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Lancet Neurol. 2018 Sep;17(9):760-772. doi: 10.1016/S1474-4422(18)30244-8. Epub 2018 Jul 23.

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

Author information

1
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain; Pediatric Neuroimmunology Unit, Neurology Department, Research Institute of Sant Joan de Déu Children's Hospital, University of Barcelona, Barcelona, Spain.
2
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain; University of Lausanne, Lausanne, Switzerland.
3
Immunology Department, Centre of Biomedical Diagnosis, Hospital Clínic, University of Barcelona, Barcelona, Spain; Functional Unit of Clinical Immunology, Research Institute of Sant Joan de Déu Children's Hospital, University of Barcelona, Barcelona, Spain.
4
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain; Section of Child Neuropsychiatry, Department of Medical Surgical and Experimental Medicine, University of Sassari (Sassari), Italy.
5
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.
6
Laboratory of Advanced Imaging in Neuroimmunological Diseases (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.
7
Laboratory of Advanced Imaging in Neuroimmunological Diseases (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain; Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
8
Department of Radiology, Research Institute of Sant Joan de Déu Children's Hospital, University of Barcelona, Barcelona, Spain.
9
Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Spain.
10
Department of Neurology, Hospital Vall d'Hebron, Barcelona, Spain.
11
Department of Neurology, Hospital Central de Asturias, Oviedo, Spain.
12
Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
13
Hospital Universitario Ramon y Cajal, Madrid, Spain.
14
Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
15
Pediatric Neuroimmunology Unit, Neurology Department, Research Institute of Sant Joan de Déu Children's Hospital, University of Barcelona, Barcelona, Spain.
16
Microbiology Department, Hospital Clínic, University of Barcelona, Barcelona, Spain.
17
Functional Unit of Clinical Immunology, Research Institute of Sant Joan de Déu Children's Hospital, University of Barcelona, Barcelona, Spain.
18
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain; Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
19
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain; Department of Neurology, University of Pennsylvania, PA, USA.
20
Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain; Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain; Department of Neurology, University of Pennsylvania, PA, USA; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. Electronic address: jdalmau@clinic.cat.

Abstract

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.

PMID:
30049614
PMCID:
PMC6128696
[Available on 2019-09-01]
DOI:
10.1016/S1474-4422(18)30244-8
[Indexed for MEDLINE]

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