Anti-NMDAR Anti-NMDAR Encephalitis:Encephalitis:The McGill The McGill ExperienceExperience

Dr. Amy Yu, R2 NeurologyDr. Amy Yu, R2 NeurologyDr. Suhail Al-Rukn, R5 Dr. Suhail Al-Rukn, R5

NeurologyNeurologyFebruary 12February 12thth 2010 2010

Case presentationCase presentation IDID: 29F presents to ER September 20: 29F presents to ER September 20thth 2009 2009 RFCRFC: Persistent headache, memory changes, : Persistent headache, memory changes,

and sensations of “dand sensations of “déjàéjà vu” vu” PMHxPMHx::

Vaginal delivery July 6Vaginal delivery July 6thth 2009 (11 weeks post- 2009 (11 weeks post-partum)partum) Headache (CSF leak from epidural, Rx with caffeine Headache (CSF leak from epidural, Rx with caffeine

pills)pills) Married for 3 years, denies EtOH/drugs/tobaccoMarried for 3 years, denies EtOH/drugs/tobacco Works as Program Coordinator at McGill Works as Program Coordinator at McGill

Genetics DepartmentGenetics Department No medications, NKDANo medications, NKDA

Case presentation – HPICase presentation – HPI 2-3 weeks difficulty dealing with the 2-3 weeks difficulty dealing with the

newborn, newborn, decreased decreased sleep/energy/appetitesleep/energy/appetite

Patient reported 3/10 constant Patient reported 3/10 constant headacheheadache, , bilateral fronto-occipital, worse in the bilateral fronto-occipital, worse in the morning, relieved with Tylenol, no N/Vmorning, relieved with Tylenol, no N/V

Denies hallucinations, infanticidal Denies hallucinations, infanticidal thoughts/actionsthoughts/actions

During the H&P, patient appears During the H&P, patient appears anxiousanxious, repetitive questioning E.g. , repetitive questioning E.g. “Why “Why did I loose my memory?” “Haven’t you did I loose my memory?” “Haven’t you asked me this before?”asked me this before?”

Case presentation – Case presentation – Physical examPhysical exam

Vitals were within normal limits, afebrileVitals were within normal limits, afebrile Unremarkable cardiopulmonary examUnremarkable cardiopulmonary exam NeurologicalNeurological

Mental status: Oriented to time, date, place, Mental status: Oriented to time, date, place, registration 3/3, recall 0/3registration 3/3, recall 0/3

CN exam unremarkableCN exam unremarkable Motor: normal tone, 5/5 power, and 3+ reflexes Motor: normal tone, 5/5 power, and 3+ reflexes

symmetricallysymmetrically Sensory: normal to light touch and pinprickSensory: normal to light touch and pinprick No limb dysmetria, normal gaitNo limb dysmetria, normal gait

Initial labs were within normal limits (normal Initial labs were within normal limits (normal WBC)WBC)

Plain CT head were unremarkablePlain CT head were unremarkable

Overview of initial course Overview of initial course in JGHin JGH

Sept 20Sept 20: : Admission to psychiatryAdmission to psychiatry Post-partum depression with psychotic Post-partum depression with psychotic

featuresfeatures Started on antipsychotics and received ECTStarted on antipsychotics and received ECT Catatonic state, minimal PO intake, family Catatonic state, minimal PO intake, family

reports abnormal movementsreports abnormal movements Sept 28Sept 28: “Code blue” for status : “Code blue” for status

epilepticus and transfer to ICUepilepticus and transfer to ICU Continuous chewing movement around ETTContinuous chewing movement around ETT Athetotic movement of the hands and Athetotic movement of the hands and

fingersfingers Variable ocular exam (ocular bobbing, Variable ocular exam (ocular bobbing,

convergence spasm)convergence spasm)

InvestigationsInvestigations MRI head with GadoliniumMRI head with Gadolinium

3 non-specific FLAIR hyperintensities 3 non-specific FLAIR hyperintensities (occipital horn of left lateral ventricle) (occipital horn of left lateral ventricle) subcentimetric, non-enhancingsubcentimetric, non-enhancing

