presentation on Autoimmune Encephalitis.pptx

a presentation on autoimmune encephalitis, paraneoplastic syndrome. their types and various imaging and lab finding
their differential diagnosis
acute and long term management plans

1. Autoimmune Encephalitis Dr Sumeet Singh Senior Resident Neurology GMC Kota

2. Case scenario A 61-year-old male with a history of coronary artery disease, hypertension, and hyperlipidemia presented to the hospital on April of 2017 with complains of confusion and somnolence for 7 days He had delayed recall and poor concentration . Serum chemistries found hyponatremia, and cerebral edema was noted on the computed tomography (CT) scan of the head. A lumbar puncture revealed clear CSF fluid with 25 leukocytes/ μ L (88% lymphocytes), 240 erythrocytes/ μ L , and the protein level was 94 mg/dL . A Gram stain of the CSF revealed no organisms The remainder of his tests, including serum chemistry panel, liver function panel, complete blood count, serum ammonia level, thyroid function test, and urinalysis, were normal. The urine drug screen and serum toxicology screen were negative. He was empirically started on intravenous (IV) vancomycin, cefepime, and acyclovir for presumed meningoencephalitis . A magnetic resonance imaging (MRI) scan of the brain showed edema in the right frontotemporal lobes and left frontal lobe . EEG showed focal slowing in the right frontal/parietal regions without any epileptic discharges. The result of CSF HSV-1 polymerase chain reaction (PCR) test was positive, which confirmed the diagnosis of HSV-1 encephalitis . He was treated with 21 days of IV acyclovir transferred to an inpatient rehabilitation unit. At the time of his discharge from rehabilitation, he continued to demonstrate severe cognitive and linguistic deficits.  In June 2017, he was readmitted for pronounced confusion and erratic and aggressive behavior

3. So why he did not improve and presented with relapse ? A lumbar puncture was negative for HSV PCR, but a paraneoplastic CSF panel revealed anti-NMDAR antibodies suggestive of post-HSVE autoimmune encephalitis . He underwent therapy with serial plasma exchange cycles, but demonstrated mild improvement and remained far from his baseline personality and cognitive function. On discharge his MoCA score was 10/30 with significant deficits in the domains of visuospatial/executive, delayed recall, language, and orientation. The MRI of his brain at that time showed extensive signal intensities in the frontal and temporal lobes bilaterally. In January 2018, he relapsed again with worsening agitation, confusion, and frequent mood swings. Brain MRI showed worsening enhancement of the previously affected areas CSF HSV PCR remained negative, and CSF studies did not suggest acute infection. CSF and serum anti-NMDAR antibody tests were positive with titers of 1 : 10 and 1 : 80, respectively A PET/CT scan did not show any occult malignancy, and expanded testing for infectious etiologies including toxoplasmosis and Lyme disease was negative. Serial PLEX therapy alleviated his symptoms reflected by improved MoCA scores ranging from 24 to 26/30 while inpatient. Repeat brain MRI in March 2018 did not show any new changes. Outpatient therapy initiated with rituximab in April 2018 but in July 2018, had another acute decline treated with PLEX and steroid therapy. In September 2018, monthly cyclophosphamide therapy was started This is a case of post HSVE autoimmune encephalitis(anti NMDA R) presenting with recurrent relapses

4. Introduction Acute encephalitis - rapidly progressive encephalopathy(usually in <6 weeks) caused by brain inflammation. Most f r eq u ently recognized causes o f enc e p halitis are infectious . In last two decades i n cr e asing nu m ber o f non - i n fect io u s, most ly autoimmune encephalitis cases have been identified Autoimmune encephalitis is characterized by antibodies against intra cellular (classic paraneoplastic) , neuronal cell-surface or synaptic proteins. Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 2011; 10:759

5. Introduction….. These disorders can occur with and without a cancer association Can affect individuals of all ages, some syndromes preferentially affect young adults and children Patients can have complex neuropsychiatric symptoms including memory loss, changes in behaviour or cognition, psychosis, seizures and movement disorders. Initially can be diagnosed as idiopathic encephalitis, likely viral but with negative viral studies. Thes antibodies against cell surface/synaptic protein cause neuronal dysfunction by altering synaptic transmission through cross-linking and internalization of the receptors , preventing neurotransmitter binding, or disrupting ion channel function Antibodies in paraneoplastic syndrome(intracellular) causes cytotoxic T cell-mediated damage to neuronal structures or produce significant neuronal apoptosis

