Myasthenia Gravis&Other Disorders of the Neuromuscular Junction Marisa Schiller Sosinsky, MD & Petra Kaufmann, MD, MSc IEUROMUSCULAR

TRANSMISSION lie neuromuscular junction is the synaptic connection nined between a motor neuron axon and the muscle Ix-r it innervates. T h e ttansmitter used at the neuromusil. ii junction, acetylcholine, is stored in the presynaptic lotor nerve terminals. The postsynaptic muscle memlane has many folds in which receptors lor acetylcholine c- located. When a motor neive .11 lion potential reaches ic presynaptic nerve terminal, there is .1 resultant inctease 1 ( a l l i um conductance through voltage-gated calcium lannels. This increase in inliatellular calcium leads to 1.K111 ol acetylcholine lillecl presynaptic vesicles with the lumt tin inlnane- ol ilcc motor nerve terminal. 11 y111ii 111111 i'. MIII-.I IJMCIMIV telcaxed into the synaptic rll liy . , i n v i " . r. I he ,11 rtyli holinc dilluus .n HISS 1 lit- synapse and binds I the aniylc holinr 1111 pirns mi the postsynaptic muscle II iiihi.inc I In- binding <>l m nyli holinc to triese recepITI lac lltt.it> -. 1111 leased . cuidin lion ol sodium and potasIIIM I in-, leads hi iiausient depolarization ol the Mtjum lional muscle mc-nilu.inc- known as an end-plate Inn:,11'This depolarization allows for the generation and opafaiiiin ol action potentials in the postsynaptic mus "II These processes initiate a chain of events in the us. le cell that culminates in muscle contraction, isoidcis ol the neuromuscular junction result from a disunion ol this series of events. 1YASTHENIA GRAVIS (AUTOIMMUNE 1YASTHENIA) j ESSENTIALS OF DIAGNOSIS Fluctuating, fatigable weakness of commonly used muscles Often involves ocular, bulbar, and respiratory muscles Can be associated with thymoma or thymic hyperplasia Presence of circulating antibodies to the acetylcholine receptor (most patients) General Considerations Myasthenia gravis ( M G ) , the most common of the neuromuscular junction disorders, is an acquired, predominantly antibody-mediated autoimmune disease. In this

disorder, antibodies are targeted against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction, resulting in an overall reduction in the number of A C h R s and damage to the postsynaptic membrane. The prevalence o f autoimmune M G is estimated at 1 case in 10,000-20,000 people. Women ate affected more often in the second and third decades of life, and men more often in the fifth and sixth decades. Associated autoimmune diseases are present in approximately VN> of patients, and comorbid thyroid disease occurs in more than 10%. Pathogenesis In generalized M G , A C h R antibodies are detected in up to 90% of patients, whereas in purely ocular M G , only about 50% ol patients are antibody positive. Patients without ihese antibodies are classified as having seronegative M( 1. The antibodies cross-link AChRs and facilitate unusually rapid endocytosis, resulting in receptor loss on the postsynaptic membrane. In addition, complement mediated damage to the postsynaptic membrane results in fewer membrane folds and widened synaptic clefts. Antibodies to epitopes other than the A C h R have been identified in patients with M G . These include MYASTHENIA GRAVIS & OTHER DISORDERS O F T H E N E U R O M U S C U L A R JUNCTION / 351 antibodies to the muscle-specific kinase (MuSK) in seronegative M G and antibodies to the muscle proteins titin and ryanodine in patients who have thymomas. It is unclear how these other antibodies lead to clinical disease. The antibody production is a T-cell-mediated process thought to be associated with thymic dysfunction. Thymic lymphofollicular hyperplasia occurs in 70% of M G patients. Thymoma, an epithelial tumor of the thymus, occurs in 10% of patients with M G . In this subpopulation the disease can be thought of as a paraneoplastic disorder (see Chapter 13). Clinical Findings A . SYMPTOMS AND SIGNS M G is clinically characterized by fluctuating, fatigable weakness of commonly used muscles. I lallmark features include ptosis, diplopia, dysarthria, dysphagia, and respiratory and limb muscle weakness. About half of patients present with oculai findings. Others may present with respiratory symptoms, dysarthria and dyspha gia, or fatigable limb muscle weakness I'hc oculai muscle weakness is usually bilateral and asymmetric and

results in diplopia, ptosis, or both. Notably, (he pupil is spared. Eventually, almost all patients with M G develop ocular symptoms, and in some the disease is limited to the extraocular muscles. W i t h i n the first year o f disease onset, up to 7 5% of patients develop generalized symptoms. B u l b i l symptoms are common and include dysarthria, dysphagia, facial weakness, and weakness of mastication. Because of palatal weakness, patients often have nasal speech and can tegurgitate liquids through the nose. Bulbar manifestations are often the most disabling symptoms. Limb and ttunk weakness is common in a proximal greater than distal distribution. Frequenrly, the arms are more affected than the legs. T h e quadriceps, triceps, and neck extensor muscles appear to be preferentially involved. A hallmark of myasthenic weakness is its fluctuating and fatigable nature. It may increase throughout the day, wotsen with sustained activity, and improve with rest. The most serious of the symptoms is respiratory c ompromise caused by weakness of diaphragmatic and intercostal muscles. These respiratory symptoms, in ' onjunction with severe bulbar symptoms, can culmin. in- in so-called myasthenic crisis, defined as respiratory failure requiring mechanical ventilation. This complication occurs in about 15-20% of patients with M G and may be precipitated by infection or aspiration. In roughly one third of pregnant women M G is exacerbated by the pregnancy, with the greatest risk during the first trimester. In some patients, symptoms and signs improve during the second and third trimesters coincident with the relative immunosuppression that occurs during this phase o f pregnancy. A high risk then returns during the postpartum period. In addition to the effects on the mother, approximately one third of infants of mothers with autoimmune M G have transitory neonatal myasthenia, with weakness appearing within the first 4 days o f life and usually lasting for 3 weeks. Weakness is the result o f placental transfer of maternal antibodies to the fetal blood circulation, yet there is no clear association between neonatal weakness and maternal clinical status or antibody levels. Affected infants also are poor feeders and have a weak cry. B. DIAGNOSTIC STUDIES 1. Tensilon (edrophonium) testThis test evaluates the response to a short-acting cholinesterase inhibitor. The examiner must identify a clinical feature (most

