CLINICO-PATHOLOGIC CASE CONFERENCE
CASE NO. 06 - SGD GROUP 07 - Symptomatic treatment with 3,4-DAP 5 to
LOGICAL IMPRESSION
Lambert-Eaton Myasthenic Sydrome (LEMS)
DEFINITION/EPIDEMIOLOGY/PATHOLOGY
- Lambert-Eaton myasthenic syndrome
(LEMS) is an acquired, presynaptic
neuromuscular transmission disorder caused
by antibodies against the P/Q type
voltage-gated calcium channel (VGCC).
- P/Q VGCC antibodies cause reduced Ca+
influx into the presynaptic nerve terminal
resulting in decreased acetylcholine
release and neuromuscular transmission
failure.
- LEMS is associated with cancer, usually
small cell lung carcinoma, in 60% of cases.
LEMS may predate tumor detection by up
to 3 years.
- LEMS is very rare and more common in men
(3:1).
CLINICAL PRESENTATION
- LEMS should be suspected whenever the
triad of muscle weakness, dry mouth, and
decreased or absent reflexes is present.
- Patients have fluctuating weakness and
fatigability of proximal limb and trunk
muscles, with the lower limbs more severely
affected than the upper ones.
- Difficulty walking is a common symptom.
Dysphagia, dysarthria, and ocular
symptoms (ptosis, blurred vision, and
diplopia) are less common than in MG.
- Tendon reflexes are hypoactive or absent
and may increase following short exercise
of the muscle.
- Autonomic manifestations (dry mouth,
impotence, decreased sweating,
orthostatic hypotension, and slow pupillary
reflexes) occur in 75% of patients.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
- Serum antibodies against P/Q VGCCs are
found in nearly all cases of paraneoplastic
LEMS, and in about 90% of
nonparaneoplastic cases.
- Electrodiagnostic testing can help confirm
the diagnosis by demonstrating reduced
CMAP amplitudes in distal hand muscles;
CMAP facilitation of at least 100% after 10"
maximal voluntary contraction or high
frequency RNS (posttetanic facilitation);
and CMAP decrement greater than 10%
with low frequency RNS.
- Patients diagnosed with LEMS should be
screened and monitored with chest CT for
lung cancer, especially if they are smokers
and over age 50.
- LEMS and MG can be differentiated with
electrodiagnostic and antibody testing.
TREATMENT
10 mg every 3 to 4 hours and up to a
maximum daily dose of 80 to 100 mg is most
effective in improving muscle strength in
patients with LEMS.
- Side effects at doses up to 60 mg per day
are rare.
- Acral and perioral paresthesias occur within
minutes from a dose and resolve in about
15 minutes.
- It is contraindicated in patients with
seizures.
- 3,4-DAP is not currently FDA approved in
the United States, but it can be obtained in
specialized neuromuscular centers.
- Pyridostigmine 60 mg every 4 hours is also
used to improve symptoms.
- In patients in whom symptoms are not
adequately controlled with 3,4-DAP and
pyridostigmine, immunomodulation with
prednisone, azathioprine, or
mycophenolate mofetil is used.
- Severe weakness is treated with
plasmapheresis or IVIG.
- The underlying cancer should be treated.
PROGNOSIS
- In paraneoplastic LEMS the prognosis is
determined by the underlying cancer.
- The presence of LEMS in patients with small
cell lung cancer (SCLC) is associated with
longer survival from the malignancy.
- Non-paraneoplastic LEMS, when optimally
treated, has an excellent prognosis and
normal life expectancy, although patients
may continue to experience various
degrees of muscle weakness.
SOURCE
Andreoli and Carpenter’s Cecil
Essentials of Medicine (Page 1099)
LEMS
- Lambert-Eaton myasthenic-myopathic
syndrome Lambert-Eaton myasthenic-
myopathic syndrome (LEMS) is a para-
neoplastic manifestation of small-cell
bronchial carcinoma due to defective
acetylcholine release at the neuromuscular
junction.
- A smaller proportion of cases are
autoimmune without underlying
malignancy.
- Proximal limb muscle weakness, sometimes
with ocular/bulbar muscles, develops, with
some absent tendon reflexes: a cardinal
sign.
- Weakness tends to improve after a few
minutes of muscular contraction, and
absent reflexes return (compare myasthe-
nia).
- Diagnosis is confirmed by repetitive nerve
stimulation (incre-ment; see above).
 - Antibodies to voltage-gated calcium
channels are found in most cases (90%).
- Treatment with 3,4-diaminopyridine (OAP) is
reasonably safe and effective.
SOURCE
Kumar and Clark’s Clinical Medicine
9th Edition (Page 890)
LEMS
- LEMS is a presynaptic disorder of the
neuromuscular junction that can cause
weakness similar to that of MG.
- The proximal muscles of the lower limbs are
most commonly affected, but other
muscles may be involved as well.
- Cranial nerve findings, including ptosis of
the eyelids and diplopia, occur in up to 70%
of patients and resemble features of MG.
- However, the two conditions are usually
readily distinguished, because patients
with LEMS have depressed or absent
reflexes and experience autonomic
changes such as dry mouth and
impotence.
- Nerve stimulation produces an initial low-
amplitude response and, at low rates of
repetitive stimulation (2–3 Hz), decremental
responses like those of MG; however, at
high rates (50 Hz), or following exercise,
incremental responses occur.
- LEMS is caused by autoantibodies directed
against P/Q-type calcium channels at the
motor nerve terminals, which can be
detected in ~85% of LEMS patients by
radioimmunoassay.
- These autoantibodies result in impaired
release of ACh from nerve terminals.
- Many patients with LEMS have an
associated malignancy, most commonly
small-cell carcinoma of the lung, which
may express calcium channels that
stimulate the autoimmune response.
- The diagnosis of LEMS may signal the
presence of a tumor long before it would
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)
PARANAEOPLASTIC SYNDROMES
- Neurologic-myopathic syndromes are seen
in only 1% of patients but are dramatic and
include the myasthenic Eaton-Lambert
syndrome and retinal blindness with SCLC,
whereas peripheral neuropathies, subacute
cerebellar degeneration, cortical
degeneration, and polymyositis are seen
with all lung cancer types.
- Many of these are caused by autoimmune
responses such as the development of anti-
voltage-gated calcium channel antibodies
in Eaton Lambert syndrome.
- Patients with this disorder present with
proximal muscle weakness, usually in the
lower extremities, occasional autonomic
dysfunction, and rarely, cranial nerve
symptoms or involvement of the bulbar or
respiratory muscles.
- Depressed deep tendon reflexes are
frequently present. In contrast to patients
with myasthenia gravis, strength improves
with serial effort. Some patients who
respond to chemotherapy will have
resolution of the neurologic abnormalities.
- Thus, chemotherapy is the initial treatment
of choice.
SOURCE
Harrison’s Principles of Internal Medicine
19th Edition (Page 511)
PND OF NERVE AND MUSCLES
- For example, the frequent association of
Lambert-Eaton myasthenic syndrome
(LEMS) with SCLC should lead to a chest
and abdomen computed tomography (CT)
or body positron emission tomography (PET)
scan.
- If negative, periodic tumor screening for at
least 3 years after the neurologic diagnosis.
SOURCE
Harrison’s Principle’s of Internal Medicine
19TH Edition (Page 615)