A SELF-TEST IM BOARD REVIEW JAMES K. STOLLER, MD, EDITOR ON A ANDREY S. STOJIC, MD, PhD TAREK MEKHAIL, MD BRYAN E. TSAO, MD CLINICAL Department of Neurology, Cleveland Clinic Department of Hematology and Department of Neurology, Oncology, Cleveland Clinic Cleveland Clinic CASE

Leg in a 66-year-old woman: A common presentation of an uncommon disease

66-YEAR-OLD WOMAN presents with pro- Blood pressure while sitting is 153/81 mm A gressive, painless weakness of the proxi- Hg, heart rate 75; blood pressure while stand- mal legs, which began 2 years ago. The onset ing is 106/71 mm Hg, heart rate 87. She is alert was gradual: at first she had difficulty standing and appropriate, and her cognition is intact. from a sitting position, such as when rising Cranial nerves II to XII are normal except for a from a chair, but over a 1-year period the weak- soft voice. She can swallow water normally. ness progressed to the point where she could no She has no ptosis. longer stand or walk without assistance. Arm Motor examination shows normal tone strength is not impaired. Six months before her and muscle bulk throughout. There is no visit she developed numbness and tingling in pain to palpation over the spine. Strength in the legs to the mid-calf level. her neck flexors and extensors is graded 4 on Review of systems reveals she has unin- the 5-point Medical Research Council scale. She has: tentionally lost 50 pounds over the past 2 She has normal strength in her arms; both •Leg years. She reports that her mouth is dry, and her legs are weak, graded 2/5 proximally and she feels light-headed when rising from a sit- 3/5 distally. weakness ting or lying position. She denies any oculo- Deep tendon reflexes are absent in all •Weight loss bulbar symptoms, incontinence, back pain, four extremities; sustained muscle contrac- myalgias, or arthralgias. tion of the quadriceps muscles resulted in • Dry mouth Previous evaluations included an electro- trace patellar reflexes. Vibratory and propri- • Orthostasis diagnostic examination 1 year earlier that sug- oceptive sensation are diminished in the dis- gested a mild motor radiculopathy involving tal lower extremities, with normal tempera- • Diminished the left L4–S1 roots and segments. At that ture and pin testing. Finger-to-nose testing sensation time, magnetic resonance imaging (MRI) of and evaluation of rapid alternating move- the lumbar spine showed moderate spondylo- ments reveal no evidence of cerebellar dys- in arms and sis with foraminal narrowing at the L4–S1 lev- function. legs els. A multilevel hemilaminectomy (L4–L5) was performed, but it produced little improve- ■ DIFFERENTIAL DIAGNOSIS ment in her weakness. She has 80 pack-years of tobacco use. She Which is the most likely cause of this has no personal or family history of neurolog- 1 patient’s lower-extremity weakness? ic disorders. ❑ Infiltrative (metastatic) disease of the lumbar spinal cord Physical examination ❑ Amyotrophic lateral sclerosis On physical examination, the patient is ❑ Sensorimotor peripheral neuropathy cachectic and in a wheelchair. She can stand ❑ Neuromuscular junction disease with assistance but cannot walk. ❑ Inflammatory