often ptosis) to observe. One milligram o f edrophonium is given intravenously as a test dose. I f no adverse effects are noted, a 3-mg dose is given. A clinical response should be seen within 3060 seconds. If no response is seen, an additional 3 mg o f edrophonium can be given and the patient examined again. If thete is still no improvement, a final 3-mg dose can be given, for a total of 10 mg. If there is no c l i n i c a l improvement after 2 minutes, the test is negative. Studies suggest a sensitivity o f 7 0 - 9 5% for this test. Specificity is not as high; positive tests have been repotted in a variety of conditions, including Lambert-Eaton myasthenic syndrome, botulism, snake envenomation, motor neuton disease, and multiple sclerosis. Serious muscarinic cholinergic side effects can occur with the- test, including increased oropharyngeal secre1 ions and respiratory decompensation as well as bradycardia or asystole. Cardiac monitoring should be performed, and atropine should be available readily during the test. When significant ptosis is ptesent, myasthenic weakness can sometimes be evaluated by placing an ice pack over the closed ptotic eyelid for 2 minutes. The test is considered supportive of myasthenic weakness if the ptosis visibly improves. C o l d temperature is thought to decrease cholinesterase activity and promote efficiency of acetylcholine at eliciting depolarizations at the end plate. Similarly, one can evaluate for improved ptosis after 30 minutes o f sleep. 2. L a b o r a t o r y studiesSerologic testing should be performed in several steps. The first screening antibody should be- the AChR-binding antibody, because it is the most sensitive. If it is negative, then an AChR-modulating antibody test incteases the diagnostic yield. Testing for A( !liR blocking antibodies does not increase sensitivity. In patients who are seronegative for these antibodies, M11.SK antibodies may be present. Patients with thymoma may have aniihodies to the muscle proteins ryanodine and I it in. ( )f nine, die- absolute titers o f these antibodies do not c imelate well with disease course or severity. 3. KMCttlHlhglKlirlr studiesRoutine nerve conduction studies and electromyography usually do not identify dy.slnnc lion of the neuromuscular [unction. Slow repetitive i CHAPTER 22 nerve stimulation is the most commonly used test to evaluate for M G . In this test, a nerve is stimulated 6-10 times at a rate o f 2 or 3 H z , and the compound muscle action

potential (CMAP) is measured over the corresponding muscle. In normal individuals, no change occurs in the C M A P over time. In patients with M G , however, there is a decrease o f more than 10% in C M A P with the first four to five stimuli. Immediately following 10 seconds o f maximal voluntary exercise, the decrement typically repairs toward normal. This is followed by postexercise exhaustion, with progressively greater decrement when stimulating at 1-minute intervals after maximal voluntary exercise. Low-frequency repetitive stimulation has l ow sensitivity; only 7 5% of patients with generalized M G and even fewer with only ocular or distal limb weakness have a positive test. In addition, repetitive nerve stimulation is not specific for M G and can be positive in Lambert-Eaton myasthenic syndrome, myositis, or lower motor neuron disease. Abnormalities noted on repetitive nerve stimulation do not correlate well with the degree o f weakness. Single-fiber electromyography has a sensitivity of approximately 9 5% in M G . T h i s test measures the variability in synaptic transmission time, otherwise known as "jitter," between two fibers innervated by the same axon. In M G , thete is an increased variability of latencies among muscle fibers in a single motor unit. In addition, RHUI le liber potential may be blocked i f transmission at if. neuioniusc ul.it jutu l i on fails completely. As with slow repetitive nerve stimulation, abnormalities seen o n singlefiber electromyography are not specific to M G . 4 Imaging and other studiesBecause o f the association between M G and thymoma, all patients should be screened for this tumor using either a computed tomographic or magnetic resonance imaging scan o f the chest. In addition, patients should be screened for common comorbid autoimmune diseases (eg, systemic lupus erythematosus, rheumatoid arthritis) as well as thyroid disease. Differential Diagnosis For generalized M G , the differential diagnosis includes Lambert-Eaton myasthenic syndrome, botulism, and myopathy. For ocular myasthenia, alternative diagnoses include progressive external ophthalmoplegia, thyroid disease, and oculopharyngeal muscular dystrophy. Motor neuron disease, brainstem stroke, diphtheria, and botulism must be considered in patients with bulbar predominant myasthenia gravis. Treatment A . SYMPTOMATIC TREATMENT The mainstays of symptomatic treatment are the

