Neuromuscular junction disorders (NMJDs) are a diverse group of disorders associated with fluctuating weakness secondary to presynaptic, synaptic, or postsynaptic defects of neuromuscular junction (NMJ) transmission.
Autoimmune: Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS).
Paraneoplastic: LEMS occurs in the setting of a neoplasm in 70% of cases.1 Thymoma occurs in 10% of MG.
Toxins: Botulinum toxin (ingestion, infantile, iatrogenic, wound) and snake venom toxins.
Hereditary: Congenital myasthenic syndromes (CMSs) are a heterogeneous group of rare hereditary disorders.
Medications: Drug-induced MG and drug-induced exacerbation of preexisting MG.
Epidemiology including risk factors and primary prevention
MG is the most common NMJD with a prevalence of 20 in 100,000 and an incidence of 2 per 100,000.2
LEMS is rare with an estimated annual incidence of 0.17 per million and a prevalence of 2.5 per million.3
Botulism is rare with approximately 100 cases reported annually in the United States.
CMSs are rare disorders associated with genetic defects of the NMJ transmission.
At the normal NMJ, there is an overabundant release of acetylcholine (Ach), Ach receptor activation, and endplate potential generation to reach threshold for muscle fiber action potential. This redundancy is referred to as the safety factor, and in the healthy state NMJ transmission; it is an invariably reliable process. The pathophysiologic basis of failed NMJ transmission is an endplate potential that is insufficient to reach the threshold for muscle fiber action potential production.
- MG: Autoimmunity is directed toward the Ach receptor on the postsynaptic membrane.
- LEMS: Autoimmunity is directed toward voltage gated calcium channels at the presynaptic nerve terminal.
- Botulism: Botulinum toxin blocks neurotransmitter release at peripheral cholinergic nerve terminals (including skeletal muscle and autonomic nervous system).
- CMS: There are numerous CMSs with ongoing rapid discovery of additional variants related to presynaptic, synaptic, and postsynaptic defects in NMJ transmission.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
The NMJD may be associated with very mild focal weakness to severe generalized weakness associated with respiratory failure.
- Symptoms fluctuate in severity. Without treatment, symptoms may stabilize, worsen, or improve, but spontaneous remission is unusual.
- Autoimmune NMJDs often require immunomodulatory treatment to control disease progression.
- In neoplastic LEMS, prognosis and primary treatment are usually related to that of the cancer. Immunomodulatory treatment is often necessary.
- There is significant variability between subtypes of the CMSs. Symptoms may progress or regress without intervention.
Specific secondary or associated conditions and complications
Autoimmune: MG and LEMS may be associated with coexistent autoimmune disorders.
Paraneoplastic: Small-cell lung cancer is associated with 90% of paraneoplastic cases of LEMS.1 Other associated cancers are lymphoma, prostate cancer, other lung cancers, thymoma, neuroblastoma, and cervical cancer. Other paraneoplastic syndromes may occur concurrently with LEMS which can be evaluated with other laboratory or radiographic tests.
2. ESSENTIALS OF ASSESSMENT
- Fluctuating weakness is predominantly in proximal muscles and associated with fatigability.
- Ocular and bulbar muscles are frequently more severely affected.
- Generalized fatigue without true weakness is not typical.
- Symptoms of sensory loss, paresthesia, or neuropathic pain are absent.
- Autonomic symptoms of dry mouth, blurry vision, impotence, constipation, and difficulty with urination may be noted in LEMS and botulism.
- Weakness with predilection for proximal limb, ocular, and bulbar muscles is typical.
- Distal or focal weakness may occur in 12% of MG.4
- Extraocular and bulbar weakness are early and prominent in MG and botulism but less prominent in LEMS. If ocular weakness is an initial symptom, LEMS is unlikely.4
- Pupillary responses are usually reduced in botulism.
- Reflexes are characteristically absent or reduced in presynaptic NMJDs but preserved in postsynaptic NMJDs.
- Facilitation of reflexes with brief exercise is pathognomonic of LEMS.
- Sensory examination is normal.
- MG: Ach receptor antibodies (80%); muscle specific tyrosine kinase (MuSK) antibodies (10%); striational antibodies; antibody negative (5%-10%).
- LEMS: P/Q type voltage gated calcium channel antibodies are present in at least 85% of LEMS.
- Botulism: Antibody testing is available to identify exposure to common subtypes.
- Toxin and culture analysis of feces, serum, wound, and food may be considered depending on suspected route of exposure in cases of botulism.
- Genetic testing is available for some CMS disorders (see www.genetests.org for up-to-date availability).
Imaging is indicated to assess for underlying neoplasm, such as chest computed tomography for thymoma.
Supplemental assessment tools
Many diagnostic tests are needed to confirm NMJDs. Electrodiagnosis represents key confirmatory tests for these diagnoses.
