https://doi.org/10.
1093/brain/awad290
Post-herpes simplex virus encephalitis
autoimmunity: more the rule than
the exception
This scientific commentary refers to ‘Neurologic complications in
herpes simplex encephalitis: clinical, immunological and genetic
studies’ by Armangué et al. (https://doi.org/10.1093/brain/
awad238).
Serendipity is a factor in many discoveries in science and medicine,
but perseverance is the key to success. The scientific story of post-
herpes simplex virus I autoimmune encephalitis (HSVE-AE) is laden
with keen observations, chance findings and coincidences, but it is
also a story of persistence. It began with the unexpected discovery
of N-methyl-D-aspartate receptor (NMDAR) antibodies in the sera of
a number of patients with herpes simplex virus I encephalitis (HSE)
recruited as a control group during the development of a standar­
dized NMDAR antibody assay. A retrospective analysis of 44 HSE pa­
tients treated at a German university hospital then identified NMDAR
antibodies in 30% of these individuals.1 This discovery in turn led to
the prospective identification of NMDAR antibodies in the CSF of an
adult patient with a post-HSE relapse. Interestingly, NMDAR anti­
bodies had not been present in CSF obtained during this patient’s
HSE episode 4 weeks earlier. This case came to the attention of
Josep Dalmau via a visiting German neuroscientist.2
In parallel (https://doi.org/10.1016/j.jpeds.2012.10.011), Thais
Armangué—a neuropaediatrician working in Josep Dalmau’s lab
—put together a small case series of children who had developed
post-HSV choreoathetosis, a syndrome familiar to paediatricians
but mostly considered to be the result of viral relapse, rather than
autoimmunity. Some aspects of this syndrome resembled the spec­
trum of movement disorders associated with anti-NMDAR enceph­
alitis, which had been described by Josep Dalmau and colleagues3 a
few years earlier. Armangué demonstrated that these patients also
showed seroconversion, with the appearance of NMDAR antibodies
in CSF in association with clinical relapses. These observations in
children and adults were published together4 and were confirmed
almost in parallel by British5 and Australian6 groups.
Having picked up the scent, Armangué then orchestrated a
Spanish prospective observational multicentric study to recruit pa­
tients with HSV in a standardized fashion.7 This commendable ef­
fort resulted in a large prospective series of 51 patients with HSV,
27% of whom went on to experience secondary autoimmune en­
cephalitis relapses—often therapy-responsive—within 2 months
after HSE. While most harboured NMDAR antibodies in their CSF
(64%), others had antibodies targeting unknown neural antigens in­
stead or in addition (36%). None had NMDAR or other neuronal
Received August 24, 2023. Accepted August 24, 2023. Advance access publication August 28, 2023
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antibodies at the time of the HSE, yet some (30%) went on to develop
neuronal antibodies without clinical relapses. Indeed, the presence
of any neuronal antibodies at 3 weeks following HSE was predictive
of a subsequent symptomatic relapse later in the course of the dis­
ease (odds ratio, OR 11.5).8 However, the reason why some patients
developed symptomatic or asymptomatic secondary autoimmun­
ity following HSE, whereas others did not, and the factors that pre­
disposed patients to symptomatic relapses, remained unclear.
Early hypotheses for the mechanisms underlying post-HSVE-AE
considered the possibility of molecular mimicry between HSV
surface molecules and NMDARs. Yet post-viral encephalitis does
not appear to be limited to HSE but also occurs following a wide
range of other viral encephalitis variants, including Japanese
B-encephalitis,9 arguing against this idea. Instead, it is likely that
the co-occurrence of a tissue-destructive viral encephalitis releas­
ing neuronal antigens, together with the strong pro-inflammatory
stimulus mediated by viral particles via conserved pattern-
recognition receptors (PRRs), such as toll-like receptors (TLRs),
causes auto-immunization (Fig. 1). The PRR chiefly responsible for
detecting DNA viruses like HSV is TLR3. Upon detection of intracel­
lular double-stranded RNA produced during viral replication, TLR3
induces the production of type I interferons (IFN-I), the body’s first
line of antiviral defence. By regulating the expression of hundreds
of different genes, IFNs are able to block virus replication at numer­
ous levels. Correspondingly, mutations in the TLR3 gene or compo­
nents of the associated signalling cascade are known to predispose
to relapsing HSE. Furthermore, there is a strong link between hy­
peractivation of the IFN-I system and autoimmunity (systemic lu­
pus erythematosus) as well as hyperinflammation syndromes
(Aicardi-Goutières syndrome). Therefore, it was tempting to specu­
late that the TLR3/IFN pathway might have a role in the develop­
ment of secondary, post-viral autoimmunity.
