Keywords
brain metastasis, small cell lung cancer, Lambert–Eaton myasthenic syndrome, autoimmune
Outline
Introduction 244
Lambert–Eaton Myesthenic Syndrome 244
Paraneoplastic and Non-Paraneoplastic LEMS 244
Pathophysiology 245
Clinical Features 245
Investigations 246
Treatment 246
Management of PLEMS 246
Management of NPLEMS 247
LEMS and Small Cell Lung Carcinoma 247
DELTA-P Score 249
Brain Metastasis 249
Our Experience 252
References
Introduction
Small cell lung carcinoma (SCLC) is a highly aggressive tumor, with a high proliferative capability, rapid tumor doubling time, and early onset of metastases carrying a poor prognosis. These features make SCLC a systemic disease in most cases, with 70% of SCLC patients presenting with extensive disease (ED) on diagnosis. The median overall survival of treated patients in the ED stage varies between 6 and 11 months, whereas 2- and 5-year survival rates hardly reach 5% and 1%, respectively, as reported by . In spite of these discouraging statistical data, cases of long survivors have been reported, although no predictors of such a course have been identified. There are case reports to show that the prognosis in a patient with a solitary brain metastasis and occult small cell lung carcinoma is not always as dismal compared with the patients with brain metastasis occurring after the evidence of SCLC and synchronous metastasis to other sites ( ).
Lambert–Eaton myasthenic syndrome (LEMS), on the other hand, is an autoimmune disease occurring in association with a carcinoma in ≈60% of patients, the majority of which constitutes SCLC ( ). SCLC is a tumor of neuroendocrine origin which shows many features of a neuron including expression of voltage-gated calcium channel (VGCC) on the tumor cells. Antibody response to these channels triggers paraneoplastic LEMS (PLEMS). Long-term survival of patients with PLEMS associated with SCLC has been reported ( ). Rarely, both a paraneoplastic syndrome in the form of LEMS and solitary brain metastasis can occur in a patient before the primary SCLC causing its detection. Long-term follow up with palliative care is the cornerstone in managing these patients. Our experience with such a case suggests that these patients carry a better prognosis than patients with full-blown metastasis detected after the evidence of SCLC.
Lambert–Eaton Myesthenic Syndrome
LEMS is an antibody-mediated autoimmune disorder of neuromuscular transmission characterized by muscle weakness, hyporeflexia or areflexia and autonomic dysfunction. reported the case of a 47-year-old man with a bronchial neoplasm, progressive proximal muscle weakness and hyporeflexia. They concluded that there was “strong clinical evidence for believing that the severe muscle weakness was of the myasthenic type”. This patient showed the features of what we today call LEMS. In 1957, Eaton and Lambert summarized the clinical and electrophysiological characteristics of this myasthenic syndrome and concluded that the features are distinct from what is expected in cases of myasthenia gravis ( ).
Paraneoplastic and Non-Paraneoplastic LEMS
LEMS is rare with a prevalence of ≈1 per 100 000, equally common in men and women. There are two types of LEMS – LEMS associated with malignancy (PLEMS) and LEMS without malignancy (NPLEMS). Patients with either type have an autoimmune basis and similar electrophysiological characters. Approximately 60% of LEMS patients have associated SCLC. Other less commonly associated malignancy includes lymphoproliferative disorder, papillary carcinoma of thyroid, thymoma, colonic carcinoma, renal-cell carcinoma, intrathoracic carcinoid, and adenocarcinoma of lungs, pancreas, and prostate ( ).
NPLEMS is characterized by the presence of various other autoimmune diseases such as thyroiditis, Addison’s disease, vitiligo, pernicious anemia, systemic lupus erythematosus/discoid lupus erythematosus (SLE/DLE), rheumatoid arthritis and other immunological disorders which provides further evidence for autoimmunity involved in the pathogenisis of LEMS. Overall, approximately 25% of patients with LEMS have other associated autoimmune disease and approximately 35–45% have circulating organ-specific antibodies. Prevalence of autoantibodies is higher in the NPLEMS group ( ). Generally, NPLEMS occurs at a younger age as compared to PLEMS (mean ages 48 and 57.9 years, respectively). However, 80% of patients with LEMS are older than 40 years ( ). in their series of 50 cases, found a statistically significant male predominance in the group without associated carcinoma and when both groups were considered together. There is a significant association noted with HLA-B8 in both groups, which appears to be stronger in the NPLEMS group. The levels of immunoglobulin G (IgG) heavy chain marker G1m(2) are also found to be increased in both groups ( ).
Pathophysiology
The common pathogenic mechanism involved in both groups of LEMS includes antibody-mediated blockage of voltage-gated calcium channels (VGCC) at the presynaptic neurons. This results in failure of calcium influx at the channels in response to the stimulus, thereby decreasing the neurotransmitter release at the presynaptic motor nerve terminals of the neuromuscular junction and autonomic neurons producing symptoms of weakness and autonomic dysfunction ( ).
The VGCC based on their electrophysiological and pharmacological characteristics are classified as L, N, P/Q, R and T. In LEMS, IgG autoantibodies against P/Q type VGCC result in decreased release of acetylcholine both at the motor nerve terminals and at the postganglionic sympathetic and parasympathetic neurons.
