Anti-NMDA receptor encephalitis: Psychiatric presentation and

diagnostic challenge

Introduction► First reported in 2005► Severe form of autoimmune encephalitis: anti-

bodies against NR1-NR2 heteromers of the NMDA receptor

(Chapman and Vause, 2011)► Conceptualized as a condition primarily

affecting adult women with ovarian tumors► Increasingly recognized among adult males,

children, and those with the absence of tumors as well

(Barry et al., 2011)

Introduction

Why Anti-NMDA receptor encephalitis?

Typical Pathway of Care

Acute psychosis, alteredbehavior, and catatonia

Evaluated initially by a psychiatrist

Seizures, autonomic instability’ altered consciousness or dyskinesia alerts the possibility of neurological pathology

Neurologist Around 4% of the cases present with isolated psychiatric episodes without neurological involvement (Kayser et al., 2013)

Investigations

► Brain MRI In 50%, T2 or FLAIR signal hyperintensity in

various brain regions ► EEG – usually abnormal in most patients

Non-specific, slow and disorganized activity Epileptic activity in some Extreme delta brush is a novel finding The presence of this pattern is associated

with a more prolonged illness Specificity of this pattern is unclear

Extreme Delta Brush Pattern

Extreme Delta Brush Pattern

EEG showing diffuse slowing characterized by rhythmic delta activity 1-3 Hz with superimposed bursts of rhythmic 20–30 Hz beta frequency activity on each delta wave.

Investigations

► CSF Abnormal in 80% initially and in almost all in

later part of illness Moderate lymphocytic pleocytosis, mildly

increased protein, oligoclonal bands Less commonly found in children (?Earlier

recognition of illness in children)► Brain biopsy – non-specific► Serum and CSF anti-NMDAR antibody (specific and

sensitive)

Differential Diagnosis

► Infections of the brain (mainly viral)► Other autoimmune encephalitis► CNS Vasculitis► Acute transient psychotic disorder

Management► Usual management: Immunotherapy and

tumor removal (when present)► First line: corticosteroids, IV Ig or plasma

exchange Enhanced effect and speed of action

when underlying tumor removed► Patients without tumor or with delayed

diagnosis – may require 2nd line immunotherapy (Rituximab or Cyclophosphamide, or both)

(Florence et al., 2009)

Role of antipsychotic medications/ECT

► Most of the reports suggest use of antipsychotic initially during the course of illness

► Reason: misdiagnosis as a case of Psychosis or control of behavioral problems

ECT► A study reported use of ECT in 2 out of

31 cases (No further details available)(Florence et al., 2009)

Sequelae► If treated – remission in 75% cases (mild

neurological sequel may be present)► If untreated, expected outcome

Neurological sequel – 75% Relapse – 25% Mortality – 20%

(Tambi et al., 2011)► Spontaneous recovery of 4 pts over 7

months hospital stay (Iizuka et al., 2008)

Summary of course

(Kayser and Dalmau, 2011)

Sex, tumor association and triggers

► 80% of patients with anti-NMDAR encephalitis women

► Most common tumor – ovarian teratoma (>90%)

► Younger the patient, lesser the likelihood of underlying tumor association 10% in aged 7-12 years, 40% in 13-18

yearsHofmann et al., 2010; Verhelst et al., 2010;; Dalmau et al., 2011

Clinical features in children

► Temper tantrums, hyperactivity, irritability► First symptom usually non-psychiatric in

children in up to 70% cases (e.g. seizures, dystonia, decreased verbal output, mutism etc.)

► Movement disorder: comparable with adults► Autonomic manifestations are less severe► Hypersexual and violent behaviors (e.g. kicking

and biting caregivers and parents) commonArmangue et al., 2013; Baizabal-Carvallo et al., 2013

Clinical features in children

► In children, association with an infectious process Two cases developed illness after H1N1

vaccination One patient after a vaccination against

tetanus, diphtheria, pertussis A child with this illness – microdeletion in the

short arm of chromosome 6 (involving HLA cluster, suggesting a predisposition to autoimmunity)

Hofmann et al., 2010; Verhelst et al., 2010; Dalmau et al., 2011

Investigations

Antibody Specificity► Serum NMDAR antibodies in 1 of 215 patients with

CNS demyelinating diseases, suggesting that the frequency of those auto-antibodies is very low (<1%): had symptoms of NMDA encephalitis

(Ramberger et al, 2015)► Individuals with schizophrenia or schizoaffective,

bipolar, or major depressive disorders are collectively about three times more likely to have elevated NMDAR antibody titers compared with healthy controls

(Pearlman and Najjar, 2014)

Anti-NMDAR antibody and PsychosisSteiner et al, 2013:

Most antibodies bound to NR1/2B construct Vs. NR1-IgG1 in Autoimmune encephalitis

Masdau et al, 2012Unable to detect IgG Ab aginst 80 pts of schizophrenia

Dalmau et al, 2008 (Review article )Testing for IgG NR1 Ab in schizophrenia not indicated

Rhoads et al, 2011:None of 7 pts with chronic antipsychotic treated

schizophrenia had detectable NMDARNR1-IgG1 specific to Autoimmune encephalitis

Implications► The glutamatergic theories of schizophrenia:

based on the ability of N-methyl-D-aspartate receptor (NMDAR) antagonists to induce schizophrenia-like symptoms

► There is emergent literature documenting disturbances of NMDAR-related gene expression and metabolic pathways in schizophrenia

(Moghaddam and Javitt, 2012)► The early presentation of psychosis in anti-

NMDAR encephalitis might be evidence of this

Implications► There are increasing numbers of recognized

auto antibodies against receptors other than anti-NMDA that are seen in psychosis

(Endres et al., 2015)

► Studies show there is a significantly higher rate of positivity of NMDAR antibodies in child and adolescent psychosis than in adult-onset psychosis

(Pathmanandavel et al., 2015)

My experience

► There are very few reports from India for this relatively rare illness.

► A case of anti NMDAR encephalitis in a young girl without a history of systemic neoplasm- challenges faced in diagnosing and treating her.

► Onset after a traumatic stressor (incidental or related to autoimmune process?)

► Stressor incorporated in psychopathology► Treatment induced mood disorder in the patient..

Challenges

► Presence of multiple psychiatric symptoms at presentation

► No definitive neurological findings on investigations – MRI, EEG normal

► Catatonic symptoms – general understanding of being associated with psychiatric disorders

20-39% have organic disorders = 35 % in schizophrenia

Ahuja, 2000

► Seizures and dyskinesia confused with side effect of antipsychotics

Challenges – Our Context

► Lack of Lab Facilities that can detect NMDA auto antibodies

► MRI and EEG: Cost and availability issues ► ? Liaison between Psychiatrists and

Neurologists► Cost of Treatment: IV IG► Our struggles

Way Forward

► Should we have a guidelines for empirical diagnosis once some indicators are detected like delta brush in EEG or classic presentation

► Should we treat empirically?► If so our own criteria for stating empirical

steroid pulse in acute psychosis?

Thank you