cholinesterase inhibitors, which increase the concentration o f acetylcholine at the A C h R (Table 22-1). Acetylcholinesterase inhibitors are most effective early in Inble ii i.( I ) >ln i c M e r a s e inhibitors used in the symptomatic treatment of myasthenia gravis. Dosage Adverse Effects I'yililiiMliiniln.- bromide Up to (.01) nn|/i).iy I'D, with intervals and Common abdominal cramps, diarrhea, tlosi". adjusted loi symptoms (cy, (,l hypennotility,nausea, vomitini|, I- " i l ' t i i ' V i ' i y l o l i ) .K,l,iMliiil,iil,Me.,iiiiiMliMi,iinp'., Illl llM-.i-il IIIIIIII III,J M 'i li y Ml. tlMM'll s.illv.itii HI, miosis Serious bnulyi .iidl.i, i liiillni'H|li MI I Auilii'iioniuiir' 5-25 m y I'D I 4 times a clay, to Commonepigastric disliess, cj.-n.-i,,l maximum of 200 my/day malaise with anxiety and vei ticjc >, miosis, blurred vision, muscle fasciculations, cramps, sialorrhea, bronchorrhea, excessive lacrimal secretions, sweatiny, urinary uryency n i l " " 1 Upto 150 my/day PQ.with intervals and Commondiaphoresis, diarrhea, doses adjusted for symptoms flatulence, Gl hypermotility, nausea, vomiting, increased salivation, muscle twitching Seriousanaphylaxis, bronchospasm, respiratory arrest, respiratory depression, _____ cardiac arrhythmias, seizures i .1 gastrointestinal; PO = by mouth (orally) 'Ainticnniiium and neostigmine are used less < nmnionly than pyridostigmine. MYASTHENIA GRAVIS & OTHER DISORDERS O F THE N E U R O M U S C U L A R JUNCTION / 353 die disease when there are still adequate numbers ol rcccp tors present In patients with mild disease, these agents may be used alone without immunosuppressive therapy. As die disease progresses, increasing doses may be required io achieve the same therapeutic effect. Pyridostigmine is usually given at least three to four times daily, but dose intervals need to be adjusted according to symptoms. A long-acting formulation is available and may be useful with overnight symptom control. The main side effects of the cholinesterase inhibitors are iclated to excess levels of acetylcholine at nicotinic and muscarinic synapses. Muscarinic side effects include diarihea, cramping, and excessive secretions that can worsen icspiratory compromise. Nicotinic side effects include muscle fasciculations and increased blockade of neuromuscular transmission, which can lead to cholinergic crisis.

B. IMMUNOSUPPRESSIVE TREATMENT I. T h y m e c t o m y F o r patients with a neoplastic thymoma, surgical removal of the tttmot is necessary to prevent tumor spread. For patients without thymoma, thymectomy incteases the likelihood of remission. Data on the efficacy of thymectomy are confounded by factors such as variable surgical technique and lack o f controlled trials. In most experienced centers, however, perioperative morbidity and mortality ate vcty low and outweighed by the chances for improvement in most cases. There is controversy about predictors of outcome, but thymus pathology, age, or disease severity does not reliably predict temission. Unless thete are contraindications, thymectomy should be considered for patients of any age w i t h M G . T h e procedure appears to be most effective when performed during 1 lie first 2 years o f disease. Medical treatment of M G prior to surgery decreases the perioperative morbidity. Preoperative inttavenous immunoglobulin (IVIG) or plasmapheresis is often used to stabilize patients with generalized M G . There is debate about the best surgical procedure, ."id protocols have included extensive trans-steinal and 11 m i l ervical approaches as well as, more recently, endounpic techniques and combination approaches. It has I" i n suggested that more extensive resection o f thymus II..in- leads to higher remission rates, but this will i. in no a point of controversy until conclusive compariaHI . an- available. M e d i c a l therapyFor most patients, treatment tin hides inducing remission with high doses of an immunosuppressant. Once remission is achieved, the immunosuppressant can be gtadually tapered, but most patients need to continue at least a small dose o f medication. a. CorticosteroidsThese agents are the first-line immunosuppressive therapy for M G . Many patients have transient worsening o f symptoms w i i h i n the fust 2 weeks of initiating such treatmeni. < lortlcOtteroid therapy may therefore have to be initiated following stabilization w i t h a course o f plasmapheresis or inttavenous immunoglobulin. Patients should be closely monitoted when corticosteroid therapy is initiated, and hospitalization may be warranted. Corticosteroids induce remission in up to 5 0% of patients, and up to 80% of all patients benefit from the

