Jump to:

Disease/Disorder

Definition

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.

Etiology

Autoimmune: Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS).

Paraneoplastic: LEMS can occur as a paraneoplastic syndrome, most associated with Small Cell Lung Carcinoma (SCLC) or as an autoimmune phenomenon in the absence of malignancy.

Toxins: Botulinum toxin (ingestion, infantile, iatrogenic, wound) and venom toxins (snake, spider, scorpion).

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 10-20 in 100,000 and an incidence of 5-30 per 1 million person-years.2

LEMS is a rare, autoimmune disease with an estimated global prevalence of about 2.8 per million.3

Botulism is a rare, neurotoxin mediated disease, with approximately 100 cases reported annually in the United States.

CMSs are rare disorders associated with genetic defects of the NMJ transmission with a prevalence of around 1-9 / 1,000,000

Patho-anatomy/physiology

At the normal NMJ, there is an overabundant release of acetylcholine (ACh), resulting in postsynaptic ACh receptor activation, and endplate potential generation to reach threshold for muscle fiber action potential. This redundancy is referred to as the safety factor. In a healthy NMJ, itis 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.

Specific disorders

  • MG: Autoimmunity is directed toward the ACh receptor on the postsynaptic membrane, muscle-specific tyrosine kinase (MuSK), and lipoprotein-related protein 4 (LRP4).
  • LEMS: Presence of autoantibodies against presynaptic P/Q type (Cav2.1) voltage gated calcium channels (VGCC).20
  • Botulism: Botulinum toxin binds irreversibly to the presynaptic membrane and triggers a cascade of reaction which leads to failure of release of Ach, subsequently causing defect in neuromuscular transmission and skeletal muscle paralysis.3
  • CMS: There are numerous CMSs with various mutations affecting the function of either presynaptic, synaptic, and postsynaptic 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. Treatment generally varies based on severity of symptoms and form of the disease.

Specific secondary or associated conditions and complications

Autoimmune: MG and LEMS may be associated with coexistent autoimmune disorders such as thyroid disease, lupus, and rheumatoid arthritis.

Paraneoplastic: 70% of LEMS cases occur in the setting of neoplasm. Within that 70%, 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.

Essentials of Assessment

History

  • 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 typically absent.
  • Autonomic symptoms of dry mouth, dry eyes, palpitations, orthostatic hypotension, erectile dysfunction, constipation, and urinary incontinence may be noted in LEMS and botulism.

Physical examination

  • Weakness with predilection for proximal limb, ocular, and bulbar muscles is typical.
  • Two-thirds of MG patients present with ocular muscle weakness.2 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 unless it has progressed to severe weakness or crisis states.
  • Facilitation of reflexes with brief exercise is pathognomonic of LEMS.
  • Sensory examination is typically normal.

Laboratory studies

Serologic testing

  • MG: ACh receptor antibodies (75-90%); muscle-specific tyrosine kinase (MuSK) antibodies (7%); LRP4antibodies; antibody negative (5%-10%).
  • LEMS: P/Q and N-type VGCC  antibodies (85%); paraneoplastic panel that includes ACh receptor antibodies (nicotinic and ganglionic); creatinine kinase with or without aldolase.
  • Botulism: Identification of neurotoxin by either in vivo mouse lethality bioassay or in vitro ELISA or PCR techniques.

Other testing

  • 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 or other neuromuscular disorder panels for up-to-date availability).

Imaging

Age and gender appropriate malignancy screening is recommended for patients diagnosed with LEMS. A chest computed tomography (CT) or magnetic resonance imaging (MRI) should be obtained for MG patients to screen for thymoma. Routine chest, abdomen and pelvis CT should be performed, which may be followed up with a PET scan if the initial CT workup is negative for mass lesions. Interval malignancy screening at 3-to 6-month intervals for the first year following diagnosis and then periodic screening (annual) until 2 years after the initial LEMS diagnosis is desirable.3

Supplemental assessment tools

Electrodiagnostic Study

Many diagnostic tests are needed to confirm NMJDs. Electrodiagnosis represents key confirmatory tests for these diagnoses.

