Human Herpesviruses May Trigger Epilepsy

Human herpesviruses 6B and 7 (HHV-6B, HHV-7) may be implicated in some forms of epilepsy. Steven Jacobson, PhD, a senior investigator at the National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, led a team of researchers who identified HHV-6B in the hippocampus of a substantial proportion of resections from patients with mesial temporal lobe epilepsy (MTLE) but not in tissue from neocortical resections. He reported his findings at the 2006 annual meeting of the American Epilepsy Society (AES), which met in San Diego from December 1 to 5.

Of the 38 resections studied, 17 were from patients with MTLE and 21 were from patients who had types of epilepsy other than MTLE (controls). Of the patients with MTLE, researchers found that 60% tested positive for HHV-6B. The virus was not found in any surgical resections in the control group.

HHV-6B may not be a direct cause of MTLE, said Jacobson, but he thinks it may be an environmental trigger in a subset of patients. "Since the cell type found to be infected with HHV-6 in MTLE patients was astrocytes, we are now focusing on the idea that the virus could dysregulate glutamate," said Jacobson. "That ties into what we know about epilepsy as a potential disease of glutamate pathways."

"My hypothesis is that HHV-6B is an early-acquired infection that becomes latent or persists in the CNS," he said. "Herpesviruses like to reactivate, which turn on or affect a number of host genes, such as glutamate, and that may affect the neurons [causing, for example,] excitotoxicity of glutamate."

HHV-6B and HHV-7 are universally acquired viruses. Humans normally contract the virus before the age of 4 years. HHV-6B is also associated with roseola infantum and may be associated with seizures and neurologic complications including meningitis and meningoencephalitis. Two variants of HHV-6 are known; HHV-6A and HHV-6B are separated by their antigenic and genomic composition, and only HHV-6B has been associated with MTLE, while HHV-6A is more often associated with multiple sclerosis.¹

Detection of the distinct viruses is difficult, said Jacobson. "There are no good serologic assays that can differentiate HHV-6A from HHV-6B, so we can't determine whether a patient has HHV-6A or HHV-6B unless we're using a polymerase chain reaction test," he said.

THE ORIGINS OF MTLE

Previous studies have shown that between 35% and 40% of children with febrile seizures have acute HHV-6 or HHV-7 encephalitis, and infection with HHV-6B is the most common cause of first-time cases of febrile seizures in children younger than 2 years.² The prolonged febrile seizure has been previously associated with MTLE, which has been reported to be a common feature of the intractable epilepsies. "Since this is a ubiquitous virus that we all get as kids, it basically fits in with the epidemiology of epilepsy, since a lot of people start out with epilepsy early in life," said Jacobson.

Interim results of the Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study also were presented at the AES meeting. This study, presented by Leon Epstein, MD, professor in the Department of Pediatrics and Neurology at Northwestern University, Chicago, examined the incidence of HHV-6B and HHV-7 in children with prolonged febrile seizures. He reported that 32 (35%) of 91 patients had evidence of primary infection with HHV-6B or HHV-7, and 2 patients with primary HHV-7 infection had reactivation of past HHV-6B infection.

The goal of the FEBSTAT study is to define a causal relationship between prolonged febrile seizure and subsequent mesial temporal sclerosis and MTLE, according to the study's principal investigator, Shlomo Shinnar, MD, PhD, neuroscience research professor at Albert Einstein College of Medicine, Bronx, New York.

Researchers at 5 participating centers intend to evaluate HHV infection status in 200 patients aged 1 month to 5 years with febrile seizures lasting 30 minutes or longer. Within 72 hours of seizure onset, patients will undergo MRI and receive neuropsychological testing. They also will undergo virology testing for HHV-6 and HHV-7, including DNA and RNA testing, to identify evidence of acute as well as previous infection. The tests will be repeated after 1 month. Imaging, EEG, and psychological testing will be repeated after 1 year to identify evidence of hippocampal damage and temporal lobe seizures.

This astrocyte cell line was isolated from a patient with mesial temporal lobe epilepsy. The co-localization of the 2 markers in the same cell indicate that it is infected with the virus: anti–HHV-6 is green and glial fibrillary acidic protein is blue.

Epstein's laboratory has previously shown that HHV-6B and HHV-7 are the most common causes of febrile seizures in children² and also demonstrated that HHV-6B can be localized to the hippocampus of immunosuppressed patients with limbic seizures.³ "If we can positively link HHV-6B to febrile seizures, we could get to the point where we could con-duct clinical trials leading to an intervention," Jacobson said. "The question is, can we identify a subpopulation of susceptible patients so we can prevent epilepsy in these children?"

But Jacobson said he does not expect to see this type of research in the near future. "It seems to me that there are not a lot of people looking at the cause of epilepsy," said Jacobson. "They're looking at how to treat people who already have seizures, but little work is being done on the early events."

The HHV-6B was discovered in 1985. "In terms of virology, this is a pretty new virus," Jacobson said. "That creates some issues for us because there are not a lot of reagents for these things. That's the catch-22: to study a virus, you need tools. But to get the funding for the tools, you have to establish some kind of a link. So how do you get the link if you don't have the tools?" While Jacobson's resection study is ongoing, he is also examining whether the HHV-6B can be identified in serum, plasma, and cerebrospinal fluid (CSF).

Another study by Jacobson that will be published in the Journal of Infectious Diseases examines patients who had undergone bone marrow and stem cell transplantations. His team found that HHV-6 DNA in CSF and serum might not show the amount of active virus in the brain after these procedures.

Previous studies have shown that HHV-6 reactivates within 2 to 4 weeks in half of patients after bone marrow and stem cell transplantations. In Jacobson's study, active HHV-6 infection was found in the hippocampus of all autopsy cases. "We've shown that while patients' brains are loaded with the virus, the CSF did not always hold the virus," he said. "In the future, the easiest thing may be to look at whether antibodies to the virus are increased in specific patient populations or differential antibody responses are present."

Jacobson said he hopes his research will raise awareness that HHV-6B may be a trigger for epilepsy. "This is an underappreciated pathogen that we're all exposed to," he said. Now that more links are being seen between these viruses and a number of disorders, better screening tools may be developed, concluded Jacobson.

REFERENCES1. Donati D, Akhyani N, Fogdell-Hahn A, et al. Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology. 2003;61:1405-1411.
2. Hall CB, Long CE, Schnabel KC, et al. Human herpesvirus-6 infection in children: a prospective study of complications and reactivation. N Engl J Med. 1994;331:432-438.
3. Wainwright MS, Martin PL, Morse RP, et al. Human herpesvirus 6 limbic encephalitis after stem cell transplantation. Ann Neurol. 2001;50:612-619.