Journal of Neurology

https://doi.org/10.1007/s00415-019-09693-3

ORIGINAL COMMUNICATION

Possible N‑methyl‑D‑aspartate receptor antibody‑mediated

encephalitis in the setting of HIV cerebrospinal fluid escape
Patrick B. Moloney1 · Siobhan Hutchinson1 · Joseph Heskin2 · Fiona Mulcahy2 · Yvonne Langan1 · Niall P. Conlon3 ·
Benjamin P. Linas4 · Courtney Takahashi4 · Anna M. Cervantes‑Arslanian4

Received: 13 October 2019 / Revised: 20 December 2019 / Accepted: 28 December 2019

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Discordant elevations of cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) ribonucleic acid (RNA) in chroni-
cally treated patients known as ‘CSF escape’ may present as acute encephalitis. Infectious encephalitis caused by herpes
simplex virus (HSV) and other neurotropic viruses have been identified as potential triggers of anti-N-methyl-D-aspartate
receptor (NMDAR) encephalitis. Autoantibody-mediated encephalitis has been infrequently reported in HIV infected patients
and may mimic HIV encephalitis. We report two adults infected with HIV presenting with encephalopathy and seizures. Case
1 had a monophasic encephalopathy with detection of NMDAR antibodies in the context of HIV CSF escape. There was a
clinical response to immunotherapy and anti-retroviral therapy adjustment. Case 2 initially presented in non-convulsive status
epilepticus associated with HIV CSF escape. He responded to treatment with anti-epileptic drugs and anti-retroviral therapy
alteration, but had two further neurological relapses. NMDAR antibodies were detected during the relapses and a clinical
response was observed following treatment with immunotherapy. Clinicians should consider autoimmune encephalitis in
HIV infected patients presenting with encephalopathy and seizures, particularly in cases with concomitant HIV CSF escape.

Keywords  HIV · CSF escape · Anti-NMDA receptor encephalitis · Autoimmune encephalitis

Introduction (HAND) [1] and when symptomatic may mimic acute

Human immunodeficiency virus (HIV) central nervous sys-
tem (CNS) infection is generally controlled by combined
anti-retroviral therapy (cART). Independent replication of
HIV in the cerebrospinal fluid (CSF) compartment, despite
relative suppression of plasma HIV, known as ‘CSF escape’
has been linked to HIV-associated neurocognitive disorders
* Anna M. Cervantes‑Arslanian
ancervan@bu.edu
Patrick B. Moloney
patrickmoloney7@gmail.com
1
Department of Neurology and Neurophysiology, St. James’s
Hospital, Dublin, Ireland
2
Department of Genitourinary Medicine and Infectious
Diseases, St. James’s Hospital, Dublin, Ireland
3
Department of Immunology, St. James’s Hospital, Dublin,
Ireland
4
Departments of Neurology, Neurosurgery and Medicine
(Infectious Disease), Boston University Medical Center,
Boston, MA, USA
encephalitis [2]. Notably, autoantibody-mediated encepha-
litis has been infrequently reported in patients with HIV. Sin-
gle case reports have described anti-N-methyl-D-aspartate
receptor (NMDAR) encephalitis associated with CSF escape
[3] and HIV encephalitis [4].
Neurotropic viruses may trigger NMDAR encephalitis,
with herpes simplex virus (HSV) most frequently implicated.
Prospective data [5–7] and numerous case series [8, 9] dem-
onstrate the detection of NMDAR antibodies in patients with
relapsing neurological symptoms following HSV encepha-
litis. Furthermore, HSV IgG antibodies are more prevalent
in patients with NMDAR encephalitis compared to healthy
controls [10]. Conversely, a significant proportion of patients
with HSV encephalitis have NMDAR antibodies without
developing the typical syndrome of NMDAR encephalitis
[11]. Varicella zoster virus (VZV) [12], Epstein-Barr virus
(EBV) [13], and human herpes virus 6 (HHV6) [13] have
also been implicated in cases of NMDAR encephalitis. Here
we report two patients with HIV presenting with encepha-
lopathy and seizures in the context of HIV CSF escape with
associated NMDAR antibodies.

