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

[Akhter, Javeed]

Drs Seppanen, Routes, Vasconcelos and Haddad
Thank you all for taking the time to review and respond to this case.  Your input is extremely useful and highly appreciated

I am pasting a bit more of the data on this child's CSF.
Our Neurologist's diagnosis is ADEM

I will be meeting with the patient and family soon and share your thoughts and suggestions with them.  If it is OK I will share the family's response and the child's progress with you all.

Dr Routes I will be in touch with you and may be one of our residents can help write up a case report in the future.

Thanks again
Javeed Akhter
Advocate Children's Hospital, Oak Lawn. IL
JMF center

CSF SYNTH PNL W ELEC [MSCSF] Final
ALBUMIN, SERUM 3720 3430-4990 mg/dL
IGG 2010 H 694-1618 mg/dL
CSF PROTEIN 32 15-45 mg/dL
CSF ALBUMIN 11 0-35 mg/dL
CSF IgG 2.8 0.5-6.1 mg/dL
CSF IgG INDEX 0.47 <0.77
CSF IGG SYNTH.RATE 0.0 0.0-8.0 mg/24 hr
Unit: mg/day
IGG/ALB INDEX 0.25 0.09-0.25
CSF ELECTROPHORESIS
Negative for oligoclonal bands.

LYME DISEASE by PCR
NOT DETECTED

CSF CULTURE [CSFCS] Final
CSF CULTURE/SMEAR
SPECIMEN DESCRIPTION: CEREBROSPINAL FLUID
GRAM SMEAR: NO ORGANISMS SEEN
GRAM SMEAR: POLYMORPHONUCLEAR CELLS PRESENT

ENTERO VIRUS PCR NOT DETECTED NOTD
HERPES SIMPLEX PROBE NOT DETECTED NOTD
VARICELLA ZOSTER VIR NOT DETECTED NOTD
CMV QUALITATIVE NOTD
NOT DETECTED

CSF VOLUME 4.0 mL
NUMBER OF TUBES 3
PERFORMED ON TUBE 3
CSF APPEARANCE CLEAR COLORLESS
CSF RBC 30 H 0 /mcL
NUCLEATED CELL COUNT 89 H 0-10 /mcL
SEG NOT APPLICABLE
LYMPH 93 28-95 %
MONO/MACROPHAGE 7 L 16-56 %
EOS NOT APPLICABLE
BASO NOT APPLICABLE
GLUCOSE CSF [CSFGL] Final
CSF PROTEIN 32 15-45 mg/dL


From: Elie Haddad [mailto:elie.haddad at umontreal.ca]
Sent: Wednesday, September 18, 2013 9:31 AM
To: CIS-PIDD
Subject: Re: [cis-pidd] ten year old with CVID and focal white matter demyelination

We also folowed a patient with CVID and GLILD. First we treated her with steroids + antiTNF.
After 1 year, she developped seizures and the brain biopsy showed "a GLILD in the brain" as said our pathologist. He told us that the lesions in the brain were a copy/paste of the lesions in the lungs. He did not mention ADEM. Of course, all the infectious work-up was negative.
We tried Rituximab (withour Imuran) and it worked well for a while but then seizures relapsed. Therefore, we decided to transplant the patient.
More than 2 years after double cord blood transplantation, she has no relapse of GLILD (in lungs or in brain...), her immune system is very slowly recovering, she has had some GvHD and recently she developed an autoimmune hemolytic anelmia for which we had to give steroids and rituximab. Not so perfect but so far, we "cured" the brain and the lung.
All the best
Elie

Elie Haddad, MD, PhD,
Professor of Pediatrics, University of Montreal,
Head, Pediatric Immunology and Rheumatology Division,
CHU Sainte-Justine, 3175 Cote Sainte-Catherine
Montreal, QC, H3T 1C5, Canada
Ph: 1 514 345 4713
fax: 1 514 345 4897
e-mail: elie.haddad at umontreal.ca<mailto:elie.haddad at umontreal.ca>





