Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome Review Article Copyright © American Academy of Neurology

Home , Dermatomyositis, Ocular myasthenia

Y The 1 December 2016 Nerve depolarization allows calcium uture therapies might specifically target treatments in MG and LEMS. of the muscleendplate membrane produces potential, an which,cient amplitude, results if in an of allmuscle or fiber none suffi- action potentialtually and muscle even- movement.released An acetylcholine excess and AChRs of at themuscle endplate provides ator safety of fac- neuromuscular transmission. neuromuscular junction includes the presynaptic nerve terminal,containing basal synaptic cleft, lamina aptic and muscle fiber postsyn- endplate. influx through nervegated terminal calcium voltage- channelsresults (VGCCs). in This releasethe of synaptic acetylcholine into cleft.to Acetylcholine its binds receptor[AChR]), (acetylcholine opening receptor AChRproducing channels an influx and sodium, of at the cations, endplate. mostly Depolarization bert-Eaton myasthenic syndrome (LEMS). This article discusses the pathogenesis, diagnosis, and management of Recognition of new antigenic targets and improved diagnostic methods The current treatment options are so effective in most patients with MG or Michael W. Nicolle, MD Continuum (Minneap Minn) 2016;22(6):1978–2005. autoimmune myasthenia gravis (MG) andRecent Lam Findings: promise to improve the diagnosis ofnewer MG, although antibodies the have clinical phenotypes not associated yet with the been aberrant defined. immune F response.fully The explained. apparent Results increase ofperforming a in a long-awaited the thymectomy trial prevalence under of ofSummary: specific thymectomy MG conditions. support is the not practiceLEMS that of in patients with refractorymanagement disease of the MG diagnosis is should individualized, be andand reconsidered. familiarity strategies The with to mechanisms, manage adverse these effects, education commonly is used treatments important. improves LEMS, outcome. frequentlycancer, Patient associated is with uncommon, and an the underlying mainstay small of cell treatment lung is symptomatic in most patients. Purpose of Review: ABSTRACT transmission is important tothe appreciate rationale for diagnostic tests and specific antibodies. Management options for MG includeimmunosuppressive symptomatic and as immunomodu- welllatory as treatments and, instances, thymectomy. select LEMS is circum- uncommon and oftendisorder occurs with as anlung a underlying cancer. small paraneoplastic cell NEUROMUSCULAR JUNCTION AND NEUROMUSCULAR TRANSMISSION Understanding normal neuromuscular INTRODUCTION Immune myasthenia gravis (MG)best is delineated the ofdiseases. human Fatigable autoimmune weakness ismark the of hall- bothmyasthenic syndrome MG (LEMS). andpanding The Lambert-Eaton repertoire ex- ofhas antibody improved the assays diagnosismay of allow MG treatments and to be tailored to Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome Review Article Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Copyright © American Academy of Neurology. Unauthorized reproduction of this article is . www.ContinuumJournal.com 2016 American Academy * of Neurology. Products/Investigational Use Disclosure: Dr Nicolle discusses the unlabeled/investigational use of azathioprine, mycophenolate, and rituximab for the treatment of myasthenia gravis and Lambert-Eaton myasthenic syndrome and the use3,4-diaminopyridine of for the treatment of Lambert-Eaton myasthenic syndrome. in court cases forCanadian the Medical Protective Association. Unlabeled Use of Address correspondence to Dr Michael W. Nicolle, London Health Sciences Centre, University Hospital, 339 Windermere Rd, London, ON N6A 5A5, Canada, [email protected] Relationship Disclosure: Dr Nicolle has given expert medical testimony 1978

Downloaded from https://journals.lww.com/continuum by mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== on 04/25/2018 Downloaded from https://journals.lww.com/continuum by mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== on 04/25/2018 KEY POINTS Acetylcholine binds to its receptor tran- in a decrement with low-frequency re- h The function of siently and either diffuses out of the petitive nerve stimulation studies and acetylcholine at the neuromuscular junction or is hydro- weakness clinically. Second, during neuromuscular junction is lyzed by acetylcholinesterase, anchored high-frequency (20 Hz to 50 Hz) stimu- influenced by several other in the basal lamina. This terminates the lation or after brief (10 seconds) maximal key proteins, which are effects of nerve depolarization. voluntary contraction, intracellular cal- now known to be targets AChR localization at the neuromus- cium is increased in the presynaptic nerve of the autoimmune response in some patients terminal, increasing acetylcholine release. cular junction and its function are in- with myasthenia gravis. fluenced by several other proteins at the Maximal voluntary contraction mimics h Antibodies against the muscle endplate. Agrin, secreted by the high-frequency stimulation, as the nerve most common antigenic nerve terminal, interacts with muscle- fires at approximately 20 Hz during a target in myasthenia specific tyrosine kinase (MuSK) via its maximal contraction. The increased in- gravis, the acetylcholine coreceptor, low-density lipoprotein tracellular calcium may overcome defec- receptor, are found in receptor-related protein 4 (LRP4). The tive neuromuscular transmission; in 85% of patients with resultant MuSK-LRP4 complex results in MG, this results in postexercise repair generalized myasthenia the activation and clustering of AChRs at on repetitive nerve stimulation studies, gravis and 50% of the neuromuscular junction. MuSK also and in LEMS, this results in facilitation or patients with ocular myasthenia gravis and anchors acetylcholinesterase at the syn- increment after high-frequency stimu- disrupt neuromuscular aptic basal lamina. In MG, antibodies lation or maximal voluntary contraction. transmission through against the AChR or other neuromuscu- This also explains the return of a deep several mechanisms. lar junction targets reduce the number, tendon reflex after maximal voluntary function, or clustering of AChRs at the contractioninLEMS.Third,longerpe- neuromuscular junction. In LEMS, anti- riods of exercise result in less well bodies against the VGCC inhibit calcium understood pre- and postsynaptic ef- influx into the nerve terminal and re- fects, which also worsen neuromuscular duce acetylcholine release into the syn- transmission and cause postexercise aptic cleft after nerve depolarization. exhaustion as is seen in repetitive nerve Three other phenomena during nor- stimulation studies or fatigable weak- mal neuromuscular transmission are ness, which is seen clinically. important to understand; these phenomena are seen electrophysiologically and MYASTHENIA GRAVIS clinically in MG and LEMS. First, during MG is a disorder where neuromuscular low-frequency (2 Hz to 5 Hz) stimulation, transmission is disrupted as a result of an acetylcholine release gradually declines autoimmune attack on postsynaptic anti- as presynaptic stores are depleted, with genic targets, producing weakness of ske- a nadir at the fourth or fifth stimulation letal muscles. The clinical hallmark of the in a train of stimuli. In healthy individ- weakness is its variability and fatigability. uals, this never reaches significance because of the safety factor. However, when Pathophysiology the amount of acetylcholine available for In MG, antibodies against proteins at release is diminished (as in LEMS) or the the neuromuscular junction interfere number of available AChRs is reduced with neuromuscular transmission. Anti- (as in MG), muscle fiber depolarization bodies against the most common anti- may fail. If this fails at a single fiber, this is genic target in MG, the AChR, are found detected on single fiber EMG as blocking in 85% of patients with generalized MG or is detected as jitter if the endplate and 50% of patients with ocular MG and potential amplitude is sufficient to pro- disrupt neuromuscular transmission duce a delayed muscle fiber depolariza- through several mechanisms. They can tion. When many fibers fail, this results reversibly block acetylcholine binding,

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 1979

KEY POINTS 9 h In more than one-half of cross-link adjacent cell surface AChRs the pathogenesis of MG. Although not the remaining patients resulting in their internalization into the a hereditary disorder in the mendelian who have acetylcholine muscle cell, or, for some immunoglo- sense, about 3% to 5% of patients with receptorYnegative bulin subclasses, cause complement MGwillhaveafamilymemberwithim- generalized myasthenia fixation and destruction of the neuro- mune MG, similar to the data from more gravis, antibodies target muscular junction.2,3 A mixture of anti- than 800 patients in the author’s MG other proteins at the bodies with each of these mechanisms clinic.10 The prevalence of other autoim- neuromuscular junction. occurs in an individual patient, although mune disorders, especially thyroid, is The first described and still most prevalent complement-fixing antibodies are likely increased in patients with MG and their are antibodies against the most common. family members, occurring in 13% to 30% muscle-specific In more than one-half of the remain- of patients with MG compared with 5% to tyrosine kinase. ing patients who have AChR-negative 8% in the general population.11,12 This h The frequent pathologic generalized MG, antibodies target other suggests a genetic influence to autoim- involvement of the proteins at the neuromuscular junction. mune diseases, of which MG is one of thymus, especially with The first described and still most prev- the least frequent. thymic hyperplasia, in alent are antibodies against MuSK. Anti- some forms of myasthenia MuSK antibodies are mostly of the Epidemiology gravis supports the rationale nonYcomplement-fixing IgG4 subclass Studies show significant heterogeneity for its removal in select circumstances, as shown and disrupt neuromuscular transmission in the incidence and prevalence of MG, by a recent international by interfering with LRP4/MuSK interac- in part because of geographic and ethnic clinical trial. tion, reducing AChR clustering at the variation. However, recent evidence sug- 4 h The different ways of muscle endplate. More recently, anti- gests that MG is increasingly common, 13 classifying myasthenia bodies against LRP4, agrin, and cortactin especially in the elderly. The incidence 5 gravis are useful when have been described. The significance of of MG ranges between 9 to 30 out of considering the sensitivity these antibodies is less well delineated. 1 million, and the prevalence ranges of diagnostic tests as well Pathologic thymic involvement, either from 100 to 140 out of 1 million. How- as management options. thymic hyperplasia or a thymoma, is ever, recent studies have shown a pre- h Congenital myasthenic found in the majority of patients with valence of more than 200 in 1 million.7,14 syndromes are genetic AChR MG.6 Thymic hyperplasia occurs in Women are more likely to have MG than disorders with a mutation 50% to 80% of postpubertal juvenile men in the first 5 decades of life whereas in a presynaptic, synaptic, cases and early-onset adult cases of AChR men are more likely to be diagnosed or postsynaptic protein 6 9 involved in neuromuscular MG. Thymic hyperplasia is uncommon with MG after the age of 50. Ocular MG transmission. in MuSK MG and less common in sero- is more common in patients with prepu- negative and late-onset MG, where the bertal juvenile MG, especially in people of thymus is often normal, atrophic, or a Asian descent and in men with late-onset thymoma is found.6,7 The hyperplastic MG. MuSK MG is more frequent in thymus is a significant source of anti-AChR younger women and possibly in the antibodies.6,8 A thymoma is found in nonwhite population. 10% to 20% of patients with MG, and MG occurs in 30% to 50% of thymoma cases. Classification Although the etiology for MG remains MG can be classified in several ways, unknown, some subsets of AChR MG are each of which is useful when consider- associated with specific human leuko- ing diagnostic tests, therapeutic options, cyte antigen (HLA) determinants, and and prognosis.15,16 subsets of MuSK MG are associated with Age at onset. Congenital myasthenic other HLA determinants. A recent syndromes are genetic disorders with a genome-wide association survey in white mutation in a presynaptic, synaptic, or post- patients with AChR MG showed associa- synaptic protein involved in neuromus- tion with specific loci that might influence cular transmission. Congenital myasthenic