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Case 1

A 49-year-old Caucasian man with HIV presented with

progressive confusion, headache, and walking difficulties.
These symptoms were heralded by a seizure 1 month pre-
viously. He was treated with cART (emtricitabine, teno-
fovir, darunavir, and cobicistat) for 3 years, with good
viral control until quite recently. His nadir CD4 count
was 36 cells/mm 3. His last undetectable viral load was
recorded 10 months prior to this presentation and gradu-
ally increasing viraemia led to concerns regarding his
cART adherence.
At presentation, he was afebrile with stable vital
signs. Neurological examination revealed disorientation,
impaired attention, ataxia, and right-sided clonic activ-
ity involving his face and arm. His serum viral load was
916 copies/mL and CD4 count was 180 cells/mm3. Mag-
netic resonance (MR) imaging revealed extensive T2/fluid-
attenuated inversion recovery (FLAIR) signal abnormality
focused on the basal ganglia extending into the brainstem
(see Fig. 1a). CSF analysis revealed mononuclear pleo-
cytosis (160 cells/mm3) and raised protein (122 mg/dL).
Bacterial, viral, fungal, and mycobacterial testing were
negative. Cytology and flow cytometry were negative.
Electroencephalography (EEG) revealed severe encepha-
lopathy with triphasic complexes. HIV ribonucleic acid
(RNA) in CSF (42,365 copies/mL) was disproportionately
raised compared to serum, consistent with CSF escape.
NMDAR antibodies were detected in serum and CSF,
while testing for other antibodies associated with autoim-
mune encephalitis was negative (see Table 1).
He was treated with 3  days of intravenous methyl-
prednisolone followed by 10 days of intravenous immu-
noglobulin. Levetiracetam and lacosamide were initiated
to treat focal seizures. Dolutegravir was substituted for
darunavir and cobicistat to increase CNS penetration. A
computed tomography (CT) scan of chest, abdomen, and
pelvis showed no evidence of tumours. The encephalopa-
thy and seizures improved soon after commencing therapy.
His Montreal Cognitive Assessment (MOCA) score was
27/30, 8 weeks after the first seizure. Repeat CSF analy-
sis after treatment was normocellular. NMDAR antibod- Fig. 1  Magnetic resonance imaging for cases 1 and 2. MR axial
ies and HIV RNA were undetectable. Neuroimaging and FLAIR images for case 1 a demonstrate extensive signal abnormality
EEG normalized. focused on the basal ganglia extending into the brainstem with addi-
tional high signal in the sulci. MRI for case 2 during his first admis-
sion for HIV encephalitis due to CSF escape is shown at b. The MRI
demonstrates diffuse bilateral confluent slightly asymmetric white
matter FLAIR hyperintensity involving the periventricular white
Case 2 matter extending to subcortical regions. c Shows his MRI performed
during his first relapse of encephalitis, demonstrating new FLAIR
lesions within the left frontal and parietal lobes at which time he was
A 41-year-old African American man with HIV pre- diagnosed with NMDAR encephalitis. During his second relapse
sented with subacute decline in cognitive functioning, off immunotherapy, MRI d showed new FLAIR signal abnormality
characterized as confusion, change in personality, and within the left temporo-occipital white matter and within the right
corona radiata

