Brain. Autoimmune neurology. Peripheral nervous system. Spinal cord
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1 Autoimmune Epilepsy Sean J. Pittock, MD Associate Professor Neurology Co Director Neuroimmunology Laboratory Director Autoimmune Neurology Clinic Mayo Clinic
2 Disclosure Dr. Pittock receives no royalties from the sale of tests performed in the Neuroimmunology Laboratory at Mayo Clinic; however, Mayo Collaborative Services Inc. does receive revenue for conducting these. Off Label Usage I will mention use of a variety of immunotherapies..
3 Hypothalamus Cerebellum Basal ganglia Cortex Brain Brain stem Optic nerve/retina Autoimmune neurology Peripheral nervous system Spinal cord Neuromuscular junction Autonomic Somatic Muscle Spinal cord
4 Neurologic Autoimmunity Idiopathic, Paraneoplastic CNS PNSANS ENS IgG markers Plasma membrane* channels, receptors, other IgG effectors * e.g.,vgkc complex, ganglionic or muscle AChR, AQP4 Nuclear & cytoplasmic peptides* T cell effectors * surface MHC I complexes e.g., ANNA 1 (Hu), CRMP 5, ANNA 2 (Ri)
5 Neural Autoantibodies and Cancer Lung Thymoma Breast Ovarian/ Mullerian duct Testicular Hodgkin s lymphoma Neuroblastoma ANNA 1 (Hu),22 (Ri),3, CRMP 5,, amphiphysin, PCA 2, striational, recoverin, Zic4, VGCC (N type and P/Q type), type),vgkc comlex,, ganglionic/muscle AChR, AGNA, Ma2, GABAB, AMPAR,, NMO IgG Muscle/ganglionic AChR, striational, GAD65, CRMP 5, VGKC complex, ANNA N A 1, GABAB, AMPAR ANNA 2, amphiphysin, VGCC (N type), muscle AChR, VGKC complex, Ma2,, NMO IgG, AMPAR, PCA 1(Yo), VGCC (N type > P/Q type), muscle AChR, NMDAR (teratoma) Ma2 PCA Tr ANNA N A 1, muscle AChR, VGCC (N type), striational
6 THYROID papillary carcinoma VGKC Ab THYROID Hurthle cell tumor THYROID papillary carcinoma 3 3 AChR Ab TONSIL squamous cell carcinoma Unclassified Ab LUNG small cellcarcinoma CRMP 5 IgG LUNG adenocarcinoma Unclassified Ab
7 LYMPH NODE small cell carcinoma ANNA 1 LUNG squamous cell carcinoma ANNA 1 LYMPH NODE adenocarcinoma Amphiphysin Ab COLON adenocarcinoma VGKC Ab LYMPH NODE adenocarcinoma ANNA 1
8 Hypothalamus Cerebellum Basal ganglia Cortex Brain Brain stem Optic nerve/retina Autoimmune neurology Peripheral nervous system Spinal cord Neuromuscular junction Autonomic Somatic Muscle Spinal cord
9 Cortex Hypothalamus Cerebellum Autoimmune Encephalopathy Autoimmune Epilepsy Autoimmune Dementia Basal ganglia Cortex Brain Brain stem Optic nerve/retina Autoimmune neurology Menu Peripheral nervous system Spinal cord Neuromuscular junction Autonomic Somatic Muscle Spinal cord
10 Cortex Autoimmune Encephalopathy Autoimmune Epilepsy Autoimmune Dementia Hypothalamus Basal ganglia Cortex Brain Cerebellum Brain stem Optic nerve/retina Major Antibodies ANNA 1 (hu), CRMP5 NMDA R, GABAB R, AMPA R VGKC complex GAD 65 Autoimmune neurology Menu Peripheral nervous system Spinal cord Neuromuscular junction Autonomic Somatic Muscle Spinal cord
11 Cortex Autoimmune Encephalopathy Autoimmune Epilepsy Autoimmune Dementia Hypothalamus Basal ganglia Cortex Brain Cerebellum Brain stem Optic nerve/retina Major Antibodies ANNA 1 (hu), CRMP5 NMDA R, GABAB R, AMPA R VGKC complex GAD 65 Autoimmune neurology Menu Peripheral nervous system Spinal cord Neuromuscular junction Autonomic Somatic Muscle Spinal cord
12 Autoimmune Dementia Flanagan E P et al. Mayo Clin Proc 2010
13 Neuroimaging in immunotherapy responsive responsive cognitive disorders Flanagan E P et al. Mayo Clin Proc 2010
14 VGKC Complex Autoimmunity Mimicking Creutzfeldt Jacob Disease Geschwind, M. D. et al. Arch Neurol 2008
15 Diagnosis of Possible Autoimmune Neurological Disorder Consider alternative acute therapy or no further therapy No improvement Objective baseline measurements Acute treatment, Diagnostic Test IV methylprednisolone or IVIg or Plasma exchange Not evidence based Confirms diagnosis Chronic treatment Continue acute IV therapy, and taper or Oral prednisone taper and Oral azathioprine or Oral mycophenolate mofetil or Other options
16 Cortex Autoimmune Encephalopathy Autoimmune epilepsy Autoimmune Dementia Hypothalamus Basal ganglia Cortex Brain Cerebellum Brain stem Optic nerve/retina Major Antibodies ANNA 1 (hu), CRMP5 VGKC complex NMDA R, GABAB R, AMPA R GAD 65 Autoimmune neurology Menu Peripheral nervous system Spinal cord Neuromuscular junction Autonomic Somatic Muscle Spinal cord
17 CRMP 5 is Enriched in Synaptic Regions CRMP % ANNA 1(hu) 0.36% PCA 1 (yo) 0.17% PCA % Amphiphysin 0.04% ANNA 2 (ri) 0.02% ANNA % 116 Patients CRMP5 IgG + 46 had cortical involvement 24% of these had seizures SM P G M Yu et al, Ann Neurol 2001
18 ANNA 1 ANNA 2 ANNA 3 D Neuronal Nuclear Abs
