Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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Lambert-Eaton myasthenic syndrome is an autoimmune neurologic disorder characterized by dysfunction at the level of the neuromuscular junction. The unique constellation of symptoms distinctive among paraneoplastic disorders include proximal muscle weakness, autonomic dysfunction with xerostomia, and postexertional facilitation primarily in the context of small cell lung cancer, in 50% of cases. The authors review the clinical features, autoimmune etiology, and management of Lambert-Eaton myasthenic syndrome.
Lambert-Eaton myasthenic syndrome is a disorder of decreased release of acetylcholine from the presynaptic nerve terminals and is believed to be due to autoantibodies against voltage-gated calcium channels.
Lambert-Eaton myasthenic syndrome typically presents with a myopathy-like picture with proximal limb weakness, occasional ptosis, and diminished muscle stretch reflexes but is uniquely characterized by postexertion or postactivation facilitation and a transient improvement in deep tendon reflexes as a result.
At least one half of cases of Lambert-Eaton myasthenic syndrome occur as a paraneoplastic syndrome, almost always in association with small cell lung carcinoma.
Most patients with Lambert-Eaton myasthenic syndrome show improved strength with successful tumor treatment, agents that facilitate neuromuscular transmission, and immunosuppressive therapy.
Lambert, in conjunction with Eaton, was the first to clearly delineate a syndrome of weakness in patients with bronchiogenic carcinoma and its characteristic electrophysiologic abnormalities.
Clinical features. The clinical and electrophysiologic features of Lambert-Eaton syndrome among paraneoplastic and nonparaneoplastic cases generally do not differ (ONeill et al 1988; 91). The tempo of progression of weakness tends to be more rapid among patients with paraneoplastic than those with nonparaneoplastic Lambert-Eaton myasthenic syndrome (106; 94; 91).
Features that may distinguish paraneoplastic from nonparaneoplastic Lambert-Eaton myasthenic syndrome are coexisting paraneoplastic cerebellar degeneration, paraneoplastic encephalomyelitis, sensorimotor polyneuropathy, or other overlap syndromes (07; 16). There is a particular association between Lambert-Eaton myasthenic syndrome and paraneoplastic cerebellar degeneration among patients with small cell lung cancer, and in a Japanese series 9 patients had voltage-gated calcium channel antibodies and appendicular ataxia due to paraneoplastic cerebellar degeneration (44; 52).
Of note, in the era of checkpoint inhibitors, it remains unclear whether presentations of Lambert-Eaton myasthenic syndrome can occur as an immune-related adverse event or if an underlying, preexisting, paraneoplastic disorder is worsened in the context of checkpoint inhibition (53; 10; 15).
Most patients have an insidious, subacute onset of weakness and fatiguability that is suggestive of a myopathy or neuromuscular junction disorder. Early during Lambert-Eaton myasthenic syndrome there is often a discrepancy between complaints of weakness and fatigability and the minor abnormalities that are seen on neurologic examination and no clinical suspicion should be high.
The muscle weakness is typically symmetrically distributed and predominately affects the proximal leg muscles and to a lesser extent the shoulder girdle muscles. The weakness tends to progress proximally to distally over time. Patients often complain of alterations in gait and difficulty arising from a chair or managing stairs. There is often little muscle atrophy. Deep tendon reflexes are characteristically diminished or absent with transient improvement in reflexes following sustained voluntary contraction in one to two thirds of patients (64; 56). This is referred to as postexercise or postactivation facilitation and is unique to Lambert-Eaton myasthenic syndrome. This can be done via maximal isometric contraction of a muscle for 10 seconds and can be seen clinically and electrophysiologically with RNS or brief exercise.