Le 2013-09-18 à 10:18, Routes, John a écrit :


Dear Javeed
Well since Mikko broke the ice I will add my 2 cents
I agree with the workup suggested below but doubt it will reveal infection---
We were referred an 18 you female with CVID and the w/u revealed GLILD (had splenomegaly, diffuse adenopathy etc....)---she also had focal demylelination of the CNS and after an extensive w/u was diagnosed with ADEM
She has been treated with rituximab and azathioprine, which induced a remission of both the CNS disease and GLILD----interestingly, when we DC'd immunosuppressive therapy, her ADEM recurred
so we restarted Aza/RTX (recently substituted MMF due to nausea) and her CNS disease is stable and pulmonary disease essentially gone

if the dx turns out to be ADEM, let me know and we can write these cases up
Remember the adage----one patient is a case report, 2 is a series and 3 is a career.
good luck and let me know if i can be of any help
Jack


John M. Routes, MD
Chief, Section of Allergy and Clinical Immunology
Co-Director, Clinical and Translational Science Institute of Southeast Wisconsin
Professor of Pediatrics, Medicine, Microbiology and Molecular Genetics
Department of Pediatrics
Children's Hospital of Wisconsin
Medical College of Wisconsin
9000 W. Wisconsin Ave.
Milwaukee, WI  53226-4874
Phone: Office 414-266-6840
Fax: 414-456-6487 (Clinical)
Fax: 414-456-6323 (Laboratory)
Email: jroutes at mcw.edu<mailto:jroutes at mcw.edu><mailto:jroutes at mcw.edu>





On Sep 18, 2013, at 4:45 AM, Seppänen Mikko <Mikko.Seppanen at hus.fi<mailto:Mikko.Seppanen at hus.fi><mailto:Mikko.Seppanen at hus.fi>> wrote:

Dear Javeed,

Since no one seems eager to comment, a quick note:

a)      Q: values of CSF-prot, leuk, ADA, LZM, IgG index, cytology, CSF/S-oligoclonal bands? S-LD, thymidine kinase, IL2R??

b)      Seems awfully widespread for "normal" infection. Due to immune suppression, fungal and parasitic diseases are a possibility, as is PMLE (!). Neuroradiologists would suspect PMLE,
c)       .... and would recognize ADEM, in which waxing and waning as well as relapses are rarely, but occasionally seen. Of nice dgs I would seriously consider this.
d)      TBC is rare in CVIDs, but needs to be excluded.
e)      For CNS autoimmunity vs. SLE, MCTD, Sjogren, grey matter is usually also affected.
f)       For known autoimmune encephalitis forms the involvement is too widespread, too radiologically active and symptoms too few, the patient has cerebritis + rhombencephalitis (= cerbellitis and basal encephalitis) /demyelination  and  this dg seems less likely. Of course one does see peculiar AIE-like syndromes in CVIDs, I have 2 patients not conforming to any but whom I regard to suffer from such, thus exclusion 100% might be impossible, peculiar, severe and fatal cases are also in literature, at least 1 well-documented patient series published
g)      and I would sadly very actively search for CNS lymphoma, CNS granulomas, PMLE, severe hard-to-treat opportunistic infections
h)      biopsy seems to me both urgent and mandatory

i)        BTW. You might want to consider WES for the whole family... AD mode of inheritance? If interested in this, contact me?
See also recent JACI letter:
Neil Romberg et al "Gain-of-function STAT1 mutations are associated with PD-L1 overexpression and a defect in B-cell survival"

Hope this helps,

mikko
Mikko Seppänen, MD PhD, HUCH, Finland



Lähettäjä: Akhter, Javeed [mailto:javeed.akhter at advocatehealth.com<http://advocatehealth.com>]
Lähetetty: 17. syyskuuta 2013 19:26
Vastaanottaja: CIS-PIDD
Aihe: [cis-pidd] ten year old with CVID and focal white matter demyelination

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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