Autoimmune encephalitis and psychiatry

1. Autoimmune Encephalitis
and Psychiatric Practice
DR KHALID MANSOUR
PRIORY HOSPITALS CEFN CARNAU
OCTOBER 2015

2. Plan
Encephalopathy and Encephalitis:
PANDAS:
ABGA and adult OCD:
Autoimmune Encephalitis:
Limbic Encephalitis:
Anti-NMDA Receptor Antibody Encephalitis.
Implications on Psychiatry.

3. Encephalopathy,
Encephalitis
&
Autoimmune Encephalitis

4. Encephalopathy and Encephalitis
 Encephalopathy: acute global cerebral disease usually non-infective
and ill-defined in pathology.
 Can be used interchangeably with encephalitis.
 Encephalitis: acute global cerebral disease; well defined pathology
(inflammation) and aetiology.
 Types: viral, bacterial, parasitic, metabolic, toxic, etc.; and also
autoimmune.
 Symptoms:
Constitutional Symptoms: fever, headache, vomiting, sensitivity to light,
Neurological Symptoms: stiff neck and back, unsteady gait, loss of
consciousness, seizures, muscle weakness
Psychiatric Symptoms: cognitive, behavioural, mood abnormalities
changes, etc.

5. Autoimmune Encephalitis (Encephalopathy)
 Autoimmune Encephalopathy:
 associated with autoimmune disorder but NO identified antigen and/or antibodies.
 Autoimmune Encephalitis:
 associated with autoimmune disorder but WITH identified antigen and/or
antibodies.
 Antibody-mediated Autoimmune Encephalopathy.
 Post infectious Autoimmune Encephalopathy: PANDAS (Paediatric
Autoimmune Neuropsychiatric Disorders Associated with Streptococcal
Infections)
 Limbic Encephalitis:
 Infectious > e.g. herpes simplex virus (HSV)
 Non-neoplastic > poor prognosis
 Para-neoplastic > Better response to treatment

6. PANDAS
Paediatric Autoimmune
Neuropsychiatric Disorders
Associated with
Streptococcal Infections
Dr Susan Swedo NIH

7. PANDAS: History (www.nimh.nih.gov)
 Early 1990’s, Swedo, et al (NIMH) > children with OCD like symptoms &
motor or vocal tics > Symptoms usually occurred after viral or bacterial
infection.
 PITANDS (Paediatric Infection Triggered Autoimmune Neuropsychiatric
Disorders): symptoms followed influenza, varicella (chickenpox),
streptococcal bacteria, Lyme disease and mycoplasma.
1. PANDAS; Pediatric Autoimmune Neuropsychiatric Disorders Associated
with Streptococcal Infections > OCD + Tic Dis after streptococcal
infections:
2. PANS: Pediatric Acute-onset Neuropsychiatric Syndrome > all cases of
abrupt onset OCD, not just those associated with streptococcal
infections.

8. PANDAS: Definition (www.nimh.nih.gov)
Definition:
Sydenham (Rheumatic) Chorea without cardiac or
rheumatic symptoms.
Motor symptoms not chorea but motor tics.
Pathology:
“pseudo-autoimmune reaction”:
The streptococcal bacteria > “molecular mimicry” >
putting molecules on its cell wall that look nearly
identical to molecules found on the child’s heart, joints,
skin and brain tissues (particularly the basal ganglia).

9. PANDAS: Diagnosis (www.nimh.nih.gov)
 Clinical history >
 OCD and/or Tic Disorders > suddenly appear (or become worse) following a streptococcal
infection.
 Others: moody, irritable, general anxiety, separation anxiety. temper tantrums, immature behaviour,
baby talk, hyperactivity, poor attention and concentration, handwriting changes, and dyscalculia,
dyslexia and other educational problems.
 Physical examination > streptococcal infection
 Investigations:
Throat culture > group A beta-haemolytic streptococcal bacteria.
Rising anti-streptococcal antibodies titre
Inflammatory signs: high ESR and/or CRP
volumetric MRI: Increased basal ganglia volume

10. PANDAS: Treatment (www.nimh.nih.gov)
No RCT:
 Antibiotics.
 Plasmapheresis.
 Intravenous immunoglobulin (IVIG) > if evident autoimmune
response e.g. anti-streptococcal antibody titres, anti-nuclear
antibody titres, high (ESR) and/or C-reactive protein).
 Corticosteroids (debatable).
 Prophylactic Antibiotics (prevention).
 No psychiatric medications: sensitive to the side-effects; if have to
> go “LOW AND SLOW”.
 CBT.