thctapy. Most patients improve within the fitst few weeks o f treatment. Once remission is obtained, the corticosteroids are slowly tapered to the lowest dose possible that does not result i n a flare-up of disease. Complications o f corticosteroids include glucose intolerance, hypertension, cataracts, gastrointestinal ulcers, myopathy, avascular necrosis of the hip, osteoporosis, infection, and psychosis. Some of the risks can be reduced by implementation o f a low-sodium, low-sugar diet, along with calcium supplementation and exercise. The osteoporosis risk can be reduced by prophylactic treatment (eg, alendronate sodium, 5 mg/day orally). b. Nonsteroidal immunosuppressionBecause of side effects from corticosteroids, clinicians often use socalled steroid-sparing medications, such as azathioprinc (Table 22-2). A t least 50% of patients appeat to benefit from this medication. Most studies describe its use in conjunction with cotticosteroids, not as monotherapy. Side effects are generally mild but can include bone marrow and hepatic toxicity; for this reason, blood counts and liver function need to be monitored. Azathioprine acts much more slowly than corticosteroids. Improvement may begin only after several months of treatment, and maximal improvement may require 1-2 years. U p to 2 0% of patients develop an idiosyncratic reaction to azathioptine during the first weeks o f treatment, consisting o f fever, chills, rash, and gastrointestinal symptoms. In these intolerant patients, azathioprine must be discontinued immediately. More recendy, mycophenolate mofetil has been sug gested as an adjunctive or corticosteroid-sparing therapy and perhaps as monotherapy. Preliminary studies demon strate clinical improvement in approximately three quartcis of patients. The onset o f benefit is usually after 1-2 months, with a peak effect usually around 6 months. The side effect profile o f the drug is favorable to treatment alternatives and includes gastrointestinal side effects, hypertension, and peripheral edema. Patients should be advised to avoid ultraviolet-light exposure while taking this medication. Mycophenolate mofetil can cause bone marrow suppression, and monitoring o f blood counts is therefore indicated. The concurrent use o f azathioprine and mycophenolate mofetil is not tecommended. (iyclosporinc is used for patients with sevete M G who cannot be managed with less toxic fotms of thetapy. Majoi side effects include renal toxicity and hypertension.

(lyclophosphamide is an alkylating agent that has been used in patients with teftactory disease. Side effects include severe bone marrow suppression, bladder / CHAPTER 2 2 Table 22-2. Immunosuppressants used in the treatment of myasthenia gravis. Drug* Dosage Monitoring Adverse Effects Azathioprine Increase gradually up to 2-3 mg/kg/day PO Monitor CBC and liver function weekly during first month, twice monthly during second and third months, then monthly CommonGl hypersensitivity, nausea, vomiting Serioi^Tcancer (rare), hepatotoxicity, infection, leukopenia, thrombocytopenia, megaloblastic anemia, pancreatitis Mycophenolate mofetil 1-1.5 g P O twice daily Monitor CBC weekly during first month, twice monthly during second and third months, then monthly Commonconstipation, diarrhea, nausea, vomiting, headache Seriousconfusion, tremor, Gl bleeding, hypertension, peripheral edema, infection, sepsis, cancer (rare), myelosuppression Cyclosporine 2.5 mg/kg/day PO divided twice daily; after 4 weeks, dose may be increased by 0.5 mg/kg/day at 2-wk intervals, to maximum ol 'I m<|/ky/day Monitor blood pressure, CBC, uric acid, potassium, lipids, magnesium, serum creatinine, and BUN every 2 weeks during

initial 3 months of therapy and then monthly if patient is stable Commonheadache, hirsutism, nausea, diarrhea, tremor, g um hyperplasia Seriousanaphylaxis, seizure, hepatotoxicity, hyperkalemia (rare), hypomagnesemi.i, hypertension (frequent), infection, nephrotoxicity (frequent), hemolytic uremic syndrome (rare), paresthesia (rare), lymphoproliferative disorder (rare) i in iiiinpleli'liloo 'Not labeled by the 11 I it,i.l ' 111 ,1 . 11.1 A.IiII slinafPO 11.111<HI liu i by mouth (orally). II in myasthenia gravis. limit iiy, anil risk ol neoplasm. Treatment with 1 v Inq ne in cyclophosphamide should be managed B) I phyiii i.in who is familiar with their adverse effects and monitoring requirements. I'm all or these corticosteroid-sparing imniiinn.sup preilive drugs, there may be an increased long-term risk ill lymphoma or other malignancies. i , Short term treatmentsPlasmapheresis and I Vl< , en h induce rapid clinical improvement but have only short-lasting effects (Table | | r 3 ) . Bo'th are often employed in the special situation o f myasthenic crisis. In addition, either treatment can be used to stabilize patients prior to thymectomy or to treat exacerbations that occur during infection, surgery, or the tapering o f a corticosteroid regimen. I'l.i'.mapheresis usually produces clinical improve" wilhin die first week, and benefits usually last for I ' l i i i . n i l i ' , < 'omplications are uncommon but include hypotension, bradycardia, electrolyte imbalance, and infection. I V I G has similar efficacy to plasmapheresis. Side effects include malaise, hypersensitivity, aseptic meningitis, and, rarely, renal insufficiency, stroke, and myocardial infarction. In addition, patients with immunoglobulin

A deficiency can develop anaphylaxis. In most patients, however, I V I G is well tolerated. There has been debate as to whether plasma exchange or I V I G is the preferred short-term immunotherapy for myasthenia gravis. In practice, the choice o l iherapy for acute disease is often dependent on feasibility and on resources available i n a given situation. C. TREATMENT OF MYASTHENIC CRISIS Myasthenic crisis is defined as an exacerbation of weakness i liar leads to respiratory failure requiring mechanical ventilation. For patients with myasthenic exacerbation MYASTHENIA GRAVIS & OTHER DISORDERS OF THE NEUROMUSCULAR JUNCTION / 355 Table 22-3. Short-term immunosuppressive treatments for myasthenia gravis. Treatment Regimen Adverse Effects Intravenous immunoglobulin (IVIG)a 2 g/kg per course divided over 5 daily treatments Consider premedication with diphenhydramine HCI (50 m g P O once) and acetaminophen (650 mg P O once), 30 min prior to IVIG treatment Commonmalaise, headache, chills, flushing, fever, tightness of t he chest, nausea Seriousanaphylaxis; rash; thrombotic events, including stroke and myocardial infarction (risk lower with slow infusion: concentration < 5% and infusion rates <0.5 mlVkg/h); renal dysfunction (higher risk with sucrosecontaining products); hemolytic anemia; neutropenia; aseptic meningitis; transmission of infection (rare) Plasmapheresis Common regimen is 5 exchanges using an alternate-day schedule Commondizziness, nausea, vomiting, headache, citrate-induced hypocalcemia Serioushemorrhage secondary to systemic anticoagulants; cardiovascular events due to fluid shifting; risk of transmitting infection when using replacement fluids containing plasma; allergic reactions leading to anaphylaxis; activation of coagulation,

