Neurology -- Correspondence for Seeley et al., 69 (2) 156-165

Correspondence published:

Post-transplant acute limbic encephalitis: Clinical features and relationship to HHV6: Marc C. Chamberlain, Sajeel Chowdhary, Tampa, FL (2 October 2007)

Reply from the authors: William W. Seeley, Francisco M. Marty, Lindsay R. Baden, Edward B. Bromfield (2 October 2007)

Post-transplant acute limbic encephalitis: Clinical features and relationship to HHV6 2 October 2007

Marc C. Chamberlain,
University of Washington Dept of Neurol, Fred Hutchinson Cancer Research Ctr and Seattle Cancer Care
Neuro-Oncology, Seattle Cancer Care Alliance, 825 Eastlake Ave E, MS G6-800, Seattle, WA 98109-1023,
Sajeel Chowdhary, Tampa, FL
Send Correspondence to journal:
Re: Post-transplant acute limbic encephalitis: Clinical features and relationship to HHV6

chambemc{at}u.washington.edu Marc C. Chamberlain, et al.

Seeley et al present a case control series of nine patients with post-transplant acute limbic encephalitis (PALE) due to presumed reactivation of the human herpes 6 virus (HHV-6). [1] We present a case of HHV-6 encephalitis that clinically presented as a nonspecific encephalopathy that without appropriate CSF assay would have been overlooked and misdiagnosed.
A 55-year-old woman with refractory diffuse large cell non-Hodgkin’s lymphoma was treated with high-dose chemotherapy and an unmatched allogenic stem cell transplantation. At week 2, she developed post-transplant graft versus host disease (bowel and lungs) managed with oral steroids, tacrolimus and cyclosporine. Three weeks post-transplant, she developed a slowly progressive confusional state.
Routine laboratory evaluation was unremarkable except for neutropenia (530 cells/uL) and thrombocytopenia (38,000 cells/uL). CT and MR imaging of the brain were normal on two occasions over the course of 10 days. EEG revealed mild diffuse generalized slowing in the 6-7 Hz range without epileptiform abnormalities. CSF analysis revealed a white blood cell count of 10 cells/mm3 (all lymphocytes), 1 red blood cell/mm3, glucose 87 mg/dL and protein 80 mg/dL. Viral, bacterial and fungal cultures were negative. However, HHV-6 was positive by quantitative PCR assay in both blood and CSF. The patient was treated with intravenous ganciclovir and foscarnet and made a complete recovery at discharge.
HHV-6 exhibits neurotropism and is a rare cause of encephalitis predominantly seen in immunocompromised and occasionally immunocompetent patients. [1-5] Features of a limbic encephalitis with characteristic MRI have been reported by Seeley and others. [1-5] Immunosuppression secondary to solid organ or hematopoietic transplantation may permit re-activation of HHV-6, viral replication and the emergence of an HHV-6 related clinical syndrome (i.e., encephalitis, hepatitis, pneumonitis and bone marrow suppression). [1, 4]
As the majority of children have primary HHV-6 infections, most adults demonstrate antibodies to the virus. The diagnosis of acute HHV-6 clinical syndromes, like encephalitis, requires demonstration of HHV-6 in CSF via PCR or brain pathology. Alternatively, either an IgM antibody response or four-fold rise in the IgG antibody support reactivation of HHV-6. In vitro HHV-6 has a susceptibility pattern similar to CMV.
Foscarnet is active against both HHV-6 serotypes (A and B) while ganciclovir is active against HHV-6B yet in some reports HHV-6A was relatively resistant. [6] However, there is limited clinical data on the use of these antiviral drugs for the treatment or prophylaxis of HHV-6 infection. [6] Studies that have examined the use of ganciclovir for prophylaxis of CMV infection in allogeneic stem cell transplant recipients found that this antiviral therapy prevented HHV-6 reactivation and subsequent complications such as encephalitis. [6]
Because HHV-6 encephalitis may present—as in our case— as an undifferentiated encephalopathy, a viral etiology may not be considered in the differential diagnosis of subacute confusional states. CSF analysis and, in particular PCR for HHV-6, should be considered in an appropriate clinical context. In our case, other common causes of encephalopathy in this patient population including CNS-active drugs, organ failure, posterior reversible encephalopathy syndrome, and PALE were excluded.
References
1. Seeley WW, Marty FM, Holmes TM, et al. Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology 2007;69:156-165.
2. Drobyski WR, Knox KK, Majewski D, Carrigan DR. Fatal Encephalitis Due to Variant B Human Herpesvirus-6 Infection in a Bone Marrow-Transpalnt Recipient. NEJM 1994; 330:356-1360.
3. Gorniak RJ, Young GS, Wiese DE, Marty FM, Schwartz RB. MR Imaging of Human Herpesvirus – 6 – Associated Encephalitis in 4 patients with Anterograde Amnesia after Allogeneic Hematopoietic Stem Cell Transplantation. Am J Neuroradiol 2006; 27:887-891.
4. De Bolle L, Naesens L, De Clercq E. Update on Human Herpes 6 Biology, Clinical Features, and Therapy. Clinical Microbiology Reviews 2005;18:217-245.
5. Tiacci E, Luppi M, Barozzi P et al. Fatal herpesvirus-6 encephalitis in a recipient of a T-cell-depleted peripheral blood stem cell transplant from a 3-loci mismatched related donor. Haematologica 2000;85:94-97.
6. Tokimasa S, Hara J, Osugi I et al. Ganciclovir is effective for prophylaxis and treatment of human herpesvirus-6 in allogenic stem cell transplantation. Bone Marrow Transplant 2002;29:595-598.
Disclosure: The authors report no conflicts of interest.