Nerve conduction study

  • Sensory nerve conduction studies are typically normal in NMJDs and help exclude mimicking or coexistent conditions. Of note, some patients with LEMS may have a concomitant paraneoplastic sensory or sensorimotor neuropathy or chemotherapy related peripheral neuropathy.13
  • Motor nerve conduction studies are usually normal in postsynaptic NMJDs, but in severe cases, compound muscle action potential (CMAP) amplitudes may be slightly reduced while distal latencies and conduction velocities are normal. In contrast, CMAP amplitudes are usually borderline normal or reduced in presynaptic NMJDs. If a low amplitude CMAP is observed, repetitive nerve stimulation, exercise testing, or both can be performed to confirm disorder or NMJ transmission. Motor NCS amplitude may correct after brief exercise in LEMS (see Repetitive Nerve Stimulation (RNS) below). 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 as muscles are functionally denervated. Jitter studies using single-fiber EMG techniques are more sensitive for the detection of LEMS and correlate with clinical severity. Electrophysiological studies may be normal during the initial stages of botulism; therefore, a repeat study after a week is desirable. Botulism and LEMS both may present with reduced CMAP amplitude, facilitation after brief exercise with normal sensory and motor latencies and normal conduction velocities. The important differences between botulism and LEMS include less prominent and longer lasting post-activation facilitation on 2 Hz to 3 Hz repetitive nerve stimulation and an absence of post-activation exhaustion in botulism.

Repetitive nerve stimulation (RNS) is a specialized motor nerve conduction study used to assess NMJDs. An example of a RNS protocol is below

  • Establish a supramaximal CMAP
  • Perform low-frequency RNS
    • Low-frequency RNS is performed with stimuli delivered at 2-3 Hz, in trains of 5 or 10 stimuli. This step can be repeated to ensure reproducibility.
    • Exercise can then be performed on muscle being tested with a brief isometric contraction for 10-15 seconds. This is done to evaluate for facilitation and repair of decrement.
    • Muscles can also be exercised for 60 seconds if no decrement is present at rest to look for post-activation exhaustion
    • Immediately after exercise, stimulate the nerve at 2-3 Hz for 5-10 responses. This step can be repeated every minute for 5 -6 minutes.
  • Notes
    • During RNS temperature should be maintained at or above 32 degrees Celsius, and ideally at 35 degrees Celsius.
    • If feasible, acetylcholinesterase inhibitors should be held for 12 hours before repetitive stimulation is performed.5
    • Avoid RNS testing in patients with external pacing wires and intravenous or intraarterial catheters due to risk of conducting current to the heart. 
    • A decrement of >10% in amplitude between the first and fourth or fifth responses is abnormal. 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.
  • Interpretation
    • MG: Decrement may be apparent at rest. The largest decrement occurs between the first and second stimulus, and the smallest CMAP amplitude usually occurs with the fourth stimulus. 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: Best muscles to test are those that are distal and innervated by a single nerve: abductor pollicis brevis (median), adductor digiti minimi (ulnar), extensor digitorum communis (radial), and extensor digitorum brevis (fibular [peroneal]) muscles. 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). PEF 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)
    • Repeating after 10 seconds isometric exercise.
  • Interpretation: 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
  • SFEMG measures jitter, or the variability between action potential of a single muscle fiber.
  • Jitter values are normalized for age, the muscle being tested, and the needle used.6
  • SFEMG is abnormal if mean jitter is increased for muscle being investigated (i.e., if potential pair being studied has more variation between action potentials than normal) and blocking is present. These findings typically indicate abnormal NMJ transmission.
  • 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.

