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Ar Mangue 2018
Ar Mangue 2018
Summary
Background Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. Lancet Neurol 2018
We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication. Published Online
July 23, 2018
http://dx.doi.org/10.1016/
Methods We did a prospective observational study and retrospective analysis. In the prospective observational part of
S1474-4422(18)30244-8
this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or
See Online/Comment
infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, http://dx.doi.org/10.1016/
6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, S1474-4422(18)30279-5
when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared *Study group members listed at
demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and end of the Article
in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years Neuroimmunology Program,
compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors Institut d’Investigacions
Biomèdiques August Pi i
for autoimmune encephalitis after herpes simplex encephalitis. Sunyer (IDIBAPS)
(T Armangue MD, M Spatola MD,
Findings Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to S Mattozzi, MD,
Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5–68]). At onset of herpes simplex M Cárceles-Cordon BS,
H Ariño MD,
encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients E Martínez-Hernández MD,
developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor A Saiz MD,
[NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients Prof M R Rosenfeld MD,
did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to Prof F Graus MD,
Prof J Dalmau MD), Laboratory
unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor of Advanced Imaging in
for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7–48·8; p<0·001). Between Oct 7, 2011, and Neuroimmunological Diseases
Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused (IDIBAPS)
by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1–44·2]; n=27 male); 44 (92%) patients had (E Martinez-Heras PhD,
S Llufriu MD), Service of
antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both Neurology (S Llufriu,
cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently C Montejo MD, A Saiz,
presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than Prof F Graus, Prof J Dalmau),
Immunology Department,
4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes
Centre of Biomedical Diagnosis
simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24–32] vs 43 days [25–54]; (A Vlagea MD, M Juan MD), and
p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of Microbiology Department
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 (M A Marcos MD), Hospital
Clínic, University of Barcelona,
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
Barcelona, Spain; Pediatric
three [13%] of 23; p=0·001). Neuroimmunology Unit,
Neurology Department
Interpretation The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients (T Armangue, G Secondi MD),
Department of Radiology
with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented
(J Muchart MD), and Functional
within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the Unit of Clinical Immunology
neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those (A Vlagea, M Juan, L Alsina MD),
older than 4 years, can respond to immunotherapy. Research Institute of Sant Joan
de Déu Children’s Hospital,
University of Barcelona,
Funding Mutua Madrileña Foundation, Fondation de l’Université de Lausanne et Centre Hospitalier Universitaire Barcelona, Spain; University of
Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX. Lausanne, Lausanne,
Switzerland (M Spatola);
Section of Child
Copyright © 2018 Elsevier Ltd. All rights reserved.
Neuropsychiatry, Department
of Medical Surgical and Research in context
Experimental Medicine,
University of Sassari (Sassari), Evidence before this study choreoathetosis, impaired level of consciousness, and refractory
Italy (S Mattozzi); Department Some patients with herpes simplex encephalitis develop seizures (often with infantile spasms) than were patients older
of Neurology, Complejo neurological relapses a few weeks after successful treatment of than 4 years. Older children and adults were more likely to
Hospitalario de Navarra,
Pamplona, Spain (M E Erro MD);
the viral infection, but the frequency of this complication, present with cognitive changes and psychiatric symptoms. The
Department of Neurology, spectrum of symptoms, risk factors, and prognosis are largely symptoms in younger children (≤4 years) correspond to that
Hospital Vall d’Hebron, unknown. Autoimmune mechanisms were considered to be previously known as choreoathetosis after herpes simplex
Barcelona, Spain (L Abraira MD, responsible, but the evidence was circumstantial and the target encephalitis, but the frequent presence of infantile spasms had
M Toledo MD); Department of
Neurology, Hospital Central de
antigens unknown. These targets were recently identified as the not been previously reported. The clinical features in older
Asturias, Oviedo, Spain NMDA receptor (NMDAR) and other neurotransmitter children and adults were less known, and we show that
(G Moris MD); Department of receptors. We searched MEDLINE and Embase for articles psychosis is a frequent symptom presentation in this group
Neurology, Hospital published in English before April 1, 2018, using the MeSH terms (mainly if NMDAR antibodies are present). The main risk factor
Universitari i Politècnic La Fe,
Valencia, Spain
“herpes simplex encephalitis”, “relapsing encephalitis”, for autoimmune encephalitis after herpes simplex encephalitis
(L Monros-Giménez MD, “post-herpes simplex encephalitis”, “choreoathetosis”, “NMDA was the detection of autoantibodies (against NMDAR or
L Bataller MD); Hospital receptor antibodies”, or “N-methyl-d-aspartate receptor unknown cell-surface antigens) at follow-up 3 weeks after
Universitario Ramon y Cajal,
antibodies”. We restricted searches to human studies. We also diagnosis of herpes simplex encephalitis. The neurological
Madrid, Spain
(Í Corral-Corral MD); reviewed the reference lists of the papers identified by this outcome was worse in children aged 4 years or younger, as
Department of Neurology, search. indicated by worse mean modified Rankin Scale scores and
University of Pennsylvania, PA, greater number of seizures at 1 year.
