Disorders of Neuromuscular Transmission

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Copyright 2012 Elsevier Inc., Ltd., BV. All rights reserved.DOI: 10.1016/B978-1-4377-0434-1.00103-1

2046

Chapter 78

Disorders of NeuromuscularTransmissionMatthew N. Meriggioli, Donald B. Sanders

Myasthenia Gravis 2046Epidemiology of Myasthenia Gravis 2046

Clinical Presentation of Myasthenia Gravis 2047

Physical Findings in Myasthenia Gravis 2047

Immunopathology of Myasthenia Gravis 2048Myasthenia Gravis Subtypes 2049

Genetics of Myasthenia Gravis 2051

Diagnostic Procedures in Myasthenia Gravis 2051

Treatment of Myasthenia Gravis 2053

Association of Myasthenia Gravis with Other Diseases 2058

Special Situations 2059

Congenital Myasthenic Syndromes 2061

Lambert-Eaton Syndrome 2062Diagnostic Procedures in Lambert-Eaton Syndrome 2062

Immunopathology of Lambert-Eaton Syndrome 2062

Treatment of Lambert-Eaton Syndrome 2063

Myasthenia Gravis/Lambert-Eaton SyndromeOverlap Syndrome 2064

Botulism 2064Clinical Features of Botulism 2064

Electromyographic Findings in Botulism 2064

Treatment of Botulism 2065

Other Causes of Abnormal NeuromuscularTransmission 2065

CH APTER OU TL INE

Normal muscle contraction and force production require theefcient transmission of an electrical impulse from a motoraxon to the muscle bers it innervates. The neuromuscular

junction (NMJ), a specialized synapse with a complex struc-tural and functional organization, is the site of electrochemi-cal conversion of nerve impulses into muscle ber actionpotentials. The NMJ is particularly vulnerable to autoimmunedisorders caused by circulating immune factors (myastheniagravis and Lambert-Eaton myasthenic syndrome), since it hasno blood-nerve barrier. Genetic abnormalities and certaintoxins may disrupt neuromuscular transmission (NMT) aswell. Disorders of NMT produce several characteristic clinicalsyndromes, described in this chapter.

Myasthenia Gravis

Acquired myasthenia gravis (MG) is the most commonprimary disorder of NMT. In MG, the binding of autoanti-bodies to proteins, most commonly the acetylcholine receptor(AChR), disrupts normal NMT. This results in symptomaticmuscle weakness that predominates in certain muscle groupsand uctuates in response to effort and rest. The basis fordiagnosis is the recognition of a distinctive pattern of weak-ness on history and examination, and conrmation by diag-nostic tests. Several potentially effective treatments are

available, and treatment of most patients is effective withminimal long-term morbidity.

Epidemiology of Myasthenia GravisMG may begin at any age from infancy to very old age. Epi-demiological studies report considerable variability in inci-dence and prevalence around the world (Meriggioli andSanders, 2009). While methodological differences may explainsome of this variability, biological and genetic factors may alsoplay a role. Recent estimates indicate that the U.S. prevalenceis approximately 20/100,000, 60,000 patients total (Phillips,2004). Epidemiological studies have shown an increasingprevalence over the past 50 years, related to an increase in the

frequency of diagnosis in elderly patients but also likely dueto improved ascertainment, reduced mortality rates, andincreased longevity of the population. Gender and age inu-ence the incidence of MG; women are affected nearly threetimes more often than men before age 40, but the incidenceis higher in males after age 50 and roughly equal duringpuberty. As the population ages, the average age at onset hasincreased correspondingly. More men than women are nowaffected, and the majority of MG patients in the United Statesare older than 50. Detailed population-based data on clinicaland serological subtypes of MG (see Myasthenia Gravis Sub-types) are largely lacking.


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Chapter 78DisordersofNeuromuscularTransmission 2047

tests may also uctuate in diseases other than MG, especiallyif effort varies or testing causes pain. The symptoms of MGdo not always vary, particularly in long-standing diseasewhich can make the diagnosis difcult.

Ocular MusclesMost MG patients have weakness of ocular muscles

(Box 78.1). (Videos of MG-related ocular phenomena [Video78.1 and 78.2] can be found at www.expertconsult.com.Asymmetrical weakness of several muscles in both eyes istypical, the medial rectus being more frequently and usuallymore severely involved. The pattern of weakness is not loca-lizable to lesions of one or more nerves, and the pupillaryresponses are normal. Ptosis is usually asymmetrical (Fig78.1) and varies during sustained activity. To compensatefor ptosis, chronic contraction of the frontalis muscle pro-duces a worried or surprised look. Unilateral frontalis con-traction is a clue that the lid elevators are weak on thaside (see Fig. 78.1). When mild, ocular weakness may nobe obvious on routine examination and appear only uponprovocative testing (i.e., sustained upward gaze). Eyelid

closure is usually weak, even when strength is normal inall other facial muscles, and may be the only residual weak-ness in otherwise complete remission. This is usually asymptomatic unless it is severe enough to allow soap or watein the eyes during bathing. With moderate weakness ofthese muscles, the eyelashes are not buried during forcedeye closure (Fig. 78.2). Fatigue in these muscles may resulin slight involuntary opening of the eyes as the patientries to keep the eyes closed; this is called the peek sign(see Fig. 78.2).

Clinical Presentation of Myasthenia GravisPatients with MG seek medical attention for specic muscleweakness or dysfunction that typically worsens with activityand improves with rest. Although they may also have general-ized fatigue or malaise, it is not usually the major or presentingcomplaint. Ptosis or diplopia is the initial symptom in approx-imately two-thirds of patients; nearly all will develop both

within 2 years (Sanders and Massey, 2008). Difculty chewing,swallowing, or talking is the initial symptom in one-sixth ofpatients, and limb weakness in 10%. Rarely, the initial weak-ness is limited to single muscle groups such as neck or ngerextensors, hip exors, or ankle dorsiexors.

Myasthenic weakness typically uctuates during the day,usually being least in the morning and worse as the day pro-gresses, especially after prolonged use of affected muscles.Ocular symptoms may be intermittent in the early stages,typically becoming worse in the evening or while reading,watching television, or driving, especially in bright sunlight.Many patients nd that dark glasses reduce diplopia and hidedrooping eyelids. Jaw muscle weakness typically becomesworse during prolonged chewing, especially tough, brous, or

chewy foods.Careful questioning often reveals evidence of earlier unrec-

ognized myasthenic manifestations, such as frequent pur-chases of new eyeglasses to correct blurred vision, avoidanceof foods that became difcult to chew or swallow, or cessationof activities that require prolonged use of specic muscles,such as singing. Friends may have noted a sleepy or sad facialappearance caused by ptosis or facial weakness.

The course of disease is variable but usually progressive.Weakness remains restricted to the ocular muscles in approxi-mately 10% to 15% of cases (see Ocular Myasthenia Gravis,later in this chapter), although a higher proportion has beenreported in Asian populations (Meriggioli and Sanders, 2009).In the rest, weakness progresses to involve nonocular muscles

during the rst 3 years and ultimately involves facial, oropha-ryngeal, and limb muscles (generalized MG). Maximumweakness occurs during the rst year in two-thirds of patients.Before the introduction of corticosteroids for treatment,approximately one-third of patients improved spontaneously,one-third became worse, and one-third died of the disease.Improvement, even remission, may occur early on but is rarelypermanent (i.e., there is a subsequent relapse). Symptomstypically uctuate over a relatively short period and thenbecome more severe (active stage). Left untreated, an inactivestage follows the active stage, in which uctuations in strengthstill occur but are attributable to fatigue, intercurrent illness,or other identiable factors. After many years, untreated weak-ness becomes xed, and the most severely involved muscles

are frequently atrophic (burnt-out stage). Factors that worsenmyasthenic symptoms are emotional upset, systemic illness(especially viral respiratory infections), hypothyroidism orhyperthyroidism, pregnancy, the menstrual cycle, drugs affect-ing NMT (see Treatment of Associated Diseases and Medica-tions to Avoid, later in this chapter), and fever.

Physical Findings in Myasthenia GravisPerform the examination so as to detect variable weakness inspecic muscle groups. Assess strength repetitively duringmaximum effort and again after rest. Performance on such

Box78.1 Ocular Findings inMyasthenia Gravis

Weakness usually involves one or more ocular muscles,

without overt pupillary abnormality Weakness is typically variable, uctuating, and fatigable Ptosis that shifts from one eye to the other is virtually

pathognomonic of myasthenia gravis With limited ocular excursion, saccades are superfast,

producing ocular quiver After downgaze, upgaze produces lid overshoot (lid twitch) Pseudo-internuclear ophthalmoplegialimited adduction,

with nystagmoid jerks in abducting eye

In asymmetrical ptosis, covering the eye that has lid ptosismay relieve contraction of the opposite frontalis

Passively lifting a ptotic lid may cause the opposite lid

to fall (enhanced ptosis) (see Video 78.2) Edrophonium may improve only some of several weak ocular

muscles; others may actually become weaker Edrophonium may relieve asymmetrical ptosis and produce

retraction of the opposite lid from frontalis contraction The opposite lid may droop further as the more involved lid

improves after edrophonium Cold applied to the eye may improve lid ptosis
http://www.expertconsult.com/http://www.expertconsult.com/


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2048 Part IIINeurologicalDiseases

Limb MusclesWeakness begins in limb or axial muscles in about 20% of MGpatients (Kuks and Oosterhuis, 2004). Any trunk or limbmuscle may be weak, but some are more often affected thanothers. Neck exors are usually weaker than neck extensors,and the deltoids, triceps, and extensors of the wrist and ngersand ankle dorsiexors are frequently weaker than other limbmuscles. Rarely, MG presents initially with focal weakness insingle muscle groups, such as a dropped head syndrome dueto severe neck extensor weakness or isolated vocal cord orrespiratory muscle weakness. In untreated patients with long-standing disease, weakness may be xed, and severely involvedmuscles may be atrophic, giving the appearance of a chronicmyopathy; this is particularly likely in muscle-specic tyrosine

kinase (MuSK) antibodypositive MG (see MuSK AntibodyMyasthenia Gravis, later in this chapter).

