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.