USA (Prof M R Rosenfeld, Added value of this study
Prof J Dalmau); and Catalan In this study, we describe the frequency, clinical features, risk Implications of all the available evidence
Institution for Research and factors, and prognosis of autoimmune encephalitis after herpes Findings from this study should raise awareness for
Advanced Studies (ICREA),
Barcelona, Spain (Prof J Dalmau)
simplex encephalitis in two cohorts of patients. Cohort A is a autoimmune encephalitis after herpes simplex encephalitis.
prospective multicentre study of patients diagnosed with Detection of antibodies to NMDAR and other neurotransmitter
Correspondence to:
Prof Josep Dalmau, herpes simplex encephalitis. Cohort B is a retrospective study of receptors 3 weeks after the diagnosis of herpes simplex
IDIBAPS-CELLEX, Casanova 143, patients who developed neurological worsening after herpes encephalitis is associated with the development of autoimmune
Barcelona 08036, Spain simplex encephalitis. The findings show that autoimmune encephalitis. Prompt recognition of this complication is
jdalmau@clinic.cat
encephalitis after herpes simplex encephalitis is frequent, and important because patients, mainly older children and adults,
that the associated symptoms vary with patients’ age. Children respond better to immunotherapy.
aged 4 years or younger were more likely to develop
encephalitis were recruited in 19 participating centres in questionnaires on all patients suspected of having
Spain (appendix). All patients had herpes simplex autoimmune encephalitis after herpes simplex See Online for appendix
encephalitis as diagnosed by neurologists, paediatricians, encephalitis. The serum and CSF of these patients were
or infectious disease specialists, and confirmed with a analysed for autoantibodies at IDIBAPS-Hospital
PCR of CSF positive for herpes simplex virus type 1 Clinic, University of Barcelona, using the same
(HSV1) or type 2 (HSV2). We excluded patients from techniques as those used for samples from Cohort A.
Cohort A who died within the first 3 weeks of recruitment, These patients were studied while they had symptoms
or who had an interval of more than 10 days between of autoimmune encephalitis, meaning the only
symptom onset of herpes simplex encephalitis and retrospective information was about herpes simplex
recruitment. Patients from Cohort B who had an interval encephalitis.
of more than 4 months between symptom onset of In Cohort A, we calculated the frequency and risk
autoimmune encephalitis and determination of serum factors for autoimmune encephalitis, compared the
and CSF antibodies were excluded from the analysis. clinical features of herpes simplex encephalitis between
Patients in both cohorts were considered to have patients who later developed autoimmune encephaltis
probable autoimmune encephalitis after herpes simplex and those who did not, and examined the outcome of
encephalitis if, within the first 12 months after completing both groups at 1-year follow-up. We derived the clinical
treatment with aciclovir, they developed new-onset CNS features and outcome of autoimmune encephalitis after
symptoms or worsening of pre-existing deficits that lasted herpes simplex encephalitis from Cohorts A and B, and
for more than 24 h, had a negative PCR of CSF for herpes additionally, we investigated whether the clinical
simplex virus, and the symptoms could not be explained manifestations of patients with autoimmune encephalitis
by other complications (eg, metabolic derangement, drug varied according to the patient’s age.
