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UNIVERSITY OF TORONTO MEDICAL JOURNAL
Case Report and Discussion of Anti-NMDA-Receptor
Encephalitis
Dr. Michel P. Lafleche,MD, University College Dublin, Department of Pediatric
Neurology, The Hospital for Sick Children (SickKids), University of Toronto
Corresponding Author:
Michel P. Lafleche
Email: michellafleche@gmail.com
ABSTRACT
Encephalitis is a term used to describe inflammation of the brain parenchyma caused by
any etiology.1 Current studies indicate that even after thorough investigation, the majority
of patients diagnosed with encephalitis have an unknown etiology.2 We present an 11year-old girl who presented acutely to hospital after suffering generalized tonic-clonic
seizures progressing into status epilepticus requiring admission to the Intensive Care Unit
(ICU). Upon extubation, the patient had a decreased level of consciousness, was mute,
lethargic, and displayed abnormal movements. After a prolonged stay in hospital for
treatment, she was discharged to a rehabilitation center. A clinical diagnosis of limbic
encephalitis was made, and a thorough work-up failed to reveal any specific etiology.
The clinical picture was most consistent with autoimmune encephalitis. The discussion
reviews the current literature on anti-N-Methyl-D-aspartic acid receptor encephalitis
(anti-NMDA-receptor encephalitis), a syndrome recently discovered in 2007 and an
increasingly diagnosed cause of limbic encephalitis in children.
KEYWORDS: anti-NMDA-receptor, encephalitis, meningo-encephalitis, potassiumvoltage gated channel, autoimmune encephalitis
INTRODUCTION
Encephalitis is a term used to describe inflammation of the brain parenchyma caused by
any etiology, manifested by neurologic dysfunction such as decreased level of
consciousness, changes in behavior or personality, altered mental status, speech or
movement disorders, and motor or sensory deficits.1 A clinical syndrome, encephalitis
was once categorized by symptomatology and clinical progression due to the difficulty of
distinguishing and confirming the many etiologies.3 There has been a recent increase in
knowledge of the etiologies that can cause encephalitis, such as the discovery of antiNMDA-receptor encephalitis in 2007.4 With new diagnostic tests available and the
introduction of the measles and mumps vaccination programs in the last few decades, the
epidemiology of encephalitis has been changing. Even so, current studies indicate that a
large proportion of etiological causes of encephalitis are still unknown.2 It is important to
establish and differentiate the etiology quickly in order to provide appropriate and
specific treatment to maximize recovery.2, 5 Here, we present a case of an 11-year-old girl
admitted to hospital following status epilepticus and a prolonged hospital stay for
treatment of encephalitis.
CASE REPORT
The patient is an 11-year-old girl with an acute presentation of status epilepticus
requiring admission into ICU. She had a background history of a decrease in cognitive
capabilities, increase in introversion, and increasing fatigue over a three-month period.
Previously an 'A' grade student, the patient’s marks had been steadily decreasing, and the
patient had been having increasing difficulty with mathematical calculations.
