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Lambert Eaton: An Elusive Diagnosis
Julie Silverman, MDInternal Medicine R3
University of WashingtonNovember 4, 2011
Lambert-Eaton Myasthenic Syndrome (LEMS)
Lambert-Eaton Myasthenic Syndrome (LEMS)
Disorder of the neuromuscular junction in which antibodies are made against presynaptic voltage-gated calcium channels
Lambert-Eaton Myasthenic Syndrome (LEMS)
Disorder of the neuromuscular junction in which antibodies are made against presynaptic voltage-gated calcium channels
Symptoms include proximal muscle weakness, fatigue and autonomic dysfunction
Lambert-Eaton Myasthenic Syndrome (LEMS)
Disorder of the neuromuscular junction in which antibodies are made against presynaptic voltage-gated calcium channels
Symptoms include proximal muscle weakness, fatigue and autonomic dysfunction
Annual Incidence = 0.48 per million population
Lambert-Eaton Myasthenic Syndrome (LEMS)
Disorder of the neuromuscular junction in which antibodies are made against presynaptic voltage-gated calcium channels
Symptoms include proximal muscle weakness, fatigue and autonomic dysfunction
Annual Incidence = 0.48 per million population
There is a high association with malignancy
Initial Presentation
Ms. S: 70-year-old, previously healthy Japanese-American woman presented to her primary care physician with concerns of dyspnea, orthopnea and peripheral edema.
Review of systems further revealed nausea, muscle weakness, joint and back pain, and excessive thirst.
History
PMHx HTN HLD DJD Mild mitral insufficiency
PSHxUnilateral oophorectomy (s/p MVA) Appendectomy (s/p MVA)Hysterectomy (for benign reasons)L knee arthroscopyL knee arthroplasty
Social Hx
MarriedRetired from Kent school districtLifelong non-smokerRare EtOH
Family HxMother died from asthma in 40s
MedicationsLosartanAtenololTriamterene-HCTZSimvastatinOmeprazolePyridoxineCyanocobalaminVitamin CFlax seed oil
Diagnostics
Diagnostics
Diagnostics
Diagnostics
Diagnostics
Diagnostics
Diagnostics
Diagnostics
NO DIAGNOSIS
Continued Symptoms
Ms. S returned to PCP with worsening dry mouth, anorexia and unintentional 20 pound weight loss.
More Diagnostics
More Diagnostics
More Diagnostics
More Diagnostics
More Diagnostics
More Diagnostics
DIAGNOSIS: Depression?
Hospitalization # 3 CC: “nausea and fatigue”Hospitalization # 4 CC: “difficulty swallowing”Hospitalization # 5 CC: “slumped on floor”
Hospitalized again and again and again…
Hospitalization # 3 CC: “nausea and fatigue”Hospitalization # 4 CC: “difficulty swallowing”Hospitalization # 5 CC: “slumped on floor”
Workup: barium swallow, esophageal manometry, videoflouroscopy, laryngoscopy, CT neck, CT head
Consults: GI, neurology, ENT, rehab medicine, speech therapy
Diagnoses: Medication-related? Deconditioning? Poor nutrition?
Hospitalized again and again and again…
Neurology Consults
“I do not find evidence of any dysfunction of central or peripheral nervous system including any evidence of peripheral myopathy or neuromuscular junction disease.”
“At this point I would be reassured on clinical grounds that there is no significant neurological explanation and I do not recommend or see specific need to proceed with any specific neurological diagnosis… She does have a dry mouth which raises the question of a Lambert-Eaton syndrome and that unlikely possibility can be further probed with an anti-calcium channel antibody test and with neurophysiologic studies.”
