Elsevier

The Lancet Neurology

Volume 17, Issue 9, September 2018, Pages 760-772
The Lancet Neurology

Articles
Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis

https://doi.org/10.1016/S1474-4422(18)30244-8Get rights and content

Summary

Background

Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication.

Methods

We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis.

Findings

Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5–68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7–48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1–44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24–32] vs 43 days [25–54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4–4] vs 2 [2–3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001).

Interpretation

The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy.

Funding

Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.

Introduction

Herpes simplex virus encephalitis is the most frequent cause of sporadic infectious encephalitis in high-income countries, with a worldwide incidence of two to four cases per million people each year.1 It affects patients of either sex, with a bimodal age distribution in which children and elderly people are the most frequently and severely affected. The fatality rate among patients treated with aciclovir is 10–25%, and 40–55% of surviving patients are able to resume activities of daily living.2 A separate problem is the development of neurological relapses or worsening of deficits, which have been reported in 5–26% of cases.3, 4, 5, 6 These complications tend to occur within the first 2 months of completing treatment with aciclovir and can affect children and adults. In some patients, the symptoms of relapse are caused by reactivation or persistence of the herpes simplex virus, as shown by detection of viral DNA in CSF,6 but in many cases viral testing is negative and treatment with aciclovir is ineffective. The observation that symptoms can improve or stabilise after treatment with steroids suggested that inflammatory or immune mechanisms underlie some of these complications.5, 6 This hypothesis has gained support from reports describing IgG antibodies against synaptic receptors (such as the NMDA receptor [NMDAR]) and other neuronal surface proteins in serum or CSF from patients with relapsing or worsening neurological symptoms after herpes simplex encephalitis.7, 8, 9, 10, 11, 12, 13, 14 In preliminary studies, children with this type of autoimmune encephalitis predominantly developed choreoathetosis—a previously known late complication of herpes simplex encephalitis15—whereas adults developed psychiatric and cognitive deficits.8, 16 It has been reported that immunotherapy is effective in this type of autoimmune encephalitis, but most of the findings are based on small, retrospective case series in which patients were selected for autoantibody testing.7, 8, 9, 10, 11 In this study, we aimed to investigate some of the outstanding questions related to relapsing symptoms after herpes simplex encephalitis, including the frequency of these complications, main clinical symptoms in children and adults, risk factors, frequency of neuronal autoantibodies, response to immunotherapy, and long-term neurological outcomes.

Section snippets

Study design and participants

We designed a prospective multicentre observational study, in which patients with new-onset herpes simplex encephalitis were recruited in 19 participating centres in Spain (appendix). All patients had herpes simplex encephalitis as diagnosed by neurologists, paediatricians, or infectious disease specialists, and confirmed with a PCR of CSF positive for herpes simplex virus type 1 (HSV1) or type 2 (HSV2). We excluded patients from Cohort A who died within the first 3 weeks of recruitment, or who

Results

Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, of whom 51 (n=50 HSV1 and n=1 HSV2) were included in the analysis (n=3 died during the first 3 weeks of the disease; figure 1). The median time from neurological symptom onset to inclusion in the study was 4 days (range 0–10); 29 (57%) patients were male. 48 (94%) patients were followed-up for a minimum of 6 months; of the other three patients, one died at week 9, one died at week 10,

Discussion

In the prospective Cohort A, 27% of patients with herpes simplex encephalitis developed symptoms of autoimmune encephalitis within 3 months of completing treatment with aciclovir; neurological symptoms, response to immunotherapy, and long-term outcome varied according to the patients' age. Patients aged 4 years or younger developed choreoathetosis, decreased level of consciousness, and frequent seizures or infantile spasms, whereas children aged more than 4 years and adults predominantly

References (39)

  • B Skoldenberg et al.

    Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults

    J Neurol

    (2006)
  • T Armangue et al.

    Herpes simplex virus encephalitis is a trigger of brain autoimmunity

    Ann Neurol

    (2014)
  • T Armangue et al.

    Autoimmune post-herpes simplex encephalitis of adults and teenagers

    Neurology

    (2015)
  • T Armangue et al.

    Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients

    J Pediatr

    (2013)
  • Y Hacohen et al.

    N-methyl-D-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse

    Mov Disord

    (2014)
  • SS Mohammad et al.

    Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-methyl-D-aspartate receptor or dopamine-2 receptor

    Mov Disord

    (2014)
  • H Pruss et al.

    N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis

    Ann Neurol

    (2012)
  • H Alexopoulos et al.

    Postherpes simplex encephalitis: a case series of viral-triggered autoimmunity, synaptic autoantibodies and response to therapy

    Ther Adv Neurol Disord

    (2018)
  • DR Hargrave et al.

    Movement disorders in association with herpes simplex virus encephalitis in children: a review

    Dev Med Child Neurol

    (1998)
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