Lambert–Eaton myasthenic syndrome Introduction Lambert–Eaton syndrome LES is a rare disease thatcauses fatigable muscle weakness and mild autonomicdysfunction.. In about 40 – 50% of pati
Trang 1Autoimmune myasthenic syndromes 159
Immunotherapy
Immunotherapy is necessary for most patients with
MG and is generally more effective than symptomatictherapy Immunotherapy targets the autoimmunepathophysiology: either by reducing pathogenicantibody production or by reducing damage to theend plate caused by pathogenic antibodies Immun-otherapies in MG can be divided into two groupsbased on their onset and duration of response: thosethat provide rapid improvement but have short-livedbenefits; and those that have relatively slower onsetbut provide long-term benefits The therapeuticresponses of the various therapies dictate theirstrategic use in the treatment of patients with MG
Long-term immunotherapy
Thymectomy
Thymectomy has two roles in the management
of MG Thymectomy is indicated for all patients with thymoma in order to prevent local spread and invasion of the tumor Thymectomy also is anaccepted therapy for nonthymomatous MG Therationale is based on the presumed role of the thymusgland in the initiation and/or maintenance of theimmune dysfunction in MG Numerous studies givesupport for beneficial effects of thymectomy on theclinical course of MG An evidenced-based review
of 21 studies conducted between 1953 and 1998found that thymectomy led to clinical improve-ments and two times the likelihood of achieving
a medication-free clinical remission (Gronseth andBarohn, 2000) The onset of benefit tends to occur
6 to 12 months following surgery, and the maximalbenefit may require 2 to 5 years (Masaoka et al., 1996)
Unfortunately, all studies have suffered from ant confounding factors: none were randomized, manywere not controlled Thus, significant limitations andcontroversies exist regarding their interpretations
signific-Currently, most practitioners consider thymectomymore effective if performed within the first years
of symptom onset for patients who are younger (usually less than 60 years old), and if more invasiveand “complete” operative procedures are performed(Durelli et al., 1991; Maggi et al., 1989) Seronegat-ive patients may benefit from thymectomy but smallretrospective series suggest that anti-MuSK positivepatients may not benefit from thymectomy (Sanders
et al., 2003) The therapeutic response to thymectomy
may not be as favorable for patients with thymomacompared to patients with thymic hyperplasia, butthe myasthenic symptoms of thymoma-related MGare similarly responsive to medical therapy
to AChE inhibitors and are significantly disabling or indanger (i.e., have respiratory or bulbar weakness) so
as to warrant the high risk of side effects that occurwith chronic steroid use Prednisone can be initiated
at 60 to 100 mg per day with the expectation of aninitial response within two to four weeks and a maximal response in about six months With thisregimen, transient steroid-induced weakness canoccur in about one-third of patients Lower dose,slowly escalating regimens reduce this risk but takelonger to induce a response After adequate improve-ment is achieved, the dose should be minimized veryslowly and cautiously Aggressive measures should
be taken to prevent and monitor for the side effectscommon to chronic steroid use
Several immunosuppressant drugs are commonlyused in the management of MG These therapies typically take a few months to achieve a response,and many more months to reach maximum benefit.They are usually employed in combination with cor-ticosteroids as steroid-sparing agents or to produce agreater response than corticosteroids alone Patientswho are mildly disabled and stable enough to waitseveral months for treatment effect may be able
to use immunosuppressant monotherapy Patientswho tolerate corticosteroids poorly, such as diabetics
or patients with gastric ulcer disease, also may fit from this option While side effects can occasion-ally be significant, they are usually better toleratedthan long-term corticosteroid therapy
bene-Azathiopurine is a general immune suppressantthat is beneficial for MG (Kuks et al., 1991) Thispurine analog inhibits DNA synthesis and thusreduces T- and B-cell proliferation Its onset of actiontakes a few months, with maximal benefit sometimesrequiring up to one to two years Mycophenolate
Trang 2mofetil is becoming increasingly popular due to itsefficacy and favorable side-effect profile (Meriggioli
et al., 2003) Its predominant action is blockingpurine synthesis selectively in activated T and B lymphocytes by blocking the de novo pathway ofpurine synthesis upon which only lymphocytes rely
