autoimmune encephlaitis.pptx by sms medical college jaipur

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1. RECENT ADVANCES ‘AUTOIMMUNE ENCEPHALITIS INCLUDING EPILEPSY ’ MODERATOR PANDURANGA.M.S Dr.Deepa Dash

2. Search strategy Database – Pubmed , Google scholar, Journals (Neurology, Brain, Lancet, JAMA , Chinese Medical Journal etc) Textbooks – Bradley etc

3. INTRODUCTION Acute encephalitis -rapidly progressive encephalopathy(usually in<6 weeks) caused by brain inflammation. Most frequently recognised causes of encephalitis are infectious Existing diagnostic criteria and consensus guidelines for encephalitis assume an infectious origin Past 10 years increasing number of non-infectious, mostly autoimmune encephalitis cases identified & some of them do not meet existing criteria -Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies . Ann N Y Acad Sci 2015; 1338: 94–114

4. INTRODUCTION Associated with antibodies against neuronal cell-surface or synaptic proteins Can resemble infectious encephalitis Difficult clinical diagnosis -similarities in clinical, imaging and laboratory findings of many forms of autoimmune and infectious encephalitis -Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies . Ann N Y Acad Sci 2015; 1338: 94–114.

5. INTRODUCTION Generally have impaired memory and cognition Clues to specific causes on history of physical examination, but often these specific signs are absent A broad approach to testing for infectious diseases and various neuronal autoantibodies can lead to the correct diagnosis Clear autoimmune cause for the symptoms is established- treatment usually involves escalating immune therapies - The Diagnosis and Treatment of Autoimmune Encephalitis, J Clin Neurol 2016;12(1):1-13

6. INTRODUCTION Discovery of autoantibodies led to the emergence of the novel concepts of autoimmune encephalitis[1] Emergence in the recognition of immunemediated epilepsy of paraneoplastic or nonparaneoplastic etiology [2] Some have identified antibodies and others associated with syndromes having yet unidentified/unknown antibodies[2] Advances in AE research in the past 10 years led to the identification of new syndromes and biomarkers -transformed the diagnostic approach to these disorders[3] [ 1] Bien CG. Value of autoantibodies for prediction of treatment response in autoimmune epilepsy: Epilepsia 2013;54:48-55. [ 2] Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008;7:32740. [3] A clinical approach to diagnosis of autoimmune encephalitis Lancet Neurol 2016

7. Diagnostic criteria for possible autoimmune encephalitis Diagnosis can be made when all three of the following criteria have been met: 1) Subacute onset (rapid progression of less than 3 months) of working memory deficits (short-term memory loss), altered mental status, or psychiatric symptoms 2) At least one of the following: • New focal CNS findings • Seizures not explained by a previously known seizure disorder • CSF pleocytosis (WBC count of more than five cells per mm3) • MRI features suggestive of encephalitis 3 )Reasonable exclusion of alternative causes

8. EXCLUSION OF OTHER AUTOIMMUNE DISORDERS ADEM- The characteristic brain lesions, involvement of the optic nerves or spinal cord Multiple sclerosis (MS) -more focal symptoms and characteristic brain imaging findings Lupus -causing neuropathy, vasculitis , myelitis , venous sinus thrombosis,stroke , etc.... Vasculitis affecting the CNS

9. EXCLUSION OF INFECTIOUS CAUSES Most cases of infectious encephalitis are viral-HSV, VZV, enterovirus,West Nile virus (WNV),JE Bacterial - listeria , atypical presentations of streptococcus, syphilis,Lyme disease, and TB. Fungal -Cryptococcus or aspergillis are particularly likely in immunocompromised patients

10. EXCLUSION OF OTHER MEDICAL CAUSES Wernicke encephalitis Intoxications such a neuroleptic malignant syndrome and serotonin syndrome

11. SUBTYPES OF AUTOIMMUNE ENCEPHALITIS First group -classic paraneoplastic -antibodies to intracellular antigens- involve T-cell responses targeting neurons The prognosis tends to be poor due to irreversible - neuronal killing - severity of associated cancers -difficulty in controlling these sorts of immune response

