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Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden, SwedenDepartment of Neurology, Christian Doppler Medical Centre Paracelsus Medical University, and Centre for Cognitive Neuroscience Salzburg, Austria
HHV-6 DNA is associated with mesial temporal lobe epilepsy resected brain tissue.
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Higher HHV-6 DNA rate in temporal lobe epilepsy patients with hippocampal sclerosis.
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Mechanisms underlying the possible causal relationship are discussed.
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Results support future studies investigating pathological implications of HHV-6.
Abstract
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.
1. Introduction
Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of epileptic disorders [
]. Clinical characteristic features of MTLE include a history of an early initial injury secondary to prolonged febrile seizures, acute or chronic central nervous system (CNS) infections or head injury, followed by a long-lasting latent period, before refractory chronic epilepsy develops [
]. Despite extensive research, the mechanisms underlying the pathophysiology of epileptogenesis are not fully understood. MTLE is associated with a hippocampal sclerosis (HS), with the pathognomic hallmark of segmental neuronal cell loss and reactive gliosis causing atrophy.[
International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a task force report from the ilae commission on diagnostic methods.
]. Interestingly, viral encephalitis, particularly when caused by herpes viruses, is known to have a predilection for limbic structures, including the hippocampus [
]. In addition, post-encephalitic epilepsy following herpesvirus encephalitis is frequently drug resistant and often results in seizure onset in the mesial temporal regions [
Detection of human herpes virus 6 B in patients with mesial temporal lobe epilepsy in West China and the possible association with elevated NF-κB expression.
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.
]. In particular human herpes virus 6A and B (HHV-6A and B), two double-stranded DNA beta-herpes viruses which share >90% of their nucleotide sequence, have been suggested as associated with the disease [
]. In this study the abbreviation HHV-6 will be used, as not all studies included in this meta-analysis have specified or identified which HHV-6 viral DNA was detected. With the currently used serological method that cannot distinguish between serological response against HHV-6A from B, the seroprevalence is >90% [
]. The primary infection generally occurs in infancy and results in a self-limiting fever and in a portion of those infected development of exanthema subitum [
] In the immunocompetent adult population, the viruses predominantly remain latent and asymptomatic. However, associations with HHV-6 reactivation have been made with a range of neurological diseases such as encephalitis, epilepsy, febrile convulsions, multiple sclerosis, chronic fatigue syndrome and tumors [
] Given that HHV-6A and B have differential ability to reproduce in human astrocytes, where HHV-6A can give a productive infection and B seems to establish latency, it is plausible that these cells are reservoirs for the virus.[
] A possible pathogenic role could be via the ability of HHV–6 B to alter glutamate uptake in astrocytes. Epileptogenic hippocampus have been shown to have abnormally high levels of extracellular glutamate, an excitatory neurotransmitter, which might be due to impaired abilities of astrocytes to clear this transmitter.[26,27] This could be attributed to infection, not only active, but also the epigenetic modifications and integration of the virus in the chromosome might causes dysregulation of cells that would reduce their capacity to regulate neurotransmitters.[
Several studies have investigated the association between HHV-6 and MTLE, however, due to conflicting results and the relatively small sample sizes of many studies, there is a lack of consensus surrounding this relationship. The aim of this systemically review and meta-analysis was to address if there is a relationship between HHV-6 and MTLE and if so, determine the strength of it.
2. Methods
2.1 Selection strategy and criteria
In order to identify all relevant studies investigating the association between HHV-6 and epilepsy a search was conducted on MEDLINE, PubMed and Web of science databases. No date restrictions were applied and the search for studies was carried out October 2016. Key search words included the terms: herpes virus, herpesvirus, HHV, epilepsy using the following search strategy: “(((herpes virus) OR (HHV) OR (herpesvirus)) AND epilepsy)”. Two reviewers independently examined titles and abstracts and duplicates were excluded.
