Etiology and Pathophysiology

Under normal conditions, neuronal depolarization opens VGCCs on the presynaptic axon terminal membrane, resulting in calcium influx within the nerve terminal. Intracellular calcium binds to calmodulin and mobilizes acetylcholine (ACh) vesicles that are released into the synaptic cleft (Fig. 74-1). The VGCCs are the primary site of immunopathology in LEMS. Divalent IgG autoantibodies cross-link the calcium channels, disrupting their function, resulting in inadequate release of presynaptic ACh vesicles from motor and autonomic cholinergic nerve terminals. The release of fewer ACh quanta at the neuromuscular junction decreases the probability of reaching the “all or none” depolarization threshold of a muscle fiber and thus the likelihood of the muscle fiber action potential (MFAP) generation. It is this drop out of a significant number of MFAP generation that results in low CMAPs on routine NCS.

Figure 74-1 Physiology of Neuromuscular Junction.

The VGCCs expressed on SCLC cells and other neoplasms provide the presumed antigenic stimulus for antibody production to VGCC in the paraneoplastic form of LEMS. The precise antigenic stimulus in the nonparaneoplastic varieties of LEMS remains to be identified. Muscle weakness, fatigue, and autonomic symptoms result because the VGCC antibodies reduce the ACh release at motor and autonomic nerve terminals, impairing synaptic transmission.

Clinical Presentation

The clinical presentation is similar in primary autoimmune and secondary paraneoplastic LEMS. Fatigue is a prominent and early symptom in LEMS patients. Patients with LEMS also complain of proximal weakness, especially lower extremity weakness, sometimes mimicking a myopathy. The complaints of fatigue and proximal weakness often may seem disproportionate to the objective examination findings. When patients with suspected LEMS do not have objective detectable weakness, it may be better appreciated by watching individuals rise from a chair or climb stairs (Fig. 74-2). Muscle stretch reflexes are typically reduced or absent and this finding can be an important clue to the diagnosis. Postexercise potentiation of depressed or absent muscle stretch reflexes and of muscle strength is often demonstrable and signifies a presynaptic neuromuscular junction transmission disorder.

Figure 74-2 Lambert–Eaton Syndrome.

Oculopharyngeal weakness in the form of diplopia, ptosis, dysphagia, and dysarthria is frequently reported but is usually relatively mild. Autonomic symptoms, including dry mouth or erectile dysfunction in men, should prompt clinicians to consider LEMS. In fact, it is unlikely—although not impossible—for a patient with LEMS to be without symptoms of dry mouth. Patients with LEMS also sometimes complain of vague sensory symptoms, such as tingling and numbness.

Diagnostic Approach

Appropriate NCS testing is crucial in the diagnosis of LEMS (Fig. 74-3). Most patients with LEMS have low-amplitude CMAPs on routine nerve conduction studies. The identification of low baseline CMAP amplitudes should prompt postexercise facilitation testing. This is performed by having the patient isometrically contract the muscle from which the CMAP is being recorded (e.g., abductor digiti quinti minimi) for 10 seconds followed by nerve stimulation and measurement of the CMAP. In patients without LEMS (or another presynaptic neuromuscular junction transmission disorder), there will be no change or only modest increase (<100%) in the size of the CMAP amplitude. The differentiation between a presynaptic and a postsynaptic neuromuscular junction transmission disorder is that brief (10–15 seconds) voluntary exercise, or rarely, if necessary, high-frequency (20–50 Hz) repetitive motor nerve stimulation, leads to marked (>100%) facilitation of the baseline CMAP in patients with LEMS (presynaptic) but not those with myasthenia gravis (MG) (postsynaptic). In addition to testing for postexercise facilitation, slow (e.g., 2- or 3-Hz) repetitive motor nerve stimulation demonstrating decrement of CMAP amplitude of more than 10% can further support the diagnosis of a neuromuscular transmission disorder. Many electromyography (EMG) laboratories routinely combine the slow repetitive motor nerve testing with the 10-second exercise testing in order to search simultaneously for both the postexercise facilitation (of the first CMAP following brief exercise) and the decrement (of the subsequent CMAPs during slow repetitive nerve studies) seen in postsynaptic disorders.

Figure 74-3 Neuromuscular Manifestations of Bronchogenic (Small Cell) Carcinoma.

Serum VGCC antibody testing is also very helpful in diagnosing LEMS. Abnormally high titers of VGCC antibodies are found in approximately 90% of patients with LEMS. High titers of VGCC are also found in 20–40% of patients with SCLC who do not have LEMS. Therefore, a positive VGCC antibody test result does not necessarily diagnose LEMS; the typical clinical and EMG findings are needed to support the diagnosis.

