Autoimmune Diseases Josep Dalmau, MD, PhD University of Pennsylvania 2005 LE or diffuse encephalitis, treatment responsive 2001 LE, infrequently related to cancer, treatment responsive 1968 to 2000: Most LE cancer related, poorly responsive to treatment Synaptic proteins: NMDAR, AMPAR, GABA(B) receptor Cell surface antigen: VGKC Cytotoxic T cells and antibodies, Intracellular antigens Brain 1968; 91:481-498 In August 2008, Marisa became increasingly anxious and started having experiences she never had before She bought a video camera to show to the world what she felt compelled to show My mysterious lost month of madness I was a happy 24-year-old suddenly stricken by paranoia & seizures. Was I going crazy? By SUSANNAH CAHALAN Read more: http://www.nypost.com/p/news/local/item_osece Xxo6axZ8Uyig17QKL#ixzz0yaHLLVEs I was able to make people age with my thoughts I could see the wrinkles rapidly forming and disappearing in their faces Dalmau et al., Lancet Neurol, in press 1
Antibodies against the NMDA receptor Antibodies bind to the N-terminal, extracellular domain of NR1 (aa 25-380) Courtesy of Dr. German Reyes Dalmau et al. Lancet Neurol 2008 Oct 11 Anti-NMDAR encephalitis: distribution by age and tumor in 400 patients Dalmau et al., Lancet Neurol, in press 2
The Syndrome: 100 Patients Anti-NMDAR encephalitis: Dyskinesias and Catatonia 91 women; age 23 years (5-76) Acute change of personality and bizarre behavior ( psychosis ) Short-term memory loss, seizures Decreased level of consciousness, catatonia-like symptoms Prodromal symptoms 86% patients Psychiatry 77% patients Neurology 23% patients Oculofacial dyskinesias Teeth clenching/ extreme agitation Catatonia; dissociative symptoms Abnormal movements (86%) Orofacial dyskinesias Dystonic, choreoathetoid Autonomic instability (69%) Hypoventilation (66%) EEG slow activity Ventilatory support ~ 8 weeks (2-40) ICU 88% patients Dalmau et al. Lancet Neurol 2008;7:1091-1098 Seki et al. JNNP 2008;79:324 Ferioli et al., Arch Neurol 2010;67:250 MRI: 55% abnormal Courtesy of Takahiro Iizuka et al Abnormal movements without EEG correlate CSF: 95% abnormal Lymphocytic pleocytosis WBC 32 (5-480) 91% Increased proteins 32% Oligoclonal bands 67% Wong-Kisiel L, Neurology 2010;74:1550-1551. Dalmau et al. Lancet Neurol 2008;7:1091-1098 3
Intrathecal synthesis of antibodies Outcome 3 15 33 7 27 15 Dalmau et al. Lancet Neurol 2008;7:1091-1098 Number of patients with relapses 1 6 8 Dalmau et al. Lancet Neurol 2008;7:1091-1098 Patients with tumor respond faster, and less frequently require second line immunotherapy 49 patients with tumor First line treatment 39 substantial improvement 10 limited improvement, no response 7 second line Immunotherapy 2 substantial improvement 5 limited change No second line immunotherapy 41 substantial improvement 5 limited improvement, 3 no change p = 0.001 56 patients without tumor First line Immunotherapy 27 substantial improvement 29 limited improvement, no response 16 second line Immunotherapy 13 substantial improvement 3 limited change No second line immunotherapy 40 substantial improvement 9 limited improvement, 2 no change, 5 died Dalmau et al., Lancet Neurol, in press Wong-Kisiel L, Neurology in press 4
Patient s antibodies decrease the number of clusters of NMDAR Functional and Structural Effects of NMDAR Antibodies Dalmau et al. Lancet Neurol 2008;7:1091 Patients antibodies crosslink and internalize NMDAR Patients antibodies decrease NMDAR cluster density in vivo Hughes et al., J Neurosci 2010;30:5866-5875 Moscato et al., not published Hughes et al., J Neurosci 2010;30:5866-5875 5
