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, autoimmune, etc.
Infectious > e.g. herpes simplex virus (HSV)
Para-neoplastic > poor prognosis.
Non-neoplastic > Better response to treatment
Post infectious Autoimmune Encephalopathy: PANDAS (Paediatric
Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections)
Constitutional: fever, headache, vomiting,
sensitivity to light, dysautonomia, etc.
Neurological: stiff neck and back, unsteady
gait, deterioration of consciousness, seizures,
muscle weakness, etc.
Psychiatric: abnormalities in cognition,
behaviour, mood, perception, thinking,
History (Rickards et al 2014).
Term first used by Corsellis et al (1968) >
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
Upthegrove & Barnes (2014): In the past years > an increase in
ability to diagnose autoimmune encephalitis, with an increase in
number of autoantibodies identified (Irani 2011; Zandi 2011).
Baldridge 1990: Treatment with PCP (phencyclidine: a NMDA receptor
antagonist > Similar symptoms (including both motor and psychiatric
Upthegrove & Barnes (2014): NMDA receptor encephalitis > now
recognised to occur in the absence of other overt neurological symptoms.
Lennox (2012); Tsutsui (2012): a significant proportion of all psychotic
illness, including that in patients presenting to mental health services with
first-episode psychosis, may be antibody mediated.
Titulaer (2013): Treatments for autoimmune encephalitis, within weeks,
causing relief of all symptoms, achievable in the vast majority of patients.
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
Women between 18 and 40 years old at highest risk
of underlying malignancy (Titulaer 2013).
Less likely to be paraneoplastic with increasing age
and in males (Irani 2010b; Dalmau 2011).
High Risk Cases: (Rickards, 2014).
Subacute onset of:
Psychiatric / neuropsychiatric symptoms (e.g.
Sudden-onset paranoid psychosis, Cognitive
impairment, Catatonia, Seizures, Dyskinesia)
With or preceded by Constitutional Symptoms:
(e.g. prodromal headache, raised temperature,
muscular rigidity, Autonomic disturbance).
With any inflammatory signs in blood, CSF, MRI or EEG”.
Positive antibodies test in blood or CSF.
Psychiatric symptoms in Anti-NMDA-R encephalitis pts:
Dalmau 2008: 80% presented to psychiatric services (100 pts).
Titulaer 2013: (a larger series) 65%.
Kayser 2013: In 571 pts with NMDA receptor antibodies, 4% (23 pts) >
isolated psychiatric episodes (5 at disease onset and 18 during relapse)
> Delusional thinking, mood disturbance and aggression were the
45% (10 out of 22) > abnormal MRI findings.
77% (17 out of 22) > raised WBCs in CSF.
94% > improved after immunotherapy or tumour removal.
This was not a controlled study > include only patients identified as ‘at
risk’ and therefore tested.
Anti-NMDA-R antibodies in psychotic patients: Meta Analysis Studies
Pollak et al, 2014: 7 studies > 1441 patients: > 115 [7.98%] were anti-NMDA receptor
antibody positive. Prevalence rates were greater in cases than controls only for IgG
Pearlman & Najjar. 2014: (Meta-analysis study):
5 studies (3387 participants) > NMDA-R antibody seropositivity data based on high-
specificity seropositivity thresholds
> higher seropositivity among pts with schizophrenia or schizoaffective, bipolar, or major
depressive disorders. as compared with healthy controls (OR, 3.10; 95% CI 1.04–
9.27; P = .043)
4 studies (3194 participants) > data based on low-specificity seropositivity thresholds >
no significant between-group difference.
Average NR2A/NR2B (not NR1AorB) antibody titers 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
4 days in acute mania.
Lennox 2012: up to 10% of cases of first-episode psychosis have an
Investigations (Rickards, 2014).
Serum antibody assay : could be negative while CSF positive
(Also serum inflammation markers : e.g. ESR or CRP are usually normal).
CSF: specific antibodies or inflammatory processes (Pleocytosis or
EEG: Almost always “abnormal” during acute episodes (Leypoldt et al,
Encephalopathy picture: epileptiform activity, slow waves.
“Extreme delta brush”: ? a unique pattern associated with a prolonged
illness course (schmitt 2012).
MRI: better with contrast, < 50% positive. When positive > e.g. Medial
Medications (Rickards et al, 2014)
Psychosis + clear encephalopathy: e.g. reduced
consciousness level, seizures, autonomic instability, catatonia,
abnormal EEG, MRI or CSF +/- positive positive antibodies
test > Assertive immunotherapy: Intravenous
immunoglobulins, plasmapheresis, corticosteroids, Cyclophosphamide, rituxima
b (& removal of tumour) > high success rate (Tüzün & Dalmau, 2007; Titulaer et al,
Psychosis + positive serum antibody test + NO clear
features of encephalopathy) > not known. (e.g. Braakman 2010; Creten 2011)
Anecdotal evidence > no difference
Practically > joint decision between psychiatric and neurological teams
specialising in these disorders.
