eddie l. patton, m.d., m.s. yadollah harati, m.d., f.a.c.p
TRANSCRIPT
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.
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
History
Past Medical History Diabetes Mellitus 2 Diabetic peripheral neuropathy Hyperlipidemia
Surgical history Appendectomy
Medications- Metformin, ASA, Avandia, Zetia, Cymbalta
History
Family history Father: Coronary artery disease Mother: Cancer
ROS: Positive for weight loss and diarrhea
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
Physical exam
Muscle Tested Right Left
Neck flexors 4+/5 4+/5
Neck extensors 4-/5 4-/5
Deltoids 5/5 5/5
Biceps 5/5 5/5
Triceps 5/5 5/5
Digit flexion/extension 5/5 5/5
Illiopsoas 3/5 3/5
Quadriceps 5/5 5/5
Hamstrings 5/5 5/5
Tibilais anterior 5/5 5/5
Toe flexion 4+/5 5/5
Physical exam
Most of the muscles tested were easily fatigable
Positive ice pack test Clinical diagnosis was pretty
clear!
Other tests
CT Chest- No thymus identified AChR binding antibodies- > 80 H
(>0.40) Anti-striational antibodies- 1:320 H
(Neg<1:40)
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!
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
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
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
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
Hospital course
He received 5 days of IVIG with a good response
Any ideas on what made this patient worse…
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
Final Diagnosis
Myasthenia gravis crisis CLL Autoimmune hemolytic anemia Non-ST elevation myocardial
infarction
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
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
CLL and MG
The authors point to a defect in lymphoid differentiation and the thymus as the linking factor to all these conditions
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
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 patientsConley,” Genetic Factors Predisposing to Chronic Lymphocytic Leukemia
and to Autoimmune Disease” Medicine 1980
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
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
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
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
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