HHV-6 and hippocampal volume in patients with mesial temporal sclerosis.

OBJECTIVE: To study the effects of human herpes virus 6 (HHV-6) on the hippocampal volume in patients with mesial temporal sclerosis (MTS). BACKGROUND: HHV-6 may play an etiologic role in MTS. Previous studies found a possible association with febrile status epilepticus. Several investigators have reported a higher prevalence of HHV-6 in MTS resections compared to other epilepsy etiologies. DESIGN/METHODS: We used FreeSurfer to segment cortical structures and obtain whole hippocampal and subfield volumes in 41 patients with intractable epilepsy. In addition, an investigator blinded to other data traced hippocampi manually on each slice. The main study outcome measure was the asymmetry index (AI) between hippocampal volumes ipsilateral and contralateral to seizure foci compared between HHV-6 positive and negative patients. Viral DNA was isolated from fresh brain tissue obtained at temporal lobectomy. For 25 patients, viral detection was performed using quantitative real-time PCR specific for HHV-6A and HHV-6B. For 16 patients, viral DNA detection was performed using digital droplet PCR specific for HHV-6A and HHV-6B. RESULTS: Twenty-two patients were positive (14 of 25 tested with real-time PCR, and 8 of 16 with digital droplet PCR), and 19 negatives for HHV-6. HHV-6 negative patients had significantly greater AI and lower total hippocampal volume ipsilateral to seizure foci than HHV-6 positive patients. Epilepsy duration and age of onset did not affect results. INTERPRETATION: Our data suggest multiple potential etiologies for MTS. HHV-6 may have a less severe effect on the hippocampus than other etiologies.

Reactivity and increased proliferation of NG2 cells following central nervous system infection with Theiler's murine encephalomyelitis virus.

BACKGROUND: Neuron-glial antigen 2 (NG2) cells are a glial cell type tiled throughout the gray and white matter of the central nervous system (CNS). NG2 cells are known for their ability to differentiate into oligodendrocytes and are commonly referred to as oligodendrocyte precursor cells. However, recent investigations have begun to identify additional functions of NG2 cells in CNS health and pathology. NG2 cells form physical and functional connections with neurons and other glial cell types throughout the CNS, allowing them to monitor and respond to the neural environment. Growing evidence indicates that NG2 cells become reactive under pathological conditions, though their specific roles are only beginning to be elucidated. While reactive microglia and astrocytes are well-established contributors to neuroinflammation and the development of epilepsy following CNS infection, the dynamics of NG2 cells remain unclear. Therefore, we investigated NG2 cell reactivity in a viral-induced mouse model of temporal lobe epilepsy. METHODS: C57BL6/J mice were injected intracortically with Theiler's murine encephalomyelitis virus (TMEV) or PBS. Mice were graded twice daily for seizures between 3 and 7 days post-injection (dpi). At 4 and 14 dpi, brains were fixed and stained for NG2, the microglia/macrophage marker IBA1, and the proliferation marker Ki-67. Confocal z stacks were acquired in both the hippocampus and the overlying cortex. Total field areas stained by each cell marker and total field area of colocalized pixels between NG2 and Ki67 were compared between groups. RESULTS: Both NG2 cells and microglia/macrophages displayed increased immunoreactivity and reactive morphologies in the hippocampus of TMEV-injected mice. While increased immunoreactivity for IBA1 was also present in the cortex, there was no significant change in NG2 immunoreactivity in the cortex following TMEV infection. Colocalization analysis for NG2 and Ki-67 revealed a significant increase in overlap between NG2 and Ki-67 in the hippocampus of TMEV-injected mice at both time points, but no significant differences in cortex. CONCLUSIONS: NG2 cells acquire a reactive phenotype and proliferate in response to TMEV infection. These results suggest that NG2 cells alter their function in response to viral encephalopathy, making them potential targets to prevent the development of epilepsy following viral infection.

Human Herpesviruses 6A and 6B in Brain Diseases: Association versus Causation.