Patients sometimes show improvement within twomonths (Ciafaloni et al., 2000) but typically requiremany more months to achieve maximum benefits
Cyclosporine A is an immunosupressant that blocksinterleukin-2 activation of T-helper cells by inhibit-ing calcineurin While a controlled, double-blindclinical trial has shown its effectiveness in MG(Tindell et al., 1993), significant side effects and druginteractions usually render it less preferable thanazathioprine and mycophenolate mofetil for mostpatients Onset of action is often four to eight weeks,with benefits increasing over many months Otherimmunosuppressive agents sometimes consideredfor severe treatment-resistant MG patients includecyclophosphamide (Gustavo De Feo et al., 2002),tacrolimus (Evoli et al., 2002), and rituximab (Zara
et al., 2000)
Short-term immunotherapy
The two short-term immunotherapies used in thetreatment of MG are plasmapheresis (therapeuticplasma exchange) and intravenous immunoglo-bulin ( IVIg) These treatments have a rapid onset ofaction, usually within one week, and short durations
of benefit, usually between one and two months
They are used in four clinical settings:
1 in myasthenic crisis or severe exacerbations toproduce rapid improvement;
2 prior to surgery (including thymectomy) in order
to maximize strength and reduce postoperativemorbidity;
3 as bridging therapy for treatment-resistant MG
or steroid-intolerant patients, administered everymonth or so until slow-onset long-term therapytakes effect
4 when initiating corticosteroid therapy to minimizethe risk of transient steroid-induced weakness
The efficacy of plasmapheresis has been strated in several uncontrolled studies (Pinching et al.,
demon-1976, 1977) Plasma exchanges typically removeone to two plasma volumes roughly every other dayfor a total of five to six treatments The mechanism
of action of plasmapheresis is the bulk removal of
pathogenic antibodies and immune complexes Smallseries of patients with anti-MuSK antibodies reportgood response to plasmapheresis (Evoli et al., 2003).With IVIg, polyclonal human Ig is administered at
2 g/kg over two to five days Efficacy has beendemonstrated in several nonplacebo-controlled studies(Arsura, 1989; Cosi et al., 1991) While IVIg is known
to have numerous effects on the immune system,those responsible for the therapeutic response in
MG have not been established A randomized studycomparing IVIg to plasmapheresis showed equalefficacy, but IVIg had fewer and less severe sideeffects (Gajdos et al., 1997)
Lambert–Eaton myasthenic syndrome
Introduction
Lambert–Eaton syndrome (LES) is a rare disease thatcauses fatigable muscle weakness and mild autonomicdysfunction It is caused by an immune-mediatedattack against the voltage-gated calcium channels(VGCC) on the presynaptic motor nerve terminal
In about 40 – 50% of patients, LES occurs as a neoplastic syndrome (P-LES), usually associated withsmall-cell lung cancer (SCLC) Although paraneo-plastic syndromes are rare in neurology, LES is the most common and one of the best characterized.Nonparaneoplastic LES (NP-LES) accounts for app-roximately 50 – 60% of LES cases and occurs as anidiopathic autoimmune disease of unknown etiology
para-History
In 1953, Anderson and colleagues described a patientwith oat cell lung cancer who had myasthenic symp-toms (Anderson et al., 1953) From 1956 to 1961,Lambert and his colleagues described a series ofpatients who suffered from fatigable muscle weak-ness that differed from myasthenia gravis Thesepatients had a different distribution of weakness,areflexia, and autonomic dysfunction Their neuro-physiological profile was also distinctive with facil-itation of both muscle strength after exercise and the amplitude of compound muscle action potential(CMAP) after high-frequency repetitive electricalstimulation (Eaton and Lambert, 1957; Lambert et al.,
1956, 1961) In most of these patients (10 out of 17),their myasthenic syndrome was associated withmalignancies, especially small-cell lung cancer.Elmqvist and Lambert were the first to identify thatthe pathophysiology of LES involved dysfunction
Trang 3Autoimmune myasthenic syndromes 161
of the presynaptic motor nerve terminal with tion of quantal release of acetylcholine (Elmqvist and Lambert, 1968; Lambert and Elmqvist, 1971)
reduc-In 1972, Gutmann noted an association of mune disorders in patients with LES without malig-nancies, and theorized an autoimmune etiology forLES (Gutman et al., 1972) The autoimmune basisfor LES was supported by the development of clinicaland physiological features of LES in mice receivingIgG from patients with LES (Fukunaga et al., 1983;