Inclusion was limited to human studies, with DNA detection of HHV-6 in brain tissue of patients with MTLE compared with a control group. Studies were only included from peer reviewed journals. The reference lists of all identified studies were also hand-searched in attempt to find further relevant studies. For every eligible study, the following information was extracted: country and year of diagnosis of the cases; study design (cohort or case-control with population based or hospital controls) and type. Studies were excluded if they were not published in English or if the sample size was less than five participants. Additionally, studies were excluded from the meta-analysis if they did not have a suitable control group without MTLE.
2.2 Data collection
Two reviewers (PW and ND) independently screened and assessed the articles based on the eligibility criteria above. Primary screening was performed by reading the titles and abstracts of the articles. Those studies that fulfilled the inclusion criteria were selected for full review.
2.3 Statistics
In this study, we used both fixed-effect models and random-effect models to analyse the association between HHV-6 and MTLE and calculated pooled odds ratio (OR) for effect sizes extracted from the different studies. In fixed-effect models, same as random-effect models, all effect sizes are assumed to be independent, i.e. one effect per study. However, a fixed-effect model assumes, in opposite to random-effect model, that all effect sizes have a common mean and variation among data is only attributable to sampling error. We understand that the latter assumption might not be realistic for many biological meta-analyses, especially those involving different populations, however, the random-effect model needs to quantify the between-study variance and to estimate this variance correctly they require a sample size of perhaps over ten effect sizes. In this regard, random-effect models are not appropriate for our meta-analysis due to few effect sizes. On the other hand, our results indicate a moderate heterogeneity between selected studies that is against using fixed-effect models. We tried to find out the source of heterogeneity through meta-regression analysis however, due to small number of studies it was not conclusive.
To evaluate the presence of publication bias we used graphical representation as the funnel plot. The funnel plot showed an overall asymmetric distributions of the studies (Fig. 1), indicating high likelihood of publication-bias. This finding was supported by Egger’s test results that indicates a significant publication bias (p = 0.018, Fig. 2).
Fig. 1Funnel plot assessing the publication bias on HHV-6 infection and TLE risk.
The results of the Egger test used to evaluate the asymmetry of the funnel plot and the effect of the small studies. These results are suggestive of availability of publication bias in this meta-analysis.
Formal statistical significance for the Patient characteristics was assessed using two-sided Fisher’s exact test.
3. Results
The electronic search performed on 30 October 2016 resulted in a total of 585 studies being identified. Following the application of the exclusion criteria and critical analysis only 10 studies were found that were investigating the association between HHV-6 and MTLE and these were included in the systematic review (Fig. 3). These articles included detection of HHV-6 viral DNA in surgically removed tissue from pharmacoresistant patients with in the meta-analysis. Two additional studies were excluded due to lack of control material without a MTLE history.
The electronic search flow chart demonstrating the methodology used to find all appropriate studies using the studies inclusion and exclusion criteria.
Description of the participant are shown in Table 1. Pooling of the numbers from the 10 studies gave a total cohort of 645 MTLE patients with brain biopsies, including 456 patients with HS compared to 136 controls with or without another epilepsy diagnosis (14 with another form of epilepsy, 122 without epilepsy). HHV-6 DNA could be detected in surgically removed brain tissue of 19.6% of the MTLE patients. In the control group HHV-6 DNA was found in 10.3% (19.6% vs 10.3%; HHV-6 DNA positive in MTLE versus non-MTLE; p < 0.05). In all included MTLE patients with HS, HHV-6 DNA was detected in 22.1% (22.1% vs 10.3%; HHV-6 DNA positive in MTLE with HS versus non-MTLE; p < 0.01). In MTLE patients without HS, the detection rate of HHV-6 DNA was 11.8% (22.1% vs 11.8%; HHV-6 DNA positive in MTLE with HS versus HHV-6 DNA positive in MTLE without HS; p < 0.05). Additionally, a statistical analysis investigating the correlation between the proportion of non-HS MTLE and the percentage of positive HHV-6 in single studies was performed. The correlation coefficient was −0.22 however, it was not statistically significant (p = 0.63). A total of 35.7% of the MTLE patients with detectable HHV-6 DNA had a history of febrile seizure compared to 18.1% in MTLE patients without detectable HHV-6 DNA (p < 0.005). A history of meningitis or encephalitis was found in 19% of the MTLE patients with HHV-6 detection. In comparison to the 12.1% of MTLE patients without HHV-6 DNA detection, which was not significant (p = 0.08). There was also no significant difference between HHV-6 positive and negative MTLE patients in onset of epilepsy, duration of epilepsy and surgery age.