Autonomic dysfunction is a key feature of Lambert-Eaton myasthenic syndrome. Dry mouth is the most common complaint. Over the course of illness, approximately 90% of patients have symptoms of sympathetic or parasympathetic autonomic dysfunction, including dry mouth, erectile dysfunction, blurred vision, constipation, difficulty with micturition, orthostasis, and hypohidrosis (91). In men, the most common manifestation outside of dry mouth was erectile dysfunction (65). Disruption of the autonomic innervation to the eye may result in sluggishly reactive pupils (06). Sudomotor, cardiovagal, and adrenergic dysfunction can all be detected on autonomic testing.
At least one third of patients have ptosis, diplopia, dysarthria, or dysphagia; with some exceptions, ocular and bulbar symptoms are generally mild and occur after patients have developed significant limb weakness are significantly less prominent than in myasthenia gravis (04; 73).
Respiratory failure requiring ventilatory support is uncommon but can occur either spontaneously or be induced by drugs and may rarely be the presenting or predominant feature (29; 02; 81). Mild to moderate diaphragm weakness is present in patients with Lambert-Eaton myasthenic syndrome even in the absence of symptoms and respiratory dysfunction may be in part due to external factors such as chronic smoking or small cell lung cancer (29).
As with myasthenia gravis, drugs that interfere with neuromuscular transmission may cause worsening weakness in Lambert-Eaton syndrome; these agents include anesthetic neuromuscular blocking agents, aminoglycoside antibiotics, ofloxacin or other fluoroquinolone antibiotics, procainamide, quinidine, magnesium, beta-adrenergic blockers, calcium channel blockers, and iodinated contrast agents (98). Heat and febrile illnesses can also exacerbate Lambert-Eaton myasthenic syndrome (76).
The 2 major issues in the differential diagnosis of Lambert-Eaton myasthenic syndrome are: (1) to distinguish Lambert-Eaton myasthenic syndrome from other causes of weakness, especially other disorders of neuromuscular transmission; and (2) in patients with confirmed Lambert-Eaton myasthenic syndrome, to determine which patients have an underlying neoplasm. The classic clinical constellation (proximal weakness, fatigability, relative sparing of ocular and bulbar muscles, diminished tendon reflexes, and postexercise facilitation), plus the characteristic electrophysiologic abnormalities on EMG and repetitive nerve stimulation, are not easily mimicked by other disorders (102). Patients with mild or atypical Lambert-Eaton myasthenic syndrome are more challenging and are often initially diagnosed as having myasthenia gravis. Rarely, Lambert-Eaton myasthenic syndrome and myasthenia gravis coexist in the same patient; some of these overlap patients have both acetylcholine receptor antibodies and voltage-gated calcium channel antibodies (54; 23). To our knowledge, there is a single reported case of a patient with small cell lung cancer, myasthenia gravis with antibodies against muscle-specific tyrosine kinase (MuSK), and Lambert-Eaton myasthenic syndrome anti-voltage-gated calcium channel antibodies (03).
The prognosis of Lambert-Eaton myasthenic syndrome differs between paraneoplastic and nonparaneoplastic Lambert-Eaton myasthenic syndrome.
In paraneoplastic Lambert-Eaton myasthenic syndrome, the prognosis is generally dictated by prognostic factors of the cancer, most commonly small cell lung cancer, found at the time of neurologic presentation. However, prognosis in paraneoplastic Lambert-Eaton myasthenic syndrome is considered to be quite good after taking these into consideration (35). Lambert-Eaton myasthenic syndrome has been found to be an independent predictor of prolonged survival in patients with small cell lung cancer (41). In 1 report, overall median survival for patients with Lambert-Eaton myasthenic syndrome and small cell lung cancer and those with small cell lung cancer alone was 17 versus 7.0 months (33) (p < 0.0001). There is some evidence suggesting that in the context of antitumor immune suppression, limited stage cancers are more likely to be identified in patients with paraneoplastic disease, lead time bias aside, but studies on long-term prognosis have demonstrated prolonged survival of patients with Lambert-Eaton myasthenic syndrome and small cell lung cancer as compared to small cell lung cancer alone regardless of tumor stage (05; 33).
