Myasthenia Gravis&OtherDisorders of the NeuromuscularJunctionMarisa Schiller Sosinsky, MD & Petra Kaufmann, MD, MScIEUROMUSCULAR TRANSMISSIONlie neuromuscular junction is the synaptic connectionnined between a motor neuron axon and the muscleIx-r it innervates. T h e ttansmitter used at the neuromusil.ii junction, acetylcholine, is stored in the presynapticlotor nerve terminals. The postsynaptic muscle memlanehas many folds in which receptors lor acetylcholinec- located. When a motor neive .11 lion potential reachesic presynaptic nerve terminal, there is .1 resultant inctease1 ( a l l i um conductance through voltage-gated calciumlannels. This increase in inliatellular calcium leads to1.K111 ol acetylcholine lillecl presynaptic vesicles with thelumt tin inlnane- ol ilcc motor nerve terminal.• 11 y111ii 111111 i'. MIII-.I IJMCIMIV telcaxed into the synapticrll liy . , i n v i " . r.I he ,11 rtyli holinc dilluus .n HISS 1 lit- synapse and bindsI the aniylc holinr 1111 pirns mi the postsynaptic muscleII iiihi.inc I In- binding <>l m nyli holinc to triese recep-ITI lac lltt.it> -. 1111 leased . cuidin lion ol sodium and potas-IIIM I in-, leads hi iiausient depolarization ol theMtjum lional muscle mc-nilu.inc- known as an end-plate•Inn:,11'This depolarization allows for the generation andopafaiiiin ol action potentials in the postsynaptic mus-• "II These processes initiate a chain of events in theus. le cell that culminates in muscle contraction,isoidcis ol the neuromuscular junction result from a disunionol this series of events.1YASTHENIA GRAVIS (AUTOIMMUNE1YASTHENIA)j ESSENTIALS OF DIAGNOSIS• Fluctuating, fatigable weakness of commonlyused muscles• Often involves ocular, bulbar, and respiratorymuscles• Can be associated with thymoma or thymichyperplasia• Presence of circulating antibodies to the acetylcholinereceptor (most patients)General ConsiderationsMyasthenia gravis ( M G ) , the most common of the neuromuscularjunction disorders, is an acquired, predominantlyantibody-mediated autoimmune disease. In this

disorder, antibodies are targeted against the nicotinicacetylcholine receptor (AChR) at the neuromuscularjunction, resulting in an overall reduction in the numberof A C h R s and damage to the postsynaptic membrane.The prevalence o f autoimmune M G is estimated at 1case in 10,000-20,000 people. Women ate affected moreoften in the second and third decades of life, and menmore often in the fifth and sixth decades. Associatedautoimmune diseases are present in approximately VN> ofpatients, and comorbid thyroid disease occurs in morethan 10%.PathogenesisIn generalized M G , A C h R antibodies are detected in upto 90% of patients, whereas in purely ocular M G , onlyabout 50% ol patients are antibody positive. Patientswithout ihese antibodies are classified as having seronegativeM( 1. The antibodies cross-link AChRs and facilitateunusually rapid endocytosis, resulting in receptor loss onthe postsynaptic membrane. In addition, complementmediated damage to the postsynaptic membrane results infewer membrane folds and widened synaptic clefts.Antibodies to epitopes other than the A C h R havebeen identified in patients with M G . These includeMYASTHENIA GRAVIS & OTHER DISORDERS O F T H E N E U R O M U S C U L A R JUNCTION / 351antibodies to the muscle-specific kinase (MuSK) inseronegative M G and antibodies to the muscle proteinstitin and ryanodine in patients who have thymomas. It isunclear how these other antibodies lead to clinical disease.The antibody production is a T-cell-mediatedprocess thought to be associated with thymic dysfunction.Thymic lymphofollicular hyperplasia occurs in70% of M G patients. Thymoma, an epithelial tumor ofthe thymus, occurs in 10% of patients with M G . In thissubpopulation the disease can be thought of as a paraneoplasticdisorder (see Chapter 13).Clinical FindingsA . SYMPTOMS AND SIGNSM G is clinically characterized by fluctuating, fatigableweakness of commonly used muscles. I lallmark featuresinclude ptosis, diplopia, dysarthria, dysphagia, and respiratoryand limb muscle weakness. About half ofpatients present with oculai findings. Others may presentwith respiratory symptoms, dysarthria and dysphagia, or fatigable limb muscle weakness I'hc oculaimuscle weakness is usually bilateral and asymmetric and