Table 1Participant characteristics of included HHV-6 PCR-studies based on tissue removed in epilepsy surgery y.
Participant characteristics
Huang et al. (2015)
Esposito et al. (2014)
Li et al. (2011)
Donati et al. (2003)
Niehusmann et al. (2010)
Karatas et al. (2008)
Fotheringham et al. (2007)
Eeg-Olofsson (2004)
Uesugi et al. (2000)
Kawamura et al. (2015)
Sum
Mean
Study group
MTLE patients. n, (HHV-6+ %)
46 (39)
346 (9.8)
32 (28.1)
8 (50)
38 (21.1)
33 (9.1)
16 (68.8)
36 (19.4)
15 (40)
75 (34.7)
645 (19.5) *
MTLE with HS n, (HHV-6+ %)
43 (41.8)
242 (9)
26 (34.6)
8 (50)
25 (24)
33 (9.1)
13 (69)
n/a
14 (42.8)
52 (46)
456 (22.1) #
MTLE without HS n, (HHV-6+ %)
3 (0)
104 (12)
6 (0)
0 (0)
13 (15)
0 (0)
3 (67)
n/a
1 (0)
23 (9)
153 (11.8)
Male (n)
25
164
20
4
19
15
n/a
18
8
31
304
Female n.
21
182
12
4
19
18
n/a
18
9
44
327
Onset of epilepsy in HHV-6+ y (SD)
14.6 (8.3)
14 (11)
7.4 (4)
14.3 (8)
16.5 (13.2)
8.6 (8.7)
13.5 (13)
n/a
12.2 (6.9)
12 (11.3)
12.6 (9.4)
Onset of epilepsy in HHV-6- y (SD)
19.9 (13.7)
n/a
15.7 (7.9)
10.5 (9.7)
12.6 (13.6)
10.9 (6.3)
6.7 (3.4)
n/a
10.7 (3.4)
11 (10.8)
12.3 (10.9)
Duration of epilepsy in HHV-6+ y (SD)
9 (5.1)
n/a
12.6 (7)
21.5 (6.9)
12.7 (10.8)
17.7 (7.5)
12.7 (9.6)
n/a
12 (9.7)
n/a
14.8 (8.1)
Duration of epilepsy in HHV-6- y (SD)
8.4 (4.3)
n/a
8.8 (6)
15.8 (9.2)
14.7 (11.6)
13.7 (8.1)
18.3 (13.7)
n/a
14.6 (11.2)
n/a
13.5 (9.2)
Age at time of surgery in HHV-6+ y (SD)
n/a
34.4 (16.2)
20 (5.2)
35.8 (11.1)
29.1 (10.2)
26.3 (1.2)
26.2 (11.8)
15.9 (5.4)
24.2 (7.7)
35 (17.8)
27.4 (9.6)
Age at time of surgery in HHV-6- y (SD)
n/a
n/a
24.5 (6.6)
26.3 (10.9)
27.4 (15.3)
24.6 (6.6)
25 (12.9)
19.6 (9.2)
25.4 (12.2)
29 (15.4)
25.2 (11.1)
History of encephalitis/meningitis n, (HHV-6+ %)
n/a
52 (15.5)
0 (0)
0 (0)
12 (66.7)
1 (0)
1 (100)
9 (33)
7 (42)
5 (40)
87 (28)
History of febrile seizures n,
12
55
11
4
6
3
5
11
2
30
139
HHV-6+ with history of febrile seizures n, (% of all HHV–6 + )
8 (44)
8 (24)
7 (77)
1 (25)
0 (0)
3 (100)
3 (27)
2 (29)
0 (0)
13 (50)
45 (35.7) **
HHV-6- with history of febrile seizures n, (% of all HHV-6-)
4 (14)
47 (15)
4 (17)
3 (75)
6 (20)
0 (0)
2 (40)
9 (31)
2 (22)
17 (35)
94 (18.1) **
Control group
No MTLE diagnosis or other epilepsy (n) (HHV-6+ %)
19 (10.5)
62 (12.9)
12 (8.3)
7(0)
10 (0)
7 (0)
7 (0)
12 (25)
no controls
no controls
136 (10.3) *#
Mean age y (SD)
31.1 (7.7)
n/a
33.42 (9.8)
31 (18.3)
62.3 (10.6)
26.1 (6.5)
12.7 (10.9)
36.1 (31.7)
no controls
no controls
33.2 (13.6)
Male (n)
12
n/a
9
5
7
3
n/a
7
no controls
no controls
43
Female (n)
7
n/a
3
2
3
4
n/a
5
no controls
no controls
24
