HHV-6 reactivation is the most common cause of mental confusion among post-transplant patients (Zerr 2011). HHV-6 limbic encephalitis, which occurs in approximately 1-4% of all transplant patients, often results in intermittent confusion, poor coordination, flat affect and somnolence. In fact, one of the key clinical benchmarks of Chimerix’s phase three “SUPPRESS” trial of Brincidofovir (CMX001) will focus on daily assessment of mental status in conjunction with HHV-6 levels to determine the drug’s effectiveness at controlling HHV-6 reactivation, thus hopefully limiting the subsequent cognitive decline described by Zerr et al.

HHV-6 and EBV have also been identified as risk factors for cognitive deterioration and progression to Alzheimer’s disease in elderly persons (Carbone 2014). Several cases of HHV-6-associated encephalitis have also presented retrograde and anterograde amnesia. In these cases, HHV-6 DNA was detected in the CSF by PCR, which is considered substantive evidence of active CNS infection. These patients also showed signal intensity abnormalities in the medial temporal lobes, which correlates well with the presentation of anterograde amnesia (Gorniak 2006).

A clinical association between the medial temporal lobes and dysfunction of memory formation was first documented in 1957 (Scoville & Milner). Since then, dozens of studies have supported the concept that the medial temporal lobes, specifically the hippocampus and surrounding structures, are intrinsically important to the processing of declarative functions such as conscious memory–which is responsible for remembering specific facts and events. Additionally, MR imaging following seizure episodes in several patients have demonstrated cerebral volume loss disproportionately prominent in the temporal lobes; these patients also displayed lesions in the hippocampus and temporal lobes (Visser 2005, Van der Flier 2005). This data suggests that HHV-6 infection may play a role in amnesia through its pathogenesis in encephalitis.

Key Papers: HHV-6 & Cognitive Dysfunction/Delirium

Carbone 2014 Herpesvirus in Alzheimer’s disease: relation to progression of the disease
Raspall-Chaure 2013 Epileptic encephalopathy after HHV-6 PALE in children: confirmation of a new epilepsy syndrome
Clark 2013 Activation of CCR2+ human proinflammatory monocytes by HHV-6B chemokine N-terminal peptide
Tanaka 2012 Fatigue-associated alterations of cognitive function and electroencephalographic power densities
Montoya 2012 Antiviral therapy of two patients with ciHHV-6A presenting with cognitive dysfunction
Zerr 2011 HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients
Provenzale 2010 Clinical and Imaging Findings Suggesting Human Herpesvirus 6 Encephalitis
Niebuhr 2008 Results from a hypothesis generating case-control study: herpes family viruses and schizophrenia among military personnel
Zerr 2006 Human herpesvirus 6 and central nervous system disease in hematopoietic cell transplantation
Gorniak 2006 MR imaging of human herpesvirus-6-associated encephalitis in 4 patients with anterograde amnesia after allogeneic hematopoietic stem-cell transplantation.
Zerr 2005 Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation
Visser 2005 Medial temporal lobe atrophy and APOE genotype do not predict cognitive improvement upon treatment with rivastigmine in Alzheimer’s disease patients.
Leweke 2004 Antibodies to infectious agents in individuals with recent onset schizophrenia