results in diplopia, ptosis, or both. Notably, (he pupil isspared. Eventually, almost all patients with M G developocular symptoms, and in some the disease is limited tothe extraocular muscles.W i t h i n the first year o f disease onset, up to 7 5% ofpatients develop generalized symptoms. B u l b i l symptomsare common and include dysarthria, dysphagia,facial weakness, and weakness of mastication. Because ofpalatal weakness, patients often have nasal speech andcan tegurgitate liquids through the nose. Bulbar manifestationsare often the most disabling symptoms. Limband ttunk weakness is common in a proximal greaterthan distal distribution. Frequenrly, the arms are moreaffected than the legs. T h e quadriceps, triceps, and neckextensor muscles appear to be preferentially involved. Ahallmark of myasthenic weakness is its fluctuating andfatigable nature. It may increase throughout the day,wotsen with sustained activity, and improve with rest.The most serious of the symptoms is respiratoryc ompromise caused by weakness of diaphragmatic andintercostal muscles. These respiratory symptoms, in' onjunction with severe bulbar symptoms, can culmin.in- in so-called myasthenic crisis, defined as respiratoryfailure requiring mechanical ventilation. This complicationoccurs in about 15-20% of patients with M G andmay be precipitated by infection or aspiration.In roughly one third of pregnant women M G isexacerbated by the pregnancy, with the greatest risk duringthe first trimester. In some patients, symptoms andsigns improve during the second and third trimesterscoincident with the relative immunosuppression thatoccurs during this phase o f pregnancy. A high risk thenreturns during the postpartum period.In addition to the effects on the mother, approximatelyone third of infants of mothers with autoimmune M Ghave transitory neonatal myasthenia, with weaknessappearing within the first 4 days o f life and usually lastingfor 3 weeks. Weakness is the result o f placental transfer ofmaternal antibodies to the fetal blood circulation, yetthere is no clear association between neonatal weaknessand maternal clinical status or antibody levels. Affectedinfants also are poor feeders and have a weak cry.B. DIAGNOSTIC STUDIES1. Tensilon (edrophonium) test—This test evaluatesthe response to a short-acting cholinesterase inhibitor.The examiner must identify a clinical feature (most

often ptosis) to observe. One milligram o f edrophoniumis given intravenously as a test dose. I f no adverse effectsare noted, a 3-mg dose is given. A clinical responseshould be seen within 30—60 seconds. If no response isseen, an additional 3 mg o f edrophonium can be givenand the patient examined again. If thete is still noimprovement, a final 3-mg dose can be given, for a totalof 10 mg. If there is no c l i n i c a l improvement after2 minutes, the test is negative. Studies suggest a sensitivityo 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 occurwith the- test, including increased oropharyngeal secre-1 ions and respiratory decompensation as well as bradycardiaor asystole. Cardiac monitoring should be performed,and atropine should be available readily during the test.When significant ptosis is ptesent, myasthenic weaknesscan sometimes be evaluated by placing an ice packover the closed ptotic eyelid for 2 minutes. The test isconsidered supportive of myasthenic weakness if theptosis visibly improves. C o l d temperature is thought todecrease cholinesterase activity and promote efficiencyof acetylcholine at eliciting depolarizations at the endplate. Similarly, one can evaluate for improved ptosisafter 30 minutes o f sleep.2. L a b o r a t o r y studies—Serologic testing should be performedin several steps. The first screening antibodyshould be- the AChR-binding antibody, because it is themost sensitive. If it is negative, then an AChR-modulatingantibody test incteases the diagnostic yield. Testing forA( !liR blocking antibodies does not increase sensitivity.In patients who are seronegative for these antibodies,M11.SK antibodies may be present. Patients with thymomamay have aniihodies to the muscle proteins ryanodine andI it in. ( )f nine, die- absolute titers o f these antibodies do notc imelate well with disease course or severity.3. KMCttlHlhglKlirlr studies—Routine nerve conductionstudies and electromyography usually do not identifydy.slnnc lion of the neuromuscular [unction. Slow repetitivei CHAPTER 22nerve stimulation is the most commonly used test to evaluatefor M G . In this test, a nerve is stimulated 6-10 timesat a rate o f 2 or 3 H z , and the compound muscle action

potential (CMAP) is measured over the correspondingmuscle. In normal individuals, no change occurs in theC M A P over time. In patients with M G , however, there isa decrease o f more than 10% in C M A P with the first fourto five stimuli. Immediately following 10 seconds o f maximalvoluntary exercise, the decrement typically repairstoward normal. This is followed by postexercise exhaustion,with progressively greater decrement when stimulatingat 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 fewerwith only ocular or distal limb weakness have a positivetest. In addition, repetitive nerve stimulation is not specificfor M G and can be positive in Lambert-Eaton myasthenicsyndrome, myositis, or lower motor neuron disease.Abnormalities noted on repetitive nerve stimulation donot correlate well with the degree o f weakness.Single-fiber electromyography has a sensitivity ofapproximately 9 5% in M G . T h i s test measures the variabilityin synaptic transmission time, otherwise known as"jitter," between two fibers innervated by the same axon.In M G , thete is an increased variability of latenciesamong muscle fibers in a single motor unit. In addition,RHUI le liber potential may be blocked i f transmission atif. neuioniusc ul.it jutu l i on fails completely. As with slowrepetitive nerve stimulation, abnormalities seen o n singlefiberelectromyography are not specific to M G .4 Imaging and other studies—Because o f the associationbetween M G and thymoma, all patients should bescreened for this tumor using either a computed tomographicor magnetic resonance imaging scan o f the chest.In addition, patients should be screened for commoncomorbid autoimmune diseases (eg, systemic lupus erythematosus,rheumatoid arthritis) as well as thyroid disease.Differential DiagnosisFor generalized M G , the differential diagnosis includesLambert-Eaton myasthenic syndrome, botulism, andmyopathy. For ocular myasthenia, alternative diagnosesinclude progressive external ophthalmoplegia, thyroiddisease, and oculopharyngeal muscular dystrophy.Motor neuron disease, brainstem stroke, diphtheria, andbotulism must be considered in patients with bulbarpredominant myasthenia gravis.TreatmentA . SYMPTOMATIC TREATMENTThe mainstays of symptomatic treatment are the