Immunopathology of Myasthenia GravisThe neuromuscular transmitter, acetylcholine (ACh), releasesfrom the motor nerve terminal in discrete packages (quanta)that cross the synaptic cleft and bind to receptors (AChR) onthe folded muscle end-plate membrane. Muscle contractionresults when ACh-AChR binding depolarizes the end-plateregion and then the muscle membrane. Acetylcholinesteraseattached to the postsynaptic muscle membrane hydrolyzes thereleased ACh, terminating its action and preventing prolongedmuscle depolarization.

In about 80% to 85% of MG patients, weakness results fromthe effects of circulating anti-AChR antibodies. These antibod-ies bind to AChR on the terminal expansions of the junctionalfolds (Fig. 78.3) (Engel et al., 1977a) and cause complement-mediated destruction of the folds, accelerated internalizationand degradation of AChR, and in some cases, they block ACh-AChR binding. Destruction of the junctional folds results indistortion and simplication of the postsynaptic region (seeFig. 78.4) and loss of functional AChR (Engel et al., 1977b).This leads to NMT failure and muscle weakness. MG is a para-digm for an antibody-mediated disease: the physiologicalabnormality is passively transferable by injection of MG

Oropharyngeal Muscles

Oropharyngeal muscle weakness causes changes in the voice,difculty chewing and swallowing, and inadequate mainte-nance of the upper airway. The voice may be nasal, especiallyafter prolonged talking, and liquids may escape through thenose when swallowing because of palatal muscle weakness.Weakness of laryngeal muscles causes hoarseness. A history offrequent choking or throat clearing or coughing after eatingindicates difculty in swallowing. Respiratory dysfunctionand isolated dysphagia (without dysarthria) are rarely theinitial symptoms of MG.

Myasthenic patients may have a characteristic facial appear-

ance. At rest, the corners of the mouth often droop downward,giving a depressed appearance. Attempts to smile oftenproduce contraction of the medial portion of the upper lipand a horizontal contraction of the corners of the mouthwithout the natural upward curling, which gives the appear-ance of a sneer (see Fig. 78.1).

Manually opening the jaw against resistance shows jawweakness; this is not possible when strength is normal. Thepatient may support a weak jaw (and neck) with the thumbunder the chin, the middle nger curled under the nose orlower lip, and the index nger extended up the cheek, produc-ing a studious or attentive appearance.

Fig. 78.1 Typical myasthenic facies. At rest (left), there is slight bilateral

lid ptosis, which is partially compensated by asymmetrical contraction of

the frontalis muscle, raising the right eyebrow. During attempted smile

(right), there is contraction of the medial portion of the upper lip and

horizontal contraction of the corners of the mouth without the natural

upward curling, producing a sneer.

Fig. 78.2 Peek sign in myasthenia gravis. During sustained forced

eyelid closure, patient is unable to bury his eyelashes (left), and after 30

seconds, he is unable to keep the lids fully closed (right). (Reproduced from

Sanders, D.B., Massey, J.M., 2008. Clinical features of myasthenia gravis, in: Engel,

A.G. (Ed.), Handbook of Clinical Neurology, vol 91: Neuromuscular Junction

Disorders. Elsevier, Amsterdam, pp. 229-252 [Fig. 5], by permission.)

Fig. 78.3 Localization of immunoglobulin G (IgG) at a neuromuscularjunction in acquired myasthenia gravis. The immune deposits appear on

short segments of some junctional folds and on degenerate material in

the synaptic space. (Reproduced from Engel, A.G., Lambert, E.H., Howard, F.M.,

1977a. Immune complexes (IgG and C3) at the motor endplate in myasthenia

gravis: ultrastructural and light microscopic localization and electrophysiologic

correlation. Mayo Clin Proc 52, 267-280, by permission.)

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The remaining so-called double-seronegative patients haveno known antibodies by conventional assays, even thoughthey may improve with immunosuppressive treatmentsplasma exchange, or even thymectomy.

Recently, low-afnity IgG antibodies have been found inabout two-thirds of MG patients who were seronegative usingconventional anti-AChR and anti-MuSK antibody assay(Leite et al., 2008). These antibodies bind to AChRs that have

been clustered into high-density arrays, suggesting that theyhave relatively low afnity and cannot bind strongly to AChRin solution but do bind to immobilized AChRs in a nativeconformation.

The Thymus in Myasthenia Gravis

The thymus is abnormal in most MG patients; 70% havelymphoid follicular hyperplasia, and more than 10% have athymoma. Hyperplastic thymus glands from MG patientscontain all the components necessary for the development oan immune response to the AChR: T cells, B cells, and plasmacells, as well as muscle-like myoid cells that express AChR. Itis unlikely that the cellular alterations in the thymus are sec

ondary to an ongoing peripheral immune response becausethey are absent in experimental autoimmune MG (Hohlfeldand Wekerle, 2008). In addition, thymocytes in culture spontaneously generate anti-AChR antibodies. These ndingsupport the concept of an intrathymic pathogenesis and arguethat the hyperplastic thymus is involved in the initiation ofthe anti-AChR immune response in patients with thymichyperplasia. Thymic-derived AChR subunits may serve as anantigen for the autosensitization against the AChR.

Neoplastic epithelial cells in thymomas express numerousself-like antigens, including AChR, titin, and ryanodinereceptor-like epitopes. MG-associated thymomas are also richin autoreactive T cells. The regulation of potentially autoreactive T cells may be impaired in thymoma due to a deciency

in the expression of the autoimmune regulator gene (AIREand selective loss of T regulatory cells in human thymoma(Meriggioli and Sanders, 2009).

Myasthenia Gravis SubtypesA number of MG subtypes (Table 78.1) may be identiedbased on the clinical presentation, age of onset, autoantibodyprole, and thymic pathology (Meriggioli and Sanders, 2009)Interestingly, these subtypes appear to have unique geneticassociations, strengthening the concept of distinct clinicaentities and disease mechanisms.

Ocular Myasthenia Gravis

Ptosis and/or diplopia are the initial symptoms of MG in upto 85% of patients (Grob et al., 2008), and almost all patienthave both symptoms within 2 years of disease onset. Myas-thenic weakness that remains limited to the ocular muscles istermed ocular myasthenia gravis (OMG) and accounts foapproximately 10% to 15% of all MG in Caucasian popula-tions. If weakness remains limited to the ocular muscles after2 years, there is a 90% likelihood that the disease will notgeneralize. OMG is more common in Asian populations (upto 58% of all MG patients) (Zang et al., 2007).

immunoglobulin (Ig)G into mice, and clinical improvementfollows removal of circulating antibodies by plasma exchange(see Treatment of Myasthenia Gravis, later in this chapter).

T-lymphocytes play a pivotal role in the initiation andmaintenance of the autoimmune response against the AChRcomplex. However, the precise mechanism by which thisresponse initiates and is maintained is incompletely under-stood. Activation of T cells is through the T-cell receptor bymajor histocompatibility complex (MHC) class II moleculesbound with antigenic peptide, but full activation requires thepresence of a second signal (costimulatory molecules). Poten-tially autoreactive T cells are normally controlled by a variety

of immune regulatory mechanisms, including regulatory Tcells, which are likely decient or dysfunctional in MG.

Patients with MG have increased numbers of CD4+ T cells,which regulate the production of AChR antibody (AChR-Ab).The subunit of AChR contains the majority of T-cell recog-nition sites. These recognition sites may be different fromthose of the main immunogenic region that binding antibod-ies recognize. Sensitization to CD4+ T-cells spreads across theAChR complex as the disease progresses and most MG patientshave T cells that recognize multiple epitopes on the AChR-subunit (Conti-Fine et al., 1997). This epitope spread drivesthe synthesis of anti-AChR antibodies and accounts for thelarge and varied antibody repertoire of the myasthenic patient.

Approximately 10% of MG patients (up to 50% of anti-

AChR-negative, generalized MG patients) have circulatingantibodies to MuSK, a surface membrane component essentialin the development of the neuromuscular junction. Theseanti-MuSK antibodies adversely affect the maintenance ofAChR clustering at the muscle end-plate, leading to reducednumbers of functional AChRs. The precise pathophysiologyof the weakness and prominent muscle atrophy in anti-MuSKMG is unknown. Muscle biopsy studies have shown littleAChR loss, but no detailed studies of NMT in the most affectedmuscles are available. The events leading to autosensitizationto MuSK are unknown, but the thymus gland is probably notinvolved.

Fig. 78.4 Ultrastructural localization of acetylcholine receptor (AChR) at

the muscle end-plate in a control subject (A) and in a patient with

generalized myasthenia gravis (B). The AChR staining seen in A isvirtually absent in B, in which only short segments of simplied

postsynaptic membrane react. (Reproduced from Engel, A.G., Lindstrom, J.M.,

Lambert, E.H., et al., 1977b. Ultrastructural localization of the acetylcholine

receptor in myasthenia gravis and its experimental autoimmune model. Neurology

27, 307-315 [Fig. 3A/B], by permission.)

A B


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Sanders, 2010) and have recently been reported in OMG aswell (Bau et al., 2006; Caress et al., 2005). The reported inci-dence of MuSK-antibody myasthenia gravis (MMG) variesamong geographic regions, the highest being closer to theequator and the lowest closer to the poles (Vincent and Lang,2006). Genetic or environmental factors (or both) presumablyplay a role in these differences. MMG predominantly affectsfemales and begins from childhood through middle age. In

some patients, the clinical ndings are indistinguishable fromanti-AChR-positive MG, with uctuating ocular, bulbar, andlimb weakness. However, many MMG patients have predomi-nant weakness in cranial and bulbar muscles, frequently withmarked atrophy of these muscles (Fig. 78.5). Others haveprominent neck, shoulder, and respiratory weakness, withlittle or no involvement of ocular or bulbar muscles. Elec-trodiagnostic abnormalities may not be as widespread as inother forms of MG, and it may be necessary to examinedifferent muscles to demonstrate abnormal NMT (Stickler etal., 2005). The potentially more limited distribution of physi-ological abnormalities also may limit the interpretation ofmicrophysiological and histological studies in MMG, inas-much as the muscles usually biopsied for these studies may

be normal.Many MMG patients do not improve with cholinesterase

inhibitors (ChEIs); some actually become worse, and manyhave profuse fasciculations with these medications (Hatanakaet al., 2005). Disease severity tends to be worse, but mostimprove dramatically with PLEX or corticosteroids (Sanderset al., 2003). More immunosuppression is typically necessary,though long-term outcome is generally good (Guptill andSanders, 2010). Thymic changes are absent or minimal(Lauriola et al., 2005; Leite et al., 2005), and the role of thy-mectomy in MMG is not yet clear (Guptill and Sanders, 2010;Sanders et al., 2003). The diagnosis of MMG may be elusive

Conrmation of the diagnosis of OMG may be a challenge,as RNS studies and anti-AChR antibodies are often negative,and single-ber electromyography (SFEMG) testing may berequired.