Human herpesvirus 6A (HHV-6A) and human herpesvirus 6B (HHV-6B), collectively termed HHV-6A/B, are neurotropic viruses that permanently infect most humans from an early age. Although most people infected with these viruses appear to suffer no ill effects, the viruses are a well-established cause of encephalitis in immunocompromised patients. In this review, we summarize the evidence that the viruses may also be one trigger for febrile seizures (including febrile status epilepticus) in immunocompetent infants and children, mesial temporal lobe epilepsy, multiple sclerosis (MS), and, possibly, Alzheimer's disease. We propose criteria for linking ubiquitous infectious agents capable of producing lifelong infection to any neurologic disease, and then we examine to what extent these criteria have been met for these viruses and these diseases.

HSV-1 encephalitis relapse after epilepsy surgery: a case report and review of the literature.

Herpes simplex encephalitis relapses have been rarely reported, with only few cases occurring after neurosurgical interventions. A young man presented a late herpes simplex encephalitis relapse after left antero-mesial temporal resection for his refractory temporal lobe epilepsy. Eight days after surgery, he developed fever and aphasia. CSF PCR revealed more than 12,000 copies/ml of HSV-1 DNA. Intravenous acyclovir was immediately started with a complete recovery. Postoperative herpes simplex encephalitis can occur as primary infection or as relapse of previous infection. Surgical manipulation of brain parenchyma in the site of a previous infection can act as a trigger for viral reactivation. Early onset of antiviral therapy is fundamental and it is a strong predictor of clinical outcome. Despite no studies on prophylactic treatment with acyclovir in patients with previous herpes simplex encephalitis candidate to neurosurgery are available, we suggest that prophylactic treatment should be recommended.

Positive modulation of mGluR5 attenuates seizures and reduces TNF-α+ macrophages and microglia in the brain in a murine model of virus-induced temporal lobe epilepsy.

Viral encephalitis markedly increases the risk for the development of epilepsy. The Theiler's murine encephalomyelitis virus (TMEV)-induced model of seizures/epilepsy is a murine model of both viral-induced seizures/epilepsy and human Temporal Lobe Epilepsy. The inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α have been shown to play a role in seizure development in the TMEV-induced model of seizures/epilepsy, and infiltrating macrophages along with microglia have been shown to be major producers of these cytokines. The metabotropic glutamate receptor 5 (mGluR5) is a G-protein coupled receptor that has been shown to reduce IL-6 and TNF-α and to provide neuroprotection in other disease models. Therefore, we hypothesized that stimulation of mGluR5 would not only reduce seizures but attenuate IL-6 and TNF-α production in microglia and macrophages in the TMEV model. We found that pharmacological stimulation of mGluR5 with the selective positive allosteric modulator VU0360172 not only reduced acute seizure outcomes, but also reduced the percent of microglia and macrophages producing TNF-α 3 days post infection. Furthermore, treatment with VU0360172 did not alter the level of viral antigen, compared to controls, showing that this treatment does not compromise viral clearance. These results establish that mGluR5 may represent a therapeutic target in the TMEV-induced model of seizures/epilepsy.

The Viral Hypothesis of Mesial Temporal Lobe Epilepsy - Is Human Herpes Virus-6 the Missing Link? A systematic review and meta-analysis.

PURPOSE: Mesial temporal lobe epilepsy (MTLE) is a common epileptic disorder. Although likely multifactorial, the mechanisms underlying the etiology and pathogenesis of the disease remains unknown in majority of patients. Viruses, particularly Human Herpes Virus 6A and B (HHV-6), two neurotropic herpes viruses, have been implicated in MTLE due to their ubiquitous nature and ability to establish lifelong latency with risk of reactivation. However, the results of studies investigating this relationship are conflicting. This systematic review and meta-analysis was conducted to determine the relationship between HHV-6 DNA (not specifying if A or B) in brain tissue and MTLE based on the current evidence. METHOD: Two independent assessors carried out a comprehensive electronic search to identify all relevant studies. Both fixed- and random-effects models were used to determine the overall odds ratio. RESULTS: A total of 10 studies met the inclusion criteria for the systematic review and eight for the meta-analysis. In 19.6% of all MTLE patients HHV-6 DNA was detected in brain tissue compared to 10.3% of all controls (p >0.05). The pooled odds ratio of HHV-6 positive cases in MTLE patients was 2.016 [95%-CI: 1.16-3.50] in the fixed effect model. CONCLUSION: The results of this meta-analysis indicate an association between HHV-6 DNA and MTLE surgically resected tissue samples, unspecified if A or B or both. However, the casual relationship and possible pathological role of HHV-6 in MTLE are yet to be elucidated. This study's results provide a basis for future studies continuing the investigation into pathological implications of HHV-6.

