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HHV-6B & HHV-7 in Status Epilepticus HHV-6 & Mesial Temporal Lobe Epilepsy Virus Associated Seizures & Epilepsy Research Alliance
Researchers have long known that viruses can cause seizures in infants, and viruses have been suspected in epilepsy but direct evidence was lacking, in part because there are no good tests available to determine if a patient has a smoldering infection in the brain tissue. An intriguing paper by a Japanese researcher in 1993 suggested that HHV-6B plays a role in recurrent seizures, but the possibility of viral etiology was largely ignored until recently. An important paper just published by Steve Jacobson and colleagues at the NINDS demonstrates that as many as two thirds of patients with Mesial Temporal Lobe Epilepsy (MTLE) may in fact suffer from a chronic HHV-6B infection. Jacobson’s research suggests that HHV-6 causes a dysfunction in the astrocytes leading to the injury of the sensitive neuron in the hippocampus that trigger MTLE. (Fotheringham, 2007) Although this virus is ubiquitous, infecting over 95% of the population by the age of two, it can persist chronically in the brain and reactivate years after the initial infection. HHV-6 is a difficult virus to detect in the blood or even in the spinal fluid and serum, as it tends to stay in the tissues and not circulate. So Jacobson, who heads the Virology Immunology Section at the NINDS decided to look at the brain tissue from 16 patients who had portions of their brain tissue removed as treatment for refractory MTLE. He found 11 of 16 patients with MTLE (but 0 of 7 control patients) had high levels of HHV-6B DNA. Furthermore, Jacobson was able to shed some light on the mechanism by which the virus could cause epilepsy by demonstrating that HHV-6B infection induces a deficiency in the transport of glutamate. This transporter deficiency is implicated in MTLE, but the reason for the deficiency has never been understood. The glutamate transport dysfunction is believed to result in injury to neurons in the hippocampus that trigger MTLE. In a review of 416 seizure patients <3 years of age, 24% had primary HHV-6 infections. (Millichap, 2006) Another study found that 34% of 56 febrile patients with seizures had HHV-6 or 7 infections. (Murakami 2004) A study of HHV-6 & 7 infections in hospital admissions in Britain and Ireland during the first two years of life (Ward et al, 2005) found that 17% of the encephalitis cases were associated with primary infections of HHV-6 and 7, and that the two viruses were equally significant in these cases. One study in Japan found that of those patients with three or more seizures, 80% had evidence of HHV-6 in the spinal fluid compared with only 14% in patients with an isolated seizure (Kondo, 1993). A recent study in Japan found that HHV-6 could result in convulsions at the time of the rash outbreak following a primary infection with HHV-6. They propose calling this condition HEEC or “human herpesvirus-6 encephalopathy with cluster of convulsions in eruptive stage” (Nagasawa, 2006). HHV-6B & HHV-7 in Status Epilepticus A multi-center study of 200 infants with status epilepticus is currently in process to study of the role of primary HHV-6 & 7 infections in children with febrile status epilepticus (FSE). Leon Epstein reported at the 2005 Child Neurology Society conference that this group found 33% of 63 infants examined showed evidence of HHV-6 infection while 7.9% of 63 had HHV-7 primary infection. The questions that remain to be answered are: Does the virus persist in some of these cases and increase the chances of subsequent hippocampal damage, temporal lobe seizures and epilepsy? Would these children benefit from antiviral treatment? HHV-6 & Mesial temporal lobe epilepsy Japanese scientists were the first to suggest that HHV-6B may be a frequent cause of temporal lobe epilepsy (Uesugi et al, 2000). They found three out of six mesial temporal lobe resections were positive for HHV-6. Interest in the association of HHV-6B in mesial temporal lobe epilepsy grew with the publication of findings by investigators at the NINDS (Donati 2003) that HHV-6B was found at pathogenic levels a subset of patients with mesial temporal lobe epilepsy (MTLE), suggesting a possible role of HHV-6 in the development of MTLE. HHV-6 DNA was found in half of the MTLE biopsies but none of the neocortical epilepsy patients. Virus was found specifically in the astrocytes of the hippocampus and temporal lobe. Jacobson and colleagues expanded on this study in 2007 by examining the brain tissue from patients who had surgeries to remove sections of the brain as therapy when no drugs were effective. They found that 11 out of 16 patients were clearly infected with HHV-6B at what appeared to be pathogenic levels. None of the controls (brain tissue resections from other conditions) were positive for HHV-6. Furthermore, they found that the virus is concentrated in the temporal lobe and the region next to the temporal lobe but not the frontal and occipital lobes. Finally, Jacobson’s group provided a theoretical explanation for how the virus could trigger epilepsy by showing that the virus reduces glutamate transport, a phenomenon associated with MTLE. (Fotheringham, 2007) HHV-6 Cell Tropism. HHV-6B and HHV-6A have variant specific tropisms in human glial cells, suggesting that the two HHV-6 variants might be responsible for distinct disease outcomes due to the infection pattern in these cells in vivo (Donati, 2005; Ahlqvist, 2005). HHV-6A (which has been more often associated with MS) established a productive infection in astrcoytes with cytopathic effect and high virus DNA loads, while the HHV-6B infected astrocytes showed no morphological changes, but maintained low levels of intracellular viral DNA without detectable RNA. Meeuwsen et al also found that HHV-6 strongly alters the astrocyte’s response to pro-inflammatory cytokines and immune modulatory factors in the face of inflammation. (Meeuwsen, 2005) These results suggest that HHV-6B could persist at a low level of activation for years associated with a dysregulation of cellular function while HHV-6A may be more involved with destruction of key components of the nervous system.
HHV-6 & Epilepsy HHV-6 & Status Epileptiicus HHV-6 & Seizures HHV-6 and seizures. (Yamashita, 2006) Human herpesviruses-6 and -7 each cause significant neurological morbidity in Britain and Ireland (Ward, 2005) Influenza virus and febrile convulsions, (Millichap,2004) Virological and immunological aspects of seizure disorders. (Eeg-Olofsson, 2003) Phenomenology of Prolonged Febrile Seizures: Preliminary Results of the FEBSTAT Study (AES Abstract) Basic Research Neuroinvasion and persistence of human herpesvirus 6 in children. (Caserta. 1994) Key Investigators
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