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Musculoskeletal System

Lambert–Eaton myasthenic syndrome (LEMS)

Paraneoplastic or primary auto-immune neuromuscular junction disorder characterized by proximal weakness and autonomic dysfunction.

The Lambert-Eaton syndrome is an autoimmune disease that manifests itself primarily as muscle weakness in the legs. In more than half of the cases, a tumor on the bronchi is the cause of the disease. | iStockphoto

Paraneoplastic or primary auto-immune neuromuscular junction disorder characterized by proximal weakness and autonomic dysfunction.

  • Type II autoimmune diorder
  • Paraneoplastic syndrome:60% associated with small-cell lung carcinoma (SCLC)

History:

Dr. Edward H. Lambert
Dr. Lee M. Eaton

In 1953, Anderson and colleagues described a 47-year-old man with fatigable proximal weakness, dysphasia, and diminished Deep Tendon Reflex (DTRs) who improved after an oat cell (small cell) lung cancer was surgically removed. At a meeting of the American Physiologic Society in 1956, Lambert and coworkers presented a report on six patients with defective neuromuscular transmission associated with malignant neoplasms. They identified some of the clinical and electrophysiologic features that were different from what were expected in typical myasthenia gravis (MG). Subsequently, in 1957, Eaton and Lambert reported the distinctive electrophysiologic abnormalities seen with repetitive nerve stimulation (RNS) and identified a syndrome that has become known as LEMS. The diagnosis is still based on these electrophysiologic criteria. Soon after the original report, two publications from the same department highlighted the range of clinical and electrophysiologic features of this syndrome in 30 patients, including patients without lung cancer. The calcium channels as a target of the pathogenic antibodies in LEMS were first suggested by Fukunaga and colleagues in 1983. The discovery of pathogenic autoantibodies to VGCC has facilitated diagnosis and improved the understanding of the pathophysiologic mechanisms leading to LEMS (1983–1995). Subsequent studies showed antibodies against P/Q-type calcium channel as the most prominent in these patients. Over the past decade, knowledge of epidemiologic and clinical features of LEMS has expanded.

Classification

Paraneoplastic (P-LEMS) form (60% cases): SCLC-LEMS

  • ♂ (65-75%) > ♀

Autoimmune (A-LEMS) form or Nontumor (NT-LEMS) form

  • ♂ < ♀
  • Genetic association: HLA-B8-DR3 haplotype (linked to autoimmunity) and is present in around 65% of patients with young onset of NT-LEMS.12

Pathophysiology

Weakness caused by antibodies generated against the P/Q-type voltage-gated calcium channels (VGCC) present on presynaptic nerve terminals and by diminished release of acetylcholine (ACh).

Pathophysiology of LEMS and effects of symptomatic treatment
Pathophysiology of LEMS and effects of symptomatic treatment: (A) Normal depolarisation of the presynaptic nerve terminal by ion channels leads to influx of calcium ions and subsequent release of ACh-containing vesicles; ACh binds to the ACh receptor, leading to depolarisation of the postsynaptic synapse and ultimately to muscle contraction. (B) In LEMS, VGCC antibodies block calcium influx, leading to reduced ACh vesicle release from the presynaptic membrane; therefore, reduced ACh is available to bind to postsynaptic ACh receptors. (C) Treatment with 3,4-diaminopyridine (red triangle) blocks the efflux of potassium ions, prolonging the duration of depolarisation. Longer depolarisation keeps the pathologically affected calcium channels open longer, increasing calcium ion influx and intracellular calcium concentration and thereby improving the ability of the ACh vesicles to fuse and release neurotransmitter. | LEMS=Lambert–Eaton myasthenic syndrome. ACh=acetylcholine. VGCC=voltage-gated calcium channels. DAP=diaminopyridine. | Titulaer, M. J., Lang, B. and Verschuuren, J. J. G. M. (2011) ‘Lambert-Eaton myasthenic syndrome: From clinical characteristics to therapeutic strategies’, The Lancet Neurology. Elsevier, 10(12), pp. 1098–1107. doi: 10.1016/S1474-4422(11)70245-9.