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This patient presented with slowly progressive ical for amyotrophic lateral sclerosis. leg weakness (proximal greater than distal) Moreover, our patient’s distal large-fiber sen- and distal paresthesias. Several red flags were sory loss (including loss of vibration and pro- noted on the review of systems, namely signif- prioceptive sensation) and symptoms of auto- icant weight loss, dry mouth, and orthostatic nomic failure are not consistent with motor intolerance. The distribution of her weakness neuron disease. points to the lower motor neurons, which extend (proximal to distal) from the spinal Sensorimotor peripheral neuropathy cord, anterior horn cells, peripheral nerves, The most common form of sensorimotor and neuromuscular junction to the muscle. peripheral neuropathy involves loss of longer Her associated autonomic symptoms suggest a axons, manifesting as distal sensory loss, weak- more systemic disorder. ness, and loss of reflexes starting distally and Let’s look at the diagnostic possibilities. progressing proximally. However, a few notable peripheral neuropathies present with Infiltrative (metastatic) disease proximal weakness. of the lumbar spinal cord Diabetic amyotrophy is a self-limited Primary spinal cord tumors in this age group form of lumbosacral plexopathy that presents include astrocytoma and ependymoma, while with weight loss, severe thigh pain, and neu- secondary spread occurs in a number of can- rogenic weakness of the anterior thigh mus- cers, eg, cancers of the lung and breast and cles. In most cases, pain and weakness lymphomas. Patients with malignant inva- become maximal within a few months. The sion of the lumbosacral spine can present absence of pain and the duration of symp- with cauda equina syndrome, characterized toms in our patient essentially exclude this by subacute flaccid leg weakness, inconti- diagnosis. nence, and pain. In some cases, there is anes- Chronic inflammatory demyelinating thesia in the groin and perineum, with a sad- polyradiculoneuropathy, a form of acquired dle pattern of sensory loss.1 neuropathy due to demyelination (as opposed Cancer in the Our patient’s course of weakness was more to axon loss), can present with weakness lumbosacral indolent than would be expected from direct (proximal greater than distal), areflexia, and cancer spread. In addition, she had more wide- mild autonomic failure.3 spine can spread symptoms (sensory disturbance in the Thus, her differential diagnosis should cause cauda arms, dry mouth, and lightheadedness) than include this disorder, although a few notable could be accounted for by lumbosacral cord features of her case argue against it. First, her equina disease alone. prior electrodiagnostic evaluation did not syndrome show features of an acquired demyelinating Amyotrophic lateral sclerosis polyneuropathy. Second, significant weight Amyotrophic lateral sclerosis or progressive loss is atypical in this disorder and raises the motor neuron disease is a relentless neurode- concern for systemic disease. Third, the incre- generative disorder. By definition, it affects mental response of deep tendon reflexes fol- both the upper and lower motor neurons. lowing sustained muscle contraction is not Early in its course there may be a predomi- seen with this disorder. nance of either upper motor neuron signs Nutritional neuropathies (eg, vitamin (spastic weakness, hyperreflexia) or lower B12 deficiency) should be considered in any motor neuron signs (flaccid weakness, muscle patient with significant weight loss, but the atrophy, fasciculations). rapid progression over 2 years and lack of sig- However, even though amyotrophic lat- nificant involvement in her arms relative to eral sclerosis may initially present with symp- the advanced state of disease in her legs make toms and signs primarily affecting the bulbar, this unlikely. cervical, or lumbosacral segments, in the end, all are invariably affected.2 Lumbosacral Neuromuscular junction disease weakness lasting at least 2 years without any Diseases of the neuromuscular junction (the other segmental involvement would be atyp- most likely cause of this patient’s symptoms)

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LAMBERT-EATON MYASTHENIA GRAVIS MYASTHENIC SYNDROME

Weakness Yes, nonfluctuating Yes, often fluctuating Diplopia, Rare Common Tendon reflexes Absent or reduced Normal (even in severe cases) Autonomic failure Yes No (dry mouth, orthostasis, constipation, sluggish papillary reflexes) Repetitive nerve stimulation Slow Decrement Decrement Fast Increment No change Commonly associated malignancy Small-cell lung cancer Thymoma

Associated Voltage-gated calcium Acetylcholine receptor channel

are divided into presynaptic and postsynaptic drome, myasthenia gravis has a predilection disorders. for the extraocular and pharyngeal muscles; Lambert-Eaton myasthenic syndrome, diplopia, ptosis, and dysarthria are common the most common presynaptic disorder, is an in myasthenia gravis and rare in Lambert- autoimmune disease that presents with slowly Eaton myasthenic syndrome.5 Respiratory progressive proximal weakness and loss of ten- failure is another feature seen in myasthenia Lambert- don reflexes. The finding of weakness of the gravis (TABLE 1). Eaton neck flexors and extensors is sensitive but not specific for either neuromuscular junction dis- Inflammatory myopathy syndrome orders or myopathic disorders. However, ten- Inflammatory myopathy or includes affects the don reflexes tend to be preserved until the end the categories of , polymyosi- stages of and preserved in even tis, and inclusion-body myositis. presynaptic severe myasthenia gravis (see below), while Myositis and the collagen vascular dis- neuromuscular early areflexia is a pathognomonic feature of eases can overlap; dermatomyositis is associat- Lambert-Eaton myasthenic syndrome. An ed with a higher rate of malignancy, while the junction; interesting clinical finding is an increment in relationship between and malig- myasthenia previously absent reflexes following 10 sec- nancy is more variable. All of them feature onds of sustained contraction. proximal weakness, except for inclusion-body gravis is Approximately 50% to 70% of cases of myositis, which classically presents with very postsynaptic Lambert-Eaton myasthenic syndrome are slowly progressive weakness of the anterior associated with malignancy, most commonly thigh muscles and finger flexors.6 small-cell lung cancer, but cases have also Our patient does not have any cutaneous been identified in patients with lymphopro- stigmata associated with adult-onset dermato- liferative disorders. Other hallmark features myositis, and her sensory and autonomic are often autonomic such as diminished symptoms are not consistent with myositis. pupillary reflexes, orthostasis, dry mouth, and constipation.4 ■ CASE CONTINUED Myasthenia gravis is the prototypical postsynaptic neuromuscular junction disor- During rehabilitation from her previous hemi- der. Unlike Lambert-Eaton myasthenic syn- laminectomy, our patient had had an acute