On the day of admission, the patient had been skating. She fell three times, became limp,
and had tonic-clonic seizures leading to status epilepticus. She was brought by ambulance
to hospital where she was stabilized, requiring intubation. She was then transferred to the
Hospital for Sick Children, where the patient was admitted to the ICU for three days. The
patient was febrile for the first day, and was commenced on a regimen of ceftriaxone,
vancomycin and acyclovir, but an infectious etiology was thought to be quite unlikely
due to the subacute nature of the patient’s illness. The patient was investigated using the
encephalitic registry, with serum and CSF samples sent for herpes simplex virus (HSV),
cytomegalovirus (CMV), epstein-barr virus (EBV), varicella zoster virus (VZV), human
herpesvirus 6, human herpesvirus 7, respiratory viruses, measles, and West Nile, all of
which were negative. Inflammatory markers were tested and C3, C4, anti-DNA,
antinuclear antibody, anti-cardiolipin, anti-ro and anti-la were all negative. However, C
reactive protein (CRP) was above normal in several measurements. Lumbar puncture was
normal except for cerebrospinal fluid (CSF) protein, which was elevated at 0.58 g/L. CSF
and serum were sent for anti-NMDA-receptor testing. Metabolic tests were performed
including liver function tests, amino acids, organic acids, blood and CSF lactate, and
venous blood gas, which were all normal. Electroencephalography (EEG) showed
bilateral, independently occurring periodic epileptiform discharges (BiPLEDS) occurring
on the left greater than the right hemisphere and showed generalized slowing consistent
with encephalopathy. BiPLEDS are uncommon EEG findings, characterized by focal or
lateralized periodic spike, spike-wave, or sharp wave complexes throughout all or most of
the recording.24 They are usually transiently found during acute cerebral pathology, the
most common being acute ischemic stroke, followed by malignancy. CNS pathology
leading to encephalitis, such as in this case, is the third leading cause.24 The patient’s CT
was noncontributory, and the MRI showed bilateral and symmetric high signal and mild
enlargement of the amygdala and hippocampi, consistent with edema and inflammation.
There was no lateral extension to the adjacent temporal lobes or signs of hemorrhage or
necrosis. Our working diagnosis was anti-NMDA-receptor encephalitis, supported by the
clinical features and progression, EEG, and MRI scan. An abdominal ultrasound was
ordered looking for an ovarian teratoma, but it revealed normal ovaries with no masses or
focal lesions.
Upon discharge to the ward, the patient had decreased level of consciousness, was mute,
lethargic, and displayed abnormal movements such as elaborate movements of the arms
and legs. The patient was commenced on valproic acid for seizure prevention and a
methylprednisolone pulse lasting for four days, at which point the patient was treated
with tapering doses of oral prednisolone. The patient was commenced on nasogastric tube
(NGT) feeding and underwent physical rehabilitation. She slowly regained cognitive
function and functional behaviours. Nine days after admission, the patient was able to
respond to simple questions and was oriented to time and place with prompting.
However, at this time, the patient had a second episode of status epilepticus resulting in
severe respiratory distress and readmission to ICU. Methylprednisolone was
recommenced and phenytoin was given in addition to valproic acid for seizure control.
The patient was extubated and discharged back to the ward after an additional three days
in the ICU. The patient again had a severe decrease in cognitive and behavioural abilities,
and returned to being mute with new onset agitation. Repeat MRI showed interval
improvement of hippocampal swelling with atrophy of the anterior part of both
hippocampi. Upon extubation, the patient was given two doses of intravenous
immunoglobulin (IVIG) over the next two days and then commenced on a twice-monthly
regimen. The patient was given risperidone to treat agitation, and tapering doses of
prednisolone was again recommenced. The patient’s encephalopathy gradually improved.
The serum and CSF NMDA antibody tests returned as negative at this point, but
immunomodulation treatment was continued with clinical improvement. The patient was
discharged to a rehabilitation center.
DISCUSSION
This patients clinical and laboratory features were most consistent with an autoimmune
encephalitis, such as anti-NMDA-receptor encephalitis. Alternative diagnoses such as
infections, vasculitidies, or toxic-metabolic causes were considered, but the clinical
features and laboratory investigations did not support them. Other autoimmune antibodies
were not tested in this case. The patient improved with immunomodulation therapy,
giving support to there being an autoimmune inflammatory component to the etiology of
this patient’s encephalitis.