Hippocampal TNFα Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy.

Central nervous system infection can induce epilepsy that is often refractory to established antiseizure drugs. Previous studies in the Theiler's murine encephalomyelitis virus (TMEV)-induced mouse model of limbic epilepsy have demonstrated the importance of inflammation, especially that mediated by tumor necrosis factor-α (TNFα), in the development of acute seizures. TNFα modulates glutamate receptor trafficking via TNF receptor 1 (TNFR1) to cause increased excitatory synaptic transmission. Therefore, we hypothesized that an increase in TNFα signaling after TMEV infection might contribute to acute seizures. We found a significant increase in both mRNA and protein levels of TNFα and the protein expression ratio of TNF receptors (TNFR1:TNFR2) in the hippocampus, a brain region most likely involved in seizure initiation, after TMEV infection, which suggests that TNFα signaling, predominantly through TNFR1, may contribute to limbic hyperexcitability. An increase in hippocampal cell-surface glutamate receptor expression was also observed during acute seizures. Although pharmacological inhibition of TNFR1-mediated signaling had no effect on acute seizures, several lines of genetically modified animals deficient in either TNFα or TNFRs had robust changes in seizure incidence and severity after TMEV infection. TNFR2-/- mice were highly susceptible to developing acute seizures, suggesting that TNFR2-mediated signaling may provide beneficial effects during the acute seizure period. Taken together, the present results suggest that inflammation in the hippocampus, caused predominantly by TNFα signaling, contributes to hyperexcitability and acute seizures after TMEV infection. Pharmacotherapies designed to suppress TNFR1-mediated or augment TNFR2-mediated effects of TNFα may provide antiseizure and disease-modifying effects after central nervous system infection.

Acute treatment with minocycline, but not valproic acid, improves long-term behavioral outcomes in the Theiler's virus model of temporal lobe epilepsy.

OBJECTIVE: Infection with Theiler's murine encephalomyelitis virus (TMEV) in C57Bl/6J mice induces acute seizures and development of spontaneous recurrent seizures and behavioral comorbidities weeks later. The present studies sought to determine whether acute therapeutic intervention with an anti-inflammatory-based approach could prevent or modify development of TMEV-induced long-term behavioral comorbidities. Valproic acid (VPA), in addition to its prototypical anticonvulsant properties, inhibits histone deacetylase (HDAC) activity, which may alter expression of the inflammasome. Minocycline (MIN) has previously demonstrated an antiseizure effect in the TMEV model via direct anti-inflammatory mechanisms, but the long-term effect of MIN treatment on the development of chronic behavioral comorbidities is unknown. METHODS: Mice infected with TMEV were acutely administered MIN (50 mg/kg, b.i.d. and q.d.) or VPA (100 mg/kg, q.d.) during the 7-day viral infection period. Animals were evaluated for acute seizure severity and subsequent development of chronic behavioral comorbidities and seizure threshold. RESULTS: Administration of VPA reduced the proportion of mice with seizures, delayed onset of symptomatic seizures, and reduced seizure burden during the acute infection. This was in contrast to the effects of administration of once-daily MIN, which did not affect the proportion of mice with seizures or delay onset of acute symptomatic seizures. However, VPA-treated mice were no different from vehicle (VEH)-treated mice in long-term behavioral outcomes, including open field activity and seizure threshold. Once-daily MIN treatment, despite no effect on the maximum observed Racine stage seizure severity, was associated with improved long-term behavioral outcomes and normalized seizure threshold. SIGNIFICANCE: Acute seizure control alone is insufficient to modify chronic disease comorbidities in the TMEV model. This work further supports the role of an inflammatory response in the development of chronic behavioral comorbidities and further highlights the utility of this platform for the development of mechanistically novel pharmacotherapies for epilepsy.