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episode of dyspnea, and computed tomography compound muscle action potential that is uni- (CT) of the chest performed at that time found form in appearance and size. evidence of hilar adenopathy. Subsequent bron- In patients with , choscopy with mediastinal biopsy revealed impairment in the release of acetylcholine small-cell lung cancer. Staging MRIs of the brain (as in Lambert-Eaton myasthenic syndrome) and abdomen were normal. Her vitamin B12 or in the ability of acetylcholine to bind on level, thyroid function, creatine kinase level, and the muscle membrane (as in myasthenia diabetes screening tests were negative. gravis) leads to suboptimal activation of the muscle. This manifests itself as decreasing ■ DIAGNOSTIC TESTING amplitude in the compound muscle action potential with successive electrical stimula- Which test should be performed next in tion, known as a decremental response. 2this patient? However, if the frequency of stimulation is ❑ MRI of the lumbar spine increased to 30 Hz or more (the equivalent ❑ Electrodiagnostic evaluation with firing frequency of voluntary muscle contrac- repetitive nerve stimulation tion), the compound muscle action potential ❑ MRI of the brain in patients with Lambert-Eaton myasthenic ❑ MRI of the pelvis syndrome (but not myasthenia gravis) will ❑ Muscle biopsy increase by at least 100%, and sometimes greater than 200%: this is known as an MRI of the lumbar spine abnormal incremental response. This Given her recent history of back surgery and a response is due to increased release of acetyl- preoperative MRI that did not show signifi- choline into the neuromuscular junction and cant compression of the neural elements, a improved activation of the muscle.8 The repeat MRI would be of little value. incremental response is the classic electrodi- agnostic feature of a disorder of presynaptic Electrodiagnostic examination neuromuscular transmission. Proximal with repetitive nerve stimulation Accurate electrodiagnostic assessment of weakness is Electrodiagnostic evaluation with repetitive neuromuscular junction disorders requires a nerve stimulation is the best choice. skilled and experienced physician. Most elec- evident in all This test is composed of three basic com- trodiagnostic laboratories do not routinely neuromuscular ponents: sensory nerve conduction, motor perform repetitive stimulation studies or nee- nerve conduction, and direct needle electrode dle electrode examinations or interpret their junction examination of muscles. In this way, the meaning in this setting; clinicians should con- diseases integrity of the peripheral nerves, neuromus- sider referring patients with neuromuscular cular junction, and muscles is assessed. junction disorders to laboratories at academic Repetitive nerve stimulation examines centers where the electrodiagnosticians have- the response of muscles by measuring the com- considerable experience with neuromuscular pound muscle action potential or area under diseases. the curve with trains of nerve stimulation Our patient undergoes electromyography (usually two to four serial stimulations) given with repetitive nerve stimulation. The repeti- at frequencies of 2 to 4 Hz.7 Normally, stimu- tive nerve stimulation demonstrates elec- lation of a motor nerve results in release of suf- trodecremental response with low-frequency ficient amounts of acetylcholine at the neuro- stimulation (FIGURE 1), but higher frequency muscular junction to generate an action stimulation (100 Hz) produces a marked potential, thereby leading to muscle contrac- increase in the compound muscle action tion and a compound muscle action potential. potential (FIGURE 2). This confirms the diagno- With repetitive stimulation, normal individu- sis of a presynaptic neuromuscular junction als maintain efficient acetylcholine transmis- disorder such as Lambert-Eaton myasthenic sion and never go below the so-called safety syndrome. threshold necessary to generate an action Of note, botulism is another presynaptic potential. Thus, serial stimulation leads to a disorder in which the electrodiagnostic pic-