Treatment of the underlying malignancy, most commonly small cell lung cancer, may result in full but more commonly partial remission of clinical symptoms of Lambert-Eaton myasthenic syndrome and improvement in the electrophysiologic abnormalities (05). Weakness may remain after treatment of the underlying tumor and may require ongoing immunomodulatory treatment.
There does not seem to be a survival advantage for patients with small cell lung cancer and low titers of anti-voltage-gated calcium channel antibodies but no clinical Lambert-Eaton myasthenic syndrome (48). There is no indication that P/Q type calcium channel antibodies at baseline or with ongoing treatment are predictive or prognostic of disease severity or treatment response (66).
In nonparaneoplastic Lambert-Eaton myasthenic syndrome, life expectancy appears to be the same as the general population but patients can have fluctuating degrees of disability associated with the disorder over time (33). A study of patients with Lambert-Eaton myasthenic syndrome without small cell lung cancer found that patients had at least partial remission, with 88% of patients having improvement in muscle strength scores after treatment with immunomodulatory therapy for median 6 years but 30% of patients at last follow-up required a wheelchair. Clinical remission was achieved in 20 of 44 patients (43%) but was only sustained without immunosuppression in 4 and approximately one fourth of the patients were partially wheelchair dependent at last follow-up. Mean age of death was 69.7 years after symptom duration of median 11.4 years in 10 patients in this study and these deaths were not directly attributed to Lambert-Eaton myasthenic syndrome (38).
A 66-year-old woman with a long history of cigarette smoking, hypertension, and noninsulin-dependent diabetes presented with slowly progressive bilateral leg weakness and fatigability for 4 months. She complained of difficulty climbing stairs and getting out of a car and on questioning reported dry mouth and urinary hesitancy. She denied ptosis, diplopia, change in speech or swallowing, weakness of the upper extremities, or any sensory symptoms. Prior testing including serum chemistries (creatine kinase), thyroid function tests, and chest x-ray were normal.
Examination revealed normal cranial nerve exam and mental status. There was no ptosis or ocular or bulbar weakness. Strength was normal except for 4+/5 in the deltoids and 4/5 in hip flexors, hip extensors, and quadriceps bilaterally (Medical Registration Council Scale). With repeated strength testing her strength improved to 4+/5. Muscle stretch reflexes were 1+ at the biceps and absent elsewhere and after exercise were normal throughout. Sensory and cerebellar testing was normal. She was unable to arise from a chair without pushing up with her arms and could not perform deep-knee bend.
Electrodiagnostic studies included normal nerve conduction velocities. Studies of the left abductor digiti quinti showed reduced amplitude of the compound muscle action potential (20% of normal), a decremental response (55%) at 3 Hz stimulation, and an incremental response (300%) at 50 Hz stimulation. The compound muscle action potential tripled after 20 seconds of maximal voluntary contraction. Single-fiber EMG of the left extensor digitorum communis showed abnormal jitter and blocking.
The patient was diagnosed with Lambert-Eaton myasthenic syndrome and her strength improved on pyridostigmine 60 mg 3 times daily. A chest CT was performed that showed mediastinal lymphadenopathy. Needle biopsy revealed small cell lung carcinoma. Workup showed limited stage disease and she was started on systemic chemotherapy in addition to prednisone 60 mg per day and received a course of 5 sessions of plasma exchanges. One month later, her strength had improved to normal except for mild iliopsoas weakness. She attained a complete tumor remission after 4 cycles of chemotherapy and the prednisone dose was gradually tapered to 20 mg on alternate days. Eight months after tumor diagnosis she continued to function at a normal level.
