Child Neurology: Parainfectious Anti-NMDAREncephalitis With Anti-MOG and Anti-AQP4Seropositivity in an Infant
Abstract
Overlap syndromes of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis and myelin
oligodendrocyte glycoprotein (MOG) or aquaporin-4 (AQP4)–mediated demyelination, ei-
ther concurrently or sequentially, have been increasingly recognized. We report a 7-month-old
infant who presented with 7 days of fever, seizures, irritability, and signs of meningeal irritation.
Initial workup suggested acute meningoencephalitis; therefore, the child was treated with
antibiotics, antivirals, empirical antitubercular therapy, and steroids. After transient improve-
ment, the child’
s condition deteriorated including the development of new-onset choreo-
ballistic-dystonic movements, encephalopathy, sleep disturbances, and dysautonomia. CSF
analysis revealed positivity for parvovirus B19 and Epstein-Barr virus, along with autoantibodies
against the NMDA receptor. In addition, serum testing was positive for anti-MOG and anti-
AQP4 antibodies. Despite prompt immunotherapy with methylprednisolone, intravenous
immunoglobulin, rituximab, and cyclophosphamide, the child showed only moderate im-
provement and later developed drug-refractory infantile epileptic spasm syndrome. The co-
existence of multiple autoantibodies for immune-mediated encephalitis in this case illustrates
potential links to underlying disease mechanisms as well as underscores the therapeutic chal-
lenges posed by triple seropositivity (anti-NMDA receptor, anti-MOG, and anti-AQP4 IgG
autoantibodies) in an infant.
Introduction
Overlap syndromes of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis and myelin
oligodendrocyte glycoprotein (MOG) or aquaporin-4 (AQP4)–mediated demyelination, ei-
ther concurrently or sequentially during the disease course, have been increasingly recog-
nized. 1,2 We report an infant with triple seropositivity for the NMDA receptor, MOG and
AQP4 antibodies postviral encephalitis.
Correspondence
Dr. Roy Chowdhury
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Supplementary Material
Case Description
A 7-month-old, typically developing and previously healthy male infant presented with a 7-day
history of fever, loose stools, generalized tonic-clonic seizures, and irritability for 2 days. There
was no history of recent travel or exposure to any sick contact. Neurologic examination revealed
irritability, positive meningeal signs, exaggerated deep tendon reflexes, and extensor plantar
responses. A clinical possibility of acute encephalitis syndrome was considered. The child was
started on ceftriaxone, acyclovir, levetiracetam, and other supportive care. CSF analysis showed
83 cells/uL (97% monocytes), protein 49 mg/dL, and normal glucose with negative gram stain
and culture. CSF Cartridge-based nucleic acid amplification test (CBNAAT) did not detect
Mycobacterium tuberculosis. Contrast-enhanced MRI of the brain showed confluent mixed
edematous changes in the bilateral fronto-parieto-temporal lobes, corpus callosum, basal
ganglia, right internal capsule, and central thalamus with diffusion restriction predominantly in Glossary
AQP4 = aquaporin-4; CBNAAT = Cartridge-based nucleic acid amplification test; EBV = Epstein-Barr virus; HSV = Herpes
simplex virus; MOG = myelin oligodendrocyte glycoprotein; MOGAD = MOG antibody-associated disease; NMDA =
N-methyl-d-aspartate; NMDAR = antibody to anti-N-methyl-d-aspartate receptor; NMDARE = NMDA receptor encephalitis;
NMOSD = neuromyelitis optica spectrum disorder.
the cortical regions and deep gray nuclei structures and lep-
tomeningeal enhancement (Figure 1, A–E). Considering the
endemicity of tuberculosis in India and low-moderate yield of
CSF CBNAAT, antitubercular therapy (ATT) and steroids
were initiated empirically, to which the child responded
partially.