complement, and fibrinolytic cascades, or aggregation of platelets leading to intravascular coagulation, or both; problems with vascular access, including infection and sepsis Gl = gastrointestinal; PO = by mouth (orally). "Not labeled by the Food and Drug Administration for use in myasthenia gravis. involving respiratory and bulbar symptoms, hospitalization should be considered to closely monitor clinical status and pulmonary function. Once a patient is intubated, anticholinesterase medications should be discontinued because they can promote excessive secretions. Corticosteroids can actually prolong the duration i if a crisis by exacerbating weakness or predisposing to infection. The mainstay of therapy for myasthenic crisis is therefore short-term immunotherapy, either plasmapliriesis or I V I G . I). I HHIGS THAT MAY WORSEN SYMPTOMS HI MYASTHENIA GRAVIS MI.II classes of drugs are associated with clinical worse H of existing M G , and a smaller group of drugs actually causes M G in occasional patients. D Penicillamine, intetferon alpha, and bone marrow transplantation have all been implicated in causing M G . The mechanism is unclear, but there is evidence o f an autoimmune basis for both penii illaminc and interferon alpha. In most cases, thesyni| s lesnlve with discontinuation of the medication. Many other dmgs are associated willi niyasilienic worsening (Table 22-4). Because any cling i an potentially worsen symptoms, patients with M G should be warned about possible exacerbation with medication use. Prognosis Eighty percent of patients eventually develop general ized M G . For patients w i th disease limited to the en iil.u Table 22-4. Medications that can exacerbate myasthenia gravis. Antibiotics (many), most notably the aminoglycosides p-Blockers Calcium channel blockers Chloroquine D-Penicillamine lodin.iled contrast l i t h i um Nondepolarizing and depolarizing netitomuscular-blocking agents

Phenol liiti/ines PICK .iinainide Otiinicline Quinine CHAPTER 22 muscles, cholinesterase inhibitors, low-dose corticosteroids, or nonmedicinal therapy (eg, eyelid crutches) may be sufficient to control symptoms. Most patients with generalized M G enjoy a normal and productive life when adequately treated. However, quality o f life may be compromised as a result o f b o th the limited efficacy and the side effects of available drugs. Patients with an underlying thymoma often have a more aggressive disease course. Ciafaloni E, Massey JM. Myasthenia gravis and pregnancy. Neurol Clin 2004;22:771-782. {PMID 15474766] Ciafaloni E, ec al. Retrospective analysis of the use of cyclosporine in myasthenia gravis. Neurology 2000;55:448-450. [PMID 10932288] (An analysis of patients who took cyclosporine for an average of 3-5 years; clinical improvement was seen in 96%, with a median time to best clinical response of 7 months; and corticosteroids were discontinued or decreased in 95% of patients taking them.) De Baets M , Stassen M H . The role of antibodies in myasthenia gravis. J Neurol Sci 2002;202:5-11- [PMID 12220686] (Reviews the different types of autoantibodies present in patients with MG.) Djeimis J, et al. Myasthenia gravis in pregnancy: Report on 69 cases. Eur J Obstet Gynecol Reprod Biol 2002;104:21-25. [PMID 12128277] (This review of 69 prelum irs among 65 women with MG, in which 1 5% of patients showed worsening of disease in pregnancy and i lurihei 16% in the puerperium, emphasizes tliat M G patients can have normal pregnancy and drlivety bin die o m r s r is unpirdii table) I'VMII A, n .il Thymoma m pmirnti with M<: < Characteristics and |,mK i in. minmni Nmndoyj .'00\v>. 1 K44 1850. [PMID I [Ml .'.ll 1 | (A n in. p.. livr .Hiily ol /()/ myasthenic patients wim W9ti DMftttd .11 l o i thymoma, with at least 1-ycar follow UB IK-III lurtfryi MG uiociitcd thymoma was invavivr in thr HI if v n| | .. M< . was j-riu i.illy severe, and i i i MM pint nr. i. MI i I .1. | ml. in n n i itliltmippressive .h.-.ny) GIlchriM [M.kehiGM II liifnoitii itudin In thr manage IIUMI .ii i< I piiifmutis ol n r u i i i l i l i iM ulai ilistiiilcis. Muulr Nerur .'OO-U'l Id'. I'll) [PMID I 4/VJ'IH 11 (Krviews elrumphysi<ili.|.i< in Imitjiies lui prognosis and management of disorders