The primary pathophysiologic abnormality in Lambert-Eaton syndrome is a reduction of the calcium-dependent quantal release of acetylcholine triggered by a nerve impulse. Ultrastructural studies of muscle from Lambert-Eaton syndrome patients show a marked depletion of presynaptic active zones (the sites of synaptic vesicle exocytosis), paucity and disorganization of active zone intramembrane particles, and aggregation of the active zone particles into clusters (14). Lambert and Elmqvist demonstrated normal postsynaptic sensitivity to acetylcholine receptors with normal endplate potential amplitudes at the neuromuscular junction but reduced evoked endplate potential amplitudes or decreased acetylcholine release in response to stimulation (25). In biopsied intercostal muscles from patients with Lambert-Eaton myasthenic syndrome, acetylcholine release spontaneously and to potassium chloride mediated depolarization was low whereas levels of choline acetyltransferase were normal, suggesting the defect lay at the level of release of the quanta (47).
Several lines of clinical and experimental evidence support a humoral autoimmune mechanism underlying Lambert-Eaton syndrome.
Passive transfer and in vitro experiments using Lambert-Eaton syndrome patients' sera strongly support an autoantibody-mediated etiology. Purified IgG from Lambert-Eaton syndrome patients injected into mice blocks the nerve impulse-evoked release of acetylcholine in a dose-dependent manner and reproduces the electrophysiologic features of Lambert-Eaton syndrome (70). Lambert-Eaton syndrome patient IgG produces depletion of active zones and aggregation of active zone particles in the mouse diaphragm, closely resembling the presynaptic membrane lesions found in Lambert-Eaton syndrome patients (13). Aggregation and depletion of active zone particles are produced by patients' divalent fragments of immunoglobulin G after digestion with the enzyme pepsin but not by monovalent fragments of immunoglobulin G involved in antigen binding, supporting the hypothesis that autoantibodies cross-link the active zone particles with subsequent aggregation and internalization of the particles (67). Expression of a heterogeneous array of voltage-gated calcium channels is a common if not universal feature of small cell lung carcinomas, from patients with and without Lambert-Eaton syndrome (80). Serum IgG from Lambert-Eaton patients inhibits the potassium-stimulated (voltage-gated) calcium influx into cultured small cell carcinoma cells (96; 46). The degree of inhibition of calcium influx by patient's IgG correlates with the reduction in amplitude of the resting compound muscle action potential (27). Serum IgG from Lambert-Eaton patients impairs neurotransmitter release from cultured mouse neurons (97; 82). Active immunization of rats with a recombinant P/Q-type voltage-gated calcium channel produces weakness as well as the electrophysiologic features of Lambert-Eaton syndrome (24).
Clinically, in support of an autoimmune pathogenesis is the profound response patients with Lambert-Eaton myasthenic syndrome have to plasma exchange and immunosuppressive drug therapy (26; 09) The HLA-B8 histocompatibility antigen is overrepresented among patients with nonparaneoplastic Lambert-Eaton myasthenic syndrome but not in patients with small cell lung cancer and Lambert-Eaton myasthenic syndrome (105). In nonparaneoplastic Lambert-Eaton myasthenic syndrome, increased prevalence of organ-specific autoantibodies, such as antiparietal cell and antimicrosomal thyroid antibodies, and of other autoimmune disorders such as pernicious anemia, celiac disease, thyrotoxicosis, systemic lupus erythematosus, and myasthenia gravis (99).
Sera from 85% to 90% of Lambert-Eaton patients contain serum IgG antibodies against P/Q-type voltage-gated calcium channels. The antibodies are detected by an immunoprecipitation assay using a selective P/Q channel antagonist (either a cone snail toxin or a funnel-web spider toxin) and solubilized lysates of small cell lung carcinoma cells, neuroblastoma cells, or human cerebellum (31; 50). Patients antibodies bind to several subunits of the P/Q-type channels (19). Quantitative titers of anti-P/Q-type voltage-gated calcium channel antibodies do not differentiate between Lambert-Eaton patients, with or without an associated neoplasm, and do not correlate well with clinical or electrophysiologic disease severity among patients (31; 51). Clinical features of Lambert-Eaton syndrome among the 10% to 15% of patients seronegative for antivoltage-gated calcium channel antibodies do not differ from those of the seropositive patients, but the seronegative patients are less likely to have an associated neoplasm (52).
