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Autoimmune encephalitis - Dr. J. Caekebeke

This document discusses various autoimmune encephalitis conditions, including those associated with antibodies against intracellular, synaptic, and cell surface antigens. Examples discussed include NMDA receptor antibody encephalitis, which commonly affects young women and is associated with ovarian teratomas. LGI1 and CASPR2 antibody encephalitis are described along with their clinical presentations and associations with thymomas. Stiff person spectrum disorders linked to glycine receptor and gephyrin antibodies are also summarized. Throughout, the document provides details on presentations, diagnostic criteria, treatment responses, and cancer associations for the different autoimmune encephalitis subtypes.

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Autoimmune encephalitis “Brain on fire” Jo Caekebeke 02/2017 Jo Caekebeke
Autoimmune encephalopathy Jo Caekebeke • Autoimmune encephalopathy due to intracellular neuronal Ab’s • “Paraneoplastic” neurological syndromes • Indirectly pathogenic: T cell mediated neuronal killing • Autoimmune encephalopathy due to neuronal surface or synaptic Ab’s • Directly pathogenic: reversible effect on synaptic function • Autoimmune encephalopathy due to unknown Ab’s • MS, ADEM, Rasmussen, Hashimoto (SREAT), Bickerstaff, Clippers, Behçet… • Susac, lupus, sjögren, CAA-ri, vasculitis… • Sydenham chorea • Checkpoint inhibitors • PD-1 & PD-L1 inhibitors • CTLA-4 inhibitor
Autoimmune encephalopathy Jo Caekebeke a. Ab to intracellular Ag b. Ab to intracellular presynaptic antigens c. Ab to cell-surface receptors
Autoimmune encephalopathy Jo Caekebeke 5-10 / 100.000 / y
Antibodies target sites Jo Caekebeke • Intracellular Ag • Neuronal nuclear or nucleolar • ANNA1 (Hu), ANNA2 (Ri) ANNA3, Ma2 (Ta), Ma1, ZIC4 • Neuronal or muscular cytoplasmatic • PCA1 (Yo), Tr, PCA2, GAD67, AK5… • GAD65, Amphiphysin: presynaptic structures • Glial • CRMP5, AGNA, SOX1, GFAP
Antibodies target sites Jo Caekebeke • Ag located at or within cell membrane • Voltage or ligand gated ionotropic channels and receptors • NMDA-R, AMPA-R (GluR1, GluR2), GABAA-R • ACh-R, P/Q VGCC, VGKC complex, Gly-R, DPPX • Metabotropic channels and receptors • GABAB-R, mGluR1, mGluR5, D2 • Other membrane structures • AQP4, MOG, MuSK, CASPR2 • Gangliosides (GM1, GQ1b…) • Extracellular Ag • LgI1: synaptic protein
Risk of cancer: if screening negative, repeat studies Jo Caekebeke
Ab tests & assays Jo Caekebeke • TBA: tissue based assays • Rat or mouse brains stained with CSF / serum • Screening for known and “new” Ab • For intracellular and some surface and synaptic Ab’s • CBA: cell based assay • HEK293 cells transfected with: • Well-characterized surface receptor / synaptic Ag • Ab against specific Ag: membrane staining • For surface and synaptic Ab’s • New auto-Ab’s are not detected
Ab tests & assays: indirect immunohistochemistry Jo Caekebeke
Ab tests & assays: Western blots & line blots Jo Caekebeke • Antibodies against cytosolic or nuclear proteins • Recombinant or native Ag’s • Not possible for all Ag’s
Ab tests & assays: cell based assay & flow cytometry (FACS) Jo Caekebeke • Target Ag is expressed in mammalian cells (HEK293)
Ab tests & assays: ELISA Jo Caekebeke • Ag target-coated wells • Quantitative technique • D : Ab’s control place and orientation of coated Ag’s
Ab and clinical significance Jo Caekebeke
Ab and clinical significance Jo Caekebeke
Ab and clinical significance Jo Caekebeke
When to suspect ? Jo Caekebeke • None of the Ab’s is specific for a unique syndrome • Psychiatric symptoms • Behavior problems, changed personality, Ophelia syndrome • Depression, anxiety, fear, hallucinations, psychosis • ADHD, OCD • Internal medicine • Hyponatremia (SIADH) (LgI1) • Diarrhea (DPPX)
When to suspect ? Jo Caekebeke • Neurological features • Memory loss or amnesia • Dystonia, tics, chorea, myokymia, oculogyric crisis, myoclonus- opsoclonus, rigidity, catatonia, parkinsonism • Epilepsy: generalized, partial, myoclonic, faciobrachial dystonic seizures, hiccups • Aphasia, mutism • Ataxia, nystagmus • Insomnia, drowsiness, lethargy, sleep inversion • Decreased consciousness, stupor, coma • Autonomic features: tachy bradycardia, hypoventilation, respiratory failure
When to suspect ? Jo Caekebeke • Ophelia syndrome (mGluR5) • Mild limbic encephalitis • Or more diffuse encephalitis • Dependent on another person's thoughts, feelings or actions • FBDS: faciobrachial dystonic seizures (LgI1) • Brief rapid jerks 1-2 sec, >100 seizures a day • Unilateral arm (or leg) and face • AE resistant, immunotherapy responsive • May precede other symptoms by weeks or months • No EEG correlate • Atypical symptoms in MS, NMO, postpartum, HSV encephalitis relapse… • Psychiatric symptoms • Extrapyramidal signs…
