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CLINICO-PATHOLOGIC CASE CONFERENCE TREATMENT

CASE NO. 06 - SGD GROUP 07 - Symptomatic treatment with 3,4-DAP 5 to


10 mg every 3 to 4 hours and up to a
LOGICAL IMPRESSION maximum daily dose of 80 to 100 mg is most
Lambert-Eaton Myasthenic Sydrome (LEMS) effective in improving muscle strength in
patients with LEMS.
DEFINITION/EPIDEMIOLOGY/PATHOLOGY - Side effects at doses up to 60 mg per day
- Lambert-Eaton myasthenic syndrome are rare.
(LEMS) is an acquired, presynaptic - Acral and perioral paresthesias occur within
neuromuscular transmission disorder caused minutes from a dose and resolve in about
by antibodies against the P/Q type 15 minutes.
voltage-gated calcium channel (VGCC). - It is contraindicated in patients with
- P/Q VGCC antibodies cause reduced Ca+ seizures.
influx into the presynaptic nerve terminal - 3,4-DAP is not currently FDA approved in
resulting in decreased acetylcholine the United States, but it can be obtained in
release and neuromuscular transmission specialized neuromuscular centers.
failure. - Pyridostigmine 60 mg every 4 hours is also
- LEMS is associated with cancer, usually used to improve symptoms.
small cell lung carcinoma, in 60% of cases. - In patients in whom symptoms are not
LEMS may predate tumor detection by up adequately controlled with 3,4-DAP and
to 3 years. pyridostigmine, immunomodulation with
- LEMS is very rare and more common in men prednisone, azathioprine, or
(3:1). mycophenolate mofetil is used.
- Severe weakness is treated with
CLINICAL PRESENTATION plasmapheresis or IVIG.
- LEMS should be suspected whenever the - The underlying cancer should be treated.
triad of muscle weakness, dry mouth, and
decreased or absent reflexes is present. PROGNOSIS
- Patients have fluctuating weakness and - In paraneoplastic LEMS the prognosis is
fatigability of proximal limb and trunk determined by the underlying cancer.
muscles, with the lower limbs more severely - The presence of LEMS in patients with small
affected than the upper ones. cell lung cancer (SCLC) is associated with
- Difficulty walking is a common symptom. longer survival from the malignancy.
Dysphagia, dysarthria, and ocular - Non-paraneoplastic LEMS, when optimally
symptoms (ptosis, blurred vision, and treated, has an excellent prognosis and
diplopia) are less common than in MG. normal life expectancy, although patients
- Tendon reflexes are hypoactive or absent may continue to experience various
and may increase following short exercise degrees of muscle weakness.
of the muscle.
- Autonomic manifestations (dry mouth, SOURCE
impotence, decreased sweating, Andreoli and Carpenter’s Cecil
orthostatic hypotension, and slow pupillary Essentials of Medicine (Page 1099)
reflexes) occur in 75% of patients.
LEMS
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS - Lambert-Eaton myasthenic-myopathic
- Serum antibodies against P/Q VGCCs are syndrome Lambert-Eaton myasthenic-
found in nearly all cases of paraneoplastic myopathic syndrome (LEMS) is a para-
LEMS, and in about 90% of neoplastic manifestation of small-cell
nonparaneoplastic cases. bronchial carcinoma due to defective
- Electrodiagnostic testing can help confirm acetylcholine release at the neuromuscular
the diagnosis by demonstrating reduced junction.
CMAP amplitudes in distal hand muscles; - A smaller proportion of cases are
CMAP facilitation of at least 100% after 10" autoimmune without underlying
maximal voluntary contraction or high malignancy.
frequency RNS (posttetanic facilitation); - Proximal limb muscle weakness, sometimes
and CMAP decrement greater than 10% with ocular/bulbar muscles, develops, with
with low frequency RNS. some absent tendon reflexes: a cardinal
- Patients diagnosed with LEMS should be sign.
screened and monitored with chest CT for - Weakness tends to improve after a few
