1. Lambert Eaton: An Elusive Diagnosis
Julie Silverman, MD
Internal Medicine R3
University of Washington
November 4, 2011

2. Lambert-Eaton Myasthenic Syndrome (LEMS)

3. Lambert-Eaton Myasthenic Syndrome (LEMS)
Disorder of the neuromuscular junction in which antibodies are made against presynaptic voltage-gated calcium channels

4. 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

5. 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 = per million population

6. 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 = per million population
There is a high association with malignancy

7. 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.

8. History PMHx Family Hx HTN HLD DJD Mother died from asthma in 40s
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

9. Diagnostics

10. Diagnostics

11. Diagnostics

12. Diagnostics

13. Diagnostics

14. Diagnostics

15. Diagnostics

16. Diagnostics
NO DIAGNOSIS

17. Continued Symptoms
Ms. S returned to PCP with worsening dry mouth, anorexia and unintentional 20 pound weight loss.

18. More Diagnostics
Admitted for expedited workup

19. More Diagnostics

20. More Diagnostics

21. More Diagnostics

22. More Diagnostics

23. DIAGNOSIS: Depression?
More Diagnostics
DIAGNOSIS: Depression?

24. Hospitalized again and again and again…
Hospitalization # CC: “nausea and fatigue”
Hospitalization # CC: “difficulty swallowing”
Hospitalization # CC: “slumped on floor”

25. Hospitalized again and again and again…
Hospitalization # CC: “nausea and fatigue”
Hospitalization # CC: “difficulty swallowing”
Hospitalization # 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?

26. 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.”

27. Finally…

28. Finally…
Reason for admission: Na 112 (previously low 130s)

29. 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

30. 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

31. 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

32. Electrodiagnostic Evaluation with Repetitive Nerve Stimulation:
“moderately severe disorder of presynaptic neurotransmission with findings supportive of an endplate myopathy”

33. 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
Baseline
Immediately after 10 seconds of maximal voluntary exercise
Exercise testing in LEMS with median nerve stimulation and abductor pollicis brevis muscle recorded

34. 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
Precedes CA in >80% of cases

35. 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.

36. 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

37. 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
Signs
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

38. Thanks
Drs. Susan Merel, Eric Kraus, Ken Steinberg

39. Questions?

40. Extra Slides

41. Mechanism of Action
SEMINARS IN NEUROLOGY/VOLUME 24, NUMBER

42. 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.

43. Treatment for LEMS

44. 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

45. 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

46. Laboratory Workup
Antibodies to voltage-gated calcium channels (VGCCs) have been reported in % of LEMS patients who have small cell lung cancer (SCLC) and in 50-90% of LEMS patients who do not have underlying cancer.