Approximately 50–70% of patients with LEMS have an associated cancer (usually SCLC); therefore, a search for malignancy must be initiated in each patient diagnosed with LEMS. Antibodies to SOX1 have recently been identified in the majority of patients with paraneoplastic LEMS but not in patients with LEMS unassociated with cancer, and thus serological testing for SOX1 may become a valuable aid in searching for cancer in patients who present with LEMS. Imaging for cancer (e.g., chest computed tomographic [CT] scan, chest magnetic resonance imaging scan, and positron emission tomographic [PET] scan) is indicated even if the initial chest radiograph is normal. If the CT is negative, pulmonary cytologic studies, including sputum analysis and bronchial washings, may be valuable to diagnose occult lung tumors, particularly in patients who have a smoking history. Follow-up chest imaging for cancer surveillance is indicated for at least 4 years after the diagnosis of LEMS, in patients with a smoking history.

Differential Diagnosis

The combination of symptoms of weakness and dry mouth sometimes mimics the hyperventilation syndrome, hysteria, malingering, or depression. These conditions should be in the differential early in the evaluation but an appropriate history-taking and examination, combined with appropriate NCS/EMG testing, should allow the physician to easily distinguish a psychological etiology from a neurologic cause. The neurologic disorders that most often mimic LEMS are MG, myopathy, and a chronic polyneuropathy. Unlike LEMS, MG typically has a preponderance of ocular or bulbar symptoms—diplopia, ptosis, dysarthria, and dysphagia—early in its course, whereas in LEMS, oculobulbar symptoms are less commonly the presenting symptoms and usually remain mild. Prominent autonomic symptoms, such as dry mouth and erectile dysfunction, are characteristic of patients with LEMS but are often overlooked by patients and/or clinicians. Other rare presynaptic neuromuscular transmission disorders (e.g., botulism and magnesium intoxication) usually present acutely. Patients with inflammatory myopathies also have predominant proximal limb and neck weakness. However, these patients do not demonstrate facilitation of strength immediately after testing of each muscle. The muscle stretch reflexes are usually preserved in patients with myopathy. Furthermore, patients with myopathy typically do not complain of autonomic and sensory symptoms; serum CK is usually elevated, which would be unexpected in LEMS. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), with its insidious onset of proximal weakness and areflexia, also enters the LEMS differential diagnosis. Nerve conduction studies in CIDP demonstrate features of acquired demyelination (e.g., slowed conduction velocities, conduction block, temporal dispersion), findings never seen in LEMS. Moreover, patients with CIDP usually have prominent sensory nerve symptoms and signs, whereas in LEMS sensory symptoms are typically mild.

Treatment and Prognosis

Chemotherapy, radiation therapy, and surgery are the primary treatment modalities for LEMS-associated lung cancer. Cancer treatment often leads to symptomatic improvement in LEMS, presumably by removing the antigenic stimulus and thus downgrading the immune response. Symptomatic treatment of LEMS aims to improve neuromuscular transmission. The anticholinesterase medication pyridostigmine (Mestinon) can improve neuromuscular transmission by inhibiting breakdown of Ach at the neuromuscular junction. In contrast to MG, pyridostigmine alone is not very effective for LEMS but it is often worth trying because it is a relatively benign treatment option. Common and dose-limiting side effects are abdominal cramps and diarrhea.

3,4-Diaminopyridine (3,4-DAP) promotes ACh release from the presynaptic portion of the neuromuscular junction by prolonging the VGCC open time. It is available for use primarily in Europe but in the United States requires local institutional review board approval and a concomitant submission to the FDA for compassionate use. Caution is advised because central nervous system irritability, manifested by seizures, is a major adverse effect. Anticholinesterases, such as pyridostigmine, potentiate the effects of 3,4-DAP and thus may be particularly beneficial when combined with 3,4-DAP.

Immunomodulation therapy is also sometimes used to inhibit the immune system’s response directed at the neuromuscular junction. Unfortunately, for LEMS patients with cancer, immunomodulation may also inhibit the response of the host’s immune system to the cancer, potentially worsening the cancer. Corticosteroids (e.g., prednisone), intravenous immunoglobulin, and plasmapheresis are some of the immunotherapies that may be beneficial to LEMS patients with profound weakness. These treatments are more commonly prescribed to nonparaneoplastic LEMS patients.

Several medications may exacerbate LEMS symptoms and should be used cautiously in LEMS; these include cardiac drugs, that is, adrenergic and calcium channel–blocking agents, and antiarrhythmic agents, such as procainamide and quinidine. Aminoglycoside antibiotics, magnesium citrate cathartics, quinine, and lithium may also worsen the neuromuscular transmission defect, increasing weakness. Anesthesiologists must be aware of the diagnosis of LEMS in their patient and use medications that do not prolong postoperative respiratory depression. On rare occasions, postanesthesia respiratory failure is the initial manifestation of LEMS.

Prognosis depends on whether LEMS is associated with malignancy and on the stage of malignancy. Most patients with LEMS and SCLC have a median survival of a few years. However, early detection improves prognosis, and consequently it is important to diagnose LEMS quickly and to search aggressively for cancer. In contrast, the prognosis in patients with primary autoimmune LEMS without SCLC is good; some patients live for more than 20 years after diagnosis. These patients with nonparaneoplastic LEMS often respond positively to immunomodulation and symptomatic therapy.