12. SUBTYPES OF AUTOIMMUNE ENCEPHALITIS Second group - autoantibodies to extracellular epitopes of ion channels, receptors and other associated proteins (NMDA receptor) The cancer associations are variable, and the prognosis tends to be much better. Causes reversible effects on synaptic function in neurons with relatively little neuronal death

13. SUBTYPES OF AUTOIMMUNE ENCEPHALITIS Occupying an intermediate position - autoantibodies to intracellular synaptic proteins such as GAD65. A final group - other forms of AE -precise antigens are less clearly established, such as lupus cerebritis or ADEM

14. Functions of cell surface antigens Most of the novel cell surface antigens - involved in synaptic transmission, plasticity, and neuronal excitability. Immune-mediated dysfunction of these proteins results in prominent neuropsychiatric symptoms, such as catatonia, psychosis, Focal deficits-uncommon seizures, movement disorders, rapidly progressive memory loss or dementia

15. In 2005- psychiatric symptoms, memory loss, decrease consciousness and central hypoventilation described in 4 young women with ovarian teratoma .1 Named “anti-NMDAR encephalitis”, has since been recognized in patients of all ages, but frequently in young adults and children.2 -1 Paraneoplastic encephalitis,psychiatric symptoms, and hypoventilation in ovarian teratoma . Ann Neurol. 2005 - 2 Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008 Anti NMDA-R encephalitis

16. Epidemiological studies suggest M.C cause of autoimmune encephalitis after acute demyelinating encephalomyelitis (ADEM).1 center focused in the study of encephalitis of unclear etiology -frequency of anti-NMDAR encephalitis surpassed that of any specific viral etiologies in young individuals.2 1- Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis.2010 2- The Frequency of autoimmune N-Methyl-D- Aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis. 2012; Anti NMDA-R encephalitis

17. Treatment and prognostic factors for long-term outcome in patients with anti- N-Methyl-D- Aspartate (NMDA) receptor encephalitis: a cohort study, Lancet Neurol. 2013 February Of 577 patients Treatment effects and outcome were assessable in 501 (median follow-up 24 months) 212 were children (<18 years) 220(38%) - had an underlying neoplasm Of these, 213 were women (representing 46% of all women). predominated in patients b/n 12 and 45 years 207 tumors (94%) were ovarian teratomas , 4 (2%) extraovarian teratomas , and 9 (4%) other tumors (2 of each, lung, breast, testicular; 1 ovarian carcinoma, 1 thymic carcinomas,and 1 pancreatic cancer). 6 of the 9 patients with tumors other than teratomas were older than 45 years

18. N=577, <18=212, >18=365

19. Clinical Features: Neuropsychiatric features ( 80-90%) Behaviour changes Loss of memory Seizures- GTCS, status, dystonic fits Cognitive dysfunctions Psychosis Dyskinesias - orofacial Catatonia Sleep disorder- excessive day time sleepiness ( decreased hypocretin ) Mutism Autonomic dysfunction hypoventilation

20. Treatment and prognostic factors for long-term outcome in patients with anti- N-Methyl-D- Aspartate (NMDA) receptor encephalitis: a cohort study, Lancet Neurol. 2013 February MRI of the brain, EEG and CSF studies were abnormal in 180/540 (33%), 432/482 (90%) and 418/532 (79%) patients, respectively NMDAR antibodies showing more sensitivity in CSF than serum(100 % vs 85%, p<0・0001) 472 (94%)underwent first-line immunotherapy or tumor removal, resulting in improvement within four weeks in 251 (53%) Of 221 patients who failed first-line therapy, 125 (57%) received second-line immunotherapy resulting in better outcome than those who did not (OR 2・69, CI 1・24-5・80,p=0・012). During the first 24 months, 394/501 reached good outcome ( mRS 0-2; median 6 months), and 30 died.

21. Treatment and prognostic factors for long-term outcome in patients with anti- N-Methyl-D- Aspartate (NMDA) receptor encephalitis: a cohort study, Lancet Neurol. 2013 February Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (OR 0・62, CI 0・50-0・76, p<0・0001) and lack of ICU admission (OR 0.12, CI 0・06-0・22,p<0・0001). 45 patients had one or multiple relapses (representing a 12% risk within 2 years); 46/69 (67%) relapses were milder than previous episodes (p<0・0001).