Neuronal Injury, Gliosis, and Glial Proliferation in Two Models of Temporal Lobe Epilepsy.

It is estimated that 30%-40% of epilepsy patients are refractory to therapy and animal models are useful for the identification of more efficacious therapeutic agents. Various well-characterized syndrome-specific models are needed to assess their relevance to human seizure disorders and their validity for testing potential therapies. The corneal kindled mouse model of temporal lobe epilepsy (TLE) allows for the rapid screening of investigational compounds, but there is a lack of information as to the specific inflammatory pathology in this model. Similarly, the Theiler murine encephalomyelitis virus (TMEV) model of TLE may prove to be useful for screening, but quantitative assessment of hippocampal pathology is also lacking. We used immunohistochemistry to characterize and quantitate acute neuronal injury and inflammatory features in dorsal CA1 and dentate gyrus regions and in the directly overlying posterior parietal cortex at 2 time points in each of these TLE models. Corneal kindled mice were observed to have astrogliosis, but not microgliosis or neuron cell death. In contrast, TMEV-injected mice had astrogliosis, microgliosis, neuron death, and astrocyte and microglial proliferation. Our results suggest that these 2 animal models might be appropriate for evaluation of distinct therapies for TLE.

Oxidative stress in murine Theiler's virus-induced temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common form of acquired epilepsy that can be caused by several inciting events including viral infections. However, one-third of TLE patients are pharmacoresistant to current antiepileptic drugs and therefore, there is an urgent need to develop antiepileptogenic therapies that prevent the development of the disease. Oxidative stress and redox alterations have recently been recognized as important etiological factors contributing to seizure-induced neuronal damage. The goal of this study was to determine if oxidative stress occurs in the TMEV (Theiler's murine encephalomyelitis virus) model of temporal lobe epilepsy (TLE). C57Bl/6 mice were injected with TMEV or with PBS intracortically and observed for acute seizures. At various time points after TMEV injection, hippocampi were analyzed for levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and 3-nitrotyrosine (3 NT). Mice infected with TMEV displayed behavioral seizures between days 3 and 7 days post-infection (dpi). The intensity of seizures increased over time with most of the seizures being a stage 4 or 5 on the Racine scale at 6 days p.i. Mice exhibiting at least one seizure during the observation period were utilized for the biochemical analyses. The levels of GSH were significantly depleted in TMEV infected mice at 3, 4 and 14 days p.i. with a concomitant increase in GSSH levels as well as an impairment of the redox status. Additionally, there was a substantial increase in 3 NT levels in TMEV infected mice at these time points. These redox changes correlated with the occurrence of acute seizures in this model. Interestingly, we did not see changes in any of the indices in the cerebellum of TMEV-infected mice at 3 dpi indicating that these alterations are localized to the hippocampus and perhaps other limbic regions. This is the first study to demonstrate the occurrence of oxidative stress in the TMEV model of infection-induced TLE. The redox alterations were observed at time points coinciding with the appearance of acute behavioral seizures suggesting that these changes might be a consequence of seizure activity. Our results support the hypothesis that redox changes correlate with seizure activity in acquired epilepsies, regardless of the inciting insults, and suggest oxidative stress as a potential therapeutic target for their treatment.

Pathogenic Role of Human Herpesvirus 6B Infection in Mesial Temporal Lobe Epilepsy.