In their latest work, published in this issue of Brain, Armangué,
Dalmau and colleagues10 add novel and exciting findings to the
field of post-HSVE-AE, based on their extensive prospective
Spanish cohort of 93 patients with HSE and an international cohort
of 97 patients with post-HSVE-AE. They confirmed that 42% of pa­
tients in the Spanish cohort developed neuronal antibodies follow­
ing HSE, 54% of whom (23% of all HSE patients) went on to develop
symptomatic autoimmune relapses, usually within 3–6 weeks. This
figure strengthens earlier observations and supports previous
calls for the adoption of a systematic management strategy in
patients following HSV, with clinical visits and further lumbar
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Figure 1 Current hypotheses for the mechanism underlying post-viral encephalitis autoimmune encephalitis relapses. (1) Neurotropic viruses (e.g.
herpes simplex virus I) cause neuronal destruction leading to widespread release of neuronal antigens (e.g. NMDAR subunits) and viral components.
(2) Viral components, such as double-stranded RNA, activate pattern recognition receptors (PRRs, e.g. toll-like receptor 3; TLR3), which induce an inter­
feron type I (IFN-I) response as well as co-stimulatory signalling. (3) Together with the presentation of neuronal antigens by antigen-presenting cells
(dendritic cell in purple, left part of circle) to T lymphocytes (center cell in circle, green), this results in breach of tolerance. The autoreactive T cells can
in turn stimulate autoantigen-specific B cells (right cell within circle, green with surface antibodies) to develop into short-lived plasma blasts or cells (4)
whose autoantibodies then target dendritic NMDARs (5) and cause receptor internalization, net loss of surface NMDARs, synaptic and eventually net­
work dysfunction. In parallel, IFN-I causes expression of major histocompatibility complex type I (MHC-I) on the surface of neurons (not shown), there­
by rendering them susceptible to cytotoxic T cells. Many questions remain unanswered: Where does the breach of tolerance take place, in perivascular
spaces in the brain or in cervical lymph nodes? Why is the NMDAR such a frequent autoantigen and which other endogenous factors limit/propagate
autoimmunity in the context of post-HSE autoimmunity? Created with BioRender.com.

punctures. The authors delineated three somewhat distinct clinical of infectious encephalitis: a significant proportion (at least 20%) of
syndromes associated with these relapses: (i) mostly NMDAR patients with HSE will go on to develop symptomatic—sometimes
antibody-associated choreoathetosis in children; (ii) idiopathic difficult to discriminate from residual symptoms—post-HSE auto­
anti-NMDAR encephalitis-like syndromes (psychiatric symptoms, immune relapse, a treatable complication. We would all be well
seizures, decreased level of consciousness and dysautonomia) in advised to accept that post-HSVE AE is more the rule than the
teenagers/adults; and (iii) isolated neuropsychiatric/behavioural exception and to change our post-acute management of these
phenotypes (often associated with non-NMDAR, neuronal autoanti­ patients accordingly.
bodies). Intriguingly, they identified a moderate (yet significant) in­
crease in specific type I interferon signals in the blood 3 weeks Frank Leypoldt1,2 and Klaus-Peter Wandinger1
after HSE as the strongest predictor of developing symptomatic
1 Institute of Clinical Chemistry, University-Hospital Schleswig Holstein
post-HSVE-AE (OR 34.8). Patients with detectable neuronal autoanti­
Kiel/Lübeck, 24105 Kiel, Germany
bodies but without clinical relapse did not show this phenotype. Of
2 Department of Neurology, University-Hospital Schleswig Holstein,
note, a very high type I IFN signature at 3 weeks following HSE was
24105 Kiel, Germany
associated with uncontrolled viral encephalitis. Previously hypothe­
sized polymorphisms or mutations in TLR3/IFN-related genes—pre­
Correspondence to: Frank Leypoldt
disposing to HSE—were not detected in the present cohort. The
E-mail: Frank.Leypoldt@uksh.de
authors did, however, observe some additional risk of autoimmune
relapses conferred by the absence of a very common HLA class I
gene (HLA-A*02), an observation that further implicates CD8+
T-lymphocytes in the pathogenesis of post-HSVE-AE.
Funding
In summary, the discovery of post-HSVE-AE and its systematic F.L. is funded by the Bundesministerium für Bildung und Forschung
clinical characterization is of the utmost importance in the field BMBF (01GM1908A und 01GM2208), E-Rare Joint Transnational
Scientific Commentary
research support (ERA-Net, LE3064/2-1), Stiftung Pathobiochemie of
the German Society for Laboratory Medicine and HORIZON MSCA
2022 Doctoral Network 101119457 IgG4-TREAT and discloses speak­
er honoraria from Grifols, Teva, Biogen, Bayer, Roche, Novartis,
Fresenius, travel funding from Merck, Grifols and Bayer and serving
on advisory boards for Roche, Biogen and Alexion.
Competing interests
The authors report no competing interests.
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