6. Clues To An Autoimmune Etiology Change in baseline neurologic function Subacute onset (days to weeks) & fluctuating course Systemic markers of autoimmunity : elevated ANA or TPO antibodies History of tumor or concurrent malignancy CSF studies : El evated WBC (<100cells/µl), protein (<100mg/dl), IgG index, oligoclonal bands. EEG : Focal abnormalities, epileptiform discharges, slowing, etc MRI : T2/FLAIR abnormalities in temporal lobes or other part of brain Response to immunosuppression Identification of a neural autoantibody in CSF or Serum

7. Diagnosis of possible autoimmune encephalitis 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, and/or psychiatric symptoms 2 At least one of the following: New focal central nervous system findings Seizures not explained by a previously known seizure disorder CSF pleocytosis (white blood cell count of more than 5 cells/mm3) MRI features suggestive of encephalitis 3 Reasonable exclusion of alternative causes Prüss H, Dalmau J, Harms L, et al. Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin. Neurology 2010; 75:1735 .

8. Diagnosis of definite autoimmune encephalitis 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, and/or psychiatric symptoms suggesting involvement of the limbic system 2 Bilateral brain abnormalities on T2-weighted FLAIR MRI highly restricted to the mesial temporal lobes 3 At least one of the following: CSF pleocytosis (white blood cell count of more than 5 cells/mm) EEG with epileptic or slow-wave activity involving the temporal lobes Antibody positivity in serum or CSF 4 Reasonable exclusion of alternative causes Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15:391 .

9. Red Flags in Autoimmune Encephalitis Diagnosis Clinical: Insidious onset Multiple comorbidities that cause cognitive deficits such as polypharmacy, chronic pain, fibromyalgia, sleep disorders Examination results consistent with a functional neurologic disorder Features of mitochondrial disease present Normal neuropsychological test results Diagnostic: Normal MRI brain or progressive atrophy without signal abnormalities or enhancement Lesions continue to expand despite immunotherapy Noninflammatory CSF

10. Anti-NMDAR Encephalitis Anti-NMDAR encephalitis is the most frequent antibody associated encephalitis and the second most common cause of immune-mediated encephalitis after ADEM Mostly seen in young women and children( 80% of patients), but can also affect men and older individuals Approximately 45% of female patients over 18 years have uni - or bilateral ovarian teratomas compared to less than 9% of girls under 14 years of age Patients develop acute psychiatric symptoms, seizures, memory deficits, decreased level of conscious ness, and dyskinesias (orofacial, limb, and trunk) often preceded by a viral-like prodrome . Atypical symptoms such as cerebellar ataxia or hemiparesis can occur and are more common in children than in adults Autonomic instability is common and in about half of the patients results in central hypoventilation often requiring weeks of mechanical ventilation. Prüss H, Dalmau J, Harms L, Höltje M, Ahnert-Hilger G, Borowski K, Stoecker W, Wandinger KP. Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin. Neurology. 2010 Nov 9;75(19):1735-9.

11. Diagnostic Criteria For Anti-NMDAR Encephalitis Probable anti-NMDA receptor encephalitis Diagnosis can be made when all three of the following criteria have been met: 1. Sub acute onset (less than 3 months ) of at least 4 of the 6 major group of symptoms Abnormal (psychiatric) behaviour or cognitive dysfunctions Speech dysfunctions(pressured speech ,verbal reduction, mutism) Seizures Movement disorders , dyskinesis or rigidity/abnormal posture Decreased level of consciousness Autonomic dysfunction and central hypoventilation 2. At least one of the following laboratory study results: Abnormal EEG(focal or diffuse slow or disorganised activity, epileptic activity or extreme delta brush ) CSF with pleocytosis or oligoclonal band 3.Reasonable exclusion of other disorders Diagnosis can also be made in the presence of 3 of the above group of symptoms accompanied by systemic teratoma