BACKGROUND: Human herpesvirus 6B (HHV-6B) is the causative agent for exanthem subitum. HHV-6B was associated with mesial temporal sclerosis (MTS), leading to mesial temporal lobe epilepsy (MTLE). In this study, we sought to elucidate the pathogenic role of HHV-6B in patients with MTLE. METHODS: Seventy-five intractable MTLE patients, including 52 MTS patients and 23 non-MTS patients, were enrolled in this study. Resected hippocampus, amygdala, and mixed samples of amygdala and uncus samples were examined by real-time polymerase chain reaction (PCR) and reverse-transcriptase PCR to detect viral DNA and messenger RNA (mRNA), respectively. Host gene expressions, including neural markers, were measured using the TaqMan Gene Expression Assay. RESULTS: Detection of HHV-6 DNA was higher in MTS patients than non-MTS patients (median/interquartile range: 19.1/0-89.2 vs 0.0/0.0-0.0 copies/µg DNA; P = .004). HHV-6B viral DNA was determined in 12/27 HHV-6 DNA-positive samples, and no HHV-6B mRNA were detected in all samples. In MTS patients, expression of monocyte chemotactic protein-1 (P = .029) and glial fibrillary acidic protein (P = .043) were significantly higher in the amygdala samples with HHV-6 DNA than those without viral DNA. CONCLUSIONS: This study suggests that HHV-6B may play an important role in the pathogenesis of MTS via modification of host gene expression.

Evaluating an etiologically relevant platform for therapy development for temporal lobe epilepsy: effects of carbamazepine and valproic acid on acute seizures and chronic behavioral comorbidities in the Theiler's murine encephalomyelitis virus mouse model.

Central nervous system infections can underlie the development of epilepsy, and Theiler's murine encephalomyelitis virus (TMEV) infection in C57BL/6J mice provides a novel model of infection-induced epilepsy. Approximately 50-65% of infected mice develop acute, handling-induced seizures during the infection. Brains display acute neuropathology, and a high number of mice develop spontaneous, recurrent seizures and behavioral comorbidities weeks later. This study characterized the utility of this model for drug testing by assessing whether antiseizure drug treatment during the acute infection period attenuates handling-induced seizures, and whether such treatment modifies associated comorbidities. Male C57BL/6J mice infected with TMEV received twice-daily valproic acid (VPA; 200 mg/kg), carbamazepine (CBZ; 20 mg/kg), or vehicle during the infection (days 0-7). Mice were assessed twice daily during the infection period for handling-induced seizures. Relative to vehicle-treated mice, more CBZ-treated mice presented with acute seizures; VPA conferred no change. In mice displaying seizures, VPA, but not CBZ, reduced seizure burden. Animals were then randomly assigned to acute and long-term follow-up. VPA was associated with significant elevations in acute (day 8) glial fibrillary acidic protein (astrocytes) immunoreactivity, but did not affect NeuN (neurons) immunoreactivity. Additionally, VPA-treated mice showed improved motor performance 15 days postinfection (DPI). At 36 DPI, CBZ-treated mice traveled significantly less distance through the center of an open field, indicative of anxiety-like behavior. CBZ-treated mice also presented with significant astrogliosis 36 DPI. Neither CBZ nor VPA prevented long-term reductions in NeuN immunoreactivity. The TMEV model thus provides an etiologically relevant platform to evaluate potential treatments for acute seizures and disease modification.

Large-scale analysis of viral nucleic acid spectrum in temporal lobe epilepsy biopsies.

