Myasthenia gravis Treatment Recommendations Treatment Anticholinesterases Immunosuppressants Thymectomy Plasma exchange and IVIG Anticholinesterase Drugs Neostigmine (Prostigmin) mg/2 to 6 h Pyridostigmine (Mestinon) 30 to 90 mg/6 h Mild cases without thymic tumor partial remission after thymectomy purely ocular myasthenia (ocular often responds well to small doses of corticosteroids). Dose equivalent OnsetTime to maximum response Pyridostigmine (Mestinon) 60 mg40 min1 h Neostigmine (Prostigmin) 15 mg1 h1.5 h Neostigmine IM 1.5 mg30 min1 h Neostigmine IV 0.5 mg immediate 20 min Anticholinesterase Drugs Corticosteroids Corticosteroids:60 to 100 mg prednisone daily) alone or in combination with azathioprine Ocular myasthenia Moderate to severe generalized weakness responding inadequately to anticholinesterase Side effects of long-term corticosteroid Prednisone (or corresponding doses of prednisolone), beginning with 15 to 20 mg/day and increasing the dose gradually until clinical response is obtained, or a daily dose of 50 to 60 mg is reached. Worsening in the first week is common, and hospitalization and careful observation for respiratory difficulty is advisable. Improvement occurs slowly over a few weeks Corticosteroids Once the maximal effect has been attained, the dosage can be reduced gradually to the lowest effective dose. Alternate-day schedule the side effects. At the outset of steroids, anticholinesterase are given simultaneously; as the patient improves, the dosage of the latter may be adjusted downward. Corticosteroids Immunosuppressive Drugs Azathioprine Adjunct to steroids and can be effective alone Dose: 50 mg (1 tablet) twice daily for a few days; if tolerated, raised to 2 to 3 mg/ kg per day (150 to 250 mg daily). Improvement is much the same as prednisone, much more slowly, (months to a year) Liver function tests and blood cell count should be checked regularly. The most severe forms of the disease, particularly those resistant to prednisone or azathioprine alone, benefit from the combination of the two medications. Many neurologists, begin by both medications early in the illness with the plan of reducing the corticosteroid dose in the third or fourth month Immunosuppressive Drugs Mycophenolate (CellCept) An adjunct to corticosteroids ( mg/d) The clinical improvement sooner than it does with azathioprine Diarrhea was the main adverse effect. In some milder cases, may be effective alone Immunosuppressive Drugs Cyclophosphamide IV pulses, 50 mg/kg/d for 4 consecutive days followed by granulocyte-stimulating factor to reboot the immune system in refractory cases. Justified if all other measures have failed in severe instances of the disease. Liver function and white blood cell count should be monitored regularly Immunosuppressive Drugs Cyclosporine Like those of azathioprine but become evident more rapidly (month or two) Two divided doses daily, to a total of about 6 mg/kg Serious side effects (hypertension, nephrotoxicity) and its high cost. Immunosuppressive Drugs Plasma Exchange and IVIG plasma exchange Severe myasthenia, refractory to treatment Acute exacerbation (bulbar, severe generalized ) Myasthenic crisis. Before and after thymectomy At the start of immunosuppressive drug. Not adequately respond to treatment Several exchanges of 2 to 3.5 L each (totaling approximately 125 mL/kg), performed over a week. The removed plasma is replaced with albumin and saline. 2-L exchange will remove 80% of circulating antibodies Plasma Exchange and IVIG In a crisis: plasma exchanges and mechanical ventilation, discontinue or curtail the use of anticholinesterase drugs and resume them as the patient is being weaned from the ventilator. Sensitivity to these drugs may be enhanced in the hours after an exchange, so that their dosages must be adjusted accordingly Plasma Exchange and IVIG Plasma exchange is also helpful in limiting the afore mentioned weakness that is often induced by the institution of high-dose corticosteroids. A small number of patients respond so well to plasma exchange and choose to be maintained with 2 to 3 exchanges every several weeks or months. Plasma