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Autoimmune encephalitis 144

autoimmune encephalitis and psychiatric practice

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Autoimmune encephalitis 144

  1. 1. Autoimmune Encephalitis and Psychiatric Practice DR KHALID MANSOUR LETTERKENNY TEACHING HOSPITAL JUNE 2017
  2. 2. Anti-NMDA Encephalitis and Psychosis
  3. 3. PANDAS
  4. 4. My Tics
  5. 5. Schizophrenia Study Could Improve Treatment The link between immune cells and the condition could see the first major developments in treatment for six decades. Sky news: 16 October 2015
  6. 6. Autoimmune Encephalitis: Diagnostic Workup
  7. 7. The Future of Psychiatry (Dr. Frank Ochberg)
  8. 8. Index Encephalopathy and Encephalitis: Autoimmune Encephalitis: 1. Limbic Encephalitis: 2. Anti-NMDA Receptor Antibody Encephalitis. 3. PANDAS: 4. ABGA and adult OCD: Implications on Psychiatry.
  9. 9. Autoimmune Encephalopathy & Autoimmune Encephalitis
  10. 10. 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.  Limbic Encephalitis:  Infectious > e.g. herpes simplex virus (HSV)  Autoimmune > Para-neoplastic > poor prognosis. Non-neoplastic > Better response to treatment  Post infectious Autoimmune Encephalopathy: PANDAS (Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections)
  11. 11. 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, catatonia, etc. Symptoms:
  12. 12. Leypoldt et al, 2015
  13. 13. Limbic Encephalitis
  14. 14. History (Rickards et al 2014).  Term 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.  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).
  15. 15. Recent Views  Baldridge 1990: Treatment with PCP (phencyclidine: a NMDA receptor antagonist > Similar symptoms (including both motor and psychiatric phenomena).  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.
  16. 16. Antigens 1
  17. 17. Antigens 2
  18. 18. Anti-NMDA Receptor Antibody Encephalitis
  19. 19. Prevalence: 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). 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).
  20. 20. 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). “Atypical symptoms”. With any inflammatory signs in blood, CSF, MRI or EEG”. Positive antibodies test in blood or CSF.
  21. 21. 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 predominant symptoms. 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.
  22. 22. 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 antibodies.  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 autoimmune aetiology.
  23. 23. Investigations (Rickards, 2014).  Clinical presentation  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 Oligoclonal bands).  EEG: Almost always “abnormal” during acute episodes (Leypoldt et al, 2015) 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 temporal hyperintensity.
  24. 24. 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, 2013).  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.
  25. 25. General Management (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 > neurology vs psychiatry ward to be carefully considered.  Specialised Psychiatric Teams: might be necessary
  26. 26. Limbic Encephalitis & Psychiatric Studies
  27. 27. 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 patients.  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 rheumatoid arthritis).
  28. 28. 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 volunteers 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 resistant cases. 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 inflammation
  29. 29. 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 receptors reported). > 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 )
  30. 30. 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.
  31. 31. The NMDA Hypo-functioning Theory of Schzophrenia 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)
  32. 32. 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).
  33. 33. PANDAS Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections Dr Susan Swedo NIH
  34. 34. History (www.nimh.nih.gov)  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 infections:  PANS: Pediatric Acute-onset Neuropsychiatric Syndrome > all cases of abrupt onset OCD, not just those associated with streptococcal infections.
  35. 35. PANDAS (www.nimh.nih.gov) Definition: A subtype of Sydenham (Rheumatic) Chorea with prominent symptoms of OCD and 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).
  36. 36. Diagnostic Criteria (www.nimh.nih.gov)  Presence of clinically significant obsessions, compulsions and/or tics  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.
  37. 37. Investigative diagnosis (www.nimh.nih.gov) Physical examination Investigations: Throat culture > group A beta-haemolytic streptococcal bacteria. Rising anti-streptococcal antibodies titre. High ESR & CRP. Volumetric MRI: Increased basal ganglia volume
  38. 38. Treatment (www.nimh.nih.gov) (No RCT).  Antibiotics.  Plasmapheresis.  IV IGs (if evident autoimmune response e.g. anti-streptococcal antibody titres, anti-nuclear antibody titres, high (ESR) and/or C-reactive protein).  Corticosteroids (debatable).  Antibiotics as prophylaxis (prevention).  Children with PANDAS > sensitive to the side-effects of other medications; if so > “LOW AND SLOW” with psychiatric medications!!.  CBT.
  39. 39. ABGA (Anti-Basal Ganglia Antibodies) & Adult OCD
  40. 40. Antigens (Nicholson et al, 2012) Three antigens for ABGA have been described: Pyruvate kinase, Enolase, Aldolase C. Other potential antigens (Tubulin, Ganglioside and the Dopamine Receptors) (Murphy et al, 2010).
  41. 41. 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).
  42. 42. Nicholson et al, 2012: 96 OCD patients, 33 depression & 17 Schiz. > tested for Antistreptolysin-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.
  43. 43. Pearlman et al, 2014 Meta-analysis: primary OCD were ABGA seropositive > controls (OR: 4.97, 95% CI 2.88– 8.55, P50.00001). 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.
  44. 44. Autoimmune Encephalitis & Implications on Psychiatry
  45. 45. 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 with OCD.
  46. 46. 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. Experts’ Views 2
  47. 47. Upthegrove & Barnes, 2014:  schizophrenia 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.  It is important that all psychiatrists … remain up to date with understanding of the immune system.  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
  48. 48. 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 developed further.  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?
  49. 49. 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 do that?  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?
  50. 50. What Change can be done ?! Is the revolution coming?
  51. 51. The Science The concepts e.g. no more “functional vs. organic disorders” The symptomatology e.g. better symptomatology for neuropsychological symptoms. The diagnostic criteria e.g. to include autoimmune disorder symptoms in schiz. and OCD diagnostic criteria. The classifications: E,g, add autoimmune induced schiz. and OCD in psychiatric classifications. Dr. Frank Ochberg; NIMH Dr Thomas Insel; NIMH
  52. 52. The Training More general medicine More neurology More modern investigations: Dr. Bill Gallentine of Duke University Medical Centre
  53. 53. New psychiatric Subspecialties e.g. develop further NEUROPSYCHIATRY ? Start IMMUNOPSYCHIATRY . Shifting behavioural management away from main stream psychiatry to be run by psychology, specialist nurses or social workers.
  54. 54. Resources More access to sophisticated investigations e,g, MRI, EEG, immunoassays, genetic testing, etc. Prescribing , Accessing, Interpreting, etc.
  55. 55. Lessons from history Psychiatrists rigidity against new ideas: Seductions Theory. Borderline Personality Disorder. Shell Shock and PTSD Psychological vs Organic: GPI > another mental illness treated by penicillin.
  56. 56. Lessons from history: GPI (Hurn, 1998; wikipedia)  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 of paretics.  At the turn of 20th century, “new psychiatrists” were supportive of this idea of organic cause of GPI including Emil Kraepelin. This could have contributed to:  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).
  57. 57. Lessons from history: GPI (Hurn, 1998; wikipedia)  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, etc.  After WW-II the use of penicillin to treat syphilis made general paresis a rarity.  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).
  58. 58. Thank you Comments

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