11. PANDAS

13. Anti-Basal Ganglia Antibodies
(ABGA)
in adult OCD

14. ABGA & Adult OCD: (Nicholson et al, 2012)
 Central nervous system autoimmunity has been suggested to have aetiological role
in OCD and/or a risk factor.
 Many ABGA studies > associated ABGA with OCD and motor disorders:
 PANDAS: (Swedo et al, 1998; Gause et al, 2009).
 Sydenham Chorea: (Church et al, 2002)
 Tourette Syndrome: (Church et al, 2003)
 Idiopathic Movement Disorders: (Church et al, 2004)
 Dystonia: (Edwards et al, 2004)
 Encephalitis Lethargica: (Dale et al, 2004)
 OCD with Tourette: (Dale et al, 2005)
 Adult OCD: (Nicholson et al, 2012).

15. ABGA & Adult OCD: (Nicholson et al, 2012)
Three main antigens for ABGA have been
described:
Pyruvate kinase,
Enolase.,
Aldolase c.
Other potential antigens (Tubulin, Ganglioside
and the Dopamine Receptors) (Murphy et al, 2010).

16. ABGA & Adult OCD:
Nicholson et al, 2012:
 96 adult OCD, 33 depression & 17 Schiz patients > tested for
anti-streptolysin-O titres (ASOT) and ABGA.
19/96 (19.8%) OCD > Positivity for ABGA (compared to 2/50
(4%) of control) (P = 0.012).
No clinical variables were associated with ABGA positivity.
Positivity for ASOT:
Not associated with ABGA positivity
Not increased in OCD.

17. Limbic Encephalitis

18. Limbic Encephalitis: History
 First used by Corsellis et al (1968) >
neuropsychiatric syndrome.
subacute onset of memory disturbance, seizures, confusion,
disturbances of sleep
psychological problems e.g. personality changes and
hallucinations.
Was criticised > inflammation was elsewhere in the brain.
Course of illness not exact.
The term continued > to denote encephalitis with
prominent psychiatric symptoms (Rickards et al 2014).
 In the past few years > an increase in ability to diagnose
autoimmune encephalitis, with an increase in number of
autoantibodies identified (Irani 2011; Zandi 2011; Upthegrove & Barnes,
2014).

19. Limbic Encephalitis: Characteristics
 Neuropsychiatric disorder:
Initially present to psychiatric hospitals with irritability,
depression, anxiety, memory loss and psychosis (e.g.
Vincent et al, 2004; Dalmau 2007 & 2008).
Recognised to occur in the absence of other overt
neurological symptoms; e.g. NMDA-R encephalitis
Upthegrove & Barnes (2014).
A significant proportion of all psychotic illness, including
that in patients presenting to mental health services with
first-episode psychosis, may be antibody mediated illness
(Lennox 2012; Tsutsui 2012).

20. Limbic Encephalitis: History
 Autoimmune Disorder:
 Post-mortem pathology > inflammatory process of
autoimmune aetiology (Dropcho, 1989).
Discovery of exact antigens and antibodies (Antoine, 1995;
Voltz, 1999).
Same antibodies induce in animals a similar syndrome
(e.g. Vincent et al, 2004).
 Treated by immuno-suppressants:
The majority of the patients improved with
immunosuppressive therapy (Vincent et al, 2004; Titulaer 2013)

21. Limbic Encephalitis: Characteristics
 Paraneoplastic:
Brain & Henson (1958): Antibodies generated in response to
tumour antigens > molecular mimicry against autoantigens >
neurological syndromes > Non-metastatic symptoms include
neuropathy, myopathy and encephalitis.
Graus (1985): anti-Hu antibodies associated with lung cancer
Antoine (1995): anti-CRMP5/CV2 antibodies in Thymoma.
Voltz (1999): anti-Ma2 antibodies associated with testicular
cancer.
 Prognosis: High mortality rate: up to 25% (Barry et al, 2015).