The SCLC tumor cells have been shown to express VGCCs of L, N and P/Q subtypes. In patients with SCLC, LEMS is initiated by an immune reaction to these VGCC expressed on the surface of the tumor cells. The resulting antibodies react with VGCC at the presynaptic nerve terminal of the neuromuscular junction resulting in PLEMS ( ). Similarly, VGCCs are expressed in the cerebellum and patients with SCLC, with or without LEMS, may also have cerebellar dysfunction.
Clinical Features
The cardinal clinical features described by Lambert and Eaton were weakness and fatiguability of muscles, temporary increase in strength after voluntary exercise, diminished or absent tendon reflexes, marked sensitivity to curare (as in myasthenia gravis) and relatively poor response to neostigmine. Tendon reflexes show marked potentiation after sustained contraction of the appropriate muscle for ≈10–15 s ( ). It is usually gradual and insidious in onset. The weakness usually starts with the lower limbs and involves proximal more than distal muscle groups. Cranial nerve involvement is seen in ≈70% of patients which produces symptoms such as diplopia, ptosis, dysphagia, nasal regurgitation, and weakness of neck flexion. Autonomic symptoms such as dry mouth, dry eyes, and orthostatic hypotension are seen in ≈80% of patients. Autonomic dysfunction can be elicited by testing even when the symptoms are mildly present ( ).
Investigations
Serum Antibodies to VGCC
Antibodies against P/Q type VGCCs are detected in ≈90% of patients with LEMS belonging to both groups. This finding appears to be particularly strong in carcinoma-associated LEMS where almost all patients are found positive for antibodies against the P/Q type of VGCCs. Antibodies to N-type VGCCs are detected in<50 % of cases, but more commonly in patients with underlying lung carcinoma. Therefore, detection of this type of antibody increases the possibility of an underlying primary lung carcinoma ( ).
Electrodiagnostic Tests
Electrophysiological tests are used both for the diagnosis and monitoring the course of the illness. Compound muscle action potential (CMAP) after a supramaximal stimulus, postactivation potentiation (increase in the CMAP amplitude immediately after maximal voluntary contraction), repetitive nerve stimulation, and single fiber electromyography are the modalities that help to differentiate LEMS from myasthenia gravis. Postactivation exhaustion (decrease in the CMAP amplitude 2–4 min after maximal voluntary muscle contraction) can be seen in both LEMS and myasthenia gravis. The results should be interpreted taking the entire picture, including the clinical presentation, into consideration. Electrophysiological tests reveal characteristic features such as a low CMAP amplitude at rest, a decremental response at low stimulation frequency, and an incremental response at high-rate stimulation and post-tetanic potentiation ( Figure 21.1 ).
Treatment
The treatment strategy in patients with LEMS depends on the severity of symptoms, the degree of response to symptomatic treatment, and the presence or absence of an associated malignancy. 3,4 Diaminopyridine (DAP), guanidine, pyridostigmine, steroids, immunosuppresives, plasma exchange, and intravenous immunoglobulins are some of the therapeutic options available for patients with LEMS which needs to be used according to the clinical settings and availability. Except for 3,4 DAP, all others are associated with significant side effects and poor responses ( ).
Management of PLEMS
3,4-diaminopyridine is the drug of choice in these patients for symptomatic relief of weakness and autonomic dysfunction. The specific treatment of the underlying tumor usually results in improvement or remission of symptoms. In such patients, the only further treatment required may be continuation of 3, 4 DAP. When the specific tumor therapy fails to resolve symptoms, further treatment with prednisolone should be considered. Those who present with severe weakness will benefit from plasma exchange or intravenous immunoglobulin (IVIG). reported an onset of effect of IVIG in their patients at 2–4 weeks. Severity of symptoms should be the guide for the choice of therapies in these patients.
Management of NPLEMS
3,4 DAP therapy is useful in this group for symptomatic relief and, if successful, no additional treatment is required. Those who have not responded should be treated with prednisolone and/or azathioprine as long-term therapy. Once remission is achieved, prednisolone could be tapered to the minimum maintenance dose. If the weakness is severe, plasma exchange or IVIG should also be considered in this group.
Table 21.1 summarizes the distinguishing features between PLEMS and NPLEMS.
| Features | Paraneoplastic LEMS | Non-Paraneoplastic LEMS |
|---|---|---|
| Age at diagnosis (median) | 57.9 | 48 |
| Sex | Male predominance | Female predominance (less compared to PLEMS) |
| Smoking history | Present | Usually absent |
| Associated other autoimmune diseases | Usually less frequent | Strong association |
| Immunoglobulin G (IgG) heavy chain marker G1m and HLA-B8/DR3 association | Less frequently | More frequently |
| Significant weight loss | Present | Absent |
| Disease onset and progression | Subacute and progressive | Chronic and progressive |
| Laboratory investigations | Raised ESR, LDH Reduced hemoglobin, variation in total leukocyte count (high or low) | Usually absent |
| Treatment | Less satisfactory response to 3, 4 DAP. Requires treatment of underlying tumor and aggressive immunotherapy | Good response to 3, 4 DAP. |
| DELTA-P score | Usually>4 | <2 |
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