Unusual Case of Myasthenia Gravis and High White Blood Cell Count

1. Eddie L. Patton, M.D., M.S. Yadollah Harati, M.D., F.A.C.P. Unusual Case of Myasthenia Gravis and High White Blood Cell Count

2. Clinical Presentation • This is the case of a 52 year old man with a 5 week history of left eyelid droop • During this same period of time he noticed some weakness in his arms and legs with exercise. • Other intermittent symptoms include double vision, head drop, difficulties swallowing and breathing (all of which are worse in the evening) • He has also lost 14 pounds in the previous 4 weeks before presentation to clinic which he attributed to a 1 month history of diarrhea

3. History • Past Medical History • Diabetes Mellitus 2 • Diabetic peripheral neuropathy • Hyperlipidemia • Surgical history • Appendectomy • Medications- Metformin, ASA, Avandia, Zetia, Cymbalta

4. History • Family history • Father: Coronary artery disease • Mother: Cancer • ROS: Positive for weight loss and diarrhea

5. Physical exam • Cranial nerves • Weak palatal elevation • Diplopia with lateral gaze • Bilateral ptosis • Reflexes- Normal • Sensation • Vibration decreased in the feet up to the ankles, hands normal • Pin prick/Light touch- decreased in bilateral toes • Temperature- decreased in feet up to ankles

6. Physical exam

7. Physical exam • Most of the muscles tested were easily fatigable • Positive ice pack test • Clinical diagnosis was pretty clear!

8. Other tests • CT Chest- No thymus identified • AChR binding antibodies- > 80 H (>0.40) • Anti-striational antibodies- 1:320 H (Neg<1:40)

9. Diagnosis: Myasthenia gravis • Treatment: • Six plasma exchanges over 14 day period • Improved with initial PE so continued weekly boosters for 4 weeks • Started on Imuran • Mestinon • This is when the case gets more interesting!

10. About 1 month after his initial presentation he returned for follow up • Diarrhea had returned which he was experiencing on and off over past 4 months • Some worsening of ptosis and generalized weakness. • Ordered some labs • Reduced Mestinon • Decided to continue his plasma exchange boosters

11. Review of labs • Initial visit- WBC 37.48 (H) • One month later- WBC 14.96 (H) • Paraneoplastic panel- Negative • Normal liver function tests • Mildly elevated glucose

12. Three days after this last visit he called office complaining of further progression of his swallowing and breathing difficulties, slurred speech and he was admitted to the hospital. • What he didn’t tell us was that a week before his office visit his general practitioner gave him Ciprofloxacin and Metronidazole for the diarrhea and high WBC

13. Hospital course • Pt was admitted to the ICU for MG crisis and subsequently intubated due to respiratory failure • Cardiac complications • Maintained an increased heart rate • Troponins were elevated • EF was found to be between 35-39% • Diagnosed as having a non-ST elevation myocardial infarction • Placed on beta blockers and ACE inhibitors

14. Hospital course • He received 5 days of IVIG with a good response

15. Any ideas on what made this patient worse…

16. Hosptal Course • Hematological condition • During hospital course his hemoglobin began to drop and reticulocyte count was found to be high • Peripheral blood smear and flow cytometry was performed • 63% monoclonal B cells with immunophenotype positive for CD19, CD23, CD5, CD20, CD38, CD43,CD79b, kappa • CLL FISH analysis- Insertional deletion on the proximal arm of one copy of Chromosome 13 consistent with CLL

17. Final Diagnosis • Myasthenia gravis crisis • CLL • Autoimmune hemolytic anemia • Non-ST elevation myocardial infarction

18. Treatment • He was treated with Vincristine, Cytoxan and stared on Rituximab by hematology • He was also started on oral Prednisone to treat his hemolytic anemia • After discharge he received 3 weekly Rituximab infusions with good results and was continued on Cytoxan for several months • At last appointment his CLL and myasthenia gravis were in remission • Only treatment for MG- Mestinon 30-60 mg every 4 hours

19. CLL and MG • Cohen and Waxman published a case in 1967 Archives of Internal Medicine • 28 year old man who was diagnosed clinically with myasthenia gravis in 1930 • 30 years later in 1960, after a bout of cervical lymphadenopathy, he was diagnosed with CLL • In 1964, he presented with hepatosplenomegaly, pulmonary embolization, thrombophlebitis and was found to have a Coomb’s positive hemolytic anemia

20. CLL and MG • The authors point to a defect in lymphoid differentiation and the thymus as the linking factor to all these conditions

21. CLL and Autoimmune Disorders • Conley et al in 1980- “Genetic Factors Predisposing to Chronic Lymphocytic Leukemia and to Autoimmune Disease” sought to prove there was a connection • 30 patients with CLL and 28 controls who had some other chronic hematological disorder • Pedigrees were constructed from in-depth family histories and medical record reviews • Over 320 relatives

22. CLL and Autoimmune Disorders • “ A hypothesis given support by our observation is that a genetically conditioned disorder of immune regulation predisoses both to autoimmune disease and to lymphocytic leukemia and other lymphoid tumors” • Autoimmune disorders occurred in the families of about 25% CLL patients Conley,” Genetic Factors Predisposing to Chronic Lymphocytic Leukemia and to Autoimmune Disease” Medicine 1980

23. CLL and MG • Bennett et al., “Myasthenia Gravis and Chronic Lymphocytic Leukemia” Eur. J. Hemotology 1989 • 62 y/o woman diagnosed with B-cell CLL • 10 months after being treated with chlorambucil and prednisone developed symptoms consistent with MG • Positive edrophonium test and anti-ACh R antibodies high at 33.7 pmol/ml • Question raised of defect in immunoregulation

24. CLL and Autoimmune Diseases • 2005 Fujimaki et al, “Idiopathic thrombocytopenia purpura and myasthenia gravis after fludarabine treatment for chronic lymphocytic leukemia” • Up to this point only 10 reported cases of MG in CLL • They presented a case of a 60 year old man with WBC count of 30.2 and with 80 % atypical lymphocytes

25. Fujimaki et al • He was diagnosed by cytogenetic studies to have B-CLL • Treatment Fludaradine 20 mg/m² IV 5 days every 4-5 weeks • After 6 cycles, decrease in WBC (8), no improvement in lymphadenopathy • Bone marrow aspiration lead to diagnosis of ITP • Two months later he was diagnosed with MG based on diplopia and high anti-Ach receptor antibodies at 79

26. Fujimaki et al • He was initially treated with Mestinon and 3 days of IV Methylprednisolone, followed by 2 days of plasma exchanges • One month later he was started on Rituximab with good response • This was the first reported case of CLL associated with ITP and MG • Speculation was that the Fludarabine caused further immune dysregulation leading to development of myasthenia gravis and ITP

27. Summary • Keeping in mind the association between myasthenia gravis and autoimmune disorders and the association between CLL and autoimmune disorders, more extensive work-up may be appropriate in MG patients with hematologic abnormalities • Exact mechanism between this association is unknown but immune dysregulation is a very strong theory