22. Limbic Encephalitis: Antigens (Irani & Vincent, 2015)
Specific brain protein targets > different symptoms.
 Antibodies against intracellular antigen: Less common, Usually
paraneoplastic, poor prognosis
 Antibodies against neuronal surface antigen: More common, Usually
non-paraneoplastic, Better prognosis.
 Voltage-gated potassium channel complex antibodies: > Facio-Brachial Dystonic Seizures.
 LGI1 (Leucine-rich-Glioma Inactivated 1)
 CASPR2 (Contactin-Associated Protein 2).
 AMPA-R antibodies: less common, better response to treatment
 GABAB/AR antibodies: less common, better response to treatment.
 GlyR antibodies : rare
 GAD (Glutamic Acid Decarboxylase) antibodies : rare
 NMDA-R antibodies: usually involve several brain regions

23. Anti-NMDA Receptor
Antibody Encephalitis

25. Anti-NMDA-R Antibody Encephalitis
Prevalence: no exact estimates as to prevalence
rates (e.g. Barry et al, 2015).
The most common cause of autoimmune encephalitis after
acute demyelinating encephalitis (Ambrose et al, 2010).
Male to female ratio: 1:4 (Rickards, 2014).
Can appear in children as young as 7 months (Rickards,
2014).
18-40 Women > highest risk of underlying malignancy
(Titulaer 2013).
Older age and males > less likely malignancy (Irani
2010b; Dalmau 2011).
Similar symptoms after treatment with phencyclidine
(PCP) (a NMDA-R antagonist) (Baldridge 1990).

26. Anti-NMDA Receptor Antibody Encephalitis
Clinical presentation of high risk cases: (Rickards, 2014).
1. Psychiatric:
a) Sudden-onset paranoid psychosis with rapid deterioration
b) Cognitive impairment.
c) Catatonia.
2. Neurological:
a) Seizures.
b) Dyskinesia.
3. Constitutional Symptoms:
a) Prodromal headache or raised temperature.
b) Suspected neuroleptic malignant syndrome
c) Autonomic disturbance.
d) Hyponatraemia (an indicator of anti-vgkc-complex (lgi1) antibody encephalitis).

28. Anti-NMDA-R Antibody Encephalitis
Psychiatric symptoms in encephalitis patients;
 Dalmau 2008: 80% presenting to psychiatric services (100 patients).
 Titulaer 2013: (a larger series) 65%.
Psychiatric symptoms in NMDA-R +ve cases;
 Kayser 2013: In 571 pts with NMDA-R antibodies,
 4% (23 pts) > isolated psychiatric episodes > Delusional thinking, mood
disturbance and aggression were the predominant symptoms.
 45% (10 out of 22) > abnormal MRI findings.
 77% (17 out of 22) > raised WBCs in CSF.
 83% > improved after immunotherapy or tumour removal.
(This was not a controlled study > include only patients identified as ‘at risk’ and therefore tested).

29. Anti-NMDA Receptors Antibodies & Psychosis
 Anti-NMDA-R antibodies in psychotic patients (Rickards, 2014):
 Zandi 2011: 3 out of 46 first-episode psychosis pts > positive for NMDA-R
antibodies and no neurological symptoms.
 Tsutsui 2012: 4 out of 51 schizophrenia and schizoaffective pts > positive
results; 3 out of the 4 > neurological features (e.g. seizures or orofacial
dyskinesias).
 Lennox 2012: up to 10% of cases of first-episode psychosis have an
autoimmune aetiology.
 Steiner 2013: 4 of 74 pts with chronic schizophrenia and 47 with first-
episode psychosis), 2 of 70 pts with major depression, 0 of 38 pts with
borderline personality disorder and 1 of 230 healthy controls > positive.
 Beck et al, 2015: 3 (7.0%) of 43, treatment-refractory psychosis > low
positive.
 Haussleiter 2012; Masdeu 2012: Masopust et al, 2015: negative results.

