1. SEULI BOSE BRILL, MD MEDICINE AM REPORT 2/9/10 Neuropsychiatric Lupus

2. 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 13 th century to describe a wolf-like rash

3. 25-50% of all patients with SLE have some neuropsychiatric involvement.

4. Common Clinical Manifestations Cognitive dysfunction (55-80%) Headache (24-72%) Mood disorders and psychosis (14-57%) Cerebrovascular disease Acute confusional state Peripheral nervous system involvement

6. 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)

7. SLE Related Cognitive Dysfunction More prevalent in those with active compared to inactive SLE Decline is not inevitable Waxing and waning course Difficult to distinguish from other causes of cognitive dysfunction Often diagnosis of exclusion due to lack of definitive diagnostic testing

8. 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

9. Disease Mechanism

10. Diagnostic Evaluation

11. 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

12. 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 EEG Normal study does not rule out disease  Cerebral vasculitis generally not detected on MRI/MRA or even autopsy

13. Treatment Symptomatic Therapy  Anti-epileptics  Anti-psychotics  Anti-coagulation when anti-phospholipid antibodies implicated Immunosuppression (prolonged course)  High dose oral corticosteroids  May be coupled with cyclophosphamide or rituximab  Regimens derived from uncontrolled clinical studies with small numbers Cognitive Rehabilitation  In developmental stages

14. Ongoing NP-SLE Research Role of auto-antibodies and inflammatory mediators Long term patient outcomes Clinical significance in context of overall disease activity Correlation of neuroimaging in patients who meet diagnostic criteria Controlled trials of treatment modalities

15. 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.

16. Bibliography History of Lupus; http://www.lupus.org/http://www.lupus.org/ Colasanti T, Delunardo F, Margutti P, Vacirca D, Piro E, Siracusano A, Ortona E. Autoantibodies involved in neuropsychiatric manifestations associated with systemic lupus erythematosus. J Neuroimmunol. 2009 Jul 25;212(1-2):3-9.Autoantibodies involved in neuropsychiatric manifestations associated with systemic lupus erythematosus. Efthimiou P, Blanco M. Pathogenesis of neuropsychiatric systemic lupus erythematosus and potential biomarkers. Mod Rheumatol. 2009;19(5):457-68.Pathogenesis of neuropsychiatric systemic lupus erythematosus and potential biomarkers. Hanly JG. Demystifying neuropsychiatric lupus--is it possible? Bull NYU Hosp Jt Dis. 2009;67(3):276-80.Demystifying neuropsychiatric lupus--is it possible? Hanly JG, Harrison MJ. Management of neuropsychiatric lupus. Best Pract Res Clin Rheumatol. 2005 Oct;19(5):799-821.Management of neuropsychiatric lupus. 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.Accuracy of cerebrospinal fluid IL-6 testing for diagnosis of lupus psychosis. A multicenter retrospective study. Holubar K, Fatović-Ferencić S. Cazenave, Kaposi and lupus erythematosus. A centennial and a sesquicentennial. Dermatology. 2001;203(2).Cazenave, Kaposi and lupus erythematosus. A centennial and a sesquicentennial. Kajs-Wyllie M. Lupus cerebritis: a case study. J Neurosci Nurs. 2002 Aug;34(4):176-83.Lupus cerebritis: a case study. Muscal E, Brey RL. Neurologic manifestations of systemic lupus erythematosus in children and adults.; Neurol Clin. 2010 Feb;28(1):61-73.Neurologic manifestations of systemic lupus erythematosus in children and adults. Mallavarapu RK, Grimsley EW. The history of lupus erythematosus. South Med J. 2007 Sep;100(9):896-8.The history of lupus erythematosus.