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Myasthenia Gravis

Myasthenia Gravis. Shahriar Nafissi, MD Associate Professor of Neurology Tehran University of Medical Sciences. Diagnosis. “Delaying the diagnosis of ocular MG is inconsequential but making an erroneous diagnosis has serious implications”.

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Myasthenia Gravis

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  1. Myasthenia Gravis Shahriar Nafissi, MD Associate Professor of Neurology Tehran University of Medical Sciences

  2. Diagnosis • “Delaying the diagnosis of ocular MG is inconsequential but making an erroneous diagnosis has serious implications” Daroff RB. The office tensilon test for ocular MG. Arch Neurol 1986;33:843–844

  3. Clinical FeaturesWhen to question the clinical diagnosis • Acute course, spontaneously improving • Clustering of cases • Autonomic symptoms • Orthostatic hypotension • Sluggish pupils • Constipation, dry mouth • Reduced sweating • Decreased tendon reflexes • Familial • Minor symptoms since infancy/childhood

  4. Clinical Features • No objective finding • Diagnosis based solely on subjective response to Mestinon • Lack of clues pointing to the immune-mediated nature • Antibodies • Thymus • Response to IS, IVIG, PE • Associated autoimmune diseases • Does myasthenic crisis only happen in MG?

  5. Therapeutic trial Diagnosis should not be based on subjective improvement of symptoms especially with Mestinon

  6. Tensilon Test • Pitfalls • Acute decompensation • Oropharyngeal Weakness • Cholinergic Weakness • Subjective vs. objective improvement • Some believe that it should be performed only in patients with ptosis/ophthamoplegia • Technical: • Subcutaneous injection • Not adequately flushed • Expired drug • Complications • from 23,111 edrophonium tests, 37 (0.16%) were associated with a serious complication, most often bradyarrhythmias and syncope. Respiratory failure, seizures, vomiting, and TIA were also reported

  7. Sensitivity • Generalized MG: 72-95% • Ocular 60-86% • Specificity 97% • False positive results: • Ocular> Generalized • Other NMJ disorders: LEMS, Botulism, CMS • LMN syndromes e.g., MND • Others: brainstem glioma, MS, pituitary tumor, compressive aneurysm, GBS, Diabetic 6th palsy and inflammatory myopathy

  8. Anti-Acetylcholine Receptor Antibody • High Affinity AChR-Ab • Find a reliable laboratory • Sensitivity : • Ocular 39-71% (44%) • Generalized 87-98% (our data 82%) • Sometimes negative first, become positive later • Specificity 95-99% • Seronegative MG (~15%) • 30-70% MuSK-Positive • 66% of AChR- , MuSK- cases have low affinity AChRAb • Low affinity MuSKAb • False positive • SLE, RA, inflammatory neuropathy, motor neuron disease • Thymoma without MG, D-penicillamine • Relatives of patients with MG • Not useful in monitoring response to therapy

  9. Repetitive Nerve Stimulation • Sensitivity • Depends on the number of muscles tested • Ocular 11-39% • Generalized 53-98% • Specificity 95-98%

  10. Common pitfalls Technical Artifacts Submaximal stimulation Temperature < 35º C Testing 1-2 muscles, mainly distal Relying on borderline results Missing other NMJ disorders LEMS, Botulism, CMS

  11. Technical factors

  12. Repetitive CMAP After Single Stimuli

  13. False positives Denervating diseases (MND) Myopathies Channelopathies Myotonic dystrophy Metabolic (McArdle)

  14. Myotonic Dystrophy

  15. R ABD POLL BREVIS Amyotrophic Lateral Scleros R ABD POLL BREVIS

  16. Single-Fiber EMG • Sensitivity: • Ocular 86-97% • Generalized 98-100% • Specificity 94-98% • Normal jitter in a clinically weak muscle virtually excludes MG • False Positive Results • Other NMJ disorders • BTX injection • Neurogenic Processes, e.g., MND • Myopathies: PEO, Myositis • In a patient with clinical features of NMJ, specificity is high • Helpful in differentiating central and psychogenic causes of fatigue from MG

  17. R FRONTALIS

  18. MuSK-Positive MG • More severe disease, pure ocular cases rare • 30-70% AChR-Ab negative cases • 80-100% cases female • Severe involvement of facial and bulbar muscles • RNS and SFEMG negative in limb muscles • Thymus pathology rare; not responsive to thymectomy • Many cases non-responsive or non-tolerant to Mestinon • Usually requires Immunosuppressive therapy • Complete remission<10%, IS withdrawn<20%

  19. MuSK-positive patientsstrong inverse correlation with latitude north of the equator

  20. Treatment

  21. Mestinon • Symptomatic therapy; doesn’t affect underlying mechanism • No fixed dose schedule • With any dose, some muscles get stronger, some don’t change and others get weaker • Need more drug with menstruation, emotional stress, hot weather, infection • If needs too much or if response suboptimal, consider other medications