autoim-Kim, 1986; Lambert and Lennon, 1988; Lang et al.,1981), the discovery that serum IgG from patientswith LES interacts with VGCC in cell cultures ofhuman small-cell carcinoma (Roberts et al., 1985),and, in 1989, the development of a diagnostic radio-immunoassay that binds the pathogenic VGCC-directed autoantibodies in LES (Lennon and Lambert,1989) Based on its known pathophysiology, severaltreatments have been developed that positively impactthe lives of patients with LES These treatments includethose that enhance the release of acetylcholine fromthe presynaptic motor nerve terminal, plasmaphere-sis, IVIg, and immunosuppressive medications, aswell as surgical removal of associated malignancies
Clinical features
The characteristic clinical presentation of patientswith LES consists of subacute progressive proximallimb muscle weakness and fatigability, diminished
or reduced muscle stretch reflexes, and autonomicdysfunction The diagnosis is often delayed for months
or even years because the symptoms often begininsidiously and findings on physical examinationmay go undetected early in the course of the disease
The typical distribution of weakness involves the hipflexors and other hip girdle muscles, the proximalmuscles of the upper extremity, neck muscles, andthe interossei muscles The hip girdle muscles usu-ally are affected more prominently than those of the upper extremities, and account for the majority
of disability In one series of 50 patients, weaknessbegan in the lower limbs in 65% (O’Neill et al., 1988);
12% began with generalized weakness, but with hipgirdle muscles involved more than other muscles ofthe body Patients often complain of difficulty arisingfrom a sitting position and climbing stairs, and some-times even fall Patients commonly report that theweakness transiently worsens on repeated muscleexertion and improves with rest Occasionally, patientsexperience transient improvement of strength follow-ing brief exertion, followed by increasing weakness
with continued exertion; eliciting this history, though,
is not common Muscle atrophy is rare ment of depressed reflexes after brief exercise orrepeated elicitation of the reflex is strongly sug-gestive of the diagnosis and is more readily demon-strated at the bedside than facilitation of musclestrength Patients may experience aching pain intheir hips and posterior thigh Approximately 25%have cranial nerve involvement Ptosis, facial weak-ness, dysphagia, dysarthria, and difficulty chewingcan occur but are usually milder and tend to occurlater in the disease course than in MG Respiratoryinvolvement is less common and usually signific-antly milder than in MG Respiratory failure is rare.Approximately 80% of patient with LES have sym-ptoms of autonomic dysfunction In 6%, autonomicdysfunction is the presenting symptom (O’Neill et al.,1988) The most common autonomic symptoms are erectile dysfunction in men and xerostoma (drymouth) in both sexes Other features include slowpupillary reaction to light, gastrointestinal dysmotil-ity, orthostatic hypotension, and urinary retention.Autonomic testing may reveal abnormalities in sweat-ing, cardiovagal reflexes, and salivation
Enhance-As mentioned earlier, early medical descriptionnoted a clear association of malignancy in approxim-ately 40 – 50% of patients diagnosed with LES Themajority of the patients had small-cell lung cancer(SCLC) While several other types of cancer have beenreported in patients with LES, only lymphoma hasshown a possible paraneoplastic association withLES The symptoms of LES can precede the diagnosis
of malignancy by several years, but not usually morethan five years Symptoms of lung cancer itself areuncommon at the time of diagnosis of LES The sen-sory system is always spared in LES If sensory deficitsare present, their origin may lie in the presence of anadditional paraneoplastic disease such as sensoryneuronopathy, peripheral neuropathy, or myelopathy.Other paraneoplastic syndromes associated with LES include subacute cerebellar ataxia and encephalo-myelitis Organ-specific autoimmune diseases such aspernicious anemia and autoimmune thyroid diseaseare common in patients with NP-LES
Natural history
The course of LES tends to be slowly progressive
in the first year Fluctuations of symptoms are less pronounced and spontaneous remissions are lesscommon than with MG The course of NP-LES canvary considerably Approximately half of NP-LES