Finally…
Finally…
Reason for admission: Na 112 (previously low 130s)
Finally…
Reason for admission: Na 112 (previously low 130s)
Physical exam: No fatiguability or diplopia elicited with sustained upgaze x 1
min Normal muscle mass and tone Strength 4-5 in all muscle groups; poor effort with give way
weakness Declined gait assessment Lambert’s sign absent DTRs 1+ B biceps; 0 in brachioradialis, patella, Achilles
Finally…
Reason for admission: Na 112 (previously low 130s)
Physical exam: No fatiguability or diplopia elicited with sustained upgaze x 1
min Normal muscle mass and tone Strength 4-5 in all muscle groups; poor effort with give way
weakness Declined gait assessment Lambert’s sign absent DTRs 1+ B biceps; 0 in brachioradialis, patella, Achilles
Labs: ESR 82, CRP 216 CK normal ANA 1:80 with negative reflexive panel
Finally…
Reason for admission: Na 112 (previously low 130s)
Physical exam: No fatiguability or diplopia elicited with sustained upgaze x 1
min Normal muscle mass and tone Strength 4-5 in all muscle groups; poor effort with give way
weakness Declined gait assessment Lambert’s sign absent DTRs 1+ B biceps; 0 in brachioradialis, patella, Achilles
Labs: ESR 82, CRP 216 CK normal ANA 1:80 with negative reflexive panel
Rheumatology and Neurology consults
“moderately severe disorder of presynaptic
neurotransmission with findings supportive of
an endplate myopathy”
Electrodiagnostic Evaluation with Repetitive Nerve Stimulation:
“moderately severe disorder of presynaptic
neurotransmission with findings supportive of
an endplate myopathy”
Electrodiagnostic Evaluation with Repetitive Nerve Stimulation:
Exercise testing in LEMS with median nerve stimulation and abductor pollicis brevis muscle recorded
Baseline
Immediately after 10 seconds of maximal voluntary exercise
Compound Muscle Action Potentials (CMAP) Post-Exercise Facilitation
Malignancy Workup
Tumor markers (CA19-9, CA27.29, CEA)
within normal limits
CT chest/abdomen/pelvis no evidence of
malignancy
PET scan no evidence of occult malignancy
Bronchoscopy not performed
Treatment
Initially started on pyridostigmine
(anticholinesterase inhibitor)
3,4-DAP (K channel blocker) added
Once PET results returned, prednisone added
At one month follow-up, patient’s strength had returned. She was able to perform ADLs and IADLs.
Conclusions
LEMS can be difficult to diagnose. At time of diagnosis, Ms. S had
been hospitalized 6 times at 5 different hospitals seen by at least 12 specialists undergone at least 9 CT scans, ultrasounds, EGD, colonoscopy, laryngoscopy, blood work
While the prevalence is low, recognition of LEMS is critical because
treatment can be effective in reducing symptoms up to 70% of patients have an underlying malignancy
Signs and Symptoms
SymptomsProximal limb weakness
Legs > arms
Fatigue or fluctuating sx
Difficulty rising from sitting; climbing stairs
Metallic taste in mouth
Autonomic dysfunction
Dry mouth
Constipation
Blurred vision
Impaired sweating
SignsProximal limb weakness
Legs > arms
Weakness on exam is less demonstrable than pt’s level of disability
Hypoactive or absent muscle stretch reflexes
Lambert’s sign (grip becomes more powerful over several seconds)
Sluggish pupillary reflexes
Thanks
Drs. Susan Merel, Eric Kraus, Ken Steinberg
Questions?
Extra Slides
SEMINARS IN NEUROLOGY/VOLUME 24, NUMBER 2 2004
Mechanism of Action
Treatment for LEMS
Treat underlying malignancy Pyridostigmine 3,4-DAP Cochrane Review 2011 “limited but moderate to high
quality evidence” showing 3,4-DAP improved muscle strength scores and CMAP amplitudes
Other possible treatments (plasma exchange, steroids and immunosuppressive agents) have not been tested in randomized controlled trials.
Treatment for LEMS
Myastenia Gravis vs. LEMS
Both are acquired autoimmune disorders characterized by defective neuromuscular transmission
LEMS MG
Antibodies against voltage-gated Ca channels
Antibodies about acetylcholine receptors
Usually starts at extremities and moves up
Usually starts at eyes and moves down
Autonomic dysfunction present No autonomic dysfunction
Diplopia and dysphagia uncommon Diplopia and dysphagia common
Weakness improves with activity Weakness worsens with activity
Associated with SCLC Associated with thymoma
LEMS and Malignancy
non-SCLC neuroendocrine
carcinomas lymphosarcoma malignant thymoma Breast CA Stomach CA
Colon and Rectal CA Prostate CA Bladder CA Kidney CA Gallbladder CA Basal cell carcinoma Leukemia
The overwhelming majority of cancers associated with LEMS are SCLC. Other malignancies include
Laboratory Workup
Antibodies to voltage-gated calcium channels (VGCCs) have been reported in 75-100% of LEMS patients who have small cell lung cancer (SCLC) and in 50-90% of LEMS patients who do not have underlying cancer.