generalized. • If it remains restricted to the extraocular muscles for 3 years, it is likely that it will not become generalized (ocular MG). • The limb weakness is often proximal and may be asymmetric. • Despite the muscle weakness, deep tendon reflexes and sensations are preserved • Wasting is sometimes seen after many years. • Dysautonomia is a rare finding

20. If weakness of respiration becomes so severe as to require respiratory assistance, the patient is in crisis • Exposure to bright sunlight, surgery, immunization, emotional stress, menstruation, intercurrent illness and physical factors might trigger or worsen exacerbations.

21. MGFA classification of myasthenia gravis Class I MG: • Any ocular muscle weakness • May have weakness of eye closure • All other muscle strength is normal Class II MG: • Mild weakness affecting other than ocular muscles • May also have ocular muscle weakness of any severity Class IIa MG: • Predominantly affecting limb, axial muscles, or both • May also have lesser involvement of oropharyngeal muscles Class IIb MG: • Predominantly affecting oropharyngeal, respiratory muscles, or both • May also have lesser or equal involvement of limb, axial muscles, or both

22. Class III MG: • Moderate weakness affecting other than ocular muscles • May also have ocular muscle weakness of any severity Class IIIa MG: • Predominantly affecting limb, axial muscles, or both • May also have lesser involvement of oropharyngeal muscles Class IIIb MG: • Predominantly affecting oropharyngeal, respiratory muscles, or both • May also have lesser or equal involvement of limb, axial muscles, or both Class IV MG: • Severe weakness affecting other than ocular muscles • May also have ocular muscle weakness of any severity Class IVa MG • Predominantly affecting limb, axial muscles, or both • May also have lesser involvement of oropharyngeal muscles

23. Class IVb MG: • Predominantly affecting oropharyngeal, respiratory muscles, or both • May also have lesser or equal involvement of limb, axial muscles, or both Class V MG: • Defined by intubation, with or without mechanical ventilation, except when used during routine postoperative management • Use of a feeding tube without intubation places the patient in class IVb

24. Investigations • Serum anti-AChR: • Present in about 80–90% of cases of generalized MG. • Present in less than 30% of cases of ocular MG • False-positives: • Thymoma without MG • Lambert-Eaton myasthenic syndrome • Small cell lung cancer • Rheumatoid arthritis treated with penicillamine • 1-3% of the population older than 70 years

25. Serum anti-MuSK: • Positive individuals tend to have more pronounced bulbar weakness and may have tongue and facial atrophy. • They may have neck, shoulder and respiratory involvement without ocular weakness. • Less likely to respond to AChE inhibitors, symptoms may worsen with these medications • Anti–striated muscle antibody • Anti-SM Ab is present in most patients with thymoma who are younger than 40 years • In individuals older than 40 years, anti-SM Ab can be present without thymoma.

26. Anti-striational antibody • Binds in a cross-striational pattern to skeletal and heart muscle tissue sections. • Reacts with epitopes on the muscle protein titin and ryanodine receptors (RyR). • Most with thymoma and MG, and half of late-onset MG patients (≥50 years), manifest anti-striational antibody. • Rarely found in anti-AChR negative patients. • Can be used as prognostic determinants in MG. Higher antibody titers more severe disease. • Seen frequently with thymoma, therefore titin/RyR antibodies should arouse a strong suspicion of thymoma in a young patient with MG.

27. Electrodiagnostic Studies • Repetitive nerve stimulation. • A characteristic decrement in the evoked muscle action potential during repetitive stimulation. EMG is otherwise normal • Single fibre electromyography • Increased jitter (variability of time interval between the action potentials of 2 single muscle fibers in the same motor unit) and normal fiber density

28. Tensilon (edrophonium) test: • This is seldom required. • Edrophonium 10 mg is given intravenously following a 1–2 mg test dose. • When the test is positive, there is substantial improvement in weakness within seconds lasting for up to 5 minutes. • Its important to perform a control test using saline and have an observer. • The sensitivity of the test is 80%. • Occasionally, edrophonium causes bronchospasm and syncope.

29. Seconds later Before

30. Imaging: • Mediastinal MR: gold standard • Chest radiographs/ CT can also be done

32. Routine blood studies: normal. ESR - not raised • PPD skin test, TFT, pulmonary function test, SEUCr, septic screen, bone densitometry in older patients • CPK is normal. • Auto antibody screen • Intrinsic factor, thyroid antibodies, Rheumatoid factor and anti-nuclear antibody tests can be positive.

