Anti-NMDAR Encephalitis:

The McGill Experience

Dr. Amy Yu, R2 Neurology
Dr. Suhail Al-Rukn, R5 Neurology
February 12th 2010
 Case presentation
 ID: 29F presents to ER September 20th 2009
 RFC: Persistent headache, memory changes, and
sensations of “déjà vu”
 PMHx:
 Vaginal delivery July 6th 2009 (11 weeks post-partum)
 Headache (CSF leak from epidural, Rx with caffeine pills)
 Married for 3 years, denies EtOH/drugs/tobacco
 Works as Program Coordinator at McGill Genetics
Department
 No medications, NKDA
 Case presentation – HPI
 2-3 weeks difficulty dealing with the newborn,
decreased sleep/energy/appetite
 Patient reported 3/10 constant headache,
bilateral fronto-occipital, worse in the morning,
relieved with Tylenol, no N/V
 Denies hallucinations, infanticidal
thoughts/actions
 During the H&P, patient appears anxious,
repetitive questioning E.g. “Why did I loose my
memory?” “Haven’t you asked me this before?”
 Case presentation – Physical exam
 Vitals were within normal limits, afebrile
 Unremarkable cardiopulmonary exam
 Neurological
 Mental status: Oriented to time, date, place, registration 3/3,
recall 0/3
 CN exam unremarkable
 Motor: normal tone, 5/5 power, and 3+ reflexes
symmetrically
 Sensory: normal to light touch and pinprick
 No limb dysmetria, normal gait
 Initial labs were within normal limits (normal WBC)
 Plain CT head were unremarkable
Overview of initial course in JGH
 Sept 20: Admission to psychiatry
 Post-partum depression with psychotic features

 Started on antipsychotics and received ECT

 Catatonic state, minimal PO intake, family reports

abnormal movements
 Sept 28: “Code blue” for status epilepticus and
transfer to ICU
 Continuous chewing movement around ETT
 Athetotic movement of the hands and fingers

 Variable ocular exam (ocular bobbing, convergence

spasm)
 Investigations
 MRI head with Gadolinium
 3 non-specific FLAIR hyperintensities (occipital horn
of left lateral ventricle) subcentimetric, non-enhancing
 Symmetric temporal lobes, no enhancement
 MRV revealed no venous thrombosis
 Pineal region epidermoid cyst

 CSF analysis
 WBC 47 (lymphocytes mainly)
 Protein 0.42, Glucose 4.7
 Gram stain & culture negative
 HSV and enterovirus PCR negative
 Viral culture negative
 Differential diagnosis
 Infectious
 Covered broadly with antibiotics, antifungal,
acyclovir
 Viral, bacterial, fungal

 Metabolic
 Hepatic, renal failure, deficiency
 Autoimmune
 SLE, Hashimoto, CNS vasculitis
 Paraneoplastic
 ? Neuroleptic malignant syndrome
 ? Substance abuse
 Paraneoplastic workup
 CSF for paraneoplastic antibody panel negative
(Mayo clinic laboratories, Rochester)
 2 negative -hCG
 CT abdomen and pelvis October 6th 2009
 Right ovarian teratoma
 Resection October 8th 2009

 CSF and Serum positive for anti-NMDA

receptor antibodies (J Dalmau laboratory,
Pennsylvania)
Aydiner A et al, J Neuro-Onc, 37:63-66, 1998
 1st report of PLE with immature ovarian teratoma
 39F presented 1 mth following resection of Rt immature
ovarian teratoma with acute psychiatric depression,
delusions of persecution, 2ry generalized seizure
 Workup unremarkable except for CSF lymphocytic
pleocytosis and mildly elevated protein
 6mths after onset of sxs: dependant for ADL, mood
disorder, gluttony and hypersexuality, Korsakoff-like
amnestic state
 Immunologic studies with the known antibodies are
negative (Dr. J Posner in NY)
Vitaliani R et al, Ann Neurol, 58:594-604, 2005

 Identification of new antibodies in 4 cases of

young women with psychiatric sxs, seizures,
 LOC with ovarian teratoma
 Intensereactivity in hippocampal neurons
 Antigen seems to be located on the cell surface

 Decrease serum antibody titers after

neurological improvement
 Teratoma associated encephalitis
antibodies
 Immunolabeling at the plasma membrane and
dendritic processes
Dalmau J et al, Ann Neurol, 61:25-36, 2007

 Identification of the autoantigen from case

series of 12 female patients
 Antibodies mainly reacted to subunits of
NMDA receptor in the hippocampus and
forebrain
 Later studies suggestive that antibodies are more
targeted against the more widely expressed NR1
subunit
Dalmau J et al, Lancet Neurol, 7:1091-98, 2008

 Initial report of 12 patients in 2007

 Overall 159 patients identified
 Case series of 100 patients
 Anti-NMDAR encephalitis
A) Intense reactivity in
rat brain
hippocampus
B) Surface
immunolabelling of
hippocampal neurons
C) Reactivity with
HEK293 transfected
with NR1 and NR2B
 Who were the controls?
 250 individuals were used as controls
 50 limbic encephalitis (25 paraneoplastic, 25
idiopathic)
 25 Morvan’s syndrome (Voltage-gated potassium
channel antibodies)
 20 Rasmussen’s encephalitis
 10 viral encephalitis
 25 chronic epilepsy of unknown cause
 50 other paraneoplastic disorders
 50 cancer without neurological symptoms (10
ovarian teratoma)
 20 blood donors, healthy individuals
 A-NMDAR encephalitis Presentation
 Prodromal state
 H/A, low-grade fevers,
viral-like illness
 Psychiatric sxs
 Anxiety, agitation,
bizarre bhvr, delusions,
paranoia, hallucinations
 Neurologic sxs
 STM loss, seizures
A-NMDAR encephalitis Progression
A-NMDAR encephalitis Investigations
 Paraneoplastic?
 59% neoplasm
 1 patient had tumour dx
prior to neuro sxs
 Median 8 wks
 Range 1-380 wks
 All teratoma contained
nervous tissue & 25/25
positive for NMDA
receptor expression
 Take home messages
 Anti-NMDA receptor encephalitis is not as rare
as initially thought
 Young patients, mainly women
 Prominent, rapidly progressive psychiatric
manifestations
 Normal or atypical MRI findings
 Consider paraneoplastic limbic encephalitis &
search for the tumour