Anti-NMDAR Encephalitis: The McGill Experience

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

2. 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

3. 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?”

4. 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

5. 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)

6. 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

7. 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

8. 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)

9. 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 acutepsychiatric 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)

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 • Intense reactivity in hippocampal neurons • Antigen seems to be located on the cell surface • Decrease serum antibody titers after neurological improvement

11. Teratoma associated encephalitis antibodies • 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 • 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

13. 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

14. Intense reactivity in rat brain hippocampus Surface immunolabelling of hippocampal neurons Reactivity with HEK293 transfected with NR1 and NR2B Anti-NMDAR encephalitis

15. 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

16. 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 Presentation

17. A-NMDAR encephalitis Progression

18. A-NMDAR encephalitis Investigations

19. 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 Paraneoplastic?

20. 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