Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, only recently first described, is an increasingly well-recognized inflammatory encephalitis that is seen in children and adults. The highlights: Pychiatric manifestations in encephalitis and the need for the psychiatrist to a have high index of suspicion when atypical symptoms (e.g., dyskinesia, seizure, fever etc.) present in acutely psychotic patients.

1. Anti-NMDA receptor encephalitis:
Psychiatric presentation and
diagnostic challenge

2. 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)

3. Introduction

4. Why Anti-NMDA receptor encephalitis?

5. Typical Pathway of Care
Acute psychosis, altered
behavior, 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)

6. 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

7. Extreme Delta Brush Pattern

8. 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.

9. 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)

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

11. 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)

12. 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)

13. 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)

14. Summary of course
(Kayser and Dalmau, 2011)

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

16. 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)
common
Armangue et al., 2013; Baizabal-Carvallo et al., 2013

17. 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

18. Investigations

19. 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)

20. Anti-NMDAR antibody and Psychosis
Steiner et al, 2013:
Most antibodies bound to NR1/2B construct Vs. NR1-IgG1 in
Autoimmune encephalitis
Masdau et al, 2012
Unable 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 NMDAR
NR1-IgG1 specific to Autoimmune encephalitis

21. 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

22. 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)

23. 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..

24. 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

25. 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

26. 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?

27. Thank you