Rehabilitation Management and Treatments

At different disease stages

Individualized treatment plan depends on etiology, severity, and coexistent medical conditions. The primary goal of myasthenia gravis treatment is remission (no signs or symptoms) or minimal manifestation (no subjective symptoms, any weakness present is mild and does not interfere with normal function). Endpoints for measuring disease severity and treatment response include the Triple Timed Up and Go Test (reliable also in patients with LEMS), the Subject Global Impression Score, and the Quantitative Myasthenia Gravis Score.3

Symptomatic

  • Acetylcholinesterase inhibitors: Block hydrolysis of ACh at cholinergic synapses, which allows ACh to accumulate and have a prolonged effect.
    • Examples: pyridostigmine, which is typically most effective for ptosis and dysarthria in MG. Pyridostigmine is the most widely used for MG and is a useful adjunct in LEMS treatment as it prolongs the effects of potassium channel antagonists and improves oral secretion for symptomatic treatment of dry mouth.3 The increase in oral secretions also leads physicians to use these agents with caution in cases of impending crisis. These inhibitors may be effective for some forms of CMS but cause clinical deterioration in others.14 Adverse effects include abdominal cramping, diarrhea, and lacrimation. Toxicity may cause worsening weakness similar to organophosphate poisoning.
  • Potassium channel antagonist: 3,4-Diaminopyridine (3,4 DAP) prolongs the presynaptic nerve action potential thus facilitating calcium influx and optimizing ACh release.
    • 3,4-DAP is highly effective for treatment of LEMS and some forms of CMS. It was approved by the FDA for LEMS in 2018 although it has been in use since the 1980’s. Adverse effects include perioral and acral paresthesias and seizures at high doses.3
  • Bronchodilators: Beneficial effects of beta-2 agonist albuterol and beta-2 mimetic salbutamol have been reported for forms of CMS,14 but their roles in MG management require further confirmation.
  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Fluoxetine has been reported to have varying effects on different forms of CMS, including improvement of muscle weakness in patients with SCCMS.14
  • Symptomatic treatment is the mainstay of botulism management, with hospitalization required for monitoring of respiratory and autonomic dysfunction as well as opportunity for early intubation.
    • Additional considerations include timely administration of antitoxin or immunoglobulin therapy, public health notification, and wound debridement and antibiotics for wound botulism.27

Immunomodulatory

  • Corticosteroids: First escalation for patients requiring support in addition to pyridostigmine. Onset is within 2-3 weeks and there is a risk of short-term exacerbation of bulbar weakness25 Some retrospective evidence suggests that the risk of generalization of ocular MG may be reduced by prednisone.26
    • In seronegative new onset immune checkpoint inhibitor-related myasthenia gravis patients, steroids may be weaned at a more rapid rate than in idiopathic MG patients.27
  • Immunosuppressant agents: Allow for steroid sparing or additive effects in disease modification. Examples: azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, and methotrexate. Effect usually not seen until 1-14 months after initiating therapy.
  • Rescue therapies: Myasthenic crisis requires intensive care with ventilatory support. Intravenous immunoglobulin and plasma exchange are used for severe or life-threatening symptoms for rapid (but transient) improvement. These agents may also be used chronically in patients who are refractory to oral immunosuppression.
    • Plasma exchange is the treatment of choice in myasthenic crisis. Its complications are largely related to fluid overload and use of central venous catheters; it is contraindicated in patients with sepsis or hypotension.
    • Clinical improvement with IVIg may take a few days up to two weeks to manifest. IVIg is contraindicated in patients with valve disease, cardiomyopathy, or renal insufficiency for risk of volume overload.25 There is also risk for thrombotic events and thus caution should be taken when utilized in patients with suspected malignancy1.3
  • Monoclonal antibodies and other new agents: newer treatments available for MG. Examples: rituximab, complement inhibitors (e.g., eculizumab, ravulizumab, and zilucoplan), and neonatal Fc receptor inhibitors (e.g., efgartigimod and rozanolixizumab). Novel treatments for adults with anti-AChR antibody-positive generalized MG include IV complement inhibitors eculizumab, ravulizumab, and zilucoplan as well as neonatal Fc receptor inhibitors efgartigimod and rozanolixizumab. CD20 antibody rituximab has been reported to cause remission in MuSK antibody-positive patients, whereas there is less evidence for its use in LEMS patients.25
    • These agents carry risk of infection and may affect progression of malignancy in LEMS patients.3
    • Some immunosuppressant agents such as mycophenolate mofetil and methotrexate are strictly contraindicated in pregnancy, whereas other newer medications including rituximab and eculizumab have insufficient data in this population.25
    • Effects of these agents may take up to a year to manifest and laboratory monitoring may be indicated.25 The costs of these medications vary highly and may be prohibitive to some patients.

