Immune-Mediated Neurological Disorders 中醫大附醫神經部郭育呈台灣神經學會繼續教育課程中山醫大正心樓 20190907

Immune-mediated neurological disorders 中醫大附醫神經部郭育呈台灣神經學會繼續教育課程中山醫大正心樓 20190907

Encephalitis 203 cases • Infectious 42% • Immune-related 21% (ADEM 11%, anti-NMDAR 4%, VGKC 3%)

Granerod J et al, Lancet Infect Dis 20 0 Acute encephalitis/encephalopathy

• 198 patients, mean age of 58 years (41.8-69 years) • Viral encephalitis 48%, autoimmune encephalitis 22.2%, unknown etiology 29.8% • Anti-NMDAR 24.4%, VGKC 24.4%, GAD65, Purkinje cell Abs

Clin Infect Dis 2013; Neurology 2015 Possible autoimmune encephalitis

• Subacute onset (< 3 months) of working memory deficits (short-term memory loss), altered mental status (personality change), or psychiatric symptoms • At least one of the following (>= 1/4) - New focal CNS findings - Seizure - CSF pleocytosis (>5/mm3) - MRI suggestive of encephalitis • Reasonable exclusion of alternative causes

Lancet Neurology 2016;15:391-404 Dalmau Josep et al. NEJM 2016 Antibodies against cell surface antigens

Dalmau Josep et al. Physiol Rev 2017 Antibodies against cell surface antigens

Dalmau J et al. Physiol Rev 2017 Onconeural intracellular antigens (paraneoplastic)

Antibodies Tumors Neurological features Movement disorders

Anti-Hu (ANNA1) SCLC Encephalomyelitis, sensory Ataxia, pseudoathetosis neuropathy, LE, brainstem (sensory neuropathy), encephalitis cerebellar syndrome Anti-Ma2 Testis (germ- LE, brainstem encephalitis, Hypokinetic with cell); SCLC, narcolepsy, excessive supraneuclear gaze breast daytime sleepiness, palsy, cataplexy, hyperphagia cerebellar syndrome Anti-CV2/CRMP5 SCLC, LE, uveitis, retinitis, Chorea, dystonia, thymoma, polyneuropathy ballism, cerebellar lymphoma syndrome Anti-amphiphysin Breast, SCLC Encephalomyelitis with SPS, myoclonus rigidity, sensory neuropathy Anti-Yo Ovary, breast Cerebellar syndrome

Anti-Ri (ANNA2) Breast, SCLC Brainstem encephalitis, Cerebellar syndrome, rigidity opsoclonus-myoclonus- ataxia Anti-Tr Hodgkin’s Cerebellar syndrome, lymphoma LE (rare) Anti-NMDA receptor encephalitis Excitatory synapse in the CNS

Lancet Neurol 2008 Excitatory synapse in the CNS

Lancet Neurol 2008 Newman MP et al, Internal Medicine J 2015 Kayser MS et al. Curr Psychiatry Rev 2011. Abnormal movement

• Oro-lingual-facial dyskinesias: grimacing, masticatory-like movement, forceful jaw opening/closing • Choreo-athetosis, stereotyped, elaborate motions of arms/legs (arms>legs) • Oculogyric crisis, dystonia, rigidity and opisthotonus Diagnostic tools

• Brain MRI is unremarkable in 50% of patients, and in the other 50% are usually mild or transient. • Electroencephalograms (EEG) are abnormal in most patients, usually showing non-specific, slow, and disorganised activity.

• Abnormal MRI (33%), EEG (90%) and CSF (79%) • NMDAR antibodies: sensitivity 100% in CSF, 85% in serum

Lancet Neurol 2013 Extreme delta brush

Anti-NMDAR encephalitis

• GluN1 subunit of the NMDAR • 5% mono-symptomatic (e.g. psychiatric symptoms) • 14% false negative for serum antibody test • Two potential triggers: tumor and viral encephalitis • 20% HSV encephalitis  delayed complication (NMDAR antibody): children- choreoathetosis, adult-behavior change *BBB

Dalmau J, NEJM 2018 MMF or AZA 1 year

• AED • Ab titers 2 years

MMF or AZA MTX 1 year Voltage-gated potassium channels (VGKC) antibodies • VGKC-complex antibodies • LGI-1, CASPRA2 antibodies • Limbic encephalitis (LE), faciobrachial dystonic seizures (FBDS), Morvan’s syndrome and neuromyotonia • LGI-1 antibody-the most common cause of limbic encephalitis, second most common cause of autoimmune encephalitis. Anti-LGI1 encephalitis • Leucine-rich, glioma-inactivated 1 • 64 y/o, M/F= 2:1 • A more indolent course • Facio-brachial dystonic seizures (FBDS, unilateral), paroxysmal dizzy spells, memory & behavior alteration, 10-15% only cognitive dysfunction • 65% hyponatremia • Tumor 11%, thymoma & lung cancer • Some patients have Abs only in serum or only is CSF. • Relapses often occur when immunotherapy is reduced or discontinued. • Relapses may herald recurrence of associated tumor or missed tumor in the initial episode.

