Weekly clinical seminar Neurology team By Chidimma A Onwurah

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 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 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 ( ): 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

 Onyekwelu FA et al in UNTH ( ): 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: thymic hyperplasia, 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 presynaptic neurone 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.

Before Seconds later

 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 /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

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