Exchange and IVIG Immunoadsorption A technique similar to plasma exchange that removes antibodies and immune complexes by running blood over a tryptophan column Less cumbersome than plasma exchange and has been effective Plasma Exchange and IVIG Intravenous immune globulin Indications as that of plasma exchange. The usual dose is 2 g/kg given in divided doses over 3 to 5 days. The effect is equivalent to plasma exchanges. they offer only short-term benefit and are not used regularly in the treatment of most patients Plasma Exchange and IVIG Thymectomy In all patients with uncomplicated myasthenia gravis between puberty and 55 years of age. Performed electively (not during an acute deterioration of myasthenia). The remission rate after thymectomy is approximately 35% ( first year or two after onset of the disease) Another 50% will improve to some extent Ocular Myasthenia for a year or longer, thymectomy is unnecessary. The response is not evident for several months and is maximal by 3 years. In responding cases, circulating receptor antibodies are reduced or disappear entirely. A course of plasma exchange or IVIG If the patient is very weak preoperatively Thymectomy If possible, thymectomy should be postponed until puberty (importance of the gland in the development of the immune system) but juvenile myasthenia is also quite responsive. Indicated in all patients in whom thymoma is detected by CT scanning of the chest (radiation, chemotherapy) Results are not as predictable in thymoma Thymectomy Masaoka Clinical Staging of Thymoma as of Most Recent (1994) Modifications Masaoka StageDiagnostic Criteria Stage I Macroscopically and microscopically completely encapsulated Stage II A. Microscopic transcapsular invasion B. Macroscopic invasion into surrounding fatty tissue or grossly adherent to but not through mediastinal pleura or pericardium Stage III Macroscopic invasion into neighboring organs (i.e., pericardium, great vessels, lung) A. Without invasion of great vessels B. With invasion of great vessels Stage IV A. Pleural or pericardial dissemination B. Lymphogenous or hematogenous metastasis Time to Clinical Effect of Therapies for Myasthenia Gravis Treatment Time to Clinical Effect Pyridostigmine 1015 minutes Plasmapheresis 114 days IVIg 14 weeks Prednisone 28 weeks Mycophenolate mofetil 26 months Cyclosporine 26 months Azathioprine 318 months Myasthenic Crisis Rapid and severe deterioration of the myasthenia itself, can bring the patient to the brink of respiratory failure and quadriparesis in a matter of hours Respiratory infection or excessive use of sedatives or drugs blocking neuromuscular transmission may precede the myasthenic crisis, no cause could be determined in one-third Treatment of Myasthenic Crisis Careful intubation followed by mechanical ventilation in a CCU that is equipped to attend to the medical and neurologic needs of such patients. Respiratory failure : by the use of bilevel positive airway pressure (BiPAP) Anticholinergic drugs, which exaggerate secretions, are best withdrawn at the time of intubation Myasthenic Crisis Plasma exchange or IVIG a week or more is required for recovery. It is best to wait 2 or 3 weeks before committing a patient to tracheostomy. When weaning is anticipated, anticholinesterase agents are reintroduced slowly, and treatment with corticosteroids can be instituted if necessary. Myasthenic Crisis Management of generalised myasthenia gravis Management of ocular myasthenia Therapeutic recommendations in MG. Classification of Congenital Myasthenic Syndromes Presynaptic defects CMS with episodic apnea (choline acetyltransferase deficiency) Paucity of synaptic vesicles Lambert-Eaton syndrome-like CMS Synaptic defects End-plate acetylcholinesterase deficiency Postsynaptic defects Primary AChR deficiency with or without kinetic abnormality Reduced AChR expression due to AChR mutations Reduce AChR expression due to rapsyn mutations Reduced AChR expression with plectin deficiency Primary AChR kinetic abnormality with or without AChR deficiency Slow-channel CMS Fast-channel CMS Sodium-channel CMS (mutations of perijunctional sodium channels)