Prophylactic

  • Low calorie, low salt diet when managed with corticosteroids.14
  • Agents for bone health maintenance when managed with corticosteroids.
  • Antibiotic pneumocystis pneumonia prophylaxis when multiple immunomodulatory agents are implemented.14
  • Prophylactic cholinesterase inhibitors may be recommended in the case of an infection in CMS patients to prevent respiratory insufficiency and episodic apnea.14
  • Cases of new-onset MG have been reported post-COVID-19 infection. It is recommended that MG patients receive an additional dose of the COVID-19 vaccine and be observed for a prolonged period of time following the vaccine to monitor for adverse events such as induction of an MG crisis.28
  • Preoperative plasmapheresis at least 48 hours prior to surgery reduces the myasthenic crisis frequency and shortens ICU stay for qualified patients with high risk of post operative myasthenic crisis.29

Recommendations for Exercise

Literature is limited as far as exercise interventions in myasthenia gravis patients and thus far no consensus guidelines exist. However limited studies on the topic suggest the following

  • Clinically stable MG patients should benefit from physical exercise within the minimum recommended international guidelines for healthy adults (around 150 minutes of moderate intensity exercise per week).
  • MG patients are recommended to engage in aerobic exercise with periods of rest and avoid high temperatures when exercising. If unable to exercise, patients may minimize sedentary time by standing, stretching, and partaking in yoga or tai chi to improve balance.21
  • MG can involve fluctuating symptoms; sustained worsening symptoms may be a sign of progression of the disease and may require additional treatment. If worsening occurs, patients should contact their physician.

Coordination of care

An interdisciplinary approach should be implemented, including neuromuscular medicine, physical medicine and rehabilitation, pulmonary and critical care medicine, occupation/physical/speech/respiratory therapists, and genetic counseling. Timely communication with pharmacists may also help to prevent flagging of prescriptions containing both pyridostigmine and prednisone as “potentially harmful” in many North American pharmacies.26

Thymectomy

In 2016 NEJM published a study of a multicenter, randomized, rater-blinded trial of thymectomy in which MG patients < 65 years with AChR-positive (AChR-Ab+) generalized non-thymomatous MG of <5 years duration were enrolled.

66 subjects underwent extended transsternal thymectomy and received prednisone using a standard dosing schedule, whereas 60 subjects received the standardized prednisone dosing schedule alone. An effect favoring thymectomy was seen in outcome measures.

AAN has thus amended their recommendations to include

  • “a. In non-thymomatous, generalized MG patients with AChR-Ab, aged 18–50 years, thymectomy should be considered early in the disease to improve clinical outcomes and to minimize immunotherapy requirements and the need for hospitalizations for disease exacerbations (median 9, range 2–9). b. Thymectomy should be strongly considered in patients with AChR-Ab+ generalized MG if they fail to respond to an initial adequate trial of immunotherapy or have intolerable side effects from that therapy (median 9, range 5–9).
  • Thymectomy for MG is an elective procedure and should be performed when the patient is stable and deemed safe to undergo a procedure where postoperative pain and mechanical factors can limit respiratory function (median 9, range 8-9).”

Post-thymectomy clinical improvement may take up to two years 26 and utility of postoperative radiation and/or chemotherapy is determined on an individual basis.

Patient & family education

Patients should be advised of the following

  • Natural course of the condition and 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 need for immediate medical attention.
  • Symptoms which are almost certainly unrelated to the neuromuscular junction, including memory loss, generalized fatigue without weakness, and sensory symptoms.
  • Isolated subjective dyspnea, which is rarely an indicator of impending myasthenic crisis. Patients that suffer from this symptom may benefit from respiratory muscle training.21
  • Genetic counseling for CMS.
  • Environmental review for toxins and family education regarding potential Botulinum toxin concerns from foods for infants < 1 year of age.
    • Common sources of botulinum toxin include honey, fermented and home-canned foods, and fish oils.3
  • Avoidance of medications with neuromuscular blockade properties, such as general anesthetic agents, macrolides and quinolone antibiotics, and immune checkpoint inhibitors. Patients are recommended to keep a list of these contraindicated medications on their person and provide one to their primary care provider.3

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.
  • Botulism can present with variable findings on electrodiagnostic testing depending on disease severity and length of time between presentation and examination. Early in presentation CMAP amplitudes may be relatively preserved. Conversely in severe or late presentations complete facial paralysis and upper > lower extremity involvement can also be seen.