When to suspect ? Jo Caekebeke • Morvan‘s syndrome: combination of (Caspr2) • LE: may precede or follow peripheral symptoms by months to years • Peripheral nerve hyper-excitability are common • Neuromyotonia (Isaacs syndrome) • Spasms, cramps, fasciculations • Painful peripheral neuropathy • Severe insomnia • Stiff-person spectrum disorder (SP-SD) • Stiff-person syndrome (SPS), stiff-limb syndrome (SLS) • Progressive encephalomyelitis with rigidity and myoclonus (PERM) • (GAD65, Gly-R, DPPX, amphiphysin, GABAA-R…) • Fluctuating muscle rigidity, painful spasms • Exaggerated startle response, hyperekplexia (Gly-R) • Predominant brainstem and spinal cord dysfunction
Possible autoimmune encephalitis, “Ab still unknown” Jo Caekebeke • If all 2 criteria have been met: 1. Rapid progressive (< 3m): • Working memory deficit • Altered mental status • Psychiatric symptoms 2. At least 1 of following criteria • New focal CNS finding • Seizures and no previously known seizure disorder • CSF pleocytosis • MRI suggestive of autoimmune encephalitis • Out of scope: • Autoimmune cerebellopathy • PERM, SPS
Probable autoimmune encephalitis, “Ab negative” Jo Caekebeke • If all 3 criteria have been met: 1. Rapid progressive (< 3m): • Working memory deficit • Altered mental status • Psychiatric symptoms 2. Exclusion of well defined syndromes • ADEM, Bickerstaff… 3. At least 2 of following criteria • MRI suggestive of autoimmune encephalitis • CSF pleocytosis, CSF specific OCB or elevated IgG index • Brain biopsy showing inflammation and excluding tumors… • Many patients with clinical LE have CSF reacting with neurons without characterized Ab’s
Definite autoimmune “limbic encephalitis” (LE) Jo Caekebeke • If all 3 criteria have been met: 1. Rapid progressive (< 3m): • Working memory deficit • Seizures • Or psychiatric symptoms suggesting limbic involvement 2. Bilateral T2/FLAIR hyperintensity in medial temporal lobes 3. At least 1 of following criteria • CSF pleocytosis • EEG with epileptic or slow-wave activity involving temporal lobes
Probable & definite “NMDA encephalitis” Jo Caekebeke • Probable: if all 2 criteria have been met: 1. Rapid progressive (< 3m) of at least 4/6 major symptom groups or 3/6 symptom groups and teratoma: 1. Abnormal (psychiatric) behavior or cognitive dysfunction 2. Speech dysfunction, mutism, echolalia 3. Seizures 4. Movement disorders, dyskinesia, rigidity/abnormal postures 5. Decreased level of consciousness 6. Autonomic dysfunction or central hypoventilation 2. At least 1 of following criteria • Abnormal EEG: focal or diffuse slow/disorganized activity, epileptic activity or extreme delta brush • CSF pleocytosis or specific OCB • Definite: at least 1/6 major symptom groups and NMDA-R Ab’s
NMDA-R Ab’s & encephalitis: Jo Caekebeke
NMDA-R Ab’s & encephalitis: presentation & recovery Jo Caekebeke
NMDA-R Ab’s & encephalitis Jo Caekebeke • Median age 21 y, (2-40 y), female 80%, incidence 0.33/105/y • May recover completely (75%) or partially: • Memory deficits, executive dysfunction… • Relapse risk: 12% over 2 years • Tend to be milder • New seizures: should raise concern for relapse • Often treated with neuroleptics • Evolution may be mistaken for neuroleptic malignant syndrome • May be sensitive to strong dopamine antagonists • In 10-50% : ovarian teratoma >> testicular tumor, neuroblastoma, Hodgkin lymphoma… • Outcome and risk of teratoma related to CSF titer
Special cases of NMDA encephalitis Jo Caekebeke • Post herpes encephalitis • As a “pseudo” relapse or persistent disorder (in 20%) • During mycoplasma infection • Following Guillain Barré syndrome and NMO spectrum • In a MS patient on fingolimod • Overlapping syndromes can occur • May mimic neuroleptic malignant syndrome • In postpartum psychosis • Extrapyramidal symptoms following low-dose haloperidol • Polar bear “Knut” (Berlin Zoo): • died in 2011 during a seizure • suffering from NMDA encephalitis
Ab’s to cell-surface receptors, mechanism of action Jo Caekebeke (NMDA, AMPA) relocation (GABA)
Ab’s to cell-surface receptors, mechanism of action Jo Caekebeke
IgG4 mediated autoimmune neurological disorders Jo Caekebeke • Encephalitis: LgI1, Caspr2, IgLON5 • MG: MuSK • CIDP: Neurofascin155, Caspr1, contactin1 • IgG4-related hypertrophic pachymeningitis • IgG4 are functionally hetero-bispecific • Cannot activate compliment • No crosslinking • No internalization of the Ag • Direct blocking Ag function ? • Rituximab is remarkably effective
VGKC complex Ab’s Jo Caekebeke • Pathogenic Ag’s: LgI1 and Caspr2 are related but not part of VGKC • LgI1 and Caspr2 Ab’s are still detected by VGKC test • In 50% low serum VGKC Ab level without evidence of LgI1 or Caspr2 Ab’s • No evidence of autoimmune encephalitis? • But 10% with low titer have tumors • Linked to CJD ???