General Management (Rickards et al, 2014)
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 > neurology vs psychiatry ward to be carefully
Specialised Psychiatric Teams: might be necessary
The Immune System in Schizophrenia and depression:
(Upthegrove & Barnes, 2014; Khandaker et al, 2015)
Wright (1995): an autoimmune aetiology of schizophrenia were
proposed, mediated by a prenatal viral exposure.
Wekking (2010): The presence of systemic lupus erythematosus
is associated with neuropsychiatric symptoms in the majority of
Benros (2011): The presence of auto immune disease increases
the risk of schizophrenia by 29%.
Upthegrove & Barnes (2014): Schizophrenia occurs more
frequently in families with a history of autoimmune disorders, e.g.
psoriasis, Graves’ disease and coeliac disease (except
Khandaker et al, 2017
Depression is common in people with a chronic inflammatory illness, and
immuno-activation leads to depressive symptoms in patients and healthy
Elevated circulating inflammatory markers increase future risk of
depression and psychosis in healthy people
Circulating inflammatory markers are elevated in acute depression, which
tend to normalise after recovery, but continue to be elevated in treatment
Elevated circulating inflammatory markers are associated with poor
response to antidepressant.
Emerging evidence indicates anti-inflammatory agents may be effective
treatments for patients with depression particularly those with evidence of
23 studies met the inclusion criteria of patients with
neuroleptic naive first episode psychosis, and
assessed circulating cytokines (570 patients, 683
healthy control subjects, and 20 cytokine/cytokine
> significant elevation in pro-inflammatory cytokine
levels in the serum of patients with medication-
naive first episode psychosis.
The Immune System and Schizophrenia:
(Upthegrove & Barnes, 2014; Systematic Review )
Khandaker et al, 2015
Microglia, the resident immune cells of the brain, constitute 9%
of the adult human brain cells.
Neuroinflammation is characterised by the activation of microglia
cells, which show an increase in the expression of the
translocator protein (TSPO).
Neuroimaging studies using PET and a TSPO ligand provide
evidence for neuroinflammation in recent-onset schizophrenia
and in acute exacerbations of schizophrenia.
These studies report increased binding of this ligand in the entire
grey matter and hippocampus, suggesting that
neuroinflammation might contribute to grey matter volume loss
and cognitive deterioration in schizophrenia.
The NMDA Hypo-functioning Theory of
Gluatamte theory of Schizophrenia (NMDA
hypo-functioning theory): low NMDA activity
induces symptoms 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:
Randomised controlled trials of anti-inflammatory drugs
as adjuncts to standard therapy have shown promising
results in schizophrenia (Khandaker et al, 2015).
Trials of immunomodulatory drugs such as
cyclooxygenase-2 (COX-2) inhibitors has shown
promising results (akhondzadeh 2007; müller 2010b).
Minocycline, an anti-inflammatory neuroprotective
antibiotic, is currently being investigated and early results
are promising, particularly with regard to negative
symptoms (Chaudhry 2012).
Dr Susan Swedo NIH
Early 1990’s, Swedo, et al (NIMH) > children with OCD like symptoms &
motor or vocal tics > Symptoms usually occur after viral or bacterial infection.
PITANDS (Paediatric Infection Triggered Autoimmune Neuropsychiatric Disorders):
symptoms followed influenza, varicella (chickenpox), streptococcal bacteria,
Lyme disease and mycoplasma.
PANDAS; Pediatric Autoimmune Neuropsychiatric Disorders Associated
with Streptococcal Infections > OCD + Tic Dis after streptococcal
PANS: Pediatric Acute-onset Neuropsychiatric Syndrome > all cases of
abrupt onset OCD, not just those associated with streptococcal
A subtype of Sydenham (Rheumatic) Chorea with prominent
symptoms of OCD and motor tics.
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).
Diagnostic Criteria (www.nimh.nih.gov)
Presence of clinically significant obsessions, compulsions and/or
Unusually abrupt onset of symptoms or a relapsing-remitting
course of symptom severity.
Usually Prepubertal onset (could occur rarely among adolescents).
Other neuropsychiatric symptoms: OCD + tics + ADHD, separation anxiety,
bedwetting, anxiety, panic attacks, "terror-stricken look", abnormal movements, hyper-
sensitivity to light or sounds, distortions of visual perceptions, visual or auditory
hallucinations, loss of academic abilities, increased urinary frequency, bed-wetting,
aggression, emotional lability, depression, suicidal thoughts, developmental
regression, temper tantrums, "baby talk", handwriting deterioration, etc.
Association with streptococcal infection.
IV IGs (if evident autoimmune response e.g. anti-streptococcal antibody
titres, anti-nuclear antibody titres, high (ESR) and/or C-reactive protein).
Antibiotics as prophylaxis (prevention).