Low titers of anti-P/Q-type voltage-gated calcium channel antibodies are detected in up to 10% of patients with small cell lung carcinoma but without neurologic symptoms (31; 51; 100; 37; 66). Some patients with anti-P/Q-type channel antibodies additionally have antibodies against N-type calcium channels, and a few patients have anti-N-type antibodies but not identifiable P/Q-type antibodies (42). Approximately 15% of patients with small cell lung cancer and paraneoplastic encephalomyelitis or sensory neuronopathy, but with no clinical evidence for Lambert-Eaton syndrome, also have voltage-gated calcium channel antibodies (28).
Voltage-gated calcium channels may not be the sole targets of autoimmunity in Lambert-Eaton syndrome (85). The synaptic vesicle protein synaptotagmin associates with calcium channels, and plays a role in the docking of synaptic vesicles at the presynaptic membrane prior to acetylcholine release (83). Synaptotagmin is expressed by small cell lung carcinoma cells and co-immunoprecipitates with conotoxin-bound partially purified calcium channels and Lambert-Eaton patients' IgG (43). Anti-synaptotagmin antibodies are present in a minority of patients with Lambert-Eaton syndrome (11; 87; 85). Immunization of rats with synthetic synaptotagmin peptides can partially reproduce the electrophysiologic features of Lambert-Eaton myasthenic syndrome (86; 84).
Several studies have attempted to estimate the incidence and prevalence of Lambert-Eaton myasthenic syndrome in patients with and without small cell lung cancer.
A population-based study from a province in Southern Netherlands and a subsequent study corroborating the original findings encompassed all of the Netherlands and identified 52 Lambert-Eaton myasthenic syndrome patients between 1998 and 2003. Prevalence on July 1, 2003 was found to be 2.5 per million people (95% confidence interval 1.8-3.4) and annual incidence was calculated to be 0.4 per million inhabitants (95% CI 0.3-0.75 for Lambert-Eaton myasthenic syndrome with and without small cell lung cancer). The prevalence and incidence were found to be slightly higher in Lambert-Eaton myasthenic syndrome patients without small cell lung cancer and they found that the prevalence corrected for age was slightly higher in females than males up to age 60 but was equal for ages between 60 and 80, and higher for females after 80 years of age. The annual incidence of myasthenia gravis was 14 times higher than Lambert-Eaton myasthenic syndrome and the prevalence was 46 times higher than Lambert-Eaton myasthenic syndrome, underscoring the overall rarity of the disorder. A study from the United States Veterans Affairs population estimated a point prevalence of 2.6 per million confirmed cases. There are reports of Lambert-Eaton myasthenic syndrome in children, although an exact estimate of the frequency remains unknown with and without associated neoplasms such as neuroblastoma (20). Approximately 3% of small cell lung cancer cases are estimated to develop Lambert-Eaton myasthenic syndrome (12).
The only known risk factor is the strong association between cigarette smoking and small cell lung carcinoma.
Electrodiagnostic testing remains the gold standard for diagnosing Lambert-Eaton syndrome (89; 88; 76; 61; 62). The characteristic electrophysiologic profile of Lambert-Eaton syndrome includes the following:
(1) Reduced amplitude of muscle action potentials evoked by a supramaximal stimulus, sometimes to as little as 10% of normal
(2) A decremental response of greater than 7% at 2 Hz to 5 Hz repetitive nerve stimulation
(3) A greater than 100% increase in compound muscle action potentials after several seconds of maximal voluntary contraction (postexercise facilitation) or at 20 Hz to 50 Hz repetitive nerve stimulation. Some studies suggest that increments of 60% to 99% are strongly supportive of a presynaptic neuromuscular junction disorder (34).
(4) Increased jitter and impulse blocking on single-fiber EMG testing; the jitter and blocking often decrease at rapid stimulation rates.