Trang 4patients achieve sustained remissions, usually withchronic immunotherapy but sometimes spontan-eously (Maddison et al., 2001) The other half suffersvarious degrees of long-term disability Immuno-therapy is effective in reducing disability, however,less so than with MG In patients with P-LES, thecourse may be more heterogeneous compared to thosewith NP-LES The symptoms of P-LES often improvefollowing effective treatment of the underlying cancer,with 70% of patients achieving clinical remission(Chalk et al., 1990; Maddison et al., 2001) Theoverall prognosis for these patients is related to that
of the underlying cancer, which for SCLC is usuallyfatal One report notes SCLC in patients with LEStends to be less aggressive and has a greater response
to therapy than patients without LES (Maddison et al.,1999) When coexisting paraneoplastic syndromes
of peripheral neuropathy and subacute cerebellarataxia occur, their symptoms tend to be more pro-minent and disabling than LES
Epidemiology
Figures for the incidence and prevalence of LES areunknown due to its rarity Idiopathic LES occurs moreoften in females and can occur at any age (Maddison
et al., 2001) There is a frequent association with specific autoimmune disorders in these patients andfamily members Certain HLA-gene products arefound in higher prevalence than in patients with P-LES (Parsons et al., 2000; Willcox et al., 1985)
organ-P-LES occurs more often in men and in older populations at higher risk of cancer Cancer is found
in 45% of patients with LES, with SCLC accountingfor 90% (O’Neill et al., 1988) Other cancers reportedinclude lymphoproliferative disorders, thymoma,renal cell cancer, and tumors of the reproductivetract (Argov et al., 1995; Burns et al., 1999; Collins,1999; Gutmann et al., 1992; O’Neill et al., 1988;
Oyaizu, 2001) Occasionally patients with thesecancers harbor occult SCLC as well Primary small-cell carcinoma of extrapulmonary locations canoccur in patients with LES, especially when no riskfactors for lung cancer are present In patients withSCLC, LES occurs in approximately 6% (Croft andWilkinson, 1965; De La Monte et al., 1984; Hawley
et al., 1980) Eighteen percent of patients with SCLC are seropositive for antibodies to the P/Q-typecalcium channel without clinical evidence of LES
Pathophysiology
The Lambert–Eaton myasthenic syndrome is an
immune-mediated disease caused by antibodiesdirected at the α1Asubunit of the VGCC located onthe presynaptic nerve terminal As described in thepathophysiology section on myasthenia gravis, anerve impulse induces presynaptic calcium influxvia VGCCs, which triggers the release of acetyl-choline into the synaptic cleft Electrophysiologicalstudies of LES patients show a presynaptic abnormal-ity in neuromuscular transmission (Lambert et al.,1961) The miniature end-plate potentials (MEPP)have normal amplitude and frequency in LES There
is a reduced number of ACh vesicles released, leading
to a reduction of end-plate potential (EPP) amplitude.This produces a decrease in the safety margin of neuromuscular transmission High-frequency repet-itive nerve stimulation or bathing a muscle sample inhigh-calcium solutions increases the EPP amplitude.These features support the concept that VGCC anti-bodies in LEMS patients reduce calcium flux throughVGCCs on the presynaptic membrane
While the specific disruptive mechanism or anisms of these antibodies requires further study,significant evidence implicates VGCC antibodies thatbind and cross-link adjacent VGCCs This causes anacceleration in the rate of VGCC degradation, known
mech-as antigenic modulation (Fukuoka, 1987; Prior,1985) This reduces the number of available VGCCs.This process is IgG-mediated, and does not involvecomplement
Significant ultrastructural abnormalities occur inthe presynaptic membrane in patients with LES thatfurther reduce the safety margin of neuromusculartransmission Several types of VGCC exist which aredistinguished by differences in their biomolecularand pharmacological properties The P/Q-type VGCCare normally arranged in parallel arrays in the activezones of the presynaptic motor nerve terminal andsome preganglionic autonomic synapses Most patientswith LES have antibodies directed at the P/Q-typeVGCC In patients with LES, there is a reduction
in the density of active zones in the motor nerve terminals and the normally formed parallel arrays
of P/Q-type VGCCs become disordered (Fukunaga
et al., 1982) These anatomical changes reduce thenumber of functional calcium channels leading to adecrease in the release of acetylcholine
The autonomic symptoms involved in LES may
be mediated by a similar immunological process(Waterman, 2001) The neurons of the autonomicnervous system contain a different array of VGCCs.The subtype of VGCCs varies among specific tissuesand the neurotransmitters utilized The predominant
