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Anti-NMDA Receptor Encephalitis

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on 10 April 2014

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Transcript of Anti-NMDA Receptor Encephalitis

Anti-NMDA Receptor Encephalitis
Pathophysiology cont.
Ultimately auto-antibodies with cross reactivity to receptors are produced.

Often the patient has a teratoma which is an encapsulated tumor with more than one germ cell layer.

The acute inflammatory response in those with a tumor or may result in breakdown of BBB causing passive diffusion of the antibodies into the brain.

Increase in blood pressure may sometimes cause extravasation into CSF.

Some patients have intact BBB and no teratomas but high conc. of antibodies in intrathecal space(Dalmau et. al).
Epidemiology
Accounts for around 1% of encephalitides of unknown etiology.

Review done in Lancet(Dalmau et. al) of 100 cases showed 91 of 100 cases were women with a mean age of 23.

58 had a tumor predominantly an ovarian teratoma.

Showed Asian and African populations are more likely to get conditon.

Males may have testicular germ cell tumor, mediatinal teratomas or Hodgkin's Lymphoma.

only 5 cases were > 45 years of age.
Labs and Tests
NMDA receptor
N-methyl-D-aspartate receptor.
Critical for synaptic plasticity, learning, and memory.
It is both ligand gated and voltage dependent.
It requires co-activation by both glutamate and either D-serine or glycine.
Acts via calcium flux through receptor.
Rituximab
Cardiac arrest

Cytokine Release Syndrome

Tumor Lysis Syndrome

Progressive Multifocal Leukoencephalopathy

Nephrotoxicity

Myelosuppression
Cyclophosphamide
An alkylating agent which cross-links DNA

s/e include: chemo-induced N/V hemorrhagic cystitis(prevented by giving mesna), bone marrow supression, darkening of skin and nails

Carcinogenic and may cause transitional cell carcinoma of the bladder or AML
Symptoms
A prodromal phase of non-specific viral illness(fever, headaches, muscle pains)
Psychiatric disturbance with schizophrenic-like manifestations(hallucinations, disorganized thinking, bizarre behavior, delusions).
Memory impairment
most often anterograde amnesia
Decreased LOC and low Glasgow coma scale
stupor with catatonic feature
Seizures
Autonomic instability: wide BP fluctuation, hypoventilation, bradycardia, tachycardia
Pathophysiology
Autoantibodies to NMDA receptors in the brain.
Bind to NR1 subunit of NMDA receptor.

May reduce number of receptors via internalization once antibody binds.

May be a direct antagonist of NMDA receptor to prevent binding.

May recruit complement type cascade(less likely as would see more neuronal death).
Rituximab

Chimeric monoclonal antibody against the CD20 protein on the surface of immune B cells which produce antibodies

CD20 on immature B cells but not terminally differentiated plasma cells.

Receptor may modulate Ca+2 influx across membrane and can effectively kill the cell
Treatment and Management
CSF lymphocytic pleocytosis or oligoclonal bands.

EEG with infrequent epileptic activity, but frequent slow, disorganized activity.

Brain MRI often normal but may show transient FLAIR or contrast enhancing abnormalities in cortical or subcortical regions.

Most specific and sensitive tests is Detection of antibodies to NR1 subunit of NMDA-R in serum or CSF.

Titer of CSF antibodies correlates more closely with clinical outcome
Differential Diagnosis
Psychosis
Schizophrenia
Malignant Catatonia
Neuroleptic Malignant Syndrome
Viral encephalitis
Encephalitis Lethargica
Other psych disorders or encephalitides
Patients with a tumor have best prognosis with lower chance of relapse
resected tumor removes source of antibodies

After removal IVIG .4g/kg daily for five days and methylprednisolone 1g daily for 5 days

After 10 days if only minimal improvement start rituximab 375 mg IV every week for 4 weeks combined with cyclophosphamide 750mg in monthly cycles

Treatment may often take up to 18 months for substantial recovery

Cognitive impairments often more severe and permanent when there is delay in diagnosis as patients may often see psychiatrists before neurologist
Brain on Fire:
My Month of Madness
By: Susannah Callahan
Sources
Dalmau, Josep; Gleichman, Amy J; Hughes, Ethan G; Rossi, et al (2008). "Anti-NMDA-receptor encephalitis: Case series and analysis of the effects of antibodies". The Lancet Neurology 7 (12): 1091–8.

Dalmau, Josep; Tüzün, Erdem; Wu, Hai-yan et al. (2007). "Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma". Annals of Neurology 61 (1): 25–36.

Titulaer, Maarten J; McCracken, Lindseyet al. (2013). "Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: An observational cohort study". The Lancet Neurology 12 (2): 157–65.

Hacohen Y, Wright S, Waters P, et al. "Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens." J Neurol Neurosurg Psychiatry 2013; 84:748.

Vitaliani R, Mason W, Ances B, et al. "Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma." Ann Neurol 2005; 58:594.
Dalmau J, Lancaster E, Martinez-Hernandez E, et al. "Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis." Lancet Neurol 2011; 10:63.

Zandi MS, Irani SR, Follows G, et al. Limbic encephalitis associated with antibodies to the NMDA receptor in Hodgkin lymphoma. Neurology 2009; 73:2039.

FLAIR image of anti-NMDA
Full transcript