when your head hurts and your memory fails

When Your Head Hurts and When Your Head Hurts and Your Memory Fails- Is It Your Memory Fails- Is It

Your Lupus?Your Lupus?

Petros Efthimiou, MD, FACR,Petros Efthimiou, MD, FACR,Lincoln Medical and Mental Health CenterLincoln Medical and Mental Health Center

Assistant Professor of Medicine,Assistant Professor of Medicine,Weill Cornell Medical College,Weill Cornell Medical College,

New York, NYNew York, NY

LUPUSLUPUS

CHRONICCHRONIC

AUTOIMMUNEAUTOIMMUNE

The body’s autoimmune system (“defense")

attacks ITSELF

Skin

Kidney

Lung

Heart

Joints

Blood

Nervous System

Progressive

Long Standing

MULTISYSTEMIC

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

inci

den

ce

1950 2000

10

5

2

Epidemiology of SLEEpidemiology of SLE

T Cell

Abnormal Adhesion Molecule and Chemokine Expression

Tissue Specific PathologyAPC

B7

MHC

FcR

CR RES

AutoAb

DrugsUVInfectious Agents

Genetic Background

Estrogens

B CellIncreased Help

Decreased Cytotoxicity

Altered Cytokine Production

IL-6, IL-10 IL-2

DC

IFN

AutoAg

Apoptosis+ Immune

Complexes

How Does Lupus happen?

American College of Rheumatology American College of Rheumatology Criteria For LupusCriteria For Lupus

Antinuclear Antibody95%

Immunologic Disorder

70%(aDNA, LE prep, aSm,

lupus anticoagulant

Hematologic Disorder

10%

Neurologic Disorder

10%

Renal

Disorder60%

Malar Rash

Serositis

Arthritis

Oral Ulcers

Photosensitivity

Discoid Rash

Neuropsychiatric (NPS) lupusNeuropsychiatric (NPS) lupus

Why does it happen?Why does it happen? NO SINGLE PATHOGENIC MECHANISMNO SINGLE PATHOGENIC MECHANISM

Primary Manifestations Primary Manifestations

of theof the DiseaseDiseaseSecondary Complications Secondary Complications of the Disease or Therapyof the Disease or Therapy

Coincidental


NeurologicNeurologic

SeizuresSeizures StrokeStroke HeadacheHeadache Peripheral neuropathyPeripheral neuropathy Movement disordersMovement disorders Transverse myelitisTransverse myelitis Cranial neuropathyCranial neuropathy

PsychiatricPsychiatric

Neurocognitive Neurocognitive dysfunctiondysfunction

Organic brain syndromeOrganic brain syndrome PsychosisPsychosis PsychoneurosisPsychoneurosis


SEIZURES

Generalized:whole body affected

Partial: only one part or side

of the body is affected

Complexchange in level

of consciousness

Simple (focal) no change in level of consciousness

May present with:Twitching or shaking

Temporary abnormal sensations Visual disturbances


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


HEADACHE

An organic basis for the headaches in SLE is suggested by the sudden developmentin 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 disturbancesDizziness or vertigo

Tension headachePressing/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


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) lupusNeuropsychiatric (NPS) lupusNeurocognitive Neurocognitive

DysfunctionDysfunction

Manifested by impairments in mental activities

Memory JudgmentAbstract Thinking

Simple/ ComplexAttention

Language

Psychomotorspeed


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 Neuropsychiatric (NPS) lupus PathogenesisPathogenesis

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 Neuropsychiatric (NPS) lupus DiagnosisDiagnosis

STEPS:STEPS:Confirm diagnosis of LupusConfirm diagnosis of Lupus ACR Criteria

History and Physical History and Physical ExaminationExamination

Exclude systemic illness andExclude systemic illness andmedications as confounding variablesmedications as confounding variables

Use of Diagnostic tools for Specific Symptoms or SignsUse of Diagnostic tools for Specific Symptoms or Signs


