HHV-6 encephalitis is a significant consequence of transplant immunosuppression, although it is seen in immunocompetent patients as well. Interestingly, the characteristics of HHV-6 encephalitis differ between patients who develop the condition through primary infection compared to viral reactivation (Kawamura 2011). Information on HHV-6 encephalitis in both transplant and immunocompetent patients is provided below.

In Transplant Patients

The incidence of HHV-6 encephalitis is reportedly 0-11.6% after bone marrow or peripheral blood stem cell transplantation and 4.9-21.4% after cord blood transplantation (Ogata 2015). HHV-6 reactivation is associated with cognitive decline in stem cell transplant patients, especially in processing speed and executive function (Zerr 2005, 2011). HHV-6 encephalitis should be suspected in patients who present with abnormalities in the hippocampus, amygdala and limbic structures beyond the medial temporal lobe (Seeley 2007, Provenzale 2008). Mortality of HHV-6 encephalitis is high and survivors are often left with serious sequelae (Shimazu 2013, Ogata 2015). Approximately 80% of those who survive HHV-6 encephalitis suffer from permanent neurological disability (Sakai 2011). Antiviral therapy using foscarnet or ganciclovir is recommended for the treatment of HHV-6 encephalitis (Ogata 2015).

The incidence of HHV-6 encephalitis during HSCT in children is thought to be less than that in adults (Kouzuki 2014). Evaluation of CSF (detecting HHV-6 DNA by PCR) is recommended in patients younger than 13 months with possible encephalitis (Yavarian 2014). HHV-6 is the etiological agent of exanthema subitum-associated encephalopathy, which usually occurs in children younger than 3 years. However, primary HHV-6 infection can cause acute encephalopathy without exanthema subitum. When the patient shows no skin rash, this etiological diagnosis is only possibly by examining the blood and CSF. This condition should be included in the differential diagnosis of acute encephalopathy even in patients older than 3 years of age (Yamamoto 2015). It is critical to differentiate HHV-6 encephalitis from other common neurologic syndromes occurring after transplant, allowing potentially improved patient outcomes by prompt diagnosis and effective treatment (Sadighi 2015). Children who develop HHV-6 post-transplant limbic encephalitis (PALE) may be at high risk for the development of epilepsy (Howell 2012).

In a study of 130 patients involved in 147 allo-HSCT transplantation procedures, HHV-6 load at 2, 3, and 4 weeks after allo-HSCT was examined. HHV-6 reactivation occurred in 56 of 147 procedures and HHV-6 encephalopathy occurred in 9 of 147 procedures. HLA (human leukocyte antigen) mismatch (p=0.008) and unrelated donor (p=0.001) were associated with HHV-6 reactivation, but not with HHV-6 encephalopathy. The HLA class I alleles of recipients may be associated with the occurrence of HHV-6 encephalopathy after allo-HSCT (Yamamoto 2014).

HHV-6 acute limbic encephalitis after unrelated cord blood transplantation has been successfully treated with ganciclovir (Hirabayashi 2013, Camus 2015). PCR detection of HHV-6 DNA in CSF associated with brain MRI abnormalities and a clinical diagnosis of nonspecific encephalopathy must lead to the urgent initiation of systemic antiviral treatment, usually based on intravenous ganciclovir or foscarnet sodium (Camus 2015). Antiviral therapy should be started early to prevent brain damage (Ogata 2008, Ichiyama 2009, Ishiyama 2011, Hirabayashi 2013, Camus 2015) even if it cannot prevent all cases of HHV-6 encephalopathy in allo-HSCT recipients due to the dynamic kinetics of plasma HHV-6 viral load (Camus 2015). Serial quantification of HHV-6 DNA in CSF may be useful for successful treatment with ganciclovir in post-transplant HHV-6 encephalitis (Hirabayashi 2013). However, reactivation of HHV-6 can still develop even under ganciclovir treatment after bone marrow transplantation (Imataki 2015). It should be noted that, on the basis of available data, the possibility that the patient from Imataki’s case report had chromosomally integrated HHV-6 (iHHV-6) could not be ruled out. Chromosomally integrated HHV-6 (ciHHV-6) should be ruled out before making a diagnosis of HHV-6 encephalitis (Pellett 2011, Scheurer 2012).