However, within a week, his clinical condition deteriorated with
recurrent fever, extreme irritability, focal clonic seizures (in-
volving left eye and angle of the mouth), sleep disturbances and
rapid progression to a deeper encephalopathic state marked by
persistent inconsolable crying, inability to recognize his
parents, and not indicating hunger. Additional examination
findings included a hyperkinetic movement disorder charac-
terized by generalized choreo-ballistic movements, orolingual
stereotypy, and intermittent dystonia of the bilateral hands and
feet with dysautonomia (hyperpyrexia, hyperhidrosis, and facial
flushing) (Video 1, Segments A and B). Symptomatic treat-
ment with levetiracetam, tetrabenazine, pacitane, clonazepam,
and clonidine was initiated. Repeat CSF studies revealed mild
lymphocytic pleocytosis (27 cells/μL) and mildly raised
protein (53 mg/dL). Follow-up MRI at 3 weeks into the illness
demonstrated encephalomalacia; cortical thinning, and laminar
necrosis in the bilateral frontal and perisylvian regions; and
confluent white matter T2 hyperintensities predominantly in
the periventricular and deep white matter (Figure 1, F–J). CSF
viral multiplex PCR returned positive for both parvovirus B19
and Epstein-Barr virus (EBV). CSF autoimmune panel (anti-
bodies to NMDAR, AMPA 1/2 receptors, GABA-A/B recep-
tors, Caspr2, and LGI1) was sent. The child was empirically
initiated on methylprednisolone pulses (30 mg/kg/d for 5
days) and intravenous immunoglobulin (2 gm/kg over 5 days),
considering a provisional diagnosis of parainfectious autoim-
mune encephalitis. Eventually, CSF NMDA receptor antibody
by fixed cell-based (semiquantitative) assay came back strongly
positive. Notably, serum anti-AQP4 and anti-MOG IgG anti-
bodies were also strongly positive and positive, respectively,
using semiquantitative immunofluorescence assays. MRI of the
spine and optic nerves did not show any demyelinating
changes. Tumor screening and other autoimmune testing
(ESR, CRP, ANA profile, and anti-TPO antibodies) were also
negative. After 2 weeks of initial immunotherapy, the child showed
minimal improvement in irritability and chorea, although
dysautonomia had significantly remitted (Video 1, Segment
C). Rituximab was initiated with weekly doses of 375 mg/m 2
of body surface area for 4 weeks. ATT was stopped, and
neurorehabilitation with symptomatic care was continued. At
6-week postrituximab dosing, moderate improvement in
choreo-dystonic movements and encephalopathy was noted;
however, his clinical condition continued to decompensate
with any intercurrent febrile illness without any recovery of
developmental milestones. Given the partial response,
monthly intravenous cyclophosphamide pulses (500 mg/m 2 )
were started. After 2 doses of cyclophosphamide, the infant
showed dramatic improvement in movement disorders, better
sleep-wake regulation, and some developmental progress,
including social smile and recognition of the mother (Video 1,
Segment D). Unfortunately, the child subsequently de-
veloped epileptic spasms, with EEG revealing modified hyp-
sarrhythmia (Burden of Amplitudes and Epileptiform
Discharges score 4) (eFigure 1), which was managed with
vigabatrin and other antiseizure medications (topiramate and
clobazam) with partial response. Repeat CSF anti-NMDAR
antibodies 7 months into the illness remained weakly positive,
while glial antibodies (AQP4 and MOG) were negative. The
child is planned for a total 6-month course of cyclophos-
phamide therapy and ketogenic diet for refractory infantile
epileptic spasm syndrome, while he continues to show a slow
gain of developmental milestones (Video 1, Segment E)
(Figure 2 depicting the clinical course).
Discussion
Anti-NMDA receptor encephalitis (NMDARE), MOG
antibody-associated disease (MOGAD), and AQP4 antibody-
positive neuromyelitis optica spectrum disorder (NMOSD) are
all immune-mediated inflammatory disorders of the CNS-
driven by autoantibodies targeting extracellular antigens. Al-
though NMDARE is an autoimmune encephalitis caused by
IgG antibodies against the GluN1 subunit of the NMDA re-
ceptor, MOGAD is an autoimmune oligodendrocytopathy, and
AQP4+NMOSD is an immune-mediated astrocytopathy, both
of which are primarily demyelinating syndromes. 3 Overlap
syndromes with double seropositivity, such as NMDAR-IgG
and MOG-IgG or NMDAR-IgG and AQP4-IgG or MOG-IgG
and AQP4-IgG, have been rarely reported in the literature.
