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

Herpesvirus infections of central nervous system (CNS) are associated with encephalitis/myelitis and other neurological syndromes as well as lymphoproliferative diseases in immunocompromised individuals. Diagnosis is mainly based on the detection of virus-DNA in cerebrospinal fluid (CSF). Recently, some studies demonstrate that herpesvirus-associated diseases have increased in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), but these mainly focus on the systematic herpesvirus infections and lack of a large-sample prospective study of CNS herpesvirus infections.

The eligibility criteria are as following: (1)The patients after allo-HSCT; (2)The patients who were diagnosed as Epstein-Barr virus (EBV)-associated diseases; (3)The patients with other herpesvirus-associated diseases other than EBV-associated diseases accompanying CNS manifestations; (4)The patients with unexplainable CNS manifestations. According to the criteria aforementioned, fifty-four of 250 patients undergoing allo-HSCT in our single institution between July 2008 and April 2012 were enrolled in this prospective study. Moreover, 18 patients with herpesvirus-DNA-emia who did not develop herpesvirus-associated diseases volunteered to have their CSF monitored (platelet >50×10⁹/L). Herpesvirus-DNA of CSF, blood and other body fluids was monitored by polymerase chain reaction (PCR). Once herpesvirus-associated CNS diseases were considered, immunophenotypic analysis of CSF cells and magnetic resonance imaging scanning of CNS were performed.

Twenty-four patients were diagnosed as herpesvirus-associated CNS diseases, including 8 EBV encephalitis, 7 EBV-associated CNS post-transplant lymphoproliferative diseases (PTLD), 5 herpes simplex virus type 1(HSV-1) encephalitis, 2 cytomegalovirus (CMV) encephalitis, 1 CMV myelitis and 1 varicella zoster virus(VZV) encephalitis, respectively. The EBV-DNA levels of CSF were significantly higher than that of blood (82457 ± 6126 copies/ml vs. 18517 ± 3906 copies/ml, P=0.030). The virus of CSF was consistent with the virus of blood in all patients except one patient with EBV-associated CNS-PTLD, who was EBV-DNA positive of CSF but CMV-DNA positive of blood. The median time of herpesvirus-associated CNS diseases onset was 79 days post-transplants and 70.8% cases occurred within 100 days post-transplants. The 3-year cumulative incidence of herpesvirus-associated CNS diseases and EBV-associated CNS diseases was 12.8±2.6% and 7.5±2.0%, respectively. With a median follow-up of 198 days after the diagnosis of herpesvirus-associated CNS diseases, 13 patients survived and 11 died. The causes of death were related with herpesvirus in 7 cases and not related with herpesvirus in 4 cases.

PCR detection of CSF virus-DNA is a sensitive and specific method for diagnosing herpesvirus-associated CNS diseases. EBV-associated CNS diseases are more common than other herpesvirus-associated CNS diseases in the early times of allo-HSCT. The EBV-DNA negative in blood could not exclude EBV-associated CNS diseases.

No relevant conflicts of interest to declare.