When Your Head Hurts And Your Memory Fails

When Your Head Hurts and Your Memory Fails- Is It Your Lupus? Petros Efthimiou, MD, FACR, Lincoln Medical and Mental Health Center Assistant Professor of Medicine, Weill Cornell Medical College, New York, NY

LUPUS
CHRONIC
AUTOIMMUNE
The body’s autoimmune system (“defense") attacks ITSELF Skin Kidney Lung Heart Joints Blood Nervous System Progressive Long Standing MULTISYSTEMIC

Epidemiology of SLE Incidence : 7.6/100,000/year (pooled from a number of studies) Prevalence: 14.5-50.8/100,000 Hochberg’s Prevalence : 372/100,000 US: close to 1 million people SLE Lupus Foundation: probably 1.5 million incidence 1950 2000 10 5 2

How Does Lupus happen? T Cell Abnormal Adhesion Molecule and Chemokine Expression Tissue Specific Pathology APC B7 MHC FcR CR RES AutoAb Drugs UV Infectious Agents Genetic Background Estrogens B Cell Increased Help Decreased Cytotoxicity Altered Cytokine Production IL-6, IL-10 IL-2 DC IFN  AutoAg Apoptosis + Immune Complexes

American College of Rheumatology Criteria For Lupus Antinuclear Antibody 95% Immunologic Disorder 70% (aDNA, LE prep, aSm, lupus anticoagulant Hematologic Disorder 10% Neurologic Disorder 10% Renal Disorder 60% Malar Rash Serositis Arthritis Oral Ulcers Photosensitivity Discoid Rash

Neuropsychiatric (NPS) lupus Why does it happen? NO SINGLE PATHOGENIC MECHANISM Primary Manifestations of the Disease Secondary Complications of the Disease or Therapy Coincidental

Neuropsychiatric (NPS) lupus
Neurologic
Seizures
Stroke
Headache
Peripheral neuropathy
Movement disorders
Transverse myelitis
Cranial neuropathy
Psychiatric
Neurocognitive dysfunction
Organic brain syndrome
Psychosis
Psychoneurosis

Neuropsychiatric (NPS) lupus SEIZURES Generalized: whole body affected Partial: only one part or side of the body is affected Complex change in level of consciousness Simple (focal) no change in level of consciousness May present with: Twitching or shaking Temporary abnormal sensations Visual disturbances

Neuropsychiatric (NPS) lupus STROKE
May present with:
Sudden numbness or weakness especially on one side of the body
with an associated tingling sensation
Sudden confusion or trouble speaking or understanding
Sudden trouble seeing
Sudden trouble walking, dizziness, loss of balance or coordination
Sudden severe headache

Neuropsychiatric (NPS) lupus HEADACHE An organic basis for the headaches in SLE is suggested by the sudden development in someone previously free of headaches, associated with Neurologic changes or changes in personality. Migraine and tension Headaches are the most common type of presentation. Migraine: Throbbing or pounding pain Nausea and vomiting Scalp tenderness Sensitivity to light or sound Worsening of pain with movement Visual disturbances Dizziness or vertigo Tension headache Pressing/tightening (nonpulsating) quality, located on both sides of the head Mild or moderate intensity Not aggravated by routine physical activity No nausea or vomiting Possible sensitivity to light or sound but not both

Neuropsychiatric (NPS) lupus PERIPHERAL NEUROPATHY Polyneuropathy Mononeuropathy
May present as:
Temporary numbness, tingling, and pricking sensations (paresthesia)
Sensitivity to touch
Muscle weakness
Burning pain (especially at night)
Muscle wasting
Paralysis
Organ or gland dysfunction.
Difficulty digesting food, maintaining safe levels of blood pressure, sweat normally, or experience normal sexual function.
Mononeuritis Multiplex

Neuropsychiatric (NPS) lupus Neurocognitive Dysfunction Manifested by impairments in mental activities Memory Judgment Abstract Thinking Simple/ Complex Attention Language Psychomotor speed

Neuropsychiatric (NPS) lupus Psychosis Characterized by: Presence of Delusions Presence of Hallucinations False belief despite evidence to the contrary Perceptual experience occurring in the absence of external stimuli.