1980 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS syndromes are not discussed in detail in age 65, although it is often not re- h Neonatal myasthenia this article but are considered in the cognized and is most commonly mis- gravis is a self-limited 13,14,16 differential diagnosis of immune MG. diagnosed as a stroke. disorder that occurs after Neonatal MG occurs after the transpla- Thymic pathology. The likelihood the transplacental cental transmission of AChR or MuSK and type of thymic pathology is associ- transmission of antibodies and had been said to occur in ated with age at onset, clinical manifes- acetylcholine receptor or about 10% to 15% of babies of mothers tations, and serologic status. Thymic muscle-specific tyrosine kinase antibodies. with MG. However, it may be less fre- hyperplasia is present in 50% to 80% of h quent now, and in more than 50 mothers patients with AChR-positive early-onset Juvenile myasthenia that the author has managed through MG, is less common in late-onset MG, and makes up 10% to 15% 6Y8 of most series of patients pregnancy, not a single case of neonatal is rare in MuSK MG. The benefits of with myasthenia gravis MG has occurred. The antibody- thymectomy in MG are presumed to and is arbitrarily defined producing cells are not transmitted, so relate to the removal of a hyperplastic as an age of onset of neonatal MG is a self-limited disorder. thymus. A thymoma, found in 10% to less than 18, excluding Juvenile myasthenia makes up 10% to 20% of all cases of MG, is more com- congenital myasthenic 15% of most series of patients with MG mon with onset after 40 years of age, syndromes and neonatal and is arbitrarily defined as an age of where it occurs in 25% to 35% of cases.17 myasthenia gravis. onset of less than 18, excluding congen- Thymomatous MG is usually more severe h Thymic hyperplasia is ital myasthenic syndromes and neonatal and less likely to be ocular.18 Athymoma present in 50% to 80% MG. Cases of prepubertal onset are more is usually discovered at the time of MG of patients with acetylcholine receptorYpositive likely to be seronegative, have a benign diagnosis although can present later. The early-onset myasthenia clinical course, a higher prevalence of vast majority of thymomatous MG cases gravis, is less common in ocular and mild generalized disease, and have positive AChR antibodies, so AChR late-onset myasthenia aremorecommoninAsians.Postpubertal negativity essentially rules out a thy- gravis, and is rare in juvenile MG has similar rates of seropos- moma.19,20 A report of a possible medi- muscle-specific tyrosine itivity and thymic hyperplasia compared astinal abnormality on a CT chest in a kinase myasthenia gravis. to early-onset adult MG. patient negative for AChR will almost h A thymoma, found in Early-onset MG is variably defined as always turn out to be something other 10% to 20% of all cases age at onset after 18 years but before 40 than a thymoma. Patients with AChR- of myasthenia gravis, is to 60 years of age, with 50 being the positive thymoma without clinical mani- more common with onset after 40 years of age, most common age cutoff. A cutoff age of festations of MG have been described. where it occurs in 25% to 45 years was suggested by a cluster However, a careful history and examina- 35% of cases. analysis of patients with MG that con- tion will almost always reveal features h Given their high specificity, sidered age at onset and thymic hy- suggesting MG, or the patient will even- 15 20 if either acetylcholine perplasia. Women outnumber men in tually develop MG. A thymoma is receptor or muscle-specific early-onset MG. This is an important almost never found in MuSK MG. tyrosine kinase antibodies classification as the likelihood of thymic Serologic status. Serologic status is are positive, a diagnosis hyperplasia and of response to thymec- arguably the most important classifica- of myasthenia gravis tomy in nonthymomatous MG is greater tion. Given their high specificity, if either is certain. in early-onset MG. Patients with MuSK MG AChR or MUSK antibodies are positive, a arealsomorelikelytohaveanearlyonset. diagnosis of MG is certain. The specificity Late-onset myasthenia gravis. Late- of antibodies against agrin, LRP4, or cor- onset MG includes patients with onset tactin is less well defined. As described after 50 years of age who are more often previously, when AChR antibodies are neg- men and have ocular MG. In late-onset ative, an underlying thymoma is very rare, MG, a thymoma is more common than and thymic hyperplasia is less frequent. In thymic hyperplasia. Evidence exists for MuSK MG the thymus is usually normal, an increasing prevalence of MG in the the disease may be more severe, and pa- elderly, especially those older than tients are less responsive to pyridostigmine

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 1981

KEY POINTS 21 h When antibodies are or IV immunoglobulin (IVIg). In the 5% periods is sometimes spontaneously negative in myasthenia to 10% of patients with immune MG who described. However, patients commonly gravis, especially when are negative for all known antibodies, the may not remember previous symptoms patients do not respond diagnosis of MG must always be ques- unless asked specifically. They may have to treatment as expected, tioned, especially when patients do not been told that previous symptoms were the diagnosis should respond to treatment. because of a transient ischemic attack or be reconsidered. Clinical manifestations and severity. Bell’s palsy, so a careful history of both h The way in which a About 50% to 60% of patients present ini- current and previous symptoms is impor- history of fatigue is elicited tially with isolated ocular involvement, tant. The patient with unilateral ptosis is important; direct most of whom will generalize. Fifteen who had a previous episode of self- questioning about worsening weakness at percent to 25% of patients have only limited ptosis on the opposite side the end of the day may ocular involvement throughout their almost certainly has MG. 22,23 falsely suggest a diagnosis course (ocular MG). Ocular MG is Although characteristic for MG, fati- of myasthenia gravis. more likely seronegative for AChR anti- gability should be distinguished from h Most patients (50% to bodies and rarely positive for MuSK. fatigue. The way that a history of fatigue 85%) with myasthenia The role for thymectomy in ocular MG is is elicited is important. An unprompted gravis present with ocular less certain, and sensitivities of most history of significant fluctuation given by symptoms with or without diagnostic tests are lower than in gener- the patient is the most specific. Less generalized weakness. alized MG. Generalized MG includes directed questions (eg, ‘‘Are there times About 50% to 60% of patients with weakness outside of the when your weakness is better or worse?’’) patients with myasthenia gravis present with isolated ocular muscles, many of whom will also aremoreusefulthanaskingdirectly ocular involvement, have ocular manifestations. The Myas- whether the weakness is worse at the although many of these thenia Gravis Foundation of America, end of the day. No matter what the cause (50% to 60%) develop Inc classification is used mostly for for weakness, direct questions will often generalized weakness research studies but is useful when elicit a history suggesting fatigable weak- often within the first considering the management options ness and will result in MG being inap- 3 years after onset. for MG.3 propriately considered in the differential. Taking the history. When taking the Ocular symptoms. Most patients history, it is useful to have the patient (50% to 85%) with MG present with describe what they mean by weakness. A ocular symptoms with or without gener- history more suggestive of pain, lack of alized weakness. About 50% to 60% of energy, exhaustion, diffuse nonspecific patients with MG present with isolated fatigue, or somnolence may not be con- ocular involvement, although many of sistent with MG. The prevalence of ob- these (50% to 60%) develop generalized structive sleep apnea is higher in patients weakness often within the first 3 years with MG; therefore, somnolence secondary after onset. Ocular involvement in- to a sleep disorder may coexist with MG.24 cludes ptosis, diplopia, or a combina- The distinguishing clinical feature in tion of these. MG is fatigable weakness. Fluctuation in Ptosis can be unilateral and, if bilateral, symptoms is characteristic, although not is usually asymmetric. Persistently sym- universal, and can occur over short or metric ptosis is more suggestive of a longer periods of time. Worsening at myopathic etiology, especially chronic the end of the day is common, although progressive external ophthalmoplegia. some patients experience worse symp- MG is one of few disorders that can cause toms first thing in the morning. The complete unilateral (or rarely bilateral) patient who has no ptosis first thing in ptosis or a history of ptosis alternating the morning and whose eyes are sides over time. completely closed at night almost cer- Many patients describe diplopia. Milder tainly has MG. Fluctuation over longer involvement may produce blurred vision

1982 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT or a halo around objects instead. Resolu- move their jaws to chew. Fatigable dysar- h Distal weakness, which is tion of these symptoms when one eye is thria is also common. Complete aphonia sometimes surprisingly covered suggests subtle diplopia, although is extremely rare in MG. Laryngeal in- asymmetric,occursin many patients have not attempted this. volvement with stridor is rare but can be about 5% of patients with Persistent diplopia with one eye covered life-threatening. Neck weakness can af- myasthenia gravis. suggests an ophthalmic or functional fect flexors, extensors, or both. Although cause. Monocular vision is not affected flexor weakness is more common, MG in MG, and abnormalities in monocular should be considered in the differential vision require an ophthalmologic assess- of patients presenting with a head drop. ment. Photophobia, with worsening of MG is painless, although sometimes either ptosis or diplopia in bright lights, patients can develop secondary myofas- is not uncommon although the reasons cial pain including neck and shoulder for this are unclear. Some patients are so pain with a head drop without recog- troubled by this that they wear dark nizing that weakness is the cause for sunglasses. Patients with LEMS rarely, if this pain. ever, present with ocular symptoms.25 Respiratory involvement in MG usu- Generalized weakness. The weak- ally occurs associated with significant ness experienced by patients with MG bulbar weakness. Exertional dyspnea is can involve any striated muscle but char- nonspecific and can occur in elderly pa- acteristically affects some muscles more tients with comorbidities or in any patient than others. The reasons for this are not after deconditioning or weight gain. More clear given that antibodies can access useful for diagnosis is orthopnea, which any neuromuscular junction. Bulbar suggests diaphragm weakness, although weakness can affect almost any of the this too is not specific for MG. Some craniobulbar striated muscles. Facial weak- patients describe almost instantaneous ness is often not recognized subjectively. dyspnea on bending over, presumably Some patients describe difficulties keep- secondary to the abdominal contents ing water out of their eyes in the shower pushing against a failing diaphragm. or while swimming. Dysphagia when Extremity weakness in MG almost consuming solids or liquids is common always occurs along with ocular and bul- and can occur because of facial (labial), bar manifestations, although isolated tongue, masseter, or pharyngeal weak- limb-girdle weakness occurs in about ness. The temperature dependency of 5% of patients with MG. Extremity weak- neuromuscular transmission means that, ness affects proximal arms more than legs rarely, patients will describe more diffi- and is usually symmetric. Patients may culty swallowing hot liquids than cold. describe increasing difficulties with the Having patients point to where food gets prolonged use of their arms over their stuck is useful. Localization below the heads. However, fatigable weakness of sternal notch implies esophageal involve- the arms, of which the patient may be ment and is not typical for MG. Nasal unaware, may be found on examination. regurgitation when swallowing is some- Less common manifestations include times described in MG. Clearing the distal or asymmetric weakness, which throat or coughing after eating, even in happens in about 5% of patients with the absence of subjective dysphagia, sug- MG.Thisalmostalwaysoccurslaterin gests possible aspiration, which is often thecourseofthediseaseinpatients silent. Fatigable weakness of chewing is with more characteristic ocular, bulbar, also suggestive of MG, with jaw closure and proximal extremity weakness. Distal much more affected than jaw opening. weakness can produce a finger drop, When severe, patients may manually which can sometimes be surprisingly

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 1983

KEY POINTS h The diagnosis of asymmetric and even focal within a hand suspected, the examiner should look for 26 myasthenia gravis is and, very rarely, a footdrop. the characteristic and fatigable weakness. made based on clinical Muscle-specific tyrosine kinase. When To examine a patient for suspected suspicion, the history and considered as a group, clinical differences fatigable ptosis, the examiner should hold neurologic examination, exist between patients with AChR and the test object up for at least 60 seconds and is then supported by MuSK MG. However, significant overlap and watch for obvious worsening. Re- electrophysiologic and occurs with the clinical manifestations of peated blinking, which mimics a brief max- serologic studies. AChR MG so that predicting MuSK anti- imal voluntary contraction, may transiently h Myasthenia gravis can body positivity in an individual patient is improve neuromuscular transmission produce any pattern of difficult. Patients with MuSK antibodies and mask fatigable ptosis. As the differ- pupil-sparing extraocular muscle involvement, are more likely to be female, have early- ential for unilateral ptosis is different including sixth or third onset MG, and have more severe disease, than for bilateral, looking for enhanced cranial nerve palsy especially affecting bulbar and respiratory ptosis in the patient with what appears or internuclear muscles. Rarely is MuSK MG purely ocu- to be unilateral ptosis can be useful. ophthalmoplegia mimics. lar. Patients with MuSK MG may be more Manual elevation of the obviously ptotic likely to be oligosymptomatic or mono- eyelid may bring on fatigable ptosis on symptomatic. Isolated dysphagia, a head the opposite side as the patient is less drop, or dyspnea without other bulbar reliant on the compensatory use of the weakness is uncommon in AChR MG frontalis muscle, which may have ob- but occasionally occurs in MuSK MG scured ptosis on the less affected side. (Case 11-1). The specificity and sensitivity of the Cogan eyelid twitch sign (twitching of Diagnosis the upper eyelid seen when the eyes are The diagnosis of MG is made based on moved from downgaze back to the clinical suspicion, the history and neuro- primary position) is widely variable; the logic examination, and is then supported author does not find this sign useful in by electrophysiologic and serologic stud- diagnosing MG. ies. Few diagnostic tests are infallible and The first step when assessing diplo- some, such as single fiber EMG, are not pia is to establish that it is binocular. If specific for MG. Undue reliance on diag- monocular (two objects persist when nostic tests when the clinical picture does one eye is covered), an ophthalmic or not fit may lead to a false diagnosis of functional origin is likely. MG can pro- MG.27 Although diagnostic tests in pa- duce any pattern of pupil-sparing extra- tients with mild, especially ocular, MG ocular muscle involvement, including may be normal, if no objective support sixth or third cranial nerve palsy or inter- exists for the diagnosis on at least one nuclear ophthalmoplegia mimics. Down- test in a patient with significant weakness, gaze is less affected in MG. Although other diagnoses should be considered. objective limitations in extraocular mus- Clinical. The biggest delay in diagno- cle movement may be present, usually sis often results from failure to consider the weakness is subtle and not appreci- MG in the differential. MG is uncommon, ated by the examiner. It is important for and most non-neurologists are not famil- the examiner to ask the patient to report iar with its clinical features. Patients who double vision when assessing the extra- report significant weakness the previous ocular muscles. Complete symmetric oph- day but have no objective weakness the thalmoplegia, especially if early in the next morning are often labeled as func- course, is very uncommon in MG and tional. Most elderly patients with MG more suggestive of chronic progressive are first diagnosed as having a stroke or external ophthalmoplegia. Although transient ischemic attack. Once MG is ptosis can take 60 seconds to fatigue,