Generalized Myasthenia Gravis

Patients with generalized myasthenia gravis (GMG) may have

either early-onset (EOMG) or late-onset (LOMG) disease,with the cutoff age usually dened as age 40. EOMG patientsare more often female and typically have anti-AChR antibod-ies and enlarged hyperplastic thymus glands. LOMG patientsare more often male and may have antibodies to striatedmuscle proteins such as titin and the ryanodine receptor inaddition to anti-AChR antibodies. The presence of these anti-muscle antibodies, particularly antiryanodine receptor anti-bodies, has been associated with more severe generalized orpredominantly oropharyngeal weakness and frequent myas-thenic crises (Romi et al., 2005). LOMG patients withoutthymoma usually have a normal or atrophic thymus, but rela-tively few histological studies are available in this age group,as thymectomy after age 50 is unusual.

Thymomatous Myasthenia Gravis

About 10% to 15% of MG patients have a thymic epithelialtumor or thymoma. Thymoma-associated MG is equally fre-quent in males and females and may occur at any age, withpeak onset at age 50.

MuSK-Antibody Myasthenia Gravis

Antibodies to MuSK have been reported in up to 50% ofpatients with GMG who lack AChR antibodies (Guptill and

MyastheniaGravis Subtype Age at Onset

ThymicHistology

MuscleAutoantibodies

HLAAssociations Comments

Ocular AdultinUnitedStatesandEuropeChildhoodinAsia

Unknown AChR (50%) HLA-BW46 (inChinese)

?Low-afnityAChRantibodies

Earlyonset 40years Normal AChRTitinRyanodine

DR2B7 Antititin,ryanodineantibodiesassociatedwithseveredisease

Thymoma 40-60 years (usually) Neoplasia AChRTitinRyanodineKv1.4

Noneidentied

Maybeassociatedwithotherparaneoplasticdisorders

MuSK Majority


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FCGR2, CHRNA1) have also been found to be associatedwith MG; some are also associated with other autoimmunediseases and thus may represent a nonspecic susceptibility

to autoimmunity. An exception to this is the CHRNA1gene, which encodes the subunit of the AChR and mayprovide pathogenetic clues specic for MG (Meriggioli andSanders, 2009).

Diagnostic Proceduresin Myasthenia Gravis

Edrophonium Chloride TestEdrophonium and other ChEIs impede the enzymatic breakdown of ACh by inhibiting the action of acetylcholinesterasethus allowing ACh to diffuse more widely throughout thesynaptic cleft and to have a more prolonged interaction with

AChR on the postsynaptic muscle membrane. This facilitaterepeated interaction of ACh with the reduced number ofAChRs and results in greater end-plate depolarization. Weakness from abnormal NMT characteristically improves afteradministration of ChEIs, and this is the basis of the diagnosticedrophonium test.

The most important consideration in performance of theedrophonium test is the choice of endpoint. Only unequivocaimprovement in strength of an affected muscle is acceptableas a positive result. For this reason, resolution of eyelid ptosisimprovement in strength of a single paretic extraocularmuscle, or clear improvement of dysarthria have been pro-posed as the only truly valid endpoints because observedfunction in these muscles is largely independent of uctuating

effort (Fig. 78.6). Interpret changes in strength of othermuscles cautiously, especially in a suggestible patient.

The edrophonium test is reported to be positive in 60% to95% of patients with OMG and in 72% to 95% with GMG(Pascuzzi, 2003). Improvement after edrophonium is nounique to MG; it is also seen in congenital myasthenic syn-dromes, the Lambert-Eaton syndrome, intracranial aneurysmsbrainstem lesions, cavernous sinus tumors, end-stage renadisease, and in muscle diseases affecting the ocular muscles.

The optimal dose of edrophonium varies among patientand cannot be predetermined. In a study of OMG, the meandose of edrophonium that gave a positive response wa

when the clinical features, electrodiagnostic ndings, andresponse to ChEIs differ from typical MG.

Seronegative Myasthenia Gravis

MG patients who lack both anti-AChR and anti-MuSKantibodies (double-seronegative MG) are clinically het-erogeneous. The true frequency of seronegative MG maybe quite low, as certain patients may have low-afnity anti-

AChR antibodies that can only be detected using special-ized assays (see Immunopathology of Myasthenia Gravis,earlier).

Genetics of Myasthenia GravisThe transmission of MG is not by classic Mendelian inheri-tance, but family members of patients are approximately 1000times more likely to develop the disease than the general pop-ulation. In addition, 33% to 45% of asymptomatic rst-degreefamily members show jitter on SFEMG testing, and anti-AChR antibodies are slightly elevated in up to 50%. Theseobservations suggest that there is a genetically determined

predisposition to develop MG.Several correlations exist between MG and the human

leukocyte antigen (HLA) genes. Certain HLA types (-DR2,-DR3, -B8, -DR1) predispose to MG (see Table 78.1),whereas others may offer resistance to disease. HLA-B8,-DR2, and -DR3 types occur more commonly in patientswith EOMG; HLA-B7 and -DR2 in LOMG; and HLA-DR1in OMG (see Table 78.1). MMG is associated with HLA-DR14-DQ5 (Niks et al., 2006). Different HLA associationshave been reported in Asian MG patients, including anassociation of OMG with HLA-BW46 in Chinese patients(Meriggioli and Sanders, 2009). Non-HLA genes (PTPN22,

Fig. 78.6 Edrophonium test in myasthenia gravis. Before testing (leftthere is marked ptosis of the left lid and lateral deviation of the left eye

and the jaw must be supported. Within 5 seconds after injection of

0.1 mg edrophonium (right), function of both lids and left medial rectus

are improved. (Reproduced from Sanders, D.B., Massey, J.M., 2008. Clinica

features of myasthenia gravis, in: Engel, A.G. (Ed.), Handbook of Clinical Neurology

vol 91: Neuromuscular Junction Disorders. Elsevier, Amsterdam, pp. 229-252 [Fig

10], by permission.)

Fig. 78.5 Muscle-specic tyrosine kinase (MuSK) antibodypositivemyasthenia gravis with marked upper facial muscle weakness and atrophy.

At rest (upper left), there is slight bilateral lid ptosis. There is no visible (or

palpable) contraction of the frontalis muscle on attempted elevation of

the eyebrows (upper right), and patient does not bury the eyelashes during

forced eyelid closure (lower left). Tongue is markedly wasted (lower right).(Reproduced from Sanders, D.B., Massey, J.M., 2008. Clinical features of myasthenia

gravis, in: Engel, A.G. (Ed.), Handbook of Clinical Neurology, vol 91: Neuromuscular

Junction Disorders. Elsevier, Amsterdam, pp. 229-252 [Fig. 16], by permission.)


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site on the subunit of the AChR. In most patients, relativelyfew of the circulating antibodies recognize this site, resultingin a lower sensitivity for this assay. These blocking antibodiesoccur in less than 1% of MG patients who do not have mea-surable binding antibodies and thus have limited diagnosticvalue.

AChR antibodies cross-link the AChRs in the membraneand increase their rate of degradation. The AChR-modulating

antibody assay measures the rate of loss of labeled AChR fromcultured human myotubes. About 10% of MG patients whodo not have elevated binding antibodies have AChR-modulating antibodies. Many patients with thymomatous MGhave high levels of AChR-modulating antibodies, often exceed-ing 90% loss of AChR (Vernino and Lennon, 2004).

ANTISTRIATIONAL MUSCLE ANTIBODIES

Antistriational muscle antibodies (StrAbs), which react withcontractile elements of skeletal muscle, were the rst autoan-tibodies discovered in MG. These antibodies recognize musclecytoplasmic proteins (titin, myosin, actin, and ryanodinereceptors), and are found in 75% to 85% of patients withthymomatous MG. Titin is a very large lamentous protein

essential for muscle structure, function, and development;most of the thymoma-associated antibodies against striatedmuscle are against titin. The ryanodine receptor (RyR) is acalcium release channel in the sarcoplasmic reticulum of skel-etal muscle. Anti-RyR antibodies occur in 75% of MG patientswith thymoma but may also be present in LOMG patientswithout thymoma.

StrAbs are not pathogenic and are also found in one-thirdof patients with thymoma who do not have MG and in one-third of MG patients without thymoma. They are more fre-quent in older MG patients and in those with more severedisease, suggesting that disease severity is related to a morevigorous humoral response against multiple muscle antigens(Romi et al., 2005).

StrAbs are rarely elevated in MG in the absence of AChRantibodies and are therefore of limited use in conrming thediagnosis. The main clinical value of StrAbs is in predictingthymoma: 60% of patients with MG with onset before age 50who have elevated StrAbs have thymoma. However, titin andother striational antibodies are detectable in up to 50% ofelderly patients with non-thymomatous MG, so these anti-bodies are less helpful as predictors of thymoma in patientsolder than age 60. Elevated StrAbs are also present in autoim-mune liver disease and infrequently seen in Lambert-Eatonsyndrome and in primary lung cancer.

ANTI-MUSK ANTIBODIES

Antibodies to MuSK are present in up to 50% of GMG patients

who are seronegative for AChR antibodies and in somepatients with OMG (see MuSK-Antibody Myasthenia Gravis,earlier).

