SEULI BOSE BRILL, MDMEDICINE AM REPORT

2/9/10

Neuropsychiatric Lupus

Historical perspective

Initially described by Mortiz Kaposi in 1870s (delirium)

Further description by Osler in early 1903

Prior to this, lupus thought to be primarily cutaneous disease

The term “lupus” used as early as the 13th century to describe a wolf-like rash

25-50% of all patients with SLE have some neuropsychiatric involvement.

Common Clinical Manifestations

Cognitive dysfunction (55-80%)Headache (24-72%)Mood disorders and psychosis (14-57%)Cerebrovascular diseaseAcute confusional statePeripheral nervous system involvement

SLE Related Cognitive Dysfunction

Mild cognitive impairment (detected through neuropsychiatric testing) estimated to be about 80%

Variable presentation Overall cognitive slowing Decreased attention Impaired working memory Executive dysfunction (e.g. difficulty multitasking)

SLE Related Cognitive Dysfunction

More prevalent in those with active compared to inactive SLE

Decline is not inevitableWaxing and waning courseDifficult to distinguish from other causes of

cognitive dysfunctionOften diagnosis of exclusion due to lack of

definitive diagnostic testing

Pathogenesis

• Increased permeability of blood brain barrier– Pro-inflammatory cytokine mediated disruption of

global function

• Vascular injury of small and large caliber vessels– Microangiopathic– Anti-phospholipid antibodies, immune complexes, and

leukoagglutination– May cause focal or global events

Disease Mechanism

Diagnostic Evaluation

Biomarkers

Area of aggressive investigation

Many with low specificity

Many are experimental

Currently with limited clinical application

Implicated Antibodies/ Biomarkers/ Cytokines

Anti-phospholipid

Anti-ribosomal P

Anti-neuronal

Anti-glial fibrillary acidic protein (GFAP)

Anti-endothelial cell

Anti-N-methyl-D-aspartate (NMDA)

Microtubule-associated protein 2 (MAP-2)

Matrix metalloproteinase-9 (MMP-9)

Interleukins (IL) 2, 6, 8, 10

Tumor necrosis factor alpha (TNF-α)

Interferon alpha and gamma

Neuroimaging

Several possible modalities Computerized tomography (CT) Magnetic resonance imaging/angiography (MRI/MRA) Positron electron tomography (PET) Single photon emission computed tomography (SPECT)

Choice depends on focal versus global dysfunction

Supplementation with EEGNormal study does not rule out disease

Cerebral vasculitis generally not detected on MRI/MRA or even autopsy

Treatment

Symptomatic Therapy Anti-epileptics Anti-psychotics Anti-coagulation when anti-phospholipid

antibodies implicatedImmunosuppression (prolonged course)

High dose oral corticosteroids May be coupled with cyclophosphamide or

rituximab Regimens derived from uncontrolled clinical

studies with small numbersCognitive Rehabilitation

In developmental stages

Ongoing NP-SLE Research

Role of auto-antibodies and inflammatory mediators

Long term patient outcomesClinical significance in context of overall

disease activityCorrelation of neuroimaging in patients who

meet diagnostic criteria Controlled trials of treatment modalities

Take Home Points

Neuropsychiatric manifestations of SLE are very common.

Clinical diagnosis can be elusive. Presentations are varied. Diagnostic testing is often unreliable.

Prolonged immune suppression is the mainstay of therapy.

Bibliography

History of Lupus; http://www.lupus.org/

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Efthimiou P, Blanco M. Pathogenesis of neuropsychiatric systemic lupus erythematosus and potential biomarkers. Mod Rheumatol. 2009;19(5):457-68.

Hanly JG. Demystifying neuropsychiatric lupus--is it possible? Bull NYU Hosp Jt Dis. 2009;67(3):276-80.

Hanly JG, Harrison MJ. Management of neuropsychiatric lupus. Best Pract Res Clin Rheumatol. 2005 Oct;19(5):799-821.

Hirohata S, Kanai Y, Mitsuo A, Tokano Y, Hashimoto H; Accuracy of cerebrospinal fluid IL-6 testing for diagnosis of lupus psychosis. A multicenter retrospective study. Clin Rheumatol. 2009 Nov;28(11):1319-23.

Holubar K, Fatović-Ferencić S. Cazenave, Kaposi and lupus erythematosus. A centennial and a sesquicentennial. Dermatology. 2001;203(2).

Kajs-Wyllie M. Lupus cerebritis: a case study. J Neurosci Nurs. 2002 Aug;34(4):176-83.

Muscal E, Brey RL. Neurologic manifestations of systemic lupus erythematosus in children and adults.; Neurol Clin. 2010 Feb;28(1):61-73.

Mallavarapu RK, Grimsley EW. The history of lupus erythematosus. South Med J. 2007 Sep;100(9):896-8.