Presentation

Clinical triad:

  1. Proximal muscle weakness
  2. Autonomic features
  3. Areflexia

Progressive symmetrical muscle weakness (96%):

Spreads proximally to distally, involving feet and hands, and caudally to cranially, finally reaching the oculobulbar region. (In myasthenia gravis, spread in craniocaudal).
  • Leg weakness (60%)
  • Generalized weakness (18%)
  • Muscle pain or stiffness (5%)
  • Arm weakness (4%)
  • Diplopia (4%)
  • Dysarthria (2%)
Spreading of symptoms in patients with NT-LEMS and SCLC-LEMS
Spreading of symptoms in patients with NT-LEMS and SCLC-LEMS: Frequency of symptoms at 3 months (A) and 12 months (B) in patients with NT-LEMS, and frequency of symptoms at 3 months (C) and 12 months (D) in patients with SCLC-LEMS. The percentages describe the approximate proportion of patients who have that symptom within the given timeframe. NT=non-tumour. LEMS=Lambert–Eaton myasthenic syndrome. SCLC=small-cell lung cancer. | Titulaer, M. J., Lang, B. and Verschuuren, J. J. G. M. (2011) ‘Lambert-Eaton myasthenic syndrome: From clinical characteristics to therapeutic strategies’, The Lancet Neurology. Elsevier, 10(12), pp. 1098–1107. doi: 10.1016/S1474-4422(11)70245-9.

Autonomic symptoms (80-96%):

  • Dry mouth (M/C autonomic complaint, 5%)
  • Erectile dysfunction (ED) (men)
  • Constipation
  • Orthostatic dysfunction
  • Micturition difficulties
  • Dry eyes
  • Altered perspiration
Lambert Eaton Syndrome
Lambert Eaton Syndrome

Diagnosis

Electrodiagnostic studies (DIAGNOSTIC):

  • Classic triad of electrophysiologic findings:
    1. Low CMAP amplitude at rest
    2. Decremental response at low rates of RNS
    3. Incremental response at high-rate stimulation or after brief exercise
Typical repetitive nerve stimulation pattern in the abductor digiti minimi muscle in LEMS
Typical repetitive nerve stimulation pattern in the abductor digiti minimi muscle in LEMS: (A) Low compound action potential amplitude at rest, marked incremental response (+400 mg) after 30 seconds of exercise. (B) Decremental response (−46%) at low-rate stimulation (3 Hz). (C) Marked incremental response (+400%) at high-rate stimulation (50 Hz). (From Oh SJ. Treatment and management of the neuromuscular junction. In: Bertorini TE, editor. Neuromuscular disorders. Treatment and management. Philadelphia: Elsevier-Saunders; 2011. p. 323; with permission.) | Kesner, V. G., Oh, S. J., Dimachkie, M. M., & Barohn, R. J. (2018). Lambert-Eaton Myasthenic Syndrome. Neurologic Clinics, 36(2), 379–394. https://doi.org/10.1016/j.ncl.2018.01.008

Serological testing:

  • Anti-P/Q-type VGCC antibodies (80-90%)
Diagnostic algorithm for clinically suspected LEMS
Diagnostic algorithm for clinically suspected LEMS. | Abbreviations: LEMS, Lambert-Eaton Myasthenic Syndrome; VGCC, voltage-gated calcium channels. | Ivanovski, T., & Miralles, F. (2019). Lambert-Eaton Myasthenic syndrome: early diagnosis is key. Degenerative neurological and neuromuscular disease, 9, 27–37. https://doi.org/10.2147/DNND.S192588

Differential diagnosis:

  • Myasthenia gravis

Management

Presynaptic K-channel blocker:

Blocks VGCCs that lead to prolongation of depolarization of the action potential at motor nerve terminals and increase the open time of the VGCCs. This process results in increased presynaptic influx of calcium and enhancement of ACh release manifesting by improvement in muscle function.
  • Aminopyridines:
    • Amifampridine (3,4-diaminopyridine (3,4-DAP)) (DOC)
    • 4-aminopyridine 
  • Acetylcholinesterase (ACE) inhibitor: Pyridostigmine

Severe cases:

  • IV immunoglobulin therapy
  • Plasmapheresis
Treatment scheme for LEMS
Treatment scheme for LEMS | LEMS=Lambert–Eaton myasthenic syndrome. DAP=diaminopyridine. SCLC=small-cell lung cancer. | Titulaer, M. J., Lang, B. and Verschuuren, J. J. G. M. (2011) ‘Lambert-Eaton myasthenic syndrome: From clinical characteristics to therapeutic strategies’, The Lancet Neurology. Elsevier, 10(12), pp. 1098–1107. doi: 10.1016/S1474-4422(11)70245-9.

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