toxicity, stroke) or residual lesions caused by the viral Patients in both cohorts were started on a standard
encephalitis (eg, isolated new-onset epilepsy). dose of intravenous aciclovir (1500 mg/m² for patients
Procedures
Clinical information was obtained from treating physicians 54 patients with herpes simplex 53 patients with new-onset or
encephalitis (Cohort A) worsening symptoms after
in Cohort A with standardised questionnaires that were herpes simplex encephalitis
completed at different timepoints: at diagnosis of herpes (Cohort B)
simplex encephalitis; after discontinuing treatment with
aciclovir (approximately 21 days); and at 2-month, 6-month, 3 excluded 5 excluded
and 12-month follow-up from onset of herpes simplex 3 died in first 3 weeks 5 viral reactivation
encephalitis. During these timepoint follow-ups in
Cohort A, we assessed neurological function using the 51 included in analysis 48 included in analysis
modified Rankin Scale (mRS).17,18 Patients were considered 48 with 6 months of follow-up
to have a good outcome if the mRS score at the last follow- 2 died
1 did not have 6-month data
up was 0–2, and a bad outcome if the score was greater 40 with 1 year of follow-up
than 2. Brain MRI scans were obtained at the discretion of 1 died
1 lost to follow-up
the treating clinician at diagnosis and were centrally 6 did not have 1-year data
reviewed at Institut d’Investigacions Biomèdiques August
Pi i Sunyer (IDIBAPS)-Hospital Clinic, University of
Barcelona, Barcelona, Spain (appendix). IgG antibodies
against NMDAR and other neuronal surface proteins were 14 with neurological 37 neurological
complications not due improvement or
determined in serum and CSF obtained at diagnosis and to viral reactivation stable deficits*
after completing aciclovir, and in serum obtained at follow- 3 died
up at 2, 6, and 12 months; these tests were done at
IDIBAPS-Hospital Clinic, University of Barcelona, with 14 with neuronal surface 44 with neuronal surface 4 no neuronal surface
previously reported techniques (appendix).19,20 Investigators antibodies antibodies antibodies
doing the autoantibody testing were masked to clinical 9 NMDAR 34 NMDAR
5 unknown antigens 10 unknown antigens
information, and the treating physicians were masked to
antibody results unless patients developed new neuro
logical symptoms or unexplained progression of previous
deficits; if this occurred, new paired CSF and serum 58 with antibody-confirmed autoimmune encephalitis
after herpes simplex encephalitis
samples were examined and the results, along with those 43 NMDAR
of previous samples, were provided to the treating 15 unknown antigens
physician.
We obtained clinical information from treating Figure 1: Study profile
physicians in Cohort B using the indicated NMDAR=NMDA receptor. *11 with neuronal surface antibodies (n=3 NMDAR, n=8 unknown antigens).
Statistical analysis
All (N=51) Autoimmune encephalitis Comparison*
after herpes simplex We used the Fisher exact test or Wilcoxon rank-sum
encephalitis test, as appropriate, to analyse the demographics and
Yes (n=14) No (n=37) clinical features of patients who developed autoimmune
encephalitis compared with those who did not develop
Median age, years 50 (5–68) 24 (0·9–75) 51 (13–68) p=0·290
autoimmune encephalitis or these features according to
Younger children (≤4 years) 13 (25%) 6 (43%) 7 (19%) p=0·089
age group (patients ≤4 years compared with patients
Older children (5–17 years) 5 (10%) 1 (7%) 4 (11%) p=0·182
>4 years). Multivariate binary logistic regression models
Adults (≥18 years) 33 (65%) 7 (50%) 26 (70%) p=0·182
were explored to identify predictor variables of developing
Sex
autoimmune encephalitis after herpes simplex
Women 22 (43%) 6 (43%) 16 (43%) p=0·980
encephalitis. All variables with a cutoff p value of less
Men 29 (57%) 8 (57%) 21 (57%) p=0·980
than 0·1 (likelihood ratio test) in univariate binary
Symptoms during herpes simplex encephalitis logistic models and clinically meaningful variables
Fever 49 (96%) 13 (93%) 36 (97%) p=0·490 (patients’ age, % volume involvement on MRI, CSF
Altered consciousness 35 (69%) 11 (79%) 24 (65%) p=0·335 pleocytosis, and protein concentration at 21 days) were
Abnormal behaviour 21 (41%) 5 (36%) 16 (43%) p=0·624 considered for the multivariate binary logistic regression
Memory deficits† 26/36 (72%) 6/8 (75%) 20/28 (71%) p=0·841 models, and approached by forward stepwise procedure
Aphasia† 28/36 (78%) 7/8 (88%) 21/28 (75%) p=0·431 (appendix). We also explored first-order interactions
Seizures 32 (63%) 11 (79%) 21 (57%) p=0·139 between variables. We used odds ratios (ORs) and
Motor deficit 21 (41%) 8 (57%) 13 (35%) p=0·156 95% CIs to measure the effect of predictors and adjusted
CSF at diagnosis of herpes simplex encephalitis for relevant variables if there was a clinically relevant
Median white blood cell count per mm3 77 (22–170) 77 (22–122) 77 (22–190) p=0·545 change in the OR.21,22 In all analyses, we applied a bilateral
Median protein concentration, mg/dL 60 (38–78) 62 (37–74) 57 (38–82) p=0·872 type I error of 5% without a formal correction for
Brain MRI abnormalities at diagnosis of herpes simplex encephalitis‡ multiplicity. We used STATA (version 13.1) for the
FLAIR, mean % lesion volume 3·9% (3·3) 4·5% (3·9) 3·4% (2·9) p=0·344 statistical analyses.