nl i i n i i o i m iM nlar transmission.) \h t!S, Rarohn RI. Practice parameter: Thymectomy for autoimmune myasthenia gravis (an evidence-based review): RtpOrt of the Quality Standards Subcommittee ol die American Academy of Neurology. Neurology Z0O0;Vi:'/ IS. [PMID 10891896] (An evidence based icview ol ihymec COmy lor autoimmune MG.} Kiirnani JF, et al. Myasthenic crisis, tun frail Options Neurol 2004;6:3-15. [PMID: 14664765] (Reviews myasthenic crisis, a life-threatening complication that occurs in approximately 15-20% of patients with MG.) Marx A, et al. The role of thymomas in the development of myasthenia gravis. Ann N Y Acad Sci 2003;998:223-236. [PMID 14592880] (Reviews thymic pathology, which occurs in 80-90% of patients with MG.) Meriggioli MN, et al. Mycophenolate mofetil for myasthenia gravis: An analysis of efficacy, safety, and tolerability. Nmroloyy 2003;61:1438-1440. [PMID 14638974] (In this Miuly ol 8') patients taking mycophenolaie mofetil, improveini in wav seen in 73% of subjects; side effects were observed in 27% but were sufficient to require discontinuation of the drug in only 6%.) Palace J, et al. Myasthenia gravis: Diagnostic and management dilemmas. Curr Opin Neurol 2001;14:583-589. [PMID 11562569] (Reviews diagnostic tests that may help to confirm MG in patients without AChR antibodies and management dilemmas.) Pascuzzi RM. Pearls and pitfalls in die diagnosis and management of neuromuscular junction disorders. Semin Neurol 2001; 21:425-440. [PMID 11774058] (Clinical features and treatment issues in M G and other disorders of neuromuscular transmission.) Pascuzzi RM. The edrophonium test. Semin Neurol 2003;23:83-88. [PMID 12870109] (Sensitivity and specificity of the test with respect to diagnosis of MG-) Qureshi Al, et al. Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology 1999;52:629-632. [PMID 10025801] (Plasma exchange was associated with a superior ventilatory status at 2 weeks and 1,-month functional outcome compared with IVIG; however, the complication rate was also higher.) Richman DP, Agius MA. Treatment of autoimmune myasthenia gravis. Neurology 2003;61:1652-1661. [PMID 14694025] Sanders DB, et al. Clinical aspects of MuSK antibody positive seronegative M G . Neurology 2003;60:1978-1980. [PMID 12821744] (Clinical characteristics of 12 padents with serum antibodies to

muscle-specific receptor tyrosine kinase; all were women, with symptom onset between ages 21 and 59 years. Seven had prominent neck, shoulder, or respiratory muscle weakness and little or delayed ocular muscle involvement. The response to cholinesterase inhibitors was variable, and electromyographic findings suggested myopathy in several. None improved after thymectomy. All patients improved after plasma exchange, and most had a good response to selected immunotherapy.) Vincent A, et al. Antibodies in myasthenia gravis and related disorders. Ann N Y Acad Sci 2003;998:324-335. [PMID 14592891] Vincent A, et al. Seronegative myasthenia gravis. Semin Neurol 2004;24:125-133. [PMID 15229799] Wiirbiodi ET. Drugs and myasthenia gravis. An update. Arch hilnri Mnl 1997;lV/:399 408, [PMID 90468*) 1| (IV.\ ribes dtugs .iv.oi laicd with < linii al wotxniiiig ol riming- my*.tin in i giavis and dings implu altd m iln p.iili.ij;. it. '.is -.1 ,i v.ni.im "I the disease.) CONGENITAL MYASTHENIA SYNDROMES There are multiple congenital myasthenic syndromes, which ate the result o f genetic defects i n presynaptic, synaptic, and postsynaptic proteins. Symptoms are present at birth or appear in early childhood. Weakness typically affects cranial muscles, and there is often an associated high-arched palate. Similarly affected relatives can often be identified. Cholinesterase inhibitors are helpful in treatment of some, but not a l l , o f these syndromes. Engcl AG, et al. Congenital myasthenic syndromes: Progress over i he past decade. Muscle Nerve 2003;27:4-25. [PMID 12508290]) MYASTHENIA GRAVIS & OTHER DISORDERS OF THE NEUROMUSCULAR JUNCTION / 357 LAMBERT-EATON MYASTHENIC SYNDROME j ESSENTIALS OF DIAGNOSIS - Weakness of proximal limb muscles, which may improve with exercise Autonomic dysfunction (may be severe) Strong association with small cell lung cancer General Considerations Lambert-Eaton myasthenic syndrome (I.f'MS) is an mtoimmune or paraneoplastic disease caused by a presyniptic abnormality o f acetylcholine release. It is i harat let red by chronic fluctuating weakness ol the proximal limb

nuscles, especially the legs. Approximately 60% o f indents with L E M S have an associated small cell carcitoma of the lung or, less often, another type ol maliglancy. The diagnosis of L E M S often precedes clinical Irtection o f the malignancy. In those who do not have an inderlying malignancy, a concurrent autoimmune disease s common. The onset o f the disease is often midlife or ater, but it has also been reported in childhood- Younger indents are more likely to have underlying autoimmune lisease as opposedto malignancy. L E M S is caused by antibodies directed at P / Q type ullage-gated calcium channels and reduced neurotransnittet release at the neuromuscular junction and autolomic nerve terminals. L E M S in association with leoplasm is discussed further in Chapter 13. linical Findings \ SYMPTOMS AND SIGNS I In onset o f symptoms is usually insidious. Generalized II igable weakness is the major symptom. Patients often oinpl.iin of myalgia, muscle tenderness, and stiffness. I In n may be improvement in strength with exercise. Ii llloblllhar and respiratory symptoms are much less " i n ban w i t h M G , but patients with L E M S can in . nn wiih respiratory compromise. Unlike patients vith M<., (hose w i t h L E M S may complain o f a metalic taste, and often have autonomic dysfunction causing Iry mouth, orthostasis, constipation, 'and impotence. -)n examination, the elicited weakness is often mild :ompared with the patient's complaints. Deep tendon eflexes are often hypoacttvc 01 absent bin may be Jotentiated by brief conttaction. Pupils may be dilated md weakly responsive to light secondaiy CO anion ic lysfunction. B. LABORATORY AND ELECTRODIAGNOSTIC FINDINGS Antibodies against P / Q type V G C C s can be detected in over 9 0% of patients with L E M S . In addition, antibodies to N type V G C C s can be found in up to 5 0% of patients; this percentage is higher in malignancy-associated LEMS. Organ-specific autoantibodies (to thyroid, gastric parietal cells, or skeletal muscle) and non-organ-specific autoantibodies (antinuclear, antimitochondrial) are also found in patients with L E M S . Electrodiagnostic studies help confirm the diagnosis and monitor disease progression. The compound muscle action potential ( C M A P ) is low i n most muscles