12. Definite anti-NMDA receptor encephalitis Diagnosis can be made in the presence of 1 or more of the 6 major group of symptoms and IgG antibodies against GluN1(NR1) subunit of NMDA R in CSF. If only serum is available confirmatory tests like tissue immunohistochemistry in addition to cell based assay. Exclusion of recent history of Herpes simplex virus encephalitis or Japanese B encephalitis, which might result in relapsing immune mediated neurological symptoms. Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, Geis C, Lancaster E, Titulaer MJ, Rosenfeld MR, Graus F. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. The Lancet Neurology. 2019 Nov 1;18(11):1045-57 .

13. Neuroimaging About 35% of patients have increased signal on MRI FLAIR or T2 and less often, faint or transient contrast enhancement of the cerebral cortex , overlaying meninges, basal ganglia, or brainstem PET shows a characteristic increase in the frontal-occipital gradient of cerebral glucose metabolism Around 20 percent of HSV encephalitis earlier negative for anti ANDA R encephalitis go on to have positive CSF and serum antibody titers in subsequent days 14 Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008; 7:327 .

14. EEG The EEG is abnormal in 90% of cases Usually shows generalized slowing or disorganized activity without epileptic discharges that may overlap with electrographic seizures. About 30% of patients have a unique EEG pattern called extreme delta brush due to its similarity to the delta brush pattern seen in neonatal EEG . This pattern may associate with prolonged illness and it’s presence in a patient with an undiagnosed encephalopathy should raise consideration for anti-NMDAR encephalitis

15. Anti-GABA B Receptor Encephalitis Anti-gamma-aminobutyric acid B receptor (GABA B R) encephalitis affects men and women similarly More than half have an associated tumor, almost always a SCLC Older patients more likely to have cancer than younger with mean age at diagnosis around 60 years The presenting features are almost always those of typical limbic encephalitis with memory loss, confusion, and prominent seizures Most seizures appear to have a temporal-lobe onset with secondary generalization, while some patients have status epilepticus or sub clinical seizures demonstrated on EEG. van Coevorden-Hameete MH, de Bruijn MA, de Graaff E, Bastiaansen DA, Schreurs MW, Demmers JA, Ramberger M, Hulsenboom ES, Nagtzaam MM, Boukhrissi S, Veldink JH. The expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies. Brain. 2019 Jun 1;142(6):1631-43 .

16. Diagnosis MRI Brain is abnormal in almost two-thirds of the patients Unilateral or bilateral medial temporal lobe FLAIR/T2 signal consistent with limbic encephalitis CSF can show lymphocytic pleocytosis Presence of GABAB receptor antibodies in CSF and serum is diagnostic Patients often have other autoantibodies (e.g., TPO, ANA, GAD65), reflecting a tendency to autoimmunity or the presence of an underlying cancer (e.g., Sox1, Amphiphysin, and/or Ri antibodies).

17. Anti-AMPA Receptor Encephalitis Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis predominantly affects middle-aged women (median age 60 years) Patients present with subacute (<8 weeks) symptoms of limbic encephalitis including confusion, disorientation and memory loss with prominent psychiatric symptoms Seizures have been reported in just under half of cases and about 70% have an underlying tumor in the lung, breast, or thymus The antibodies target the GluR1/2 subunits of the AMPAR. Höftberger R, van Sonderen A, Leypoldt F, Houghton D, Geschwind M, Gelfand J, Paredes M, Sabater L, Saiz A, Titulaer MJ, Graus F. Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients. Neurology. 2015 Jun 16;84(24):2403-12 .