1984 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS h Although ptosis can take Case 11-1 60 seconds to fatigue, A 47-year-old woman presented for evaluation of a possible myopathy. While diplopia usually appears fishing 3 years earlier, she had developed a painless head drop after leaning within 15 to 30 seconds over a railing for several hours. This symptom had improved but several days of sustained gaze. later, after a sudden forced flexion of her neck, her head drop returned and h A single breath count, in persisted. Initially she was thought to be functional and was referred to a which the patient counts chiropractor, which did not help her condition. Shortly after, she developed out loud at approximately severe orthopnea and had to sleep in a chair, and she also developed acute 2 Hz from full inspiration dyspnea on bending over. She required bilevel positive airway pressure (BiPAP) until he or she needs to for her dyspnea and developed severe pulmonary hypertension. Her symptoms take a breath, correlates became worse at the end of the day. On questioning she reported dysphagia. roughly with the forced Studies done prior to her visit included concentric needle EMG that showed vital capacity in increases in spontaneous activity with 1+ positive sharp waves in paraspinal pulmonary function and trapezius muscles. Repetitive nerve stimulation of ulnar, axillary, and facial studies. nerves was reported as normal. Single fiber EMG in extensor digitorum communis was also reported as normal. On examination at age 47, she had no diplopia or ptosis. She had mild facial and severe neck flexor and extensor weakness and moderate fatigable deltoid and triceps weakness with equivocal hip flexor weakness. Repeat nerve conduction studies and EMG showed 1+ fibrillation potentials and numerous ‘‘myopathic’’ motor unit potentials in the cervical paraspinals, trapezius, and deltoid muscles. Repetitive nerve stimulation of the median nerve was normal, but a 40% decrement was seen in spinal accessory studies. Single fiber EMG in orbicularis oculi showed abnormal jitter in 14 of 21 fiber pairs with blocking in four of the 14. Acetylcholine receptor antibodies were negative, and the CT chest showed no thymic abnormalities. She was treated with pyridostigmine, prednisone, and azathioprine but worsened and required IV immunoglobulin (IVIg). She improved, although she required several more treatments over the next 2 years, improving after each treatment. When testing for muscle-specific tyrosine kinase (MuSK) antibodies became available 2 years after presentation, the patient was found to be positive. She slowly improved, and at follow-up 5 years later, she was off pyridostigmine and prednisone and remained on azathioprine alone. Her dyspnea improved, and she was able to sleep supine, although she remained on BiPAP for severe obstructive sleep apnea. Comment. This case demonstrates the characteristic features of MuSK myasthenia gravis with female predominance, prominent bulbar and respiratory weakness, and atypical findings on electrophysiologic studies with abnormalities much more frequent in bulbar and proximal muscles. Frequently, patients with MuSK myasthenia gravis either do not respond or may even worsen after treatment with pyridostigmine. diplopia usually appears within 15 to whether the patient can speak in full 30 seconds of sustained gaze. sentences. A single breath count, in which In any patient who reports dysphagia or the patient counts out loud at approxi- other significant bulbar weakness, bed- mately 2 Hz from full inspiration until he side testing of swallowing is best left to a or she needs to take a breath, correlates speech and language pathologist with roughly with the forced vital capacity in experience in assessing patients with MG. pulmonary function studies. Counting to A simple bedside assessment of re- 20 or more suggests that significant respiratory function involves observing spiratory involvement is unlikely. During

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 1985

KEY POINTS h The tests used to diagnose the single breath count the examiner be objectively assessed. Ideally, the myasthenia gravis include should listen for fatigable dysarthria. edrophonium test should be done dou- repetitive nerve The dysarthria in MG is bulbar and can ble blinded, with syringes of saline or stimulation and single usually be readily distinguished from edrophonium drawn up by a third per- fiber EMG. dysarthria in other disorders that might son, and the response to each assessed by h Routine nerve conduction be mistaken for MG. both patient and examiner blinded to studies and needle EMG When assessing fatigable limb weak- what is being administered. As there is are usually normal in ness in patients with possible MG, the often a subjective element to the inter- patients with myasthenia author prefers the hands-on method, in pretation of this test, by blinding the gravis but should almost which the patient contracts repeatedly edrophonium test, the risk of examiner always be done first as myopathic or neurogenic for at least five contractions against resis- and patient bias is reduced. In the ice conditions may confuse tance. The examiner then looks for grad- pack test, crushed ice in a plastic bag is the interpretation of ual worsening in power with the last few applied over a ptotic eyelid for 2 to repetitive nerve stimulation contractions. With profound weakness 5 minutes and then removed.30 PreY and single fiber EMG. at baseline, demonstrating additional and postYice pack test eyelid positions h Reduced motor fatigue is difficult. Others prefer to are then compared, ideally by a blinded amplitudes on motor assess power of a single contraction examiner looking at photographs. nerve conduction study followed by the patient exercising (eg, Electrophysiologic studies. The tests is suggestive of clapping hands over the head 20 times) used to diagnose MG include repetitive Lambert-Eaton andthenreassessingpower.Thehands-on nerve stimulation and single fiber EMG.1 myasthenic syndrome. technique allows a better assessment of Routine nerve conduction studies and h Abnormalities on needle the pattern of fatigue to differentiate from needle EMG are usually normal in pa- EMG, including fibrillation nonorganic fatigue, which is often sudden tients with MG but should almost always potentials, positive sharp waves, and with tremulous recruitment. Muscles eas- be done first as myopathic or neurogenic ‘‘myopathic’’ motor unit ily assessed for fatigue include deltoids, conditions may confuse the interpreta- potentials, can be seen in triceps, and hip flexors. It is more tion of repetitive nerve stimulation and some patients with difficult to convincingly demonstrate fa- single fiber EMG. Reduced motor ampli- myasthenia gravis, tigue in distal muscles, which are easily tudes on motor nerve conduction study especially in patients with overcome in normal individuals. Limb is suggestive of LEMS. Both LEMS and muscle-specific tyrosine weakness in MG is almost always proximal amyotrophic lateral sclerosis may also kinase myasthenia gravis. and symmetric and affects arms more than produce a decrement on repetitive nerve legs. In the arms, involvement of deltoids stimulation and an abnormal single fiber and triceps is typical for MG, whereas EMG. Denervation on needle EMG sug- myopathies more commonly cause weak- gests motor neuron disease. However, ness of deltoids and biceps. abnormalities on needle EMG, including The quantitative myasthenia gravis test fibrillation potentials, positive sharp waves, and similar scales incorporate measures and ‘‘myopathic’’ motor unit potentials, of ocular, bulbar, respiratory, and ex- can be seen in some patients with MG, es- tremity strength and fatigue.28 Although pecially in patients with MuSK MG.31 used mostly for research trials, the When a diagnosis of MG is serologi- quantitative myasthenia gravis test score cally proven, electrophysiologic testing can be used in clinical practice to follow may not be necessary. However, repet- patients during treatment. itive nerve stimulation is a useful exten- The ice pack and edrophonium tests sion of the clinical examination when have similar sensitivities and specific- determining whether the patient’s symp- ities.29 Increasing difficulties in obtain- toms are secondary to MG. However, ing edrophonium means that this test is many muscles, including extraocular and rarely done. If performed, there must be a most bulbar and leg muscles, are not clear end point (usually ptosis) that can accessible for repetitive nerve stimulation

1986 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT studies. Normal repetitive nerve stimula- fiber EMG is higher in proximal or h Although highly sensitive, tion results in a weak muscle suggests bulbar muscles. and sometimes the only that the weakness is not related to MG. Single fiber EMG provides no addi- positive diagnostic test in Patients with MG who have what appears tional diagnostic information when the ocular myasthenia gravis, to be severe weakness should have at diagnosis has been established serolog- abnormalities on single least one objective abnormality on diag- ically or if a significant decrement is seen fiber EMG are nonspecific nostic testing, particularly electrophysi- on repetitive nerve stimulation, both of and can be seen in many other myopathic or ologic testing. which have a higher specificity for MG. As neurogenic conditions. Repetitive nerve stimulation can be single fiber EMG is most useful when all Single fiber EMG results performed in several different nerve- other tests are negative, it is used mostly should always be muscle pairs. Sensitivities are higher to diagnose ocular MG. Studies of orbi- correlated with the in proximal muscles. If accessible, the cularis oculi or frontalis are more sensi- clinical presentation. weakest muscles should be studied. With tive than distal muscles. Although highly oculobulbar and mild proximal arm sensitive, an abnormal single fiber EMG weakness, normal studies in a distal is not specific for MG, and results need hand muscle do not exclude MG. Useful to be correlated with the clinical features proximal nerve-muscle pairs are facial to (Figure 11-1). The performance and in- nasalis or orbicularis oculi, spinal acces- terpretation of single fiber EMG requires sory to trapezius, axillary to deltoid, and an experienced electromyographer. One sometimes radial to extensor forearm of the reasons for a false diagnosis of MG muscles. In the leg, studies of the fibular is undue reliance on abnormal single (peroneal) nerve to tibialis anterior are fiber EMG studies without considering possible, but for technical reasons it is specificity. Single fiber EMG can be ab- not possible to study proximal leg mus- normal in a wide range of neurogenic cles. In ocular MG, the sensitivity of and myopathic conditions including con- repetitive nerve stimulation is low genital myasthenic syndromes, LEMS, (approximately 20%) but in generalized progressive external ophthalmoplegia, MG, the sensitivity is higher (approxi- and amyotrophic lateral sclerosis.32Y34 mately 80%), providing that studies of Abnormalities on single fiber EMG can symptomatic or proximal muscles are persist for at least a year after botuli- done. In MuSK MG the yield of both num toxin injection, especially with re- repetitive nerve stimulation and single peated injections, and can be found in

FIGURE 11-1 Single fiber EMG showing A, jitter at more than 200 sec; B, jitter at more than 700 sec and blocking in more than 60% of muscle fiber action potentials.

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 1987

KEY POINTS h The acetylcholine receptor muscles remote from the injection site or MuSK as well as in other disorders, 42 antibody titer does not so that an abnormal single fiber EMG including amyotrophic lateral sclerosis. correlate well with clinical must always be considered with caution It is uncertain whether a specific clinical severity in an individual after botulinum toxin.35 phenotype is associated, although early patient, and it is not useful Serologic studies. Although the sen- evidence suggests that LRP4 is found to follow antibody sitivity of antibody testing is low in some in ocular as well as in mild to moderate levels serially. situations (eg, ocular MG), the specific- generalized MG.42 h Novel antigenic targets ity for the diagnosis of MG is very high Even more recently, antibodies against have been recently (more than 99% for AChR antibodies).29,36 agrin or cortactin have been reported in MG. discovered in patients In the right clinical context, positive anti- Their pathogenic relevance and associated with myasthenia gravis. bodies confirm a diagnosis of MG. Posi- clinical phenotype are uncertain21,45,46 h Positive serologic tests in tive AChR antibodies also correlate with Although often used as a diagnostic myasthenia gravis both thymic pathology (either thymic hyper- criterion in published studies of MG, confirm the diagnosis as well as help guide plasia or a thymoma), whereas MuSK especially ocular MG, a frequent diag- 15 management options. antibodies, for the most part, do not. nostic pitfall is overreliance on ‘‘response’’ h Response to treatment, Thus, knowledge of the serostatus guides to treatment. This false-positive response especially to pyridostigmine investigations and treatment options. is especially common with pyridostigmine and IV immunoglobulin, AChR antibodies are present in approx- and IVIg (Case 11-2) for several reasons, may be useful as a imately 50% of patients with ocular MG including a placebo effect, especially in diagnostic test but only and 85% of patients with generalized patients with ‘‘pseudo-MG.’’ Many patients when supported by MG.29 A small percentage of initially with nonspecific fatigue pursue an Inter- clinical features and, AChR-negative patients may become se- net diagnosis leading to a self-diagnosis preferably, other objective ropositive, usually in the first year.37 More of MG. Improvement with treatment is diagnostic tests. recent improvements in the assay using taken to confirm the diagnosis of MG, clustered AChRs in cell-based assays re- even when all other diagnostic tests are veal positive AChR antibodies in 50% of negative. Some patients come to the previously seronegative patients. This neurologist well versed in the symptoms assay is more demanding technically and of MG, and asking about specific details is not yet widely available.7,38 The AChR of each symptom is essential to help antibody titer does not correlate well with patients differentiate what is occurring clinical severity in an individual patient, from what they have read about. Subjec- and it is not useful to follow antibody tive response to treatment should only be levels serially.39 Negative AChR antibodies used to diagnose MG if it is unequivocally make a thymoma extremely unlikely.15,40 and objectively verified. IVIg may pro- MuSK antibodies are found in approx- duce a nonspecific sense of well-being, imately 40% (range of 0% to 70%) of the independent of its specific benefits in 15% AChR-negative generalized MG MG. Finally, some disorders in the differ- group but are rarely positive in patients ential for immune MG may also respond with ocular MG.21,37,41 The range of MuSK to symptomatic treatments including sensitivities may reflect geographic and congenital myasthenic syndromes, mito- ethnic variation as MuSK is more com- chondrial myopathies, and LEMS. If in mon in the nonwhite population.14,21,42,43 doubt, with the patient’s consent, a More recently, LRP4 antibodies have blinded trial of active therapy versus been found in a small number (approxi- placebo can sometimes establish whether mately 18%) of patients who are negative the benefit is biological (Case 11-2). for AChR and MuSK,42 although other Ancillary investigations. A CT chest studies suggest a lower frequency.44 Their is indicated in patients with AChR MG, role in MG is less certain as they may oc- although many neurologists will arrange cur in patients who are positive for AChR one in all MG patients. Its main indication

