Fahad Muhamed Shareef AT, MD
(Pediatrics),
1 Shaji Thomas John, MD (Pediatrics),
FIAP,
2 KA Salam, MD (Gen. Medicine), DM
(Neurology)
3
1Junior Consultant, Department
of Pediatrics, 2Chief of Pediatrics, 3Chief
of Neurological Sciences, Baby Memorial Hospital, Calicut,
Kerala
Address for Correspondence: Dr.
Shaji Thomas John, Chief of Pediatrics, Baby Memorial
Hospital, Calicut - 673011, Kerala, India. E- mail:
doctorshaji@hotmail.com
Keywords: autoimmune, encephalitis, ANTI-NMDAR,
psychiatric symptoms
Abstract
Background: The etiology of encephalitis
are numerous and extensive investigations for infectious
agents and other causes are often negative.
Case characteristics: Five year old girl
presented with abnormal / aggressive behaviour and seizures.
Investigations revealed Anti-NMDAR positive encephalitis.
Outcome: The child improved with
immunosuppressant; along with speech and behavioural therapy.
Message: In any child presenting with prominent
psychiatric symptoms, we should rule out a possibility of
autoimmune encephalitis.
Introduction
Auto immune encephalitis comprises an expanding group of
clinical syndromes that can occur at all ages. These disorders
are associated with antibodies against neuronal cell surface
proteins and synaptic receptors involved in synaptic
transmission, plasticity, or neuronal excitability [1].
Case report
Four year 8 months old female child presented with history of
abnormal behavior of about 1 month duration, comprising of
screaming and night mares, usually within 1-2 hours of sleep
associated with urinary incontinence. She was reluctant to
play with peers after the onset of symptoms and was lethargic
during daytime. The child later developed one episode of focal
seizures and intermittent gait abnormality (with circumduction
of right foot). She had history of neonatal hypoglycemia
(mother had gestational diabetes mellitus), managed in NICU
and resolved within 5 days. Developmental history was normal.
Examination findings were normal. MRI Brain was normal and EEG
showed bilateral epileptiform dysfunction, more on left side.
The child improved with antiepileptics and was sent home. One
week later the child presented with excessive talkativeness,
reduced communication and aggressive behavior. CSF study done
was normal. Further investigations revealed a positive
reaction to NMDA type of glutamate receptor antibody in serum.
USG and MRI pelvis did not show any obvious ovarian mass
lesions. The child was started on corticosteroids and
immunosuppressant, with which she improved. She had residual
speech impairment for which speech therapy was initiated and
on follow up after 1 month her speech and behaviour had
improved.
Discussion
Autoimmune encephalitis are mostly severe in nature and
potentially fatal, but has good response to immunotherapy [1].
The age of presentation ranges from less than 1 year to 70
years of age, but most frequently children or teenagers are
affected. Causes include idiopathic, post-infectious,
paraneoplastic, genetic predisposition and possible
immunodeficiency.
The clinical presentation is variable and may be mild with
only a few symptoms or mimick a psychiatric disorder with
delayed diagnosis of encephalitis. More complex symptomatology
may be present and it can also have a fulminant course with a
fatal outcome [2].
Anti-N-Methyl-D-Aspartate Receptor Encephalitis is a type of
autoimmune encephalitis, first described by Joseph Dalmau et
al (2007), characterized by antibodies targeting the NR1
subunit of NMDA receptor [1]. It is considered to be the
second most common cause of autoimmune encephalitis. In a
study from UK, 23% of patients were under 18 years of age [3].
Studies have established the cellular mechanisms through which
antibodies of patients with anti-NMDAR encephalitis cause a
specific, titer-dependent, and reversible loss of NMDARs [4].
Complement-mediated mechanisms do not appear to play a
substantial pathogenic role. In contrast, there are copious
infiltrates of antibody-secreting cells (plasma
cells/plasmablasts) in the CNS of these patients. The
demonstration of these cells provide an explanation for the
intrathecal synthesis of antibodies and has implications for
treatment [5]. Onset of anti-NMDAR encephalitis may occur
during an acute mycoplasma infection or following
Guillain-Barre Syndrome [6]. NMDAR antibodies of the
immunoglobulin (Ig) subtypes IgA, IgG, or IgM have been
reported in 13 of 44 patients (30%) in the course of herpes
simplex encephalitis, suggesting secondary autoimmune
mechanisms [7]. IgA-type NMDAR (NR1) may be a feature of
schizophrenia [8]. A paraneoplastic origin has also been
reported [9].
The disease evolves in stages and is characterized by a
prodromal stage with fever (phase 1). Later in phase 2, the
child manifests usually with prominent psychiatric symptoms
like anxiety, aggression, labile affect, mood variations,
memory deficit, catatonic features and sleep disturbances.
Within a few days or weeks, decreased level of consciousness,
seizures and movement disorders tend to develop. Later
autonomic symptoms develop but are usually rare in children
[1].
Investigations reveal abnormal brain MRI in approximately 35%
of cases, characterized by non specific cortical and
subcortical T2 FLAIR signal abnormalities. CSF shows moderate
lymphocytic pleocytosis (in 80% of cases) and occasionally
increased protein synthesis. EEG is abnormal in virtually all
patients, and usually shows focal or diffuse slow activity in
the delta and theta range along with epileptiform discharges.
A characteristic EEG pattern called "extreme delta brush"
occurs in 30% adults and in few children. The diagnosis is
established by demonstrating NMDAR antibodies in CSF or serum
[1].
Although anti-NMDAR encephalitis has a mortality rate of 7%,
80% of cases have substantial or full recovery. Recovery is
usually slow and may take upto 2 years. The last symptoms to
improve are social interactions, language and executive
functions. Relapses occur in 24% of cases [5].
The differential diagnosis include viral encephalitis,
neuroleptic malignant syndrome, acute psychosis and drug
abuse.
Treatment strategies include intravenous immunoglobulins,
corticosteroids, or plasmapheresis. However, because these
treatments fail in 50% cases, other modalities like rituximab,
cyclophosphamide have been found helpful.
Conclusion
Anti-NMDAR autoimmune encephalitis is one of the most common
causes of autoimmune encephalitis. With early detection and
immunotherapy, 80% of patients show full recovery.
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