DWI, mean % lesion volume 3·7% (3·3) 3·6% (2·9) 3·8% (3·6) p=0·904
Contrast enhancement 21/34 (62%) 6/8 (75%) 15/26 (58%) p=0·368 Role of the funding source
Treatment of herpes simplex encephalitis The funders of the study had no role in study design,
Median time to start aciclovir, days§ 1 (0–2) 2 (1–2) 1 (0–3) p=0·193 data collection, data analysis, data interpretation, or
Median duration of aciclovir treatment, 21 (16–21) 21 (18–23) 21 (15–21) p=0·548 writing of the report. The corresponding author had full
days access to all the data in the study and had final
Steroids¶ 20 (39%) 5 (36%) 15 (41%) p=0·752 responsibility for the decision to submit for publication.
ICU admission 27 (53%) 9 (64%) 18 (49%) p=0·315
Antiepileptic drugs 40 (78%) 12 (86%) 28 (76%) p=0·422 Results
Median modified Rankin Scale Between Jan 1, 2014, and Oct 31, 2017, 54 patients with
At 6 months (n=48) 2 (1–3) 3 (3–4) 2 (1–3) p<0·001 herpes simplex encephalitis were recruited to Cohort A,
At 12 months (n=40) 2 (1–3) 3 (3–4) 2 (1–2) p<0·001 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
Data are median (IQR), n (%), n/N (%), or mean (SD). FLAIR=fluid-attenuated inversion recovery.
DWI=diffusion-weighted imaging. ICU=intensive care unit. *Likelihood ratio test. †Not assessable in 15 patients
disease; figure 1). The median time from neurological
(<3 years old, or severe decrease of the level of consciousness). ‡For lesion volume calculation, axial FLAIR sequences were symptom onset to inclusion in the study was 4 days
available in 33 patients (19 without autoimmune encephalitis and 14 with autoimmune encephalitis), and axial DWI (range 0–10); 29 (57%) patients were male. 48 (94%)
sequences in 46 patients (32 without autoimmune encephalitis and 14 with autoimmune encephalitis). §The number
patients were followed-up for a minimum of 6 months;
of days from onset of herpes simplex encephalitis symptoms to initiation of aciclovir. ¶17 patients were treated with
intravenous dexamethasone and three patients with intravenous methylprednisolone (with two also treated with of the other three patients, one died at week 9, one died at
intravenous immunoglobulins). week 10, and one had less than 6 months of follow-up.
40 (78%) were followed-up for 1 year; of the other eight
Table 1: Demographics and clinical features of patients in Cohort A
patients, one died at 9 months, one was lost to follow-up,
and six had less than 1 year of follow-up.
aged 12 years or younger, and 30 mg/kg per day for In Cohort A, 37 (73%) of the 51 patients included in
patients older than 12 years, divided every 8 h for the analysis had progressive neurological improvement
14–21 days) as soon as herpes simplex encephalitis was or stable deficits; one patient died at week 9, from
diagnosed. Concomitant use of steroids, intravenous aspiration pneumonia (an 11-year-old patient), one died
immunoglobulins, or both was at the physician’s at week 10, from malignant thymoma (a 30-year-old
discretion. patient), and one died at week 36, from lung
Written informed consent was obtained from all complications (an 84-year-old patient; figure 1). 14 (27%)
patients or their guardians. Studies were approved by the patients developed new-onset CNS symptoms or
Internal Review Board of Hospital Clinic, University of worsening of previous deficits consistent with probable
Barcelona. autoimmune encephalitis after herpes simplex
encephalitis (table 1). Median time from herpes patients who developed autoimmune encephalitis and
simplex encephalitis until probable autoimmune those who did not (table 1; appendix). Among patients
encephalitis was 32 days (IQR 22–43; range 7–61). who developed autoimmune encephalitis (n=14), MRI
Whereas all younger children (≤4 years; n=6; median scans at onset showed that nine (82%) of 11 patients had
age 9 months [IQR 3–12, range 2–15]) developed contrast enhancement comparable with that found
symptoms associated with choreoathetosis, all older during the viral encephalitis; similar findings were
children (>4 years) and adults (n=8, median age observed in patients who did not develop autoimmune
66 years [IQR 40–78, range 13–81]) developed symptoms encephalitis and had MRI at 1–3 months’ follow-up
without choreoathetosis in which behavioural and (six [60%] of ten patients, p=0·269; figure 2). Patients
psychiatric manifestations predominated (table 2). who developed auto immune encephalitis were more
Brain MRI scans at onset of herpes simplex likely to have necrosis with cystic lesions in MRI scans
encephalitis, with fluid-attenuated inversion recovery obtained at follow-ups later than 4 months after herpes
(FLAIR) and diffusion-weighted imaging (DWI), showed simplex encephalitis, compared with patients who did
