Herpesvirus-Associated Central Nervous System Diseases after Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Herpesvirus infections of the central nervous system (CNS) are associated with encephalitis/myelitis and lymphoproliferative diseases in immunocompromised individuals. As of now, data of herpesvirus-associated CNS diseases in transplant recipients is limited. Hence, in this prospective study, we investigated the incidence of herpesvirus-associated CNS diseases and explored the diagnosis of these diseases in 281 allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Herpesvirus-DNA and cerebrospinal fluid (CSF) cells were sampled from 58 recipients with herpesvirus-associated diseases or with unexplainable CNS manifestations. Results showed that 23 patients were diagnosed as herpesvirus-associated CNS diseases, including 15 Epstein-Barr virus (EBV)-associated diseases (4 encephalitis and 11 lymphoproliferative diseases), 5 herpes simplex virus type 1 encephalitis, 2 cytomegalovirus encephalitis/myelitis and 1 varicella zoster virus encephalitis. The median time of diseases onset was 65 (range 22-542) days post-transplantation. The 3-year cumulative incidence of herpesvirus-associated encephalitis/myelitis and post-transplant lymphoproliferative disorder (PTLD) was 6.3% ±1.9% and 4.1% ±1.2%, respectively. Of the evaluable cases, CSF cells mainly consisted of CD19+CD20+ B cells (7/11) and had clonal rearrangement of immunoglobulin genes (3/11) in patients with CNS-PTLD. On the contrary, in patients with encephalitis/myelitis, CSF cells were comprised of different cell populations and none of the gene rearrangement was detected. Herpesvirus-associated CNS diseases are common in the early stages of allo-HSCT, wherein EBV is the most frequent causative virus. The immunophenotypic and clonal analysis of CSF cells might be helpful in the differential diagnosis between encephalitis and lymphoproliferative diseases.

HHV‐6 encephalitis may complicate the early phase after allogeneic hematopoietic stem cell transplantation: Detection by qualitative multiplex PCR and subsequent quantitative real‐time PCR

“…Although the presence of HHV‐6 DNA in CSF was detected in only two of four patients, a definite 1.9% (2/105) and a probable 3.8% (4/105) of cases developed HHV‐6 encephalitis in out HSCT population. These incidences were similar to or slightly higher than observed in previous studies [Schmidt‐Hieber et al, ; Ogata et al, ; Wu et al, ].…”

“…Several previous studies have shown the significance of HHV‐6 reactivation and subsequent HHV‐6 encephalitis in post‐HSCT patients [Schmidt‐Hieber et al, ; Zerr et al, ; Ogata et al, ; Wu et al, ]. In the present prospective study, we coupled a multiplex PCR capable of simultaneously detecting 13 kinds of viruses with a follow‐up quantitative PCR for HHV‐6, and demonstrated the importance of HHV‐6 infection in post‐HSCT subjects who experienced CNS dysfunction.…”

Central Nervous System Complications of Hematopoietic Stem Cell Transplant

“…10,50 However, more recent, albeit smaller, studies show the incidence of EBV-associated PTLD to be higher at 3% to 4%. 6,32,33 Increased incidence of cancers after allogenic transplantation, including those involving the CNS, has also been observed in a large study of 19,229 subjects in which the investigators noted the risk to be higher 5 or more years after transplantation. This increased risk was thought to be likely related to conditioning with radiation, altered immune function, and prior treatment of the primary disease.…”

“…Causative viruses included herpes simplex virus 1, cytomegalovirus (CMV), varicella-zoster virus, and Epstein-Barr virus (EBV). 6,32 In another study, the incidence of EBV-associated CNS disease, including encephalitis or myelitis, has been reported to be 3.4%, with the median time of disease onset being 49 days (22-184) post-transplant. 33 Although MRI of the brain may be normal in these subjects, focal or diffuse signal FLAIR hyperintensities or space-occupying lesions may also be seen.…”

Viral encephalitis after haplo‐identical hematopoietic stem cell transplantation: Causative viral spectrum, characteristics, and risk factors

“…Notably, HHV‐6, which is a causative virus in the preponderance of retrospective studies by M. Schmidt‐Hieber et al., was not prevalent in the VE virus spectrum in this study. Likewise, in a prospective study from China about the incidence of herpes virus‐associated CNS diseases in allo‐HSCT recipients, HHV‐6 was not among the causative virus spectrum for VE . Although the basis for the viral spectrum differences remains unclear, the causative spectrum discrepancies might be partly due to regional disparities.…”