OBJECTIVE: Chronic inflammatory processes are important promotors of temporal lobe epilepsy (TLE) development. Based on human herpesvirus 6 (HHV-6) DNA detection in brain tissue from patients with TLE, an association of persistent viral infection with TLE has been discussed. Individual studies reported increased HHV-6 DNA in patients with clinical signs of previous inflammatory brain reaction, that is, febrile seizures or meningoencephalitis. However, detection rates vary considerably between different studies. Here we performed a large-scale analysis of viral DNA/RNA spectrum in high-quality TLE biopsies. In addition to all Herpesviridae, we addressed potentially relevant neurotropic RNA viruses. METHODS: DNA and RNA were extracted from 346 fresh-frozen tissue samples removed by epilepsy surgery. Real-time polymerase chain reaction (PCR) and nested PCR were performed for Herpesviridae and RNA viruses, respectively. Clinical data were analyzed for earlier signs of inflammatory brain reactions. Fresh-frozen hippocampal tissue samples from patients without chronic central nervous system (CNS) disease served as controls (n = 62). Seven previous PCR studies with overall 178 TLE patients were additionally analyzed regarding a correlation of clinical parameters and HHV-6 detection. RESULTS: PCR revealed HHV-6B DNA in 34 specimens (9.8%) from TLE patients. HHV-6B DNA was also present in eight control samples (12.9%; p > 0.05), but showed a lower virus concentration (p < 0.001). Other herpesviruses and RNA viruses were virtually absent. In patients with clinical signs of previous brain inflammation, HHV-6B DNA was observed in 15.0%, whereas only 6.3% of the samples from patients without febrile seizures or meningoencephalitis were positive for HHV-6B DNA (p < 0.05). A meta-analysis of the eight HHV-6 PCR studies revealed similar results. SIGNIFICANCE: This biopsy-based study shows no differences in frequency of HHV-6B DNA detection between TLE patients and controls. These results do not support the hypothesis of a persistent HHV-6B infection as a major pathogenetic factor in TLE. However, the higher virus load in TLE patients and the increased detection rate of HHV-6B DNA in patients with previous inflammatory brain reactions require further investigations.

Epilepsia del lóbulo temporal: déjà vu en atención primaria / Epilepsy in the temporal lobe: déjà vu in Primary Care

La epilepsia es una enfermedad frecuente en la población general. Un 10% de la población va a presentar una crisis epiléptica a lo largo de su vida, aunque tan solo un 1% presentará una enfermedad epiléptica. Podemos dividir la epilepsia en generalizada y en focal. Es en esta última la que mayores dificultades diagnósticas y de manejo puede plantear en la práctica clínica, por su gran variedad de síntomas y su difícil identificación. Estos síntomas pueden ser referidos de una manera distinta por cada paciente, restándole importancia en muchas ocasiones. Dentro de la epilepsia focal, la más prevalente es la epilepsia que se origina en el lóbulo temporal. La identificación y el estudio de esta enfermedad es muy importante, ya que el paciente puede sufrir episodios de desconexión del medio y en un tercio de los casos crisis secundariamente generalizadas. Aunque en la mayor parte de los pacientes la lesión causante es la esclerosis mesial temporal, hay que descartar otras causas, como neoplasias o infecciones (AU)

Epilepsy is a common disease in the general population. 10% of the population will present a seizure throughout his life, although only 1% will have an epileptic condition. We can divide the generalized epilepsy and focal. Es in the latter that more diagnostic and management difficulties may arise in clinical practice, for its wide variety of symptoms and their identification difficult. These symptoms may be referred to differently by each patient, often dismissively. In focal epilepsy, the most prevalent epilepsy that originates in the temporal lobe. The identification and study of this pathology is very important because the patient may have episodes of disconnecting means and in one third of cases secondarily generalized crises. Although most patients the culprit lesion is mesial temporal sclerosis, one must rule out other causes such as tumors or infections (AU)

Detection of human herpes virus 6B in patients with mesial temporal lobe epilepsy in West China and the possible association with elevated NF-κB expression.