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Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. ture may be very similar to that of Lambert- Lambert-Eaton myasthenic syndrome: Eaton myasthenic syndrome. The clinical pre- Electrodiagnostic evaluation sentation of botulism, however, is quite differ- with repetitive nerve stimulation ent and consists of descending paralysis with a predilection for early oculomotor and bulbar Postcontraction involvement. Right tibialis anterior Interestingly, our patient was also found to have evidence of severe polyneuropathy Precontraction (discussed below). Postcontraction Other studies Precontraction Right extensor digitorum brevis MRI of the brain has no direct role at this point. MRI of the pelvis is reasonable; howev- Postcontraction Precontraction er, the diagnostic yield would be enhanced if the electrodiagnostic evaluation pointed Right thenar towards a lumbosacral plexus lesion or if there was a concern for a primary gynecologic or Postcontraction other pelvic malignancy. In myopathies, the Precontraction role of the electrodiagnostic evaluation is to Right hypothenar confirm the diagnosis and help determine which specific muscle might be appropriately affected, to optimize the yield of the muscle biopsy.

■ AUTOANTIBODIES AND OTHER DIAGNOSTIC FEATURES FIGURE 1. Improved motor nerve conduction responses (as Lambert-Eaton myasthenic syndrome is reflected in increased compound muscle action potentials) 3associated with autoantibodies directed with 10-second, sustained contraction of selected test muscles. against which protein? Note the significant increase in compound muscle action ❑ Nicotinic cholinergic receptors potentials following sustained muscle contraction that is commonly seen in Lambert-Eaton myasthenic syndrome. ❑ Voltage-gated potassium channels ❑ P/Q-type voltage-gated calcium channels ❑ M3 subtype muscarinic acetylcholine receptors Left extensor digitorum

Nicotinic cholinergic receptors Nicotinic cholinergic receptors are found in all autonomic ganglia (parasympathetic and sympathetic) and also in neuromuscular junc- tions.9 Antibodies against postsynaptic acetyl- choline receptors are found in most patients with generalized myasthenia gravis, whereas the antiacetylcholine ganglionic receptor (known as alpha-3) has been linked to autonomic neuropathies.10 FIGURE 2. The classic electrodiagnostic confirmation of Lambert- Voltage-gated potassium channels Eaton myasthenic syndrome with high-frequency repetitive Antibodies against voltage-gated potassium nerve stimulation. The left extensor digitorum was stimulated channels are described in Isaacs syndrome, a at 40 Hz, which resulted in significant increase in compound disorder of muscle membrane hyperex- muscle action potential response (reflected as rising slope of citability. the response in the first 8 milliseconds of the tracing).