Reply from the authors 2 October 2007

William W. Seeley,
UCSF
Box 1207, UCSF, San Francisco, CA 94143-1207,
Francisco M. Marty, Lindsay R. Baden, Edward B. Bromfield
Send Correspondence to journal:
Re: Reply from the authors

wseeley{at}memory.ucsf.edu William W. Seeley, et al.

We thank Drs. Chamberlain and Chowdhary for their interest in our recent report of post-transplant acute limbic encephalitis. [1] They report a patient who had undergone allogeneic hematopoietic stem-cell transplantation (HSCT) for treatment of non-Hodgkin lymphoma who developed a subacute confusional state beginning three weeks after transplant while being treated for graft-versus-host disease. The period of symptomatic progression is not provided.
Confusion during HSCT is not uncommon, is not a specific clinical finding, and may be multi-factorial. The confusion in this patient appears to have fully resolved with time and concurrent with the use of ganciclovir and foscarnet (triggered by HHV-6 DNA detected in a CSF sample).
Blood HHV-6 DNA detection following allogeneic HSCT occurs in 40-60% of patients [7], for whom antiviral treatment does not seem to be routinely warranted. However, encephalitis associated with CSF HHV6 DNA detection is uncommon [8] but given the potentially devastating neurological consequences, antiviral treatment is prescribed in such settings at transplant centers despite the absence of controlled trials. Efficacy of combination antiviral therapy for potential HHV-6 encephalitic syndromes is unknown.
In 2003, we incorporated routine CSF HHV-6 DNA detection following allogeneic HSCT. In our reported and subsequent experience, no patient has had detectable HHV-6 DNA in CSF samples outside of the context of PALE’s clinical or radiological manifestations. However, we cannot exclude the possibility of other clinical syndromes as suggested by Chamberlain and Chowdhary.
HHV6-associated limbic encephalitis is believed to reflect viral reactivation in the setting of intense immunosuppression. More diffuse encephalitis syndromes have been described after HSCT [9] and with new HHV-6 acquisition in immunocompetent adults. [10]
Recently, Fotheringham et al performed postmortem evaluations of three patients who died with active encephalitis following HSCT. [11] Although HHV-6 DNA was detected in many parts of the brain, HHV-6 mRNA and HHV6 specific proteins were detected only in the hippocampus and adjacent areas.
This suggests that when HHV6 causes encephalitis, it reactivates and damages limbic areas preferentially, as observed and proposed for PALE. HHV-6 infection may be associated with a variety of other syndromes. However, careful characterization of these potential syndromes is required to move the field forward.
References
7. Zerr DM, Corey L, Kim HW, Huang ML, Nguy L, Boeckh M. Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation. Clin Infect Dis 2005;40:932-940.
8. Zerr DM, Gupta D, Huang ML, Carter R, Corey L. Effect of antivirals on human herpesvirus 6 replication in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002;34:309-317.
9. Singh N, Paterson DL. Encephalitis caused by human herpesvirus-6 in transplant recipients: relevance of a novel neurotropic virus. Transplantation 2000;69:2474-2479.
10. Isaacson E, Glaser CA, Forghani B, et al. Evidence of human herpesvirus 6 infection in 4 immunocompetent patients with encephalitis. Clin Infect Dis 2005;40:890-893.
11. Fotheringham J, Akhyani N, Vortmeyer A, et al. Detection of active human herpesvirus-6 infection in the brain: correlation with polymerase chain reaction detection in cerebrospinal fluid. J Infect Dis 2007;195:450-454.
Disclosure: The authors report no conflicts of interest.