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NeurolupusSLEPrevalence rate of around 130/100000 in USACan affect multiple organs, neurological damage is common in adults as well as in children

NPSLE/ Neurolupus Associated with worse prognosis and more cumulative damage in children and adults

Lupus Cerebritis: Term used in SLE patients with broad central nervous system symptoms rather than more specific diagnostic terms, not included by ACR in the definitions for NPSLE Muscal, E., & Brey, R. L. (2010). Neurological manifestations of systemic lupus erythematosus in children and adults.Neurologic clinics,28(1), 61.Prevalence of NPSLEWide variation in different studiesbecause of substantial differences in the criteria used to designate nervous system involvementRegional differences: African american, Asians more proneRanging from 14% to 80% in adultsRanging from 22% to 95% in childrenA retrospective study on 185 Chinese children:11% had NPSLE at the time of diagnosis of SLEAnother 17% developed NPSLE in a yearMortality rate:45% in children with NPSLE17.4% in children without NPSLE(1) Danchenko N, Satia JA, Anthony MS. Lupus 2006;15:308318. [PubMed: 16761508] (2) Brey RL, Holliday SL, Saklad AR, et al. Neurology 2002;58:12141220. [PubMed: 11971089](3) Petri M, Naqibuddin M, Carson KA, et al. J Rheumatol 2008;35(9):177681. [PubMed: 18634154] (4) Costallat L, Bertolo M, Appenzeller S. Lupus 2001;10:S32.Pathology of NPSLELikely to be multifactorial

May involve autoantibody production, microangiopathy, intrathecal production of proinflammatory cytokines and premature atherosclerosis

Postmortem histopathologic studies: Wide range of of brain abnormalities caused by multifocal microinfarcts, cortical atrophy, gross infarcts, hemorrhage, ischemic demyelination and patchy multiple-sclerosis-like demyelination in people with SLE

Damage can be caused by antineuronal antibodies, cytokine effects, and abnormal hypothalamic pituitary axis response

Muscal, E., & Brey, R. L. (2010). Neurological manifestations of systemic lupus erythematosus in children and adults.Neurologic clinics,28(1), 61.Autoantibodies in NPSLEDementia in NPSLE: Documented to be related to antiphospholipid syndromeCognitive dysfunction significantly associated with persistently positive aPL (1) and aCL (2)

Antiglutamate receptors may also have a significant role (3)40% of lupus patients possess serum titers of anti-NR2A/B antibody. (4)Anti NR2A/B presence is an indication of the potential for neuropsychiatric manifestations during the course of the SLE

McLaurin EY et al. Neurology 2005;64:297303.(2) Menon S et al. Arthritis Rheum 1999(3) Husebye ES, et al. Ann Rheum Dis 2005;64:12101213(4) Robin, C., et al., 1995. Rev. Neurol. 1995; 151 (12), 699707.NPSLE associated with CNS Defined by American College of RheumatologyAseptic MeningitisCerebrovascular diseaseStrokeTransient Ischemic AttackCerebral Venous Sinus ThrombosisCognitive DisordersDelirium (Acute confusional state)DementiaMild Cognitive ImpairmentTransverse Myelopathy

Demyelinating syndromesHeadachesTension HeadachesMigraine HeadachesMovement disorders (Chorea)Psychiatric DisordersPsychosisMood DisordersAnxiety DisorderSeizure Disorders

The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599608.NPSLE associated with PNS Defined by American College of Rheumatology Autonomic Neuropathy Myasthenia Gravis Peripheral neuropathy

Commoner: Psychiatric disorders, headache, seizures (1425% (Joseph and Scolding, 2010)), ischemia (associated with antiphospholipid syndrome), and peripheral neuropathy (Mills, 1994). Rare: Aseptic meningitis, myelopathy, myasthenic syndrome, and myositis (Mills, 1994).

The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599608.Laboratory EvaluationNo diagnostic test sensitive and specific for SLE-related neuropsychiatric manifestations

Assessment based on Clinical evaluation, immunoserologic testing, brain imaging, and psychiatric and neuropsychological assessment. Muscal, E., & Brey, R. L. (2010). Neurological manifestations of systemic lupus erythematosus in children and adults.Neurologic clinics,28(1), 61.Brain ImagingA reduction in cerebral and corpus callosum volumes associated with disease duration and cognitive impairment

Structural MRI: The majority (40% to 80%) of abnormalities in NPSLE are small focal lesions concentrating in periventricular and subcortical white matter

Cortical atrophy, ventricular dilation, diffuse white matter and gross infarctions are also common.

