The Viral Hypothesis of Mesial Temporal Lobe Epilepsy – Is Human Herpes Virus-6 the Missing Link? A systematic review and meta-analysis
Introduction from Dr Markus Reuber, editor-in-chief of Seizure
Mesial temporal lobe epilepsy (mTLE) continues to be the most prevalent form of focal-onset epilepsy worldwide. A range of different pathologies including tumours, malformations, infections and autoimmune processes can cause the condition, although one of the commonest structural abnormalities found in mTLE is that of hippocampal sclerosis (HS) (1). Most patients with HS will develop pharmacological resistance and would be considered candidates for epilepsy surgery.
Although mTLE with HS has been the focus of much research and continues to be a commonly encountered condition (especially in the developing world) some surprisingly basic questions about the condition remain unanswered. These include the questions “what causes it?” and “why is its prevalence declining in high-income countries?”: Mirroring evidence from several other parts of the world, Helmstaedter et al. reported recently that there has been a marked decrease in the incidence of mTLE with HS seen in major three German epilepsy surgery centres between 1988 and 2008 (2).
My Editor’s Choice from the present volume of Seizure, a systematic review and meta-analysis by Wipfler et al., makes a contribution to addressing these mysteries (3). It examines the possible link between Human Herpes Virus-6 (HHV-6) and mTLE. The primary infection with this virus usually occurs in infancy, when it causes a self-limiting fever, sometimes associated with a skin rash. While the signs of infection settle quickly, the herpes virus has a remarkable ability to persist in various body tissues including cells in the central nervous system. In adults with a healthy immune system, HHV-6 usually causes no symptoms or pathological changes. However, HHV-6 reactivation has been associated with a range of neurological diseases including encephalitis, multiple sclerosis, chronic fatigue syndrome and even tumors. Given the predilection of herpes viruses for limbic structures of the brain including the hippocampus, a link between HHV-6 infection or reactivation and mTLE with HS would also be plausible. Further support for this idea was provided by a meta-analysis indicating an association between febrile seizures and HHV-6 (4).
Higher HHV-6 DNA levels in mTLE brain tissue of patients with epilepsy could be explained by febrile seizures in the context of a primary HHV-6 infection causing chronic brain lesions and the development of mTLE. Alternatively, recurrent reactivation of persistent HHV-6 infection could cause repeated neuroinflammation or neurodegeneration and the development of chronic epilepsy.
Unfortunately, the HHV-6 hypothesis is proving difficult to test. Evidence of previous HHV-6 infection is found in over 90% of members of the general population, and the research studies summarized and meta-analysed in this Editor’s Choice paper are likely to have been affected by a number of biases (including the bias to publish studies with positive findings). Nevertheless, a possible association of HHV-6 and surgically treated mTLE is suggested by the analysis and HHV-6 may therefore be at least part of the answer to the questions asked above.
1) Wieser HG. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia. 2004;45:695–714.
2) Helmstaedter C, May TW, von Lehe M, Pfaefflin M, Ebner A, Pannek HW, Elger CE, H. Stefan H, Schramm J. Temporal Lobe Surgery in Germany from 1988 to 2008: Diverse Trends in Etiological Subgroups. European Journal of Neurology 2014;21:827–834.
3) Wipfler P, Dunn N, Beiki O, Trinka E, Fogdell-Hahn A,. The Viral Hypothesis of Mesial Temporal Lobe Epilepsy – Is Human Herpes Virus-6 the Missing Link? A systematic review and meta-analysis. Seizure 2018
4) Mohammadpour Touserkani F, Gaínza-Lein M., Jafarpour S., Brinegar K, Kapur K, Loddenkemper T. HHV-6 and seizure: A systematic review and meta-analysis. Journal of Medical Virology 2017; 89: 161–169.