1988 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Case 11-2 A 45-year-old woman was referred for a neurologic consultation after receiving a diagnosis of myasthenia gravis (MG) made by her internist 1 year earlier and because of ongoing symptoms despite treatment. Her symptoms included a hoarse voice with aphonia after prolonged talking, dysphagia for solids and liquids with choking, weakness of jaw muscles when chewing, facial weakness, exertional dyspnea without orthopnea, and a head drop. No diplopia or ptosis had occurred. In addition, the patient had described generalized exhaustion, fatigue, and daytime somnolence. Because of her extremity weakness, she would often fall to the ground and could not work. She had read extensively about MG. She had thought that pyridostigmine had made a ‘‘huge difference’’ in her symptoms. Despite continued use of pyridostigmine, she had worsened and had become unable to walk. Prednisone and azathioprine had been started by her previous physician, and she was also being treated with IV immunoglobulin (IVIg), which she had continued on a monthly basis thereafter. Both the patient and her previous physician had perceived significant benefit after IVIg, although it had caused headaches requiring narcotics. Because of worsening weakness, her frequency of IVIg treatments had been increased to every 2 weeks prior to referral for the second opinion. On examination, she had blepharospasm but no objective weakness. All investigations were normal including repetitive nerve stimulation (several times), single fiber EMG, CT chest, acetylcholine receptor (AChR) (several times) antibodies, and muscle-specific tyrosine kinase (MuSK) antibodies. A speech and language pathology consultation did not show any objective evidence of dysarthria or dysphagia consistent with MG. When suggested by the neurologist, she agreed to an n-of-1 (ie, double blinded trial of treatment in a single patient) placebo versus IVIg trial in which she would receive IVIg or placebo every 3 weeks for a total of three treatments of each, with each treatment received in randomized order and with a standardized objective clinical and electrophysiologic assessment at each visit. Both she and the neurologist were blinded to the treatment received. After the fourth scheduled treatment, she asked for the trial to be stopped as she was convinced that IVIg produced significant improvement (as well as a headache requiring narcotics) on each of the three occasions that she felt she had received it. No significant changes in the clinical examination were noted by the neurologist, and no changes in the quantitative MG scoring or any abnormalities on repetitive nerve stimulation were noted with any of the four treatments. When the neurologist was unblinded to her treatment, she had received placebo each of the three times she felt that she had improved and had received IVIg on the occasion she perceived no benefit. She chose not to continue follow-up with the neurologist as she disagreed with his opinion that she did not have MG. She sought a second opinion with another neurologist. Despite being told again by that neurologist that her condition was not MG, 3 years later she continued to be treated with pyridostigmine, prednisone, azathioprine, and IVIg every 2 to 4 weeks, prescribed by her first physician for a ‘‘myasthenialike syndrome.’’ Comment. This case demonstrates the perils of accepting a patient’s response to treatment as definitive evidence that the diagnosis is MG. Ultimately, response is often subjective and, if it is the only diagnostic clue, may lead to a false-positive diagnosis of MG. is to look for a thymoma, although it can plasia is a pathologic diagnosis made at be difficult to distinguish focal hyperplasia the time of thymectomy. A normal thy- from a small thymoma.47 Thymic hyper- mus in a young, healthy control can look

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 1989

KEY POINT h Vitamin B deficiency enlarged, and a normal or small thymus Differential Diagnosis 12 47 or thyroid disease may on CT may still be hyperplastic. Thymic With a characteristic history of fluctuat- produce nonspecific hyperplasia can occur in other autoim- ing weakness and an appropriate pattern symptoms that can mune conditions including systemic lupus of weakness, a clinical diagnosis of MG complicate the erythematosus and autoimmune thyroid often seems secure. However, many management of disease. If considering thyroid eye disease, patients report worsening of their weak- myasthenia gravis if looking for enlarged extraocular muscles ness at the end of the day even when the not recognized. on a CT or MRI of the orbits is useful. ultimate diagnosis is not MG, and some The prevalence of other autoimmune conditions can mimic the symptoms and diseases is increased in MG. Without sug- signs of MG. gestive clinical features, the yield of Ocular. Ocular MG is often more dif- screening for most autoimmune diseases ficult to diagnose than generalized MG, is low. However, the routine determina- and the sensitivity of diagnostic tests is tion of vitamin B12 and thyroid levels is lower. Many conditions can mimic ocu- 27 useful as vitamin B12 deficiency or thy- lar MG (Table 11-1). Ophthalmologic roid disease may produce nonspecific conditions, including levator dehiscence or symptoms that can complicate the man- a decompensated phoria, are common agement of MG if not recognized. eventual diagnoses when ocular MG is

TABLE 11-1 Differential for Myasthenia Gravis

Generalized Myasthenia Anatomic Ocular Myasthenia Gravis Gravis Ophthalmic Thyroid eye disease, levator Not applicable dehiscence, phoria, tropia Central nervous Blepharospasm, brainstem Amyotrophic lateral sclerosis, system lesion (eg, multiple sclerosis, Parkinson disease/parkinsonism ischemia, mass lesion, Wernicke encephalopathy) Peripheral nervous system Nerve Microvascular/diabetic cranial Amyotrophic lateral sclerosis, neuropathies, Horner syndrome, Guillain-Barre´ syndrome, Miller Fisher syndrome, focal neuropathies affecting isolated/combined III, IV, and craniobulbar function VI cranial neuropathies Neuromuscular Lambert-Eaton myasthenic Lambert-Eaton myasthenic junction syndrome,a botulism, congenital syndrome, botulism, congenital myasthenic syndrome myasthenic syndrome, organophosphate toxicity Muscle Chronic progressive Chronic progressive external external ophthalmoplegia, ophthalmoplegia, other oculopharyngeal muscular mitochondrial myopathies, dystrophy, myotonic dystrophy oculopharyngeal muscular dystrophy, myotonic dystrophy Other Idiopathic, convergence spasm Systemic disease, thyroid disease, idiopathic, chronic fatigue, functional/conversion disorder a Ocular manifestations are rare at onset of Lambert-Eaton myasthenic syndrome.

1990 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS being considered. Microvascular neurop- history and examination. Functional weak- h A congenital myasthenic athies, including diabetic or hypertensive ness is also commonly in the differential. syndrome should be microvascular cranial neuropathies, af- considered in patients fecting the III, IV, or VI cranial nerves Management who are seronegative and should be considered, especially with The crucial first steps in managing MG who have onset at birth, periorbital pain or headache at the onset are to ensure that the diagnosis is cor- early in life, and even in of diplopia. Symmetric restriction in rect and that the symptoms being treated adulthood. extraocular muscles and progressive sym- are those of MG. Causes of refractory MG h Causes of refractory metric ptosis, even with a history of minor include an incorrect diagnosis or symp- myasthenia gravis include fluctuations, suggests chronic progressive toms that are not due to MG. When an incorrect diagnosis or symptoms that are not external ophthalmoplegia. Thyroid eye patients do not improve as expected, it due to myasthenia gravis. disease may mimic or coexist with ocular is useful to reconsider the diagnosis, When patients do not MG. In about 25% of patients who have a especially if the patient is seronegative. improve as expected, it is combination of ptosis and diplopia, no If a patient is seropositive, it is important useful to reconsider the diagnosis is determined.48 to establish that the symptoms are con- diagnosis, especially if the Generalized. In a typical case of gen- sistent with MG. A patient with MG who patient is seronegative. eralized MG, the differential is limited improves with treatment but then reports (Table 11-1), and the sensitivity of diag- increasing weakness may be describing nostic tests is higher.27 A congenital fatigue, exhaustion, or daytime somno- myasthenic syndrome should be consid- lence, which may be symptoms of ob- ered in patients who are seronegative structive sleep apnea.24 In addition to a and who have onset at birth, early in life, clinical assessment, repeat electrophysio- andeveninadulthood.Somecongenital logic studies (ie, repetitive nerve stimula- myasthenic syndromes can present in tion) may help determine whether the adolescence or even adulthood caused weakness is secondary to MG. Other rea- by mutations in the genes RAPSN, DOK7, sons for worsening symptoms include or COLQ.Whenocularsymptomsare adverse effects from medications (pred- absent and hyporeflexia or areflexia and nisone in particular), mood disorders, autonomic dysfunction occur, consider and social circumstances. LEMS. Other conditions to be consid- Education of patients and primary care ered when the deep tendon reflexes are physicians is crucial. Expectations of the reduced include Guillain-Barre´syn- treating physician or patient about when drome and its Miller Fisher variant and treatments should start being effective rare cases of multifocal neuropathy with are sometimes unreasonable.49 Under- conduction block with cranial nerve mus- dosing (or occasionally overdosing) or cle involvement. In oculopharyngeal mus- abandoning a treatment too early can cular dystrophy, ptosis and generalized both result in treatment ‘‘failure.’’ A weakness can occur, but extraocular discussion about each medication, pos- muscle involvement is usually absent. sible adverse effects and strategies to Mitochondrial myopathies can be difficult manage them, expected time course of to distinguish clinically from MG, and benefits (hours to days for pyridostig- single fiber EMG can be abnormal in mine, weeks to many months for predni- many myopathic disorders including sone, and many months to a year or more oculopharyngeal muscular dystrophy for azathioprine) is crucial. For some med- and mitochondrial myopathies.34 Central ications, monitoring for adverse effects is nervous system disorders such as Parkinson essential, and a discussion of the impor- disease, progressive supranuclear palsy, tance of this increases compliance. For or brainstem lesions are usually not diffi- physicians managing many patients with cult to distinguish from MG after a careful MG, having this educational information

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 1991

KEY POINTS h A complete lack of in print form in addition to a verbal Rarely, patients need lower initial doses response to treatment is discussion saves time and reinforces the or a slower rate of escalation. Having unusual in patients with message. Sending a list of the medica- already discussed the next options with myasthenia gravis and tions that should be avoided in patients the patient at the time of medication should prompt physicians with MG to the primary care physician initiation, the author has the patient call to reconsider the diagnosis is useful, although this is not infre- to provide an update on his or her re- of myasthenia gravis in quently ignored. Finally, a discussion sponse 2 weeks after starting the medica- patients who are of which symptoms might be secondary tion. Even when a complete response seronegative or reconsider whether myasthenia to MG (weakness) and which almost never occurs, occasionally symptoms will break gravis is the cause of the occur (eg, pain, memory loss, sensory through over the next several months. If a symptoms in patients who symptoms, systemic disorders) maximizes partial response occurs, further increases are seropositive. efficiency of the neurologist’s time. of 30 mg to 60 mg at each dose can be h Many treatments of Management of ocular myasthenia made at intervals of 1 to 2 weeks up to myasthenia gravis take gravis. Although not life-threatening, ocu- a maximum of 480 mg/d, depending on time to reach maximal lar MG can be disabling. The first decision tolerance. Higher doses are unlikely to efficacy, and another is whether symptoms require treatment. produce additional benefit. Diarrhea, cause for nonresponse to When symptoms are mild and infrequent, one of the more common side effects, treatment is unreasonable it may be best to defer treatment until is often self-limited, but loperamide helps expectations about how long it should take before they become troublesome. A trial of in most cases. If no response occurs, the improvement begins. pyridostigmine may be warranted, but author moves on to immunosuppression, the medication is often ineffective or usually adding to pyridostigmine, although minimally effective, especially for diplo- if it is clear that no response has oc- pia. The risk to benefit ratio of prednisone curred, the medication could be stopped. may not be worth accepting. Retrospective Prednisone is very useful in patients evidence suggests that prednisone may with ocular MG, although patience is re- reduce the risk of generalization.50 How- quired. The evidence in adults that pred- ever, it may be better to avoid predni- nisone given on alternate days is less sone when not required, knowing that it likely to cause adverse effects is prac- is just as likely to be effective if and when tically nonexistent, but starting low doses MG becomes generalized. (eg, 25 mg every other day) of prednisone MG is treated symptomatically with will help most patients in about 3 to 4 pyridostigmine, which inhibits acetyl- months.51 Occasionally, patients fluctu- cholinesterase at the neuromuscular ate and are worse on the off day, and junction and increases available acetylcho- glycemic control using the alternate-day line but does not treat the underlying approach is difficult in diabetics, so immunopathogenesis. Pyridostigmine is sometimes starting or reverting to an the usual first step in treating ocular MG. equivalent daily dose is required. If at It has few serious side effects and, if ef- 3 to 4 months the symptoms are not fective, works quickly. Starting at 30 mg improving (they may not be completely every 4 hours during the waking day, with gone), doubling the dose to either 25 mg/d the first tablet taken within an hour of or 50 mg on alternate days helps most of arising, is a reasonable strategy. Unless the remaining patients. Physicians should nocturnal symptoms occur, a bedtime be familiar with common side effects of tablet is wasted. If required, the dose prednisone and discuss these with the can be increased to 60 mg every 4 hours patient.3 Anticipating worsening in hy- in3to7days.Theregular60mgpyri- pertension and glycemic control and dostigmine pills have a more consistent enlisting the help of the primary care bioavailability, and the author rarely physician in managing these is helpful. uses the sustained-release formulation. Individuals older than age 50 taking more