HHV = Human herpes virus, y = Year, SD = Standard deviation, n = number * p < 0.01 (comparing HHV-6+ cases between all MTLE patients versus all non-MTLE) ** p < 0.005 (comparing history of febrile seizure between MTLE patients with HHV-6 versus MTLE patients without HHV-6) # p < 0.01 (comparing HHV-6+ cases between MTLE patients with HS versus non-MTLE)
The pooled OR from eight case control studies is shown in Fig. 4 in the fixed-effect model and in Fig. 5 in the random-effect model. A total of eight studies with 555 MTLE patients were included in the analysis and the results identify a positive association between HHV-6 DNA detection in brain tissue and MTLE (fixed-effect model: summary OR = 2.016; 95% CI = 1.16 to 3.50; random-effect model: summary OR = 2.705; 95% CI = 0.98 to 7.45).
Fig. 4Forest plot of HHV-6 infection and TLE for overall analysis by fixed model.
A forest plot demonstrating the results of the fixed-effect model. This shows a pooled OR ratio from the eight included case control studies is OR = 2.016; 95% CI = 1.16 to 3.50.
A forest plot demonstrating the results of the random-effect model. This shows a pooled OR ratio from the eight included case control studies is OR = 2.705; 95% CI = 0.98 to 7.45.
The results from this study demonstrate a significantly greater positive HHV-6 DNA detection rate in surgically removed tissue from patients with MTLE than in the control group. This is suggestive of a positive association between HHV-6 and MTLE, which is in line with most recent studies [
Detection of human herpes virus 6 B in patients with mesial temporal lobe epilepsy in West China and the possible association with elevated NF-κB expression.
]. Although we are unable to confirm a causal relationship, the increased frequency of HHV-6 DNA detection in a specific subgroup of TLE patients with HS indicates a possible pathophysiologic role of HHV-6 in these patients. In particular, the relatively high detection rate of HHV-6 DNA in MTLE patients with HS compared to MTLE patients without HS support the theory of a causal relationship especially in this subgroup. The mechanism underlying HS is likely multifactorial, as a range of insults including status epilepticus, inflammation and tissue damage can all lead to the same endpoint. However, the results of this study, another recent meta-analysis, as well as the FEBSTAT study demonstrated that it is possible that a latent HHV-6 infection in the hippocampus tissue could play a role in the pathogenesis of the HS [
]. As HHV-6 are neurotropic herpesviruses, which establish lifelong latency in neural cells and have ability to reactivate, such connection is plausible. However, these association studies cannot determine if such reactivation is the cause of the epilepsy or if the epilepsy is causing the reactivation.
