ELECTRONIC SUBMISSION
FOR CONSIDERATION IN THE
UNIVERSITY OF TORONTO MEDICAL JOURNAL
Case Report and Discussion of Anti-NMDAReceptor Encephalitis
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 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
for rehabilitation. 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-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 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 effective 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 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,
including mycoplasma, HSV, CMV, EBV, VZV, HHV6, HHV7, respiratory viruses,
measles, and West Nile, all of which were negative. Inflammatory markers were
tested and C3, C4, anti-DNA, ANA, anti-cardiolipin, anti-ro and anti-la were all
negative. CRP was high in several measurements, and lumbar puncture was
normal except for a CSF protein was elevated at 0.58 g/L. CSF and serum were
sent for anti-NMDA-receptor testing. Metabolic tests were performed including
LFTs, amino acids, organic acids, blood and CSF lactate, and VBG, which were
all normal. EEG showed BiPLEDS occurring on the left greater than the right
hemisphere and generalized slowing in keeping with encephalopathy. The 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, 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 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 IVIG over the next two days and then commenced on a twicemonthly regimen. The patient was given risperidone to treat the agitation, and
tapering doses of prednisolone was again recommenced. The patient’s
encephalopathy gradually improved and she was discharged to rehabilitation.
DISCUSSION
EPIDEMIOLOGY
A study in England of 203 adult patients with encephalitis indicated that in 37%
the cause was unknown, 42% had infectious causes including 19% HSV, 5%
VZV, and 5% mycobacterium tuberculosis, 14% had acute disseminated
encephalomyelitis (ADEM) and 9% of patients had antibody-associated
encephalitis.2 The etiologies are slightly different in children. The encephalitis
registry at Sick Kids indicates that 44% of encephalitis results from unknown
etiologies.6 The California encephalitis registry and studies in Helsinki and
Sweden all demonstrate that M. pneumonia and enterovirus are more common
causes in children, with HSV being relatively rarer.7, 8
PATHOGENESIS
Anti-NMDA-receptor encephalitis is a subset of encephalitis, a 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 In these patients, the immune system
is 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 receptor 13,
y-amino-butyric acid-B receptor14, and leucine-rich, glioma-inactivated 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. The literature indicates that 70% of patients
commonly have a non-specific flu-like prodrome of subfebrile temperatures,
headache, vomiting, diarrhea, fatigue, or upper respiratory-tract 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, 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 and 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
LABORATORY FINDINGS
Lumbar puncture in these patients often shows a moderate lymphocytic
pleocytosis, with normal or mildly increased protein concentrations with CSF to
serum glucose levels often normal.5 EEG is often abnormal, showing nonspecific, 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
cortex, 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 who died.11
ASSOCIATION WITH TUMORS
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
SCLC, 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 greater number of patients have shown the disease occurs more
frequently than originally thought in males, and without neoplastic origins. Recent
studies have also shown ovarian teratomas are actually only associated with
20% of cases. Histological analysis shows that the tumours express NMDA
receptors, allowing immune system activation. Other triggers are also thought to
be involved, since many patients developing the disease have no tumour found
on diagnostic testing.11 The presence of a tumour is very important prognostically
because removal and cure has been associated with better outcomes.
TREATMENT
Current evidence supports first-line therapy with high dose corticosteroids and
intravenous immunoglobulin (IVIg), given simultaneously in some centers.
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
better outcome.5, 11, 17, 18, 21, 22 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
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 actually found to be anti-NMDA-receptor antibody negative,
and no other cause was found. This is currently a very active field of research
due to the recent discovery of previously unknown etiologies, the possibility of
discovering more, and our better 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.
REFERENCES
1.
Cherry JD SW, Bronsetine DE. Encephalitis and meningoencephalitis. In:
Feigin and Cherry's Textbook of Pediatric Infectious Diseases. 6th edition ed.
Philadelphia: Saunders; 2009.
2.
Granerod J, Ambrose HE, Davies NW, Clewley JP, Walsh AL, Morgan D,
et al. Causes of encephalitis and differences in their clinical presentations in
England: a multicentre, population-based prospective study. Lancet Infect Dis.
2010 Dec;10(12):835-44.
3.
Whitley RJ. Viral encephalitis. N Engl J Med. 1990 Jul 26;323(4):242-50.
4.
Corsellis JA, Goldberg GJ, Norton AR. "Limbic encephalitis" and its
association with carcinoma. Brain. 1968 Sep;91(3):481-96.
5.
Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, BaliceGordon R. Clinical experience and laboratory investigations in patients with antiNMDAR encephalitis. Lancet Neurol. 2011 Jan;10(1):63-74.
6.
Kolski H, Ford-Jones EL, Richardson S, Petric M, Nelson S, Jamieson F,
et al. Etiology of acute childhood encephalitis at The Hospital for Sick Children,
Toronto, 1994-1995. Clin Infect Dis. 1998 Feb;26(2):398-409.
7.
Koskiniemi M, Rautonen J, Lehtokoski-Lehtiniemi E, Vaheri A.
Epidemiology of encephalitis in children: a 20-year survey. Ann Neurol. 1991
May;29(5):492-7.
8.
Fowler A, Stodberg T, Eriksson M, Wickstrom R. Childhood encephalitis in
Sweden: etiology, clinical presentation and outcome. Eur J Paediatr Neurol. 2008
Nov;12(6):484-90.
9.
Lau CG, Zukin RS. NMDA receptor trafficking in synaptic plasticity and
neuropsychiatric disorders. Nat Rev Neurosci. 2007 Jun;8(6):413-26.
10.
Waxman EA, Lynch DR. N-methyl-D-aspartate receptor subtypes: multiple
roles in excitotoxicity and neurological disease. Neuroscientist. 2005
Feb;11(1):37-49.
11.
Dalmau J, Tuzun E, Wu HY, Masjuan J, Rossi JE, Voloschin A, et al.
Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with
ovarian teratoma. Ann Neurol. 2007 Jan;61(1):25-36.
12.
Pruss H, Dalmau J, Harms L, Holtje M, Ahnert-Hilger G, Borowski K, et al.
Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown
origin. Neurology. 2010 Nov 9;75(19):1735-9.
13.
Lai M, Hughes EG, Peng X, Zhou L, Gleichman AJ, Shu H, et al. AMPA
receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann
Neurol. 2009 Apr;65(4):424-34.
14.
Lancaster E, Lai M, Peng X, Hughes E, Constantinescu R, Raizer J, et al.
Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case
series and characterisation of the antigen. Lancet Neurol. 2010 Jan;9(1):67-76.
15.
Lai M, Huijbers MG, Lancaster E, Graus F, Bataller L, Balice-Gordon R, et
al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed
to potassium channels: a case series. Lancet Neurol. 2010 Aug;9(8):776-85.
16.
Vincent A, Buckley C, Schott JM, Baker I, Dewar BK, Detert N, et al.
Potassium channel antibody-associated encephalopathy: a potentially
immunotherapy-responsive form of limbic encephalitis. Brain. [Case Reports
Research Support, Non-U.S. Gov't]. 2004 Mar;127(Pt 3):701-12.
17.
Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, et al.
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of
antibodies. Lancet Neurol. [Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't]. 2008 Dec;7(12):1091-8.
18.
Florance NR, Davis RL, Lam C, Szperka C, Zhou L, Ahmad S, et al. AntiN-methyl-D-aspartate receptor (NMDAR) encephalitis in children and
adolescents. Ann Neurol. 2009 Jul;66(1):11-8.
19.
Bayreuther C, Bourg V, Dellamonica J, Borg M, Bernardin G, Thomas P.
Complex partial status epilepticus revealing anti-NMDA receptor encephalitis.
Epileptic Disord. 2009 Sep;11(3):261-5.
20.
Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J.
Paraneoplastic limbic encephalitis: neurological symptoms, immunological
findings and tumour association in 50 patients. Brain. [Clinical Trial
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.]. 2000 Jul;123 ( Pt 7):1481-94.
21.
Seki M, Suzuki S, Iizuka T, Shimizu T, Nihei Y, Suzuki N, et al.
Neurological response to early removal of ovarian teratoma in anti-NMDAR
encephalitis. J Neurol Neurosurg Psychiatry. 2008 Mar;79(3):324-6.
22.
Smith JH, Dhamija R, Moseley BD, Sandroni P, Lucchinetti CF, Lennon
VA, et al. N-methyl-D-aspartate receptor autoimmune encephalitis presenting
with opsoclonus-myoclonus: treatment response to plasmapheresis. Arch Neurol.
2011 Aug;68(8):1069-72
23.
Ishiura H, Matsuda S, Higashihara M, Hasegawa M, Hida A, Hanajima R,
et al. Response of anti-NMDA receptor encephalitis without tumor to
immunotherapy including rituximab. Neurology. 2008 Dec 2;71(23):1921-3.