Trang 5Autoimmune myasthenic syndromes 163
subtype found in the autonomic nervous system isthe N-type VGCC, but P/Q-type and R-type VGCCsare present to lesser degrees Autoantibodies frompatients with LES may impair neurotransmitter releasethrough downregulation of one or more subtypes ofVGCCs at the presynaptic sympathetic and parasym-pathetic autonomic nerve terminal This inhibition
of autonomic nervous system transmission likely is thebasis for their autonomic symptoms Interestingly,most patients with autonomic symptoms in LES donot possess antibodies to the N-type VGCC, whereasthe majority possess antibodies to the P/Q-type recep-tor The degree of autonomic dysfunction does notseem to correlate with the presence of the P/Q-type
or the N-type VGCC
In P-LEMS, evidence supports the hypothesis thatantigens expressed on the underlying neoplasm mayprovoke and maintain the autoimmune response towards the VGCCs First, P/Q-type VGCCs are ex-pressed in SCLC cells (McCann et al., 1981; Roberts
et al., 1985) Immunoglobulins obtained from LEMSpatients with SCLC bind to P/Q-type VGCCs and pro-duce downregulation of these channels in SCLCcells Patients with LEMS often experience improve-ments in muscle strength with effective treatment ofthe underlying cancer This evidence suggests thatVGCCs on the SCLC cells trigger an autoimmune process in which pathogenic antibodies cross-reactwith VGCCs on the SCLC cells and the presynapticnerve terminals
In NP-LES, the etiology of the autoimmune regulation has not been elucidated Patients withNP-LES are known to have an increased frequency
dys-of autoimmune disease and autoantibodies in theirpersonal or family history compared to patients withP-LES (Lennon et al., 1982; O’Neill et al., 1988)
Clinically, no major features differ between NP-LESand P-LES except the age and sex differences notedabove and the presence of P/Q-type VGCCs is more commonly found in P-LES While an immune-mediated process has been established as the cause,the primary cause of this immune dysregulation hasnot been found
Diagnosis
Clinical manifestations
The basis for the diagnosis of LES is the clinical triad
of fatigable proximal limb muscle weakness, reduced
or absent muscle stretch reflexes, and autonomicdysfunction Ancillary tests for LES are distinctive and
usually provide reliable confirmation of the diagnosis.Cases of prolonged apnea following surgery withexposure to neuromuscular blocking agents shouldprompt suspicion of LES (as well as MG) LES shouldalso be considered in patients with another lung cancer associated paraneoplastic syndrome whodevelop significant weakness or have antibodies
to the P/Q-type calcium channel Sometimes LES isdiagnosed in patients previously misdiagnosed withseronegative MG
Electrodiagnostic studies
Electrodiagnostic studies provide the most specificand rapid confirmation of the diagnosis of LEMS The distal hand muscles often provide the most pro-nounced findings CMAPs have a low amplitude atbaseline CMAPs display a decremental response atslow rates of repetitive nerve stimulation and markedpostactivation facilitation of greater than 100–200%following high-frequency repetitive nerve stimulation(at rates of 20 – 50 Hz) or about 10 seconds of briefexercise (Harper, 1999) Single-fiber electromyo-graphy demonstrates increased jitter and blockingthat transiently improve with high firing rates Thiscombination of findings is the hallmark of LES
Serum testing
Antibodies directed towards the P/Q-type VGCC aredetectable in greater than 90% of patients with LES(Lennon et al., 1995) In LES patients with SCLC, up
to 100% have antibodies to VGCC, whereas 50 – 90%
of LES patients without associated cancer have bodies to VGCC In P-LEMS, antibodies directed tothe N-type VGCC are present in 75% of patients withSCLC and generally not seen in patients with othertypes of cancer Forty percent of NP-LES have anti-bodies to the N-type VGCC Antibody titers tend todiminish with improving disease severity, the admini-stration of immunotherapy, and effective treatment
anti-of an underlying malignancy It is, thus, imperative
to test for VGCC antibodies early in the evaluation ofall patients under consideration for LES
The interpretation of positive serum antibody testsrequires correlation with the clinical picture Anti-bodies to VGCC can occur in other conditions not inassociation with clinical LEMS In SCLC patientswithout LEMS, 18% have P/Q-type VGCC antibodiesand 22% have N-type VGCC antibodies VGCC anti-bodies occur in 15 – 40% of patients with paraneo-plastic cerebellar ataxia, and rarely in autoimmune
Trang 6MG or other autoimmune disorders (Yu et al., 2001).
