Central Nervous System (CNS) and Lupus: Learn from the Experts. Betty Diamond, M.D. Feinstein Institute for Medical Research

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1 Central Nervous System (CNS) and Lupus: Learn from the Experts Betty Diamond, M.D. Feinstein Institute for Medical Research

2 Stages in SLE Pathogenesis Crow MK, Arth Res & Tx. 2009

3 ACR Criteria for the Classification of SLE Malar rash Discoid rash Photosensitivity Oral Ulcers Arthritis Serositis Renal disorder Neuropsychiatric disorder Hematologic disorder Immunologic disorder Antinuclear antibody

4 ACR Criteria for the Classification of NPSLE Central Nervous System Brain & Spinal Cord Cognitive dysfunction Headache Mood disorder Anxiety Psychosis Acute Confusion-Delirium Demyelinating syndrome Seizures Aseptic meningitis Movement disorder (chorea) Myelopathy Vascular disease* Peripheral Nervous System Cranial neuropathy Polyradiculopathy Plexopathy Autonomic disorder Mononeuropathy Polyneuropathy Myasthenia gravis

5 Neuropsychiatric SLE Over 80% of SLE patients experience some type of nervous system manifestation at some time during the disease course Seizures and psychosis are the only manifestations that are part of the diagnostic criteria for the diagnosis of SLE

6 Neuropsychiatric SLE: Risk Factors Antiphospholipid antibodies: thrombosis, thrombocytopenia, recurrent fetal loss, cognitive problems Anti-ribosomal P antibodies: psychosis Anti-glutamate receptor antibodies: cognitive problems, depression Secondary effects of renal disease, vascular disease infection and medication side effects

7 Prevalence of Neuro-Psychiatric SLE using ACR nomenclature Number of Patients Disease duration Tampere, Finland SanAntonio, US London,UK Caligari, Italy Albuquerque, US Halifax, Canada ±8 8 11±8 7±8 10±1 Total with NP-SLE 91% 80% 57% 95% 37% Hanly J. Lupus 2004

8 Prevalence of Neuropsychiatric SLE NPSLE manifestations occur as single or multiple events even during periods of no non-nervous system disease activity 40% of NPSLE manifestations develop before diagnosis of SLE 63% occur within first year of diagnosis

9 Most Common Manifestations of Neuropsychiatric SLE Central Nervous System Percent Cognitive dysfunction (n=249) 55-80% Headache (n=683) 24-54% Mood disorder (n=314) 14-57% Cerebrovascular Disease (n=490) 5-18% Seizures (n=509) 6-51% Anxiety (n=128) 24% Psychosis (n=323) 8% Peripheral Nervous System Polyneuropathy (n=46) 28%

10 Cognitive Dysfunction NPSLE Syndromes: Cognitive Attention Concentration Memory Word-finding Importance of corticosteroid use controversial Impairment not always progressive Waxing and waning symptoms not always associated with flare. Confounding influences of depression, medication, pain, fatigue, and now age as patient survival has increased.

11 Pathophysiology for the Most Common Neuropsychiatric Symptoms Vascular Pathology (n=141; 75%) Thrombosis, Infarct; micro (49%), macro (18%) Hemorrhagic Infarct; micro (28%), macro (17%) Inflammation Vasculitis (7%) Atherosclerosis (2-7 fold prevalence) Blood-Brain Barrier Breach and Direct Neurotoxicity Medications

12 Immunopathology B cells & Autoantibodies Anti-phospholipid Ab (APL)= vascular disease Anti-ribosomal-P Antibody CROSS REACTS with neuron surface protein 331 Anti-DNA antibody CROSS REACTS with N methyl D aspartate receptor (NMDAR) on neurons

13 Anti-brain Antibodies Cause Cognitive and Behavioral Problems in Laboratory Models lupus antibody no antibody lupus antibody lupus antibody The blood-brain barrier protects the brain from antibodies in the blood. Infection or stress can compromise the blood-brain barrier.

14 Lupus Ab Binds NMDAR and Causes Neuronal Death or Dysfunction in vivo Antibody Induced Neuron Death Enhancement of NMDAR Responses SLE Control

15 Anti-brain Antibodies from SLE Patients Cause Neuronal Death In Vitro Hu anti-pep serum cerebrospinal fluid brain tissue SLE CSF Non-SLE CSF +MK801 SLE CSF Hu control Non-SLE CSF CSF titers of antibody correlate with CNS symptoms

16 Anti-brain Antibodies in CSF of Patients with SLE CNS = central nervous system SLE PNS = peripheral nervous system SLE S = SLE patients undergoing surgery (no NPSLE) NA = non-autoimmune controls

17 Anti-brain Antibodies in CSF of Patients with SLE Yoshio et al. Arthritis & Rheumatism, 2006

18 Therapy for NPSLE There are no specific drugs for NPSLE manifestations. Drugs used are the same ones we use to treat other serious lupus manifestations Steroids Imuran Cytoxan Cellcept Others

19 Symptomatic Treatments Medications Drugs used to treat headache, seizures, stroke and other NPSLE manifestations work as well in SLE patients as in people without SLE Many SLE patients (up to 66%!) use alternative medicines Non-Pharmacologic Stress management Life-style changes Psychotherapy Cognitive rehabilitation

20 Summary Brain involvement in SLE is frequent and the sequelae may increase with disease severity and duration. Pathophysiology depends on cytokines, stress hormones, drugs and also on the specificity and concentration of antibrain antibodies and their ability to penetrate the bloodbrain barrier. CSF antibody titers may better reflect brain symptoms than serum antibody titers. Vascular compromise and subsequent brain injury results from APL Ab; rarely inflammatory vasculitis. Novel therapeutic opportunities include antibody blockade.

21 Project Collaborators Betty Diamond Czeslawa Kowal Eva Bertini Paola Mina- Osorio Meggan Mackay Cynthia Aranow Jorge Sanchez- Guerrero Matthew Scharff John Hardin Patricio Huerta Roseann Berlin Tom Faust Eric Chang Lori DeGiorgio Mark Edgar

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