Electrodiagnostic Testingin Myasthenia GravisRepetitive nerve stimulation (RNS) is the most commonlyused electrophysiological test of NMT. At low rates of stimula-tion (2-5 Hz), RNS depletes the store of readily releasable AChat diseased motor end-plates, causing failure of NMT. Char-acteristically in MG, there is a decrementing response of at

3.3 mg for ptosis and 2.6 mg for ocular muscle dysfunction(Kupersmith et al., 2003). The lowest effective dose can bedetermined by injecting small incremental doses up to amaximum total of 10 mg. Inject an initial test dose of 2 mg,and monitor the response for 60 seconds. Subsequent injec-tions of 3 and 5 mg may then be given, but if clear improve-ment is seen within 60 seconds after any dose, the test ispositive, and no further injections are necessary (see Video

78.1). Weakness that develops or worsens after injection of10 mg or less also indicates an NMT defect, as this dosewill not weaken normal muscle.

Common side effects of edrophonium are increased saliva-tion and sweating, nausea, stomach cramps, and fascicula-tions. Serious complications (bradyarrhythmia or syncope)have been reported in only 0.16% of edrophonium tests (Inget al., 2005). These symptoms generally resolve with rest in thesupine position. Atropine (0.4-2 mg) should be available forintravenous (IV) injection if bradycardia is severe.

Some patients who do not respond to IV edrophonium mayimprove after injection of neostigmine methylsulfate, 0.5 mgintramuscularly (IM) or subcutaneously (SQ), which has alonger duration of action. Onset of action after IM injection

is 5 to 15 minutes. The longer duration of action is particularlyuseful in children.

Autoantibodies in Myasthenia GravisACETYLCHOLINE RECEPTOR ANTIBODIES

Assays measuring antibodies that react with AChR proteinsare generally regarded as specic serological markers for MG.The most widely utilized test for MG is the AChR-Ab bindingassay. This assay tests serum for binding to puried AChRfrom human skeletal muscle labeled with radioiodinated-bungarotoxin. The reported sensitivity of this assay isapproximately 85% for GMG and 50% for OMG (Stlberg etal., 2010). Nearly all thymomatous MG patients have elevated

AChR antibodies.Finding elevated AChR antibodies in a patient with com-

patible clinical features essentially conrms the diagnosis ofMG, but normal antibody measurements do not exclude thedisease. Assays for AChR antibodies may be normal atsymptom onset and become abnormal later in the disease, sorepeat testing is appropriate when values obtained within 6 to12 months of symptom onset were normal.

AChR antibody levels tend to be lower in patients withocular or mild generalized MG, but these values vary widelyamong patients with similar degrees of weakness and do notpredict the severity of disease in individual patients. Antibodylevels fall in most patients after immunosuppressive treatmentand may even become normal in some. However, the AChR

antibody level is not a consistent marker of overall responseto therapy and may actually rise in some patients as theirsymptoms improve.

False-positive AChR-Ab tests are rare but have been reportedin autoimmune liver disease, systemic lupus erythematosus(SLE), inammatory neuropathies, amyotrophic lateral scle-rosis, penicillamine-treated patients with rheumatoid arthri-tis, patients with thymoma but without MG, and in rst-degreerelatives of patients with acquired autoimmune MG.

Another assay for AChR antibodies measures inhibition ofbinding of radiolabeled -bungarotoxin to the AChR. Thistechnique measures antibody directed against the ACh binding


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this test to have high sensitivity and specicity in MG, sug-gesting that it may be useful in patients with lid ptosis, particularly if the edrophonium test is negative or contraindicated(Larner, 2004).

Comparison of Diagnostic Techniquesin Myasthenia Gravis

Plan diagnostic testing based on the clinical presentation anddistribution of weakness (Table 78.2). The edrophonium tesis often diagnostic in patients with ptosis or ophthalmoparesibut is less useful in assessing other muscles. The presence oserum AChR or anti-MuSK antibodies virtually ensures thediagnosis of MG, but their absence does not exclude it. RNSconrms impaired NMT but is frequently normal in mild orpurely ocular disease. Almost all patients with MG haveincreased jitter, and normal jitter in a weak muscle excludesMG as the cause of the weakness. Neither electrodiagnostictest is specic for MG, because increased jitter, even abnormaRNS, occurs in other motor unit disorders that impair NMT

Other Diagnostic Proceduresin Myasthenia GravisPatients diagnosed with MG should have thyroid functiontests and a chest imaging study (computed tomography [CTor magnetic resonance imaging [MRI]) to assess for a possiblethymoma. A tuberculin skin test for tuberculosis is required ithe use of immunosuppression is contemplated.

Treatment of Myasthenia GravisThe outlook for patients with MG has improved considerablyin recent years, largely due to advances in intensive care medicine and the use of immunomodulating agents. The therapeu

tic goal is to return the patient to normal function as rapidlyas possible while minimizing the side effects of therapy. Anumber of therapeutic options are available (Table 78.3), butreatment must be individualized according to the extent(ocular versus generalized) and severity (mild to severe) ofdisease, and the presence or absence of concomitant disease(including but not limited to other autoimmune diseases andthymoma). The basis of treatment decisions for individuapatients is the predicted course of disease and the predictedresponse to specic treatments. Successful treatment of MG

least 10% to trains of 2- to 3-Hz stimulation (see Chapter32B). This may be present at baseline or after a period ofexercise (postactivation exhaustion). Although a seeminglysimple test, careful attention to proper technique is importantto avoid technical errors. The sensitivity of RNS for diagnos-ing MG reportedly ranges from 53% to 100% in GMG and10% to 48% in OMG (Meriggioli and Sanders, 2004; Stlberget al., 2010). RNS is more likely to be abnormal in a proximal

or facial muscle and in clinically weak muscles. For maximaldiagnostic yield, test several muscles, particularly those thatare weak. If RNS is normal and there exists a high suspicionfor an NMJ disorder, perform SFEMG of at least one symp-tomatic muscle.

SFEMG (see Chapter 32B) is the most sensitive clinical testof NMT and shows increased jitter in some muscles in almostall patients with MG (Stlberg et al., 2010). Jitter is greatest inweak muscles but is usually abnormal even in muscles withnormal strength. Sixty percent of patients with OMG showincreased jitter in a limb muscle, but this does not predict thesubsequent development of generalized myasthenia.

In the rare patient who has weakness restricted to a few limbmuscles, only a weak muscle may show abnormal jitter. This

is particularly true in some patients with MMG (Stickler et al.,2005) (see MuSK-Antibody Myasthenia Gravis, earlier).

Increased jitter is a nonspecic sign of abnormal NMT andcan occur in other motor unit diseases. Therefore, when jitteris increased, perform other electrodiagnostic tests to excludeneuronopathy, neuropathy, and myopathy. Normal jitter in aweak muscle excludes abnormal NMT as the cause ofweakness.

Recently, measuring jitter with concentric needle electrodes(CNE) has been proposed as an alternative to the speciallydesigned (reusable) single-ber electrode (Stlberg andSanders, 2009). Interpret the results with caution, particularlyin borderline cases, as signals recorded with the CNE mayrepresent the summation of more than one single-ber action

potential, which will decrease the apparent jitter.

Ocular CoolingMyasthenic weakness typically improves with muscle cooling.This is the basis of the ice-pack test, in which cooling of aptotic lid improves lid elevation. Assess improvement in ptosisafter placing an ice pack over the ptotic eyelid, usually for 2minutes. Positive responses can occur even when edropho-nium tests are negative. A meta-analysis of six studies showed

AChR-Ab, Acetylcholine receptor antibody; MuSK, muscle-specic tyrosine kinase; RNS, repetitive nerve stimulation; Sens, sensitivity; SFEMG, single-berelectromyography.

Weakness Bedside Test Sens (%)ElectrodiagnosticTest (Muscle) Sens (%) Immunological Test Sens (%)

Ocular 1.Edrophonium2.Icepack*

60-9589

SFEMG(facial) 90 AChR-Ab 50

Oropharyngealorgeneralized

None 1.RNS(limb/cranial)2.SFEMG(limb/facial)

6099

1.AChR-Ab2.MuSK-Ab

(ifaboveneg.)

8540-50

Table78.2 Diagnostic Testing Based on Distribution of Weakness

*Only if ptosis is present.


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neostigmine is 0.3 mg/kg (Table 78.4). Pyridostigmine isavailable as syrup (60 mg/5 mL) for children or for nasogas-tric tube administration in patients with impaired swallowing.A timed-release tablet of pyridostigmine (180 mg) is useful as

a bedtime dose for patients who are too weak to swallow inthe morning. Its absorption is erratic, however, leading topossible overdosage and underdosage, and it is not usefulduring waking hours.

No xed dosage schedule suits all patients. The need forChEIs varies from day to day and during the same day. Dif-ferent muscles respond differently; with any dose, somemuscles get stronger, others do not change, and still othersmay become weaker. The drug schedule should be titrated toproduce an optimal response in muscles causing the greatestdisability. Patients with oropharyngeal weakness may requiredoses timed to provide optimal strength during meals. Aim

requires close medical supervision and long-term follow-up.Consider the return of weakness after a period of improve-ment as a herald of further progression requiring reassessmentof current treatment and evaluation for underlying systemic

disease or thymoma.