Titulaer MJ et al. Nat Rev Neurol 2017 50-80%

Titulaer MJ et al. Nat Rev Neurol 2017 Anti-CASPR2 encephalitis

• Contactin-associtaed protein-like 2, CNS & PNS • 66 y/o, M/F= 9:1 (strong predominance in men) • A more indolent course • Cognition decline (80%), insomnia, dysautonomia, ataxia, nerve hyper-excitability (50%), neuropathic pain, body weight loss • CNS and PNS manifestations with ANS dysfunction & insomnia  Morvan’s syndrome • Increased signal in medial temporal lobes • 20%-32% thymoma Titulaer MJ et al. Nat Rev Neurol 2017 Anti-GABAAR encephalitis

• Children and young adults, 40 y/o (2 mon-88 yr), M/F= 1:1 • Refractory status epilepticus, confusion, behavior changes • Multifocal cortical and subcortical signal abnormalities, mainly in frontal & temporal lobes, less in cerebellum & basal ganglia, diffusion restriction(-), enhancement(-) • Resemble the lesions in ADEM • Thymoma Anti-GABABR encephalitis

• 61 y/o (16-77), M/F= 1.5:1 • Seizure, memory loss, confusion-limbic encephalitis; seizure or status epilepticus • Increased signal in medial temporal lobes • 50% of patients- small cell lung cancer • Good respond to immunotherapy and tumor removal Anti-AMPAR encephalitis

• 56 y/o (23-81), M/F= 1:2.3 • Limbic encephalitis (most), rare rapid dementia or psychosis • Increased signal in medial temporal lobes • 70% of patients- SCLC, thymoma or breast cancer • 70% respond to immunotherapy or tumor removal Anti-DPPX encephalitis

• Dipeptidyl-peptidase-like protein 6 • 52 y/o (13-76), M/F= 2.3:1 • A more indolent course • Prodromal severe diarrhea and body weight loss • Myoclonus, tremor, exaggerated startle responses (hyperekplexia) • Normal MRI and CSF studies • B-cell neoplasms # LGI-1 & DPPX  most frequently normal MRI/CSF studies

Anti-D2R encephalitis

• Dopamine 2 receptor • 6 y/o (2-15) • Children with symptoms like anti-NMDAR encephalitis but brain MRI changes involving basal ganglia & brainstem • PDism, dystonia, psychiatric symptoms • No associated cancer Stiff person spectrum disorders (SPSD)

• Stiffness, spasms and heightened stimulus sensitivity including hyperekplexia • Stiff limb syndrome (SLS) • Progressive encephalomyelitis with rigidity and myoclonus (PERM) • GAD65 antibody-SPSD, ataxia, focal seizure, T1DM, thyroid disease • DPPX antibody- hyperekplexia, ataxia, sensory or memory disturbance, prolonged diarrhea • Amphiphysin antibody- DTR loss, sensory ataxia • Glycine receptor (GlyR) antibody- all disease types • Triad of treatment: symptomtic Tx, immunotherapy and tumor removal.

Balint B et al, Movement Disorder Clin Pract 2018 GAD65 Glycine Amphiphysin DPPX receptor Frequency 70-80% 10% 5% 3%

Tumor Very rare Thymoma, lung Breast cancer B cell neoplasm cancer, breast cancer, Lung cancer lymphoma

Red flag 80% 20% - 20% T1DM, Thyroid Thyroid disease > RA > Thyroid disease, features disease, pernicious Sarcoid pernicious anemia anemia Neurological Ataxia, focal epilepsy Prominent brainstem Sensory Diarrhea (less (rare limbic signs neuronopathy, constipation), symptoms encephalitis) myelopathy stimulus sensitivity, ataxia Management -Tumor rare but keep -Good response to -Paraneoplastic -good response to in mind immunotherapy syndrome immunotherapy -Typical chronic course -PERM with thymoma -Good response to -need long-term  thymectomy (good) tumor removal & immunosuppressant immunotherapy

Balint B et al, Movement Disorder Clin Pract 2018 IgLON5 antibody-related tauopathy

• Prominent sleep movement disorders (NREM sleep parasomnia, REM sleep behavior disorders, PLMS) • Breathing problem- sleep apnea, stridor, respiratory insufficiency • Bulbar involvement- oculomotor disturbance, dysarthria, dysphagia, vocal cord palsy • Dysautonomia • Gait instability-loss of postural reflex • Parkinsonism (PSP phenotype), chorea

Brain 2018;141:13-36. Brain 2018;141:13-36. Newman MP et al, Internal Medicine J 2015 Newman MP et al, Internal Medicine J 2015 Take home massage

• Subacute memory decline, mentality change or psychiatric symptoms  infection & inflammation • Check autoimmune encephalitis antibodies if no obvious improvement even viral encephalitis confirmed (as HSV encephalitis) • Oro-lingual-facial dyskinesias, movement disorder  anti-NMDAR encephalitis • Immunotherapy and tumor removal (if exists) • Diarrhea, hyperekplexia  DPPX antibody

Take home massage

• Faciobrachial dystonic seizure (FBDS), hyponatremia  LGI1 antibody • Neuromyotonia  LGI-1, CASPRA2 antibodies • CNS and PNS hyperexcitability, dysautonomia, insomnia  Morvan’s syndrome • Stiff person spectrum disorders (SPSD)- GAD65, amphiphysin, glycin receptor (GlyR), DPPX • Parasomnia, dysautonomia, breathing problems, bulbar involvement, PSP-like PDism  IgLON5 antibody

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