[CIS PIDD] [cis-pidd] ten year old with CVID and focal white matter demyelination

[Akhter, Javeed]

Hi colleagues
I need help with this 10 yr old with CVID who is experiencing focal demyelination of the white matter with headaches and two seizures.  Infectious disease work up is negative.

Here is a brief summary of this patient who I initially saw at 8 years of age.  She had a diagnosis of Evan's syndrome and was starting to have sino-pulmonary infections.
Her initial labs were

IGG  374                              IGA 16 L               IGM 40                 mg/dL
Isohemagglutinins            Anti A 16       Anti B  16

Tetanus antibody: 2.54
PNEUMOCOCCAL antibodies: 2/23 were above 1.3
Post immunization tiers: 7/23

FLOW CYTOMETRY - THE PATIENT HAS INCREASED PERCENTAGES OF
CD3+ T CELLS AT 80%, NORMAL RANGE EQ (54-79%) AND CD4+ T CELLS AT 61%,
NORMAL RANGE EQ (28-49%).  THE ABSOLUTE NUMBERS OF CD4+ T CELLS WERE
INCREASED.  THE PROPORTION OF T CELLS EXPRESSING HLA-DR IS ABOVE
NORMAL AND CONSISTENT WITH RECENT IMMUNE ACTIVATION.  NO OTHER
SIGNIFICANT ABNORMALITIES WERE OBSERVED IN ANY OF THE LYMPHOCYTE

MEMORY B CELLS: APPROXIMATELY 23.1% (NORMAL RANGE: 5.6-33%)
OF THE PATIENT'S B CELLS EXPRESS A MEMORY PHENOTYPE (I.E., CD27+).
THE PATIENT HAS DECREASED PERCENTAGES OF THE MEMORY B CELLS
EXPRESSING AN IMMUNOGLOBULIN "CLASS SWITCHED" EXPRESSION PROFILE AT
14.6% (NORMAL RANGE: 28.7-65.6%).

As a part of the initial w/u a CT chest and abdomen were done.

CT chest revealed mediastinal lymph nodes and small nodules in the lung parenchyma
There is thoracic lymphadenopathy. This includes lymphadenopathy in both axilla as well as in both hila. There are also at least mildly prominent nodes in the mediastinum. For reference purposes, one of the larger axillary nodes is identified on the left measuring approximately 2.5 x 1.4 cm. No pleural effusions are seen. There are hazy ground glass opacities throughout both lung fields. Superimposed upon this are innumerable patchy and nodular densities. These appear more prominent in the lower lungs. While cavitary changes are difficult to fully exclude, these are not clearly evident.
CT abdomen revealed heapto spenomegaly and no abdominal lymph nodes

A lung and lymph node biopsy revealed non-caseating granulomas that are negative for infection

A lymphoma w/u done by our hem/onc service is negative

Because of the Granulomas in the lung and splenomegaly and persistent thrombocytopenia she was started on long term oral steroids in a dose of 1mg/kg initially once daily and then qod.  She was also give 4 doses of Rituximab

Another interesting f/h is that her dad has CVID also.  He has had only infections but no auto immune problems, non-caseating granuloms or GI issues.  I have started taking care of him as well.  Father's brother I am told has CVID also but I have not seen him and do not have access to his labs

The patient responded very nicely to the therapy.  Her lung lesions have cleared up and her spleen has shrunk.

In August of 2012 she came in with a seizure. .MRI of the brain showed the following:
Poorly defined left temporal lobe lesion associated with mild mass effect as describe above. Finding may represent encephalitis, possibly viral in nature. Underlying mass lesion is not entirely excluded. MRI of the brain is recommended for further evaluation. All of the infectious disease w/u including PCR on the CSF were negative.

She improved.  Was continued on the same therapy of IVIG and tapering systemic steroids qod
Her headaches returned and she had another seizure. The repeat MRI (there have been four MRIs) reveled the following.

Technique: Diffusion, T1 sagittal, T2 axial, SWI, axial FLAIR, T2 coronal, coronal FLAIR, T1 axial PRE and postcontrast, T1 coronal fat-sat postcontrast, T1 sagittal postcontrast, Magnevist 10 mL

There is redemonstration of the abnormal FLAIR hyperintensity involving the left cerebellum, left temporal lobe, left posterior basal ganglia, right posterior parietal occipital lobe as well right medial parietal lobe. There is residual enhancement in these regions. Some of the enhancement appears to be improved compared to prior exam. However there also appears to be region of subtle increased enhancement in the left cerebellum compared to the prior exam.
There are also now a new regions of focal abnormal FLAIR hyperintensity in the right subfrontal lobe, left medial parietal lobe adjacent to the body and splenium of the corpus callosum as well as a along the right posterior parietal convexity. There is corresponding enhancement in these regions. This again may reflect immunodeficiency post inflammatory or infectious etiology. Close interval followup suggested.
1. New regions of abnormal FLAIR hyperintensity and enhancement in the right subfrontal lobe, right posterior parietal lobe and along the left medial parietal lobe as described above.
2. The previously descried regions of FLAIR hyperintensity and enhancement are also again noted as described above.

The lesions are strictly in the white matter.  New lesions are being seen.

Repeat w/u including CSF analysis shows no evidence of infection in particular enterovirus.

Is this auto-immune process? (she is on steroids and has had rituximab)
Is there another condition that I am missing?
Should I suggest a brain biopsy?
Is she a candidate for azathioprine?

Any suggestions would be highly appreciated.

Javeed Akhter, M.D.
JMF Immunology Referal Center



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