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Case Report and Discussion of Anti-NMDAReceptor Encephalitis
Dr. Michel P. Lafleche1
1MD, University College Dublin, Department of Pediatric Neurology, The Hospital
for Sick Children (SickKids), University of Toronto
Corresponding Author:
Michel P. Lafleche
Email: [email protected]
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 11-year-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-Daspartic 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,
potassium-voltage 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 anti-NMDA-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 NG 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 twicemonthly 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, as seen in table 1, indicates that in 37% of
cases the cause remains unknown.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, as shown in table 2.6
Table 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%
Table 2. Etiology of Acute Childhood Encephalitis at the Hospital for Sick Kids,
1994-1995. (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-NMDAreceptor encephalitis becomes sensitized to the NR1-NR2 heteromers resulting
in a neuro-psychiatric syndrome.11 Diagnosis of anti-NMDA-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 antiNMDA-receptor encephalitis, as outlined in Table 3. 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 respiratorytract symptoms. This is followed by psychiatric symptoms, at which point patients
often present ending up in psychiatric care. Frequently seen symptoms include
bizarre behaviors, disorientation, anxiety, insomnia, grandiose delusions, hyperreligiosity, 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 3. Clinical syndrome consistent with NMDA encephalitis5, 11, 17, 18
Prodromal illness
Subfebrile temperatures, headache, vomiting, diarrhea,
(occurs in 70%)
fatigue, 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
Hyperthermia, tachycardia, hypersalivation, hypertension,
manifestations
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 anti-epileptic 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-NMDAreceptor 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 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 anti-NMDA-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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