no significant differences in lesion volume between not develop autoimmune encephalitis (nine [100%] of
mRS 3 weeks Day of onset and main Maximum Antibody findings at Day immunotherapy was mRS at Outcome at 12 months’
after herpes symptoms of mRS during diagnosis of autoimmune started 12 months follow-up after herpes
simplex autoimmune autoimmune encephalitis after herpes simplex encephalitis
encephalitis* encephalitis after herpes encephalitis simplex
simplex encephalitis encephalitis
Serum (titre) CSF (titre)
Patient #1 male, 2 Day 7: choreoathetosis 3 NMDAR NMDAR Not treated with 4 Developmental delay,
2 months old (1/200) (1/40) immunotherapy refractory epilepsy,
infantile spasms, cortical
blindness, microcephaly
Patient #2 male, 2 Day 24: choreoathetosis, 5 NMDAR NMDAR (titre Day 26: intravenous 3 Developmental delay,
3 months old refractory seizures, LCE, (1/1600) not available) methylprednisolone, plasma right-sided hemiparesis,
hypotonia, dysphagia exchange, rituximab microcephaly
Patient #3 female, 2 Day 25: choreoathetosis, 5 NMDAR NMDAR Day 25: intravenous 4 Developmental delay,
7 months old refractory seizures, status (1/800) (1/20) methylprednisolone, spastic tetraparesis,
epilepticus, infantile intravenous anarthria, and controlled
spasms, LCE, hypotonia, immunoglobulins; day 60: epilepsy
dysphagia rituximab, cyclophosphamide
Patient #4 male, 2 Day 19: refractory 5 NMDAR NMDAR Day 20: intravenous 5 Developmental delay,
11 months old seizures, infantile spasms, (1/200) (1/160) methylprednisolone, spastic tetraparesis,
LCE, hypotonia, intravenous refractory epilepsy
dysphagia, immunoglobulins, rituximab,
choreoathetosis cyclophosphamide; day 70:
plasma exchange
Patient #5 male, 2 Day 39: choreoathetosis, 5 NMDAR NMDAR Day 32: intravenous 3 Delay in language skills
12 months old loss of language skills, (1/800) (1/160) methylprednisolone,
LCE, hypotonia, dysphagia intravenous
immunoglobulins, rituximab
Patient #6 male, 2 Day 27: refractory status 5 NMDAR† NMDAR† Day 28: intravenous 4 Developmental delay,
15 months old epilepticus, hypotonia, (1/200) (1/80) methylprednisolone; day 44: refractory epilepsy
LCE, dysphagia, plasma exchange, rituximab
choreoathetosis
Patient #7 male, 4 Day 43: aggressive 5 NMDAR NMDAR Day 190: intravenous 3 Residual motor and
13 years old behaviour, psychosis, (1/800) (1/160) methylprednisolone cognitive deficits
headache, high blood
pressure
Patient #8 female, 2 Day 45: insomnia, anxiety, 3 NMDAR NMDAR Day 60: inatravenous 0 Complete recovery
34 years old irritability, fear, sleep (1/200) (1/80) methylprednisolone
fragmentation and
nightmares
Patient #9 male, 3 Day 44: headache, 4 Negative NMDAR Day 140: intravenous 3 Residual aphasia
45 years old confusion, agitation, (1/20) methylprednisolone
psychosis, insomnia,
delusional thoughts
Patient #10 4 Day 39: emotional lability, 4 Negative Unknown Day 160: intravenous 3 Anterograde amnesia
female, 56 years suicidal ideation, antigen (1/40) methylprednisolone
old psychosis, confusion
(Table 2 continues on next page)
mRS 3 weeks Day of onset and main Maximum Antibody findings at Day immunotherapy was mRS at Outcome at 12 months’
after herpes symptoms of mRS during diagnosis of autoimmune started 12 months follow-up after herpes
simplex autoimmune autoimmune encephalitis after herpes simplex encephalitis
encephalitis* encephalitis after herpes encephalitis simplex
simplex encephalitis encephalitis
Serum (titre) CSF (titre)
(Continued from previous page)
Patient #11 4 Day 37: confusion, 4 Negative Unknown Day 180: intravenous 4 Anterograde amnesia
female, 75 years aggressive behaviour, antigen (1/20) methylprednisolone,
old insomnia intravenous
immunoglobulins, rituximab,
cyclophosphamide
Patient #12 male, 3 Day 22: progressive 4 Unknown Unknown Day 159: intravenous 4 Anterograde amnesia
77 years old irritability, paranoid antigen antigen (1/20) methylprednisolone and irritability
thoughts, psychosis (1/800)
Patient #13 3 Day 17: fever, seizures, 5 Negative Unknown Day 21: steroids, intravenous 3 Anterograde amnesia
female, 78 years irritability, decreased level antigen (1/10) immunoglobulins, rituximab,
old of consciousness, cyclophosphamide
abnormal behaviour,
confusion, apathy
Patient #14 4 Day 63: progressive 4 Negative Unknown Day 90: intravenous steroids, 3 Anterograde amnesia
female, 80 years depression, apathy antigen intravenous
old (1/160) immunoglobulins
mRS=modified Rankin Scale. NMDAR=NMDA receptor. LCE=loss of contact with environment. *Except for patients 1, 4, and 13, who developed autoimmune encephalitis before the 3-week follow-up (figure
3A). †Coexisting GABAA receptor antibodies.