22. EEG “ Extreme delta brush” pattern : - 7 of 23 (30%) adult patients - Did not vary with sleep-wake cycles, and did not change significantly with stimulation or level of arousal. - Detection of the EDB pattern significantly associated with prolonged hospitalization - The pattern resolved when the patients improved. (Schmitt SE, Pargeon K, Frechette ES, et al. “Extreme Delta Brush”: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology (in press 2012).

23. DELTA BRUSH PATTERN EXTREME DELTA BRUSH PATTERN Seen in premature infants disappear by 1 month post-term Seen in NMDA-R encephalitis Combination of delta frequency transients with superimposed 8−20 Hz fast activity Nearly continuous combination of delta activity (1–3 Hz) with superimposed fast activity (20–30 Hz) usually in the [beta] range; They are frequently symmetric but are not typically synchronous. It is most often symmetric and synchronous,  They can be seen in any head region but are less common in the frontal regions Detected broadly across all head regions with predominance in frontal regions

24. DELTA BRUSH PATTERN EXTREME DELTA BRUSH PATTERN

25. FDG-PET Relative frontal and temporal glucose hypermetabolism associated with occipital hypometabolism . This gradient of brain glucose metabolism correlated with clinical disease severity, and normalized when the patients recovered. ( Leypoldt F, Buchert R, Kleiter I, et al. Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D- aspartate receptor encephalitis: distinct pattern of disease. J Neurol Neurosurg Psychiatry Epub 2012 May 7 )

26. Anti-NMDAR (NR1) encephalitis

27. 250 patients with anti-NMDA receptor encephalitis All 250 patients had NMDA receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100·0% [98·5—100·0%]  vs  85·6% [80·7—89·4%], p<0·0001). Nuria et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study The Lancet Neurology, 2014,Volume 13, Issue 2;167-77 Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study

28. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study CSF and serum titres were higher in patients with poor outcome than in those with good outcome ( p=0·0025) In patients with teratoma than in those without teratoma (CSF 395  vs  110, difference 285 [134—437], p=0·0079; serum 5515  vs  1644, difference 3870 [548—7193], p=0·024). Nuria et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study The Lancet Neurology, 2014,Volume 13, Issue 2;167-77

29. Relapses were associated with a change in titre more often in CSF than in serum (14 of 19  vs  seven of 16, p=0·037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Nuria et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. The Lancet Neurology, 2014,Volume 13, Issue 2;167-77 Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study

30. Interpretation The sensitivity of NMDA receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour . The titre change in CSF was more closely related with relapses than was that in serum. Nuria et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study The Lancet Neurology, 2014,Volume 13, Issue 2;167-77

31. HERPES SIMPLEX ENCEPHALITIS TRIGGERS SYNAPTIC AUTOIMMUNITY There is recent evidence that HSE triggers synaptic autoimmunity This finding likely explains cases with prolonged or atypical neurological symptoms after successful control of the viral infection. Patients who develop a syndrome described as relapsing post-HSE or choreoathetosis post-HSE .

32. HERPES SIMPLEX ENCEPHALITIS These disorders are important to recognize because the outcome without immunotherapy is usually poor [1] In contrast, aggressive immunotherapy appears to be beneficial, sometimes with substantial recoveries [1] Choreoathetosis post-HSE usually develops a few weeks after patients have recovered from HSE [1] 13/44(30%) had anti NMDA,suggesting secondary autoimmune mechanisms[2] [ 1] Thaı´s Armanguea et al. Autoimmune encephalitis as differential diagnosis of infectious encephalitis Curr Opin Neurol 2014, 27:361–368 (n-203) -[2] Armangue T, Leypoldt F, Malaga I, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol 2014; 75:317–323 .

