HHV-6 Encephalitis

HHV-6 encephalitis is a rare consequence of transplant immunosuppression and is also found as a complication of AIDS. Subacute encephalitis is fairly common in allogeneic stem cell transplant patients who do not receive prophylactic antiviral therapy. Acute and subacute HHV-6 encephalitis is also found rarely in immunocompetent adults. There have been 11 case reports of HHV-6 related meningoencephalitis in immunocompetent adults.

There have been 44 published reports of HHV-6 related encephalitis, 14 reports of HHV-6 related meningeoencephalitis and 5 on HHV-6 associated PML. The highest rate is reported in allogeneic bone marrow stem cell transplants.  Sporadic cases of encephalitis have been reported in various conditions such as exanthum subitum and drug induced hypersensitivity syndrome. Typical symptoms include lethargy, confusion, coma seizure and focal neurological signs. HHV-6 encephalitis is often associated with drug hypersensitivity, organ disease, encephalitis, bone marrow suppression, rash and lysis of CD4 cells.

Singh et al reviewed 14 cases of transplant related HHV-6 encephalitis (13 bone marrow and 1 liver transplant) and found the following symptoms:

• Mental status changes – 92%

• Seizures – 25%

• Headache-25%

• Mortality – 58%

More recently, Isaacson et al (2005) reported 4 out of 1000 patients enrolled in the California Encephalitis Project were immunocompetent adults with encephalitis caused by HHV-6. In a previous study 9 of 138 patients with encephalitis had HHV-6 DNA in the CSF (McCullers 1995). These patients had outcomes that ranged from full recovery to severe impairment and death.

A significant limitation to all these studies is the variability and inconsistencies associated with either PCR or serological based assays.  As there is no ‘gold standard’ for the detection of HHV-6 it is unclear as to the true extent of infection and the role this virus plays in encephalitis.  Indeed, HHV-6 has been suggested to be an under-appreciated pathogen (Fotheringham 2007). Molecular and immunological methodologies have become more sensitive.  As these technologies become standardized we can begin to fully ascertain the scope of HHV-6 infection in disorders of the nervous system.

Several cases of HHV-6-associated encephalitis have also presented retrograde and anterograde amnesia. In many of these patients, encephalitis developed post-transplantation. 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 abnormality in the medial temporal lobes which correlates well with the presentation of anterograde amnesia (Gorniak 2006). The clinical association between the medial temporal lobes and dysfunction of memory formation is was first documented in 1957 (Scoville & Milner) and since then dozens of studies have supported the concept that the medial temporal lobes, specifically the hippocampus and surrounding structures, are intrinsically important in the processing of declarative memory functions such as conscious memory for facts and events. Additionally, MRI imaging in several patients post seizure have demonstrated cerebral volume loss that was disproportionately prominent in the temporal lobes as well as lesions in the hippocampus and temporal lobes (Visser 2005, Bollen 2005).  This data suggests that HHV-6 may play a role in amnesia through its pathogenesis in encephalitis.

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