Symptom Management:Cholinesterase InhibitorsPyridostigmine bromide and neostigmine bromide are themost commonly used ChEIs. Pyridostigmine is generally pre-ferred because it has a lower frequency of gastrointestinal sideeffects and longer duration of action. The initial oral dose inadults is 30 to 60 mg every 4 to 8 hours. The equivalentdose of neostigmine is 7.5 to 15 mg. In infants and children,the initial oral dose of pyridostigmine is 1 mg/kg, and of

Table78-3 Therapeutic Agents Used in Myasthenia Gravis

Treatment Initial Dosing/Frequency Onset of Action Comments

Symptomatic Pyridostigmine 30-90mgevery4-6hours 20-30minutes CausesworseninginsomeMuSKMGpatients

Short-termimmune Plasmaexchange(PLEX)

4-6exchangesonalternatedays

1-5 days Treatment of choice inmyastheniccrisis

IVIG 1-2g/kg(over2-5days) 3-10days UseinexacerbatingMGLong-termimmune Prednisone a.0.75-1.0mg/kg/day

b.60-100mgonalternatedays(gradualescalation)

c.20-40mg/dayforOMG

3-6weeks First-lineimmunetherapy;short-termuseofhighdoses;frequentsideeffects

Azathioprine (AZA) 2-3 mg/kg/day 6-12 months First-line steroid-sparing

Mycophenolatemofetil(MMF)

2-2.5g/dayindividedtwicedailydoses

4-12months ?First-linesteroid-sparing;widelyusedinU.S.

Cyclosporine(CyA) 4-6mg/kg/dayindividedtwicedailydoses

2-3months Steroid-sparinginpatientsintolerantorunresponsivetoAZAorMMF

Tacrolimus 3-5mg/day 4-8weeks Steroid-sparinginpatientsintolerantorunresponsivetoAZA,MMF,orCyA

Cyclophosphamide a.500mg/m2b.50mg/kg4

2-4weeks Useinrefractory/severeMG

Rituximab 1000mgIV2doses(separatedby2weeks)

?? Useinrefractory/severeMG

Modied from Meriggioli, M.N., Sanders, D.B., 2009. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol 8, 475-490.

Table78.4 Equivalent Doses of Anticholinesterase Drugs

Route and Dose (mg)

Oral Intramuscular Intravenous Syrup

Neostigmine bromide (Prostigmin bromide) 15

Neostigminemethylsulfate(Prostigminmethylsulfate) 1.5 0.5

Pyridostigminebromide(Mestinonbromide) 60 2 0.7 60mg/5mL

MestinonTimespan 90-180

Ambenonium chloride (Mytelase chloride) 5

NOTE: These values are approximations only. Appropriate doses should be determined for each patient based on the clinical response.


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Specic removal of circulating anti-AChR pathogenicfactors may be accomplished using immunoadsorptioncolumns, some of which use immobilized AChR to removeautoantibodies from MG serum. Further development of thistechnique may provide a more efcient and safer alternativeto PLEX.

INTRAVENOUS IMMUNOGLOBULIN

Improvement in MG occurs in 50% to 100% of MG patientsafter infusion of high-dose intravenous immunoglobulin(IVIG), typically given at a dose of 2 g/kg given over 2 to 5days. Improvement usually begins within 1 week and lasts forseveral weeks or months. Class I evidence supports the use ofIVIG to treat patients with refractory exacerbations of MG(Donofrio et al., 2009), but there is little evidence to advisethe clinician on the proper dosing of IVIG and duration oftherapy. A recent double-blind placebo-controlled trial in MGpatients with worsening weakness showed that IVIG inducedrapid improvement in muscle strength, but this effect wasmore pronounced and likely more clinically signicant inpatients with moderate to severe MG (Zinman et al., 2007).

IVIG induces rapid improvement in patients with severe

disease or crisis, reduces perioperative morbidity prior tosurgery, and may be used chronically in selected refractorypatients. IVIG may be particularly useful as an alternative toPLEX in children with limited vascular access. Although IVIGhas demonstrated similar efcacy to PLEX in the treatment oMG exacerbations, it is unclear whether it is as effective in trueMG crisis, since the published comparison studies generallyused suboptimal PLEX regimens and did not directly compareonset of improvement. Common side effects of IVIG includeheadaches, chills, and fever, which usually improve if infusionrates are slowed. Serious side effects are rare but include renatoxicity, stroke, leukopenia, and aseptic meningitis. Lyophi-lized forms of IVIG may be associated with greater prevalenceof adverse events in patients with neuromuscular disease

(Nadeau et al., 2010).

Long-Term Immune Therapies

A number of medications are useful in MG, based on theirability to suppress the immune system nonspecically. Whileoften quite benecial, these medications require careful attention and should be tapered to the minimum effective dose toreduce long-term risk and toxicity.

CORTICOSTEROIDS

Corticosteroids were the rst immunosuppressants to bewidely used in MG and remain the most commonly usedimmune therapy today. Prednisone produces marked improve

ment or complete relief of symptoms in more than 75% ofMG patients (Pascuzzi et al., 1984) and some improvement inmost of the rest. Much of the improvement occurs in the rs6 to 8 weeks, but strength may increase to total remission inthe following months, even while tapering the dose. Patientswith recent onset of symptoms have the best responses, butthose with chronic disease also may respond. The severity odisease does not predict the ultimate improvement. Patientwith thymoma usually respond well to prednisone, before orafter removal of the tumor.

The initial prednisone dose (0.75-1 mg/kg/day) is highand continued until sustained improvement occurs, which i

for a dose that provides denite improvement in the mostimportant muscle groups within 30 to 45 minutes and whichwears off before the next dose. Acute overdosage may causecholinergic weakness of respiratory muscles and apnea.

Adverse effects of ChEIs result from ACh accumulationat muscarinic receptors on smooth muscle and autonomicglands and at nicotinic receptors of skeletal muscle. Centralnervous system side effects are rare with the doses used

to treat MG. Gastrointestinal complaints are common: quea-siness, nausea, vomiting, abdominal cramps, loose stools,and diarrhea. Increased bronchial and oral secretions maybe a serious problem in patients with swallowing or respi-ratory insufciency. These symptoms of muscarinic overdos-age may indicate that nicotinic overdose (weakness) is alsooccurring. Drugs that suppress the gastrointestinal side effectsinclude loperamide hydrochloride, propantheline bromide,glycopyrrolate, and diphenoxylate hydrochloride with atro-pine. Some of these drugs themselves produce weakness athigh dosages.

Bromism, presenting as acute psychosis, is a rare complica-tion of large amounts of pyridostigmine bromide. Measure-ment of the serum bromide level conrms the diagnosis. Some

patients are allergic to bromide and develop a rash even atmodest doses; for these patients, ambenonium chloride is analternative medication.

Preliminary studies of an antisense oligonucleotide (EN101)that blocks expression of a splice isoform of acetylcholinester-ase have been published (Sussman et al., 2008). The drugappears to be safe and the benecial effects long lastingmany hours compared to 3 to 5 hours for pyridostigmine.Further studies are ongoing.

Short-Term (Rapid-Onset) Immune TherapiesPLASMA EXCHANGE

Plasma exchange (PLEX) temporarily reduces the levels of

circulating antibodies and produces improvement in a matterof days in the vast majority of patients with acquired MG. Itis generally used for short-term treatment of severe MG,myasthenic crisis, in preparation for surgery (e.g., thymec-tomy), or to prevent corticosteroid-induced exacerbations. Atypical course of PLEX consists of 5 to 6 exchanges adminis-tered on an every-other-day schedule, during which 2 to 3 Lof plasma are removed. Decisions regarding the total numberof exchanges depend upon clinical response and tolerability,but more than 6 exchanges may be required in some patients.

The benet from a course of PLEX typically begins to wearoff after 4 weeks but may persist for as long as 3 months.Nevertheless, longer-lasting immune therapy maintainscontrol of symptoms. Most patients who respond to the rst

course of PLEX respond again to subsequent courses. Repeatedexchanges do not have a cumulative benet, and we do notuse PLEX as chronic maintenance therapy unless other treat-ments fail or are contraindicated.

Side effects during PLEX include paresthesias from citrate-induced hypocalcemia, symptomatic hypotension, transitorycardiac arrhythmias, nausea, lightheadedness, chills, and pedaledema. The major complications relate to the use of large-bore venous access. The risks of subclavian lines, arteriove-nous shunts, or grafts for venous access include thromboses,thrombophlebitis, subacute bacterial endocarditis, andpneumothorax.


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are useful to counter osteopenia, particularly in postmeno-pausal women. Treat patients with peptic ulcer disease orsymptoms of gastritis accordingly. Prednisone is contraindi-cated in patients with untreated tuberculosis.

Prednisone given with azathioprine, cyclosporine, myco-phenolate mofetil (MMF), or other immunosuppressantdrugs may produce more benet than either drug alone (seenext section, Immunosuppressant Drugs).

IMMUNOSUPPRESSANT DRUGS

Several immunosuppressant drugs are reportedly effective inMG (see Table 78.3). Azathioprine (AZA) is a purine antime-tabolite that interferes with T- and B-cell proliferation and isthe nonsteroidal immunosuppressant with the longest trackrecord in MG. It improves weakness in most patients, butbenet may not be apparent for 6 to 12 months. The initialdose is 50 mg/day, which increases by 50 mg/day every 7 daysto a total of 150 to 200 mg/day (2-3 mg/kg/day). After achiev-ing maximum benet, slowly taper the dose to the minimaleffective dose, which may be as low as 50 mg/day. Symptomrecurrence follows discontinuation or reduction below theminimal effective dose. Patients may respond better and more

rapidly when starting prednisone concurrently. An idiosyn-cratic reaction with ulike symptoms occurs within 10 to 14days after starting AZA in 15% to 20% of patients; this reac-tion requires stopping the drug. The use of divided doses aftermeals or by dose reduction minimizes gastrointestinal irrita-tion. Leukopenia and even pancytopenia can occur at any timeduring treatment but are not common. Liver toxicity is alsopossible and heralded by elevations in the serum transami-nases. To guard against this, monitor complete blood cellcounts and liver enzymes every week during the rst month,every 1 to 3 months for a year, and every 3 to 6 months there-after. Reduce the dose if the peripheral white blood cell (WBC)count falls below 3500 cells/mm3, and then gradually increaseafter the WBC count rises. Stop the drug immediately if counts

fall below 1000 WBC/mm3. Also discontinue treatment if theserum transaminase concentration exceeds twice the upperlimit of normal, and restart at lower doses after values becomenormal. There are rare reports of AZA-induced pancreatitis,but the cost-effectiveness of monitoring serum amylaseconcentrations is not established.