Many labs rely on testing for facilitation after maximal voluntary contraction rather than performing 20 Hz to 50 Hz stimulation (40; 88; 21). In other studies, the exercise test was less sensitive than 50 Hz rapid stimulation in some patients (61). The electrophysiologic abnormalities are often detected in clinically unaffected muscles, though not all muscles are equally affected. Electrophysiologic tests cannot distinguish between the paraneoplastic and nonparaneoplastic forms of Lambert-Eaton syndrome. Seronegative patients without voltage-gated calcium channel antibodies may have less severe reduction in muscle action potential amplitudes and a lesser degree of incremental EMG response to rapid stimulation than seropositive patients (58). In these patients single-fiber EMG may support the diagnosis of a presynaptic defect in neuromuscular transmission (62).
Serial measurements of compound muscle action potential amplitudes or single-fiber EMG generally correlate well with clinical response to treatment (05).
Autonomic testing in Lambert-Eaton myasthenic syndrome may reveal abnormalities in all subcategories of autonomic reflex screening with sudomotor abnormalities being most frequent (83%) followed by cardiovagal (75%) and adrenergic (37%). Severity of autonomic failure ranged from mild to severe as quantified by composite autonomic scoring scale scores ranging from 0 to 10 with a median of 3. Interestingly, adrenergic failure correlated with more severe sudomotor and cardiovagal impairment in these patients. Evaluation of xerostomia is another important measure of autonomic function in these cases (65).
Cancer evaluation. In patients with confirmed Lambert-Eaton syndrome, the search for a tumor should focus on small cell lung cancer. Approximately one half of patients with Lambert-Eaton myasthenic syndrome have an associated neoplasm (64; 18; 88; 101; 103; 92). Small cell lung cancer is the associated tumor in at least 90% of well-documented cases of paraneoplastic Lambert-Eaton myasthenic syndrome. Factors predictive of small cell lung cancer include present or prior cigarette smoking, age over 50 years, poor performance status, erectile dysfunction in men, and early bulbar weakness and the use of the Dutch-English LEMS Tumor Association Prediction Score (DELTA-P) score based on these predictive factors may be helpful in identifying which patients are at highest risk of having an underlying tumor (92).
Lambert-Eaton myasthenic syndrome may also occur rarely in patients with other neoplasms, including prostate carcinoma (07), non-small cell lung cancer (79; 08), thyroid carcinoma (59), small cell carcinoma of the cervix, lymphoma (07; 16), thymic tumors, Merkel cell carcinoma, and germinoma (60). Lambert-Eaton myasthenic syndrome has been reported in a small number of children, with or without an associated neuroblastoma or other neoplasm (49; 20).
Initial evaluation should begin with chest CT or MRI for detection of small cell lung carcinoma (95; 93). If clinical suspicion for malignancy remains high, FDG-PET can be used to identify a tumor despite normal or equivocal chest CT or MR (32; 108; 95). "Blind" bronchoscopy in the absence of a definite radiographic pulmonary lesion occasionally discovers small cell lung carcinoma in smokers with Lambert-Eaton syndrome (76), but is not generally considered standard care (95; 93).
It is not uncommon for initial evaluation for an occult lung tumor to be unrevealing; in these cases the workup should be repeated at regular intervals of approximately every 6 months to 1 year (93). Some studies suggest that if no tumor was discovered after 5 years, the Lambert-Eaton syndrome was most likely nonparaneoplastic (64). In another series, the associated small cell lung cancer was diagnosed in nearly 100% of patients within 1 year after onset of Lambert-Eaton syndrome (95).
Antibody evaluation. The finding of a high serum titer of antibodies against P/Q-type voltage-gated calcium channels strongly supports the diagnosis of Lambert-Eaton myasthenic syndrome (31; 50; 51). A negative assay does not rule out Lambert-Eaton myasthenic syndrome; conversely, low antibody titers may be present in patients without the syndrome.