19 ANNA 1 (hu) associated paraneoplastic epilepsy 23 of 162 patients with ANNA 1 antibodies had limbic encephalitis Extratemporal Seizures Before 48% had seizures Lucchinetti et al, Neurology 1998 After McKeon et al, Arch Neurol 2009
20 EEG features in 30 ANNA 1 + patients Abnormal 83% Slowing Diffuse Focal Epileptiform discharges % of total 63% 53% 40% PLEDS 13% Recorded Seizures 13% Focal Slowing 40%Temporal only 20% Extratemporal only 40% both Epileptiform discharges 33%Temporal only 25% Extratemporal only 42% both EPS 7%
21 Cortex Autoimmune Encephalopathy Autoimmune epilepsy Autoimmune Dementia Hypothalamus Basal ganglia Cortex Brain Cerebellum Brain stem Optic nerve/retina Major Antibodies ANNA 1 (hu), CRMP5 NMDA R, GABAB R, AMPA R VGKC complex GAD 65 Autoimmune neurology Menu Peripheral nervous system Spinal cord Neuromuscular junction Autonomic Somatic Muscle Spinal cord
22 The clinical spectrum of VGKC complex autoimmunity Manifestations % Tan et al, Neurology 2008 N=72 Cerebral Cortex Dementia Seizures Morvan syndrome 3% PN hyperexcitability 17% Hypothalamic 38 Dyssomnia 26 Extrapyramidal 21 GL ML C Cerebellum 8 Brainstem 19 Somatic PN 25 Autonomic 33
23 The tip of the ice berg 54yo/M memory problem (1m) 2 GTC seizures levetiracetam MRI: subtle T2 signal L hippocampus CSF: Protein Partial seizures daily EEG electrographic seizures of midline frontal, midline central, and indeterminate onset. VGKC complex Ab 0.33nmol/L Prostate adenocarcinoma. Immunotherapy IVMP (pulsed intervals) Improved, but when dosing interval increased to 4 weeks, spells returned Symptoms resolved reduction in steroid interval Mycophenylate mofetil Antiepileptic therapy: optimised Brachytherapy for prostate cancer 2 months after immunotherapy was initiated. Currently: Seizure free. Back at work
24 No. LGI1 CASPR2 Limbic Encephalitis VGKC ab VGKCAb + neuromyotonia Movan Encephalitis Acute encephalopathies Anti NMDAR encephalitis Viral Encephalitis Anti AMPAR encephalitis Rasmussen s encephalitis Acquired neuromyotonia Lai et al, Lancet neurology 2010
25 VGKC complex autoimmunity and epilepsy 96 VGKC Ab + LGI1=55 Caspr2=19 Tag 1/contactin 2=5 KV1=3 Negative=18 LGI1 N=55 Caspr2 N=19 Limbic encephalitis 89% 37%* Morvan s syndrome 4% 16% Neuromyotonia 2% 37%* Epilepsy only 2% 10% Irani S R et al. Brain 2010;133:
26 Anti NMDA Receptor Encephalitis Females (5 76) Features Neurological Seizures, Cognitive decline Dyskinesias Autonomic Hypoventilation Psych symptoms catatonia MRI and EEG Temporal Lobe Cancer Teratomas (usually ovarian) Serology Dalmau et al, Lancet Neurol 2008 CSF > Serum C C/P T GL H
27 Anti GABAB Receptor Encephalitis Age (24 75 yrs) History/Exam Seizures Confusion Memory loss CSF Inflammatory MRI Limbic encephalitis EEG Temporal lobe onset Cancer Small cell lung (33%) Serology Lancaster et al. Lancet Neurol 2010 CSF > serum C H T
28 Anti AMPA Receptor Encephalitis Females (38 87) yrs History/Exam Seizures Memory loss Confusion CSF Inflammatory MRI and EEG Temporal lobe Cancer Lung Breast Thymus Serology Serum or CSF T C/P Lai et al., Annals Neurol 2009
29 Mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features Kalachikov et al. Nat Genet 2002 Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies
30 Conclusions Autoimmune Neurology Rapidly evolving field of Neurology Immunotherapy responsive/reversible disease Autoimmune Epilepsy Should be considered in patients with focalonset epilepsy of undetermined etiology Institution of immunotherapy may complement anti epileptic medications to optimize seizure control. Neural autoantibody evaluation may assist in diagnosis and direct cancer search
31 Acknowledgements Neuroimmunology Laboratory and Division of MS and Autoimmune Neurology Vanda A Lennon, MD PhD Andrew McKeon, MD Clinical Laboratory and Development technologists Division of Epilepsy Jeffrey W. Britton, MD Elson. So, MD Cheolsu Shin, MD Terrence D. Lagerlund, MD Gregory D. Cascino, MD Gregory A. Worrell, MD PhD Elaine C. Wirrell, MD Kate Nickels, MD;
32 NMDAR Abs and nonconvulsive status epilepticus Cultured rat hippocampal neuron incubated with patient's CSF demonstrates antibodies to the NR1/NR2 heteromers. After 5 months in pentobarbital induced burst suppression oopherectomy (ovarian teratoma) recovery. Johnson, N. et al. Neurology 2010
33 VGKC complex autoimmunity and epilepsy Immunocytochemistry and immunoprecipitation of LGI1 with serum from patients with encephalitis previously attributed to VGKC antibodies Lai et al, Lancet neurology 2010
34 Immunoabsorption confirms that LGI1 is the autoantigen Lai et al, Lancet neurology 2010
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