Symmetric temporal lobes, no enhancementSymmetric temporal lobes, no enhancement MRV revealed no venous thrombosisMRV revealed no venous thrombosis Pineal region epidermoid cystPineal region epidermoid cyst

CSF analysisCSF analysis WBC 47 (lymphocytes mainly)WBC 47 (lymphocytes mainly) Protein 0.42, Glucose 4.7Protein 0.42, Glucose 4.7 Gram stain & culture negativeGram stain & culture negative HSV and enterovirus PCR negativeHSV and enterovirus PCR negative Viral culture negativeViral culture negative

Differential diagnosisDifferential diagnosis InfectiousInfectious

Covered broadly with antibiotics, Covered broadly with antibiotics, antifungal, acyclovirantifungal, acyclovir

Viral, bacterial, fungalViral, bacterial, fungal MetabolicMetabolic

Hepatic, renal failure, deficiencyHepatic, renal failure, deficiency AutoimmuneAutoimmune

SLE, Hashimoto, CNS vasculitisSLE, Hashimoto, CNS vasculitis ParaneoplasticParaneoplastic ? Neuroleptic malignant syndrome? Neuroleptic malignant syndrome ? Substance abuse? Substance abuse

Paraneoplastic workupParaneoplastic workup CSF for paraneoplastic antibody panel CSF for paraneoplastic antibody panel

negative (Mayo clinic laboratories, negative (Mayo clinic laboratories, Rochester)Rochester)

2 negative 2 negative -hCG-hCG CT abdomen and pelvis CT abdomen and pelvis October 6October 6thth 2009 2009

Right ovarian teratomaRight ovarian teratoma Resection October 8Resection October 8thth 2009 2009

CSF and SerumCSF and Serum positive for anti-NMDA positive for anti-NMDA receptor antibodiesreceptor antibodies (J Dalmau laboratory, (J Dalmau laboratory, Pennsylvania)Pennsylvania)

Aydiner A et al, J Neuro-Onc, 37:63-66, 1998Aydiner A et al, J Neuro-Onc, 37:63-66, 1998

11stst report of PLE with immature ovarian teratoma report of PLE with immature ovarian teratoma 39F39F presented 1 mth following resection of Rt presented 1 mth following resection of Rt

immature ovarian teratoma with immature ovarian teratoma with acuteacute psychiatric psychiatric depressiondepression, , delusionsdelusions of persecution, 2ry of persecution, 2ry generalized generalized seizureseizure

Workup unremarkable except for Workup unremarkable except for CSF CSF lymphocytic pleocytosislymphocytic pleocytosis and mildly elevated and mildly elevated proteinprotein

6mths after onset of sxs: dependant for ADL, 6mths after onset of sxs: dependant for ADL, mood disorder, gluttony and hypersexuality, mood disorder, gluttony and hypersexuality, Korsakoff-like amnestic stateKorsakoff-like amnestic state

Immunologic studies with the known antibodies Immunologic studies with the known antibodies are negative (Dr. J Posner in NY)are negative (Dr. J Posner in NY)

Vitaliani R et al, Ann Neurol, 58:594-604, 2005Vitaliani R et al, Ann Neurol, 58:594-604, 2005

Identification of Identification of new antibodiesnew antibodies in 4 in 4 cases of young women with cases of young women with psychiatric sxs, seizures, psychiatric sxs, seizures, LOC with LOC with ovarian teratomaovarian teratoma Intense reactivity in Intense reactivity in hippocampal hippocampal

neuronsneurons Antigen seems to be located on the Antigen seems to be located on the cell cell

surfacesurface Decrease serum antibody titers after Decrease serum antibody titers after

neurological improvementneurological improvement

Teratoma associated Teratoma associated encephalitis antibodiesencephalitis antibodies