18. MRI brain- abnormal FLAIR signal involving cortex, subcortical, and deep white matter in the medial temporal lobes, posterior temporal and parieto-occipital regions CSF often reveals lymphocytic pleocytosis Half of the patients have a concurrent findings of systemic autoimmunity such as insulin-dependent diabetes with GAD antibodies, hypothyroidism, Raynaud syndrome, or stiff-person syndrome

19. Anti-LGI1 Limbic Encephalitis Anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis pre dominantly occurs in older men (median age 60 years) who develop memory loss, confusion, and temporal lobe seizures About 60-65 %of patients develop hyponatremia and less often rapid eye movement (REM) sleep behavior disorders Some patients develop brief tonic or myoclonic-like seizures (also called Faciobrachial dystonic seizures ) that precede the memory and cognitive deficits The disorder is usually not cancer associated and less than 10% of patients have an underlying neoplasm, usually a thymoma The associated antibodies mostly IgG4 class target the LGI1 protein, a secreted neuronal protein that functions as a ligand for two epilepsy-related proteins, ADAM22 and ADAM23 . The binding of the antibodies to LGI1 disrupts pre- and postsynaptic LGI1 signalling, resulting in neuronal hyperexcitability. Jacob S, Irani SR, Rajabally YA, et al. Hypothermia in VGKC antibody-associated limbic encephalitis. J Neurol Neurosurg Psychiatry 2008; 79:202

20. The MRI shows findings typical of limbic encephalitis 70% of patients show high signal intensity in the bilateral hippocampus of T2 and Flair sequences on MRI. In addition to the medial temporal lobe, the basal ganglia can also be affected EEG may show no ictal findings even during focal seizures or may show temporal epileptic discharges or slowing The gold standard for diagnosis is a positive anti LGI1 antibody in serum or CSF Navarro V, Kas A, Apartis E, Chami L, Rogemond V, Levy P, Psimaras D, Habert MO, Baulac M, Delattre JY, Honnorat J. Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. Brain. 2016 Apr 1;139(4):1079-93 .

21. Semiquantitative measurement of Putaminal hypermetabolism with FDG-PET may be used to distinguish LGI1-AE from other pathologies Metabolic abnormalities in LGI1-AE also extend beyond putamen and MTL into other subcortical and cortical regions FDG-PET may be used in evaluating disease evolution in LGI1-AE.

22. Anti-CASPR2 Associated Encephalitis Patients with Contactin -associated protein-like 2 (CASPR2) antibodies usually develop Morvan syndrome characterized by rigidity, fasciculations, neuromyotonia , etc Symptoms involve both the central nervous system (encephalopathy, hallucinations, seizures, insomnia, autonomic dysfunction) and peripheral nervous system (PNH, neuropathy, allodynia) More than half of the patients complain of muscle hyperexcitability , neuropathic pain while some develop severe insomnia with abnormal motor activation Patients may have other coexisting immune mediated disorders such as Myasthenia gravis with anti acetylcholine ( AChR ) or muscle-specific kinase ( MuSK ) antibodies Anti-CASPR2 associated encephalitis is usually not cancer related and those with a tumor (most commonly thymoma) likely have Morvan syndrome

23. Over 50% of adult patients in anti-CASPR2-related encephalitis have intensity changes in temporal lobe and hippocampus Patterson KR, Dalmau J, Lancaster E. Mechanisms of C aspr2 antibodies in autoimmune encephalitis and neuromyotonia . Annals of neurology. 2018 Jan;83(1):40-51.

24. Anti-GABA A Receptor Encephalitis Usually presents with rapidly progressive, severe encephalopathy that results in refractory seizures, stiff-person syndrome and opsoclonus myoclonus. Most of the patients had coexisting autoimmunity including antibodies to GAD, TPO, and GABA B R. Seizures are preceded by or associated with a change in behavior or cognition. Can affect children and elderly( 2 years – 75 years) CSF shows pleocytosis, increased proteins, and/or oligoclonal bands Most patients have high titers of antibodies to the gamma-aminobutyric acid A receptor (GABA A R) in both CSF and serum Spatola M, Petit- Pedrol M, Simabukuro MM, Armangue T, Castro FJ, Barcelo Artigues MI, Julià Benique MR, Benson L, Gorman M, Felipe A, Caparó Oblitas RL. Investigations in GABAA receptor antibody-associated encephalitis. Neurology. 2017 Mar 14;88(11):1012-20 .

