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

[Elie Haddad]

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





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>

> 

> 

> 

> 

> 

> On Sep 18, 2013, at 4:45 AM, Seppänen Mikko <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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