MMF selectively blocks purine synthesis, thereby suppress-ing both T- and B-cell proliferation. Pilot studies and retro-spective series indicate efcacy in MG (Hehir et al., 2010;Meriggioli et al., 2003). However, data from two randomizedcontrolled trials failed to show additional benet of MMF over20 mg daily prednisone as initial immunotherapy of MG (TheMuscle Study Group, 2008) and did not show a signicantsteroid-sparing effect of MMF in patients on prednisone

(Sanders et al., 2008). Several factors have been cited as pos-sible explanations for these negative results, including the gen-erally mild disease of the patients, the better-than-expectedresponse to relatively low-dose daily prednisone, and the shortduration of the studies (Sanders and Siddiqi, 2008). The clini-cal efcacy of MMF in MG remains an open question, but itcontinues to be widely used in the treatment of MG as mono-therapy or as a steroid-sparing agent, mainly because manyexperts are convinced that it is effective, and it has a favorableside-effect prole.

The typical MMF dose is 1000 mg twice daily, but doses upto 3000 mg/day have been used. In general, side effects are

usually within 2 weeks. Then taper the dose over many monthsto the smallest amount necessary to maintain improvement,which is ideally less than 20 mg every other day. The rate ofdose decrease is individualized; patients who have a rapidinitial response may reduce the dose on alternate days by20 mg each month to 60 mg every other day. If the initialresponse is less dramatic, it may be preferable to change to analternate-day dose of 100 to 120 mg and taper this by 20 mg

each month to 60 mg every other day, then taper the dose moreslowly to a target dose of 10 mg every other day as long asimprovement persists. If any weakness returns during dosereduction, the dose should be increased, another immunosup-pressant should be added, or both, to prevent further worsen-ing. Stopping the drug almost invariably leads to return ofweakness, but a very low dose (5-10 mg every other day) maybe sufcient to maintain good improvement in many patients.

Transitory worsening of weakness occurs in approximatelyone-third to half of patients treated with high-dose daily pred-nisone (Pascuzzi et al., 1984). This usually begins within therst 7 to 10 days with high prednisone doses and lasts forseveral days. In mild cases, ChEIs usually manage this worsen-ing. However, hospitalization or administration of PLEX or

IVIG during steroid initiation is advisable in patients withsignicant oropharyngeal or respiratory symptoms.

An alternative approach favored by some is to begin pred-nisone with 20 mg/day and increase the dose by 10 mg every1 to 2 weeks until improvement begins. The dose is main-tained until improvement is maximum, and then tapered asabove. Exacerbations still may occur with this protocol, butthe onset of such worsening and the therapeutic response areless predictable. A similar dose schedule is common in OMG(see Ocular Myasthenia Gravis, later in this chapter).

Prednisone is inexpensive, has a quick onset of response,and an established track record in MG, but its use is limitedby the numerous and frequent side effects (Table 78.5), theseverity and frequency of which increase when high doses are

given for more than 1 month. Most side effects improve withdose reduction and become minimal at less than 20 mg everyother day. A low fat, low-sodium diet, and exercise will mini-mize the weight gain associated with prednisone use. Supple-mental calcium and vitamin D with bisphosphonate therapy

Table78.5 Common Side Effectsof Corticosteroids

Side Effect Treatment/Prevention

Weightgain/uid

retention

Lowcalorie,low-fat,

sodium-restricteddiet;exerciseGlucoseintolerance Monitorbloodglucose/treat

Osteopenia/osteoporosis/avascularnecrosis

CalciumandvitaminDsupplementation,bisphosphonates

Hypertension Monitor/treat

Cataracts/glaucoma Atleastyearlyophthalmologicalevaluation

Steroidmyopathy Exercise/high-proteindiet

Pepticulcerdisease Protonpumpinhibitors,H2blockers


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Evoli, 2010). Prednisone was used in the great majority othese patients, and AZA was the rst-choice nonsteroidaimmunosuppressant; MMF and CYA were used as secondchoice agents. Treatment was ultimately discontinued innearly 20% of anti-AChR-Ab-positive EOMG patients, but inonly 7% of thymoma cases. The risk of complications wasrelated to drug dosage, treatment duration, and patient char-acteristics, the highest rate of serious side effects (20%) occur

ring in LOMG and the lowest (4%) in early-onset disease.Effective use of immunosuppressants in MG requires a

long-term commitment; few patients maintain improvemenunless continuing therapy at effective doses. The long-termrisk of malignancy is not established, so use the minimamaintenance dose of immunosuppressant medicationrequired to keep the MG in control.

ThymectomySuspected thymoma requires surgical resection regardless oage. In addition to removing all tumor tissue, remove anyresidual normal thymus tissue via an extended complete thymectomy. Since most patients will require long-term immunosuppression, it is reasonable to begin treatment (e.g., AZA

with steroids) before or immediately after surgery.Thymectomy is widely used as treatment for nonthymoma-

tous MG, although no prospective controlled study of efcacyexists. Based on review of existing studies, the Quality Standards Subcommittee of the American Academy of Neurologyconcluded that MG patients undergoing thymectomy aretwice as likely to attain medication-free remission, 1.6 timesas likely to become asymptomatic, and 1.7 times as likely toimprove (Gronseth and Barohn, 2000). However, the authorexpressed uncertainty as to whether the observed improve-ment was due to thymectomy or explicable by differences inbaseline characteristics. Their practice recommendations werethat for patients with nonthymomatous autoimmune MGthymectomy is recommended as an option to increase the

probability of remission or improvement. An internationaprospective single-blinded randomized trial of thymectomy innonthymomatous MG is currently ongoing, and will hopefully clarify this issue (Newsom-Davis et al., 2008).

The response to thymectomy is unpredictable, and impairment may continue for months or years after surgery, even inpatients who do ultimately improve. The best responses are in

young people, especially women, early in the disease, buimprovement can occur even after many years of symptoms.

The preferred surgical approach has traditionally been atransthoracic sternal-splitting procedure that allows wideexploration of the anterior mediastinum. Transcervical andendoscopic approaches have less postoperative morbidity andshorter recovery times but may not allow sufcient exposure

for total thymic removal and are not recommended whenthere is a thymoma. However, it has yet to be determinedwhether the extent of thymic removal determines outcome innonthymomatous MG. Robotic video-assisted thorascopicthymectomy combines the advantages of minimally invasivetechniques with added maneuverability and enhanced visualization, which reportedly permits an extended thymectomysimilar to that using a transsternal approach. Without a prospective study comparing different techniques, the value odifferent surgical approaches remains unclear.

In nonthymomatous MG, we recommend thymectomy invirtually all early-onset anti-AChR-positive MG patients, and

relatively mild and most commonly consist of diarrhea,nausea, and abdominal pain. However, PML has occurred inpatients treated with MMF, although most patients were onmultiple nonsteroidal immunosuppressant medications.

Cyclosporine (CYA) is a potent immunosuppressant thatbinds to the cytosolic protein, cyclophilin (immunophilin), ofimmunocompetent lymphocytes, especially T lymphocytes.This complex of CYA and cyclophilin inhibits calcineurin,

which activates transcription of interleukin 2 (IL-2). It alsoinhibits lymphokine production and interleukin release andleads to reduced function of effector T cells. Retrospectiveanalyses have reported improvement in most MG patientstaking CYA, with or without corticosteroids (Ciafaloni et al.,2000). Many medications interact with CYA and must beavoided or used with caution. Hypertension and cumulativerenal toxicity are common reactions of CYA, and we use thisagent in MG only when other immunosuppressants are con-traindicated or ineffective.

The initial dose of CYA is 5 to 6 mg/kg in two divided doses12 hours apart. Measure the serum trough level of CYA after 1month, and adjust the dose to produce a CYA concentration of75 to 150 ng/mL. Monitor blood pressure and serum creatinine

monthly, and adjust the dose to keep the creatinine below 150%of pretreatment values. Thereafter, measure the serum creati-nine concentration at least every 2 to 3 months, more fre-quently if a medication is started known to interact with CYA.

Improvement begins within 2 to 3 months in most patients;maximum improvement requires 6 months or longer. As withAZA, prednisone may be started simultaneously with CYA,and the dose tapered or discontinued altogether after CYA hasbecome effective. Then taper the CYA dose to the minimumeffective dose, which may be as little as 50 mg/day.

Recent reports indicate that tacrolimus (FK506) may beeffective in the treatment of MG (Evoli et al., 2002; Ponseti etal., 2005), including a randomized (though unblinded) studyin 36 de novo MG patients (Nagane et al., 2005). Use of doses

from 3 to 5 mg/day have a favorable side effect prole. Tacro-limus is in the same class of immunosuppressants as CYA,with a similar mechanism of action. It appears to be less neph-rotoxic than CYA at doses used in published MG reports, buthyperglycemia due to transcriptional inhibition of insulin isrelatively common in transplant patients receiving tacrolimus.Pending further study, it should be considered as adjunctivetherapy in refractory MG and as a steroid-sparing agent inpatients intolerant or unresponsive to AZA, MMF, and CYA.

Cyclophosphamide (CP) given IV in monthly pulsed doseshas been used in severe refractory GMG (de Feo et al., 2002;Drachman et al., 2002). In a randomized controlled trial,patients with refractory MG had improved muscle strengthand reduced steroid requirement after pulsed doses of IV CP

(500 mg/m2). There are reports of therapeutic responses inrefractory MG after a one-time, high-dose (50 mg/kg) IVcourse of CP for 4 days, followed by rescue therapy. Side effectsof CP are common and potentially serious and include myelo-suppression, hemorrhagic cystitis, and an increased risk forinfection and malignancy. For this reason, CP should bereserved for patients with truly refractory severe disease.

In a recent review of 1000 MG patients who received immu-nosuppressants for at least 1 year, all forms of MG benetedfrom immunosuppression: the rate of remission or minimalmanifestations (Jaretzki et al., 2000) ranged from 85% inOMG to 47% in thymoma-associated disease (Sanders and


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mellitus before corticosteroid treatment, 6% have thyroiddisease, 3% have an extrathymic neoplasm, and less than 2%have rheumatoid arthritis. Reports of MG cases related tohuman immunodeciency virus and after allogeneic bonemarrow transplantation suggest a more than coincidentalrelationship. Extrathymic malignancies have been reported tobe common in MG patients, especially in the older age group,possibly owing to a common background of immune dysregu-

lation (Levin et al., 2005).