  22. Mestinon • Cholinergic Weakness • Don’t forget irreversible damage to NMJ • MuSK-Positive Patients • When used in combination to IS, try to discontinue Mestinon as soon as the patient becomes symptom-free

  23. Thymectomy • Before deciding about thymectomy, make sure that the patient has autoimmune MG • R/O: • LEMS • Congenital myasthenic syndrome • Botulism • Neurasthenia • Mitochondrial disease

  24. Thymectomy in MG • Indicated • Thymoma • Seropositive MG onset 15-50 years with moderate or severe disease “For patients with non-thymomatous autoimmune MG, thymectomy is recommended as an option to increase the probability of remission or improvement (class II evidence)”

  25. Thymectomy in MG • Not indicated • Ocular MG • MuSK-Positive MG • Mild generalized non-thymomatous MG • Late-onset non-thymomatous MG (> 50 or 60) • No effect of thymectomy • Titin and Ryanodine Ab positive cases even deteriorated • Controversial • Seronegative generalized MG • Generalized MG with good response to other treatment modalities

  26. Wait a while before deciding for thymectomy but not too long • Before thymectomy, the patient has to be in a stable condition • If the patient is not thymectomized, F/U CT scan every 2 years • Any MG patient undergoing thoracotomy for other causes (e.g., CABG), should have thymus removed.

  27. Corticosteroids • Corticosteroid-related exacerbations in the first 2 weeks : 15-30% • Patients with weakness in bulbar and respiratory muscles need PE first • Some don’t tolerate alternate day regimen • Suboptimal response to steroid < 20% • Steroid dependency

  28. Cyclosporine • Response begins after 1-2 months • Contraindicated in renal impairment and uncontrolled hypertension • Important drug interactions • NSAIDs • Statins • ACE inhibitors

  29. Mycophenolate Mofetil (Cellcept) • Relatively safe drug but Good for MG or not?

  30. Azathioprine • Particularly used as a steroid-sparing agent • Active metabolite 6-mercaptopurine • Competes with hypoxanthine and inhibits DNA/RNA synthesis • Induces B and T-cell lymphopenia

  31. 10% of population have genetically reduced activity of enzyme thiopurine methyltransferase (TPMT) • AZA metabolism is reduced  vulnerable to myelosuppression • 1/300 have undetectable TPMT activity. AZA contraindicated • Important interaction with allopurinol • Increased toxicity and myelosuppression • Dose reduced to 25%

  32. Contraindications • Known hypersensitivity to azathioprine. • Pregnancy, except where benefit outweigh risk • Breastfeeding • Very low or absent TPMT activity • Dose adjustment needed with allopurinol • Malignancy. • Renal or hepatic insufficiency (relative contraindication

  33. Risks • Cancer • Infection • Hypersensitivity reactions • Megaloblastic changes, leukopenia • Hepatotoxicity • Acute pancreatitis

  34. Cancer • Risk of malignancy for treatment duration < 10 yrs is small • Lymphoma risk increased 4-fold or 1 case/1000 patient years • AML/ myelodysplasia rare • Increased risk of skin cancer • Skin protection with UVA blockers

  35. Infection • When used in combination with steroids, increased susceptibility to viral, bacterial and fungal infection • Live vaccines contraindicated • Diminished response to killed vaccines (e.g., Hepatitis B)

  36. Dosage • TPMT activity should be measured • Usual dosage 1-3 mg/kg • Slow onset of action • Wait several months, usually 4-6 but up to 18 months for response • Is a good choice when delayed response is acceptable • Start Prednisone + AZT in moderate to severe cases from the beginning • Weekly CBC, LFT for 4 weeks

  37. Mycophenolate Mofetil(Cellcept)

  38. Mycophenolate mofetil • Active metabolite: mycophenolic acid • Inhibits inosine monophosphate dehydrogenase and depletes guanine inhibition of DNA synthesis • lymphocyte selective immunosuppressive agent • Compared to AZA: • More selective- less adverse effects • Hepatotoxicity lower • Risk of lymphoma slightly higher

  39. Dosage • Expensive drug • 1-3 gr/day • Usually effect starts in two months • CBC, LFT, blood chemistry monitored • Dose reduction in renal insufficiency • Should not be taken with azathioprine

  40. Side effects • GI upset 20% • Hematologic < 5% • Anemia, leukopenia, thrombocytopenia • Usually mild, dose-dependent, reversible • Genitourinary symptoms • dysuria, urgency, frequency, sterile pyuria, hematuria • Hepatotoxicity, respiratory failure rare • Allergic reactions

  41. Infections • In > 2 g/day • CMV and other herpes family viruses • Bacterial, fungal • PML (10 confirmed, 7 possible)

  42. Cancer risk • Mainly in transplant patients receiving multiple immunosuppressives • Lymphoma • Solid organ tumors • Skin cancer

  43. Pregnancy • FDA pregnancy category D • only use MMF in pregnant women if the potential benefit outweighs the potential risk to the fetus (e.g., transplant patients) • Fetal malformation in 4/15 live born infants • Breast feeding contraindicated

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