cholinesterase inhibitors, which increase the concentrationo f acetylcholine at the A C h R (Table 22-1).Acetylcholinesterase inhibitors are most effective early inInble ii i.( I )• >ln i c M e r a s e inhibitors used in the symptomatic treatment of myasthenia gravis.Dosage Adverse EffectsI'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'lls.illv.itii HI, miosisSerious bnulyi .iidl.i, i liiillni'H|li MI IAuilii'iioniuiir' 5-25 m y I'D I 4 times a clay, to Common—epigastric disliess, cj.-n.-i,,lmaximum of 200 my/day malaise with anxiety and vei ticjc >,miosis, blurred vision, musclefasciculations, cramps, sialorrhea,bronchorrhea, excessive lacrimalsecretions, sweatiny, urinary uryencyn i l " " 1 Upto 150 my/day PQ.with intervals and Common—diaphoresis, diarrhea,doses adjusted for symptoms flatulence, Gl hypermotility, nausea,vomiting, increased salivation, muscletwitchingSerious—anaphylaxis, bronchospasm,respiratory arrest, respiratory depression,_____ cardiac arrhythmias, seizuresi .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 / 353die disease when there are still adequate numbers ol rcccptors present In patients with mild disease, these agentsmay be used alone without immunosuppressive therapy.As die disease progresses, increasing doses may be requiredio achieve the same therapeutic effect. Pyridostigmine isusually given at least three to four times daily, but doseintervals need to be adjusted according to symptoms. Along-acting formulation is available and may be usefulwith overnight symptom control.The main side effects of the cholinesterase inhibitors areiclated to excess levels of acetylcholine at nicotinic andmuscarinic synapses. Muscarinic side effects include diarihea,cramping, and excessive secretions that can worsenicspiratory compromise. Nicotinic side effects includemuscle fasciculations and increased blockade of neuromusculartransmission, which can lead to cholinergic crisis.

B. IMMUNOSUPPRESSIVE TREATMENTI. 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 toprevent tumor spread. For patients without thymoma,thymectomy incteases the likelihood of remission. Dataon the efficacy of thymectomy are confounded by factorssuch as variable surgical technique and lack o f controlledtrials. In most experienced centers, however,perioperative morbidity and mortality ate vcty low andoutweighed by the chances for improvement in mostcases. There is controversy about predictors of outcome,but thymus pathology, age, or disease severitydoes not reliably predict temission. Unless thete arecontraindications, thymectomy should be consideredfor patients of any age w i t h M G . T h e procedureappears to be most effective when performed during1 lie first 2 years o f disease. Medical treatment of M Gprior to surgery decreases the perioperative morbidity.Preoperative inttavenous immunoglobulin (IVIG) orplasmapheresis is often used to stabilize patients withgeneralized M G .There is debate about the best surgical procedure,."id protocols have included extensive trans-steinal and11 m i l ervical approaches as well as, more recently, endounpictechniques and combination approaches. It hasI" i n suggested that more extensive resection o f thymusII..in- leads to higher remission rates, but this willi. in no a point of controversy until conclusive compari-aHI . an- available.M e d i c a l therapy—For most patients, treatmenttin hides inducing remission with high doses of animmunosuppressant. Once remission is achieved, theimmunosuppressant can be gtadually tapered, butmost patients need to continue at least a small dose o fmedication.a. Corticosteroids—These agents are the first-lineimmunosuppressive therapy for M G . Many patientshave transient worsening o f symptoms w i i h i n the fust2 weeks of initiating such treatmeni. < lortlcOtteroidtherapy may therefore have to be initiated following stabilizationw i t h a course o f plasmapheresis or inttavenousimmunoglobulin. Patients should be closely monitotedwhen corticosteroid therapy is initiated, and hospitalizationmay be warranted.Corticosteroids induce remission in up to 5 0% ofpatients, and up to 80% of all patients benefit from the