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P/Q-type voltage-gated calcium channel Several reports have described patients Lambert-Eaton myasthenic syndrome is an with small-cell lung cancer and Lambert-Eaton autoimmune disorder characterized by myasthenic syndrome with overlapping para- impaired presynaptic function at the neuro- neoplastic syndromes, most commonly pro- muscular junction.11 Antibodies against the gressive cerebellar degeneration, as well as lim- P/Q-type voltage-gated calcium channel bic encephalitis, brainstem encephalomyelitis, reduce the influx of calcium into the presy- and sensory neuropathy.11,12 Thus, these naptic terminal, which is key to the release autoantibodies appear to predict an underlying of acetylcholine. Insufficient release of malignancy but do not predict a single parane- acetylcholine into the neuromuscular junc- oplastic syndrome. tion produces the characteristic features of this disease (TABLE 1). The other features of Vitamin deficiency Lambert-Eaton myasthenic syndrome, Vitamin or nutritional deficiencies (ie, of vit- including autonomic dysfunction, are due amin B12, thiamine, and vitamin E) can cause to a similar effect of these autoantibodies peripheral neuropathy. on the same voltage-gated calcium chan- The sine qua non of vitamin B12 defi- nels in the autonomic ganglia. ciency (also called subacute combined degen- To some extent, the effects of these eration) is a myelopathy (presenting with autoantibodies can be transiently overcome spastic weakness and hyperreflexia), enceph- by sustained contraction of muscles, resulting alopathy, and varying degrees of peripheral in transiently induced tendon reflexes, or by neuropathy. Our patient had a normal vita- high-frequency repetitive stimulation of the min B12 level. nerves, resulting in the incremental response. Thiamine deficiency is associated with peripheral neuropathy and (in isolation or M3 subtype muscarinic acetylcholine with other nutritional deficiencies) with neu- receptors ritic or dry beri-beri and the classic Wernicke- There are at least four subtypes of muscarinic Korsakoff syndrome. 3,4-DAP receptor (M1–M4); all are tied mainly to the Deficiency of vitamin E causes a slowly provides only parasympathetic system. No muscarinic anti- progressive spinocerebellar syndrome. body is linked to a neurologic disease. Although these deficiencies are associated symptomatic with polyneuropathies, none of them would be treatment for ■ WHAT IS CAUSING associated with voltage-gated calcium channel HER NEUROPATHY? antibodies or the incremental responses seen Lambert-Eaton with electrodiagnostic testing. syndrome The patient’s sensory loss and the findings 4of polyneuropathy on her electromyogram Lumbar spinal disease can be best explained by which of the fol- lowing? Polyneuropathies can be difficult to distin- guish from lumbar spinal disease in elderly ❑ Overlapping paraneoplastic sensory patients; the sensory responses that indicate neuropathy whether the disease process is located with- ❑ Vitamin deficiency due to poor nutrition in the spinal canal (radiculopathy) or distal ❑ History of lumbar spinal disease to it (polyneuropathy) can be absent in ❑ A medication side effect patients over age 60. Nevertheless, our patient had sensory symptoms in her arms Paraneoplastic sensory neuropathy that could not be explained by lumbar spine Many patients with Lambert-Eaton myas- disease alone. thenic syndrome and small-cell lung cancer have overlapping paraneoplastic syndromes. Medication side effect Our patient tested positive for antineuronal Although several chemotherapeutic agents antibodies (anti-Hu) in addition to having can cause sensory neuropathy, including those autoantibodies against the voltage-gated calci- commonly used in the treatment of small-cell um channel. carcinoma (vincristine and cisplatin, among

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THERAPY* DOSING COMMENTS AND SIDE EFFECTS

3,4-Diaminopyridine15,16 Start at 10 mg by mouth Effective symptomatic treatment, (3,4-DAP) twice a day; increase to lasting 3–4 hours goal of 80 mg per day, Not readily available in United States divided into two or three Paresthesias, gastrointestinal symptoms, doses and rare seizures at doses of >100 mg/day Pyridostigmine17,18 30–60 mg by mouth three times a day Limited efficacy but may prolong effect of 3,4-DAP when used in conjunction Fasciculations, bradycardia, gastrointestinal symptoms (diarrhea, abdominal pain). Prednisone19 Start at 1–1.5 mg/kg daily Good efficacy Well-known side effects with long-term use Azathioprine20 Titrate to 2.5 mg/kg daily Moderate efficacy Used to treat autonomic-predominant Lambert- Eaton myasthenic syndrome Cyclosporine20 3–4 mg/kg Modest efficacy for patients failing to respond to Intravenous 400 mg/kg/day for 5 days, Limited studies; probably moderately effective immunoglobulin21,22 then 400–1,000 mg/kg/monthly Anaphylaxis, thromboembolism, stroke, aseptic meningitis Plasma exchange20 No established guidelines Limited studies; probably good efficacy We use every-other-day exchanges Risks of catheter placement, line infection, for 5–7 total treatments hemodynamic instability in patients at risk (which exchanges the equivalent of total body plasma)

*See Maddison and Newsom-Davis23 for meta-analysis review of current treatment options. others), our patient was not taking these at immunoglobulin for 1 month and then the time of her diagnosis. treat her underlying malignancy ❑ Treat the underlying malignancy and ■ HER DIAGNOSIS provide graded medical therapy directed against Lambert-Eaton myasthenic Paraneoplastic Lambert-Eaton myasthenic syndrome syndrome with associated sensory neuropathy due to small-cell carcinoma of the lung. Treatment of the patient’s cancer is the first step in management. A small case series has ■ TREATMENT shown that cancer treatment produces signifi- cant improvement of symptoms in patients Which is the most appropriate treatment with paraneoplastic Lambert-Eaton myas- 5 for Lambert-Eaton myasthenic syndrome thenic syndrome.13,14 in this patient? Specific treatments for Lambert-Eaton ❑ Start oral cyclosporine 3 mg/kg myasthenic syndrome are listed in TABLE 2.15–23 ❑ Start oral azathioprine 2.5 mg/kg First-line symptomatic treatment includes ❑ Give a course of intravenous 3,4-diaminopyridine (3,4-DAP), which inhibits