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Journal of Neurology

Table 1  Serum and CSF results for cases 1 and 2

Case 1 Case 2 Case 2 Case 2
Admission 1 Admission 2 Admission 3

Serum HIV (copies/mL) 916 31  < 20  < 20

CD4 count & % (­ mm3) 180 (25%) 878 (22%) 1093 (24%) 948 (24%)
CSF HIV (copies/mL) 42,365 15,800 185  < 20
CSF white cells ­(mm3) 160 (mononuclear) 105 (mononuclear) 9 (mononuclear) 29 (mononuclear)
CSF protein (mg/dL) 122 129 48 65
CSF infection ­testinga Negative EBV (9142 copies/mL) Negative Negative
Serum NMDAR antibodies Positiveb Not tested Positivec Positivec
CSF NMDAR antibodies Positiveb Not tested Positivec Positivec
a
 CSF analysis included: bacterial culture; PCR testing for HSV-1, HSV-2, EBV, VZV, John Cunningham virus, cytomegalovirus, enterovirus,
parechovirus, and HHV6; cryptococcal antigen; mycobacterium culture and nucleic acid amplification test (GeneXpert)
b
 NMDAR antibodies were detected by indirect immunofluorescence technique (fixed cell) using a HEK transfected cell line. AMPA, GABAb,
LGI1, CASPR2, and DPPX antibodies were negative. (commercial: EUROIMMUN)
c
 NMDAR antibodies were detected by indirect immunofluorescence staining on a recombinant cell line expressing the antigen. (commercial:
Quest Diagnostics)

language difficulties. He was admitted with progressive
somnolence and myoclonic jerking of his right face and
body. He became comatose and was diagnosed with non-
convulsive status epilepticus. It had been 7 years since his
initial HIV diagnosis, at which time he was profoundly
immunosuppressed with a nadir CD4 count of 0 cells/mm3.
Since initiation of treatment, he had good viral control. At
admission, his serum viral load was 31 copies/mL and his
CD4 count was 878 cells/mm3 (see Table 1). He reported
compliance with cART (abacavir–lamivudine, atanazavir,
and ritonavir).
Neurological examination was notable for impaired atten-
tion, tangential speech, and perseveration. His speech was
fluent with several paraphasic errors and difficulty with
repetition. Motor examination showed increased tone in the
right arm with occasional myoclonic jerks seen in the right
hand and right lower face. Imaging initially showed sym-
metric T2/FLAIR signal abnormalities within the splenium
of the corpus callosum, bilateral occipital, and parietal lobes.
10 days later, the MR imaging showed progressive diffuse
bilateral confluent white matter hyperintensities involving
periventricular, internal and external capsules, and subcorti-
cal regions (see Fig. 1b). The brainstem and middle cerebel-
lar peduncles were also involved. CSF analysis showed a
lymphocytic pleocytosis (105 cell/mm3) and elevated pro-
tein (129 mm/dL). Bacterial, viral, fungal, and mycobacte-
rial testing was negative with the exception of EBV RNA
(9142 copies/mL). Cytology and flow cytometry were nega-
tive. HIV RNA in CSF was 15,800 copies/mL, consistent
with CSF escape (see Table 1).
Seizures were treated with levetiracetam, oxcarbaz-
epine, and valproic acid. The cART regimen was changed
to abacavir–lamivudine/raltegravir to increase CNS
penetration. He was discharged to a nursing home. MR
imaging 1 month later showed resolution of the signal
abnormalities. The patient’s cognitive functioning grad-
ually improved such that 1 year after this episode, the
patient was able to live independently.
One year later he was hospitalized with abnormal
movements and progressive somnolence. Neurological
examination revealed impaired attention, automatisms,
facial twitching, and tremor. EEG revealed no epilep-
tiform abnormalities. MR imaging demonstrated new
hyperintensities in the left frontal and temporal lobes (see
Fig. 1c). CSF analysis showed 9 cells/mm3 (91% lympho-
cytes). CSF HIV RNA was elevated at 185 copies/mL and
undetectable in serum. All testing for potential infection
was negative, including EBV. NMDAR antibodies were
detected in serum and CSF (see Table 1). A CT scan of
chest, abdomen, and pelvis revealed no tumours. He was
treated with pulse steroids and continued on prednisone
in the outpatient setting. Valproic acid was stopped due
to tremor, but he continued on oxcarbazepine and leveti-
racetam. He made gradual clinical improvements. Steroids
were stopped after 1 year due to complications (avascular
necrosis of the shoulder and hip).
Three months later he was admitted with generalized sei-
zures followed by mania. MR imaging showed new scattered
punctate abnormalities (see Fig. 1d). EEG was unremark-
able. CSF analysis showed 29 cells/mm3 (atypical lympho-
cytes noted) and CSF HIV RNA was undetectable. NMDAR
antibodies were detected again in the serum and CSF (see
Table 1). No infectious cause was identified. Steroids were
restarted and rituximab was added. He has made neurologic
improvement though he is unable to live independently
due to impulsivity. Since initiation of rituximab 18 months