tested, and C M A P amplitude at rest is the best marker o f disease severity. As in M G , most patients have a decrementing response to slow rates o f repetitive stimulation. Following exercise or repetitive stimulation at 20-50 H z , there is usually a marked facilitation, with doubling o f the C M A P amplitude. T h e preceding findings are useful in distinguishing L E M S from M G . Conventional needle electromyography demonstrates unstable motor unit action potentials that change configuration from impulse to impulse due to blocking o f individual muscle fibers. When many muscle fibers are blocked, the motor units can be small, polyphasic, and o f short duration. As with M G , increased jitter and impulse blocking are seen on single-fiber electromyography. Differential Diagnosis The main alternative diagnosis to consider is M G . L E M S can often be distinguished from M G by its m i ld oculobulbar symptoms and often prominent autonomic symptoms and signs. In addition, electrodiagnostic abnormalities are often more prominent in L E M S than in M G despite the often more severe weakness in M G . L E M S is often misdiagnosed as a myopathy because ol the predominanrly proximal weakness. Treatment The first step in management should be an evaluation for malignancy, especially in older patients or those with a history o f smoking. If L E M S is associated with a malignancy, symptoms often improve dramatically with tumor removal. If no malignancy is found at initial presentation, patients should undergo regular surveillance, because the presentation of L E M S can predate detection o f neoplasm by years. For those with no underlying neoplasm, or insufficient symptom control with tumor removal, Pharmacollicrapy is employed. 3/l-1 >iaminopyradine (3,4-DAP) improves muscle strength and autonomic symptoms in approximately 80% of patients with L E M S . By blocking voltage-gated potassium channels, the drug prolongs action potentials CHAPTER 22 at motor nerve terminals. Perioral paresthesias are the most common side effect, but seizures can occur at h i gh doses. 3,4-DAP is not approved by the Food and D r ug Administration i n the U n i t e d States but can be obtained for compassionate use. Guanidine hydrochloride inhibits mitochondrial calcium

uptake, facilitating release o f acetylcholine at the motot nerve terminal. Guanidine effectively increases strength in patients with L E M S , but its use is l i m i t e d by side-effects that include bone marrow suppression. Unlike M G , L E M S is not very responsive to anticholinesterase drugs, which, however, do potentiate the effects o f 3,4-DAP and guanidine, allowing for use o f lower doses. If the preceding symptomatic therapy is insufficient, immunosuppressive therapy can be attempted, but it is less effective i n L E M S than in M G . If weakness is severe, plasmapheresis or high-dose I V I G often provides rapid, although usually transitory, improvement. Prognosis Prognosis in patients with underlying malignancy is determined by the prognosis ol that malignancy. Because L E M S is less responsive to immunosuppressive therapy than M G , most patients with L E M S have residual weakness even with optimal immunosuppression. Sunders I H I lalnhrrr I-'aliiii inyatlhriiii syndrome: Diagnosis and i i . i n . i i I.I Ann N I' . I,././ ,Vi i .MMI t|'W8:500-508. [PMID I -t V I " l (A , .inijH, li.ir.ivi' 11 vii w ol pathophysiology, clin11'i ' I ' ' I'I1 . 'I A r 11Hl<1,111,*,11 iii.il i, l 1.4 diaminopyridine in I ""I" II I > .-.tI tymltome, Neurology 20O0;54: mil 1,11' [PMID I06M I l l ' . p i . i i n l . i .study showing that V I I >,\V l. . i n ,11,, n v i ..ml ..,1, lie.munil |, LEMS.) I n n I'V' ., , ,| | UHIH-H |.',U,,I, myasthenic syndtninr: I'lectrixliagnostic lii..lmK> ,n, l response to treatment. Neurology 2000;54: I I /I. ,' I ,'H H'MII l Villi (In this study of 73 patients [31 with limn i " i n . . " I with small cell), treatment with 3,4-DAP I'i|>|I'n i t ' moth-late to marked self reported funaional improve iiirni iii 79% ul'tlic S I treated patients.) ItOIULISM ESSENTIALS OF DIAGNOSIS History of ingestion of home-canned foods or > honey (in infants) Rapid onset of ocular symptoms (diplopia, ptosis, blurry vision) and bulbar symptoms (dysarthria and dysphagia) "Descending" pattern of weakness from oculobulbar to limb involvement Dilated pupils General Considerations Botulism is caused by ingesting the neurotoxin o f the bacterium C l o s t r i d i um b o t u l i n u m , an obligate anaerobic, robust, spore-forming bacillus commonly found in

