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Herpes Simplex Encephalitis and Alzheimer's Disease: Is There a Link?
Ruth F Itzhaki1 and Naji Tabet2
Nuffield Department of Clinical Neurosciences, University of Oxford, and Centre for Dementia Studies, Brighton & Sussex Medical School, University of Sussex.
Corresponding author: Professor Ruth F Itzhaki, Nuffield Dept. Clinical Neurosciences, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Oxford OX3 9DU. UK. Email: Tel 01865 250853
Key Words: Herpes simplex encephalitis; encephalitis sequelae; herpes simplex virus; Alzheimer's disease; apolipoprotein E; epilepsy; herpes labialis.
Dear Editor
There is ongoing debate as to whether common viruses such as herpes simplex virus type 1 (HSV1) contribute to the aetiopathology of Alzheimer's disease (AD) [1]. We therefore decided to find if individuals with a history of the acute HSV1 infection, herpes simplex encephalitis (HSE), have a greater risk of developing age-related cognitive decline, and greater risk specifically of dementia or AD.
Herpes simplex virus (HSV) accounts for 5–10% of all cases of encephalitis (but HSV-1 encephalitis is far more frequent in adults than is HSV2)and is the most common known cause of viral encephalitis.We suggest here that there is evidence that survivors of herpes simplex encephalitis (HSE) in particular, and possibly of other forms of encephalitis, can lead to AD, and that its occurrence might be particularlylikely in those who are carriers of the type 4 allele of the gene for apolipoprotein E (APOE-ε4).
Cognitive deterioration almost always occurs during the acute phase of any type of encephalitis, but its persistence has rarely been investigated. It iswell known thata large proportion of survivors suffer from epilepsy, from depression and from various cognitive impairments. However,few studies have sought evidence of dementia, and usually,survivors from mixed types of encephalitis have been investigated, often withoutspecifying the numbers with HSE or other types, or even the subjects' ages.
Granerodet al.[1]recently presented interesting data aiming to find if encephalitis sequelae exceeded that of the same disorders in the general population. They investigated 2460 survivorsof encephalitis (causes of the disease were not sought),using the Clinical Practice Research Datalink collected between 1988 and 2012; their control group numbered47,914.Median duration of follow-up was 3.5 years.Theyfoundthat survivors had a significantly greater likelihood ofdementia,which was highest in the 1st year after the event.The adjusted rate ratiowas 2.66 (C.I., 1.94–3.65).
Hahn et al.[2]examined 47 patients, 8 of whom (17%) were diagnosed as HSE cases, at 6-84 months after encephalitis,and 39 healthy controls. They assessed clinical outcome by interview,by a modified Rankin Scale (MRS), and by the latency of the P3 component of the auditoryevoked potential; the latter was based on the data ofGoodin et al.[3], which showeda correlation of P3 latency delay with mental status decline for dementia patients.Hahn et al. found no significant difference in P3 latency between patient and control groups, butmore patients with HSE had abnormal P3 values compared to other subgroups,indicating an unfavourable cognitive outcome. Also, patientswith a longer P3 latency were on average older than thosewith favourable outcome.
Hokkanen and Launes[4] investigated 39 encephalitis survivors, 8 of whom (21%) were cases of HSE,at 3.7 years on average after onset of the disease. They were assessedfor difficulties in everyday life, using theBlessed dementia scale (BDS). The 11 patients with disability in BDS hadneuropsychological reassessment, and the results were compared with assessments done after the acute stage. Five patients(13%) (including two of the HSE patients), had apronounced memory impairment, together with other cognitive deficits,and were diagnosed with dementia.
Skoldenbergexamined 17 HSE survivors at 7.4 years after disease onset and 29 subjects with acute febrile focal encephalopathy of other aetiology (controls) initially suspected of HSE, at 4.3years after onset: 5/17HSE patients (29%) and 2/29controls (7%) developed dementia [5].
Hospital Episode Statistics (UK)data showed a higher rate of Alzheimer's disease(AD) for HSE survivors than for controls(R. Goldacre, personal communication, 2016), although the rate ratiodifference was not statistically significant:of 2086 people with HSE, 13 had a subsequent record of AD over a total person-time of 9433 years at risk; compared with the standard reference cohort, the expected number with AD would be 8people.
The fact that thesestudies showed an increase in dementia or, specifically, of AD amongst survivorsof HSE suggests that the survivors might have shared anothercharacteristic which added to a risk conferred by HSE. One possibility is thatthey were carriers of the type 4 allele of the apolipoprotein E (APOE-ε4) gene,a known risk factor for AD. APOE is a major determinant of susceptibility to infection or severity of outcome, in the case of several microbial diseases[6]. Further,APOE-ε4 carriage in those harbouringHSV1 in brain (some 70% of the elderly population [7]) confers a major risk of AD, and APOE-ε4 is a risk also for herpes labialis, which is usually caused by HSV1[7]. It might well be relevant that APOE-ε4 is implicated in temporal lobe epilepsy, as is HSV1(Itzhaki, RF, in proof for FASEB J).Indeed there are many overlaps in the characteristics of HSE and AD, such as seizures(andsubclinical epileptiform activity too has been detected in AD patients [8]),and changes in cognition and behaviour.
Only two studies have investigated APOE genotypes of HSE patients. The first, apreliminary study on a very small number of patients, suggested that APOE-ε2 confers a risk of HSE[9], but this would not invalidate the hypothesis as AD might develop mainly in those HSE patients (some 52%) who are not ε2 carriers. However, the second study [10] investigated APOE of 57 patients of similar mean age and similar age range and found no significant difference between their genotypes and those of controls. The reason for the different result is unknown.
As for the development of dementia amongst some survivors of non-HSE encephalitis (which can be caused by other herpesviruses, bacteria or parasites), this could be attributable to encephalitic damage in the CNS, causing reactivation of latent HSV1 resident there.
To elucidate further the suggested link between HSE, HSV1 in brain, APOE-ε4 and AD, we propose that the relationship between HSE and AD be investigated in detail, ensuring that APOE genotypes of patients are determined concomitantly. If the relationship were to be confirmed, it would greatly strengthen the case for the major role of HSV1, together with APOE-ε4, in AD, and hence the case for antiviral treatment of AD patients.
Yours sincerely
Ruth Itzhaki and N Tabet
Professor Ruth Itzhaki and Dr Naji Tabet
References
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