1. Anti-NMDAR Encephalitis: The McGill Experience Dr. Amy Yu, R2 Neurology Dr. Suhail Al-Rukn, R5 Neurology February 12 th 2010

2. Case presentation ID: 29F presents to ER September 20 th 2009 ID: 29F presents to ER September 20 th 2009 RFC: Persistent headache, memory changes, and sensations of “déjà vu” RFC: Persistent headache, memory changes, and sensations of “déjà vu” PMHx: PMHx: Vaginal delivery July 6 th 2009 (11 weeks post-partum) Vaginal delivery July 6 th 2009 (11 weeks post-partum) Headache (CSF leak from epidural, Rx with caffeine pills) Headache (CSF leak from epidural, Rx with caffeine pills) Married for 3 years, denies EtOH/drugs/tobacco Married for 3 years, denies EtOH/drugs/tobacco Works as Program Coordinator at McGill Genetics Department Works as Program Coordinator at McGill Genetics Department No medications, NKDA No medications, NKDA

3. Case presentation – HPI 2-3 weeks difficulty dealing with the newborn, decreased sleep/energy/appetite 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 Patient reported 3/10 constant headache, bilateral fronto-occipital, worse in the morning, relieved with Tylenol, no N/V Denies hallucinations, infanticidal thoughts/actions 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?” During the H&P, patient appears anxious, repetitive questioning E.g. “Why did I loose my memory?” “Haven’t you asked me this before?”

4. Case presentation – Physical exam Vitals were within normal limits, afebrile Vitals were within normal limits, afebrile Unremarkable cardiopulmonary exam Unremarkable cardiopulmonary exam Neurological Neurological Mental status: Oriented to time, date, place, registration 3/3, recall 0/3 Mental status: Oriented to time, date, place, registration 3/3, recall 0/3 CN exam unremarkable CN exam unremarkable Motor: normal tone, 5/5 power, and 3+ reflexes symmetrically Motor: normal tone, 5/5 power, and 3+ reflexes symmetrically Sensory: normal to light touch and pinprick Sensory: normal to light touch and pinprick No limb dysmetria, normal gait No limb dysmetria, normal gait Initial labs were within normal limits (normal WBC) Initial labs were within normal limits (normal WBC) Plain CT head were unremarkable Plain CT head were unremarkable

5. Overview of initial course in JGH Sept 20: Admission to psychiatry Sept 20: Admission to psychiatry Post-partum depression with psychotic features Post-partum depression with psychotic features Started on antipsychotics and received ECT Started on antipsychotics and received ECT Catatonic state, minimal PO intake, family reports abnormal movements Catatonic state, minimal PO intake, family reports abnormal movements Sept 28: “Code blue” for status epilepticus and transfer to ICU Sept 28: “Code blue” for status epilepticus and transfer to ICU Continuous chewing movement around ETT Continuous chewing movement around ETT Athetotic movement of the hands and fingers Athetotic movement of the hands and fingers Variable ocular exam (ocular bobbing, convergence spasm) Variable ocular exam (ocular bobbing, convergence spasm)

6. Investigations MRI head with Gadolinium MRI head with Gadolinium 3 non-specific FLAIR hyperintensities (occipital horn of left lateral ventricle) subcentimetric, non-enhancing 3 non-specific FLAIR hyperintensities (occipital horn of left lateral ventricle) subcentimetric, non-enhancing Symmetric temporal lobes, no enhancement Symmetric temporal lobes, no enhancement MRV revealed no venous thrombosis MRV revealed no venous thrombosis Pineal region epidermoid cyst Pineal region epidermoid cyst CSF analysis CSF analysis WBC 47 (lymphocytes mainly) WBC 47 (lymphocytes mainly) Protein 0.42, Glucose 4.7 Protein 0.42, Glucose 4.7 Gram stain & culture negative Gram stain & culture negative HSV and enterovirus PCR negative HSV and enterovirus PCR negative Viral culture negative Viral culture negative

7. Differential diagnosis Infectious Infectious Covered broadly with antibiotics, antifungal, acyclovir Covered broadly with antibiotics, antifungal, acyclovir Viral, bacterial, fungal Viral, bacterial, fungal Metabolic Metabolic Hepatic, renal failure, deficiency Hepatic, renal failure, deficiency Autoimmune Autoimmune SLE, Hashimoto, CNS vasculitis SLE, Hashimoto, CNS vasculitis Paraneoplastic Paraneoplastic ? Neuroleptic malignant syndrome ? Neuroleptic malignant syndrome ? Substance abuse ? Substance abuse