Immunolabeling at the plasma Immunolabeling at the plasma membrane and dendritic processesmembrane and dendritic processes

Dalmau J et al, Ann Neurol, 61:25-36, 2007 Dalmau J et al, Ann Neurol, 61:25-36, 2007

Identification of the autoantigen from Identification of the autoantigen from case series of 12 female patientscase series of 12 female patients

Antibodies mainly reacted to subunits Antibodies mainly reacted to subunits of NMDA receptor in the of NMDA receptor in the hippocampushippocampus and and forebrainforebrain

Later studies suggestive that Later studies suggestive that antibodies are more targeted against antibodies are more targeted against the more widely expressed the more widely expressed NR1 NR1 subunitsubunit

Dalmau J et al, Lancet Neurol, 7:1091-98, 2008Dalmau J et al, Lancet Neurol, 7:1091-98, 2008

Initial report of 12 patients in 2007Initial report of 12 patients in 2007 Overall 159 patients identifiedOverall 159 patients identified Case series of 100 patientsCase series of 100 patients

Anti-NMDAR Anti-NMDAR encephalitisencephalitis

A)A) Intense reactivity Intense reactivity in rat brain in rat brain hippocampushippocampus

B)B) Surface Surface immunolabelling immunolabelling of hippocampal of hippocampal neuronsneurons

C)C) Reactivity with Reactivity with HEK293 HEK293 transfected with transfected with NR1 and NR2BNR1 and NR2B

Who were the controls?Who were the controls? 250 individuals were used as controls250 individuals were used as controls

50 limbic encephalitis (25 50 limbic encephalitis (25 paraneoplastic, 25 idiopathic)paraneoplastic, 25 idiopathic)

25 Morvan’s syndrome (Voltage-gated 25 Morvan’s syndrome (Voltage-gated potassium channel antibodies)potassium channel antibodies)

20 Rasmussen’s encephalitis20 Rasmussen’s encephalitis 10 viral encephalitis10 viral encephalitis 25 chronic epilepsy of unknown cause25 chronic epilepsy of unknown cause 50 other paraneoplastic disorders50 other paraneoplastic disorders 50 cancer without neurological 50 cancer without neurological

symptoms (10 ovarian teratoma)symptoms (10 ovarian teratoma) 20 blood donors, healthy individuals20 blood donors, healthy individuals

A-NMDAR encephalitis A-NMDAR encephalitis PresentationPresentation

Prodromal stateProdromal state H/A, low-grade H/A, low-grade

fevers, viral-like fevers, viral-like illnessillness

Psychiatric sxsPsychiatric sxs Anxiety, agitation, Anxiety, agitation,

bizarre bhvr, bizarre bhvr, delusions, paranoia, delusions, paranoia, hallucinationshallucinations

Neurologic sxsNeurologic sxs STM loss, seizuresSTM loss, seizures

A-NMDAR encephalitis A-NMDAR encephalitis ProgressionProgression

A-NMDAR encephalitis A-NMDAR encephalitis InvestigationsInvestigations

Paraneoplastic?Paraneoplastic?

59% neoplasm59% neoplasm 1 patient had 1 patient had

tumour dx prior to tumour dx prior to neuro sxsneuro sxs Median 8 wksMedian 8 wks Range 1-380 wksRange 1-380 wks

All teratoma All teratoma contained nervous contained nervous tissue & 25/25 tissue & 25/25 positive for NMDA positive for NMDA receptor expressionreceptor expression

Take home messagesTake home messages Anti-NMDA receptor encephalitis is Anti-NMDA receptor encephalitis is

not as rare as initially thoughtnot as rare as initially thought Young patients, mainly womenYoung patients, mainly women Prominent, rapidly progressive Prominent, rapidly progressive

psychiatric manifestationspsychiatric manifestations Normal or atypical MRI findingsNormal or atypical MRI findings Consider paraneoplastic limbic Consider paraneoplastic limbic

encephalitis & search for the tumourencephalitis & search for the tumour