lung cancer, especially if they are smokers minutes of muscular contraction, and
and over age 50. absent reflexes return (compare myasthe-
- LEMS and MG can be differentiated with nia).
electrodiagnostic and antibody testing. - Diagnosis is confirmed by repetitive nerve
stimulation (incre-ment; see above).
- Antibodies to voltage-gated calcium PARANAEOPLASTIC SYNDROMES
channels are found in most cases (90%). - Neurologic-myopathic syndromes are seen
- Treatment with 3,4-diaminopyridine (OAP) is in only 1% of patients but are dramatic and
reasonably safe and effective. include the myasthenic Eaton-Lambert
syndrome and retinal blindness with SCLC,
SOURCE whereas peripheral neuropathies, subacute
Kumar and Clark’s Clinical Medicine cerebellar degeneration, cortical
9th Edition (Page 890) degeneration, and polymyositis are seen
with all lung cancer types.
LEMS - Many of these are caused by autoimmune
- LEMS is a presynaptic disorder of the responses such as the development of anti-
neuromuscular junction that can cause voltage-gated calcium channel antibodies
weakness similar to that of MG. in Eaton Lambert syndrome.
- The proximal muscles of the lower limbs are - Patients with this disorder present with
most commonly affected, but other proximal muscle weakness, usually in the
muscles may be involved as well. lower extremities, occasional autonomic
- Cranial nerve findings, including ptosis of dysfunction, and rarely, cranial nerve
the eyelids and diplopia, occur in up to 70% symptoms or involvement of the bulbar or
of patients and resemble features of MG. respiratory muscles.
- However, the two conditions are usually - Depressed deep tendon reflexes are
readily distinguished, because patients frequently present. In contrast to patients
with LEMS have depressed or absent with myasthenia gravis, strength improves
reflexes and experience autonomic with serial effort. Some patients who
changes such as dry mouth and respond to chemotherapy will have
impotence. resolution of the neurologic abnormalities.
- Nerve stimulation produces an initial low- - Thus, chemotherapy is the initial treatment
amplitude response and, at low rates of of choice.
repetitive stimulation (2–3 Hz), decremental
responses like those of MG; however, at SOURCE
high rates (50 Hz), or following exercise, Harrison’s Principles of Internal Medicine
incremental responses occur. 19th Edition (Page 511)
- LEMS is caused by autoantibodies directed
against P/Q-type calcium channels at the PND OF NERVE AND MUSCLES
motor nerve terminals, which can be - For example, the frequent association of
detected in ~85% of LEMS patients by Lambert-Eaton myasthenic syndrome
radioimmunoassay. (LEMS) with SCLC should lead to a chest
- These autoantibodies result in impaired and abdomen computed tomography (CT)
release of ACh from nerve terminals. or body positron emission tomography (PET)
- Many patients with LEMS have an scan.
associated malignancy, most commonly - If negative, periodic tumor screening for at
small-cell carcinoma of the lung, which least 3 years after the neurologic diagnosis.
may express calcium channels that
stimulate the autoimmune response. SOURCE
- The diagnosis of LEMS may signal the Harrison’s Principle’s of Internal Medicine
presence of a tumor long before it would 19TH Edition (Page 615)
otherwise be detected, permitting early
removal.
- Treatment of LEMS involves plasmapheresis
and immunosuppression, as for MG. 3,4-
Diaminopyridine (3,4-DAP) and
pyridostigmine may also be
symptomatically helpful.
- 3,4-DAP acts by blocking potassium
channels, which results in prolonged
depolarization of the motor nerve terminals
and thus enhances ACh release.
- Pyridostigmine prolongs the action of ACh,
allowing repeated interactions with AChRs.

SOURCE:
Harrison’s Principles of Internal Medicine
19th Edition (Page 2703)