In 13% of patients with LEMS, muscle or ganglionicnicotinic AChR antibodies or striational antibodiesare present
Differential diagnosis
While the characteristic clinical features of LES are quite distinctive, LES is frequently misdiagnosedinitially due to its insidious onset and rarity The dif-ferential diagnosis of LES includes such disorders
as MG, myopathies, polymyalgia rheumatica, andbotulism Several features distinguish LES from thesedisorders With MG, the distribution of weakness and fatigability with early involvement of ocular andbulbar muscles, as well as typical electrodiagnosticand autoimmune serological profile differentiate itfrom LES Myopathies may present with a similar distribution of weakness However, the lack of auto-nomic dysfunction, different electrodiagnostic findings,and reflexes which are proportional to the degree
of weakness and do not exhibit potentiation afterbrief voluntary exertions, distinguish them from LES
Botulism causes progressive weakness, autonomicdysfunction, and some similar electrodiagnostic fea-tures The course, however, is more fulminant, andprominent respiratory involvement, early pupillaryinvolvement, and a descending progression of weak-ness are not typical features of LEMS Polymyalgiarheumatica can present with muscle pain, but anelevated erythrocyte sedimentation rate (ESR) andthe lack of true muscle weakness and fatigability dif-ferentiate it from LEMS
Treatment and management
Once the diagnosis of LES has been established, anextensive investigation for an underlying malignancyshould be implemented For patients with an under-lying malignancy, symptoms of LES often improvewith treatment of the malignancy If the evaluationdetects no malignancy, repeated testing should beperformed at regular intervals for at least five years,especially in persons with significant risk factors forcancer In patients with P-LES, treatment should bedirected towards the underlying malignancy Patients
in whom the underlying malignancy is not ively treated tend not to improve substantially withimmunotherapy Conversely, effective treatment ofthe underlying malignancy usually leads to signific-ant improvement of the neurological symptoms, and,
effect-in some cases, to complete remission Some of these
patients may not require further treatment for LES.Immunotherapy should be considered for patientswhose malignancies respond to therapy but theirneurological symptoms not improve adequately It
is also indicated for patients without malignancywho suffer from significant disability despite symp-tomatic therapy Therapy of LES must be indi-vidualized, with consideration given to the degree ofdisability, associated underlying medical conditions,and life expectancy The therapeutic strategies forimmunotherapy are generally similar to those usedwith MG, although the response to treatment is oftenless dramatic
Symptomatic treatment
3,4-Diaminopyridine (3,4-DAP) has been shown toimprove symptoms in patients with LES in placebo-controlled prospective trials (Lundh, 1990; McEvoy,1989) Many practitioners consider 3,4-DAP first-line therapy for LES 3,4-DAP blocks voltage-gatedpotassium channels in the nerve terminal, which leads
to prolongation of the action potential and opening
of VGCC, increased calcium entry and, ultimately,
to enhanced ACh release Dosing schedules vary,and repeated dosages are titrated to optimize patientresponse (Lundh et al., 1993; Sanders, 1998) 3,4-DAP is usually well tolerated but it is not approvedfor clinical use in the United States Thus, it is avail-able only for compassionate use as an investiga-tional drug
Guanidine hydrochloride also enhances therelease of ACh from the presynaptic nerve terminal.Guanidine increases calcium within the nerve ter-minal by inhibiting uptake of calcium by subcellularorganelles (Kamenskaya et al., 1975) While guani-dine is occasionally utilized in the management ofLES, its use has been significantly limited due topotential hematopoietic and renal toxicity
Cholinesterase inhibitors are sometimes tered in LES Potential benefits are limited, perhapsbecause it is an attempt to slow the metabolism of analready-reduced amount of ACh Clinically, CIs arenot particularly effective as monotherapy Enhancedbenefits can occur when CIs are combined with med-ications that facilitate the release of acetylcholine,such as the 3,4-diaminpyridine or guanidine
adminis-Immunotherapy
For patients who fail to respond adequately to tomatic treatments, immunotherapy is an option
Trang 7symp-Autoimmune myasthenic syndromes 165
Therapeutic plasma exchange and IVIg are bothused for short-term immunotherapy because theyprovide relatively quick onset but short-term benefits(Bain et al., 1996; Newsom-Davis and Murray, 1984)
Clinical response to plasma exchange occurs around
10 days and for IVIg around 2 weeks, somewhatslower than with MG The benefit of both lasts about
6 – 8 weeks Plasma exchange and IVIg both are typically utilized for patients with severe weakness,
or bulbar or respiratory muscle involvement Repeatedtreatments sometimes have been employed formaintenance therapy or until long-term immuno-therapy takes effect
Patients with long-standing disabling symptomsshould consider chronic immunosuppressive therapy
In patients with known malignancy or at high riskfor malignancy, it is important to be contemplative
of the theoretical risk of immunosuppression moting tumor growth Although not considered highrisk, some practitioners reserve immunosuppress-ive therapy only for the most disabled patients who fail to respond to other therapies Prednisone is often the choice immunosuppressive (Lundh et al., 1990)
pro-It is administered at dosages of 0.75 –1 mg/kg/day,typically 60 – 80 mg per day After clinical responseoccurs, the dosing schedule may be converted toalternate days (i.e 100 –120 mg every other day)
Starting on alternate-day dosing usually delays theonset of the clinical response The dose of prednisoneshould be gradually tapered over many months tothe minimal dose required for adequate disease control The administration of an additional im-munosuppressive agent may help minimize steroidexposure and is usually better tolerated than steroids
Azathioprine is often utilized and has shown benefit
in this role in a retrospective study (Lee et al., 2001)
Azathioprine also can be used as monotherapy forthose patients who can wait months for clinicalresponse The therapeutic efficacies of mycopheno-late mofetil, cyclosporine, and other immunosup-pressive agents have not been adequately investigatedfor use in patients with LES Some practitioners haveemployed these medications on the theoretical basisthat treatments efficacious in MG should show simi-lar efficacy in LES
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Trang 11Idiopathic inflammatory myopathies share the topathological feature of inflammation in striatedmuscle The three major subgroups are dermato-myositis (DM), polymyositis (PM), and inclusionbody myositis (IBM) This chapter focuses on der-matomyositis and polymyositis Dermatomyositis wasfirst noted in the literature when Wagner (1863)published a description of a patient with the disease.