Neuropsychiatric (NPS) lupus Pathogenesis Vascular Abnormalities Noninflamatory Vasculopathy Vasculitis Thrombosis Autoantibodies Inflammatory Mediators Antineuronal antibodies Antiribosomal P antibodies Antiphospholipid antibodies IL-2 IL-6 IL-10 IFN- α TNF- α Matrix Metalloproteinase

Neuropsychiatric (NPS) lupus Diagnosis
STEPS:
Confirm diagnosis of Lupus ACR Criteria History and Physical Examination Exclude systemic illness and medications as confounding variables Use of Diagnostic tools for Specific Symptoms or Signs

Neuropsychiatric (NPS) lupus Diagnosis
Diagnostic tools for Specific Symptoms or Signs
STROKE CT Scan MRI Echocardiogram Blood tests (to assess for coagulopathy) Carotids Ultrasonography SEIZURE EEG NEUROPATHY EMG COGNITIVE ABNORMALITIES Psychometric Testing Differentiates organic from psychosocial disease MRI EEG Blood tests (to assess for coagulopathy) ANXIETY / DEPRESSION Psychometric Testing Differentiates organic from psychosocial disease

Neuropsychiatric (NPS) lupus Diagnosis Predominantly fixed lesions in the periventricular and Subcortical White Matter Focal Neurologic Disease More Sensitive than CT Scan and T1- Weighted MRI for detecting Abnormalities in NP-SLE T2- Weighted MRI : Findings: Diffuse Neurologic Disease Transient Subcortical White Matter Lesions and patchy Hyperintensities in the Gray Matter

Systemic lupus erythematosus: brain (MRI)

Neuropsychiatric (NPS) lupus Diagnosis CT SCAN Findings: Detects structural and focal abnormalities Brain atrophy

Neuropsychiatric (NPS) lupus Diagnosis SEROLOGIC STUDIES Antiphospholipid ANTIBODIES ASSOCIATION CVA, Vascular Dementia, Seizures, Thromboses, headache, Chorea, Transverse Myelitis Antiribosomal P Psychosis, Severe depression Antineuronal, anti-neural-tissue-specific, anti-N-mrthyl-D-aspartate receptor (NMDA) Organic Brain Syndrome, Cognitive Dysfunction

Treatment of SLE-Summary
Corticosteroids
Antimalarials (Plaquenil)
Traditional DMARDs (AZA, Methotrexate, etc)
Cyclophosphamide
- + CS: gold standard(changing)
- best regimen unknown
MMF (Cellcept)
-encouraging short term results
Anti-B cell strategies
Stem-Cell transplantation

Neuropsychiatric (NPS) lupus Management Chronic Anticoagulation Therapy STROKE SEIZURE Phenytoin & Barbiturates Carbamazepine – Clonazepan – Valproic Acid - Gabapentin NEUROPATHY High Doses Corticosteroids

Alternative Approach: Capitalize on information gained from the study of the pathogenesis of the disease.

Possible Biologic Interventions in SLE
T cell Targets
Anti-CD3
Anti-CD4
Anti-CD40L
CTLA4-Ig
B Cell Targets
Anti-CD20
Anti-CD22
Anti-B7
Anti-Blys
TACI-Ig
LJP394
Cytokine Targets
Anti-IFN (  or  )
Anti-TNF 
Anti-IL6-R
Anti-IL-10
Complement Targets
Anti-C5
C3 convertase inhibitor (Crry-Ig)
T Regulatory Cell Targets
CD4+CD25+ Tcells
Stem Cell Transplantation

The Future in the Treatment of SLE
Limitations
Lack of biomarkers/surrogate endpoints
Difficulty in conducting trials (number of patients)
Heterogeneity of the disease
Control group
Add-on studies
Expectations
Develop suitable biomarkers
Increase federal funding for multi-center trials
Increase industry/angel funding
Better understanding of pathogenic processes
New biologics/drugs

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When Your Head Hurts And Your Memory Fails

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