LgI1 Ab’s (leucine-rich glioma-inactivated 1) Jo Caekebeke • Median age 60 y, (30-80 y), male 65% • Incidence 0.10/105/y • LE: limbic encephalitis: 90% • Morvan syndrome: < 10% • FBDS: faciobrachial dystonic seizures: 47% • Focal seizures: 66%, TC seizures: 63% • Rapidly progressive dementia, CJD-like • Sleep disorders: 65%, RBD • Hyperhidrosis • Hyponatremia: 65%, SIADH • In 5 - 10% : thymoma… • Relapse rate: 35% • Ab’s reoccurred at relapse
LgI1 Ab’s: presenting symptoms and disease course Jo Caekebeke
Caspr2 Ab’s & encephalitis Jo Caekebeke • Median age 66 y, (45-80 y), male 85% • Slower progressive, to disease nadir : median 4 months • LE: may precede or follow peripheral symptoms by months to years • Cerebellar dysfunction • Morvan syndrome: combination of • Cognitive symptoms or seizures (LE) • Peripheral nerve hyper-excitability • Myokymia, cramps, fasciculations • Neuromyotonia (Isaacs syndrome) • Dysautonomia and insomnia • Painful peripheral neuropathy • Weight loss
Caspr2 Ab’s (contactin-associated protein-like 2) Jo Caekebeke • Relapse rate: 25% • Occurred up to 7 years after initial episode • Lower rate in treated vs untreated patients • Low risk of cancer: 0-35% • Some have thymoma and other thymoma related autoimmunities (MG..) • Juxtaparanodal region • Ab: IgG4 in 100% • VGKC number & density ↓
AMPA-R Ab’s & encephalitis Jo Caekebeke • Median age 55 y, (23-81 y), female 66% • Limbic encephalitis (≈ LGI1 encephalitis) • And multifocal / diffuse encephalopathy • Less frequent seizures, psychosis, hyponatremia • MRI: mesiotemporal T2/FLAIR signal • In 64% : SCLC, thymoma, breast ca, ovarian teratoma… • Coexistence of paraneoplastic or other cell surface Ab’s in 32% • Additional paraneoplastic Ab’s: main negative prognostic factor • Aggressive treatment: lower relapse rate • Intensive immune/chemotherapy and tumor removal
GABAB-R Ab’s & encephalitis Jo Caekebeke • Median age 60 y, (25 – 75 y), male 50% 1. LE with seizures in 80% (temporal, status epilepticus) 2. Ataxia, opsoclonus myoclonus, brainstem encephalitis 3. Chorea, myelopathy, neuropathy, myopathy • In 56% Ab’s co-exist : GAD65, VGCC-R, LGI1, CASPR2, ANNA1, ANNA3, CRMP5, AGNA/SOX1, amphiphysin… • In 62% : SCLC… • Responsive to immunotherapy and cancer treatment
GABAA-R Ab’s & encephalitis Jo Caekebeke • 50% in children • Rapid, severe encephalopathy with refractory seizures, status epilepticus • Similar to anti GABAB-R encephalitis and SPS • MRI : multifocal cortical / subcortical T2/FLAIR signals • In 70% Ab’s co-exist : NMDA-R, Ach-R, GABAB-R, GAD65, LGI1, CASPR2… • In 40% : thymoma, Hodgkin lymphoma • In 80% partial or complete responsive to immunotherapy and antiepileptic drugs
Gly-R (glycine) and gephyrin Ab’s & encephalitis Jo Caekebeke • Median age 49 y, (5 – 69 y), sensitivity: CSF > serum • Stiff-person spectrum disorder (SP-SD) 1. Progressive encephalomyelitis with rigidity and myoclonus (PERM) 2. Stiff-person syndrome (SPS), stiff-limb syndrome (SLS) • Optic neuropathy, seizures, cognitive impairment, autonomic disturbance, myelitis • Dif diagnosis: GAD65, GABAA-R, DPPX, amphiphysin encephalitis • Ab’s may (rarely) co-exist : GAD65, MOG-R, NMDA-R, AQP4-R, LGI1, CASPR2… • Immunotherapy response : anti Gly-R > anti GAD65 • In 10-20% : breast, lymphoma, lung, melanoma… • Gephyrin allows Gly-R’s to cluster together • Anti gephyrin Ab‘s are extremely rare
GAD65 (glutamate decarboxylase) Ab’s & encephalitis Jo Caekebeke • Median age 23 y, mainly female • LE or encephalomyelitis • Refractory seizures • Ataxia • Stiff-person spectrum disorder (SP-SD) 1. Stiff-person syndrome (SPS), stiff-limb syndrome (SLS) 2. Progressive encephalomyelitis with rigidity and myoclonus (PERM) • Dif diagnosis: Gly-R, GABAA-R, DPPX, amphiphysin encephalitis • High serum Ab titers: associated with autoimmune neurological disorders • Supported by CSF anti GAD65 Ab’s or OCB • Low serum Ab titers in 80% of type 1 diabetes • Presynaptic location, synthesizes GABA • Tumor: SCLC, thymoma, breast ca… • Especially if > 50 y or coexisting GABAB-R Ab’s
mGlu-R1, mGlu-R5 Ab’s & encephalitis Jo Caekebeke • mGlu-R1 Ab: • Median age 58 y • Ataxia • Occasionally dysgeusia, limbic symptoms • Hodgkin lymphoma • Homer-3 organizes mGlu-R1 • Homer-3 Ab’s may co-exist • mGlu-R5 Ab: • Mild LE : ophelia syndrome • Hodgkin lymphoma • No cross reaction with mGlu-R1
DPPX (DPP6, dipeptidyl-peptidase-like protein 6) Jo Caekebeke • Weight loss, diarrhea… • Memory deficit • Central hyperexcitability : • Hyperekplexia • Agitation • Myoclonus • Tremor • Seizures • PERM: progressive encephalomyelitis with rigidity and myoclonus • Predominant brainstem and spinal cord dysfunction • Exaggerated startle response, hyperekplexia • Immunotherapy responsive, often relapse when immunotherapy is tapered • A subunit of Kv4.2 potassium channel