How does a decrease of NMDAR result in the multistage syndrome? Increase of levels of glutamate after intracerebral injection of patient s antibodies Olney JW. Environ Health Perspect 108:383-388 (2000) Gunduz-Bruce H. Brain Res Rev doi: 10.1016/j.brainresrev.2008.07.006 Manto et al., submitted Clinical correlates of NMDAR hypofunction Implications Blockade of NMDAR Effect on dopaminergic, noradrenergic, and cholinergic systems Inactivates GABAergic neurons Disinhibits brainstem central pattern generator Autonomic instability Increases extracellular glutamate, disinhibits excitatory pathways Semi-rhythmic movements Bulbar, limb, trunk Psychosis, catatonia mutism, rigidity, dystonia Frontostriatal syndrome Defines a new syndrome Provides a model to study how antibodies affect memory, learning, and behavior Strengthens theories (NMDAR hypofunction and psychosis) Reclassifies syndromes known only by descriptive terms Identification of other disorders of synaptic autoimmunity Effect on pontine-medullary respiratory network Respiratory dysfunction, hypoventilation 6
Disorders of Synaptic Autoimmunity AMPA receptor (limbic/ psychiatric) Lai et al., Ann Neurol 2009;65:424 Graus et al., Neurology 2010;74:857 GABAB receptor (limbic/ seizures) Lancaster et al., Lancet Neurol 2010;9:67 Glycine receptor (encephalomyelitis/ rigidity) Hutchinson M et al., Neurology 2008;71:1291 (?) VGKC Buckley et al., Ann Neurol 2001;50:73 Thieben et al., Neurology 2004;62:1177 Antibodies attributed to VGKC Limbic encephalitis Neuromyotonia Morvan s syndrome Other (RPD) Patient s serum Kv1.1 Mab Merged Hek VGKC Kv1.1/1.4 Serum from patients with VGKC antibodies precipitate LGI1 What is LGI1? Secreted synaptic protein Associates with VGKCs and AMPA receptors via the ADAM proteins LGI1-null mice have seizures, early death Human mutations associate with autosomal dominant lateral temporal lobe epilepsy Pre-synaptic LGI1 VGKC ADAM23 LGI1 LGI1 ADAM22 AMPA-R Lai M, Huijbers MGM, et al. Lancet Neurol 2010;9:776-785 Fukata et al., 2010 Post-synaptic 7
LGI1 antibodies: Features of 57 patients Demographics: 65% males, age (30-80, median 60) Symptoms: 100% had memory loss, limbic encephalitis 40% had myoclonus 60% had hyponatremia 82% had seizures Only 6 had tumors MRI: 84% had temporal lobe T2 hyperintensity CSF: 41% had lymphocytic pleocytosis and/or elevated protein Outcomes: 24% full recovery, 54% mild disability, 16% moderate disability, 6% died Lgi1 Antigens of disorders previously attributed to VGKC antibodies CASPR2 Limbic encephalitis Encephalitis/ Morvan s Neuromyotonia Lai M, Huijbers MGM, et al. Lancet Neurol 2010;9:776-785 Lancaster etal., Ann Neurol Irani et al., Brain 2010:133;2734-2748 CASPR2 Expression in Brain and Peripheral Nerve CASPR2 antibodies: Features of 8 patients Demographics: 7 males, age (46-77, median 60.5) Symptoms: 5 had encephalitis AND peripheral nerve hyper-excitability 2 had only encephalilits 1 had only PNH MRI: 2/5 with CNS symptoms had temporal T2 hyperintensity EMG: 4/5 with PNS symptoms had evidence of PNH Outcomes: 7 healthy or mildly disabled; 1 died untreated after 7 years Tumor: 1 superficial bladder CA identified Lancaster et al., Ann Neurol Lancaster et al., Ann Neurol 8
Morvan s syndrome with CASPR2, AChR, and MuSK antibodies Neuromuscular synapse CNS synapse Diaz-Manera et al., Nat Clin Pract Neurol 2007;3:405-410 3 of 8 patients with CASPR2 antibodies were initially suspected to have ALS Myasthenia gravis LEMS NMDAR AMPAR GABA(B) receptor LGI1, CASPR2 Acknowledgments: M Lai, E Martinez, L McCracken, JE Rossi, L Zhou, E Lancaster, MR Rosenfeld R Balice-Gordon, E Hughes, X Peng, E Moscato, A Jain S Scherer, E Lancaster DR Lynch, A Gleichman T. Parsons Funding: - NIH RO1CA89054 - NIH RO1CA107192 - NIH 1RC1NS068204-01 - McKnight Neuroscience of Brain Disorders Award 9