Children with PANDAS > sensitive to the side-effects of other
medications; if so > “LOW AND SLOW” with psychiatric medications!!.
Antigens (Nicholson et al, 2012)
Three antigens for ABGA have been described:
Other potential antigens (Tubulin, Ganglioside and the
Dopamine Receptors) (Murphy et al, 2010).
ABGA, OCD & Motor Disorders (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).
Nicholson et al, 2012:
96 OCD patients, 33 depression & 17 Schiz. >
tested for Antistreptolysin-O titres (ASOT) and
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 for ASOT:
Not associated with ABGA positivity
Not increased in OCD.
Pearlman et al, 2014
Meta-analysis: primary OCD were ABGA
seropositive > controls (OR: 4.97, 95% CI 2.88–
Results of one study testing CSF showed greater
proportion of primary OCD patients were ABGA
CSF-positive compared with controls (OR: 5.60,
95% CI 1.04–30.20, P = 0.045).
Further experimental studies are needed to
ascertain whether this relationship is causal.
Implications on Psychiatry
Experts’ Views 1
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
Rickards et al,2014:
Signal a significant change in the approach to disorders such as
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 … .
All patients testing positive for these serum antibodies should be referred to
neurological centres with expertise in managing these cases.
Experts’ Views 2
Upthegrove & Barnes, 2014:
schizophrenia as a ‘non-organic psychosis’; is significantly challenged.
Interconnections between brain and the immune system … not recognised by current
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.
It is important that all psychiatrists … remain up to date with understanding of the
Routine screening of all patients with psychosis for autoimmune encephalitis, and the
investigation of novel treatments, need to advance at a similarly brisk pace.
Experts’ Views 3
Questions and Challenges
“Functional Psychosis”; does it mean “definitely not organic” or “
we do not know what the aetiology is” ?
“Organic Psychiatry”: does not also have clear diagnostic and
management guidelines in psychiatry and properly needs to be
When someone is diagnosed with psychosis; “functional or
idiopathic”; do we need to continue, from time to time, to review
the possibility that they can have an organic aetiology, and could
be better treated with other medications?
Questions and Challenges
How can we meet our professional commitments to adequately
exclude organic causes of psychiatric disorders, like
Autoimmune encephalitis, if we are not equipped or trained to
If we are not supposed to investigate such possible aetiology,
who then should do it; GP?, Neurologist?, Rheumatologist?.
How can this be achieved?
If we diagnose some one with a psychiatric disorder and treat
with antipsychotic and later it discovered that the diagnosis was
an autoimmune disorder, could we be accused of negligence?
What Change can be done ?!
Is the revolution coming?
The concepts e.g. no more “functional vs.
The symptomatology e.g. better
symptomatology for neuropsychological
The diagnostic criteria e.g. to include
autoimmune disorder symptoms in schiz.
and OCD diagnostic criteria.
E,g, add autoimmune induced schiz. and
OCD in psychiatric classifications.
Dr. Frank Ochberg; NIMH
Dr Thomas Insel; NIMH
More general medicine
Dr. Bill Gallentine of Duke
University Medical Centre
New psychiatric Subspecialties
e.g. develop further
? Start IMMUNOPSYCHIATRY .
Shifting behavioural management
away from main stream psychiatry to
be run by psychology, specialist
nurses or social workers.
More access to sophisticated investigations e,g,
MRI, EEG, immunoassays, genetic testing, etc.
Lessons from history
Psychiatrists rigidity against new ideas:
Borderline Personality Disorder.
Shell Shock and PTSD
Psychological vs Organic:
GPI > another mental illness treated by
Lessons from history: GPI (Hurn, 1998;
1822: GPI was first described as a distinct disease by Bayle.
1857: Esmarch & Jessen asserted that syphilis caused it.
1883: general acceptance was accomplished by Alfred Fournier.
1913: Noguchi and Moore identified the syphilitic spirochetes in the brains
At the turn of 20th century, “new psychiatrists” were supportive of this idea
of organic cause of GPI including Emil Kraepelin. This could have
The gradual decline in psychoanalysis
The rise of “medical” approach to mental illnesses.
1927: Julius Wagner-Jauregg was given the first Nobel Prize awarded to
a clinical psychiatrist when he discovered a “treatment” of GPI (through
infecting patients with malaria).
Lessons from history: GPI (Hurn, 1998;
Early 20th century: GPI > 26% of psychiatric admissions.
Originally, the cause was believed to be an inherent weakness of character
or constitution. Later: alcoholism, depression, psychosis, BAD, Dementia,
After WW-II the use of penicillin to treat syphilis made general paresis a
Since GPI and infectious delirium represented a high proportion of
psychiatric patients, use of penicillin, changing diagnostic distribution of
patients and discovery of major tranquilisers, led to:
Massive reduction in psychiatric beds (Taylor 2011).
Shift in priorities in psychiatric research from the “organic” to the “functional”
psychiatric disorders by the mid 20th century (ban 2006).