Cutting Edge/Emerging and Unique Concepts and Practice

New antibodies emerging in diagnosis of Myasthenia Gravis

  • LRP-4 antibody 18% of seronegative patients18
  • Anti Agrin
  • Contactin

Growing trends of iatrogenic botulism.

Novel immunosuppressive agents targeting complement, FcRn, and other targets for use in MG patients

Gaps in the Evidence-Based Knowledge

  • Quality of Life
    • Mortality in Myasthenia has declined significantly, but quality of life remains reduced in MG patients This is thought to be due to a number of factors, but particularly due to weakness, impaired mobility, and depression.19 Finding interventions and functional evaluations that are able to measure exercise capacity and its improvement in MG is challenging. Some studies have looked into objective measurements of fatigue, such as performance fatigability and fatigue perception, but further investigation is warranted into objective ways to improve quality of life in these patients. Some research has begun to investigate the quality of life in MG based on the MG-QOL15 scale (Myasthenia Gravis-Quality of Life) given that health related quality of life decreases significantly with MG. It is found that MG-QOL15 increases with proper treatment, however, given the fluctuation that occurs with MG, more studies need to be conducted on the MG-ADL and QOL scales.20
  • Therapies
    • Therapy efficacy and resources has increased significantly in recent years, however, there remains advances in treatment of Neuromuscular Junction disorders that need to be unveiled. Corticosteroids have been effective at producing systemic immunosuppression. Newer therapies have been effective at creating immunosuppression at higher specificity, however additional therapies can be created that reduce or expel the immune response responsible for the pathogenesis.21 In recent years, new treatments have been approved that are complement inhibitors and FcRn inhibitors. However, clinical trials are ongoing that focus on similar pathways, but also focusing on B cell targets and even antisense oligonucleotides to name a few. Ongoing barriers to specialist access, costs, prior authorization, and the fact that most newly approved treatments (aside from rozanolixizumab which can be used in MuSK positive cases) are approved only for generalized myasthenia gravis patients that are AChR antibody positive.22