13

ago, he has had no further relapses and his MOCA score
improved to 20, having scored 11 12 months ago.
Discussion
These two cases illustrate a possible association between
HIV CSF escape and NMDAR encephalitis. In the first
case, NMDAR antibodies were detected during the episode
of encephalopathy, with clinical improvement following
treatment with immunotherapy and alteration of the cART
regimen. While HIV encephalitis could account for the
encephalopathy, CSF pleocytosis and radiological appear-
ance in this case, the improvement with immunotherapy was
suggestive of a concomitant antibody-mediated process. In
the second case, we can only speculate about the presence of
NMDAR antibodies during the first hospital admission but
subsequent attacks of encephalopathy, seizures, and abnor-
mal movements were associated with NMDAR antibodies
and a clinical response to immunotherapy, in the absence
of significant HIV CSF escape or EBV viraemia. Limited
evidence suggests that the frequency of autoantibodies may
decline with anti-retroviral therapy [14]. This could hypo-
thetically explain how the patient’s clinical syndrome ini-
tially improved with reduction in CSF HIV load alone.
While both cases fulfil diagnostic criteria for definite
NMDAR encephalitis [15], there are caveats worth men-
tioning. HIV infection is associated with an increased inci-
dence of autoantibodies typically without corresponding
rheumatic manifestations [16]. NMDAR antibodies may
also be detected in patients with alternative autoimmune
disorders and neurodegenerative disease [17], although less
likely when both sera and CSF are tested [15]. In those with
alternative diagnoses, the antibodies are likely to be epiphe-
nomena and not pathogenic [17].
CSF escape as a trigger for NMDAR encephalitis is
plausible, particularly given the well-described association
between encephalitis caused by HSV and other neurotropic
viruses and NMDAR encephalitis. As has been hypothe-
sized in HSV encephalitis, virus-induced inflammation and
destruction may expose neuronal antigens in CSF escape,
initiating humoral autoimmunity [11]. Furthermore, the
NMDAR subunit 2A has been implicated in HIV-related
neurotoxicity and HAND through its interaction with the
viral transactivator, tat [18]. Further studies are warranted to
determine the frequency of NMDAR antibodies in patients
with HIV, particularly those with cognitive impairment.
Clinicians should consider autoimmune encephalitis in
HIV infected patients presenting with encephalopathy, sei-
zures, and movement disorders, particularly in cases with
concomitant CSF escape. Symptomatic HIV CSF escape
may be clinically indistinguishable from autoimmune
encephalitis and testing for NMDAR antibodies is advisable.
13
Journal of Neurology
Author contributions  PBM and AMCA contributed to the article con-
ception and design. All authors contributed to the interpretation of
the data. The first draft of the manuscript was written by PBM and all
authors commented on previous versions of the manuscript. All authors
read and approved the final manuscript.
Compliance with ethical standards 
Conflicts of interest  The authors declare that they have no conflict of
interest.
Ethical standards  The authors declare that they acted in accordance
with the ethical standards of the institutional research committee and
with the 1964 Helsinki declaration and its later amendments or com-
parable ethical standards.
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