Table 2: Clinical features of patients with autoimmune encephalitis after herpes simplex encephalitis in Cohort A
nine patients vs seven [50%] of 14 patients; p=0·019; positive for IgG antibodies during follow-up (p<0·001),
figure 2). There were no differences in progression of including three (27%) with NMDAR antibodies and
local white-matter or grey-matter abnormalities or local eight (73%) with antibodies against unknown antigens
atrophy between patients who developed autoimmune (figure 3B). Compared with patients with autoimmune
encephalitis and those who did not (appendix). encephalitis, only five (14%) of 37 patients tested positive
CSF studies at onset of herpes simplex encephalitis for neuronal surface antibodies at the 3-week follow-up
and at 3 weeks’ follow-up showed no significant (p=0·0010). At 1-year follow-up, seven (50%) of 14 patients
differences in white blood cell count or total protein with autoimmune encephalitis and one (4%) of 26 patients
concentration between patients who subsequently dev without autoimmune encephalitis had antibodies
eloped autoimmune encephalitis and those who did not detectable in serum (p=0·0010; figure 3). The outcome of
(table 1; appendix). At the onset of autoimmune patients with autoimmune encephalitis who had
encephalitis, the PCR of CSF for HSV1 and HSV2 was persistent antibodies at 1-year follow-up was worse than
negative in all patients, and all patients had mild that of patients who became antibody negative (median
pleocytosis (median white blood cell count 17 per mm³ mRS 4 [IQR 3–5] vs 3 [3–3]; p=0·030).
[IQR 7–54]) and increased protein concentration (median The longest interval between herpes simplex
61 mg/dL [IQR 39–88]). encephalitis and autoimmune encephalitis was 61 days,
At onset of herpes simplex encephalitis, none of the and the sensitivity, specificity, positive predictive value,
51 patients included in the analysis of Cohort A had and negative predictive value for the detection of
antibodies against neuronal surface antigens. During neuronal surface antibodies within 2 months after
follow-up, all 14 (100%) patients who developed symptoms herpes simplex encephalitis are shown in the appendix.
consistent with autoimmune encephalitis tested positive In paired serum and CSF testing, neuronal surface
for IgG antibodies at or before the time of symptom antibodies were always present in CSF (19 [100%] of
onset, including nine (64%) patients with NMDAR 19 patients) and less frequently in serum (11 [58%] of
antibodies (n=1 with co-existing GABAA receptor 19 patients; figure 3). In six patients who did not develop
antibodies), and five (36%) with antibodies against autoimmune encephalitis, the antibodies were detected
unknown antigens (figures 3A, 4). Nine (64%) of these during the clinical follow-up when only serum was
14 patients were already antibody positive at the 3-week tested, according to the study design.