Several plausible mechanisms warrant further investigation to determine if this association may be due to causation. For example, some experimental models indicate a common final pathway for seizure generation despite a range of causes, of which viruses could be one [
]. One example, is the induction of febrile seizures by hyperthermia in animal models involves activation of the interleukin 1β (IL-1β)/interleukin 1R1 (IL-1R1) axis. Mice lacking of IL-1R1 showed an increased temperature threshold for seizure induction, and treatment with IL-1β before hyperthermia lowered seizure threshold [
]. HHV-6 is known to be a potent inducer of interleukin-1 beta (IL-1 beta), and thus reactivation of HHV-6 in the CNS might contribute to the progression of epilepsy by activation of this axis. The theory of HHV-6 reactivation contributing to development of MTLE fits well with the prolonged latent period, before refractory chronic epilepsy develops [
There are at least two additional hypotheses explaining the higher HHV-6 DNA levels seen in MTLE compared to controls. One hypothesis, is that initial injury is caused by the primary HHV-6 infection giving rise to a febrile seizure that is so severe that it results in chronic brain lesions and development of MTLE. Alternatively, recurrent reactivation of latent HHV-6, causing repeated neuroinflammation or neurodegeneration, could attribute to the development of chronic epilepsy. These hypotheses are supported by the finding of higher virus DNA load in MTLE patients compared to controls [
Detection of human herpes virus 6 B in patients with mesial temporal lobe epilepsy in West China and the possible association with elevated NF-κB expression.
]. However, due to limited quantification of the virus load in majority of the included studies of our review we were unable to include levels of DNA in our analysis.
On the molecular level, there are several suggested mechanisms supporting a possible role of HHV-6 infection in the development or exacerbation of epilepsy. Firstly, in MTLE brain tissue, active infection of HHV–6 B has been found in astrocytes, demonstrated by the detection of viral proteins in these cells [
]. Furthermore, HHV–6 B infected astrocytes have been shown to induce dysregulation of glutamate uptake, giving an interesting link between HHV-6 and epilepsy [
]. Glutamate is an excitatory neurotransmitter of which the extracellular levels need to be tightly regulated and if infected astrocytes are not able to clear glutamate, epileptic symptoms might occur. There is evidence that epileptogenic hippocampus has abnormally high levels of extracellular glutamate indicating insufficient glutamate clearing in the epileptic tissue as a possible issue connected to the pathophysiology [
]. Epigenetic changes are being recognized in MTLE, with a wide array of genes involved in neuronal/synaptic transmission, cell survival/death and transcriptional regulation differentially methylated in the brains of MTLE patients [
]. There is evidence that herpes viruses, like CMV and HHV-6B, have the potential to influence the epigenetic mechanism resulting in persistent genomic methylation and altering gene expression [
]. Although experimental evidence is lacking in epilepsy, such mechanisms are well characterized in cancer, either as a result of anti-cancer drugs themselves or cancer-related intrinsic signals. Similar mechanisms might also play a role in MTLE and further studies are needed to explore this possibility [
]. Apart from viral infections directly affecting brain cells, the influence of brain inflammation in the epileptogenesis is also possible and this could be a response to a viral infection or totally independent of such. A key role of inflammation in the development of epilepsy have been suggested [
]. Evidence exists for an active role for IL-1β, TNF, IL-6, prostaglandin E2 in seizure generation and exacerbation. In vitro studies have shown that HHV-6 productively infects human glial cells, especially astrocytes [
]. Since one of the roles of astrocytes in the CNS is as an inflammatory regulator, effects of astrocyte-mediated inflammatory responses on epileptogenesis are discussed [
].The impairment of astrocytes regulatory function in inflammation can predispose and/or directly contribute to seizure and epilepsy due to neuronal damage. Because surgically removed tissue from MTLE patients demonstrate marked reactive astrogliosis, it is conceivable that astrocytes have a role in seizure generation and/or seizure spread [
]. Significant expression of genes related to astroglial activation and inflammatory response were found in brain resections from MTLE patients and it would be interesting to investigate if these have any correlation to changes induced by HHV-6A or B in brain cells [
]. Viral infections in CNS might lead to activation B cells specific against CNS antigens, which have potential to cause epilepsy. Autoantibody-related encephalopathies are an increasingly recognized differential diagnosis in adult onset epilepsy. Herpes simplex virus infections of the brain can antedate the development of pathogenic autoantibodies against neuronal surface proteins leading to an autoantibody- related encephalopathy with neuronal dysfunction and relapsing symptoms [
]. A recent case report on an autoantibody- related encephalopathy showed a common occurrence of autoantibodies against glutamic acid decarboxylase (GAD) in cerebral spinal fluid and serum, and evidence of chromosomally integrated HHV-6 [
]. If we speculate HHV-6 infection may trigger a non-paraneoplastic form of limbic encephalitis in a parallel cascade (e.g. molecular mimicry), this might be another way, HHV-6 could lead to MTLE.