his-Several other clinical descriptions followed in the latenineteenth century and were further classified as der-matomyositis, polymyositis, pseudotrichinosis, andmyositis universalis acute infectiosa ( Jackson, 1887;
Unverricht, 1887; Wagner, 1887) It seems that thecriteria for classification of the inflammatory myopa-thies are “a work in progress” A general schema based
on clinical features and disease associations was useduntil the landmark article written by Bohan and Peter(1975) was published In their description of the dis-ease they ascribed the probability of having the diseasebased on a number of clinical features being present(Box 10.1) New efforts in further defining the dis-ease have included exhaustive search for myositis-associated antibodies and pathological findings Bohanand Peter’s criteria have been criticized for beinginadequate in excluding other conditions presenting
as polymyositis Additionally, muscle biopsy was sidered to be the gold standard in the diagnosis and
con-now it has been shown that a muscle biopsy may not distinguish polymyositis from some toxic, necro-tizing, or dystrophic myopathies (Dalakas, 2002).More recently interest has centered on the presence
of MHC-I/CD8 complex as an immunopathologicalmarker which seems to be specific for polymyositisand inclusion body myositis, as well as central to theimmunopathogenesis (Dalakas, 2004) The latestcriteria for diagnosis are shown in Box 10.2
Clinical phenotype
The clinical manifestations of polymyositis are sentative of all idiopathic inflammatory myopathies.Patients with polymyositis usually present with grad-ual onset of proximal muscle weakness involvingboth the upper and lower extremities Patients oftennote trouble with their daily activities The muscles
repre-of the oropharynx, esophagus, diaphragm, and costals can also be involved, resulting in dysphagiaand dyspnea Involvement of the neck flexors maymake it difficult for the patient to lift his or her head.Ocular and facial muscles are spared, and there is noinvolvement of the nerves (Dalakas, 1991)
inter-Extramuscular manifestations such as fever,anorexia, and weight loss may be prominent Thedevelopment of pulmonary and cardiac symptoms
5 Cutaneous eruption typical ofdermatomyositis.*
Definite PM/DM: Fulfill four criteria
Probable PM/DM: Fulfill three criteria
Possible PM/DM: Fulfill two criteria
*Criterion 5 must be one of the stated number
of criteria in patients with definite, probable,
or possible dermatomyositis.