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presynaptic voltage-gated potassium channels, mine. For those with greater disability or thus prolonging the action potential duration. It weakness, prednisone 1.0 to 2.0 mg/kg is has been shown in placebo-controlled trials to given orally once in the morning along with improve the symptoms of Lambert-Eaton myas- a histamine2 receptor antagonist. In cases of thenic syndrome significantly, but it is not autoimmune Lambert-Eaton myasthenic syn- approved by the US Food and Drug drome, azathioprine is either started at the Administration and is available only at tertiary- same time as prednisone or delayed until sub- care neuromuscular centers that have an inves- sequent prednisone taper results in recur- tigational drug approval for its use.15,16 rence of weakness. Pyridostigmine17,18 is an acetyl- In severe cases, nonrandomized data sup- cholinesterase inhibitor primarily used in myas- port the use of plasma exchange to treat thenia gravis. Pyridostigmine works by increas- Lambert-Eaton myasthenic syndrome, although ing available acetylcholine in the synaptic cleft, its efficacy is moderate and often less dramatic thereby increasing the probability of binding to than in myasthenia gravis.20 muscle membrane receptors and of muscular Intravenous immunoglobulin is another contraction. For most patients with Lambert- option: a small placebo-controlled study in 10 Eaton myasthenic syndrome, pyridostigmine patients with nonparaneoplastic Lambert- alone produces little improvement. However, Eaton myasthenic syndrome demonstrated when taken together with 3,4-DAP, pyridostig- improved strength and reduction in serum lev- mine appears to prolong the effects of 3,4-DAP els of voltage-gated calcium channel after two and thus may serve as a useful adjuvant. treatments with intravenous immunoglobulin In summary, the effects of 3,4-DAP for 1 g/kg. The effects were maximal at 2 to 4 Lambert-Eaton myasthenic syndrome are equiv- weeks, but declined by 8 weeks. In general, alent to the effects of pyridostigmine for myas- there are no guidelines for long-term use of thenia gravis: both are short-acting therapies and intravenous immunoglobulin in Lambert- do not treat the underlying disease. The side Eaton myasthenic syndrome, and treatment effects of these medications are listed in TABLE 2. should be designed specifically for each The severity Immunomodulating therapy is required patient. of Lambert- for patients with Lambert-Eaton myasthenic We recommend plasma exchange as the syndrome who do not benefit from 3,4-DAP initial therapy for severe cases. If there is a Eaton or pyridostigmine alone. The decision when contraindication such as hemodynamic syndrome to initiate such treatment, especially in instability or venous access, then intra- patients with malignancy, is difficult and venous immunoglobulin is a reasonable is not affected should be made in concert with the patient, alternative. by tumor the treating oncologist, and the neurologist. In our patient, both plasma exchange or Prednisone and azathioprine are frequently intravenous immunoglobulin are appropriate volume used in patients with nonparaneoplastic and therapies, but only if they are given in con- paraneoplastic Lambert-Eaton myasthenic junction with cancer-related treatment. syndrome.18,19 Prednisone has shown moder- ate benefit, although no data from random- Drugs that adversely affect ized control trials are available. Azathioprine Lambert-Eaton syndrome has also demonstrated modest benefit for As with other myasthenic syndromes, the patients who do not respond to steroids or symptoms of Lambert-Eaton myasthenic syn- who cannot tolerate their side effects. drome may worsen when patients are exposed Cyclosporine has modest benefit in patients to new medications. Some medications can failing to respond to azathioprine.20 Thus, exacerbate myasthenic symptoms. Interferon- these choices would be inappropriate as ini- alfa, botulinum toxin, and D-penicillamine are tial therapy. absolutely contraindicated. Neuromuscular In our institution, patients with mild blocking agents, aminoglycosides, quinine, cal- Lambert-Eaton myasthenic syndrome who cium channel blockers, and beta-blockers, as are still ambulatory are generally treated with well as quinidine, procainamide, and magne- 3,4-DAP first, with or without pyridostig- sium salts, are relatively contraindicated.