Diagnostic tools for Specific Symptoms or SignsDiagnostic 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 Differentiate

s organic from

psychosocia

l disease


Predominantly fixed lesions in the periventricular and Subcortical White Matter

Focal Neurologic DiseaseFocal Neurologic Disease

More Sensitive than CT Scan and T1- Weighted MRI More Sensitive than CT Scan and T1- Weighted MRI for detecting Abnormalities in NP-SLEfor detecting Abnormalities in NP-SLE

T2- Weighted MRIT2- Weighted MRI::

Findings:

Diffuse Neurologic DiseaseDiffuse Neurologic Disease Transient Subcortical White Matter Lesions and patchyHyperintensities in the Gray Matter

Systemic lupus erythematosus: Systemic lupus erythematosus: brain (MRI)brain (MRI)


CT SCAN

Findings:

Detects structural and focal abnormalities

Brain atrophy


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-aspartatereceptor (NMDA)

Organic Brain Syndrome, Cognitive Dysfunction

Treatment of SLE-SummaryTreatment of SLE-Summary

I.I. CorticosteroidsCorticosteroidsII.II. Antimalarials (Plaquenil)Antimalarials (Plaquenil)III.III. Traditional DMARDs (AZA, Methotrexate, etc)Traditional DMARDs (AZA, Methotrexate, etc)IV.IV. CyclophosphamideCyclophosphamideV.V. - + CS: gold standard(changing)- + CS: gold standard(changing)

VI.VI. - best regimen unknown- best regimen unknown

VII.VII. MMF (Cellcept)MMF (Cellcept)

VIII.VIII. -encouraging short term results-encouraging short term results

IX.IX. Anti-B cell strategiesAnti-B cell strategies

X.X. Stem-Cell transplantationStem-Cell transplantation

Neuropsychiatric (NPS) lupus Neuropsychiatric (NPS) lupus ManagementManagement

Chronic AnticoagulationTherapy

STROKE

SEIZURE

Phenytoin & Barbiturates

Carbamazepine – Clonazepan – Valproic Acid - Gabapentin

NEUROPATHY High Doses Corticosteroids

Alternative Approach:Alternative Approach:

Capitalize on information gained Capitalize on information gained from the study of the from the study of the

pathogenesis of the disease.pathogenesis of the disease.

Possible Biologic Interventions in Possible Biologic Interventions in SLESLE

T cell TargetsT cell Targets Anti-CD3Anti-CD3 Anti-CD4Anti-CD4 Anti-CD40LAnti-CD40L CTLA4-IgCTLA4-Ig

B Cell TargetsB Cell Targets Anti-CD20Anti-CD20 Anti-CD22Anti-CD22 Anti-B7Anti-B7 Anti-BlysAnti-Blys TACI-IgTACI-Ig LJP394LJP394

Cytokine TargetsCytokine Targets Anti-IFN (Anti-IFN ( or or )) Anti-TNF Anti-TNF Anti-IL6-RAnti-IL6-R Anti-IL-10Anti-IL-10

Complement TargetsComplement Targets Anti-C5Anti-C5 C3 convertase inhibitor (Crry-Ig)C3 convertase inhibitor (Crry-Ig)

T Regulatory Cell TargetsT Regulatory Cell Targets CD4+CD25+ TcellsCD4+CD25+ Tcells

Stem Cell TransplantationStem Cell Transplantation

The Future in the Treatment of SLEThe Future in the Treatment of SLE

LimitationsLimitations

Lack of Lack of biomarkers/surrogate biomarkers/surrogate endpointsendpoints

Difficulty in Difficulty in conducting trials conducting trials (number of patients)(number of patients)

Heterogeneity of the Heterogeneity of the diseasedisease

Control group Control group Add-on studiesAdd-on studies

ExpectationsExpectations

Develop suitable Develop suitable biomarkersbiomarkers

Increase federal Increase federal funding for multi-funding for multi-center trialscenter trials

Increase Increase industry/angel fundingindustry/angel funding

Better understanding Better understanding of pathogenic of pathogenic processesprocesses

New biologics/drugsNew biologics/drugs

when your head hurts and your memory fails

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