33. INFECTIOUS ENEPHALITIS AUTOIMMUNE ENCEPHALITIS Can occur both in immunocompetent & immunocompromised patients Immunocompetent (22% ) > immunocompromised (3%) Most patients have fever on presentation 50 % have fever during the course of the disease. Prodromal symptoms such as headache or flu-like symptoms occur frequently Seizures can occur in HSE VERY COMMON(88%) (HHV6), neurosyphilis , and HSE- MRI features like AIE Uni /bilateral increased T2/ (FLAIR) signal in the medial temporal lobes without contrast enhancement or abnormal diffusion-weighted images CSF lymphocytic pleocytosis , skin lesions CSF lymphocytic pleocytosis-mild,skin lesions uncommon

34. Hashimoto’s encephalitis Also k/a steroid responsive encephalopathy Case series of 15 patients ( 2005 to 2011) Median age – 44 yrs( 9-78yrs ) Pediatric presentation: 22% Females(81% ) Relapsing remitting type ( 60% ) Tang Y et al. Clinical features and outcomes of patients with Hashimoto's encephalopathy, Zhonghua Yi Xue Za Zhi . 2014 Mar 11;94(9):670-3

35. Hashimoto’s encephalitis Thyroid status : goiter - 62 % subclinical hyperthyroidism- 35% euthyroid - 30% overt hypothyroidism - 20% hyperthyroidism - 7% Tang Y et al. Clinical features and outcomes of patients with Hashimoto's encephalopathy, Zhonghua Yi Xue Za Zhi . 2014 Mar 11;94(9):670-3

36. Clinical features: Tremor - 84% Transient aphasia - 73% Seizures- status 12%, myoclonus 38% Hypersomnolence 63% Gait ataxia - 63% Psychosis( paranoid, visual hallucinations) - 36% Stroke like episodes (partial right paralysis) - 27% Tang Y et al. Clinical features and outcomes of patients with Hashimoto's encephalopathy, Zhonghua Yi Xue Za Zhi. 2014 Mar 11;94(9):670-3

37. Hashimoto’s encephalitis Antithyroid antibodies: elevated anti TPO – 100 % elevated anti-M – 95% elevated anti TG- 73% 10 patients on steroid therapy, recovery (n = 5), improvement with residual deficits (n = 2) and relapse or no effect (n = 3). Among 5 patients on non-steroid, there were stable remission with antiepileptic drugs (n = 3) and continuous deterioration (n = 2) Tang Y et al. Clinical features and outcomes of patients with Hashimoto's encephalopathy, Zhonghua Yi Xue Za Zhi . 2014 Mar 11;94(9):670-3

38. VGKC-complex/LGI1-antibody encephalitis: Clinical manifestations and response to immunotherapy Journal of Neuroimmunology;2013,oct

39. Anti AMPA –R( alfa-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid )encephalitis Behavioral change Confusion, confabulation, agitation, combativeness, perseveration Short term memory loss Epilepsy: focal motor, GTCS Dysdiadochokinesias , gait ataxia Insomnia, lethargy, decreased level of consciousness

40. Encephalitis and AMPA receptor antibodies Novel findings in a case series of 22 patients Neurology®2015;84:2403–2412 Median age was 62 years (range 23–81 12 (55%) presented with distinctive limbic encephalitis (LE) 8 (36%) with limbic dysfunction along with multifocal/diffuse encephalopathy, 1 with LE preceded by motor deficits, and 1 with psychosis with bipolar features

41. Encephalitis and AMPA receptor antibodies Novel findings in a case series of 22 patients Neurology®2015;84:2403–2412 14 (64%) had a tumor (5 lung, 4 thymoma , 2 breast, 2 ovarian teratoma,1 lung) Treatment and outcome were available from 21 patients (median follow-up 72 weeks) 5 had good response to immunotherapy and tumor therapy 10 partial response, and 6 did not improve Eventually 5 patients died; all had a tumor or additional paraneoplastic symptoms

42. Brain MRI -Mild increased signal in medial temporal lobes

43. Limbic Encephalitis Associated with Anti‑γ‑aminobutyric Acid B Receptor Antibodies: A Case Series from China Patients with encephalitis of unknown etiology /suspected AE Sera, CSFs, and sera‑CSFs pairs from 4320 patients b/n Sept 2012 and Sept 2014 18 patients anti‑GABA B-R antibodies 404 others- NMDAR n = 360, LGI1 n = 35; CASPR2 n = 6, AMPAR n = 3 Anti‑GABABR antibodies -found in both serum and CSF of 16 patients. Anti‑GABA B-R antibodies only present in serum in 1 pt and 1 only in CSF