25. Neuroimaging MRI abnormalities on FLAIR and T2 imaging with multifocal cortical-subcortical involvement without contrast enhancement and no significant diffusion restriction Around 50% respond to immunotherapy

26. Anti-DPPX Encephalitis Associated with antibodies to dipeptidyl peptidase-like protein-6 (DPPX) Affects adults age 45–76 years Patients present with prominent neuropsychiatric symptoms preceded by intense diarrhea Clinical symptoms include agitation, paranoia, hallucinations, myoclonus, tremor, and/or seizures, cerebellar signs such as ataxia or nystagmus and hyperekplexia . Rarely associated with cancer and has high rates of relapses MRI shows lesions in hippocampus, amygdala, cingulum, and temporo-occipital cortex and milder involvement of the pons, cerebellum, and medulla. Hara M, Ariño H, Petit- Pedrol M, Sabater L, Titulaer MJ, Martinez-Hernandez E, Schreurs MW, Rosenfeld MR, Graus F, Dalmau J. DPPX antibody–associated encephalitis: Main syndrome and antibody effects. Neurology. 2017 Apr 4;88(14):1340-8.

27. Encephalitis with Antibodies to IgLON5 Characterized by antibodies targeting IgLON5, a member of the IgLON family, which is part of the immunoglobulin superfamily of cell adhesion molecules Patients have REM and NREM sleep disturbances characterized by abnormal movements and behaviors that predominated in the early hours of sleep Video polysomnography shows poorly structured NREM stage N2, along with REM parasomnias and sleep breathing disorders( obstructive sleep apnoea) The brain MRI, EEG, and CSF studies and electromyography are usually normal. A possibility of atypical tauopathy mainly involving the tegmentum of the brainstem and the hypothalamus is proposed Prognosis is bad with poor response to immunotherapy and patients usually have sudden death during wakefulness. Grüter T, Möllers FE, Tietz A, Dargvainiene J, Melzer N, Heidbreder A, Strippel C, Kraft A, Höftberger R, Schöberl F, Thaler FS. Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease. Brain. 2023 Feb 1;146(2):600-11 .

28. Stiff-Person Spectrum Disorder and Antibodies to Glycine Receptors These include Stiff-person syndrome (SPS), progressive encephalomyelitis with rigidity and myoclonus (PERM), stiff-leg syndrome (SLS) Mostly associated with antibodies to GAD65 and Amphiphysin, both intracellular neuronal antigens A small group of patients with features consistent with PERM have been reported with antibodies to the alpha subunit of the cell surface glycine receptor Clinical features- alterations of behavior and sleep, seizures, trismus , or neurogenic pruritus, optic neuritis, and cerebellar degeneration Mostly not related to cancer and often have good responses to immunotherapy. Carvajal-Gonzalez A, Leite MI, Waters P, Woodhall M, Coutinho E, Balint B, Lang B, Pettingill P, Carr A, Sheerin UM, Press R. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain. 2014 Aug 1;137(8):2178-92.

29. Other Autoimmune Encephalitis Anti-mGluR5 encephalitis  : Presents with prominent neuropsychiatric features, prosopagnosia, headaches, involuntary movements, and seizures. Most commonly associated with Hodgkin lymphoma ( Ophelia syndrome ) or SCLC but can also occur in the absence of a tumor CSF shows pleocytosis and MRI brain- FLAIR abnormalities in limbic or extralimbic regions Anti-mGluR1 encephalitis  : Ataxia accompanied by cognitive changes, seizures, or psychiatric symptoms. Both sexes are affected, with a slight predominance of men and a median age of 55 years CSF- abnormal in 75% with pleocytosis, oligoclonal bands or increased IgG index Brain MRI is normal in most patients but can show cerebellar T2 hyperintensities or, less frequently, leptomeningeal enhancement Mat A, Adler H, Merwick A, Chadwick G, Gullo G, Dalmau JO, Tubridy N. Ophelia syndrome with metabotropic glutamate receptor 5 antibodies in CSF. Neurology. 2013 Apr 2;80(14):1349-50 .