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Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. Neurologic prognosis cer, and it can be associated with either limit- O’Neill et al24 reported in 1988 that 18 of 25 ed or extensive stages of the disease. In con- patients with paraneoplastic Lambert-Eaton trast to the paraneoplastic endocrine syn- myasthenic syndrome died an average of 10 dromes, in which successful treatment of the months after diagnosis, most from malignan- tumor effectively controls the symptoms, the cy-related complications. Only 3 of the 5 sur- severity of the neurologic symptoms is unre- viving patients had complete responses to lated to the tumor volume and may not treatment of their malignancy 3 to 4 years improve despite control of the malignancy. after tumor diagnosis. Chalk et al,25 in 1990, Likewise, the prognosis of patients with small- demonstrated a similar improvement in neu- cell lung cancer does not appear to be affect- rologic symptoms with combined treatment of ed by the presence or the absence of neuro- the underlying malignancy and Lambert- logic paraneoplastic syndromes. Eaton myasthenic syndrome. These findings support the conclusion ■ CASE FOLLOW-UP that patients with paraneoplastic Lambert- Eaton myasthenic syndrome whose underly- Our patient received four cycles of carboplatin ing malignancy responds to therapy may and etoposide (VP-16) and had tumor remis- expect improvement in their neurologic sion on subsequent chest CT scans. symptoms as well. Initial therapy for Lambert-Eaton myas- For patients with nonparaneoplastic or thenic syndrome included prednisone 60 autoimmune Lambert-Eaton myasthenic syn- mg every morning and pyridostigmine. The drome, a recent study of 47 patients showed institutional review board granted approval that medical therapy (including 3,4-DAP, for using 3,4-DAP; however, the patient prednisone, or azathioprine in various combi- had poor compliance and the pyridostig- nations) improved muscle strength and elec- mine and 3,4-DAP were eventually stopped trophysiologic variables in 88% of patients. because they did not produce significant Twenty percent of these patients achieved a benefit. sustained, complete medical remission, Because her weakness continued, though only 4 were able to come off immuno- plasmapheresis was started. She received suppressive therapy.26 exchanges every other day for 7 days, once a Overall, these data suggest that medical week for 2 months, then every other week treatment of Lambert-Eaton myasthenic syn- for 1 month. Her strength improved signifi- drome (whether or not associated with malig- cantly, and prednisone was tapered at her nancy) can provide substantial benefit to request. patients. Two years after diagnosis, she continues to have weakness thought to be secondary to Cancer prognosis in paraneoplastic Lambert-Eaton myasthenic syndrome and Lambert-Eaton myasthenic syndrome deconditioning, but she is able to ambulate at Lambert-Eaton myasthenic syndrome may home and is better overall. To date, she has no precede the diagnosis of small-cell lung can- evidence of recurrence of her malignancy.

■ REFERENCES 1. Brazis PW, Masdeu JC, Biler J. Localization in Clinical Neurology, 4th 5. Wirtz PW, Sotodeh M, Nijnuis M, et al. Difference in distribution of ed. Philadelphia: Lippincott Williams & Wilkins, 2001:101–127. between myasthenia gravis and the Lambert-Eaton 2. Pioro EP. Motor neuron disorders. In: Levin KH, Lüders HO, editors. myasthenic syndrome. J Neurol Neurosurg Psychiatry 2002; 73:766–768. Comprehensive Clinical Neurophysiology. Philadelphia: W.B. 6. Amato AA, Brooke MH. Disorders of . In: Bradley WG, Saunders, 2000:235–250. Daroff RB, Fenichel GM, Jankovic J, editors. Neurology in Clinical 3. Bosch EB, Smith BE. Disorders of peripheral nerves. In: Bradley WG, Practice, 4th ed. Philadelphia: Butterworth-Heinemann, Daroff RB, Fenichel GM, Jankovic J, editors. Neurology in Clinical 2004:2463–2510. Practice, 4th ed. Philadelphia: Butterworth-Heinemann, 7. Chiou-Tan F, Tim RW, Gilchrist JM, et al. Literature review of the use- 2004:2299–2402. fulness of repetitive nerve stimulation and single fiber EMG in the 4. Sanders DB, Howard JF Jr. Disorders of neuromuscular transmission. electrodiagnostic evaluation of patients with suspected myasthenia In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, editors. gravis or Lambert-Eaton myasthenic syndrome. AAEM Quality Neurology in Clinical Practice, 4th ed. Philadelphia: Butterworth- Assurance Committee, American Association of Electrodiagnostic Heinemann, 2004:2441–2462. Medicine. Muscle Nerve 2001; 24:1239–1247.

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ADDRESS: Bryan E. Tsao, MD, Department of Neurology, S90, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e- mail [email protected].

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