soil. After absorption into the bloodstream, botulinum toxin binds irreversibly to the presynaptic nerve endings of the peripheral nervous system and cranial nerves. Once internalized, the toxin inhibits the release of acetylcholine through the cleavage of polypeptides essential for the docking of synaptic vesicles to the presynaptic membrane o f the nerve terminal. Food-borne botulism is caused by ingestion o f preformed toxin. The most frequent source is home-canned or home-processed low-acid foods. In the infant form o f botulism, C Botulinum spores enter and colonize the immature gastrointestinal tract and produce toxin. This is most often associated with the ingestion of honey. In wound botulism, the toxin is produced from C botulinum infection o f a wound. Inadvertent botulism has been reported in patients treated with intramuscular injections o f b o t u l i n um toxin. Clinical Findings A . SYMPTOMS AND SIGNS The initial symptoms of food-borne botulism (but not the wound-acquired form) may be gastrointestinal nausea, vomiting, and diarrheaand generally appear w i t h i n 2-36 hours o f ingestion. Constipation is mote common once neurologic symptoms are present. The earliest neurologic symptoms are oculobulbar and include dry mouth, blutred vision, diplopia, dysarthria, dysphagia, and dysphonia. In contrast to most cases o f Guillain-Barre syndrome, botulism is chatacterized by a descending paralysis. Weakness begins in the cranial nerves, followed by the upper extremities, respiratory muscles, and finally lower extremities. The weakness progresses from proximal lo distill muscles, Kespiiatniy weakness can be severe anil require prolonged i i u u lu tion. Botulism also affects autonomic synapiii ii,ui',iui\ sion, resulting in constipation, postural hypotension, and urinary retention. On examination, pupils are nine active and tendon reflexes are absent. Most infantile cases occur before the age o f 6 months, and the first signs may be constipation, weak cry, and poor feeding. Weakness then progresses over days, causing poor suck and head control, hypotonia, and deceased movement. Autonomic signs and symptoms include hypotension, tachycardia, and dry mouth. The symptoms of wound botulism are similar to those of food-borne botulism except that gastrointestinal manifestations are usually absent, the incubation

period is longer, and symptoms are gradual i n onset. B. LABORATORY AND ELECTRODIAGNOSTIC FINDINGS Both blood and stool can be sent for detection of the botulinum toxin. C botulinum itself can be detected in MYASTHENIA GRAVIS & OTHER DISORDERS OF T H E N E U R O M U S C U L A R JUNCTION / 359 stool. I f possible, a f o o d sample should also be sent for identification o f the toxin. Elettrodiagnostic studies can support the diagnosis ol botulism and help rule out odier possible diagnoses such as Guillain-Barre syndrome. T h e most consistent finding is a small C M A P in response to a supramaximal stimulus. As w i t h L E M S , repetitive stimulation testing may show a decrement of the C M A P to l ow rates o f stimulation and postexercise facilitation o f the C M A P amplitude. Differential Diagnosis Botulism must be distinguished from M G , LEMS, Guillain-Barre syndrome (particulatly the M i l l e r Fisher ["one-and-a-half"] variant), tick paralysis, diphtheritic neuropathy, and intoxication (including paralytic shellfish poisoning and organophosphates). Treatment The major treatment is intensive supportive care. Patients should be closely monitored lor respiratory decompensation. If the ingestion is recent, removal id unabsorbed gut toxin can be considered, flic Centers for Disease C o n t r o l and Prevention can provide a niva lent botulinum antitoxin, which, however, must be given early while toxin is still in the blood. The antitoxin can dectease severity o f disease and overall mortality, but side effects include anaphylaxis. Prognosis Although significantly reduced, mortality from botulism remains high at 5-10%. Type A toxin is associated with a more severe course and higher mortality than other toxins. Clinical recovery is often prolonged over months, because it requires rhe formation o f new presynaptic end plates and neuromuscular junctions. Recovery of autonomic function may take longer than recovery o f muscle sttength. For those who survive, the recovery is generally complete. Cherington M. Botulism: Update and review. Semin Neurol 2004;24:155-163. [PMID 15257512] (Review of botulism as both an old and an emerging disease; five clinical forms of botulismfood-borne, wound, infant, hidden, and inadvertent as well as the actions of botulinum toxins, electrodiagnostic:

methods, treatments, and possible future directions ate discussed.) TICK PARALYSIS Tick paralysis is a rare disease that usually affects children. Often a prodrome of gait instability is followed by ascending paralysis and hyporeflexia or areflexia. Bulbar structures are eventually affected, leading to dysphagia, dysarthria, facial paralysis, and ocular weakness. If the l i ck is not removed, fatal respiratory failure can develop, 'fhe engorged tick attached to the patient produces a neurotoxin that acts on the neuromuscular junction. Removal o f the tick is usually followed by rapid improvement. This disease is most often confused with GuillainBarre syndrome. Felz M W, et al. A six-year-old girl with tick paralysis. NEngl] Med 2000;342:90-94. [PMID 10631277) Greenstein E Tick paralysis. Med Clin North Am 2002;86:441-446. [PMID 11982312] Vedanarayanan V, et al. Tick paralysis. Semin Neurol 2004;24:181-184. [PMID 15257515] (Reviews pathophysiology, dinical presentation, electrophysiology, and treatment of tick paralysis.)