GFAP Ab’s (glial fibrillary acidic protein ) & astrocytopathy & meningoencephalomyelitis Jo Caekebeke • Median age 42 y (21 – 73 y); m 50% • Incidence = anti Yo = 1/3 anti Hu • Sensitivity in CSF > serum • Headache • Encephalitis, papillitis (no intracranial hypertension) • Myelopathy • Rarely HANDL-like (transient headache, neurologic deficit, CSF lymphocytosis) • 1/3 coexisting Ab’s : TPO, GAD, P/Q VGCC-R, NMDA-R. • In 2% of AQP4+ NMO-SD • In 33% : paraneoplastic • Steroid (immunotherapy) responsive ! • Astrocytic cytoplasmic intermediate filament protein • Via GFAP-specific CD8+ T cells ? • Via accompanied pathogenic membrane Ag ? • Canine equivalent : necrotizing meningoencephalitis
IgLON5 Ab’s & tauopathy Jo Caekebeke • Median age 53 y, (48 – 77 y) • Chronic and slow progressive disease (years) • Non-REM & REM parasomnias, sleep apnea, stridor • Very abnormal at the beginning and close to normal by the end of the night • Gait instability, chorea and brainstem symptoms, (parkinsonism) • Ab’s against IgLON5: neuronal cell-adhesion molecule (function unknown) • All have HLA-DRB1*1001 and HLA-DQB1*0501 haplotype • MRI : normal • No response to immunotherapy ? • Tauopathy restricted to neurons in: • Hypothalamus • Tegmentum of brainstem • Cervical cord
AK5 Ab’s (adenylate kinase 5) & encephalitis Jo Caekebeke • Median age > 50 y • Limbic encephalitis • Subacute anterograde amnesia • No seizures • Sometimes prodromal asthenia or mood disturbances • Some patients with prosopagnosia, anxiety, abnormal behavior • MRI : bilateral medial temporal T2/FLAIR signal • CSF : OCB, high tau levels • Treatment : unfavorable response, persistence of severe anterograde amnesia • No associated cancer • Neuronal intracellularly in the cytosol • Involvement in the pathophysiology ? • Direct involvement or consequence of CD8+ induced neuronal death
Hashimoto encephalitis, SREAT Jo Caekebeke • Steroid-responsive encephalopathy associated with autoimmune thyroiditis • Anti α-enolase 1 Ab (ENO1) ? • On cell surface and in cytoplasm in variety of tissues: brain, thyroid… • Associated with anti thyroglobulin (TG), thyroid peroxidase (TPO) Ab’s • Thyroid Ab’s could be associated with (or co-occurrence): • NMDA-R, LgI1, Caspr2, GABAB-R, GABAA-R, GAD65 Ab’s • Broad screening when considering Hashimoto or GAD65 encephalitis • Diagnostic criteria: if all 6 criteria have been met: 1. Encephalopathy with seizures, myoclonus, hallucinations or stroke-like episodes 2. Subclinical or mild thyroid disease, usually hypothyroidism 3. Normal MRI or non-specific findings 4. Serum TPO, TG Ab’s, no cutoff value 5. Absence of neuronal Ab’s in serum and CSF 6. Reasonable exclusion of alternative causes
Gluten associated autoimmune encephalitis ? Jo Caekebeke • Neurological symptoms in 10% • Celiac disease and non-celiac gluten sensitivity (NCGS) ? • Anti TG6 (neuronal transglutaminase 6) Ab ? • Anti TG2, anti gliadin Ab’s • Ataxia • Polyneuropathy • ALS like • Myopathy • Stiff-man syndrome • Chorea, myoclonus, palatal tremor • Complex partial seizures • Fatigue, anxiety, depression • Hallucinations, psychosis • ADHD ?
Ab in serum and/or CSF Jo Caekebeke • Intracellular (paraneoplastic) Ab’s • Always prevalent in serum • Cell surface Ab’s • All patients should have serum and CSF tested • CSF preferred: NMDA, AMPA, GABAB, Gly, GFAP • Serum preferred: LgI1, Caspr2, GABAA • NMDA-R Ab’s • Always present in CSF; negative in serum in 14% • Changes in CSF titers correlate roughly to disease status • CSF important in HSV-induced NMDA encephalitis • GAD65 Ab’s • If neurological symptoms: high CSF titer • Low CSF and serum titer may not be specific for neurological disease • Provide little information in patients with type 1 diabetes • IV IG treatment does not affect CSF interpretation
EEG and autoimmune encephalitis Jo Caekebeke • Status epilepticus • Highest risk with GABAA-R and GABAB-R Ab’s • Lower risk with NMDA-R Ab’s, but much higher incidence • Faciobrachial dystonic seizures (LgI1) • EEG may show multifocal onset seizures • Extreme delta brush: δ waves with superimposed bursts of 20 – 30 Hz β waves • NMDA encephalitis, especially when in coma
MRI Jo Caekebeke • MRI with NMDA-R, AMPA-R, LgI1, Caspr2, GABAB-R Ab’s: • May be normal • Or FLAIR/T2 hyperintensities, especially in medial temporal lobes • Mesiotemporal sclerosis as possible long-term outcome • MRI with DPPX, GABAA-R Ab’s: less characteristic LgI1 AMPA-R GABAB-R GABAA-R
MRI : AIE & mimics Jo Caekebeke LE Ab neg Glioma ADEM Susac NMDA+MOG AMPA
Stepwise or comprehensive immunotherapy ? Jo Caekebeke • First-line therapy • Steroids: (cave infectious encephalitis, CNS lymphoma) • IV Ig and/or plasmapheresis (PE) • Wait 10 - 14 days to allow first-line therapies time to work ? • Second-line therapy, indicated in > 50% • Rituximab: 375 mg/m2 weekly for 4 weeks “and/or” • Cyclophosphamide: 750 mg/m2 monthly for 4 – 6 months • Comprehensive immunotherapy: rituximab and IV Ig or PE and steroids all at the same time (or rituximab and IV Ig and PE) ? • Early aggressive treatment to alter natural course and prevent relapses • IV IG and plasmapheresis reduce Ab’s in circulation > in CSF • More effective in LgI1 than in NMDA encephalitis ?
Thanks Jo Caekebeke

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Autoimmune encephalitis - Dr. J. Caekebeke

  • 1.