Clinical Vignette

A 4-month-old boy was brought to the emergency room by his parents because of a 2-day history of decreased activity and constipation. He was born at 39 weeks’ gestation; development prior to admission was normal. On admission to the hospital, he appeared lethargic and dyspneic. His respiratory rate was 32 per minute and heart rate was 156 beats per minute. His oxygen saturation was 89% on room air and 100% on oxygen administered nasally.

Examination was remarkable for bilateral ptosis, sluggishly reactive pupils of 4 mm diameter, and bilateral facial weakness. He demonstrated minimal spontaneous movement. He was hypotonic and hyporeflexic. Baseline laboratory studies were unremarkable. NCS/EMG demonstrated an abnormality in neuromuscular transmission with modest posttetanic facilitation with rapid repetitive motor nerve stimulation of the ulnar nerve. Infantile botulism was suspected. He was treated with meticulous supportive care and intravenous human botulism immune globulin. Stool cultures later confirmed the diagnosis of Clostridium botulinum (type E) intoxication.

Etiology and Pathophysiology

Botulism is caused by the toxin from C. botulinum, which is found ubiquitously in soil and water sediments. There are seven distinct toxins, designated by letters A–G, produced by C. botulinum, but human cases of botulism are caused only by toxin types A, B, E, and rarely F. Under normal conditions in the human intestine, any ingested spores of C. botulinum are excreted without germination or toxin production, and thus cause no harm. It is only rarely, more so in infants, that C. botulinum colonizes and produces enough toxin in the intestine to produce botulism.

Infant botulism is the most common form of botulism, with approximately 100 cases reported in the United States each year. Colonization of C. botulinum is believed to occur in some infants because the normal gut flora has not yet been entirely established and thus is unable to prevent the colonization of C. botulinum. The colonization of C. botulinum allows for elaboration of the toxins and development of infant botulism.

Food-borne botulism is caused by the ingestion of food contaminated with C. botulinum. Home-canned foods are a common source of intoxication. There are approximately 20 cases per year of foodborne botulism in the United States. Wound botulism is another form of botulism that occurs almost exclusively among injection drug users. Other less common forms of botulism are adult intestinal toxemia botulism, inhalation botulism, and iatrogenic botulism.

Clinical Presentation, Diagnostic Approach, and Differential Diagnosis

The presentation of botulism is distinctive with symmetrical cranial motor nerve palsies followed by descending flaccid paralysis, including the respiratory muscles. Extraocular muscle weakness (cranial nerves 3, 4, and 6) causes diplopia. Bilateral ptosis is common. Pupillary response is often impaired, resulting in blurry vision. Facial and oropharyngeal weakness, causing dysphagia and dysarthria, are prominent. Limb and axial weakness often develop; diaphragmatic and accessory breathing muscle weakness can cause respiratory compromise. Muscle stretch reflexes are lost. Autonomic nervous system dysfunction, including dry mouth, constipation, and postural hypotension, also occur. Cognition and the sensory system are unaffected.

The differential diagnosis includes MG, Guillain–Barré syndrome (GBS), LEMS, stroke syndromes, and tick paralysis. The very rapid progression of relatively symmetric cranial motor neuropathies followed by axial and limb weakness and dysautonomias (pupillary abnormalities, dry mouth, and constipation) are atypical for MG. On NCS/EMG testing, the presence of, or absence of, significant postexercise or posttetanic facilitation also helps to differentiate a presynaptic from postsynaptic neuromuscular junction transmission disorder. Furthermore, infants are unlikely to develop autoimmune MG and adults are unlikely to develop botulism, so age of onset is an important consideration. Demonstration of C. botulinum in a patient’s stool sample or in cultures of a wound strongly favors botulism, whereas antibodies in serum for the acetylcholine receptor support a diagnosis of MG. GBS, particularly the Miller Fisher variant of GBS, can mimic botulism. Age of onset can again be helpful as GBS is uncommon in infants. Cerebrospinal fluid (CSF) protein is elevated in most cases of GBS, including most cases of Miller Fisher syndrome, whereas CSF protein is normal in botulism. NCS/EMG is often very helpful in detecting evidence of demyelination in GBS and the characteristic electrodiagnostic features of a presynaptic disorder of neuromuscular transmission in botulism (as discussed above in the LEMS section). Tick paralysis can essentially be excluded by a meticulous skin examination, including the scalp; in cases of North American tick paralysis, tick removal leads to a rapid recovery. However in Australia, the inciting tick’s toxin has an effect sometimes lasting a few months.

Treatment and Prognosis

Meticulous supportive care is the mainstay of treatment, with most patients requiring treatment in the intensive care setting. About half of infants with botulism will require intubation and mechanical ventilation. Infants who require ventilator support will do so for a median of 11 weeks. The vast majority will require nasogastric tube feeding for a median of 3 weeks. Antitoxin therapy can arrest progression of weakness and decrease the duration of paralysis, and requires consideration, especially if given within the first 24 hours of symptom onset. Human botulism intravenous immunoglobulin is approved by the United States Food and Drug Administration for the treatment of infant botulism. Almost all patients will recover completely without residual deficits, but this occurs slowly over weeks to months because the toxin binding to the nerve terminal is noncompetitive and irreversible, necessitating nerve terminal regeneration for recovery.