1992 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT than 7.5 mg/d for more than 3 months author avoids combining more than two h With patience, most should be on osteoporosis prophylaxis at (prednisone and one other) immuno- patients with myasthenia 52 the outset. suppressants because of the increased gravis will respond to With patience, prednisone doses risk of infections. lower doses of prednisone, higher than 25 mg/d to 30 mg/d are Management of generalized myas- although this may take rarely required in patients with ocular thenia gravis. The treatment of MG is several months. MG. About 2 to 3 months after the highly individualized, and only general symptoms have resolved, it may be guidelines are discussed. The options appropriate to start tapering the dose. chosen depend on serostatus (AChR ver- With doses of more than 20 mg/d, taper sus other), age, comorbidities, and dis- by 10 mg a month, and with doses of less ease severity. For most choices, no trial than 20 mg/d, taper by 5 mg a month evidence exists to establish effective- (10 mg on the alternate day). It is often ness.53 However, the collective experi- useful to taper by 2.5 mg or even 1 mg ence supports the most commonly used reductions every 1 to 2 months with medications and treatments. The choice doses of less than 5 mg/d to 10 mg/d. often comes down to physician experi- Symptoms often recur at doses of less ence and familiarity as well as patient than 5 mg/d to 10 mg/d, and many pa- tolerance. For all treatment options, a tients require long-term low-dose pred- discussion of expected benefits, includ- nisone. Tapering too quickly or while ing the time frame that is involved, as the patient is still symptomatic will almost well as common adverse effects and always result in a relapse, often several monitoring required, is useful. months after a reduction. Symptomatic. As is the case for ocular The databases used by most pharma- MG, in mild to moderate generalized cies in North America sometimes flag the MG, pyridostigmine may be the only combination of prednisone and pyridos- treatment at first. The same strategy and tigmine as a potentially harmful interac- advice about pyridostigmine previously tion. The vast majority of patients with discussed for ocular MG also applies to MG will be on this combination at some the treatment of generalized MG. A cho- point. The literature supporting this linergic crisis, in which weakness is warning is decades old and likely relates worsened by increased doses of pyri- to the early worsening that can be seen dostigmine, rarely occurs. Almost always, with the use of high-dose prednisone and a careful history will reveal worsening in not to an interaction between the two. MG symptoms prior to increases in the To avoid future telephone calls and con- dose of pyridostigmine. In mild to mod- fusion on the part of the patient, the erate generalized MG, the concomitant author often sends a form letter with the use of prednisone and sometimes another prescription politely suggesting that immunosuppressant is often required. the pharmacist ignore this warning. In more severe MG, immunosuppres- Azathioprine can be used in ocular sion and sometimes immunomodula- MG, either alone (if the patient is willing tion should be started at the same time to wait) or along with prednisone in pa- as pyridostigmine. tients where long-term/high-dose predni- Immunosuppression. For mild gen- sone is best avoided. Azathioprine can eralized MG, when pyridostigmine alone also be added later if no response to is not helpful, low-dose alternate-day prednisone occurs by 6 to 9 months or prednisone is useful. For moderate gen- if the patient worsens when tapering. eralized MG, higher doses may be re- Other immunosuppressants can also be quired. For severe MG, especially if bulbar used in patients with ocular MG. The or respiratory weakness occurs, higher

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 1993

KEY POINT h Caution is advised when doses are effective more rapidly. How- effects. In the author’s experience, about starting patients with ever, if high doses (the author considers 1% to 2% of patients, higher in others’ myasthenia gravis who doses higher than 30 mg/d as the cutoff experience, will experience a flulike re- have any bulbar or for concerns about this phenomenon) action within the first 2 weeks that almost respiratory weakness on are used initially, about 40% of patients always requires discontinuation. Monitor high doses of prednisone with MG may worsen initially before they hepatic transaminases (alanine amino- as patients may start to improve, and 10% overall worsen transferase [ALT], aspartate amino- worsen initially. significantly.54 This usually starts 4 to 5 transferase [AST], and most importantly days after beginning prednisone and ,-glutamyltransferase [GGT]) and a com- lasts about 4 to 7 days before improve- plete blood count and differential weekly ment then occurs. Strategies to avoid for the first 8 weeks and monthly there- this initial worsening of symptoms in- after. Hepatotoxicity, usually mild and clude starting at low doses (eg, 10 mg/d) reversible, occurs in 15% and mye- with increases every 3 to 5 days in 10 mg losuppression in 10% at a median of steps until the desired dose is reached.55 about 6 weeks after starting.58 Both will The use of IVIg or plasma exchange when resolve after a dose reduction, although prednisone is started may also prevent if these adverse effects are rapid or initial worsening. Prednisone doses of significant, discontinuation may be re- more than 1 mg/kg/d are rarely required, quired. Neutropenia is the main concern, and the author usually uses a maximum whereas lymphopenia and macrocytosis dose of 0.5 mg/kg/d to 0.75 mg/kg/d. are common and benign findings that are Recent trial evidence suggests that, with seen when monitoring blood work with patience, most patients respond to rela- long-term azathioprine use. After 6 to tively low doses of prednisone.56 Predni- 12 months on azathioprine, if no im- sone takes months (usually 3 to 6 months provement occurs at 150 mg/d, in most and sometimes longer) before maximum patients not at maximal doses based on benefit occurs. Higher doses might accel- weight (ie, the patient weighs more than erate this slightly but definitely increase 50 kg [110 lb]), the dose can be increased the risk of adverse effects. With bulbar or in 50 mg to 100 mg steps every 3 to 6 respiratory weakness, when a more rapid months to a maximum of 2.5 mg/kg/d to response is required, immunomodulatory 3.0 mg/kg/d based on actual body weight. treatments should be used (see the fol- Long-term azathioprine use may increase lowing section on immunomodulation). the risk of malignancies, particularly der- In mild generalized MG, if predni- matologic, although the absolute risk of sone is best avoided, azathioprine can this is low.59 Strategies to reduce this are be used alone provided the patient can prudent.60 If a risk of or previous wait the 12 to 18 months (or more) that it history of skin cancers already exists, may take before optimal benefit is seen.57 using mycophenolate might pose a Starting prednisone and azathioprine at lower risk.61 the same time takes advantage of the In patients who do not respond to or earlier benefits from prednisone as tolerate azathioprine, other immuno- well as the eventual steroid-sparing suppressants can be used. Mycophenolate effects of azathioprine. Tapering regi- (either mofetil or sodium) is a common mens are similar to ocular MG (larger next step. Although two trials failed to reductions at doses of more than 30 mg/d show an additional benefit compared and smaller below this). Starting aza- to prednisone alone over 36 weeks, thioprine at 25 mg/d with increases this may reflect the efficacy of predni- every 2 weeks to 50 mg/d, 100 mg/d, sone in relatively mild MG within the and 150 mg/d lessens some adverse first 9 months rather than a failure of

1994 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 56 KEY POINT mycophenolate. Mycophenolate is medications, which can interfere with h In a myasthenic crisis, 64 widely used in MG and likely takes at neuromuscular transmission. In al- pyridostigmine is often least 6 months and perhaps longer to pro- mostone-thirdofcases,acauseis not sufficient, and duce significant benefit. Mycophenolate not identified. immunosuppressive is generally well tolerated and may be For patients who have an acute exac- options, although more suitable in patients with skin erbation of MG, pyridostigmine is often effective, can take months cancer. Other immunosuppressants used insufficient, and its adverse effects of to produce benefit. Immunomodulation, with frequently in MG include cyclosporine, increased oral and tracheobronchial either IV immunoglobulin tacrolimus, methotrexate, and cyclophos- secretions may worsen the situation. or plasma exchange, phamide. Some retrospective and limited Immunosuppressants may take months; produces earlier trial evidence supports the efficacy of therefore, in addition to treating the un- improvement in most each of these. Most of these agents have derlying precipitant, immunomodulatory patients and bridges the greater toxicity than azathioprine and treatments are useful for a crisis or severe gap while waiting for mycophenolate and require more in- exacerbation and include IVIg and plasma immunosuppression tense monitoring. exchange.65,66 Both treatments are simi- to work. Patients with MuSK antibodies larly effective, although plasma exchange may be less likely to respond to (and maybeslightlyfasterandmoreeffective may even worsen) and have more in a myasthenic crisis and more useful in adverse effects from pyridostigmine.42,62 patients with MuSK MG.42,67 Either IVIg MuSK MG may also be less likely to or plasma exchange is also used pre- respond to IVIg and perhaps immuno- operatively, before thymectomy or other suppressants in general, but azathio- urgent surgery, in a patient with MG who prine in particular.42,63 is significantly symptomatic. Neither is re- Immunomodulation. In a myasthen- quired routinely, and their use should be ic crisis, respiratory weakness requires restricted to those patients with signifi- intubation. Historically, a myasthenic crisis cant preoperative respiratory or bulbar occurredin15%to30%ofpatientswith weakness. IVIg or plasma exchange have MG but is less common now with effective no effect on the long-term course of MG management options. A myasthenic crisis and, with few exceptions, are not indi- usually occurs within the first few years cated for the chronic management of after disease onset and is sometimes MG.68 Rarely, a patient will require on- the presenting incident. Along with going treatment with IVIg or plasma severe bulbar weakness producing as- exchange for refractory MG. piration, a myasthenic crisis was the Immunomodulatory treatments target- cause of mortality rates of 50% or more ing B lymphocytes have shown significant prior to effective treatment. With the promise in patients with MuSK or AChR current options and improved intensive MG. Rituximab, which targets CD20 on the care, mortality from a myasthenic crisis B lymphocyte cell surface, works in many is less than 5%. Severe MG with dyspnea patients with MG with severe disease managed with noninvasive ventilation and who are refractory to the usual or severe dysphagia should be managed treatments. It has been suggested that similarly to a crisis. Common precipi- MuSK MG is more likely to respond to tants for a myasthenic crisis include rituximab.21,42 However, a meta-analysis underlying infection (often pneumo- showed efficacy of rituximab in more than nia), aspiration, surgery including thy- 80% of patients with MG regardless of mectomy, hormonal changes during or which antibody was positive.69 The onset after pregnancy, tapering or dis- of action is probably slower than IVIg or continuation of MG medications, and plasma exchange but the duration of high doses of prednisone or other improvement is often 6 to 12 months or