Finally, we have to mention the possibility that the HHV-6 infection has no causal relationship with MTLE. Because of the ubiquitous occurrence of HHV-6 the statistical association could be due to an epiphenomenon.
5. Limitations
The heterogeneity of the tissue handling and DNA analysis between studies is a limitation of this systematic review and meta-analysis. This potentially implicates on the consistency of results, as seen in studies that analysed fresh frozen tissue tended to have greater detection rates of HHV-6 DNA compared to formalin-fixed and paraffin-embedded tissue. As most studies did not differentiate between HHV-6A and B, we were unable to analyse the data of HHV–6 B separately, although this virus has been suggested to have a larger impact on epilepsy than HHV-6A. Furthermore, the DNA virus load, which also could have an influence, was not available in all studies. Additional limitation is the publication bias, where studies of negative findings most likely are not published to the same extent as those with a positive finding. This in conjunction with the publication bias explored in this meta-analysis could indicate that the pooled estimates from this study may be more optimistic than in reality.
In the end, we suggest the necessity of quality criteria for scientific descriptions of encephalitis HHV-6 cohorts associated to MTLE. A precise characterization of this cohort would allow a much more solid conclusion of such a meta-analysis and make the studies more informative and comparable. The characterization of this cohort should include (1) a separation of HHV–6 A and B and the information of the virus load, (2) a classification of the HS subtypes, (3) an exact classification of the history of encephalitis.
6. Conclusion
HHV-6 is a ubiquitous neurotropic virus, of which based on the results of this meta-analysis, HHV-6 DNA is associated with MTLE surgically resected tissue samples. 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.
7. Author conflict of interests
PW: No conflicts of interest with respect to the research, authorship, and/or publication of this article.
ND: No conflicts of interest with respect to the research, authorship, and/or publication of this article.
OB: Has received salary from Cognizant Technology Solutions for Epidemiological consulting services for the Pharma companies.
ET: Has acted as paid consultant to Eisai, Ever Neuropharma, Biogen, Medtronics, Bial, Sunovion, Marinus Pharmaceuticals, Upsher-Smith, and UCB; received speakers honoraria from Bial, Eisai, GL Pharma, GlaxoSmithKline, Boehringer, Viropharma, Actavis, Newbridge, Novartis, and UCB Pharma; received research funding from UCB Pharma, Biogen, Novartis, Red Bull, Merck, the EU, and FWF; and is involved in planning of the ESETTrial.
AFH: No conflicts of interest with respect to the research, authorship, and/or publication of this article.
8. Funding for this study
Austrian Society of Neurology (ÖGN) Post-doctoral grant.
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Neuropathologic and clinical features of human medial temporal lobe epilepsy.
International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a task force report from the ilae commission on diagnostic methods.
Detection of human herpes virus 6 B in patients with mesial temporal lobe epilepsy in West China and the possible association with elevated NF-κB expression.
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.
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