Treatment of Associated Diseasesand Medications to AvoidIt is important to recognize the effect of concomitant diseasesand their treatment on myasthenic symptoms. Thyroid diseaserequires vigorous treatment; both hypo- and hyperthyroidismadversely affect myasthenic weakness. Intercurrent infectionsrequire immediate attention because they exacerbate MG andcan be life threatening in immunosuppressed patients.

Use drugs that adversely affect NMT (Box 78.2) withcaution. Many antibiotics fall into this category, particularly

as an option in anti-AChR-positive MG with onset betweenages 40 to 60. Others also recommend thymectomy for olderpatients. AChR-antibody-negative patients also may improveafter thymectomy, some to the point of remission, and we donot base the decision to perform thymectomy on the presenceor level of these antibodies alone. The role of thymectomy inMuSK antibodypositive MG has not yet been determined.

We consider repeat thymectomy when relapse follows a

good response to the initial surgery or if there is concern thatthymic tissue removal had been incomplete. MRI with appro-priate cardiac gating may be useful in identifying residualthymus tissue, although many authors believe that the clinicalsuspicion should be the basis upon which repeat surgery isconsidered (Jaretzki, 2003).

Thymectomy is generally not a recommendation for ocularMG, but these patients also may improve after thymectomy.

Evolving TreatmentsRituximab is a chimeric monoclonal antibody directed againstthe B-cell surface marker, CD20. Case reports and small caseseries suggest that MG patients, particularly those with anti-MuSK antibodies, may improve after treatment with ritux-

imab (Guptill and Sanders, 2010; Meriggioli and Sanders,2009). Controlled trials are needed in both anti-AChR andanti-MuSK-positive disease.

A single case series reports improvement in MG followingtreatment with etanercept (recombinant human tumor necro-sis factor (TNF) receptor:Fc) (Tuzun et al., 2005). Patientswith lower pretreatment plasma IL-6 and interferon (IFN)-levels responded better. The mechanism of action in MG isunknown, and its role in treatment is yet unproven.

Complement inhibition has been shown to be effective inexperimental MG (Soltys et al., 2009), and clinical trials inhuman MG are underway. Autologous stem cell transplanta-tion has been performed in refractory MG patients (Pringleand Atkins, 2005), but the role of this procedure for MG and

other autoimmune disorders is unclear at this time.

Treatment Plan for Myasthenia GravisIndividualize the treatment of MG according to the clinicalpresentation/subtype; this requires a comprehensive assess-ment of the patients functional impairment and its effect ondaily life. ChEIs may be sufcient in some patients with OMGor mild generalized disease (before or after thymectomy), butmost will ultimately require immunotherapy. The therapeuticgoal is to return the patient to normal function as rapidly aspossible while minimizing side effects of therapy. In the long-term management of patients treated with immunotherapies,the lowest effective dose should always be determined. As

noted, long-term risks of infections and malignancy, while notclearly dened, have been associated with the immunosup-pressants commonly used in MG.

Association of Myasthenia Graviswith Other DiseasesMG is often associated with other immune-mediated diseases,especially hyperthyroidism and rheumatoid arthritis. Seizuresoccur with increased frequency in children with MG. One-fth of our MG patients have another disease: 7% had diabetes

Box78.2 Medications That Adversely AffectNeuromuscular Transmission

1. Alpha-interferon, botulinum toxin, d-penicillamine, and

telithromycin (Ketek) should never be used in myasthenic

patients.

2. The following drugs produce worsening of myasthenic

weakness in most patients who receive them. Use with

caution, and monitor patient for exacerbation of myasthenic

symptoms:

Succinylcholine, d-tubocurarine, or other neuromuscular

blocking agentsQuinine, quinidine, and procainamide

Antibiotics

Aminoglycosides, particularly gentamicin, kanamycin,

neomycin, tobramycin and streptomycin

Fluoroquinolones (e.g., ciprooxacin, levooxacin,

noroxacin, ooxacin, peroxacin, moxioxacin)

Macrolides (erythromycin, azithromycin) and ketolides

(especially telithromycin)

Beta-blockers (systemic and ocular preparations):

propranolol, timolol maleate eyedrops

Calcium channel blockers

Magnesium salts (including laxatives and antacids with high

Mg2+ concentrations, and especially IV Mg2+ replacement)

LithiumIodinated contrast agents

Statin drugs (causal relationship not clear, given widespread

use of these drugs)

3. Many other drugs are reported to exacerbate the weakness

in some patients with myasthenia gravis (MG). All MG

and Lambert-Eaton syndrome patients should be observed

for increased weakness whenever any new medication is

started. An up-to-date reference document for such adverse

interactions is maintained on the web site of the Myasthenia

Gravis Foundation of America (http://www.myasthenia.org/

drugs/reference.htm).
http://www.myasthenia.org/drugs/reference.htmhttp://www.myasthenia.org/drugs/reference.htmhttp://www.myasthenia.org/drugs/reference.htmhttp://www.myasthenia.org/drugs/reference.htm


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fall below 70 mm Hg. Humidify the inspired gas to at leas80% at 37C to prevent drying of the tracheobronchial treeRemove tracheal secretions periodically using aseptic aspiration techniques. Low-pressure, high-compliance endotracheatubes may be tolerable for long periods and usually obviatethe need for tracheostomy.

Many case series report short-term benet from PLEX andIVIG in myasthenic crisis. Retrospective studies suggest tha

both are equally effective in disease stabilization (Murthy eal., 2005). Others suggest that PLEX is superior, producingmore rapid respiratory improvement (Qureshi et al., 1999)We recommend PLEX in the treatment of crisis except whenthere is hemodynamic instability, sepsis, coagulopathy, orduring the rst trimester of pregnancy.

Once ventilated, discontinuing ChEIs is safe and recommended. This eliminates the possibility of cholinergic over-dose and permits determination of disease severity. Afteraddressing the precipitating factors causing crisis, add ChEIin low doses and titrate to the optimal dose. When respiratorystrength improves, begin the weaning from the respirator for2 or 3 minutes at a time, and increase as tolerated. Considerextubation when the patient has a NIF greater than 20 cm

H2O and an expiratory pressure greater than 35 to 40 cm H2OThe tidal volume should exceed 5 mL/kg; this usually corre-sponds to a vital capacity of at least 1000 mL. If the patientcomplains of fatigue or shortness of breath, defer extubationeven if these values and blood gas measurements are normal

Prevention and aggressive treatment of medical complications offer the best opportunity to improve the outcome omyasthenic crisis.

Anesthetic Managementin Myasthenia GravisThe stress of surgery and some drugs used perioperatively mayworsen myasthenic weakness. As a rule, local or spinal anes

thesia is preferred over inhalation anesthesia. Avoid the use ofneuromuscular blocking agents or use them sparingly; inhalation anesthetic agents alone provide adequate muscle relaxation. The required dose of depolarizing blocking agents maybe greater than that needed in nonmyasthenic patientswhereas low doses of nondepolarizing agents cause pro-nounced and long-lasting blockade that may require extendedpostoperative assisted respiration.

Ocular Myasthenia Gravis

Treatment of OMG requires an accurate assessment of thepatients functional impairment and its effects on daily lifeChEIs may control symptoms adequately in some patients, bu

the benet is often partial and not long lived, whereas prednisone is often quite effective. The decision to initiate steroidtherapy will depend upon the risk/benet assessment, whichis signicantly different in patients considering treatment forpurely cosmetic reasons versus those in whom diplopia has aprofound bearing on their livelihood (pilots, surgeons, etc.)Existing evidence suggests that prednisone treatment maydelay or reduce the frequency of progression of OMG to gen-eralized disease (Kupersmith et al., 2003). Start prednisone atan initial dose of 10 to 20 mg/day, with gradual increases every3 to 5 days until achieving a clinical response. Alternativelybegin treatment at a dose of 30 to 60 mg, since the risk of

aminoglycosides, uoroquinolones, and macrolides. Ophthal-mic preparations of beta-blockers and aminoglycoside antibi-otics may cause worsening of ocular symptoms. Never used-penicillamine, because it can induce MG. When using cor-ticosteroids to treat concomitant illness, anticipate and explainthe potential adverse and benecial effects to the patient.

MG may develop in patients during IFN-2b treatment formalignancy and chronic active hepatitis C. In some, MG has

presented with myasthenic crisis. The mechanism is unknown,but the expression of IFN-at motor end-plates of transgenicmice results in weakness and abnormal NMJ function thatimprove with ChEIs. This suggests an autoimmune humoralresponse, similar to that in human MG.

The administration of botulinum toxin injections topatients with neuromuscular disease such as MG risks sys-temic side effects including dysphagia and respiratory com-promise. Administer only with great caution.

We recommend annual vaccination against inuenza(including H1N1) for most patients with MG. Vaccinationagainst pneumococcus is a recommendation for at-risk patientsbefore starting prednisone or other immunosuppressive drugs.Never give live attenuated vaccines to immunosuppressed

patients. The Centers for Disease Control and Preventionreport that those taking less than 2 mg/kg/day of prednisone orevery-other-day prednisone are not at risk. Patients with priorthymectomy should not receive the yellow fever vaccine.

Special Situations

Myasthenic CrisisMyasthenic crisis is respiratory failure from myasthenic weak-ness. An identiable precipitating event such as infection,aspiration, surgery, or medication change precedes most epi-sodes of crisis. Cholinergic crisis is respiratory failure fromoverdose of ChEIs and was more common before the intro-

duction of immunosuppressive therapy, when using very largedosages of ChEIs.