Multiple discrete white matter lesions in periventricular, cortical/subcortical junction, and frontal lobe - seen more commonly in patients with past NPSLE manifestations, than in SLE patients without history of NPSLEMuscal, E., & Brey, R. L. (2010). Neurological manifestations of systemic lupus erythematosus in children and adults.Neurologic clinics,28(1), 61.Diagnostic ToolsDiagnostic ToolDescriptionAnti nuclear factorsNonspecific in older peopleAnti SmComparatively higher specificityRheumatoid factorHigher prevalence in late-onset SLEAnti-double stranded DNALower prevalence in neurolupusCSFAbnormal in 30-90% of casesLymphocytic pleiocytosis and oligoclonal IgG bands MRIMultifocal and nonspecific gray and white matter lesionsHypersignal in T2 (57.4%)Frontal atrophy (52%)SPECTFrontal lobe hypoperfusion, which resolves in the same time than the resolution of the psychiatric symptomsCohen-Sohal and Diamond, 2011; Joseph and Scolding, 2010; Mills, 1994; Rovensky and Tuchynova, 2008.Treatment of NPSLECorticosteroids, several immunosuppressants (intravenous pulse of cyclophosphamide, azathioprine, and methotrexate), or plasmapheresis

Evidence of treatment efficacy is limited to uncontrolled clinical trials and anecdotal experience

Key to treatment: To establish the correct diagnosis by carefully following the guidelines set in the ACR 1999 Case Definitions

For many NPSLE syndromes, symptomatic treatment may also be needed in addition to immuno-modulatory therapyMuscal, E., & Brey, R. L. (2010). Neurological manifestations of systemic lupus erythematosus in children and adults.Neurologic clinics,28(1), 61.Treatment of NPSLECyclophosphamide: (1) i.v. (5001000 mg/m^2) for a six month induction followed by quarterly maintenance doses for a period of two yearsCytotoxic immunosuppression with documented therapeutic benefits in the severe NPSLE manifestations unresponsive to other treatment modalities (nephritis and CNS manifestations)

RCT on long-term use of cyclophosphamide and methylprednisolone (2): Better overall therapeutic control of SLE-related neurological manifestations (refractory seizures, peripheral and cranial neuropathy, and optic neuritis) with monthly intravenous cyclophosphamide, with a similar incidence of new infections.

(1) Petri M, Brodsky R. High-dose cyclophosphamide and stem cell transplantation for refractory systemic lupus erythematosus. JAMA 2006;295:559560(2) Barile-Fabris L, Ariza-Andraca R, Olguin-Ortega L, et al. Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. Ann Rheumatic Dis 2005;64(4):6205.Adjunctive Treatment in NPSLEPsychotropic medications (i.e anti-depressants and atypical antipsychotics) may have an important adjunctive role in SL patients with affective or psychotic disorder manifestations.

Non-pharmacologic approaches:Haupt et al. demonstrated the ability to improve coping using a psychological group interventionPatients receiving this intervention showed a significant and sustained improvement on a number of symptoms, such as depression, anxiety and overall mental burden.Haupt M, Millen S, Janner M, et al. Improvement of coping abilities in patients with systemic lupus erythematosus: A prospective study. Ann Rheum Dis 2005;64:16181623. [PubMed: 15829575]Prognosis in NPSLEMortality: 7 to 19%

Cause of death is usually not the NPSLE itself but infections, cardiovascular disorders and drug induced complications

It is also important to control risk factors like hypertension and diabetes (often corticoinduced in these patients) and to add acetylsalicyl acid.

Treatment in older people Challenging because of drug interactions, the frailty of older people and side effects of treatment (like sarcopenia, malnutrition, bedsore and decreased healing processes, impaired renal function, decreased immune function, osteoporosis, etc.)Compte, Nathalie, et al. "Cognitive decline in an old woman: Do not miss a rare etiology!."Experimental gerontology47.7 (2012): 534-535.Thank You