Concurrent or sequential demyelinating episodes were identi-
fied in 3.3% (23/691) of NMDARE cases. Among 11 patients
of the study cohort in whom NMDARE co-occurred with
clinicoradiologic features of demyelination, 5 were AQP4-
positive and 2 were MOG-positive, indicating a mixed phe-
notype with distinct immunopathogenic mechanisms. 1 In these
overlap syndromes, treatment responses and outcomes may
vary due to the complex interplay of various immune pathways,
such as reversible antibody-mediated effects on NMDAR,
AQP4 complement-mediated toxicity, or additional cytotoxic
T-cell effects on myelin, underscoring the need for an in-
dividualized therapeutic approach. 1
Neurology.org/N Another study reported that 4%–7.5% of patients with
NMDARE also had concurrent glial or neuronal surface
antibodies. A notable number of patients with coexistent glial
antibodies (MOG, AQP4, or GFAP) exhibited clinical fea-
tures solely attributable to NMDARE, suggesting that glial
antibody positivity was likely due to remote and/or inactive
disease. 2 This may explain our index case scenario, which
resembled that of parainfectious NMDARE, with the pres-
ence of other glial antibodies (MOG and AQP4) possibly
being an epiphenomenon. 4 These autoantibody associations,
whether indicative of true pathogenicity or merely a bystander
phenomenon, may indicate a more severe disease and warrant
consideration of long-term maintenance immunomodulation.
The presence of supratentorial brain lesions with diffusion
restriction and leptomeningeal enhancement on this
patient’
s initial MRI could be attributed to viral encephalitis
or partially resemble MOG-associated cortical encephalitis.
Although MOGAD typically occurs without any apparent
inciting illness, it has been linked to postinfectious de-
myelination following herpes simplex virus (HSV), Borrelia,
and EBV infections. 5 However, cerebral cortical encephalitis,
a phenotype of MOGAD distinct from ADEM, is more
frequently seen in older children, often presenting with fe-
ver, seizures, and lymphocytic pleocytosis, along with an
increased risk of remote symptomatic epilepsy. 6 The rapid
changes of gliosis and encephalomalacia within a 2-week
timeframe in this case suggest a more direct viral cytopathic
effect leading to extensive tissue necrosis, rather than the
inflammatory nature of MOGAD. In addition, the positive
CSF viral PCR and the repeat negative MOG but positive
NMDAR antibodies at follow-up may further support the
bystander effect of glial antibody positivity. Compared with
patients with isolated NMDAR antibodies, those with con-
current glial-Ab have been reported to experience frequent
prodromal symptoms, a shorter duration of symptoms at
diagnosis, and more frequent CSF pleocytosis- findings
which align with our case.
2
Triple autoantibody positivity in autoimmune neurologic
conditions has been previously described in adult case
reports: 2 with anti-NMDAR, anti-MOG, and anti-Caspr2
antibodies, and 1 with anti-NMDAR, anti-AQP4, and anti-
acetylcholine receptor antibodies. 4,7,8 In a large retrospective
cohort (1862 children and 13,736 adults), the dual positivity
rate of glial antibodies (MOG and AQP4) was only 0.06%,
and this was exclusively observed in adult women. 9 Thus,
triple seropositivity for NMDAR, MOG, and AQP4 anti-
bodies in a male infant is likely very rare.
NMDARE in infants is a rare occurrence, with the youngest
reported case being just 2 months old. 10 This age group poses
a unique therapeutic challenge due to immature host immune
responses, risks of withholding immunization, and poor re-
sponse to immunotherapy. 11,12 Despite receiving prompt and
intensive immunomodulation, the infant showed a staggered
clinical response, incomplete neurologic recovery and slow
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