thctapy. Most patients improve within the fitst fewweeks o f treatment. Once remission is obtained, the corticosteroidsare slowly tapered to the lowest dose possiblethat 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 reducedby implementation o f a low-sodium, low-sugar diet, alongwith calcium supplementation and exercise. The osteoporosisrisk can be reduced by prophylactic treatment (eg,alendronate sodium, 5 mg/day orally).b. Nonsteroidal immunosuppression—Because ofside effects from corticosteroids, clinicians often use socalledsteroid-sparing medications, such as azathioprinc(Table 22-2). A t least 50% of patients appeat tobenefit from this medication. Most studies describe itsuse in conjunction with cotticosteroids, not asmonotherapy. Side effects are generally mild but caninclude bone marrow and hepatic toxicity; for this reason,blood counts and liver function need to be monitored.Azathioprine acts much more slowly thancorticosteroids. Improvement may begin only after severalmonths of treatment, and maximal improvementmay require 1-2 years. U p to 2 0% of patients developan idiosyncratic reaction to azathioptine during the firstweeks o f treatment, consisting o f fever, chills, rash, andgastrointestinal symptoms. In these intolerant patients,azathioprine must be discontinued immediately.More recendy, mycophenolate mofetil has been suggested as an adjunctive or corticosteroid-sparing therapyand perhaps as monotherapy. Preliminary studies demonstrate clinical improvement in approximately three quartcisof patients. The onset o f benefit is usually after 1-2 months,with a peak effect usually around 6 months. The side effectprofile o f the drug is favorable to treatment alternativesand includes gastrointestinal side effects, hypertension,and peripheral edema. Patients should be advised toavoid ultraviolet-light exposure while taking this medication.Mycophenolate mofetil can cause bone marrowsuppression, and monitoring o f blood counts is thereforeindicated. The concurrent use o f azathioprine andmycophenolate mofetil is not tecommended.(iyclosporinc is used for patients with sevete M Gwho cannot be managed with less toxic fotms of thetapy.Majoi side effects include renal toxicity and hypertension.

(lyclophosphamide is an alkylating agent thathas been used in patients with teftactory disease. Sideeffects include severe bone marrow suppression, bladder/ CHAPTER 2 2Table 22-2. Immunosuppressants used in the treatment of myasthenia gravis.Drug* Dosage Monitoring Adverse EffectsAzathioprine Increase gradually up to2-3 mg/kg/day POMonitor CBC and liver functionweekly during first month,twice monthly during secondand third months, thenmonthlyCommon—Gl hypersensitivity,nausea, vomitingSerioi^T—cancer (rare),hepatotoxicity, infection,leukopenia,thrombocytopenia,megaloblastic anemia,pancreatitisMycophenolatemofetil1-1.5 g P O twice daily Monitor CBC weekly during firstmonth, twice monthly duringsecond and third months, thenmonthlyCommon—constipation,diarrhea, nausea, vomiting,headacheSerious—confusion, tremor,Gl bleeding, hypertension,peripheral edema, infection,sepsis, cancer (rare),myelosuppressionCyclosporine 2.5 mg/kg/day POdivided twice daily;after 4 weeks, dosemay be increased by0.5 mg/kg/day at 2-wkintervals, to maximumol 'I m<|/ky/dayMonitor blood pressure, CBC, uricacid, potassium, lipids,magnesium, serum creatinine,and BUN every 2 weeks during

initial 3 months of therapy andthen monthly if patient is stableCommon—headache,hirsutism, nausea, diarrhea,tremor, g um hyperplasiaSerious—anaphylaxis, seizure,hepatotoxicity, hyperkalemia(rare), hypomagnesemi.i,hypertension (frequent),infection, nephrotoxicity(frequent), hemolytic uremicsyndrome (rare), paresthesia(rare), lymphoproliferativedisorder (rare)i in iiiinpleli'liloo'Not labeled by the 11I it,i.l ' 111,1 . 11.1 A.IiII•slinafPO11.111<HI liu iby mouth (orally).II in myasthenia gravis.limit iiy, anil risk ol neoplasm. Treatment with1 v Inq ne in cyclophosphamide should be managedB) I phyiii i.in who is familiar with their adverse effectsand monitoring requirements.I'm all or these corticosteroid-sparing imniiinn.suppreilive drugs, there may be an increased long-term riskill lymphoma or other malignancies.i , Short term treatments—Plasmapheresis andI Vl< , en h induce rapid clinical improvement but haveonly short-lasting effects (Table | | r 3 ) . Bo'th are oftenemployed in the special situation o f myasthenic crisis. Inaddition, either treatment can be used to stabilizepatients prior to thymectomy or to treat exacerbationsthat occur during infection, surgery, or the tapering o f acorticosteroid regimen.I'l.i'.mapheresis usually produces clinical improve-" wilhin die first week, and benefits usually last forI ' l i i i . n i l i ' , < 'omplications are uncommon but includehypotension, bradycardia, electrolyte imbalance, andinfection.I V I G has similar efficacy to plasmapheresis. Sideeffects include malaise, hypersensitivity, aseptic meningitis,and, rarely, renal insufficiency, stroke, and myocardialinfarction. 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 plasmaexchange or I V I G is the preferred short-termimmunotherapy for myasthenia gravis. In practice, thechoice o l iherapy for acute disease is often dependent onfeasibility and on resources available i n a given situation.C. TREATMENT OF MYASTHENIC CRISISMyasthenic crisis is defined as an exacerbation of weaknessi liar leads to respiratory failure requiring mechanicalventilation. For patients with myasthenic exacerbationMYASTHENIA GRAVIS & OTHER DISORDERS OF THE NEUROMUSCULAR JUNCTION / 355Table 22-3. Short-term immunosuppressive treatments for myasthenia gravis.Treatment Regimen Adverse EffectsIntravenous immunoglobulin(IVIG)a2 g/kg per course divided over5 daily treatmentsConsider premedication withdiphenhydramineHCI (50 m g P O once) andacetaminophen (650 mgP O once), 30 min prior toIVIG treatmentCommon—malaise, headache, chills, flushing,fever, tightness of t he chest, nauseaSerious—anaphylaxis; rash; thrombotic events,including stroke and myocardial infarction (risklower with slow infusion: concentration < 5%and infusion rates <0.5 mlVkg/h); renaldysfunction (higher risk with sucrosecontainingproducts); hemolytic anemia;neutropenia; aseptic meningitis; transmissionof infection (rare)Plasmapheresis Common regimen is 5exchanges using analternate-day scheduleCommon—dizziness, nausea, vomiting,headache, citrate-induced hypocalcemiaSerious—hemorrhage secondary to systemicanticoagulants; cardiovascular events due tofluid shifting; risk of transmitting infectionwhen using replacement fluids containingplasma; allergic reactions leading toanaphylaxis; activation of coagulation,

