Contents
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:


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).

Presentation
Clinical triad:
- Proximal muscle weakness
- Autonomic features
- 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%)

Autonomic symptoms (80-96%):
- Dry mouth (M/C autonomic complaint, 5%)
- Erectile dysfunction (ED) (men)
- Constipation
- Orthostatic dysfunction
- Micturition difficulties
- Dry eyes
- Altered perspiration

Diagnosis
Electrodiagnostic studies (DIAGNOSTIC):
- Classic triad of electrophysiologic findings:
- Low CMAP amplitude at rest
- Decremental response at low rates of RNS
- Incremental response at high-rate stimulation or after brief exercise

Serological testing:
- Anti-P/Q-type VGCC antibodies (80-90%)

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