follow-up (six were antibody positive preceding onset of In the exploratory multivariate logistic regression
symptoms of autoimmune encephalitis); an example of analysis, the presence of autoantibodies at the 3-week
progressive NMDAR antibody development is shown in follow-up was identified as a risk factor for autoimmune
the appendix. By contrast, among the 37 patients who did encephalitis (OR 11·5, 95% CI 2·7–48·8; p<0·001;
not develop autoimmune encephalitis, 11 (30%) tested appendix). Adjustment by patient’s age and other possible
HSE 1–3 months 6–9 months HSE 1–3 months 6–9 months
Case 1
(patient 4)
Case 2
(patient 10)
Case 3
Case 4
(patient 24)
Figure 2: MRI in patients who developed autoimmune encephalitis after herpes simplex encephalitis compared with those who did not develop autoimmune
encephalitis
Each row corresponds to a different patient and includes MRI scans obtained at diagnosis of herpes simplex encephalitis, at 1–3 month follow-up, and at 6–9 month
follow-up. The first three columns of images correspond to FLAIR sequences, and the last three columns to T1 sequences, all with contrast (except for the 6–9 month
T1 follow-up for patient 4). Case 1 (patient 4) was an 11-month-old boy who developed autoimmune encephalitis with NMDAR antibodies after herpes simplex
encephalitis. Case 2 (patient #10) was a 56 year-old woman who developed autoimmune encephalitis with antibodies against unknown neuronal surface antigens
after herpes simplex encephalitis. Case 3 (no patient number) was a 49 year-old woman who developed herpes simplex encephalitis without autoimmune
encephalitis or neuronal antibodies (she had history of lung adenocarcinoma, brain metastasis, and cranial radiotherapy). Case 4 (patient #24) was a 66 year-old
woman who developed NMDAR and GAD65 antibodies but did not have symptoms of autoimmune encephalitis. These patients were chosen because there was
good MRI follow-up and they were representative of the indicated subgroups. In all patients, MRI scans obtained at the 1–3 month follow-up show areas of FLAIR
hyperintensity (larger or similar to those obtained at diagnosis of herpes simplex encephalitis); however, MRIs of patients who developed autoimmune encephalitis
(first and second rows) show more extensive areas of post-necrotic cystic abnormalities than those who did not develop autoimmune encephalitis (third and fourth
rows). Note that all patients, except patient 24, have areas of contrast enhancement at 1–3 month follow-up. FLAIR=fluid-attenuated inversion recovery. HSE=herpes
simplex encephalitis. NMDAR=NMDA receptor.
effect modifiers was not associated with a clinically developed new-onset or worsening neurological
meaningful change in OR (appendix). symptoms not caused by herpes simplex virus
At 1-year follow-up, patients who developed autoimmune reactivation after completing treatment with aciclovir
encephalitis had more neurological deficits (median (figure 1). Of these 48 patients, 44 (92%) had neuronal
mRS 3 [IQR 3–4] vs 2 [1–2]; p<0·001; table 1) and were surface antibodies; 34 (77%) of 44 had antibodies
more frequently treated with anti-epileptic drugs than against NMDAR and the other ten (23%) had antibodies
were those who did not develop autoimmune encephalitis against unknown antigens (appendix). Antibodies were
(ten [71%] of 14 patients vs nine [35%] of 26; p=0·046). more frequently detected in CSF (44 [100%] of
Between Oct 7, 2011, and Oct 31, 2017, 48 patients 44 patients; median titres 1/40 [IQR 1/10 to 1/160]) than
were included in Cohort B (median age 8·8 years in serum (25 [76%] of 33 patients, median titres 1/800
[IQR 1·1–44·2]; 26 male patients). These patients [1/400 to 1/3200]; appendix).
A
Patient Sex Age Sample HSE Day 21 Day 60 Day 180 Day 365 Antigen Serum titres
Highest* Day 365
1 Male 2 months CSF – + NMDAR 1/3200 1/800
Day 7
Serum – + + + +
mRS 0 mRS 1 mRS 2 mRS 3 mRS 4 mRS 5 Day of onset of autoimmune encephalitis
The median time from herpes simplex encephalitis hypotonia, dysphagia, and frequent refractory seizures
until symptoms of probable autoimmune encephalitis in (table 3). Six (22%) of these 27 patients developed infantile
Cohort B was 31 days (IQR 25–49, range 11–306). Similar spasms during the acute phase of autoimmune en
to patients from Cohort A, patients who were aged 4 years cephalitis, and another two at later stages (6–12 months’
or younger (n=21, median age 10·6 months [IQR 7–20, follow-up). By contrast, patients older than 4 years (n=31)
range 4·5–48]) developed symptoms associated with developed prominent change of behaviour and psychiatric
choreoathetosis, whereas those older than 4 years (n=23, symptoms, had less frequent seizures or decreased level of
median age 34 years [16–56, range 6–69]) developed consciousness, and no choreoatherosis. 18 (58%) of these
symptoms in which behavioural and psychiatric 31 patients presented with psychosis (in younger children,
manifestations predominated (appendix). Of the total psychosis was not assessable). Compared with patients
48 patients in Cohort B, the remaining four (8%) patients older than 4 years, patients aged 4 years or younger (all
without neuronal surface antibodies had main clinical with choreoathetosis) were more likely to have a shorter
features of epileptic seizures (n=3) and behavioural interval between herpes simplex encephalitis and
change (n=1; appendix). autoimmune encephalitis, seizures, decreased level of
Considering all 58 patients from both cohorts who consciousness, NMDAR antibodies, and worse outcome at
developed antibody-associated autoimmune encephalitis 1 year, including a higher mRS score and more frequent
after herpes simplex encephalitis, we identified symptoms seizures than patients older than 4 years (table 3).