complement, and fibrinolytic cascades, oraggregation of platelets leading tointravascular coagulation, or both; problemswith vascular access, including infection andsepsisGl = gastrointestinal; PO = by mouth (orally)."Not labeled by the Food and Drug Administration for use in myasthenia gravis.involving respiratory and bulbar symptoms, hospitalizationshould be considered to closely monitor clinical statusand pulmonary function. Once a patient isintubated, anticholinesterase medications should be discontinuedbecause they can promote excessive secretions.Corticosteroids can actually prolong the durationi if a crisis by exacerbating weakness or predisposing toinfection. The mainstay of therapy for myasthenic crisisis therefore short-term immunotherapy, either plasmapliriesisor I V I G .I). I HHIGS THAT MAY WORSEN SYMPTOMSHI MYASTHENIA GRAVISMI.II classes of drugs are associated with clinical worseH of existing M G , and a smaller group of drugsactually causes M G in occasional patients.D Penicillamine, intetferon alpha, and bone marrowtransplantation have all been implicated in causing M G .The mechanism is unclear, but there is evidence o f anautoimmune basis for both penii illaminc and interferonalpha. In most cases, thesyni| s lesnlve with discontinuationof the medication.Many other dmgs are associated willi niyasilienicworsening (Table 22-4). Because any cling i an potentiallyworsen symptoms, patients with M G should be warnedabout possible exacerbation with medication use.PrognosisEighty percent of patients eventually develop generalized M G . For patients w i th disease limited to the en iil.uTable 22-4. Medications that can exacerbatemyasthenia gravis.Antibiotics (many), most notably the aminoglycosidesp-BlockersCalcium channel blockersChloroquineD-Penicillaminelodin.iled contrastl i t h i umNondepolarizing and depolarizingnetitomuscular-blocking agents