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 1995

KEY POINTS 70 h Although the specifics of more. Rituximab may offer significant Other surgical approaches are used each indication are still benefits in severe or refractory MG, in some centers. Most consider a cervical somewhat controversial, especially in those being treated with thymectomy suboptimal because of the the most accepted long-term IVIg or plasma exchange. risk that thymic tissue will be left behind. indications for a IgG3 and, to a lesser extent, IgG1 The role for minimally invasive approaches trans-sternal thymectomy and IgG2 AChR antibodies, which fix (robotic or video-assisted thoracoscopy) include patients with complement, can destroy the muscle remains to be proven, although these generalized early-onset endplate. Therapies targeting comple- approaches are increasingly used in myasthenia gravis who are acetylcholine receptor ment including eculizumab have been many centers. Despite occasional reports antibody positive and assessed in MG and its experimental of efficacy of thymectomy in MuSK MG, 70 within 5 years of model and appear promising. given the lack of thymic pathology in disease onset. Thymectomy. Indications for a thy- MuSK MG this remains a controversial 21 h Many commonly used mectomy in patients with MG include indication. Thymectomy in seronega- medications to treat removal of a thymoma and to increase tive MG, where thymic hyperplasia is myasthenia gravis, the chance of a sustained drug-free remis- less prominent, is also less proven and a including pyridostigmine, sion, but these two indications are not chance always exists that a patient who is prednisone, and synonymous. Removing a thymoma prob- seronegative does not have MG. azathioprine, are safe for ably does not improve the course of MG Pregnancy. For the most part MG is use during pregnancy. but is almost always indicated to reduce managed during pregnancy as usual. Plan- the chance of local growth, invasion, ning any changes in management in ad- and metastases.71 If removed at an early vance, including before conception when stage, the long-term survival is good. possible, is important. When MG is well Once local invasion or metastases occur, controlled, the risks to mother and child adjuvant therapy with radiation or che- are minimal. Vaginal deliveries are en- motherapy is usually indicated. couraged, and indications for a cesarean Given its role in the production of delivery are no different than in a mother AChR antibodies, removal of a hyper- without MG.75 Although neonatal MG is plastic thymus has long been considered rare in the author’s experience, mothers a management option for generalized with MG should be managed as a high- MG. The evidence supporting this is risk pregnancy in a center capable of mostly retrospective, and evidence-based caring for both neonate and mother. reviews concluded that thymectomy Most medications used in MG, including may be a management option in some pyridostigmine, prednisone, and azathio- patients with MG.72,73 Arecentlycon- prine, appear to be safe in pregnancy.21,76,77 cluded randomized trial supports the Methotrexate and mycophenolate must role for thymectomy under specific con- be avoided as they are teratogenic. IVIg ditions in MG.74 Although the specifics and plasma exchange are also relatively of each indication are still somewhat safe in pregnancy. The severity of the controversial, the most accepted indica- weakness in MG may improve or worsen, tions for a trans-sternal thymectomy the latter especially in the puerperium, include patients with generalized early- during pregnancy. onset MG who are AChR antibody pos- Other medications and myasthenia itive and within 5 years of disease onset. gravis. There are many lists of drugs to The role for thymectomy outside these avoidinMGastheymightworsenthe indications is less certain. Improvement weakness in a patient with MG. The may take 1 to 2 years after thymectomy. evidence supporting inclusion of some Patients with MG should be medically of these is often weak. Many patients well controlled and ideally on lower doses with MG, especially the elderly, will be of prednisone prior to thymectomy. on one or more of these (beta-blockers

1996 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT and calcium channel blockers in parti- Pathophysiology h Although some 78 cular) with no worsening in their MG. The antigenic target in LEMS is the P/Q medications might Some antibiotics (aminoglycosides, type voltage-gated calcium channel produce worsening in macrolides, and fluoroquinolones, for (VGCC) on the presynaptic nerve termi- patients with myasthenia instance) are probably best avoided if nal.79 VGCC antibodies reduce calcium gravis, few medications possible but even then, many patients influx into the nerve terminal and, there- are absolutely contraindicated, and with MG have been on one or more of fore, reduce the amount of acetylcholine the potential benefits these without ill effect. Most should released into the synaptic cleft. At the of a medication should be considered a relative contraindica- neuromuscular junction of skeletal mus- be weighed against tion, and patients and physicians should cle, this can result in neuromuscular the evidence that it weigh the benefits of that specific medi- transmission failure. Involvement of the might produce cation versus the risk that the MG may same VGCC at autonomic synapses pro- worsening weakness. be worsened while on the medication. If duces autonomic dysfunction. VGCC worsening does occur, it is sometimes antibodies can be found in other para- difficult to exclude worsening because neoplastic disorders including subacute of an underlying infection, which is a cerebellar degeneration. common reason for exacerbation in MG. LEMS is divided into paraneoplastic Patients with MG undergoing a general and primary autoimmune groups. In anesthetic may be more sensitive to paraneoplastic LEMS, an underlying nondepolarizing neuromuscular blocking small cell lung cancer is almost always agents and less sensitive to depolarizing present. In children with LEMS, lym- neuromuscular blocking agents. Spinal phoproliferative disorders may be asso- or local anesthetics are generally safer ciated instead. options. Any patient with MG who has significant weakness, especially if bulbar Epidemiology or respiratory, and who is started on one LEMS is rare, with an estimated incidence of the potentially offending medications of 0.5 out of 1 million and a prevalence should be monitored carefully. of 2.3 out of 1 million. Relative to MG, theprevalenceofLEMSisreduced Trends compared to its incidence.80 This reflects Recent advances in identifying new anti- the poor survival in paraneoplastic genic targets and improved assays for LEMS. Approximately 40% to 50% of existing antibodies promise to further patients with LEMS have a primary reduce the cases of generalized MG that autoimmune disorder, and in 50% to are difficult to diagnose. Therapies that 60%, LEMS occurs as a paraneoplastic are directed to specific components of disorder, almost always with an under- the aberrant immune response, includ- lying small cell lung cancer.81 Studies ing complement and CTLA4, may prove suggest that LEMS occurs in 2% to 3% interesting. Trials that demonstrate ef- of small cell lung cancer cases and is ficacy of current off-label options will likely underrecognized.81,82 expand the list of available treatments for many patients with MG. Clinical Features The clinical triad characteristic for LEMS LAMBERT-EATON is best remembered by the three A’s: MYASTHENIC SYNDROME apraxia, areflexia, and autonomic involve- Although much less common than MG, it ment.83,84 Although not true apraxia, is important for neurologists to recognize this is a useful way of remembering that the clinical features of LEMS and be leg weakness producing difficulties familiar with its management. with gait is the most prominent clinical

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 1997

KEY POINT h Patients with feature and that, frequently, patients Clinical. The biggest delay to a diag- Lambert-Eaton with LEMS have more functional diffi- nosis of LEMS is not suspecting the myasthenic syndrome culties than predicted by the strength condition. Abnormalities on the neuro- often present with of individual muscles. logic examination will usually be most difficulty walking and The clinical features of LEMS usually prominent in the extremities, especially with leg weakness, with precede the diagnosis of underlying small the legs. Reduced deep tendon reflexes areflexia and autonomic cell lung cancer, which is more often at a in a patient where MG is being consid- involvement comprising limited stage or occult when compared ered suggests LEMS instead. Prominent the other two key features. to small cell lung cancer without LEMS. ocular findings at onset is against a diag- Weakness almost always begins in the nosis of LEMS.25 Characteristic in LEMS proximal legs and causes difficulties is the paradox between significant func- walking.83,85 Arm weakness is also com- tional impairment with walking but only mon. The onset is often subacute, and mild weakness on examination. fluctuation is less prominent than in MG. The author has not found clinical However, ocular and bulbar weakness facilitation in strength, in which the may be absent or, if present, occur as a second contraction of a muscle group late manifestation. The presence of ocu- has increased power relative to the first, lar and perhaps bulbar involvement at to be a reliable sign when elicited by an onset is strongly against a diagnosis of unbiased examiner. However, in up to LEMS and suggests MG.25 Thus, LEMS 40% of patients with LEMS, a previously starts in the legs and ascends while MG absent or significantly reduced deep often starts with craniobulbar involve- tendon reflex will return to normal after ment and descends. Respiratory involve- 10 seconds of maximal voluntary con- 84 ment is uncommon. traction. Autonomic involvement is Deep tendon reflexes are almost al- best established by a careful history. ways reduced or absent, especially in Many patients will not volunteer symp- the legs. Involvement of sympathetic toms suggesting autonomic involvement and perhaps more frequently parasympa- unless asked. thetic systems occurs eventually in 80% Weakness in a patient with small cell to 90% of patients with LEMS and can lung cancer is often blamed on cachexia, produce almost any autonomic manifes- malnutrition, or chemotherapy, and para- tation. A dry mouth, constipation, and neoplastic LEMS is often not suspected. erectile dysfunction in men are par- LEMS should be considered when a ticularly common but loss of sweating, patient with an underlying small cell lung orthostatic hypotension, and pupillary cancer develops prominent leg weakness abnormalities are also seen.84 and the deep tendon reflexes are reduced Sensory loss or cerebellar features are or autonomic involvement occurs. not features of LEMS but might suggest The prediction of an underlying an overlapping paraneoplastic disorder small cell lung cancer in patients with associated with an underlying small cell LEMS may be increased when the pa- lung cancer. tient has a higher Dutch-English LEMS Tumor Association Prediction (DELTA-P) Diagnosis score. This uses clinical features such as Once suspected, the diagnosis of bulbar weakness (dysarthria, dysphagia, LEMS can often be made based on chewing weakness, and neck weakness), characteristic electrophysiologic abnor- autonomic involvement (erectile dys- malities, which distinguish it from MG. function), weight loss, tobacco use, age Serologic confirmation of the diagnosis of older than 50 years, and a Karnofsky is important. Performance Status Scale score of less

1998 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT than 70, with 1 point allocated for each. often less than 50% of the h Although a decrement A total score of 3 or more predicted a laboratory’s lower limits of normal. on repetitive nerve greater than 90% chance of an underly- & Decrement with low-frequency stimulation can be seen in ing small cell lung cancer.86 stimulation; as opposed to MG, where either myasthenia gravis the decrement is usually maximal at or Lambert-Eaton Electrophysiologic studies. As for MG, the fourth or fifth stimulation in the myasthenic syndrome, a routine nerve conduction studies and train, in LEMS the maximal decrement reduction in baseline needle EMG should be done first. The may occur later in the train.87 motor amplitudes and increment after either triad of electrophysiologic abnormali- & Increment with high-frequency ties in LEMS consists of the following: maximal voluntary stimulation or facilitation after contraction or & Diffusely reduced motor amplitudes 10 seconds of maximal voluntary high-frequency on motor nerve conduction studies, contraction (Figure 11-2); stimulation are characteristic of Lambert-Eaton myasthenic syndrome.

Y Y FIGURE 11-2 Pre and post maximal voluntary contraction ulnar motor nerve conduction study in a patient with Lambert-Eaton myasthenic syndrome. A 32-year-old woman presented with a 1-year history of fatigable weakness of her legs. She also described a dry mouth. She was a lifetime nonsmoker. On examination, in addition to mild weakness of hip flexors, she was areflexic. PreY and postYmaximal voluntary contraction motor nerve conduction studies of the ulnar nerve with stimulation at the wrist and recording over abductor digiti minimi are shown, demonstrating an over 500% increment in motor amplitude after maximal voluntary contraction.

MVC = maximal voluntary contraction.

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 1999

KEY POINT Y h Whereas pyridostigmine post maximal voluntary contraction clinical features of LEMS are often may not produce studies are as sensitive and better attributed to the effects of cachexia and significant benefit, tolerated than high-frequency malnutrition. Electrolyte and metabolic 88 3,4-diaminopyridine is a stimulation. Increments of more abnormalities affecting calcium or mag- very effective than 100% are very suggestive for nesium, as well as hypothyroidism are symptomatic treatment LEMS but not specific for LEMS also in the differential. of Lambert-Eaton and occur in some cases of myasthenic syndrome. botulism and MG. Management Theabnormalitiesmaybesubtle The most effective symptomatic treat- early in the disease course. Although ment in LEMS is 3,4-diaminopyridine leg weakness is most predominant in (3,4-DAP).92 Through blocking voltage- LEMS, electrodiagnostic studies of the gated potassium channels, 3,4-DAP ulnar or median nerves have the highest prolongs nerve terminal depolarization sensitivities.89 Single fiber EMG abnor- and increases acetylcholine release.79,92,93 malities usually do not distinguish LEMS In small trials, 3,4-DAP has been shown from MG. to produce clinical and electrophysio- Serologic studies. VGCC antibodies logic benefit in patients with LEMS.92,94 are more than 90% sensitive in primary Improvement after each dose is usually autoimmune LEMS and approach 100% in seen within 30 minutes and is maximal 84 paraneoplastic LEMS. VGCC antibodies at 90 minutes.92 Starting doses are are not specific and are found in small usually 5 mg to 10 mg three to four cell lung cancer without LEMS as well as times a day, with gradual increases up other paraneoplastic disorders.83,90 to 80 mg/d, divided into four to six Ancillary investigations. Given its doses. Many patients respond to 40 mg/d association with LEMS, patients should to 60 mg/d. Common adverse effects be investigated for an underlying small include perioral and acral paresthesia, cell lung cancer, especially in elderly maximal about an hour after each dose, smokers with weight loss. If an initial CT nausea, abdominal pain, tachycardia, and chest is negative, a bronchoscopy or palpitations.92,95 Insomnia is minimized positron emission tomography (PET) by avoiding the last dose at bedtime. scan may be indicated in high-risk Doses of more than 100 mg/d may patients. When initial investigations are increase the risk of seizures, although negative in a high-risk patient, repeating this is likely a rare adverse effect.92,95 the CT chest every 3 to 6 months for at Seizures are more likely with other pre- least the first 2 years is suggested, after dispositions, so caution is advised with which the chance of a small cell lung brain metastases or the use of other cancer being found is less.91 medications that might lower the thresh- old for seizures. Differential Diagnosis In theory, pyridostigmine should be MG is the disorder most commonly in the synergistic with 3,4-DAP but many pa- differential for LEMS. A myopathy, espe- tients with LEMS have no benefit from cially dermatomyositis, might present like pyridostigmine either on its own or in LEMS in the setting of an underlying small combination with 3,4-DAP.96,97 cell lung cancer. Guillain-Barre´ syndrome, Given its immunopathogenesis, im- chronic inflammatory demyelinating poly- munosuppression may also be useful to radiculoneuropathy (CIDP), and other treat LEMS.97 The choice of immunosup- motor predominant subacute neuropa- pressant drugs in LEMS is similar to thies occasionally mimic LEMS. In the MG. However, avoiding immunosup- context of small cell lung cancer, the pression in paraneoplastic LEMS may