    Autoimmune encephalitis “Brain onfire” Jo Caekebeke 02/2017 Jo Caekebeke
  • 2.
    Autoimmune encephalopathy Jo Caekebeke •Autoimmune encephalopathy due to intracellular neuronal Ab’s • “Paraneoplastic” neurological syndromes • Indirectly pathogenic: T cell mediated neuronal killing • Autoimmune encephalopathy due to neuronal surface or synaptic Ab’s • Directly pathogenic: reversible effect on synaptic function • Autoimmune encephalopathy due to unknown Ab’s • MS, ADEM, Rasmussen, Hashimoto (SREAT), Bickerstaff, Clippers, Behçet… • Susac, lupus, sjögren, CAA-ri, vasculitis… • Sydenham chorea • Checkpoint inhibitors • PD-1 & PD-L1 inhibitors • CTLA-4 inhibitor
  • 3.
    Autoimmune encephalopathy Jo Caekebeke a.Ab to intracellular Ag b. Ab to intracellular presynaptic antigens c. Ab to cell-surface receptors
  • 4.
  • 5.
    Antibodies target sites JoCaekebeke • Intracellular Ag • Neuronal nuclear or nucleolar • ANNA1 (Hu), ANNA2 (Ri) ANNA3, Ma2 (Ta), Ma1, ZIC4 • Neuronal or muscular cytoplasmatic • PCA1 (Yo), Tr, PCA2, GAD67, AK5… • GAD65, Amphiphysin: presynaptic structures • Glial • CRMP5, AGNA, SOX1, GFAP
  • 6.
    Antibodies target sites JoCaekebeke • Ag located at or within cell membrane • Voltage or ligand gated ionotropic channels and receptors • NMDA-R, AMPA-R (GluR1, GluR2), GABAA-R • ACh-R, P/Q VGCC, VGKC complex, Gly-R, DPPX • Metabotropic channels and receptors • GABAB-R, mGluR1, mGluR5, D2 • Other membrane structures • AQP4, MOG, MuSK, CASPR2 • Gangliosides (GM1, GQ1b…) • Extracellular Ag • LgI1: synaptic protein
  • 7.
    Risk of cancer:if screening negative, repeat studies Jo Caekebeke
  • 8.
    Ab tests &assays Jo Caekebeke • TBA: tissue based assays • Rat or mouse brains stained with CSF / serum • Screening for known and “new” Ab • For intracellular and some surface and synaptic Ab’s • CBA: cell based assay • HEK293 cells transfected with: • Well-characterized surface receptor / synaptic Ag • Ab against specific Ag: membrane staining • For surface and synaptic Ab’s • New auto-Ab’s are not detected
  • 9.
    Ab tests &assays: indirect immunohistochemistry Jo Caekebeke
  • 10.
    Ab tests &assays: Western blots & line blots Jo Caekebeke • Antibodies against cytosolic or nuclear proteins • Recombinant or native Ag’s • Not possible for all Ag’s
  • 11.
    Ab tests &assays: cell based assay & flow cytometry (FACS) Jo Caekebeke • Target Ag is expressed in mammalian cells (HEK293)
  • 12.
    Ab tests &assays: ELISA Jo Caekebeke • Ag target-coated wells • Quantitative technique • D : Ab’s control place and orientation of coated Ag’s
  • 13.
    Ab and clinicalsignificance Jo Caekebeke
  • 14.
    Ab and clinicalsignificance Jo Caekebeke
  • 15.
    Ab and clinicalsignificance Jo Caekebeke
  • 16.
    When to suspect? Jo Caekebeke • None of the Ab’s is specific for a unique syndrome • Psychiatric symptoms • Behavior problems, changed personality, Ophelia syndrome • Depression, anxiety, fear, hallucinations, psychosis • ADHD, OCD • Internal medicine • Hyponatremia (SIADH) (LgI1) • Diarrhea (DPPX)
  • 17.
    When to suspect? Jo Caekebeke • Neurological features • Memory loss or amnesia • Dystonia, tics, chorea, myokymia, oculogyric crisis, myoclonus- opsoclonus, rigidity, catatonia, parkinsonism • Epilepsy: generalized, partial, myoclonic, faciobrachial dystonic seizures, hiccups • Aphasia, mutism • Ataxia, nystagmus • Insomnia, drowsiness, lethargy, sleep inversion • Decreased consciousness, stupor, coma • Autonomic features: tachy bradycardia, hypoventilation, respiratory failure
  • 18.
    When to suspect? Jo Caekebeke • Ophelia syndrome (mGluR5) • Mild limbic encephalitis • Or more diffuse encephalitis • Dependent on another person's thoughts, feelings or actions • FBDS: faciobrachial dystonic seizures (LgI1) • Brief rapid jerks 1-2 sec, >100 seizures a day • Unilateral arm (or leg) and face • AE resistant, immunotherapy responsive • May precede other symptoms by weeks or months • No EEG correlate • Atypical symptoms in MS, NMO, postpartum, HSV encephalitis relapse… • Psychiatric symptoms • Extrapyramidal signs…
  • 19.
    When to suspect? Jo Caekebeke • Morvan‘s syndrome: combination of (Caspr2) • LE: may precede or follow peripheral symptoms by months to years • Peripheral nerve hyper-excitability are common • Neuromyotonia (Isaacs syndrome) • Spasms, cramps, fasciculations • Painful peripheral neuropathy • Severe insomnia • Stiff-person spectrum disorder (SP-SD) • Stiff-person syndrome (SPS), stiff-limb syndrome (SLS) • Progressive encephalomyelitis with rigidity and myoclonus (PERM) • (GAD65, Gly-R, DPPX, amphiphysin, GABAA-R…) • Fluctuating muscle rigidity, painful spasms • Exaggerated startle response, hyperekplexia (Gly-R) • Predominant brainstem and spinal cord dysfunction
  • 20.