In MG patients with progressive respiratory symptoms, nosingle factor determines the need for ventilatory support. Thesafest approach is to admit the patient to an intensive care unitand observe closely for impending respiratory insufciency.Serial measurements of negative inspiratory force (NIF)provide the best measure of deteriorating respiratory functionin MG. Respiratory assistance is needed when the NIF is lessthan 20 cm H2O, when tidal volume is less than 4 to 5 mL/kg body weight and maximum breathing capacity is less thanthree times the tidal volume, or when the forced vital capacityis less than 15 mL/kg body weight. Use a mask and breathingbag acutely. Noninvasive mechanical ventilation using bilevel

positive-pressure ventilation (BiPAP) may avoid the need forintubation in patients in crisis without hypercapnia (Rabin-stein and Wijdicks, 2002). In patients with Pco2 greater than50 mm Hg, tracheal intubation should be done with a low-pressure, high-compliance cuffed endotracheal tube. Avolume-controlled respirator set to provide tidal volumes of400 to 500 mL and automatic sighing every 10 to 15 minutesis preferred. Check the pressure of the tube cuff frequently,and verify the tube position daily by chest radiographs. Useassisted respiration whenever possible so that the patientsown respiratory efforts trigger the respirator. Use an oxygen-enriched atmosphere only when arterial blood oxygen values


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worsening is more common in rst pregnancies, whereasthird-trimester worsening and postpartum exacerbations aremore common in subsequent pregnancies. Complete remis-sion may occur late in pregnancy. The clinical status at onsetof pregnancy does not reliably predict the course during preg-nancy. Pregnancy is more difcult to manage at the beginningof MG, and women with MG should delay pregnancy untilafter the disease is stable.

Therapeutic abortion is rarely if ever needed because ofMG, and the frequency of spontaneous abortion isnot increased. Oral ChEIs are the rst-line treatmentduring pregnancy. Intravenous ChEIs may produce uterinecontractions and are contraindicated. Prednisone is theimmunosuppressive agent of choice. We do not use immu-nosuppressive drugs during pregnancy because of theoreti-cal potential mutagenic effects, although others feel thatAZA and even CYA can be used safely during pregnancy(Ferrero et al., 2005). Increased risk of fetal malformationhas been reported when men used AZA prior to concep-tion (Norgard et al., 2004). MMF can cause birth defectsand is contraindicated during pregnancy. PLEX or IVIGare useful when requiring an immediate (albeit temporary)

improvement during pregnancy, but avoid PLEX during therst trimester.

Magnesium sulfate has neuromuscular blocking effectsand is not recommended to manage preeclampsia. Barbi-turates usually provide adequate treatment. Labor and deliv-ery are usually normal. Cesarean section is useful only forobstetrical indications. Regional anesthesia is preferred fordelivery or cesarean section. MG does not affect uterinesmooth muscle and therefore does not compromise the rststage of labor. In the second stage, voluntary muscles areat risk for easy fatigue, and outlet forceps or vacuum extrac-tion may be necessary. In our experience, breastfeeding isnot a problem for myasthenic mothers, despite the theoreti-cal risk of passing maternal AChR antibodies in breast milk

to the newborn.

Transient Neonatal Myasthenia Gravis

A temporary form of MG affects 10% to 20% of newbornswhose mothers have immune-mediated MG. The severityof symptoms in the newborn does not correlate with theseverity of symptoms in the mother. The maternal antibodylevel correlates with the frequency and severity of transientneonatal myasthenia gravis (TNMG), and TNMG occursonly rarely in infants of seronegative mothers. Weaknessmay manifest in utero, particularly when maternal antibod-ies are directed against the fetal AChR, and may lead toarthrogryposis multiplex congenita (Barnes et al., 1995).

Consider decreased fetal movement as a possible indicationfor PLEX or IVIG. Birth of a child with arthrogryposisshould also prompt a search for MG in the mother. Anaffected mother who delivers an infant with TNMG is likelyto have similarly affected subsequent infants. Consider pro-phylactic treatment with PLEX and/or steroids in a womanwith a previously affected child, as the risk of recurrentTNMG is high.

Affected newborns are typically hypotonic and feed poorlyduring the rst 3 days. In some newborns, symptoms maydelay for 1 or 2 days. Symptoms usually last less than 2 weeksbut may continue for as long as 12 weeks, which correlates

steroid-associated exacerbation is less in OMG. In OMG, usea maintenance dosage of corticosteroids that does not signi-cantly suppress the immune system and causes few majorsystemic adverse effects. Consider a steroid-sparing agent ifthis is not the case. In general, OMG is not an indication forthymectomy, but this may be effective in some patients.

Childhood Myasthenia GravisThe onset of immune-mediated MG before age 18 is referredto asjuvenile myasthenia gravis (JMG) (Andrews and Sanders,2002). Some 20% of JMG and almost 50% of those with onsetbefore puberty are seronegative; the distinction from a con-genital myasthenic syndrome is most challenging in the lattergroup (see Congenital Myasthenic Syndromes, later in thischapter). Electrodiagnostic studies identify a defect in NMTbut have distinguishing features in only a few forms of con-genital MG. A benecial response to PLEX exchange or IVIGmay help to establish the diagnosis of autoimmune MG. Manychildren who are initially seronegative later develop AChRantibodies. Thymomas are rare in this age group.

Treatment decisions in children with autoimmune MG are

more difcult because the rate of spontaneous remission ishigh. We recommend ChEIs alone in prepubertal children notdisabled by weakness. For patients who remain symptomaticdespite optimal dosing of ChEIs, prednisone is efcacious andcost-effective, although the chronic side effects potentially havea long-term impact in children (growth stunting, weight gain,mood alteration, hyperglycemia, hypertension, etc.). A sug-gested starting dose is 0.5 mg/kg/day, with a maximum startingdose in older children of 30 mg/day. Use steroid-sparing immu-nosuppressive drugs in more severe or refractory cases, as inadult MG. PLEX and IVIG are effective short-term therapies inJMG. Thymectomy has reported favorable results in JMG, evenin patients younger than 5 years of age, although the high ratesof spontaneous remission in JMG make the assessment of

benet difcult. No reported adverse effects on the immunesystem by removing the thymus at this early age exist.

D-Penicillamine-Induced Myasthenia Gravis

d-Penicillamine is used in the treatment of rheumatoid arthri-tis, Wilson disease, and cystinuria. Rarely, patients treated withd-penicillamine for several months develop a myasthenic syn-drome that resolves after stopping the drug. d-Penicillamine-induced myasthenia is usually mild and often restricted to theocular muscles. Often the diagnosis is unsuspected becausesevere arthritis may hide the weakness. Establishing the diag-nosis is from the response to ChEIs, characteristic EMGabnormalities, and elevated AChR antibodies. It is likely thatd-penicillamine stimulates or enhances an immunologicalreaction against the neuromuscular junction. ChEIs usuallyrelieve the symptoms. The myasthenic response induced byd-penicillamine usually remits within a year after stopping thedrug. If myasthenic symptoms persist thereafter, treat thepatient as for acquired MG.

Pregnancy

Myasthenia may improve, worsen, or remain unchangedduring pregnancy. It is common for the rst symptoms of MGto begin during pregnancy or postpartum. First-trimester


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Mutations Resulting in AChR Deciency

This is a genetically heterogeneous group with patients havingvarious AChR subunit or rapsyn mutations. The age osymptom onset ranges from infancy to adulthood. Clinicamanifestations include hypotonia, respiratory insufciencyweakness of ocular and bulbar muscles, and skeletal deformities. The ndings on electrodiagnostic studies are variable

and depend on the severity and distribution of weaknessRNS studies usually demonstrate a decrement, but the decre-ment may be absent or restricted to facial muscles in mildcases. Jitter is increased in all reported cases (Stlberg et al.2010).

These disorders respond variably to symptomatic therapywith pyridostigmine or 3,4-DAP. Ephedrine produces benein some cases. Immunotherapy has no effect.

Choline Acetyl Transferase Deciency

This condition, previously called congenital myasthenic syndrome with episodic apnea or familial infantile myasthenia, iscaused by mutations in the CHAT gene, which codes for end

plate choline acetyltransferase (ChAT), the rate-limitingenzyme in the resynthesis of acetylcholine within the nerveterminal. Generalized hypotonia, ptosis, and feeding difculties are present at birth, and the early course of the disease ispunctuated by sudden episodes of severe bulbar and generalized weakness with life-threatening apnea triggered by infections or stress. Arthrogryposis may be present. Within weeksafter birth, the child becomes stronger and ultimately breatheunassisted. However, episodes of life-threatening apnea occurepeatedly throughout infancy and childhood, even into adullife, and there may be a history of sudden infant death syndrome in siblings.

A decremental response to RNS is usually present in weakmuscles. The decrement may repair with brief exercise bu

becomes more marked with prolonged exercise or continuourepetitive stimulation at 3 Hz for 3 to 5 minutes. Jitter alsobecomes progressively worse during continuous nerve stimulation (Stlberg et al., 2010). ChEIs improve strength in moschildren with ChAT deciency. Symptoms tend to lessen inadolescence and adulthood, when the disease resembles mildautoimmune myasthenia gravis or a congenital myopathy. Wehave seen sustained symptomatic improvement in childrenfrom several families with this syndrome when 3,4-DAP igiven with pyridostigmine.

Slow-Channel CongenitalMyasthenic Syndrome

Variable expression results in a wide spectrum of clinical manifestations and severity in slow-channel congenital myasthenisyndrome (SCCMS), which is the only form of CMS withautosomal dominant inheritance. Severe cases present ininfancy or early childhood, but mild cases may present inadulthood, as late as the seventh decade. Characteristically, theweakness in SCCMS involves muscles of the neck and distaregions of the upper limbs, and the intrinsic hand muscles anddigit extensors are particularly weak and atrophic. Ptosis, ophthalmoparesis, dysarthria, dysphagia, proximal limb weaknessand respiratory insufciency also occur in some cases. Worsening of weakness occurs with ChEI administration. RNS

with the half-life of neonatal antibodies. It is not clear whysome newborns develop weakness and others with equallyhigh antibody concentrations do not. Some mothers withantibodies directed specically against fetal AChR mightthemselves be asymptomatic, which makes diagnosis ofTNMG more difcult.

Examine all infants born of myasthenic mothers carefull

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Disorders of Neuromuscular Transmission