ArticlesFrequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis
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.
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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
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Study group members listed at end of the Article