EPIDEMIOLOGY
Although diagnostics have improved substantially in recent years, a large proportion of
etiologies causing encephalitis remain unknown. A study in England of 203 adult patients
with encephalitis indicated that in 37% of cases the cause remains unknown (Figure 1).2
The etiologies are slightly different in children, with the California encephalitis registry
and studies in Helsinki and Sweden all demonstrating that M. pneumonia and enterovirus
are more common, with HSV being relatively rarer.7, 8 The encephalitis registry at Sick
Kids indicates that 44% of encephalitis results from unknown etiologies(Figure 2).6
Figure 1. Etiology of Encephalitis in Adults2
Unknown
Herpes Simplex Virus
Varicella zoster virus
mycobacterium tuberculosis
Acute disseminated encephalomyelitis
Antibody-associated eoncephalitis
Other
9%
11%
37%
14%
5%
5%
19%
Figure 2. Etiology of Acute Childhood Encephalitis at the Hospital for Sick Kids, 19941995. (N=50)6
Unknown
Mycoplasma pneumonia
M. pneumoniae and enterovirus
herpes simplex virus
epstein-barr virus
human herpes-virus 6
HHV-6 and influenza virus type A
influenza viruz type A
Powassan virus
2% 2%2% 2%2%
8%
42%
22%
18%
PATHOGENESIS
Anti-NMDA-receptor encephalitis is a subset of limbic encephalitis, referring to
inflammation localized to the limbic structures including the hippocampus, amygdala,
anterior thalamic nuclei, septum, limbic cortex and fornix. The NMDA receptor is a
ligand-cation channel with a role in synaptic plasticity and transmission. Overactivity of
these receptors has been a proposed mechanism for epilepsy and dementia.9, 10 The
immune system in patients with anti-NMDA-receptor encephalitis becomes sensitized to
the NR1-NR2 heteromers resulting in a neuro-psychiatric syndrome.11 Diagnosis of antiNMDA-receptor encephalitis is confirmed by the detection of antibodies to the NR1
subunit in the serum or CSF.12 There have also been recent discoveries of antibodies to
other synaptic receptors thought to be the cause of encephalitides such as antibodies
against the AMPA receptor13, amino-butyric acid-B receptor14, and leucine-rich, gliomainactivated 1 (previously thought to be caused by antibodies to voltage-gated potassium
channels).5, 15, 16
CLINICAL FEATURES
This patient’s clinical progression resembled those patients diagnosed with anti-NMDAreceptor encephalitis (Table 1). The literature indicates that 70% of patients commonly
have a non-specific flu-like prodrome of subfebrile temperatures, headache, vomiting,
diarrhea, fatigue, and/or upper respiratory-tract symptoms. This is followed by
psychiatric symptoms, at which point patients often require psychiatric care. Frequently
seen symptoms include bizarre behaviors, disorientation, anxiety, insomnia, grandiose
delusions, hyper-religiosity, memory deficits and mania.17, 18, 6 Symptoms of social
withdrawal are sometimes seen.11 Other patients, especially younger patients, can present
with headache, seizures, status epilepticus, lethargy, personality or behavioral changes,
and verbal reduction or mutism as seen with the patient described.5, 18 Acutely, these
patients are often managed in the ICU.2, 5 Of note, seizures in the absence of fever are
most consistent with antibody-associated encephalitis.2 This initial phase is followed by
decreased responsiveness with abnormal movements including choreoathetosis,
dyskinesias, oculogyric crisis, opisthotonic posturing and elaborate movements of the
arms and legs.5 Complex seizures tend to occur at the beginning of the disease and
decrease as the disease evolves. However, as with this patient, they may resurface at any
time.19 Autonomic instability such as hyperthermia, tachycardia, hypersalivation,
hypertension, bradycardia, hypotension, urinary incontinence, and erectile dysfunction
have also been described as the disease progresses.5
Table 1. Clinical syndrome consistent with NMDA encephalitis5, 11, 17, 18
Prodromal illness (occurs
Subfebrile temperatures, headache, vomiting, diarrhea, fatigue,
in 70%)
and/or upper respiratory symptoms
Psychiatric symptoms
Bizzare behaviors, personality change, disorientation, anxiety,
insomnia, grandiose delusions, memory deficits, social
withdrawal and mania
Neurological symptoms
Headache, seizure, status epilepticus, autonomic instability,
lethargy, verbal reduction, mutism
Movement disorders
Oro-lingual-facial dyskinesias, choreoathetosis, oculogyric
crisis, dystonia, rigidity, and opisthotonic postures
Autonomic manifestations
Hyperthermia, tachycardia, hypersalivation, hypertension,
bradycardia, hypotension, urinary incontinence, and erectile
dysfunction
LABORATORY FINDINGS
Lumbar puncture in patients with NMDA encephalitis often shows a moderate
lymphocytic pleocytosis, with normal or mildly increased CSF protein concentrations and
often normal CSF glucose levels.5 EEG is often abnormal, showing non-specific, slow
and disorganized activity.17 The pattern of EEG does not tend to change with antiepileptic treatment.17 In 50% of patients, brain MRI is unremarkable. In the other 50% of
patients, T2 or FLAIR hyperintensity can be seen most commonly in the hippocampi.
