Transcript Lambert Eaton: An Elusive Diagnosis

Lambert Eaton:
An Elusive Diagnosis
Julie Silverman, MD
Internal Medicine R3
University of Washington
November 4, 2011
Lambert-Eaton
Myasthenic Syndrome (LEMS)
Lambert-Eaton
Myasthenic Syndrome (LEMS)
Disorder of the neuromuscular junction in which
antibodies are made against presynaptic voltagegated calcium channels
Lambert-Eaton
Myasthenic Syndrome (LEMS)
Disorder of the neuromuscular junction in which
antibodies are made against presynaptic voltagegated 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 voltagegated 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 voltagegated 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 JapaneseAmerican 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
PSHx
Unilateral oophorectomy (s/p MVA)
Appendectomy (s/p MVA)
Hysterectomy (for benign reasons)
L knee arthroscopy
L knee arthroplasty
Social Hx
Married
Retired from Kent school district
Lifelong non-smoker
Rare EtOH
Family Hx
Mother died from asthma in 40s
Medications
Losartan
Atenolol
Triamterene-HCTZ
Simvastatin
Omeprazole
Pyridoxine
Cyanocobalamin
Vitamin C
Flax 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?
Hospitalized again and again and again…
Hospitalization # 3
Hospitalization # 4
Hospitalization # 5
CC: “nausea and fatigue”
CC: “difficulty swallowing”
CC: “slumped on floor”
Hospitalized again and again and again…
Hospitalization # 3
Hospitalization # 4
Hospitalization # 5
CC: “nausea and fatigue”
CC: “difficulty swallowing”
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?
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
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:
“moderately severe disorder of presynaptic
neurotransmission with findings supportive of
an endplate myopathy”
Compound Muscle Action Potentials (CMAP) Post-Exercise Facilitation
Exercise testing in
LEMS with median
nerve stimulation and
abductor pollicis brevis
muscle recorded
Baseline
Immediately after 10
seconds of maximal
voluntary exercise
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
Symptoms
Signs
Proximal 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
Proximal 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
Mechanism of Action
SEMINARS IN NEUROLOGY/VOLUME 24, NUMBER 2 2004
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
The overwhelming majority of cancers associated
with LEMS are SCLC. Other malignancies include
 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
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.