Phenol liiti/inesPICK .iinainideOtiiniclineQuinineCHAPTER 22muscles, 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 normaland productive life when adequately treated. However,quality o f life may be compromised as a result o f b o ththe limited efficacy and the side effects of availabledrugs. Patients with an underlying thymoma often havea more aggressive disease course.Ciafaloni E, Massey JM. Myasthenia gravis and pregnancy. NeurolClin 2004;22:771-782. {PMID 15474766]Ciafaloni E, ec al. Retrospective analysis of the use of cyclosporinein myasthenia gravis. Neurology 2000;55:448-450. [PMID10932288] (An analysis of patients who took cyclosporine foran average of 3-5 years; clinical improvement was seen in 96%,with a median time to best clinical response of 7 months; andcorticosteroids were discontinued or decreased in 95% ofpatients taking them.)De Baets M , Stassen M H . The role of antibodies in myastheniagravis. J Neurol Sci 2002;202:5-11- [PMID 12220686](Reviews the different types of autoantibodies present inpatients with MG.)Djeimis J, et al. Myasthenia gravis in pregnancy: Report on 69 cases.Eur J Obstet Gynecol Reprod Biol 2002;104:21-25. [PMID12128277] (This review of 69 prelum irs among 65 womenwith MG, in which 1 5% of patients showed worsening of diseasein pregnancy and i lurihei 16% in the puerperium,emphasizes tliat M G patients can have normal pregnancy anddrlivety 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. [PMIDI [Ml .'.ll 1 | (A n in. p.. livr •.Hiily ol /()/ myasthenic patientswim W9ti DMftttd •.11 l o i thymoma, with at least 1-ycarfollow UB IK-III lurtfryi MG uiociitcd thymoma was invavivrin thr HI if v n| | •.. M< . was j-riu i.illy severe, andi 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 manageIIUMI .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 forautoimmune myasthenia gravis (an evidence-based review):RtpOrt of the Quality Standards Subcommittee ol dieAmerican Academy of Neurology. Neurology Z0O0;Vi:'/ IS.[PMID 10891896] (An evidence based icview ol ihymecCOmy lor autoimmune MG.}Kiirnani JF, et al. Myasthenic crisis, tun frail Options Neurol2004;6:3-15. [PMID: 14664765] (Reviews myasthenic crisis,a life-threatening complication that occurs in approximately15-20% of patients with MG.)Marx A, et al. The role of thymomas in the development of myastheniagravis. Ann N Y Acad Sci 2003;998:223-236. [PMID14592880] (Reviews thymic pathology, which occurs in80-90% of patients with MG.)Meriggioli MN, et al. Mycophenolate mofetil for myastheniagravis: An analysis of efficacy, safety, and tolerability.Nmroloyy 2003;61:1438-1440. [PMID 14638974] (In thisMiuly ol 8') patients taking mycophenolaie mofetil, improveiniin wav seen in 73% of subjects; side effects were observedin 27% but were sufficient to require discontinuation of thedrug in only 6%.)Palace J, et al. Myasthenia gravis: Diagnostic and managementdilemmas. Curr Opin Neurol 2001;14:583-589. [PMID11562569] (Reviews diagnostic tests that may help to confirmMG in patients without AChR antibodies and managementdilemmas.)Pascuzzi RM. Pearls and pitfalls in die diagnosis and managementof neuromuscular junction disorders. Semin Neurol 2001;21:425-440. [PMID 11774058] (Clinical features and treatmentissues in M G and other disorders of neuromusculartransmission.)Pascuzzi RM. The edrophonium test. Semin Neurol 2003;23:83-88.[PMID 12870109] (Sensitivity and specificity of the test withrespect to diagnosis of MG-)Qureshi Al, et al. Plasma exchange versus intravenousimmunoglobulin treatment in myasthenic crisis. Neurology1999;52:629-632. [PMID 10025801] (Plasma exchange wasassociated with a superior ventilatory status at 2 weeks and1,-month functional outcome compared with IVIG; however,the complication rate was also higher.)Richman DP, Agius MA. Treatment of autoimmune myastheniagravis. Neurology 2003;61:1652-1661. [PMID 14694025]Sanders DB, et al. Clinical aspects of MuSK antibody positive seronegativeM 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, withsymptom onset between ages 21 and 59 years. Seven had prominentneck, shoulder, or respiratory muscle weakness and little ordelayed ocular muscle involvement. The response tocholinesterase inhibitors was variable, and electromyographicfindings suggested myopathy in several. None improved afterthymectomy. All patients improved after plasma exchange, andmost had a good response to selected immunotherapy.)Vincent A, et al. Antibodies in myasthenia gravis and relateddisorders. Ann N Y Acad Sci 2003;998:324-335. [PMID14592891]Vincent A, et al. Seronegative myasthenia gravis. Semin Neurol2004;24:125-133. [PMID 15229799]Wiirbiodi ET. Drugs and myasthenia gravis. An update. Arch hilnriMnl 1997;lV/:399 408, [PMID 90468*) 1| (IV.\ ribes dtugs.iv.oi laicd with < linii al wotxniiiig ol riming- my*.tin in igiavis and dings implu altd m iln p.iili.ij;. it. '.is -.1 ,i v.ni.im "Ithe disease.)CONGENITAL MYASTHENIASYNDROMESThere are multiple congenital myasthenic syndromes,which ate the result o f genetic defects i n presynaptic,synaptic, and postsynaptic proteins. Symptoms are presentat birth or appear in early childhood. Weakness typicallyaffects cranial muscles, and there is often anassociated high-arched palate. Similarly affected relativescan often be identified. Cholinesterase inhibitorsare helpful in treatment of some, but not a l l , o f thesesyndromes.Engcl AG, et al. Congenital myasthenic syndromes: Progress overi he past decade. Muscle Nerve 2003;27:4-25. [PMID12508290])MYASTHENIA GRAVIS & OTHER DISORDERS OF THE NEUROMUSCULAR JUNCTION / 357LAMBERT-EATON MYASTHENICSYNDROMEj ESSENTIALS OF DIAGNOSIS- Weakness of proximal limb muscles, which mayimprove with exercise• Autonomic dysfunction (may be severe)• Strong association with small cell lung cancerGeneral ConsiderationsLambert-Eaton myasthenic syndrome (I.f'MS) is anmtoimmune or paraneoplastic disease caused by a presynipticabnormality o f acetylcholine release. It is i harat letred by chronic fluctuating weakness ol the proximal limb