Hyperintensity can also sometimes be seen in the frontobasal and insular regions, basal
ganglia, cerebellar or cerebral cortices, brainstem, and infrequently in the spinal cord.11
Some reports have shown brain atrophy in those patients with refractory seizures or those
who did not recover or died.11
ASSOCIATION WITH TUMOURS
The association between neurologic disorders and tumours has long been known, being
discovered in the late 1960’s.4 Paraneoplastic syndromes resulting in limbic encephalitis
have been associated with many different cancers including small cell lung cancer
(SCLC), non-small cell lung cancer (non-SCLC), testicular germ-cell tumours, breast
cancer, thymoma, and ovarian teratoma.20 Anti-NMDA-receptor encephalitis was
originally described in case studies of twelve individuals in 2007, 80% of whom were
female, and 59% of them had a tumour, most commonly an ovarian teratoma.11 More
recent studies with a greater number of patients have shown the disease occurs more
frequently than originally thought in males, and sometimes without neoplastic origins.
Ovarian teratomas are actually only associated with 20% of cases. Histological analysis
shows that the tumours express NMDA receptors, stimulating immune system activation.
Other triggers are potentially involved, since many patients who develop the disease are
never found to have a tumour on further diagnostic testing.11 The presence of a tumour is
very important prognostically, because removal and cure has been associated with
improved outcomes.
TREATMENT
Treating patients with NMDA encephalitis is a dynamic area with ongoing research. No
standard of care currently exists for patients with NMDA encephalitis. Evidence supports
first-line therapy with high dose corticosteroids and IVIG, given simultaneously in some
centers.5, 21 Plasma exchange can also be used instead of IVIG, but is used less frequently
due to the invasive nature of administering this treatment. It is important to investigate
for the presence of tumours, since removal and cure will allow for a more complete and
rapid return to baseline.5, 11, 17, 18, 21, 22 In those cases where no tumour is found, more
aggressive immunotherapies are often required because these patients outcomes are
usually worse. Concurrent symptomatic management of seizures and psychiatric
symptoms with anti-epileptic drugs and anti-psychotics can also be used. Second line
immunomodulation therapy includes rituximab and cyclophosphamide, both having been
associated with benefit.5, 17, 18, 23 Second line treatment is increasingly used early in the
course of treatment because first line therapy often shows a slow or incomplete response.
CONCLUSIONS
Encephalitis is a clinical syndrome caused by many etiologies that, for the majority, have
not been fully elucidated. In children, it can be a devastating illness for the patient and
family. The clinical symptoms and progression of this patient’s illness were very similar
to those with anti-NMDA-receptor encephalitis. However, she was found to be antiNMDA-receptor antibody negative, and no other cause was found. Encephalitis,
especially auto-immune causes, is currently a very active field of research due to the
recent discovery of previously unknown etiologies, the possibility of discovering
additional etiologies, and our improving ability to understand and treat them.
ACKNOWLEDGEMENTS
I would like to thank the entire neurology department at Sick Kids for the great
experience. A special thanks to Dr. Jiri Vajsar, Dr. Rand Askalan, and Dr. Yair Sadaka
CONFLICT OF INTEREST
None declared
Parental informed consent was obtained.
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