    Possible autoimmune encephalitis,“Ab still unknown” Jo Caekebeke • If all 2 criteria have been met: 1. Rapid progressive (< 3m): • Working memory deficit • Altered mental status • Psychiatric symptoms 2. At least 1 of following criteria • New focal CNS finding • Seizures and no previously known seizure disorder • CSF pleocytosis • MRI suggestive of autoimmune encephalitis • Out of scope: • Autoimmune cerebellopathy • PERM, SPS
  • 21.
    Probable autoimmune encephalitis,“Ab negative” Jo Caekebeke • If all 3 criteria have been met: 1. Rapid progressive (< 3m): • Working memory deficit • Altered mental status • Psychiatric symptoms 2. Exclusion of well defined syndromes • ADEM, Bickerstaff… 3. At least 2 of following criteria • MRI suggestive of autoimmune encephalitis • CSF pleocytosis, CSF specific OCB or elevated IgG index • Brain biopsy showing inflammation and excluding tumors… • Many patients with clinical LE have CSF reacting with neurons without characterized Ab’s
  • 22.
    Definite autoimmune “limbicencephalitis” (LE) Jo Caekebeke • If all 3 criteria have been met: 1. Rapid progressive (< 3m): • Working memory deficit • Seizures • Or psychiatric symptoms suggesting limbic involvement 2. Bilateral T2/FLAIR hyperintensity in medial temporal lobes 3. At least 1 of following criteria • CSF pleocytosis • EEG with epileptic or slow-wave activity involving temporal lobes
  • 23.
    Probable & definite“NMDA encephalitis” Jo Caekebeke • Probable: if all 2 criteria have been met: 1. Rapid progressive (< 3m) of at least 4/6 major symptom groups or 3/6 symptom groups and teratoma: 1. Abnormal (psychiatric) behavior or cognitive dysfunction 2. Speech dysfunction, mutism, echolalia 3. Seizures 4. Movement disorders, dyskinesia, rigidity/abnormal postures 5. Decreased level of consciousness 6. Autonomic dysfunction or central hypoventilation 2. At least 1 of following criteria • Abnormal EEG: focal or diffuse slow/disorganized activity, epileptic activity or extreme delta brush • CSF pleocytosis or specific OCB • Definite: at least 1/6 major symptom groups and NMDA-R Ab’s
  • 24.
    NMDA-R Ab’s &encephalitis: Jo Caekebeke
  • 25.
    NMDA-R Ab’s &encephalitis: presentation & recovery Jo Caekebeke
  • 26.
    NMDA-R Ab’s &encephalitis Jo Caekebeke • Median age 21 y, (2-40 y), female 80%, incidence 0.33/105/y • May recover completely (75%) or partially: • Memory deficits, executive dysfunction… • Relapse risk: 12% over 2 years • Tend to be milder • New seizures: should raise concern for relapse • Often treated with neuroleptics • Evolution may be mistaken for neuroleptic malignant syndrome • May be sensitive to strong dopamine antagonists • In 10-50% : ovarian teratoma >> testicular tumor, neuroblastoma, Hodgkin lymphoma… • Outcome and risk of teratoma related to CSF titer
  • 27.
    Special cases ofNMDA encephalitis Jo Caekebeke • Post herpes encephalitis • As a “pseudo” relapse or persistent disorder (in 20%) • During mycoplasma infection • Following Guillain Barré syndrome and NMO spectrum • In a MS patient on fingolimod • Overlapping syndromes can occur • May mimic neuroleptic malignant syndrome • In postpartum psychosis • Extrapyramidal symptoms following low-dose haloperidol • Polar bear “Knut” (Berlin Zoo): • died in 2011 during a seizure • suffering from NMDA encephalitis
  • 28.
    Ab’s to cell-surfacereceptors, mechanism of action Jo Caekebeke (NMDA, AMPA) relocation (GABA)
  • 29.
    Ab’s to cell-surfacereceptors, mechanism of action Jo Caekebeke
  • 30.
    IgG4 mediated autoimmuneneurological disorders Jo Caekebeke • Encephalitis: LgI1, Caspr2, IgLON5 • MG: MuSK • CIDP: Neurofascin155, Caspr1, contactin1 • IgG4-related hypertrophic pachymeningitis • IgG4 are functionally hetero-bispecific • Cannot activate compliment • No crosslinking • No internalization of the Ag • Direct blocking Ag function ? • Rituximab is remarkably effective
  • 31.
    VGKC complex Ab’s JoCaekebeke • Pathogenic Ag’s: LgI1 and Caspr2 are related but not part of VGKC • LgI1 and Caspr2 Ab’s are still detected by VGKC test • In 50% low serum VGKC Ab level without evidence of LgI1 or Caspr2 Ab’s • No evidence of autoimmune encephalitis? • But 10% with low titer have tumors • Linked to CJD ???
  • 32.
    LgI1 Ab’s (leucine-richglioma-inactivated 1) Jo Caekebeke • Median age 60 y, (30-80 y), male 65% • Incidence 0.10/105/y • LE: limbic encephalitis: 90% • Morvan syndrome: < 10% • FBDS: faciobrachial dystonic seizures: 47% • Focal seizures: 66%, TC seizures: 63% • Rapidly progressive dementia, CJD-like • Sleep disorders: 65%, RBD • Hyperhidrosis • Hyponatremia: 65%, SIADH • In 5 - 10% : thymoma… • Relapse rate: 35% • Ab’s reoccurred at relapse
  • 33.
    LgI1 Ab’s: presentingsymptoms and disease course Jo Caekebeke
  • 34.
    Caspr2 Ab’s &encephalitis Jo Caekebeke • Median age 66 y, (45-80 y), male 85% • Slower progressive, to disease nadir : median 4 months • LE: may precede or follow peripheral symptoms by months to years • Cerebellar dysfunction • Morvan syndrome: combination of • Cognitive symptoms or seizures (LE) • Peripheral nerve hyper-excitability • Myokymia, cramps, fasciculations • Neuromyotonia (Isaacs syndrome) • Dysautonomia and insomnia • Painful peripheral neuropathy • Weight loss
  • 35.