Antibodies against the SOX1 transcription factor are present in nearly two thirds of patients with Lambert-Eaton myasthenic syndrome associated with small cell lung cancer but only in 5% of patients with nonparaneoplastic Lambert-Eaton myasthenic syndrome (74; 90; 17). Antibodies to SOX are also present in 40% of patients with small cell lung cancer but without neurologic symptoms. Anti-SOX antibodies are not directly involved in the pathogenesis of Lambert-Eaton myasthenic syndrome but this seems to be a valuable serologic marker for small cell lung cancer. Literature suggests that N-type voltage gated calcium channels, SOX2 antibodies, or GABAb antibodies in patients with Lambert-Eaton myasthenic syndrome can be highlighted sensitive and specific for the detection of small cell lung cancer (36).
Management of patients with Lambert-Eaton syndrome includes pharmacologic facilitation of neuromuscular transmission, removal of autoantibodies, suppression of autoantibody production, and treatment of the underlying tumor (88; 76). The clinical and electrophysiologic features of paraneoplastic Lambert-Eaton syndrome often improve with successful treatment of small cell lung carcinoma or other associated tumors. Tumor recurrence is not usually accompanied by a relapse of Lambert-Eaton syndrome (05). Rarely, the course of the neurologic syndrome fluctuates independently of the status of an individual patient's tumor.
One of the major reasons for the successful treatment of the Lambert-Eaton syndrome, relative to other paraneoplastic disorders, is that several agents enhance neuromuscular transmission independent of suppression of the autoimmune response. Dosage amounts of pyridostigmine that are effective for myasthenic gravis also improve strength in the majority of patients with Lambert-Eaton syndrome, although most of them require additional treatment.
For patients with mild weakness or minimal functional impairments, close monitoring can be considered.
For patients with more severe functional impairment, the first line treatment is a medication known as 3,4-diaminopyridine (amifampridine) blocks potassium channels and prolongs the action potential at motor nerve terminals, thereby increasing the release of acetylcholine by a nerve impulse. The drug may also directly stimulate presynaptic voltage-gated calcium channels to potentiate acetylcholine release (107). The drug is a derivative of 4-aminopyradine, which was he first recognized drug in the family to be recognized for a beneficial effect in Lambert-Eaton syndrome but was limited by CNS toxicity, primarily seizures. Diaminopyridine produces some degree of sustained symptomatic improvement in nearly all patients with Lambert-Eaton syndrome, with or without an associated neoplasm (45; 05; 75; 76; 77; 57; 104; 63). Up to 50% of patients may function normally in daily activities. The optimal dose of diaminopyridine in individual patients varies widely, from 5 mg 3 times a day and can be titrated upward every 3 to 4 days by 5 mg, to 25 mg 4 times a day or more (although the maximum approved dose is 80 mg) in most clinical practice based on efficacy and tolerability). Most patients have transient perioral and digital paresthesias after doses greater than 10 mg (63). Insomnia may occur if diaminopyridine is taken near bedtime. The most serious side effect is seizure, which usually, but not always, occurs at daily doses of greater than or equal to 100 mg. Cholinergic side effects include abdominal cramps, diarrhea, and blurred vision. Liver function abnormalities can occur.
In some patients, the addition of pyridostigmine enhances and prolongs the effect of diaminopyridine and permits dose reduction, although patients may have additional gastrointestinal side effects with combined treatment (75; 76; 88; 104). In isolation, the drug is minimally effective for the treatment of Lambert-Eaton myasthenic syndrome.
Guanidine facilitates neuromuscular transmission and has been used in treatment of Lambert-Eaton syndrome for more than 20 years. Guanidine is given in an oral dose of 5 mg/kg to 30 mg/kg per day. The addition of guanidine to a maximally effective dose of pyridostigmine may permit a lower dose of both drugs, with reduction in the risk of serious guanidine toxicity (59). The side effects of guanidine are dose-related and include myelosuppression, renal tubular acidosis, interstitial nephritis, cardiac arrhythmias, hepatotoxicity, ataxia, and confusion. Hematologic, hepatic, and renal parameters must be monitored regularly.
