Myasthenia Gravis

Weekly clinical seminar Neurology team By Chidimma A Onwurah Myasthenia Gravis

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

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.

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

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

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%.

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.

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

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

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

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

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.

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

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

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.

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

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.

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

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

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

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

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.

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.

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

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.

Seconds later Before

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

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.

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

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

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

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

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.

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

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

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

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

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.

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.

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.

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

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

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

Thank you

Myasthenia Gravis