30. Autoimmune encephalitis cont …. Anti-neurexin-3 alpha encephalitis : Young patients(40-45 years) with severe encephalitis with rapid decline in consciousness, orofacial dyskinesias, and central hypoventilation Encephalopathy with antibodies against GFAP : Antibodies against glial fibrillary acidic protein (GFAP) have been described as a marker for a relapsing autoimmune meningoencephalitis or encephalitis , with or without myelitis Anti-SEZ6L2 encephalitis : Antibodies against seizure-related 6 homolog like 2 (SEZ6L2) presenting with subacute cerebellar ataxia with retinopathy Anti-AK5 encephalitis : Antibodies to adenylate kinase 5 (AK5) s with the subacute onset of a severe limbic encephalitis refractory to therapy . Present in elderly's with predominant symptoms of severe episodic amnesia, depression, anorexia, and weight loss with a male predominance Anti-Dopamine-2R encephalitis-Basal ganglia encephalitis

31. Hashimoto encephalopathy Steroid-responsive encephalopathy associated with autoimmune thyroiditis ( STREAT ) Associated with antithyroid peroxidase antibodies and antithyroglobulin antibodies A progressive or relapsing and remitting course of tremor, myoclonus, transient aphasia, stroke- lik e episodes, psychosis, seizures, encephalopathy, hypersomnolence, stupor, or coma CSF most often shows an elevated protein level with almost no nucleated cells, with oligoclonal bands . EEG shows generalized slowing ,triphasic waves, focal slowing, epileptiform abnormalities or frontal intermittent rhythmic delta activity. MRI brain is often normal but may reveal hyperintensities on T2-weighted or FLAIR in subcortical white matter or at the gray/white matter junction Serum TSH is usually normal( can be high in some cases) Patients respond to Inj. Methylprednisolone 1g/ day for 3-5 days followed by a taper of oral Prednisone

32. Paraneoplastic Neurological Syndromes Paraneoplastic neurological syndromes (PNSs) are a heterogeneous group of disorders caused by cancers not located in the central nervous system. The symptoms of PNS often occur before the presence of a systemic cancer Antibodies that target intracellular antigens (e.g., anti-Hu, Ri, Ma2) are most commonly associated Mediated by cytotoxic T-cell with prominent infiltrates of CD8+ and CD4+ T-cells The prognosis tends to be poor due to irreversible neuronal killing , severity of associated cancers

33. Paraneoplastic Anti-neuronal Antibodies, Associated Syndromes, and Cancers

34. Paraneoplastic Cerebellar Degeneration Clinical features include truncal and appendicular ataxia, dysarthria, and downbeat nystagmus preceded by dizziness and vertigo SCLC , cancer of the breast and ovary, and Hodgkin lymphoma are the most commonly associated tumors Anti- Yo is the most frequent and well-characterized antibody associated with PCD Other antibodies associated are anti-Ri, anti-Hu, anti-CV2/CRMP5 antibodies, anti-Tr or Sox1 antibodies

35. Paraneoplastic Encephalomyelitis Patient can present with cerebellar dysfunction(gait ataxia), limbic and/or brainstem encephalopathy(33%) , sensory neuronopathy, myelitis(20%) Approximately one-fourth of patients develop autonomic nervous system dysfunction Can be associated with almost any tumor, but mostly associated with lung carcinoma, particularly SCLC Patients often have anti-Hu antibodies (SCLC), and at a much lower frequency, anti-CV2/CRMP5 antibodies(thymoma), or both. Saiz A, Bruna J, Stourac P, Vigliani MC, Giometto B, Grisold W, Honnorat J, Psimaras D, Voltz R, Graus F. Anti-Hu-associated brainstem encephalitis. Journal of Neurology, Neurosurgery & Psychiatry. 2009 Apr 1;80(4):404-7 .

36. Paraneoplastic Limbic and Brainstem Encephalitis Patients have memory deficits, confusion, depression, agitation, and anxiety, complex partial seizures. Brainstem encephalitis is characterized by oscillopsia, diplopia, dysarthria, dysphagia, gaze abnormalities, and subacute hearing loss Most commonly associated with SCLC , testicular germ-cell tumors, teratoma (usually of the ovary), thymoma, and Hodgkin lymphoma The main intracellular antigens involved are Hu, Ma2, and less commonly CV2/CRMP5 Antibodies to CV2/CRMP5 occur in association with encephalomyelitis, sensorimotor neuropathy, cerebellar ataxia, chorea, uveitis, and optic neuritis Patients with anti-Hu antibodies the lower brainstem is predominantly affected and symptoms progress in an upward direction Patients with anti-Ma antibodies often present with an upper brainstem syndrome with vertical gaze palsy Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, Thiessen B, Saiz A, Meneses P, Rosenfeld MR. Clinical analysis of anti-Ma2-associated encephalitis. Brain. 2004 Aug 1;127(8):1831-44.

