Lambert Eaton: An Elusive Diagnosis

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 = 0.48 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 = 0.48 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 Family Hx Mother died from asthma in 40s Medications Losartan Atenolol Triamterene-HCTZ Simvastatin Omeprazole Pyridoxine Cyanocobalamin Vitamin C Flax seed oil 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

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

19. More Diagnostics

20. More Diagnostics

21. More Diagnostics

22. More Diagnostics

23. More Diagnostics DIAGNOSIS: Depression?

24. Hospitalized again and again and again… Hospitalization # 3 CC: “nausea and fatigue” Hospitalization # 4 CC: “difficulty swallowing” Hospitalization # 5 CC: “slumped on floor”

25. 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?

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. Immediately after 10 seconds of maximal voluntary exercise Baseline 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

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

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. Symptoms 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 Signs and Symptoms

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

39. Questions?

40. Extra Slides

41. Mechanism of Action SEMINARS IN NEUROLOGY/VOLUME 24, NUMBER 2 2004

42. 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

43. Treatment for LEMS

44. Myastenia Gravis vs. LEMS Both are acquired autoimmune disorders characterized by defective neuromuscular transmission

45. 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 LEMS and Malignancy The overwhelming majority of cancers associated with LEMS are SCLC. Other malignancies include

46. 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.