    Caspr2 Ab’s (contactin-associatedprotein-like 2) Jo Caekebeke • Relapse rate: 25% • Occurred up to 7 years after initial episode • Lower rate in treated vs untreated patients • Low risk of cancer: 0-35% • Some have thymoma and other thymoma related autoimmunities (MG..) • Juxtaparanodal region • Ab: IgG4 in 100% • VGKC number & density ↓
  • 36.
    AMPA-R Ab’s &encephalitis Jo Caekebeke • Median age 55 y, (23-81 y), female 66% • Limbic encephalitis (≈ LGI1 encephalitis) • And multifocal / diffuse encephalopathy • Less frequent seizures, psychosis, hyponatremia • MRI: mesiotemporal T2/FLAIR signal • In 64% : SCLC, thymoma, breast ca, ovarian teratoma… • Coexistence of paraneoplastic or other cell surface Ab’s in 32% • Additional paraneoplastic Ab’s: main negative prognostic factor • Aggressive treatment: lower relapse rate • Intensive immune/chemotherapy and tumor removal
  • 37.
    GABAB-R Ab’s &encephalitis Jo Caekebeke • Median age 60 y, (25 – 75 y), male 50% 1. LE with seizures in 80% (temporal, status epilepticus) 2. Ataxia, opsoclonus myoclonus, brainstem encephalitis 3. Chorea, myelopathy, neuropathy, myopathy • In 56% Ab’s co-exist : GAD65, VGCC-R, LGI1, CASPR2, ANNA1, ANNA3, CRMP5, AGNA/SOX1, amphiphysin… • In 62% : SCLC… • Responsive to immunotherapy and cancer treatment
  • 38.
    GABAA-R Ab’s &encephalitis Jo Caekebeke • 50% in children • Rapid, severe encephalopathy with refractory seizures, status epilepticus • Similar to anti GABAB-R encephalitis and SPS • MRI : multifocal cortical / subcortical T2/FLAIR signals • In 70% Ab’s co-exist : NMDA-R, Ach-R, GABAB-R, GAD65, LGI1, CASPR2… • In 40% : thymoma, Hodgkin lymphoma • In 80% partial or complete responsive to immunotherapy and antiepileptic drugs
  • 39.
    Gly-R (glycine) andgephyrin Ab’s & encephalitis Jo Caekebeke • Median age 49 y, (5 – 69 y), sensitivity: CSF > serum • Stiff-person spectrum disorder (SP-SD) 1. Progressive encephalomyelitis with rigidity and myoclonus (PERM) 2. Stiff-person syndrome (SPS), stiff-limb syndrome (SLS) • Optic neuropathy, seizures, cognitive impairment, autonomic disturbance, myelitis • Dif diagnosis: GAD65, GABAA-R, DPPX, amphiphysin encephalitis • Ab’s may (rarely) co-exist : GAD65, MOG-R, NMDA-R, AQP4-R, LGI1, CASPR2… • Immunotherapy response : anti Gly-R > anti GAD65 • In 10-20% : breast, lymphoma, lung, melanoma… • Gephyrin allows Gly-R’s to cluster together • Anti gephyrin Ab‘s are extremely rare
  • 40.
    GAD65 (glutamate decarboxylase)Ab’s & encephalitis Jo Caekebeke • Median age 23 y, mainly female • LE or encephalomyelitis • Refractory seizures • Ataxia • Stiff-person spectrum disorder (SP-SD) 1. Stiff-person syndrome (SPS), stiff-limb syndrome (SLS) 2. Progressive encephalomyelitis with rigidity and myoclonus (PERM) • Dif diagnosis: Gly-R, GABAA-R, DPPX, amphiphysin encephalitis • High serum Ab titers: associated with autoimmune neurological disorders • Supported by CSF anti GAD65 Ab’s or OCB • Low serum Ab titers in 80% of type 1 diabetes • Presynaptic location, synthesizes GABA • Tumor: SCLC, thymoma, breast ca… • Especially if > 50 y or coexisting GABAB-R Ab’s
  • 41.
    mGlu-R1, mGlu-R5 Ab’s& encephalitis Jo Caekebeke • mGlu-R1 Ab: • Median age 58 y • Ataxia • Occasionally dysgeusia, limbic symptoms • Hodgkin lymphoma • Homer-3 organizes mGlu-R1 • Homer-3 Ab’s may co-exist • mGlu-R5 Ab: • Mild LE : ophelia syndrome • Hodgkin lymphoma • No cross reaction with mGlu-R1
  • 42.
    DPPX (DPP6, dipeptidyl-peptidase-likeprotein 6) Jo Caekebeke • Weight loss, diarrhea… • Memory deficit • Central hyperexcitability : • Hyperekplexia • Agitation • Myoclonus • Tremor • Seizures • PERM: progressive encephalomyelitis with rigidity and myoclonus • Predominant brainstem and spinal cord dysfunction • Exaggerated startle response, hyperekplexia • Immunotherapy responsive, often relapse when immunotherapy is tapered • A subunit of Kv4.2 potassium channel
  • 43.
    GFAP Ab’s (glialfibrillary acidic protein ) & astrocytopathy & meningoencephalomyelitis Jo Caekebeke • Median age 42 y (21 – 73 y); m 50% • Incidence = anti Yo = 1/3 anti Hu • Sensitivity in CSF > serum • Headache • Encephalitis, papillitis (no intracranial hypertension) • Myelopathy • Rarely HANDL-like (transient headache, neurologic deficit, CSF lymphocytosis) • 1/3 coexisting Ab’s : TPO, GAD, P/Q VGCC-R, NMDA-R. • In 2% of AQP4+ NMO-SD • In 33% : paraneoplastic • Steroid (immunotherapy) responsive ! • Astrocytic cytoplasmic intermediate filament protein • Via GFAP-specific CD8+ T cells ? • Via accompanied pathogenic membrane Ag ? • Canine equivalent : necrotizing meningoencephalitis
  • 44.