44. Limbic Encephalitis Associated with Anti‑γ‑aminobutyric Acid B Receptor Antibodies: A Case Series from China All the 18 patients presented with a clinical feature of LE. 17 (94.4%) presented with new‑onset seizure 16 (88.9%) presented with seizure as the initial symptom. All the 17 patients eventually developed GTCS None achieved seizure‑free on initial anti‑epileptic medication. 4 patients developed generalized status epilepticus refractory to multiple anticonvulsants 12 (66.7%) patients had memory deficits and 11 (61.1%) had personality change(confusion or hallucinations). 7 (38.9%)had a disturbance of consciousness. Speech problems /aphasia were observed in 4 (22.2%) patients. 3 (16.6%)patients showed cerebellar dysfunction

45. Anti-GAD encephalitis : presynaptic encephalitis Anti-GAD is associated with: Encephalomyelitis/limbic encephalitis with/without associated neoplasm Paraneoplastic cerebellar ataxia (PCD) Refractory seizures SPS including variants: Progressive encephalomyelitis with rigidity and myoclonus (PERM) Diabetes mellitus Malter MP, Helmstaedter C, Urbach H, et al. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol. 2010; 67(4): 470-8 .

46. Anti-GAD encephalitis (n-9)

47. ANTI GABA-A RECEPTOR ENCEPHALITIS The most recently identified autoimmune encephalitis. High titers -result in refractory seizures and status epilepticus , along with extensive MRI cortical/ subcortical FLAIR changes. Low titers -associate with encephalitis and seizures, but also with opsoclonus and stiff-person syndrome 40% of the patients are children Patients with GABA A-R antibodies are often misdiagnosed as having anti-GAD65-associated encephalitis or Hashimoto’s encephalitis due to the frequent co-occurrence of GAD65 or thyroid peroxidase (TPO) antibodies Philippa Pettingill , Dphil et al ,Antibodies to GABAA receptor alfa1 and gamma2 subunits, Neurology, January 30, 2015

48. Philippa Pettingill , Dphil et al ,Antibodies to GABAA receptor alfa1 and gamma2 subunits, Neurology, January 30, 2015 GABAAR-Abs were identified in 40 of 2,046 (2%) referred sera previously found negative for neuronal antibodies The clinical features of 15 patients included seizures (47%), memory impairment (47%), hallucinations (33%), or anxiety (20%) Most patients had not been given immunotherapies Future prospective studies, detecting GABAAR-Abs at onset and testing CSF, with judicious use of immunotherapy will be important in determining their clinical relevance

49. The Diagnosis and Treatment of Autoimmune Encephalitis J Clin Neurol 2016

50. Typical MRI of limbic encephalitis (A) with bilateral abnormalities in the medial temporal lobe on T2-weighted FLAIR; this patient with autopsy-proven limbic encephalitis did not have serum or CSF antineuronal antibodies. Patient with final diagnosis of glioma (B) who presented with unilateral right hippocampal involvement mimicking limbic encephalitis. Typical MRI of acute disseminated encephalomyelitis (C) with bilateral large lesions in the white matter.

51. Multiple lesions involving the corpus callosum in a patient with Susac’s syndrome (D). MRI of a patient with overlapping syndrome (NMDA receptor and myelin oligodendrocyte glycoprotein antibodies; E) showing a right frontal abnormality compatible with demyelination . Diffusion MRI sequence in a patient with AMPA receptor antibody-associated encephalitis (F) mimicking MRI changes seen in patients with Creutzfeldt-Jakob disease

52. New-onset refractory status epilepticus ; Etiology , clinical features, and outcome . 2015 American Academy of Neurology Retrospective review of patients with RSE without etiology identified within 48 hours of admission between January 1, 2008, and December 31, 2013, 13 academic medical centers The primary outcome measure was poor functional outcome at discharge (defined as a score >3 on the modified Rankin Scale)