that were age-dependent: patients aged 4 years or younger Compared with patients with antibodies other than
(n=27) developed prominent choreoathetosis, behavioural NMDAR (n=15), patients with NMDAR antibodies (n=43)
change, decreased level of consciousness, truncal were more likely to be younger and develop psychosis,
B
Patient Sex Age Sample HSE Day 21 Day 60 Day 180 Day 365 Antigen Serum titres
Highest* Day 365
15 Female 12 CSF – + NA Unknown 1/12 800 NA
months Serum – + + +
mRS 0 mRS 1 mRS 2 mRS 3 mRS 4 mRS 5 Day of onset of autoimmune encephalitis
Figure 3: Timing of antibody detection, development of autoimmune encephalitis, and follow-up of serum testing and neurological status
(A) Patients from Cohort A who developed neuronal surface antibodies in association with autoimmune encephalitis. None of the patients had neuronal surface antibodies at the time of onset of
herpes simplex encephalitis, but all were antibody-positive at or before onset of symptoms of autoimmune encephalitis. In all patients, the presence (+) or absence (–) of neuronal cell-surface
antibodies in serum was followed for 1 year. The neurological status was measured with the mRS and is colour-coded. (B) Patients from Cohort A who developed neuronal surface antibodies without
autoimmune encephalitis. These patients became antibody-negative sooner (as measured in serum) than did patients with autoimmune encephalitis. HSE=herpes simplex encephalitis.
NMDAR=NMDA receptor. NA=not available. mRS=modified Rankin Scale. *In all patients, the highest serum titres were identified within the first 2 months of follow-up. †NMDAR antibodies with
co-existing GABAA receptor antibodies. ‡NMDAR antibodies with co-existing GAD65 antibodies; at 1 year follow-up only GAD65 antibodies remained detectable (not shown).
choreoathetosis, decreased level of consciousness, and different outcomes in the retrospective Cohort B, in
dysautonomia (appendix). No differences in neurological which patients who developed unexplained neurological
outcome (mRS) were noted between patients with symptoms after treatment of herpes simplex encephalitis
autoimmune encephalitis with NMDAR antibodies and were investigated for antibodies against neuronal
those with other neuronal surface antibodies (appendix). surface proteins.
When Cohort A was examined for risk factors of
Discussion autoimmune encephalitis, the main feature identified
In the prospective Cohort A, 27% of patients with herpes was the detection of neuronal antibodies at 3-week
simplex encephalitis developed symptoms of auto follow-up. Considering that none of the patients tested
immune encephalitis within 3 months of completing positive for these antibodies at onset of herpes simplex
treat
ment with aciclovir; neurological symptoms, encephalitis, this finding suggests the viral infection
response to immunotherapy, and long-term outcome triggered the immune response. We do not know
varied according to the patients’ age. Patients aged 4 years whether any of these immune responses occurred as a
or younger developed choreoathetosis, decreased level result of viral-induced release of NMDAR and other
of consciousness, and frequent seizures or infantile proteins, or by mechanisms of molecular mimicry, such
spasms, whereas children aged more than 4 years and as similarity between NMDAR and herpes simplex virus
adults predominantly developed a change of behaviour proteins. The high frequency of antibodies against
and psychiatric symptoms sometimes accompanied by different neuronal antigens supports the first possibility
seizures. Additionally, older children and adults were but does not rule out that molecular mimicry might also
more likely to respond to immunotherapy. There were be involved. One study23 showed that patients with
similar findings regarding age-related symptoms and classic anti-NMDAR encephalitis (not herpes simplex
A B
C D
E F
500 µm 10 µm
encephalitis-related) were more likely to have herpes preceded the onset of autoimmune encephalitis, and
simplex virus anti bodies than were an age-matched that not all antibody-positive patients developed neuro
control population, suggesting the possibility of logical worsening. Moreover, at 1-year follow-up,
molecular mimicry between herpes simplex virus and seven (50%) of 14 patients who developed autoimmune
NMDAR.23 Although the role of human leukocyte encephalitis remained IgG antibody positive despite the
antigen in predisposing people to anti-NMDAR use of immunotherapy in 13 cases, whereas one (4%) of
encephalitis is still unclear,24,25 future studies should 26 patients who did not develop autoimmune
determine whether there is a predisposition among encephalitis and therefore did not receive immuno
patients with herpes simplex encephalitis to develop therapy remained antibody positive. These findings
autoimmune encephalitis. indicate that herpes simplex encephalitis can initiate, in
In Cohort A, clinical and immunological follow-up some patients, a transient and subclinical synthesis of
showed that the development of autoantibodies neuronal antibodies that becomes undetectable several
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