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CONGENITAL MYASTHENIC SYNDROMES
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Identi cation of CMS is therapeutically important, as these are not immune-mediated disorders and use of immune-modulating therapies exposes the patient to risk without potential bene t Therapies are largely supportive or directed at increasing cholinergic effects at the end plate by augmenting ACh release or delaying its degradation Even this strategy has associated risk, as cholinesterase inhibitors may have no effect or may actually worsen patients with AChE, rapsyn de ciency, or the slow channel syndrome Increased oropharyngeal secretions may be a particularly signi cant source of morbidity from these drugs in these young patients Edrophonium and pyridostigmine may improve strength in patients with presynaptic defects such as choline acetyltransferase de ciency, primary AChR de ciency, and the fast channel syndrome185 In contrast, drugs that block open channels such as quinidine or uoxetine may truncate the prolonged EPP duration and represent both a rational and an effective treatment in slow channel syndrome163,764 Ephedrine may have nonspeci c bene cial effects in occasional patients with CMS including those with AChE de ciency Patients with Dok-7 have variable including worsening responses to pyridostigmine Many of these patients will respond
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favorably to 3,4 diaminopyridine (DAP) and ephedrine Carbonic anhydrase inhibitors may be effective in the rare patients of CMS associated with sodium channel mutations Familial limb-girdle myasthenia is responsive to cholinesterase medications In view of its ability to enhance ACh release, 3,4 DAP has been tried in different CMS subtypes765,766 The drug works on potassium channels in the presynaptic nerve terminal to prolong depolarization, increase calcium entry, and facilitate ACh release It was used to treat 31 patients with various forms of CMS including 10 with fast channel syndrome, 17 with primary AChR de ciency, and four other patients with CMS765 All patients improved after a single test dose of 3,4 DAP at a dose of 025 g/kg A maintenance divided, daily dose of 1 mg/kg/d, provided the best and most sustained response in fast channel patients Patients with primary AChR de ciency responded less frequently and less robustly, while the other patients with CMS failed to improve Patients with slow channel syndrome worsened on the drug Understandably, side effects may relate to enhanced neural activity in other systems including cholinergic, adrenergic, and CNS neurons, with seizure activity being the potential adverse effect of most concern Parents of children at risk of apneic episodes should obtain and familiarize themselves with the use of an apnea monitor and be instructed in the use of parenteral cholinesterase inhibitors and positive pressure bag and mask resuscitation As with any chronic neuromuscular disease, noninvasive or invasive positive pressure ventilation, spinal instrumentation, and percutaneous enteral feeding tubes are therapeutic options for patients in whom the respective needs arise
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If a tumor is identi ed in a patient with LEMS it should be removed if respectable, assuming that the patient s overall medical condition warrants it Following tumor resection and appropriate chemotherapeutic and radiation therapy intervention, a number of patients recover quite well from the muscle symptoms and demonstrate improvements in their electrophysiologic studies346,767 769 Their CMAP amplitudes at rest increase and their decremental and incremental responses diminish Additionally, the degree of jitter and blocking improve with SFEMG In patients without de nable tumor, careful observation and serial evaluations are necessary to ensure the earliest possible identi cation of tumor appearance In both patients with and without tumor, a number of therapeutic medications can be given to assist with the symptoms of weakness and fatigue197,212,567 In most cases, the medication must be given on a long-term ba-
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sis and is directed at both increasing the safety factor for NMJ transmission and suppressing the autoimmune response Anticholinesterase medication can be tried in LEMS in an attempt to increase the amount of ACh in the NMJ194,329,330,332,334,337,338,346,770 Anywhere from a 50% to 100% CMAP amplitude increase can be seen The response is variable and often modest in comparison to MG The amount of ACh released per neural stimulation can be augmented by administering guanidine This is believed to prolong the nerve terminal action potential, allowing more calcium to enter, thus facilitating an increase in quantal content332,334,346 Although this medication may be symptomatically effective, there are a number of unfortunate side effects such as bone marrow, renal, and hepatic toxicity as well as gastrointestinal dysfunction that limit its use The aminopyridines block voltage-dependent potassium conductance, thereby prolonging nerve terminal depolarization and facilitating ACh release 4-DAP can be effective in improving muscle strength Its use is limited by the increased incidence of CNS side affects including seizures and agitated confusion608,771,772 3,4 DAP is a related medication with limited CNS side effects Several studies purport clinical and electrophysiological improvement in LEMS with 3,4 DAP335,344,346,726,727,770,773,774 A prospective, randomized placebo-controlled trial of 3,4 DAP in 26 patients with LEMS (paraneoplastic and nonparaneoplastic) revealed improvement in strength and summated CMAP amplitudes726,727 The starting dose was 20 mg three times daily and was gradually adjusted to achieve a maximal bene t The medication is generally well tolerated, with a few patients experiencing perioral and acral paresthesias It is recommended that doses should not exceed 80 mg/d, as higher doses may result in seizures726,727 3,4 DAP is not as yet FDA approved, and its availability is limited in the United States It is available on a compassionate-use basis for patients with LEMS from Jacobus Pharmaceutical Company, Inc, Princeton, NJ, pending approval from the FDA Information regarding the application process to receive 3,4 DAP can be obtained by faxing the drug company at (609)-799-1176 An alternative pharmacologic approach is attempted immunosuppression with corticosteroids or other agents described in the MG section209,212,346,775,776 These drugs must be given over a long time period, and although of bene t, relapses do occur with their withdrawal Dosing is similar to that described in the MG section One theoretical concern is that suppressing the patient s immune system may have a deleterious effect on the patient s immune response to their underlying neoplasm One hypothesis as to why LEMS often precedes tumor detection is that the same immune response that produces LEMS has the bene cial effect of suppressing
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