nuscles, especially the legs. Approximately 60% o findents with L E M S have an associated small cell carcitomaof the lung or, less often, another type ol maliglancy.The diagnosis of L E M S often precedes clinicalIrtection o f the malignancy. In those who do not have aninderlying malignancy, a concurrent autoimmune diseases common. The onset o f the disease is often midlife orater, but it has also been reported in childhood- Youngerindents are more likely to have underlying autoimmunelisease as opposedto malignancy.L E M S is caused by antibodies directed at P / Q typeullage-gated calcium channels and reduced neurotransnittetrelease at the neuromuscular junction and autolomicnerve terminals. L E M S in association withleoplasm is discussed further in Chapter 13.linical Findings\ SYMPTOMS AND SIGNSI In onset o f symptoms is usually insidious. GeneralizedII igable weakness is the major symptom. Patients oftenoinpl.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 canin . nn wiih respiratory compromise. Unlike patientsvith M<., (hose w i t h L E M S may complain o f a metalictaste, and often have autonomic dysfunction causingIry mouth, orthostasis, constipation, 'and impotence.-)n examination, the elicited weakness is often mild:ompared with the patient's complaints. Deep tendoneflexes are often hypoacttvc 01 absent bin may beJotentiated by brief conttaction. Pupils may be dilatedmd weakly responsive to light secondaiy CO anion iclysfunction.B. LABORATORY AND ELECTRODIAGNOSTIC FINDINGSAntibodies against P / Q type V G C C s can be detected inover 9 0% of patients with L E M S . In addition, antibodiesto N type V G C C s can be found in up to 5 0% ofpatients; this percentage is higher in malignancy-associatedL E M S .Organ-specific autoantibodies (to thyroid, gastricparietal cells, or skeletal muscle) and non-organ-specificautoantibodies (antinuclear, antimitochondrial) are alsofound in patients with L E M S .Electrodiagnostic studies help confirm the diagnosisand monitor disease progression. The compound muscleaction potential ( C M A P ) is low i n most muscles

tested, and C M A P amplitude at rest is the best markero f disease severity. As in M G , most patients have adecrementing response to slow rates o f repetitive stimulation.Following exercise or repetitive stimulation at20-50 H z , there is usually a marked facilitation, withdoubling o f the C M A P amplitude. T h e preceding findingsare useful in distinguishing L E M S from M G .Conventional needle electromyography demonstratesunstable motor unit action potentials that change configurationfrom impulse to impulse due to blocking o f individualmuscle fibers. When many muscle fibers areblocked, the motor units can be small, polyphasic, and o fshort duration. As with M G , increased jitter and impulseblocking are seen on single-fiber electromyography.Differential DiagnosisThe main alternative diagnosis to consider is M G .L E M S can often be distinguished from M G by its m i ldoculobulbar symptoms and often prominent autonomicsymptoms and signs. In addition, electrodiagnosticabnormalities are often more prominent in L E M S thanin M G despite the often more severe weakness in M G .L E M S is often misdiagnosed as a myopathy because olthe predominanrly proximal weakness.TreatmentThe first step in management should be an evaluation formalignancy, especially in older patients or those with a historyo f smoking. If L E M S is associated with a malignancy,symptoms often improve dramatically with tumorremoval.If no malignancy is found at initial presentation,patients should undergo regular surveillance, becausethe presentation of L E M S can predate detection o f neoplasmby 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 musclestrength and autonomic symptoms in approximately80% of patients with L E M S . By blocking voltage-gatedpotassium channels, the drug prolongs action potentialsCHAPTER 22at motor nerve terminals. Perioral paresthesias are themost common side effect, but seizures can occur at h i ghdoses. 3,4-DAP is not approved by the Food and D r ugAdministration i n the U n i t e d States but can be obtainedfor compassionate use.Guanidine hydrochloride inhibits mitochondrial calcium