53. New-onset refractory status epilepticus , Etiology , clinical features and outcome . 2015 American Academy of Neurology The inclusion criteria were as follows: (1) age 18 years or older; (2) SE refractory to appropriate doses of 2 lines of anti-seizure treatment (3) No definite etiology identified by history and ancillary tests within the first 48 hours after admission ( excluding acute brain injury, bacterial meningitis or abscess, herpes encephalitis,known seizure disorder, acute medical condition); (4) >24 hours of continuous EEG (CEEG) monitoring; and (5) paraneoplastic /autoimmune panel ordered

54. New-onset refractory status epilepticus , Etiology , clinical features and outcome. 2015 American Academy of Neurology Of 130 cases, 67 (52%) remained cryptogenic. The most common identified etiologies were autoimmune (19%) and paraneoplastic (18%) encephalitis Poor outcome occurred in 77 of 125 cases (62%), and 28 (22%)died. Among the 63 patients with available follow-up data (median 9 months), functional status improved in 36 (57%); 79% had good or fair outcome at last followup Epilepsy developed in 37% with most survivors (92%) remaining on anti-seizure medications. Immune therapies were used less frequently in cryptogenic cases

55. Autoimmune encephalitis: A potentially reversible cause of status epilepticus , epilepsy, and cognitive decline Awadh Kishor Pandit 1 ,  Kavish Ihtisham 1 ,  Ajay Garg 2 ,  Sheffali Gulati 3 ,  Madakasira Vasantha Padma 1 ,  Manjari Tripathi 1 1  Department of Neurology, All India Institute of Medical Sciences, New Delhi, India  15 (males = 10) The mean age - 24 years (range: 2-64 years). subacute (64%) and four (29%) patients presented as SE. Predominant clinical presentations were seizures (100%) CSF was normal in 60%. (6/10, mild raised protein & raised cell counts ) Brain MRI was done in all patients, in 6 (40%) normal, six (40%) T2W and FLAIR hyperintensities in B/L limbic areas.( b/l BG atrophy , rt insular cortex hyperintensities , B/L post hyperintensities )

56. NMDA R antibody in seven (50%), VGKC antibody in five (36%), two of anti GAD, and one patient with ds-DNA antibodies. None showed evidence of malignancy. Patients received immunotherapy, either steroids, intravenous immunoglobulin, or both. Follow-up showed significant improvement in majority of cases(67%) Autoimmune encephalitis: A potentially reversible cause of status epilepticus , epilepsy, and cognitive decline Awadh Kishor Pandit 1 ,  Kavish Ihtisham 1 ,  Ajay Garg 2 ,  Sheffali Gulati 3 ,  Madakasira Vasantha Padma 1 ,  Manjari Tripathi 1 1  Department of Neurology, All India Institute of Medical Sciences, New Delhi, India

57. -A clinical approach to diagnosis of autoimmune encephalitis,lancet neuro 2016

58. Panel 1: Diagnostic criteria for possible autoimmune encephalitis Diagnosis can be made when all three of the following criteria have been met: 1) Subacute onset (rapid progression of less than 3 months) of working memory deficits (short-term memory loss), altered mental status, or psychiatric symptoms 2) At least one of the following: • New focal CNS findings • Seizures not explained by a previously known seizure disorder • CSF pleocytosis (WBC count of more than five cells per mm3) • MRI features suggestive of encephalitis 3 )Reasonable exclusion of alternative causes -A clinical approach to diagnosis of autoimmune encephalitis,lancet neuro 2016

59. Panel 2: Diagnostic criteria for definite autoimmune limbic encephalitis Diagnosis can be made when all four of the following criteria have been met: 1) Subacute onset (rapid progression of less than 3 months) of working memory deficits, seizures, or psychiatric symptoms suggesting involvement of the limbic system 2) Bilateral brain abnormalities on T2-weighted fluid-attenuated inversion recovery MRI highly restricted to the medial temporal lobes 3) At least one of the following: CSF pleocytosis (white blood cell count of more than five cells per mm3) EEG with epileptic or slow-wave activity involving the temporal lobes 4) Reasonable exclusion of alternative causes