37. Paraneoplastic Opsoclonus-Myoclonus Opsoclonus-myoclonus consists of spontaneous, arrhythmic, large-amplitude conjugate saccades occurring in all directions of gaze that are associated with myoclonus of the head, trunk, or extremities. In children, opsoclonus-myoclonus is usually a manifestation of neuroblastoma In adults, several underlying tumors have been reported, but the most common are SCLC and cancers of the breast and ovary. Anti-Ri and anti-Hu antibodies have been implicated in pathogenesis

38. Management of Autoimmune Encephalitis and Paraneoplastic syndromes Diagnosis: The diagnosis of autoimmune encephalitis is confirmed by the detection of respective antibodies in CSF (serum is less reliable) After treatment or in advanced stages of the disease, the CSF antibodies usually remain elevated if there is no clinical improvement, while serum antibodies may be substantially decreased by treatments The titer of CSF antibodies appears to correlate more closely with the clinical outcome than serum titers

39. Management cont …. USG, MRI and computed tomography (CT) of the abdomen, pelvis and chest to locate tumour or malignancies Brain MRI is often normal or shows transient FLAIR or contrast-enhancing abnormalities in cortical (brain, cerebellum) or subcortical (hippocampus, basal ganglia, white matter) regions Positron emission tomography (PET) reportedly shows a characteristic increase in cerebral glucose metabolism, which correlates with disease severity EEG can be diagnostic in some cases of anti NMDAR encephalitis Basu S, Alavi A. Role of FDG-PET in the clinical management of paraneoplastic neurological syndrome: detection of the underlying malignancy and the brain PET-MRI correlates. Mol Imaging Biol 2008; 10:131

40. Acute and long term treatment plan First line treatment: Maintain ABC, consider IV Acyclovir and higher antibiotics Main treatment consists of immunosuppression and tumor resection/chemotherapy when indicated Intravenous methylprednisolone ( e.g. 1 gram daily for five days in an adult) Intravenous immunoglobulin G (IVIG; e.g. 400 mg/kg per day for five days) or plasma exchange Second line therapies : Rituximab (either 375 mg/m weekly for 4 weeks, or 1 g twice two weeks apart) Cyclophosphamide (500-1000 mg/m 2 monthly for 4 to 6 months depending on results ), or both. An alternative approach to stepwise escalation of immunotherapy is to use rituximab in combination with steroids and IVIG or plasma exchange as initial therapy 3 rd line therapy : Tocilizumab- 4 mg/kg, followed by an increase to 8 mg/kg monthly based on clinical response (maximum dose: 800 mg) Intrathecal methotrexate-10–12 mg weekly for 3–4 weeks Nosadini M, Eyre M, Molteni E, et al. Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor Antibody Encephalitis: A Meta-analysis. JAMA Neurol 2021; 78:1333 .

41. Maintenance therapy Corticosteroids – Continued after the induction phase if a response has occurred as 1-g IV methylprednisolone infusion every 7 to 14 days with gradually increasing intervals as allowed by the clinical course. OR Daily oral prednisone at 1mg/kg may also be used if IV preparations are not easily accessible and tapered after 3 month over a period of 6-12 months . IVIg – If found effective after induction, it can be continued with gradually increasing inter dose intervals while response is monitored, most commonly monthly over the following 6 to 12 months. Dose of IVIg is 0.4g/kg . Rituximab – If found effective at induction, it needs to be readministered every 6 months to prevent relapse , given that B cells will regenerate eventually and antibody production will resume. During this time, CD19 levels can be monitored to assess for B-cell recovery. Dose of Rituximab 375mg/m 2 Nosadini M, Mohammad SS, Ramanathan S, et al. Immune therapy in autoimmune encephalitis: a systematic review. Expert Rev Neurother 2015; 15:1391 .