uptake, facilitating release o f acetylcholine at themotot nerve terminal. Guanidine effectively increasesstrength in patients with L E M S , but its use is l i m i t e d byside-effects that include bone marrow suppression.Unlike M G , L E M S is not very responsive to anticholinesterasedrugs, which, however, do potentiate theeffects o f 3,4-DAP and guanidine, allowing for use o flower doses.If the preceding symptomatic therapy is insufficient,immunosuppressive therapy can be attempted, but it isless effective i n L E M S than in M G . If weakness issevere, plasmapheresis or high-dose I V I G often providesrapid, although usually transitory, improvement.PrognosisPrognosis in patients with underlying malignancy isdetermined by the prognosis ol that malignancy.Because L E M S is less responsive to immunosuppressivetherapy than M G , most patients with L E M S have residualweakness even with optimal immunosuppression.Sunders I H I lalnhrrr I-'aliiii inyatlhriiii syndrome: Diagnosis andi i . i n . i i I.I Ann N I' . I,././ ,Vi i .MMI t|'W8:500-508. [PMIDI -t V I " l (A , .inijH, li.ir.ivi' 11 vii w ol pathophysiology, clin-11'i ' I ' ' I'I1 . 'I A r 11Hl<1,111,*,11 iii.il i, l 1.4 diaminopyridine inI ""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 thatV 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'lectrixliagnosticlii..lmK> ,n, l response to treatment. Neurology 2000;54:I I /I. ,' I ,'H H'MII l Villi (In this study of 73 patients [31with limn i " i n . . " I with small cell), treatment with 3,4-DAPI'i|>|I'n i t ' moth-late to marked self reported funaional improve -iiirni iii 79% ul'tlic S I treated patients.)I t O I U L I S MESSENTIALS OF DIAGNOSISHistory of ingestion of home-canned foods or >honey (in infants)Rapid onset of ocular symptoms (diplopia, ptosis,blurry vision) and bulbar symptoms (dysarthriaand dysphagia)"Descending" pattern of weakness from oculobulbarto limb involvementDilated pupilsGeneral ConsiderationsBotulism is caused by ingesting the neurotoxin o f thebacterium 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, botulinumtoxin binds irreversibly to the presynaptic nerve endingsof the peripheral nervous system and cranial nerves.Once internalized, the toxin inhibits the release ofacetylcholine through the cleavage of polypeptidesessential for the docking of synaptic vesicles to thepresynaptic membrane o f the nerve terminal.Food-borne botulism is caused by ingestion o f preformedtoxin. The most frequent source is home-cannedor home-processed low-acid foods. In the infant form o fbotulism, C Botulinum spores enter and colonize theimmature gastrointestinal tract and produce toxin. Thisis most often associated with the ingestion of honey. Inwound botulism, the toxin is produced from C botulinuminfection o f a wound. Inadvertent botulism hasbeen reported in patients treated with intramuscularinjections o f b o t u l i n um toxin.Clinical FindingsA . SYMPTOMS AND SIGNSThe initial symptoms of food-borne botulism (but notthe wound-acquired form) may be gastrointestinal—nausea, vomiting, and diarrhea—and generally appearw i t h i n 2-36 hours o f ingestion. Constipation is motecommon once neurologic symptoms are present. Theearliest neurologic symptoms are oculobulbar andinclude dry mouth, blutred vision, diplopia, dysarthria,dysphagia, and dysphonia. In contrast to most cases o fGuillain-Barre syndrome, botulism is chatacterized by adescending paralysis. Weakness begins in the cranialnerves, followed by the upper extremities, respiratorymuscles, and finally lower extremities. The weaknessprogresses from proximal lo distill muscles, Kespiiatniyweakness can be severe anil require prolonged i i u u lution. Botulism also affects autonomic synapiii ii,ui',iui\sion, resulting in constipation, postural hypotension,and urinary retention. On examination, pupils are nineactive 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, andpoor feeding. Weakness then progresses over days, causingpoor suck and head control, hypotonia, anddeceased movement. Autonomic signs and symptomsinclude hypotension, tachycardia, and dry mouth.The symptoms of wound botulism are similar tothose of food-borne botulism except that gastrointestinalmanifestations are usually absent, the incubation

period is longer, and symptoms are gradual i n onset.B. LABORATORY AND ELECTRODIAGNOSTIC FINDINGSBoth blood and stool can be sent for detection of thebotulinum toxin. C botulinum itself can be detected inMYASTHENIA GRAVIS & OTHER DISORDERS OF T H E N E U R O M U S C U L A R JUNCTION / 359stool. I f possible, a f o o d sample should also be sent foridentification o f the toxin.Elettrodiagnostic studies can support the diagnosis olbotulism and help rule out odier possible diagnoses suchas Guillain-Barre syndrome. T h e most consistent findingis 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 adecrement of the C M A P to l ow rates o f stimulation andpostexercise facilitation o f the C M A P amplitude.Differential DiagnosisBotulism 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, diphtheriticneuropathy, and intoxication (including paralytic shellfishpoisoning and organophosphates).TreatmentThe major treatment is intensive supportive care.Patients should be closely monitored lor respiratorydecompensation. If the ingestion is recent, removal idunabsorbed gut toxin can be considered, flic Centersfor Disease C o n t r o l and Prevention can provide a nivalent botulinum antitoxin, which, however, must begiven early while toxin is still in the blood. The antitoxincan dectease severity o f disease and overall mortality,but side effects include anaphylaxis.PrognosisAlthough significantly reduced, mortality from botulismremains high at 5-10%. Type A toxin is associatedwith a more severe course and higher mortality thanother toxins. Clinical recovery is often prolonged overmonths, because it requires rhe formation o f new presynapticend plates and neuromuscular junctions. Recoveryof autonomic function may take longer than recovery o fmuscle sttength. For those who survive, the recovery isgenerally complete.Cherington M. Botulism: Update and review. Semin Neurol2004;24:155-163. [PMID 15257512] (Review of botulism asboth an old and an emerging disease; five clinical forms ofbotulism—food-borne, wound, infant, hidden, and inadvertentas well as the actions of botulinum toxins, electrodiagnostic:

methods, treatments, and possible future directions atediscussed.)TICK PARALYSISTick paralysis is a rare disease that usually affects children.Often a prodrome of gait instability is followed byascending paralysis and hyporeflexia or areflexia. Bulbarstructures are eventually affected, leading to dysphagia,dysarthria, facial paralysis, and ocular weakness. If thel i ck is not removed, fatal respiratory failure can develop,'fhe engorged tick attached to the patient produces aneurotoxin that acts on the neuromuscular junction.Removal o f the tick is usually followed by rapid improvement.This disease is most often confused with Guillain-Barre syndrome.Felz M W, et al. A six-year-old girl with tick paralysis. NEngl] Med2000;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.)