BACKGROUND: There has been a long-standing suspicion that an association exists between mesial temporal lobe epilepsy (MTLE) and the herpes virus. Evidence for HHV-6B involvement has been reported. However, no investigation has been performed in China. METHODS: We used nested PCR and immunohistochemistry to detect viral DNA of human herpes virus (HHV)-6B, HHV-6A, herpes simplex virus (HSV)-1 and HSV-2 in resected brain tissues from patients with MTLE and control. A principal transcription factor, NF-κB, that is associated with the inflammatory response was also investigated by real-time PCR, western blotting and immunohistochemistry. RESULTS: HHV-6B DNA was detected in hippocampal samples from 9 out of 32 (28.1%) patients with MTLE and in 1 of 12 (8.3%) control samples. Immunoreactivity for HHV-6B was consistently present in MTLE patients positive for HHV-6 detected by PCR. Significant staining for HHV-6B antigen was distributed mainly around or in the nucleus of cells that morphologically resembled astrocytes and microglia. HHV-6B positivity was related to febrile convulsion history of patients with MTLE. The expression of NF-κB was up-regulated and distributed in the nucleus of glial cells in MTLE patients positive for HHV-6B. CONCLUSION: This study was first to find HHV-6B in MTLE patients from West China and demonstrate a possible association between HHV-6B positivity and activation of NF-κB. The detailed role of HHV-6B and its association with NF-κB in the development of chronic MTLE requires further investigation.

Febrile status epilepticus: current state of clinical and basic research.

Febrile status epilepticus occurs in up to 5% of all cases of febrile seizures and has been linked to the development of focal epilepsy. This article reviews the clinical characteristics and treatment issues of febrile status. Controversy exists regarding the relationship of febrile status epilepticus to the subsequent development of epilepsy. This subject is discussed by first reviewing the clinical research literature and then highlighting the basic science research regarding this controversial question. The current literature appears to support a role for febrile status in the development of focal epilepsy but is clearly neither necessary nor sufficient in the focal epileptogenisis process. Multiple insults are likely necessary for a child with febrile status epilepticus to develop epilepsy later in life.

Presence of human herpes virus 6 DNA exclusively in temporal lobe epilepsy brain tissue of patients with history of encephalitis.

Temporal lobe epilepsy (TLE) is frequently associated with mesial temporal sclerosis (MTS). Many etiologic aspects of TLE are still unresolved. Here, we aimed to analyze the presence of human herpes virus 6 (HHV-6) DNA in distinct TLE pathologies. Nested polymerase chain reaction (PCR) in surgical tissue from 38 pharmaco-resistant TLE patients and 10 autopsy controls revealed HHV-6 DNA in 55.6% of the TLE patients with a history of encephalitis, involving MTS and gliotic hippocampi without substantial neurodegeneration, but not in lesion-associated TLE or nonlesional MTS with or without a history of complex febrile seizures (CFS). HHV-6 protein was present in only one patient's tissue. Our data argue against HHV-6 as a major local pathogenetic factor in MTS hippocampi after CFS. The high detection rate of HHV-6 DNA suggests a potential pathogenetic role of HHV-6 in TLE patients with a history of encephalitis.

Investigation of HSV-1, HSV-2, CMV, HHV-6 and HHV-8 DNA by real-time PCR in surgical resection materials of epilepsy patients with mesial temporal lobe sclerosis.

OBJECTIVE: The objective of this study is to investigate the presence of viral DNAs of HSV-1, HSV-2, HHV-6, HHV-8, and CMV in hippocampus of the patients with mesial temporal lobe epilepsy (MTLE) syndrome. METHODS: Pathological specimens were obtained from 33 patients with MTLE undergone temporal lobectomy with amygdalo-hippocampectomy due to intractable seizures. Autopsy materials from the hippocampus of 7 patients without neurological disease were used as controls. The data was also correlated with the clinical history of patients including febrile convulsions, age, and history of CNS infections. Real-time polymerase chain reaction method was performed for detection of DNAs of these viruses. RESULTS: HHV-6, HSV-1 and HHV-8 were detected in the hippocampus of 3, 2 and 1 patients with MTLE respectively. None of the hippocampus of patients with MTLE was positive for DNA of HSV-2 and/or CMV. Three patients with positive HHV-6 DNAs had febrile convulsions and family history for epilepsy. None of our control specimens showed PCR positivity to any of the 5 tested viruses. CONCLUSIONS: Our study is the first to report the presence of HHV-8 viral genome in the brain tissue of patient with MTLE. Viral DNAs were detected in a total of 18% of the patients in this study; we can conclude that activity of the latent virus in patients with hippocampal sclerosis should be more extensively studied to establish its role in active infection.