Nerve conduction study
- Sensory nerve conduction studies are normal in NMJDs and help exclude mimicking or coexistent conditions
- Motor nerve conduction studies are usually normal in postsynaptic NMJDs, but in severe cases, compound muscle action potential (CMAP) amplitudes may be slightly reduced. In contrast, CMAP amplitudes are usually borderline normal or reduced in presynaptic NMJDs. Distal latencies and conduction velocities are normal. In either case, normal CMAPs do not rule out the presence of neuromuscular junction disorders.
Needle electromyography is frequently normal in mildly affected muscles, but if significant muscle fiber action potential blocking occurs, motor unit action potentials may appear short in duration, small in amplitude, and with normal to early recruitment. These features may mimic myopathy. Instability of motor unit action potentials, referred to as jiggle, can been seen in a triggered analysis. Fibrillation potentials are unusual in MG and LEMS but may occur with severe weakness. Abnormal spontaneous activity is often a distinguishing feature seen in botulism.
Repetitive nerve stimulation (RNS) is a specialized motor nerve conduction study used to assess NMJDs.
- Low-frequency RNS is performed with stimuli delivered at supramaximal, 2-3 Hz, in trains of 5 or 10 stimuli. Trains are delivered at rest, immediately following brief isometric contraction exercise for 10-30 seconds, and every minute for 5 minutes with rest after exercise. Temperature should be maintained at or above 32 degrees C, and as close to 35 degress C as possible. If feasible, acetylcholinesterase inhibitors should be held for 12 hours.5 Abnormal decrement is >10% amplitude decrement between the first and fourth or fifth responses. Usually a distal limb, proximal limb, and bulbar muscles are assessed, and, when feasible, an affected muscle should be tested. Proximal muscles are more sensitive in MG, but distal upper limb muscles are more sensitive in LEMS.6,7 Each lab should have a standardized method of performing RNS.
- MG: Decrement may be apparent at rest. The largest decrement occurs between the first and second stimuli, and the smallest CMAP amplitude usually occurs with the fourth stimuli. Decrement will slightly repair or stabilize between the fourth and tenth stimuli, and this pattern is often described as U-shaped. Following brief isometric exercise, there may be slight CMAP amplitude increment (usually <40%) and repair of decrement. With rest after exercise, slowly worsening decrement may become apparent. This phenomenon is called post-exercise exhaustion (PEE).
- LEMS: Decrement may occur at rest but usually demonstrates progressive decline rather than a U-shaped pattern.8 Following brief isometric exercise, there is usually CMAP amplitude increment termed post-exercise facilitation (PEF; see below). PEE is not evident in LEMS.
- Botulism: Similar to LEMS.
- Denervation: Decrement may be seen in partially denervated muscles (i.e., motor neuron disease), but repair of decrement with brief exercise and PEE are characteristically absent.
- Rapid frequency RNS is performed with stimuli delivered at 20-50 Hz. Usually the distal limb nerve-muscle pairs are assessed. Rapid frequency RNS is an uncomfortable test and should only be considered in select cases when 10 seconds isometric exercise is not possible. A simple screening test for presynaptic NMJDs includes obtaining CMAP at rest (single supramaximal stimulation) and after 10 seconds isometric exercise. The findings after rapid frequency RNS or 10 seconds isometric exercise are listed below:
- LEMS: Increment in amplitude of 60% in three muscles or 300% in one muscle is diagnostic.9
- Botulism: Increment is usually less prominent and may be absent, particularly in severe cases or later in the course of disease.10
- MG: Increment and PEF are typically absent.
- Denervation: Increment and PEF are absent.
- Single fiber electromyography (SFEMG) is a specialized test performed using a single fiber needle electrode or a small size concentric needle electrode (pediatric or facial needle), along with narrow filter settings to allow for analysis of single muscle fiber action potentials.
- SFEMG is the most sensitive test for myasthenia gravis (95%-99%).6
- Findings of jitter and blocking indicate abnormal NMJ transmission.
- Normative jitter values are specific to age, the muscle being tested, and the needle used.6
- Normal SFEMG in a weak muscle excludes the diagnosis of a NMJD.
- It is important to note that the findings are not specific, because secondary NMJ transmission failure may sometimes occur in disorders of the peripheral nerve, motor neuron, or muscle mimicking a primary NMJD.
- Edrophonium (tensilon) testing is performed at the bedside by administering edrophonium and observing for improvement of weakness.
- Most appropriate in cases with extraocular muscle weakness or ptosis, making assessment of improvement unequivocal.
- Heart rate should be monitored for bradycardia or arrhythmia.
- Atropine should be readily available.
- Cholinergic side effects of lacrimation, salivation, sweating, flushing, and fasciculations may occur.
