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

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