60. Panel 3: Diagnostic criteria for definite acute disseminated encephalomyelitis Diagnosis can be made when all five of the following criteria have been met: 1) A first multifocal, clinical CNS event of presumed inflammatory demyelinating cause 2) Encephalopathy that cannot be explained by fever 3) Abnormal brain MRI: • Diffuse, poorly demarcated, large (>1–2 cm) lesions predominantly involving the cerebral white matter • T1-hypointense lesions in the white matter in rare cases • Deep grey matter abnormalities ( eg , thalamus or basal ganglia) can be present 4) No new clinical or MRI findings after 3 months of symptom onset 5) Reasonable exclusion of alternative causes

61. Panel 4: Diagnostic criteria for anti-NMDA receptor encephalitis Probable anti-NMDA receptor encephalitis* Diagnosis can be made when all three of the following criteria have been met 1) Rapid onset (less than 3 months) of at least four of the six following major groups of symptoms • Abnormal (psychiatric) behaviour or cognitive dysfunction • Speech dysfunction (pressured speech, verbal reduction, mutism ) • Seizures • Movement disorder, dyskinesias , or rigidity/abnormal postures • Decreased level of consciousness • Autonomic dysfunction or central hypoventilation 2) At least one of the following laboratory study results • Abnormal EEG (focal / diffuse slow or disorganised activity, epileptic activity, or extreme delta brush) • CSF with pleocytosis or oligoclonal bands 3) Reasonable exclusion of other disorders Diagnosis can also be made in the presence of three of the above groups of symptoms accompanied by a systemic teratoma

62. Panel 5: Diagnostic criteria for Bickerstaff ’s brainstem encephalitis Probable Bickerstaff ’s brainstem encephalitis Diagnosis can be made when both of the following criteria have bee met 1) Subacute onset (rapid progression of less than 4 weeks) of all the following symptoms • Decreased level of consciousness • Bilateral external ophthalmoplegia • Ataxia 2) Reasonable exclusion of alternative causes Definite Bickerstaff ’s brainstem encephalitis Diagnosis can be made in the presence of positive IgG anti-GQ1b antibodies even if bilateral external ophthalmoplegia is not complete or ataxia cannot be assessed, or if recovery has occurred within 12 weeks after onset

63. Panel 6: Diagnostic criteria for Hashimoto’s encephalopathy Diagnosis can be made when all six of the following criteria have been met: 1) Encephalopathy with seizures, myoclonus , hallucinations,or stroke-like episodes 2) Subclinical or mild overt thyroid disease (usually hypothyroidism) 3 )Brain MRI normal or with non-specific abnormalities 4) Presence of serum thyroid (thyroid peroxidase,thyroglobulin ) antibodies 5 )Absence of well characterised neuronal antibodies in serum and CSF 6) Reasonable exclusion of alternative causes

64. Panel 7: Criteria for autoantibody-negative but probable autoimmune encephalitis Diagnosis can be made when all four of the following criteria have been met: 1) Rapid progression (less than 3 months) of working memory deficits (short-term memory loss), altered mental status, or psychiatric symptoms 2 )Exclusion of well defined syndromes of autoimmune encephalitis ( eg , typical limbic encephalitis, Bickerstaff ’s brainstem encephalitis, acute disseminated encephalomyelitis) 3) Absence of well characterised autoantibodies in serum and CSF, and at least two of the following criteria: • MRI abnormalities suggestive of autoimmune encephalitis • CSF pleocytosis , CSF-specific oligoclonal bands or elevated CSF IgG index, or both • Brain biopsy showing inflammatory infiltrates and excluding other disorders ( eg , tumour) 4) Reasonable exclusion of alternative causes

65. Take home messages Proper diagnosis and management of autoimmune encephalitis requires an organized approach Autoimmune encephalitis is an important differential for those with Neuropsychiatric features with abnormal movements Sensitivity of NMDA receptor antibody testing is higher in CSF than in serum Risk of neoplasm should always be considered during initial treatment HSE triggers synaptic autoimmunity - relapsing post-HSE NORSE- Autoimmune encephalitis Most patients with autoimmune encephalitis respond to immunotherapy.