1. Unusual Case of Myasthenia Gravis and High White Blood Cell Count
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 Surgical history
Diabetes Mellitus 2
Diabetic peripheral neuropathy
Hyperlipidemia
Surgical history
Appendectomy
Medications- Metformin, ASA, Avandia, Zetia, Cymbalta

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

5. Physical exam Cranial nerves Reflexes- Normal Sensation
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 Muscle Tested Right Left Neck flexors 4+/5
Neck extensors
4-/5
Deltoids
5/5
Biceps
Triceps
Digit flexion/extension
Illiopsoas
3/5
Quadriceps
Hamstrings
Tibilais anterior
Toe flexion

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 (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 mg every 4 hours

19. CLL and MG
Cohen and Waxman published a case in 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 “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