References

  1. 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.
  2. Phillips LH. The epidemiology of myasthenia gravis. Ann NY Acad Sci. 2003;99:407-412.
  3. Raja SM. Lambert-Eaton Myasthenic Syndrome and Botulism. Continuum (Minneap Minn). 2022 Dec 1;28(6):1596-1614. doi:10.1212/CON.0000000000001205. PMID: 36537971. 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.
  4. 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.
  5. 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 Lambert–Eaton myasthenic syndrome: summary statement. Muscle Nerve. 2001;24:1236-1238
  6. Benatar M. A systematic review of diagnostic studies in myasthenia gravis. Neuromuscul Disord. 2006;16:459-467.
  7. Maddison P, Newsom-Davis J, Mills KR. Distribution of electrophysiological abnormality in Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. 1998;65:213-217.
  8. 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.
  9. Oh SJ, Kurokawa K, Claussen GC, Ryan HF Jr. Electrophysiological diagnostic criteria of Lambert-Eaton myasthenic syndrome. Muscle Nerve. 2005;32:515-520.
  10. 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.
  11. 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.
  12. 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.
  13. Dumitru D, Amato A, Zwarts M. (2001). Electrodiagnostic Medicine, 2nd Ed. Philadelphia: Hanley & Belfus.
  14. Finsterer, Josef. (2019, February 26) Congenital myasthenic syndromes. Orphanet Journal of Rare Diseases. https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1025-5 .
  15. Westerberg E, Molin CJ, Lindblad I, Emtner M, Punga AR. Physical exercise in myasthenia gravis is safe and improves neuromuscular parameters and physical performance-based measures: a pilot study. Muscle Nerve. (2017) 56:207–14.
  16. Wolfe, et al. “Randomized Trial of Thymectomy in Myasthenia Gravis.” New England Journal of Medicine 2016; 375: 511-522.
  17. International Consensus Guidance for Management of Myasthenia Gravis: 2020 update. Neurology; 2021: 96.
  18. Rivner, M et al. “Clinical features of LRP4/agrin antibody-positive myasthenia gravis: A multicenter Study.” Muscle and Nerve (2020) 62: 333-343
  19. Twork, S et al. “Quality of life and life circumstances in German Myasthenia Gravis patients.” Health Qual Life Outcomes. (2010)  8:129.
  20. Y.K. Nakao, M. Motomura, T. Fukudome, et al. Seronegative Lambert-Eaton myasthenic syndrome: study of 110 Japanese patients. Neurology, 59 (2002), pp. 1773-1775
  21. Hehir MK 2nd, Li Y. Diagnosis and Management of Myasthenia Gravis. Continuum (Minneap Minn). 2022;28(6):1615-1642.
  22. Diez Porras L, Homedes C, Alberti MA, Velez Santamaria V, Casasnovas C. Quality of Life in Myasthenia Gravis and Correlation of MG-QOL15 with Other Functional Scales. J Clin Med. 2022;11(8):2189. Published 2022 Apr 14. doi:10.3390/jcm11082189
  23. Verschuuren J, Strijbos E, Vincent A. Neuromuscular junction disorders. Handb Clin Neurol. 2016;133:447-466. doi:10.1016/B978-0-444-63432-0.00024-4
  24. Verschuuren JJ, Palace J, Murai H, Tannemaat MR, Kaminski HJ, Bril V. Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders. The Lancet Neurology. 2022;21(2):189-202. doi:10.1016/s1474-4422(21)00463-4
  25. Ciafaloni E. Myasthenia Gravis and Congenital Myasthenic Syndromes. Continuum (Minneap Minn). 2019 Dec;25(6):1767-1784. doi: 10.1212/CON.0000000000000800. PMID: 31794470.
  26. Nicolle MW. Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome. Continuum (Minneap Minn). 2016 Dec;22(6, Muscle and Neuromuscular Junction Disorders):1978-2005. doi: 10.1212/CON.0000000000000415. PMID: 27922503.
  27. Guidon AC. Lambert-Eaton Myasthenic Syndrome, Botulism, and Immune Checkpoint Inhibitor-Related Myasthenia Gravis. Continuum (Minneap Minn). 2019 Dec;25(6):1785-1806. doi: 10.1212/CON.0000000000000807. PMID: 31794471.
  28. Huang EJ, Wu MH, Wang TJ, Huang TJ, Li YR, Lee CY. Myasthenia Gravis: Novel Findings and Perspectives on Traditional to Regenerative Therapeutic Interventions. Aging Dis. 2023 Aug 1;14(4):1070-1092. doi: 10.14336/AD.2022.1215. PMID: 37163445; PMCID: PMC10389825.
  29. Claytor B, Cho SM, Li Y. Myasthenic crisis. Muscle Nerve. 2023 Jul;68(1):8-19. doi: 10.1002/mus.27832. Epub 2023 Apr 28. PMID: 37114503.

Original Version of the Topic

William D. Arnold, MD. Electrodiagnostic studies in neuromuscular junction disorders. 7/26/2012.

Previous Revision(s) of the Topic

Matthew McLaughlin, MD. Electrodiagnostic studies in neuromuscular junction disorders. 8/19/2016.

Gabrielle Nguyen, MD. Electrodiagnostic Studies in Neuromuscular Junction Disorders. 6/29/2021

Author Disclosures

Christopher D. Meserve, MD
Nothing to Disclose

Erinn Ton, MD
Nothing to Disclose

Neha Singh, MD
Nothing to Disclose

Jai Narain
Nothing to Disclose

Rachel M Thompson
Nothing to Disclose

Michael V. Nguyen, MD, MPH
Nothing to Disclose

Gregory T Carter, MD, MS
Nothing to Disclose