    IgLON5 Ab’s &tauopathy Jo Caekebeke • Median age 53 y, (48 – 77 y) • Chronic and slow progressive disease (years) • Non-REM & REM parasomnias, sleep apnea, stridor • Very abnormal at the beginning and close to normal by the end of the night • Gait instability, chorea and brainstem symptoms, (parkinsonism) • Ab’s against IgLON5: neuronal cell-adhesion molecule (function unknown) • All have HLA-DRB1*1001 and HLA-DQB1*0501 haplotype • MRI : normal • No response to immunotherapy ? • Tauopathy restricted to neurons in: • Hypothalamus • Tegmentum of brainstem • Cervical cord
  • 45.
    AK5 Ab’s (adenylatekinase 5) & encephalitis Jo Caekebeke • Median age > 50 y • Limbic encephalitis • Subacute anterograde amnesia • No seizures • Sometimes prodromal asthenia or mood disturbances • Some patients with prosopagnosia, anxiety, abnormal behavior • MRI : bilateral medial temporal T2/FLAIR signal • CSF : OCB, high tau levels • Treatment : unfavorable response, persistence of severe anterograde amnesia • No associated cancer • Neuronal intracellularly in the cytosol • Involvement in the pathophysiology ? • Direct involvement or consequence of CD8+ induced neuronal death
  • 46.
    Hashimoto encephalitis, SREAT JoCaekebeke • Steroid-responsive encephalopathy associated with autoimmune thyroiditis • Anti α-enolase 1 Ab (ENO1) ? • On cell surface and in cytoplasm in variety of tissues: brain, thyroid… • Associated with anti thyroglobulin (TG), thyroid peroxidase (TPO) Ab’s • Thyroid Ab’s could be associated with (or co-occurrence): • NMDA-R, LgI1, Caspr2, GABAB-R, GABAA-R, GAD65 Ab’s • Broad screening when considering Hashimoto or GAD65 encephalitis • Diagnostic criteria: if all 6 criteria have been met: 1. Encephalopathy with seizures, myoclonus, hallucinations or stroke-like episodes 2. Subclinical or mild thyroid disease, usually hypothyroidism 3. Normal MRI or non-specific findings 4. Serum TPO, TG Ab’s, no cutoff value 5. Absence of neuronal Ab’s in serum and CSF 6. Reasonable exclusion of alternative causes
  • 47.
    Gluten associated autoimmuneencephalitis ? Jo Caekebeke • Neurological symptoms in 10% • Celiac disease and non-celiac gluten sensitivity (NCGS) ? • Anti TG6 (neuronal transglutaminase 6) Ab ? • Anti TG2, anti gliadin Ab’s • Ataxia • Polyneuropathy • ALS like • Myopathy • Stiff-man syndrome • Chorea, myoclonus, palatal tremor • Complex partial seizures • Fatigue, anxiety, depression • Hallucinations, psychosis • ADHD ?
  • 48.
    Ab in serumand/or CSF Jo Caekebeke • Intracellular (paraneoplastic) Ab’s • Always prevalent in serum • Cell surface Ab’s • All patients should have serum and CSF tested • CSF preferred: NMDA, AMPA, GABAB, Gly, GFAP • Serum preferred: LgI1, Caspr2, GABAA • NMDA-R Ab’s • Always present in CSF; negative in serum in 14% • Changes in CSF titers correlate roughly to disease status • CSF important in HSV-induced NMDA encephalitis • GAD65 Ab’s • If neurological symptoms: high CSF titer • Low CSF and serum titer may not be specific for neurological disease • Provide little information in patients with type 1 diabetes • IV IG treatment does not affect CSF interpretation
  • 49.
    EEG and autoimmuneencephalitis Jo Caekebeke • Status epilepticus • Highest risk with GABAA-R and GABAB-R Ab’s • Lower risk with NMDA-R Ab’s, but much higher incidence • Faciobrachial dystonic seizures (LgI1) • EEG may show multifocal onset seizures • Extreme delta brush: δ waves with superimposed bursts of 20 – 30 Hz β waves • NMDA encephalitis, especially when in coma
  • 50.
    MRI Jo Caekebeke • MRIwith NMDA-R, AMPA-R, LgI1, Caspr2, GABAB-R Ab’s: • May be normal • Or FLAIR/T2 hyperintensities, especially in medial temporal lobes • Mesiotemporal sclerosis as possible long-term outcome • MRI with DPPX, GABAA-R Ab’s: less characteristic LgI1 AMPA-R GABAB-R GABAA-R
  • 51.
    MRI : AIE& mimics Jo Caekebeke LE Ab neg Glioma ADEM Susac NMDA+MOG AMPA
  • 52.
    Stepwise or comprehensiveimmunotherapy ? Jo Caekebeke • First-line therapy • Steroids: (cave infectious encephalitis, CNS lymphoma) • IV Ig and/or plasmapheresis (PE) • Wait 10 - 14 days to allow first-line therapies time to work ? • Second-line therapy, indicated in > 50% • Rituximab: 375 mg/m2 weekly for 4 weeks “and/or” • Cyclophosphamide: 750 mg/m2 monthly for 4 – 6 months • Comprehensive immunotherapy: rituximab and IV Ig or PE and steroids all at the same time (or rituximab and IV Ig and PE) ? • Early aggressive treatment to alter natural course and prevent relapses • IV IG and plasmapheresis reduce Ab’s in circulation > in CSF • More effective in LgI1 than in NMDA encephalitis ?
  • 53.