2000 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. be advisable because of concerns about with pyridostigmine helps many patients reduced immunosurveillance and tumor with MG, although it is less effective for progression. Immunosuppressants can patients with ocular MG. Many options be useful in primary autoimmune LEMS exist for immunosuppression, the choice if 3,4-DAP alone is insufficient. IVIg, of which often depends on practitioner plasma exchange, and rituximab might familiarity. The goal should be to balance also be useful, although the evidence benefits with potential adverse effects; for their efficacy in treating LEMS is with patience, most patients will respond weaker.94,97 Treatment of the underlying to lower doses than are commonly used. small cell lung cancer may improve An underlying small cell lung cancer will paraneoplastic LEMS, although it is diffi- be found in more than one-half of cult to distinguish an effect of this from patients with LEMS. 3,4-DAP is the most immunosuppression.97,98 effective symptomatic treatment in LEMS, and immunosuppression is best reserved Prognosis for nonparaneoplastic LEMS that does Primary autoimmune LEMS has an ex- not respond to 3,4-DAP. cellent prognosis, and most patients respond well to treatment, although lifelong REFERENCES treatment is often required. The prog- 1. Keesey JC. AAEE Minimonograph #33: nosis in paraneoplastic LEMS is poor electrodiagnostic approach to defects of neuromuscular transmission. Muscle Nerve and is determined by the underlying 1989;12(8):613Y626. doi:10.1002/mus.880120802. 97 small cell lung cancer. Thepresenceof 2. Drachman DB, Adams RN, Stanley EF, et al. LEMS may improve the prognosis com- Mechanisms of acetylcholine receptor loss pared with small cell lung cancer without in myasthenia gravis. J Neurol Neurosurg Y LEMS.97,99,100 Psychiatry 1980;43(7):601 610. doi:10.1136/ jnnp.43.7.601. 3. Nicolle MW. Myasthenia gravis. Neurologist Trends 2002;8(1):2Y21. 3,4-DAPislikelytoremainthemainstay 4. Koneczny I, Cossins J, Vincent A. The role of of symptomatic treatment in patients muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. J Anat with LEMS. Current trials hope to obtain 2014;224(1):29Y35. doi:10.1111/joa.12034. regulatory approval, making it easier to 5. Berrih-Aknin S. Cortactin: a new target in obtain, although concerns exist about autoimmune myositis and Myasthenia Gravis. whether the cost of approved products Autoimmun Rev 2014;13(10):1001Y1002. will be out of reach of many patients. doi:10.1016/j.autrev.2014.08.037. Experimental approaches to pharmaco- 6. Berrih-Aknin S, Le Panse R. Myasthenia gravis: a comprehensive review of immune logic improvement of calcium influx dysregulation and etiological mechanisms. and presynaptic acetylcholine release J Autoimmun 2014;52:90Y100. doi:10.1016/ are also being investigated.79 j.jaut.2013.12.011. 7. Binks S, Vincent A, Palace J. Myasthenia gravis: a clinical-immunological update. J Neurol 2016; CONCLUSION 263(4):826j834. doi:10.1007/s00415-015-7963-5. The diagnosis and, to a certain extent, 8. Hohlfeld R, Wekerle H. The thymus in myasthenia gravis. Neurol Clin 1994;12(2):331Y342. specifics of management of MG are aided 9. Renton AE, Pliner HA, Provenzano C, et al. significantly by results of serologic assays. A genome-wide association study of myasthenia Most patients with MG respond to treat- gravis. JAMA Neurol 2015;72(4):396Y404. ment, and a lack of response may mean doi:10.1001/jamaneurol.2014.4103. that the diagnosis is incorrect or that the 10. Salvado M, Canela M, Ponseti JM, et al. Study of the prevalence of familial autoimmune target symptoms are not directly related myasthenia gravis in a Spanish cohort. J Neurol to the disease. Symptomatic treatment Sci 2016;360:110Y114. doi:10.1016/j.jns.2015.11.049.

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 2001

11. Nacu A, Andersen JB, Lisnic V, et al. 24. Nicolle MW, Rask S, Koopman WJ, et al. Complicating autoimmune diseases in Sleep apnea in patients with myasthenia myasthenia gravis: a review. Autoimmunity gravis. Neurology 2006;67(1):140Y142. Y 2015;48(6):362 368. doi:10.3109/ doi:10.1212/01.wnl.0000223515.15691.26. 08916934.2015.1030614. 25. Wirtz PW, Sotodeh M, Nijnuis M, et al. 12. Gilhus NE, Nacu A, Andersen JB, et al. Difference in distribution of muscle Myasthenia gravis and risks for comorbidity. weakness between myasthenia gravis Y Eur J Neurol 2015;22(1):17 23. doi:10.1111/ and the Lambert-Eaton myasthenic ene.12599. syndrome. J Neurol Neurosurg Psychiatry Y 13. Pakzad Z, Aziz T, Oger J. Increasing incidence 2002;73(6):766 768. doi:10.1136/ of myasthenia gravis among elderly in jnnp.73.6.766. British Columbia, Canada. Neurology 2011; 26. Nicolle MW. Wrist and finger drop in Y 76(17):1526 1528. doi:10.1212/ myasthenia gravis. J Clin Neuromuscul Dis WNL.0b013e318217e735. 2006;8(2):65Y69. doi:10.1097/ 14. Carr AS, Cardwell CR, McCarron PO, et al. 01.cnd.0000245218.70927.97. A systematic review of population based 27. Engstrom JW. Myasthenia gravis: epidemiological studies in Myasthenia diagnostic mimics. Semin Neurol 2004;24(2): Gravis. BMC Neurol 2010;10:46. doi:10.1186/ 141Y147. doi:10.1055/s-2004-830903. 1471-2377-10-46. 28. Barohn RJ, McIntire D, Herbelin L, et al. 15. Gilhus NE, Verschuuren JJ. Myasthenia gravis: Reliability testing of the quantitative subgroup classification and therapeutic myasthenia gravis score. Ann NY Acad Sci strategies. Lancet Neurol 2015;14(10): 1998;841:769Y772. doi:10.1111/ 1023Y1036. doi:10.1016/S1474-4422(15)00145-3. j.1749-6632.1998.tb11015.x. 16. Akaishi T, Yamaguchi T, Suzuki Y, et al. 29. Benatar M. A systematic review of Insights into the classification of myasthenia diagnostic studies in myasthenia gravis. gravis. PLoS One 2014;9(9):e106757. Neuromuscul Disord 2006;16(7):459Y467. doi:10.1371/journal.pone.0106757. doi:10.1016/j.nmd.2006.05.006

17. Vincent A, Clover L, Buckley C, et al. Evidence 30. Larner AJ. The place of the ice pack test in of underdiagnosis of myasthenia gravis in the diagnosis of myasthenia gravis. Int J Clin Y older people. J Neurol Neurosurg Psychiatry Pract 2004;58(9):887 888. doi:10.1111/ 2003;74(8):1105Y1108. doi:10.1136/ j.1742-1241.2004.00053.x. jnnp.74.8.1105. 31. Sanders DB, El-Salem K, Massey JM, et al. Clinical aspects of MuSK antibody positive 18. Mao ZF, Mo XA, Qin C, et al. Incidence seronegative MG. Neurology of thymoma in myasthenia gravis: a 2003;60(12):1978Y1980. doi:10.1212/ systematic review. J Clin Neurol 2012;8(3): 01.WNL.0000065882.63904.53. 161Y169. doi:10.3988/jcn.2012.8.3.161. 32. Stalberg EV, Trontelj J, Sanders DB. Single 19. Evoli A, Batocchi AP, Provenzano C, et al. fiber electromyography. Studies in healthy Thymectomy in the treatment of myasthenia and diseased muscle. 3rd ed. Fiskeba¨ ckskil, gravis: report of 247 patients. J Neurol 1988; Sweden: Edshagen Publishing House, 2010. 235(5):272Y276. doi:10.1007/BF00314173. 33. Sanders DB, Stålberg EV. AAEM minimonograph 20. Somnier FE. Clinical implementation of #25: single-fiber electromyography. Muscle anti-acetylcholine receptor antibodies. J Nerve 1996;19(9):1069Y1083. doi:10.1002/ Neurol Neurosurg Psychiatry 1993;56(5): (SICI)1097-4598(199609)19:9G1069:: 496Y504. doi:10.1136/jnnp.56.5.496. AID-MUS193.0.CO;2-Y.

21. Evoli A, Minicuci GM, Vitaliani R, et al. 34. Ukachoke C, Ashby P, Basinski A, et al. Paraneoplastic diseases associated with Usefulness of single fiber EMG for thymoma. J Neurol 2007;254(6):756Y762. distinguishing neuromuscular from other doi:10.1007/s00415-006-0429-z causes of ocular muscle weakness. Can J Neurol Sci 1994;21(2):125Y128. 22. Nagia L, Lemos J, Abusamra K, et al. 35. Sanders DB, Massey EW, Buckley EG. Prognosis of ocular myasthenia gravis: Botulinum toxin for blepharospasm: retrospective multicenter analysis. Ophthalmology single-fiber EMG studies. Neurology 1986; 2015;122(7):1517Y1521. doi:10.1016/ 36(4):545Y547. doi:10.1212/WNL.36.4.545. j.ophtha.2015.03.010. 36. Vincent A, Newsom-Davis J. Acetylcholine 23. Grob D, Arsura EL, Brunner NG, et al. The receptor antibody as a diagnostic test for course of myasthenia gravis and therapies myasthenia gravis: results in 153 validated cases affecting outcome. Ann N Y Acad Sci and 2967 diagnostic assays. J Neurol Neurosurg 1987;505:472Y499. doi:10.1111/ Psychiatry 1985;48(12):1246Y1252. doi:10.1136/ j.1749-6632.1987.tb51317.x. jnnp.48.12.1246.

2002 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 37. Chan KH, Lachance DH, Harper CM, et al. 49. Hilton-Jones D. When the patient fails to Frequency of seronegativity in adult-acquired respond to treatment: myasthenia generalized myasthenia gravis. Muscle Nerve gravis. Pract Neurol 2007;7(6):405Y411. 2007;36(5):651Y658. doi:10.1002/mus.20854. doi:10.1136/jnnp.2007.134130. 38. Rodrı´guez Cruz PM, Al-Hajjar M, Huda S, 50. Kupersmith MJ. Does early immunotherapy et al. Clinical features and diagnostic reduce the conversion of ocular usefulness of antibodies to clustered myasthenia gravis to generalized acetylcholine receptors in the diagnosis of myasthenia gravis? J Neuroophthalmol seronegative myasthenia gravis. JAMA Neurol 2003;23(4):249Y250. 2015;72(6):642Y649. doi:10.1001/ 51. Benatar M, Mcdermott MP, Sanders DB, jamaneurol.2015.0203. et al. Efficacy of prednisone for the 39. Sanders DB, Burns TM, Cutter GR, et al. treatment of ocular myasthenia (EPITOME): a Does change in acetylcholine receptor randomized, controlled trial. Muscle Nerve antibody level correlate with clinical change 2016;53(3):363Y369. doi:10.1002/mus.24769. in myasthenia gravis? Muscle Nerve 2014;49(4):483Y486. doi:10.1002/mus.23944. 52. Papaioannou A, Morin S, Cheung AM, et al. 2010 clinical practice guidelines for the 40. Choi Decroos E, Hobson-Webb LD, Juel VC, diagnosis and management of osteoporosis in et al. Do acetylcholine receptor and striated Canada: summary. CMAJ 2010;182(17): muscle antibodies predict the presence of 1864Y1873. doi:10.1503/cmaj.100771. thymoma in patients with myasthenia gravis? Muscle Nerve 2014;49(1):30Y34. doi:10.1002/ 53. Hart IK, Sathasivam S, Sharshar T. mus.23882. Immunosuppressive agents for myasthenia gravis. Cochrane Database Syst Rev 41. Luchanok U, Kaminski H. Ocular myasthenia: diagnostic and treatment recommendations and 2007;(4):CD005224. the evidence base. Curr Opin Neurol 54. Arsura E, Brunner NG, Namba T, et al. Y 2008;21(1):8 15. doi:10.1097/WCO. High-dose intravenous methylprednisolone 0b013e3282f4098e. in myasthenia gravis. Arch Neurol 42. Evoli A, Iorio R. Characteristics of 1985;42(12):1149Y1153. doi:10.1001/ myasthenia gravis with antibodies to archneur.1985.04060110031011. muscle-specific kinase and low-density 55. Seybold ME, Drachman DB. Gradually lipoprotein-related receptor protein 4. increasing doses of prednisone in Clin Exp Neuroimmunol 2015;6(1):40Y48. doi:10.1111/cen3.12173. myasthenia gravis. Reducing the hazards of treatment. N Engl J Med 1974;290(2):81Y84. 43. Stickler DE, Massey JM, Sanders DB. doi:10.1056/NEJM197401102900204. MuSK-antibody positive myasthenia gravis: clinical and electrodiagnostic patterns. 56. Sanders DB, Siddiqi ZA. Lessons from Clin Neurophysiol 2005;116(9):2065Y2068. two trials of mycophenolate mofetil in doi:10.1016/j.clinph.2005.06.003. myasthenia gravis. Ann N Y Acad Sci 2008;1132:249Y253. doi:10.1196/ 44. Rodriguez Cruz PM, Huda S, Lo´ pez-Ruiz P, annals.1405.031. et al. Use of cell-based assays in myasthenia gravis and other antibody-mediated 57. Palace J, Newsom-Davis J, Lecky B. diseases. Exp Neurol 2015;270:66Y71. A randomized double-blind trial of doi:10.1016/j.expneurol.2015.01.011. prednisolone alone or with azathioprine in 45. Gallardo E, Martı´nez-Herna´ ndez E, myasthenia gravis. Myasthenia Gravis Study Titulaer MJ, et al. Cortactin autoantibodies Group. Neurology 1998;50(6):1778Y1783. in myasthenia gravis. Autoimmun Rev doi:10.1212/WNL.50.6.1778. Y 2014;13(10):1003 1007. doi:10.1016/ 58. Jack KL, Koopman WJ, Hulley D, et al. A j.autrev.2014.08.039. review of azathioprine-associated hepatotoxicity and myelosuppression in 46. Zhang B, Shen C, Bealmear B, et al. myasthenia gravis. J Clin Neuromusc Dis Autoantibodies to agrin in myasthenia gravis 2016;18(1):12Y20. doi:10.1097/ patients. PLoS One 2014;9(3):e91816. CND.0000000000000133. doi:10.1371/journal.pone.0091816. 59. Pedersen EG, Pottegård A, Hallas J, et al. 47. Priola AM, Priola SM. Imaging of thymus in Risk of non-melanoma skin cancer in myasthenia gravis: from thymic hyperplasia to myasthenia patients treated with thymic tumor. Clin Radiol 2014;69(5): azathioprine. Eur J Neurol 2014;21(3): Y e230 e245. doi:10.1016/j.crad.2014.01.005. 454Y458. doi:10.1111/ene.12329. 48. Batocchi AP, Evoli A, Majolini L, et al. Ocular 60. McGurgan IJ, McGuigan C. Nonmelanoma palsies in the absence of other neurological skin cancer risk awareness in or ocular symptoms: analysis of 105 cases. azathioprine-treated myasthenia gravis J Neurol 1997;244(10):639Y645. doi:10.1007/ patients. Brain Behav 2015;5(10):e00396. s004150050160 doi:10.1002/brb3.396.