In a recent prospective study, researchers investigated the correlation of post-HSCT viral reactivation in blood with CNS dysfunction. 591 whole blood samples were collected from 105 patients from before until 42 days after HSCT. 7 patients developed CNS dysfunction such as altered consciousness and in 6 of these 7, their multiplex PCR test detected HHV-6 DNA in at least one sample. Quantitative measurement of whole blood HHV-6 DNA levels showed that 4 of the 6 HHV-6 DNA loads were elevated at successive time points during CNS dysfunction. Additionally, the virus DNA peaks were temporally associated with the development of CNS dysfunction. After testing CSF from 2 of the 4 patients for HHV-6 DNA, these 4 patients were thus suspected to have developed HHV-6 encephalitis, a rate of 3.8% in the study population. These results suggest that early diagnosis of probable HHV-6 encephalitis can be improved by confirming high HHV-6 DNA load in blood (Inazawa 2015). Early diagnosis (by repeated head MRI and by quantitative HHV-6 PCR of both serum and CSF), early reduction of immunosuppressive agents, and early initiation of effective treatment might be key factors for successful resolution when HHV-6 encephalitis is suspected (Yamamoto 2014).

In the Immunocompetent

HHV-6 encephalitis should be considered even among immunocompetent patients presenting with encephalitis and having signs of temporal lobe involvement (Shahani 2014). A NINDS study found HHV-6 DNA in the CSF of 40% of 35 immunocompetent patients with encephalitis of unknown etiology (Yao 2009). HHV-6 encephalitis/encephalopathy associated with primary infection in infants has an unexpectedly poor outcome. In a nationwide survey in Japan, 46.9% of 81 cases resulted in neurological sequelae or death (Yoshikawa 2009). One study found that out of 983 cases of acute encephalopathy in Japan, 17% were caused by HHV-6. 64% of the severe cases with biphasic seizures in this study were attributed to HHV-6, only half of which survived without permanent neurological sequelae (Hoshino 2012).

Opsoclonus-myclonus Syndrome (OMS) associated with human herpesvirus-6 rhomboencephalitis
Opsoclonus-myoclonus syndrome (OMS) is characterized by opsoclonus and arrhythmic-action myoclonus that predominantly involves the trunk, limbs, and head. Human herpes virus-6 (HHV-6) can rarely cause encephalitis in immunocompetent children and adults. A case study by Belcastro, et al., reports on a case of OMS associated with HHV-6 rhomboencephalitis (Belcastro 2014). HHV-6 infection should be considered in OMS adults and detection of cell-free viral DNA, indicative of active infection, is mandatory in such cases.

In cancer patients, neurological symptoms are usually due to brain metastases. A case report by Mordenti, et al., showed that in a cancer patient, any non-specific neurological symptoms should be carefully evaluated in order to exclude a non-oncologic cause. This is particularly true if the therapies for the oncological and neurological diseases are effective (Mordenti 2013).

POLG Mutations (Alpers-Huttenlocher Syndrome)
POLG mutations are associated with Alpers-Huttenlocher syndrome. A study reports two previously healthy young boys with human herpesvirus 6-associated encephalitis who developed a progressive, and ultimately fatal, encephalopathy with refractory movement disorder concurrent with acquisition of acute human herpesvirus 6 infection. Both children were treated with the antiviral ganciclovir without improvement of their neurological symptoms, although quantitative HHV6 PCR of CSF and/or blood confirmed a decline in viral load with treatment. The clinical course in both cases was most consistent with Alpers-Huttenlocher syndrome, given the intractable seizures, developmental regression, and, ultimately, death due to liver and renal failure. Postmortem analysis identified both children to be compound heterozygous for mutations in the mitochondrial polymerase gamma-gene, POLG. It is possible the POLG mutation phenotype becomes unmasked and/or exacerbated by human herpesvirus 6 infection in these 2 patients, potentially contributing to a more rapid clinical deterioration (Al-Zubeidi 2014)

Tick-borne Encephalitis and Enteroviral Meningoencephalitis
In a study investigating the frequency of HHV DNA detection in CSF of immunocompetent patients with meningoencephalitis of other than HHV origin, 96 patients with clinically and laboratory proven tick-borne encephalitis (TBE) and 77 patients with a confirmed diagnosis of enteroviral meningitis, along with a control group of 107 patients without evidence of inflammation in the CSF were retrospectively tested by nested PCR for the presence of DNA of the neurotropic herpesviruses HSV1, HSV2, VZV, and HHV6 in the CSF. HHV DNA was found in the CSF of 12 (6.9%) patients (6.3% and 7.8% in the TBE and EVM groups, respectively) and in 1 (0.9%) control patient. In all patients, the disease had a mild course without permanent sequelae. The presence of herpesviral DNA in the CSF had no significant influence on disease outcome. Low frequency and negligible impact of herpesvirus reactivation in TBE or EVM patients do not argue for routine herpesvirus testing in these diseases (Labska 2015).

Key Papers: HHV-6 Encephalitis