Autoimmune Encephalitis and Psychiatric Practice

DR KHALID MANSOUR PRIORY HOSPITALS CEFN CARNAU

OCTOBER 2015

PlanEncephalopathy and Encephalitis:PANDAS:ABGA and adult OCD:Autoimmune Encephalitis:Limbic Encephalitis:Anti-NMDA Receptor Antibody Encephalitis.Implications on Psychiatry.

Encephalopathy, Encephalitis

& Autoimmune Encephalitis

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 weaknessPsychiatric Symptoms: cognitive, behavioural, mood abnormalities changes,

etc.

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

PANDASPaediatric Autoimmune

Neuropsychiatric Disorders Associated with

Streptococcal InfectionsDr Susan Swedo

NIH

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.

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).

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 titreInflammatory signs: high ESR and/or CRP volumetric MRI: Increased basal ganglia volume

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.

PANDAS

Anti-Basal Ganglia Antibodies

(ABGA) in adult OCD

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).

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).

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.

Limbic Encephalitis

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).

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).

Limbic Encephalitis: HistoryAutoimmune 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)

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).

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

Anti-NMDA Receptor Antibody Encephalitis

Anti-NMDA-R Antibody EncephalitisPrevalence: 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).

Anti-NMDA Receptor Antibody EncephalitisClinical presentation of high risk cases: (Rickards, 2014).

1. Psychiatric: a) Sudden-onset paranoid psychosis with rapid deteriorationb) Cognitive impairment.c) Catatonia.

2. Neurological: a) Seizures. b) Dyskinesia.

3. Constitutional Symptoms: a) Prodromal headache or raised temperature.b) Suspected neuroleptic malignant syndromec) Autonomic disturbance. d) Hyponatraemia (an indicator of anti-vgkc-complex (lgi1) antibody

encephalitis).

Anti-NMDA-R Antibody EncephalitisPsychiatric 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).

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.

Anti-NMDA Receptors Antibodies & PsychosisAnti-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.

Anti-NMDA Receptor Antibody EncephalitisDiagnosis: 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.

Anti-NMDA Receptor Antibody EncephalitisTreatment: (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).

Anti-NMDA Receptor Antibody EncephalitisTreatment: (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.

Anti-NMDA Receptor Antibody EncephalitisTreatment (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

Anti-NMDA Encephalitis and Psychosis

 

Anti-NMDA-R Antibody Encephalitis

& Psychiatric Studies

  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)

 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).

 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.

 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).

Implications on Psychiatry:

Two Possible Scenarios.1. Experts views

2. No change scenario.3. Need to change scenario.

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.

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.

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.

No ChangeThe 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”.

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.

Start Working on a ChangeDevelopments 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.

If We Have to Change ?!

The ScienceThe concepts e.g.

functional psychosis

The symptomatology.

The diagnoses. The classifications. Dr. Frank Ochberg

The Training More general

medicineMore neurology

More modern investigations.

Dr. William Gallentine Duke University Medical Centre

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.

Resources More access to sophisticated

investigations e,g, MRI, EEG, immunoassay, genetic testing, etcPrescribing , Accessing, Interpreting.

Legal CoverMay be more cover for misdiagnosis of medical conditions associated with mental illnesses

May be less emphasis on risk management

Thank You