8. Paraneoplastic workup CSF for paraneoplastic antibody panel negative (Mayo clinic laboratories, Rochester) CSF for paraneoplastic antibody panel negative (Mayo clinic laboratories, Rochester) 2 negative  -hCG 2 negative  -hCG CT abdomen and pelvis October 6 th 2009 CT abdomen and pelvis October 6 th 2009 Right ovarian teratoma Right ovarian teratoma Resection October 8 th 2009 Resection October 8 th 2009 CSF and Serum positive for anti-NMDA receptor antibodies (J Dalmau laboratory, Pennsylvania) CSF and Serum positive for anti-NMDA receptor antibodies (J Dalmau laboratory, Pennsylvania)

9. Aydiner A et al, J Neuro-Onc, 37:63-66, 1998 1 st report of PLE with immature ovarian teratoma 1 st 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 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 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 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) Immunologic studies with the known antibodies are negative (Dr. J Posner in NY)

10. 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 Identification of new antibodies in 4 cases of young women with psychiatric sxs, seizures,  LOC with ovarian teratoma Intense reactivity in hippocampal neurons Intense reactivity in hippocampal neurons Antigen seems to be located on the cell surface Antigen seems to be located on the cell surface Decrease serum antibody titers after neurological improvement Decrease serum antibody titers after neurological improvement

11. Teratoma associated encephalitis antibodies Immunolabeling at the plasma membrane and dendritic processes Immunolabeling at the plasma membrane and dendritic processes

12. Dalmau J et al, Ann Neurol, 61:25-36, 2007 Identification of the autoantigen from case series of 12 female patients Identification of the autoantigen from case series of 12 female patients Antibodies mainly reacted to subunits of NMDA receptor in the hippocampus and forebrain 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 Later studies suggestive that antibodies are more targeted against the more widely expressed NR1 subunit

13. Dalmau J et al, Lancet Neurol, 7:1091-98, 2008 Initial report of 12 patients in 2007 Initial report of 12 patients in 2007 Overall 159 patients identified Overall 159 patients identified Case series of 100 patients Case series of 100 patients

14. 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

15. Who were the controls? 250 individuals were used as controls 250 individuals were used as controls 50 limbic encephalitis (25 paraneoplastic, 25 idiopathic) 50 limbic encephalitis (25 paraneoplastic, 25 idiopathic) 25 Morvan’s syndrome (Voltage-gated potassium channel antibodies) 25 Morvan’s syndrome (Voltage-gated potassium channel antibodies) 20 Rasmussen’s encephalitis 20 Rasmussen’s encephalitis 10 viral encephalitis 10 viral encephalitis 25 chronic epilepsy of unknown cause 25 chronic epilepsy of unknown cause 50 other paraneoplastic disorders 50 other paraneoplastic disorders 50 cancer without neurological symptoms (10 ovarian teratoma) 50 cancer without neurological symptoms (10 ovarian teratoma) 20 blood donors, healthy individuals 20 blood donors, healthy individuals

16. A-NMDAR encephalitis Presentation Prodromal state Prodromal state H/A, low-grade fevers, viral-like illness H/A, low-grade fevers, viral-like illness Psychiatric sxs Psychiatric sxs Anxiety, agitation, bizarre bhvr, delusions, paranoia, hallucinations Anxiety, agitation, bizarre bhvr, delusions, paranoia, hallucinations Neurologic sxs Neurologic sxs STM loss, seizures STM loss, seizures

17. A-NMDAR encephalitis Progression

18. A-NMDAR encephalitis Investigations

19. Paraneoplastic? 59% neoplasm 59% neoplasm 1 patient had tumour dx prior to neuro sxs 1 patient had tumour dx prior to neuro sxs Median 8 wks Median 8 wks Range 1-380 wks Range 1-380 wks All teratoma contained nervous tissue & 25/25 positive for NMDA receptor expression All teratoma contained nervous tissue & 25/25 positive for NMDA receptor expression

20. Take home messages Anti-NMDA receptor encephalitis is not as rare as initially thought Anti-NMDA receptor encephalitis is not as rare as initially thought Young patients, mainly women Young patients, mainly women Prominent, rapidly progressive psychiatric manifestations Prominent, rapidly progressive psychiatric manifestations Normal or atypical MRI findings Normal or atypical MRI findings Consider paraneoplastic limbic encephalitis & search for the tumour Consider paraneoplastic limbic encephalitis & search for the tumour