42. Some other proposed treatment Mycophenolate mofetil orally 500mg/day for 2 weeks followed by 1000mg per day for 3-5 years Measure Blood cell counts, renal and liver function tests at baseline, weekly for 1 month, every other week for 2 months then monthly. If Cyclophosphamide was used during the initial treatment phase, it is typically continued as part of the maintenance therapy for 6 months . Dose 1-2mg/kg/day or 500-1000mg/m 2 iv per month. Oral azathioprine 2-3 mg/kg/d once daily or in divided doses 3-5 years. Measure thiopurine S-methyltransferase enzyme activity before initiation; blood cell counts, RFT and LFT at baseline then weekly for 1 month, every other week for 2 months, and monthly thereafter. The use of these medications has not been established for any of these indications in prospective trials to date. Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, Geis C, Lancaster E, Titulaer MJ, Rosenfeld MR, Graus F. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. The Lancet Neurology. 2019 Nov 1;18(11):1045-57.

43. Long term Seizure control protocol Immunotherapy controls seizure in 50% of patients and rest are controlled with anti seizure medications Higher responder rates have been reported with sodium channel blockers, particularly carbamazepine and Lacosamide compared with levetiracetam. Long-term antiseizure medication administration is not always necessary in many patients after resolution of acute encephalitis, and discontinuation can be considered after 6 months or a greater period of seizure cessation. de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH, et al. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology 2019; 92:e2185 .

44. Relapse More common among: Who did not receive immunotherapy with the initial presentation . In whom the primary tumor was not completely treated Adolescent age at presentation has also been associated with increased risk for relapse Treatment: Treat similarly as in a newly diagnosed patients Lower threshold to initiate second-line therapies early in the course of the relapse

45. Prognosis and long term outcome Despite the severity of many patients’ symptoms, the majority of patients respond to treatment. Over half of patients who receive first-line immunotherapy and tumor treatment when appropriate have improvement within the first 4 weeks of treatment Relapses occur in up to one-third of patients with median time to relapse around 36 months. Cognitive deficits and disability persist in many patients The risk of long-term epilepsy appears to be low in the absence of disease relapse. Long-term antiseizure medication administration is not always necessary in many patients after resolution of acute encephalitis, and discontinuation can be considered after 6 months or a greater period of seizure cessation. Maintenance oral or iv steroids can be given at increasing intervals over 6-12 month duration. Ariño H, Armangué T, Petit- Pedrol M, et al. Anti-LGI1-associated cognitive impairment: Presentation and long-term outcome. Neurology 2016; 87:759 .

46. Mimics and differential diagnosis of Autoimmune Encephalitis Infectious encephalitis : Viral- HSV, VZV, Enterovirus, West Nile virus (WNV), JE Bacterial – listeria, atypical presentations of streptococcus, syphilis, Lyme disease, and TB. Fungal- Cryptococcus or aspergillus are particularly likely in immunocompromised patients Demyelinating disorders- ADEM, MS Neoplastic - Primary CNS lymphoma, Brain metastasis Neuroinflammatory -Neurosarcoidosis CNS Vasculopathies- CNS vasculitis, PRES, Lupus Epilepsy -Non convulsive status epilepticus Toxin or metabolic causes- alcohol, opiates, amphetamines, neuroleptic malignant syndrome etc Primary psychiatric disorders

47. Conclusion and take home message Autoimmune encephalitis can occur in individuals of all ages with or without a cancer association Most common cancer associated with paraneoplastic syndromes is SCLC in most of the cases Corticosteroids and/or intravenous immunoglobulins (IVIg) or plasma exchange are considered first-line therapies and should be considered in all patients. Majority of the patients respond to treatment and around 1/3 rd have relapses Autoimmune encephalitis should be included in the differential diagnosis of any patient, especially if young, with a rapidly progressive encephalopathy of unclear origin The spectrum of autoimmune encephalitis continues to rapidly expand with the growing discovery of neuronal autoantibodies. Early recognition and treatment are paramount to improve outcomes and achieve complete recovery from these debilitating, occasionally life threatening, disorders

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49. Thank you