Q:

2/18/2013
I recently saw a 49 year old male with history of encephalitis x 2 in 2008 and 2012. Both times, no specific diagnosis was made but presumed viral on basis of elevated WBC. Had pneumonia once but was during hospitalization for encephalitis. No other history of pneumonia, sinusitis, GI or skin infections. No history of trauma or other risk factor for infectious encephalitis. He was referred to me for immune work up.

CBC, T and B cell numbers, complement and neutrophil function were all normal. TLR 3 function was normal. Titers to S. pneumo, Haemphilus, Diptheria and pertussis all normal. IgGAM all slightly low.

Normally I would say that slightly low IgGAM in light of good titers is probably of no concern. However, this patient may have had enteroviral encephalitis twice and I'm not sure if there is any further work up I should do. Is there any justification for putting this patient on IVIG? Thank you.

A:
Thank you for your inquiry.

I am not aware of nor could I find in the literature recurrent encephalitis related to an antibody deficiency unless that deficiency was severe and evident on measurement of immunoglobulins and immune response to immunizations. So, at least from what I could find in the literature, it is unlikely that immunoglobulin replacement therapy would be of help to your patient in view of the fairly normal immunoglobulin pattern and response to immunization seen in your patient.

As you know, based upon your looking at toll-receptor 3, other immunologic defects responsible for recurrent herpes simplex encephalitis have been related to defective production of or aberrant synthesis of interferons. Toll-receptor 3 mutations are one of these; there are others that have been described which are summarized in a recent article in the Journal of Allergy and Clinical Immunology (1).

These defects, like TLR-3 abnormalities, are of innate immunity. The defects include those in TOLL/IL-1 receptor domain-containing adapter inducing interferon beta (TRIF) protein and mutations in TANK-binding kinase 1 (TBK1). However, in looking at these individual reports, it does not appear that they are at all similar to the patient you have described.

Nonetheless, I have no personal expertise in this area, and therefore I am going to ask for help from Dr. Mary Ellen Conley, one of the authors of the reference cited above, for her thoughts regarding whether or not there is any other measure you might take to evaluate or treat your patient. As soon as I hear from Dr. Conley, I will forward her response to you.

Thank you again for your inquiry.

Reference:
1.Parvaneh N, et al. Primary immunodeficiencies: a rapidly evolving story. J Allergy Clin Immunol 2013; 131:314-323.

Sincerely,
Phil Lieberman, M.D.

We received a response from Dr. Mary Ellen Conley regarding your Ask the Expert inquiry. Thank you again for your inquiry and we hope this response is helpful to you.

Sincerely,
Phil Lieberman, M.D.

Response from Dr. Mary Ellen Conley:
I agree with you that IVIG is not warranted in this case. My criteria for starting gammaglobulin therapy include 1) infections that are typical of antibody deficiency and 2) failure to make antibody to vaccine antigens. The patient does not fit either criteria. Although it is possible that the patient has had viral encephalitis, I wonder about an autoimmune etiology.

Mary Ellen Conley, MD
West Research Tower
LeBonheur Children's Hospital
AAAAI - American Academy of Allergy Asthma & Immunology