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 2003

61. Chockalingam R, Downing C, Tyring SK. 73. Skeie GO, Apostolski S, Evoli A, et al. Cutaneous squamous cell carcinomas in Guidelines for treatment of autoimmune organ transplant recipients. J Clin Med neuromuscular transmission disorders. Eur J 2015;4(6):1229Y1239. doi:10.3390/ Neurol 2010;17(7):893Y902. doi:10.1111/ jcm4061229. j.1468-1331.2010.03019.x.

62. Guptill JT, Sanders DB, Evoli A. Anti-MuSK 74. Wolfe GI, Kaminski HJ, Aban IB, et al. antibody myasthenia gravis: clinical Randomized trial of thymectomy in findings and response to treatment in myasthenia gravis. N Engl J Med two large cohorts. Muscle Nerve 2011;44(1): 2016;375(6):511Y522. doi:10.1056/ 36Y40. doi:10.1002/mus.22006. NEJMoa1602489. 63. Evoli A, Bianchi MR, Riso R, et al. Response 75. Ferrero S, Pretta S, Nicoletti A, et al. to therapy in myasthenia gravis with Myasthenia gravis: management issues during anti-MuSK antibodies. Ann N Y Acad Sci pregnancy. Eur J Obstet Gynecol Reprod Biol 2008;1132:76Y83. doi:10.1196/annals.1405.012. 2005;121(2):129Y138. doi:10.1016/ j.ejogrb.2005.01.002. 64. Thomas CE, Mayer SA, Gungor Y, et al. Myasthenic crisis: clinical features, mortality, 76. Norwood F, Dhanjal M, Hill M, et al. complications, and risk factors for prolonged Myasthenia in pregnancy: best practice intubation. Neurology 1997;48(5): guidelines from a UK multispecialty 1253Y1260. doi:10.1212/WNL.48.5.1253. working group. J Neurol Neurosurg Psychiatry 2014;85(5):538Y543. doi:10.1136/ 65. Gajdos P, Chevret S, Toyka KV. Intravenous jnnp-2013-305572. immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev 2012;12: 77. Sussman J, Farrugia ME, Maddison P, et al. CD002277. doi:10.1002/14651858. Myasthenia gravis: Association of British CD002277.pub4. Neurologist’s management guidelines. Pract Neurol 2015;15(3):199Y206. doi:10.1136/ 66. Bril V, Barnett-Tapia C, Barth D, et al. IVIG practneurol-2015-001126. and PLEX in the treatment of myasthenia gravis. Ann N Y Acad Sci 2012;1275:1Y6. 78. Jonkers I, Swerup C, Pirskanen R, doi:10.1111/j.1749-6632.2012.06767.x. et al. Acute effects of intravenous injection of beta-adrenoreceptor- and 67. Dhawan PS, Goodman BP, Harper CM, calcium channel at antagonists and et al. IVIG versus PLEX in the treatment agonists in myasthenia gravis. Muscle of worsening myasthenia gravis: what Nerve 1996;19(8):959Y965. doi:10.1002/ is the evidence?: a critically appraised (SICI)1097-4598(199608)19:8G959:: Y topic. Neurologist 2015;19(5):145 148. AID-MUS493.0.CO;2-7. doi:10.1097/NRL.0000000000000026. 79. Tarr TB, Wipf P, Meriney SD. Synaptic 68. Dalakas MC. IVIg in the chronic management pathophysiology and treatment of of myasthenia gravis: is it enough for your Lambert-Eaton myasthenic syndrome. money? J Neurol Sci 2014;338(1Y2):1Y2. Mol Neurobiol 2015;52(1):456Y463. doi:10.1016/j.jns.2013.12.034. doi:10.1007/s12035-014-8887-2. 69. Iorio R, Damato V, Alboini PE, et al. 80. Wirtz PW, Nijnuis MG, Sotodeh M, et al. Efficacy and safety of rituximab for The epidemiology of myasthenia gravis, myasthenia gravis: a systematic review and meta-analysis. J Neurol 2015;262(5):1115Y1119. Lambert-eaton myasthenic syndrome and doi:10.1007/s00415-014-7532-3. their associated tumours in the northern part of the province of South Holland. J 70. Dalakas MC. Future perspectives in Neurol 2003;250(6):698Y701. doi:10.1007/ target-specific immunotherapies of s00415-003-1063-7. myasthenia gravis. Ther Adv Neurol Disord 2015;8(6):316Y327. doi:10.1177/ 81. O’Neill JH, Murray NM, Newsom-Davis J. 1756285615605700. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 1988;111(Pt 3): 71. Cosi V, Romani A, Lombardi M, et al. 577Y596. doi:10.1093/brain/111.3.577. Prognosis of myasthenia gravis: a retrospective study of 380 patients. 82. Payne M, Bradbury P, Lang B, et al. J Neurol 1997;244(9):548Y555. Prospective study into the incidence of doi:10.1007/s004150050142. Lambert Eaton myasthenic syndrome in small cell lung cancer. J Thorac Oncol 72. Gronseth GS, Barohn RJ. Practice 2010;5(1):34Y38. doi:10.1097/ parameter: thymectomy for autoimmune JTO.0b013e3181c3f4f1. myasthenia gravis (an evidence-based review): report of the quality standards 83. Gilhus NE. Lambert-Eaton myasthenic subcommittee of the American Academy syndrome; pathogenesis, diagnosis, and of Neurology. Neurology 2000;55(1):7Y15. therapy. Autoimmune Dis 2011;2011:973808. doi:10.1212/WNL.55.1.7. doi:10.4061/2011/973808.

2004 www.ContinuumJournal.com December 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 84. Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome. Expert Lambert-Eaton myasthenic syndrome: from Opin Orphan Drugs 2014;2(3):293Y300. clinical characteristics to therapeutic strategies. doi:10.1517/21678707.2014.887464. Lancet Neurol 2011;10(12):1098Y1107. doi:10.1016/S1474-4422(11)70245-9. 93. Lindquist S, Stangel M. Update on treatment options for Lambert-Eaton myasthenic 85. Titulaer MJ, Wirtz PW, Kuks JB, et al. syndrome: focus on use of amifampridine. The Lambert-Eaton myasthenic syndrome Neuropsychiatr Dis Treat 2011;7:341Y349. 1988Y2008: a clinical picture in 97 patients. doi:10.2147/NDT.S10464. J Neuroimmunol 2008;201Y202:153Y158. doi:10.1016/j.jneuroim.2008.05.025. 94. Keogh M, Sedehizadeh S, Maddison P. Treatment for Lambert-Eaton myasthenic 86. Titulaer MJ, Maddison P, Sont JK, et al. Clinical syndrome. Cochrane Database Syst Rev Dutch-English Lambert-Eaton Myasthenic 2011;(2):CD003279. doi:10.1002/ syndrome (LEMS) tumor association prediction 14651858.CD003279.pub3. score accurately predicts small-cell lung 95. Flet L, Polard E, Guillard O, et al. cancer in the LEMS. J Clin Oncol 2011;29(7): 3,4-Diaminopyridine safety in clinical 902Y908. doi:10.1200/JCO.2010.32.0440. practice: an observational, retrospective 87. Baslo MB, Deymeer F, Serdaroglu P, et al. cohort study. J Neurol 2010;257(6):937Y946. Decrement pattern in Lambert-Eaton doi:10.1007/s00415-009-5442-6. myasthenic syndrome is different from 96. Wirtz PW, Verschuuren JJ, van Dijk JG, myasthenia gravis. Neuromuscul Disord et al. Efficacy of 3,4-diaminopyridine 2006;16(7):454Y458. doi:10.1016/ and pyridostigmine in the treatment of j.nmd.2006.05.009. Lambert-Eaton myasthenic syndrome: 88. Tim RW, Sanders DB. Repetitive nerve a randomized, double-blind, stimulation studies in the Lambert-Eaton placebo-controlled, crossover study. Clin Y myasthenic syndrome. Muscle Nerve Pharmacol Ther 2009;86(1):44 48. doi:10.1038/clpt.2009.35. 1994;17(9):995Y1001. doi:10.1002/ mus.880170906. 97. Verschuuren JJ, Wirtz PW, Titulaer MJ, et al. Available treatment options for the 89. Tim RW, Massey JM, Sanders DB. management of Lambert-Eaton myasthenic Lambert-Eaton myasthenic syndrome (LEMS). syndrome. Expert Opin Pharmacother Clinical and electrodiagnostic features and 2006;7(10):1323Y1336. doi:10.1517/ response to therapy in 59 patients. 14656566.7.10.1323 Ann N Y Acad Sci 1998;841:823Y826. doi:10.1111/j.1749-6632.1998.tb11024.x. 98. Chalk CH, Murray NM, Newsom-Davis J et al. Response of the Lambert-Eaton myasthenic 90. Elrington GM, Murray NM, Spiro SG, syndrome to treatment of associated et al. Neurological paraneoplastic syndromes small-cell lung carcinoma. Neurology 1990; in patients with small cell lung cancer. 40(10):1552Y1556. doi:10.1212/WNL.40.10.1552. A prospective survey of 150 patients. J Neurol 99. Maddison P, Lang B. Paraneoplastic neurological Neurosurg Psychiatry 1991;54(9):764Y767. autoimmunity and survival in small-cell lung doi:10.1136/jnnp.54.9.764. cancer. J Neuroimmunol 2008;201Y202:159Y162. 91. Titulaer MJ, Soffietti R, Dalmau J, et al. doi:10.1016/j.jneuroim.2008.05.024. Screening for tumours in paraneoplastic 100. Wirtz PW, Lang B, Graus F, et al. P/Q-type syndromes: report of an EFNS task force. calcium channel antibodies, Lambert-Eaton Eur J Neurol 2011;18(1):19Ye3. doi:10.1111/ myasthenic syndrome and survival in small cell j.1468-1331.2010.03220.x. lung cancer. J Neuroimmunol 92. Lindquist S, Stangel M. 3,4-Diaminopyridine 2005;164(1Y2):161Y165. doi:10.1016/ (amifampridine) for the treatment of j.jneuroim.2005.04.001.

Continuum (Minneap Minn) 2016;22(6):1978–2005 www.ContinuumJournal.com 2005