3. REHABILITATION MANAGEMENT AND TREATMENTS
At different disease stages
Individualized treatment plan depends on etiology, severity, and coexistent medical conditions.
- Cholinesterase inhibitors: Block hydrolysis of Ach at cholinergic synapses, which allows Ach to accumulate and have a prolonged effect.
- Potassium channel antagonist: 3,4-Diaminopyridine (3,4 DAP) prolongs the presynaptic nerve action potential thus facilitating calcium influx. 3,4 DAP is very effective in the treatment of LEMS and some forms of CMSs, but it is an investigation medication available only on a compassionate use basis in the United States.11
- Immunosuppressant agents: Allow for steroid sparing or additive effects in disease modification. Examples: azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, and methotrexate.
- Rescue therapies: Intravenous immunoglobulin and plasma exchange are used for severe or life threatening symptoms for rapid (but transient) improvement.
- Low calorie, low salt diet when managed with corticosteroids.12
- Agents for bone health maintenance when managed with corticosteroids.
- Antibiotic pneumocystis pneumonia prophylaxis when multiple immunomodulatory agents are implemented.12
Coordination of care
An interdisciplinary approach should be used, including neuromuscular medicine, physical medicine and rehabilitation, pulmonary and critical care medicine, occupation/physical/speech/respiratory therapists, and genetic counseling.
Patient & family education
Patients should be advised of the following:
- Long-term complications, as well as prevention of these complications associated with immunomodulatory and corticosteroid treatment.
- Worsening symptoms or crisis, which indicate emergency and the patient should seek immediate medical attention.
- Genetic counseling for CMS.
- Environmental review for toxins, family education regarding potential Botulinum toxin concerns from foods for infants < 1 year of age.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
- NMJDs may present with variable clinical features depending on etiology.
- Generalized fatigue without weakness is not typical for a NMJD.
- Treatment is diagnosis-specific, with some forms of treatment having negative effect in some cases.
- Diagnostic modalities include serologic, pharmacologic, and electrodiagnostic testing.
- SFEMG is the most sensitive test, but abnormal findings on RNS and SFEMG are not specific to NMJDs and may be mimicked by other disorders, such as motor neuron disease.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
- Titulaer MJ, Wirtz PW, Willems LNA, van Kralingen KW, Smitt PAES, Verschuuren JJGM. Screening for small-cell lung cancer: a follow-up study of patients with Lambert-Eaton myasthenic syndrome. J Clin Oncol. 2008;26:4276-4281.
- Phillips LH. The epidemiology of myasthenia gravis. Ann NY Acad Sci. 2003;99:407-412.
- Wirtz PW, van Dijk JG, van Doorn PA, et al. The epidemiology of the Lambert-Eaton myasthenic syndrome in the Netherlands. Neurology. 2004;63:397-398.
- Wirtz PW, Sotodeh M, Nijnuis M, et al. Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. 2002;73:766-768.
- AAEM Quality Assurance Committee. American Association of Electrodiagnostic Medicine. Practice parameter for repetitive nerve stimulation and single fiber EMG evaluation of adults with suspected myasthenia gravis or Lambertâ€“Eaton myasthenic syndrome: summary statement. Muscle Nerve. 2001;24:1236-1238
- Benatar M. A systematic review of diagnostic studies in myasthenia gravis. Neuromuscul Disord. 2006;16:459-467.
- Maddison P, Newsom-Davis J, Mills KR. Distribution of electrophysiological abnormality in Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. 1998;65:213-217.
- Baslo MB, Deymeer F, Serdaroglu P, Parman Y, Ozdemir C, Cuttini M. Decrement pattern in Lambert Eaton myasthenic syndrome is different from myasthenia gravis. Neuromuscul Disord. 2006;16:454-458.
- Oh SJ, Kurokawa K, Claussen GC, Ryan HF Jr. Electrophysiological diagnostic criteria of Lambert-Eaton myasthenic syndrome. Muscle Nerve. 2005;32:515-520.
- Kongsaengdao S, Samintarapanya K, Rusmeechan S, Sithinamsuwan P, Tanprawate S. Electrophysiological diagnosis and patterns of response to treatment of botulism with neuromuscular respiratory failure. Muscle Nerve. 2009;40:271-278.
- Quartel A, Turbeville S, Lounsbury D. Current thereapy for Lambert-Eaton myasthenic syndrome: development of 3,4-diaminopyridine phosphate salt as first-line symptomatic treatment. Current Medical Research and Opinion. Mar 2010;26(10):1363-1375.
- Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn E, Leigh R, Brown J, Cohen A, Kim H. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9(1):30.
Original Version of the Topic:
William D. Arnold, MD. Electrodiagnostic studies in neuromuscular junction disorders. Publication Date: 2012/07/26.
Matthew McLaughlin, MD
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