Trang 12has been well described (Box 10.3) Primary monary involvement can take the form of a diffusealveolitis or a more slowly evolving interstitial lungdisease Dyspnea in these patients may be related
pul-to respirapul-tory muscle weakness, aspiration, cardiacprocess, or drug-induced (such as with methotrex-ate) (Dickey, 1984; Tazelaar et al., 1990) The most
frequent cardiac abnormalities are conduction turbances (Yale et al., 1993) Gastrointestinal involve-ment with dysphagia and heartburn secondary topharyngeal dysfunction and esophageal dysmotility
dis-is common Primary renal involvement dis-is unusual,but renal failure from massive deposition of myo-globin in the renal tubules can occur The arthritis
1 Myopathic weakness, which:
a evolves over weeks to months
b spares facial and eye muscles
c is manifested in patients above the age of 18
2 Patient does not have:
a rash, characteristic of dermatomyositis
b a family history of neuromusculardiseases
c exposure to myotoxic drugs (D-pencillamine, zidovudine, statins)
d endocrine disease (hypothyroid,hyperthyroid, hypoparathyroid,hyercortisolism)
e neurogenic disease (excluded byelectromyographic (EMG) andneurological exam)
f dystrophies and metabolic myopathies (excluded by history and muscle biopsy)
g IBM (excluded by clinical examinationand muscle biopsy)
3 Disease can be associated with:
a another autoimmune disease or viral infection
4 Polymyositis is rare, as a standalone entity
5 Reconsider polymyositis if:
a disease onset below the age of
18 years
b myopathy has slow onset and evolves over months to years (think of IBM or dystrophy)
c patient has fatigue and myalgia,without muscle weakness, even if
a transient creatine kinase elevation
is seen (such patients may havefibromyalgia or fasciitis and theirmuscle biopsy is either normal
or nonspecific)
d there are no typical histologic features of polymyositis, expeciallywhen there is an absence of MHC-1
or MHC-1/CD8 complex
Respiratory manifestations: Interstitial lung
disease (bronchiolitis obliterans organizingpneumonia, interstitial pneumonia, diffusealveolar damage); aspiration pneumonia;
ventilatory insufficiency; drug-inducedreaction (secondary to methotrexate use);
malignancy; pleural effusions; opportunisticinfection; pulmonary hypertension;
spontaneous penumothorax; pulmonary alveolar proteinosis (Dickey, 1984;
Tazelaar et al., 1990)
Cardiac manifestations: Conduction
abnormalities; arrhythmias; myocarditis;
congestive heart failure; hyperkinetic state, pericardial tamponade; pericardialeffusions; pericarditis (Yale et al., 1993)
Gastointestinal manifestations:
Esophageal reflux; delayed gastric emptying; dysphagia; esophageal dysmotility; decreased intestinal motility; rectal incontinence
Ocular manifestations: Conjunctival
edema; nystagmus; extraocular muscleimbalance; iritis; cotton-wool spots; opticatrophy; conjunctival pseudopolyposis
Trang 13Polymyositis and dermatomyositis 171
associated with the anti-Jo-1 antibody tends to beprominent, chronic and deforming, but lacks theextensive bone erosions that characterize rheuma-toid arthritis
Although dermatomyositis and polymyositis differ in immunopathogenesis, clinically dermato-myositis is phenotypically polymyositis with typicalskin changes The primary skin lesion is a violaceous
macular erythema distributed symmetrically that overtime becomes more poikilodermatous and induratedsecondary to mucin depositon The pathognomonicskin lesions are Gottron’s papules (violaceous papulesoverlying the dorsal surface of the interphalangeal,metacarpophalangeal (MCP), elbow, or knee joints),Gottron’s sign (atrophic macules or plaques in the same distribution) (Fig 10.1), heliotrope rash(erythematous/violaceous rash with associated edema
of the eyelids) (Fig 10.2), shawl sign (erythematouspoikilodermatous macules distributed in a “shawl”pattern involving the shoulder, arms, and upperback) (Fig 10.3), and the V sign (same changes in a Vpattern on the anterior neck and chest) Nonspecificfindings include mechanic’s hands (scaly, fissuredlesions involving the hands), cuticular changes, andphotosensitivity The rash is often the presentingcomplaint and may precede the onset of muscularsymptoms by more than a year The severity of the skin findings does not always correlate with theextent of muscle involvement (Euwer and Sontheimer,1996; Kovacs and Kovacs, 1998)
The presentation of muscle involvement in matomyositis is clinically indistinguishable from that
der-of polymyositis, with symmetrical weakness ving the proximal muscles that develops over weeks
invol-to months Myalgias can occur with an acute onset,but the hallmark presentation is that of weakness.Patients with classic skin changes of dermatomyositiswithout weakness or laboratory evidence of muscledisease are described as having amyopathic der-matomyositis (ADM) (also called dermatomyositissine myositis) “Hypomyopathic DM” (HDM) refers
to patients with the presence of skin disease for atleast six months who have no muscle weakness, but
on testing are found to have some evidence of muscleinvolvement Clinically amyopathic DM (CADM) hasbeen proposed by Gerami et al (2006) to emphasizethe clinically active component at that time – the
Fig 10.1 Gottron’s sign (a) Violaceous plaques over the dorsal surface of the metacarpal phalangeal joints and interphalangeal regions (b) Gottron’s papules and plaques over knee joint.
Fig 10.2 Heliotrope rash of dermatomyositis demonstrating violaceous erythema overlying the upper eyelids with associated periorbital edema.