33. Ice pack test and rest test: • Placing ice over the lid. The rationale behind this test is that cooling might improve neuromuscular transmission. • Rest improves symptoms/signs

35. Differentials • Lambert-Eaton Myasthenic Syndrome: P/Q-type calcium channels • Congenital myasthenic syndromes • Botulism • Dermatomyositis/Polymyositis • Psychologic (neurasthenia) • Compressive lesions of cranial nerves • Depression • Multiple Sclerosis • Sarcoidosis and Neuropathy • Thyroid Disease

36. Management • Multidisciplinary • One of the most treatable neurologic disorders. • No clear consensus exists on treatment strategies

37. Drug therapy • AChE inhibitors and immunomodulating therapies - mainstays of treatment . • Frequency and dose is tailored with patients response. • Pyridostigmine: Dose: 30–60 mg three to four times daily max. 120 mg every 4–6 h during daytime • Neostigmine - used only when pyridostigmine is unavailable

38. Steroids: the lowest effective dose should be used on a long term basis. May cause initial ‘exacerbations’. • The mainstay of therapy is azathioprine, usually after an initial dose of corticosteroids. • The beneficial effects of steroid sparing agents begin after many months (up to 1 year), but are beneficial in the long term • Azathioprine : 50mg/day increased gradually to about 2–3 mg/kg of total body weight, or until the white blood count falls to 3000 - 4000/L.

39. Cyclosporine A (methotrexate, tacrolimus, cyclophosphamide) is used for severe cases • Cyclosporine: 4–5 mg/kg per day • Tacrolimus: 0.07–0.1 mg/kg per day • No evidence-based studies fully prove the usefulness of AChE inhibitors, corticosteroids, and other immunosuppressive agents in improving ocular symptoms. • The effect of immunosuppressants on the progression to generalized MG is still uncertain

40. Rituximab has been used with variable success in the treatment of MG, especially in patients with anti-MuSK antibody.

41. Plasmapharesis • Five exchanges (3–4 L per exchange) administered over a 10- to 14-day period • Produces a short-term reduction in anti-AChR antibodies, with clinical improvement. • Useful as a temporary expedient in seriously affected patients or to improve the patient's condition prior to surgery

42. IvIg • Usual dose is 2 g/kg, typically administered over 5 days (400 mg/kg per d). • If tolerated, can be given over a 3- to 4-day period • Mechanism of action of IVIg is not known • Recommended for: • MG crisis • Severe weakness poorly controlled with other agents • In lieu of plasma exchange

43. Thymectomy • In the absence of a tumor, most patients experience improvement after thymectomy • Of these, 35% achieve drug-free remission. • Improvement is typically delayed for months to years. • Patients with MuSK antibody–positive MG may respond less well to thymectomy.

44. MG in pregnancy • Course during pregnancy is hard to predict • Risks of exacerbation, respiratory failure, adverse drug response, crisis, and death • The fetus is predisposed to abnormalities; (pulmonary hypoplasia and arthrogryposis) • Breastfeeding is safe if treatment utilizes pyridostigmine or corticosteroids • IvIg, plasmapharesis, thymectomy when the disease is controlled • Women with MG are advised to delay child bearing till after 2 years of disease onset.

45. Myasthenic crisis • Exacerbation of weakness sufficient to endanger life • Consists of respiratory failure caused by diaphragmatic and intercostal muscle weakness. • Should be managed in an ICU • Commonest cause : intercurrent infection. Rule out excessive anticholinesterase medication (cholinergic crisis) • Early and effective antibiotic therapy, respiratory assistance (noninvasive, using BiPAP), and pulmonary physiotherapy are essentials of the treatment program. • Plasmapheresis or IVIg is helpful in hastening recovery.

47. Complications • Myasthenic crises • Cholinergic crises • Pneumonia • Respiratory failure • Complications from therapy • Death

48. Prognosis • With appropriate therapy, these patients have a normal life span • Mortality is now 3-4%, with principal risk factors being age older than 40 years, short history of progressive disease, and thymoma; previously, it was as high as 30-40%. • In patients with generalized weakness, the nadir of maximal weakness usually is reached within the first 3 years of the disease. • As a result, half of the disease-related mortality also occurs during this period

49. Conclusion • An autoimmune disease affecting the AChR in the neuromuscular junction • Presents as progressive weakness of the muscles to prolonged stimulation • AChR antibodies are found in most patients • Associated with thymus abnormalities • One of the treatable neurologic disorders

50. Thank you