30. Anti-NMDA Receptors Antibodies & Psychosis
Anti-NMDA-R antibodies in psychotic patients: Meta analysis studies
 Pollak et al, 2014: 7 studies > 1441 patients: > 115 [7.98%] were anti-NMDA-
R antibody positive. Prevalence rates were greater in cases than controls
only for IgG antibodies.
 Pearlman & Najjar. 2014:
 4 studies (3194 participants) > data based on low-specificity
seropositivity thresholds > no significant between-group difference.
 5 studies (3387 participants) > NMDA-R antibody seropositivity on high-
specificity seropositivity thresholds among pts with schizophrenia or
schizoaffective, bipolar, or major depressive disorders compared with
healthy controls.
Average NR2A/NR2B antibody titres determined by ELISA were
significantly higher among participants with first-episode
schizophrenia (P<.0001) and acute mania (P<.01) compared with
healthy controls.
Levels decreased by 58% at 8weeks in first-episode schizophrenia,
and by about 13% at 4days in acute mania.

31. Anti-NMDA Receptor Antibody Encephalitis
Diagnosis: Investigations: (Rickards, 2014).
1. Clinical presentation
2. Serum antibody assay.
3. EEG:
a) Encephalopathic picture: epileptiform activity, slow waves.
b) “Extreme delta brush”: ? a unique pattern associated with a prolonged illness course (schmitt
2012).
4. MRI: Medial temporal hyperintensity.
5. Blood tests:
a) Pleocytosis: (increased white blood cells),
b) Serum markers of inflammation: e.g. ESR or CRP are usually normal.
6. CSF:
a) Specific antibodies
b) Oligoclonal bands > inflammatory process.

32. Anti-NMDA Receptor Antibody Encephalitis
Treatment: (Rickards et al, 2014)
I. Psychosis + clear encephalopathy and/or +ve
investigations >
A. Assertive Immunotherapy:
i. Intravenous Immunoglobulin,
ii. Plasmapheresis,
iii. Corticosteroids,
iv. Cyclophosphamide, Rituximab
B. Removal of Tumour > high success rate (Tüzün & Dalmau, 2007;
Titulaer et al, 2013).

33. Anti-NMDA Receptor Antibody Encephalitis
Treatment: (Rickards et al, 2014)
II. Psychosis + positive serum antibody test but No clear
features of encephalopathy and/or -ve blood and/or CSF
investigations) >
Not known.
No difference: Anecdotal evidence > (e.g. Braakman
2010; creten 2011).
Joint decision: Practicality > between psychiatric and
neurological teams.

34. Anti-NMDA Receptor Antibody Encephalitis
Treatment (Other): Rickards et al, 2014:
Immunotherapies >
complex + side effects.
need cooperation from the patient.
 Psychiatric Medications: symptomatic treatment might be
necessary (Chapman 2011).
Rehabilitation: e.g. physical, occupational and speech and
language therapy > accelerate recovery.
Special Ward > to be carefully considered.
Specialised Psychiatric Teams: might be necessary

35. Anti-NMDA Encephalitis and Psychosis

36. Anti-NMDA-R Antibody
Encephalitis
&
Psychiatric Studies

37. The NMDA Hypo-functioning Theory of
Schzophrenia
Glutamate Theory of Schizophrenia:
The NMDA hypo-functioning theory > low NMDA
activity > induce chnagesin dopamine activity > both
positive and negative sy,ptoms of schizophrenia (e.g. Coyle
2006; Dalmau 2008).
Anti NMDA-R antibodies > can be the pathology
explaining the NMDA hypo-functioning (Upthegrove & Barnes, 2014)

38. The Immune System and Schizophrenia:
(Upthegrove & Barnes, 2014; Khandaker et al, 2015)
The autoimmune theory of schizophrenia:
1. 29% increasesd risk of schizophrenia in auto immune disease
(Benros, 2011).
a) Systemic Lupus Erythematosus > associated with
neuropsychiatric symptoms in the majority of patients (Wekking,
2010): .
b) Schizophrenia > more frequent in families with a history of
autoimmune disorders, e.g. psoriasis, Graves’ disease and
coeliac disease (except rheumatoid arthritis) (Upthegrove & Barnes,
2014).
2. Autoimmune pathology higher in schizophrenia:
a) Higher rate of prenatal viral exposure (Wright ,1995).