For patients with paraneoplastic Lambert-Eaton syndrome who are receiving or will receive tumor treatment, it is usually reasonable to use pyridostigmine, diaminopyridine, or guanidine and to defer immunotherapy because many of these patients will improve if tumor treatment is successful.
If this is not an option or patients still have severe weakness, there are several therapies for removal of autoantibodies or suppression of autoantibody production similar to those for myasthenia gravis.
Initial treatment with plasma exchange can be considered. Plasma exchange (3-5 L of plasma exchanged over 5 exchanges) produces an improvement in strength and electrophysiologic parameters in the majority of patients with Lambert-Eaton myasthenic syndrome, usually beginning within 1 to 3 weeks and persisting for as long as 2 to 3 months (09; 55).
Similarly, due to its ease of use, intravenous immunoglobulin (IVIG) can be considered as initial therapy. Intravenous immunoglobulin (0.4 gm/kg per day for 5 days) has been shown to be effective (01; 72), with peak clinical improvement seen within 2 to 4 weeks and beneficial effects usually lasting from 2 to 3 months. Intravenous immunoglobulin can be limited by infusion reactions and thrombosis risk and its use is limited in patients with renal disease, cardiovascular disease, or if there are concerns about fluid shifts.
Prednisone (60 to 80 mg per day; 1 mg/kg per day or 1.5 mg/kg every other day) and azathioprine (2-3 mg/kg per day) are generally effective, but improvement is not apparent for several weeks or longer. Some patients benefit from combined treatment with both agents (55; 88) but prednisone in isolation is often preferred if acute therapies such as plasma exchange or intravenous immunoglobulin are not trialed or in addition to these. There is characteristically a lag of 3 to 6 months (or even longer) before any beneficial clinical effect of azathioprine becomes apparent. Cyclosporine has been used occasionally for treatment of patients with Lambert-Eaton syndrome who do not respond to or tolerate corticosteroids or azathioprine (88; 38; 91). Improvement occurs within 1 or 2 months and maximum benefit is usually apparent within 4 months. There are anecdotal reports of response to rituximab (69; 39).
In patients with concomitant Lambert-Eaton syndrome and paraneoplastic encephalomyelitis, the central nervous system manifestations rarely improve despite a good response of the neuromuscular symptoms to chemotherapy and immunosuppression (16).
The options for pharmacologic and immunosuppressive treatment of patients with nonparaneoplastic Lambert-Eaton syndrome are the same as those for paraneoplastic cases (38; 68).
The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted numerous questions regarding the ongoing management of patients with Lambert-Eaton myasthenic syndrome, particularly given their variable degree of immunosuppression and hospitalization risk. At present, there is no evidence to suggest major modification to immunotherapeutics are warranted or that patients with Lambert-Eaton myasthenic syndrome are at higher risk of contracting the virus and guidelines now exist to aid clinicians in their decision-making (22).
There are several reported cases of nonparaneoplastic Lambert-Eaton syndrome during pregnancy. Some women continued taking immunosuppressive agents and/or 3,4-diaminopyridine during pregnancy. There is no obvious deleterious effect of pregnancy on the course of Lambert-Eaton syndrome, though increased maternal weakness has occurred after tocolysis with fenoterol and magnesium sulfate (78). Transient hypotonia and/or mild weakness may occur in the newborn infant (30; 71).
Patients may have pronounced sensitivity to neuromuscular blocking anesthetic agents. Lambert-Eaton syndrome may be first discovered in patients with severe prolonged weakness or ventilatory failure after anesthesia with neuromuscular blocking agents (81; 98).
Rimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novocure for speaking engagements, honorariums from Novocure and Merck for advisory board membership, and research support from BMS as principal investigator.See Profile
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