Sequential Stages of Progression and Resolution of symptoms in anti-nmdar encephalitis Prodrome Agitation, psychosis, hallucinations, catatonia, memory deficit, speech reduction, +/- seizures Clinical Worsening Clinical Improvement Abnormal movements, coma, hypoventilation, +/- dysautonomia Serum PCP levels: 0.01-0.2 µm >0.2 µm Positive serum antibodies http://penncancer.org/pnd/ Dalmau et al., Lancet Neurol, in press Consider alternate diagnosis Negative NMDAR antibody testing (serum and CSF) NMDAR antibodies activate complement in vitro Positive Patient s Abs Complement Merged Abdomen/pelvis MRI/ CT/ US Supportive care, chronic immunosuppression, yearly tumor surveillance Good response Negative Positive Methylprednisolone/ Tumor removal + IVIg Methylprednisolone/ IVIg Limited/ no Good response response Good response Rituximab and/or cyclophosphamide Supportive care, yearly tumor surveillance Limited/ no response Supportive care, chronic immunosuppression, yearly tumor surveillance Consider alternative Immunosuppressants, yearly tumor surveillance 10
Deposits of IgG in the hippocampus of a patient Deposits IgG Complement activation in tumor but not in brain B-cells Microgliosis T-cell Rare T-cell infiltrates infiltrates Control Dalmau et al., Ann Neurol 2007; 61:25-36 Infiltrates of Plasma Cells in anti-nmdar encephalitis NMDAR antibody synthesis and effects in the CNS Patient 1 Patient 2 Moscato E, et al., Eur J Neurosci 2010;32:298-309 11
Mechanical ventilation: 9 months Duration of hospital stay: 14 months Transferred to nursing home in vegetative state Gradually improved, became independent in 6 years Iizuka et al, Neurology 2008;70:504-511 Mechanical ventilation: 7 months Duration of hospital stay: 9 months Gradually improved, back to work 4 years later Iizuka et al, Neurology 2008;70:504-511 12
Patient s antibodies alter the localization of AMPAR in synapses Activation of GABA B receptors inhibits electrical activity in cultured neurons Control CSF (1%), 24 hours Baclofen 100 µm 20 mv 5 sec Lai et al., Ann Neurol 2009;65:424-434 Patients antibodies block GABA B receptor function Control CSF (1%), 24 hours Patient CSF (1%), 24 hours Baclofen 100 µm 20 mv 5 sec Isaacs Unexplained Syndrome Isaacs Syndrome Unexplained Morvan s Syndrome Other Other LGI1 Limbic Encephalitis encephalitis Morvan s Syndrome Baclofen 100 µm CASPR2 syndromes 13
Serum absorption with LGI1 abrogates reactivity with brain Patients antibodies react with soluble LGI1 bound to ADAM Lai M, Huijbers MGM, et al. Lancet Neurol 2010;9:776-785 Lai M, Huijbers MGM, et al. Lancet Neurol 2010;9:776-785 CASPR2 Patient CSF Wild-type Caspr2 -/- CASPR2 antibodies do not react with Caspr2-null peripheral nerves CASPR2 Patient serum CASPR2 LGI1 patient Control CSF Lancaster et al., Ann Neurol Lancaster et al., Ann Neurol 14
Antibody effects correlate with titer and are independent of complement Hughes et al., J Neurosci 2010;30:5866-5875 Hughes et al., J Neurosci 2010;30:5866-5875 Patients antibodies decrease synaptic NMDAR currents Patients antibodies recognize the LGI1-ADAM complex LGI 1 ADAM22 LGI 1 ADAM23 LGI 1 ADAM22 ADAM23 VGKC mepsc Moscato et al., Eur J Neurosci, in press Lai M, Huijbers MGM, et al. Lancet Neurol 2010;9:776-785 15
CASPR2 antibodies recognize CASPR2 in transfected cells Patients serum do not react with Lg1-null mice Patient CSF CASPR2 Merge LGI1-null mice express Kv1.1 Patient Sera CASPR2 Merge Control CSF CASPR2 Merge 20 µm Lai M, Huijbers MGM, et al. Lancet Neurol 2010;9:776-785 Lancaster et al., Ann Neurol 16