39. The Immune System and Schizophrenia:
(Bloomfield et al, 2015)
Microglial activity (using translocator-protein PET imaging) is
elevated in
Patients with schizophrenia.
Persons with subclinical symptoms who are at ultra high risk
of psychosis.
Is related to at-risk symptom severity.
> Neuroinflammation is linked to
Psychosis and related disorders,
Subclinical symptoms.

40. The Immune System and Schizophrenia:
(Upthegrove & Barnes, 2014)
RCT trials of immunomodulatory drugs in
Schiziphrenia:
Trials of drugs such as cyclooxygenase-2 (COX-2)
inhibitors > promising results (akhondzadeh 2007; müller 2010b).
Minocycline, an anti-inflammatory neuroprotective
antibiotic, is currently being investigated > promising,
particularly with regard to negative symptoms (chaudhry 2012).

41. Implications on Psychiatry:
Two Possible Scenarios.
1. Experts views
2. No change scenario.
3. Need to change scenario.

42. Implications to Psychiatric Services:
Experts’ Views:
Nicholson et al: Prevalence of anti-basal ganglia antibodies in adult
obsessive–compulsive disorder: cross-sectional study; The British
Journal of Psychiatry, May 2012,
This study provides > significant proportion of adults
with OCD are associated with ABGA.
The association found does not imply causality.
It would be premature for these findings to suggest
additional investigations or different treatments in
adults with OCD.

43. Implications to Psychiatric Services:
Experts’ Views:
Rickards et al,2014:
 Signal a significant change in the approach to disorders such as
schizophrenia.
 Psychiatrists and neurologists need to work together:
Lennox et al, 2012:
 All individuals with a first presentation of psychosis, … should be assessed with
the possibility of antibody-mediated encephalitis in mind:
 A neurological and cognitive examination,
 Early serum testing for antibodies … .
 EEG.
 MRI.
 All patients testing positive for these serum antibodies should be referred to
neurological centres with expertise in managing these cases.

44. Implications to Psychiatric Services:
Experts’ Views:
Upthegrove & Barnes, 2014:
 Schiz as a ‘non-organic psychosis’ is significantly challenged.
 Interconnections between brain and the immune system … not
recognised by current nosological boundaries.
 The investigation of immune dysfunction in psychosis > greatest
potential for advancing our understanding of schizophrenia in the
21st century.
 The potential for … improved treatments may be within our grasp.
 Routine screening of all patients with psychosis for autoimmune
encephalitis, and the investigation of novel treatments, need to
advance at a similarly brisk pace.

45. No Change
The science is still young: these new developments
are still provisional and needs much more
clarifications before it turns into facts.
Not cost effective; need a lot of resources for little
gain.
Excluding organicity at such level is not the
psychiatrist job but the GP, the physician or the
neurologist.
No guidelines telling us differently: NICE > “exercise
a degree of skill that would be reasonably
expected of a doctor in similar circumstances”.

46. Start Working on a Change
“Adults with psychosis or schizophrenia have
specific comprehensive physical health assessments
(List of quality statements; Statement 6; NICE; Feb 2015).
“You must keep your professional knowledge and
skills up to date” (GMC; Good medical practice).
Many, including psychiatrist, demand the change.
Even a few schizophrenic patients re-diagnosed as
encephalitis is a serious challenge to our profession.

47. Start Working on a Change
Developments in neuropsychological studies
and new treatable mental illnesses keep
coming all the time.
Litigations will follow soon.
Insurance companies might also follow.
The sooner we start the change the better.

48. If We Have to Change ?!

49. The Science
The concepts e.g.
functional
psychosis
The
symptomatology.
The diagnoses.
The classifications.
Dr. Frank Ochberg

50. The Training
More general
medicine
More
neurology
More modern
investigations.
Dr. William Gallentine
Duke University Medical Centre

51. New Subspecialties
e.g. enhance NEUROPSYCHIATRY
or even develop
IMMUNOPSYCHIATRY .
Separating behavioural management
from psychiatry to be run by
psychology, specialist nurses or
social workers.

52. Resources
More access to sophisticated
investigations e,g, MRI, EEG,
immunoassay, genetic testing, etc
Prescribing ,
Accessing,
Interpreting.

53. Legal Cover
May be more cover for misdiagnosis of
medical conditions associated with
mental illnesses
May be less emphasis on risk
management

54. Thank You