NEUROPSYCHIATRIC LUPUS

1. By Prof. MEDHAT SHALABY Al-azhar university NEUROPSYCHIATRIC LUPUS

2. NEUROPSYCHIATRIC LUPUS • INTRODUCTION • EPIDEMIOLOGY • PATHOGENESIS • CLINICAL PERSENTATIONS • MANAGEMENTS

3. CNS LUPUS Neurologic and psychiatric (NP) features of systemic lupus erythematousus (SLE), collectively referred to as neuropsychiatric SLE (NPSLE) • INTRODUCTION

4. CNS LUPUS Among the Collagen Vascular Diseases neurological manifestations have been most commonly recognized and well-studied in Systemic Lupus Erythematosus • INTRODUCTION

5. CNS LUPUS

6. CNS LUPUS • Neuropsychiatric lupus (NPSLE) manifestations can occur in in the absence of either serologic activity systemic disease manifestations

7. NPSLE, EPIDEMIOLOGY

8. NPSLE, cause of death • The most common cause of death is thrombosis and were always associated with APS • common thrombotic events in those patients were

9. PATHOPHYSIOLOGY

11. Pathophysiology and Pathogenesis • multifactorial and may involve autoantibody production, microangiopathy, intrathecal production of proinflammatory cytokines and premature atherosclerosis

12. Processes leading to brain dysfunction in SLE • Probably involve abnormal endothelial-white blood cell interactions that allow proteins or cells access to the central nervous system (CNS). This may be a mechanism whereby autoantibody-mediated CNS effects can occur. • Vascular endothelial cells can be stimulated by proinflammatory cytokines or autoantibodies that up-regulate the expression of adhesion proteins on their surface facilitating lymphocyte entry into the central nervous system • Soluble serum levels of ICAM-1 increase with systemic disease activity in patients with SLE, (normalize with remission ) strengthening the hypothesis that activated endothelial cells and a lack of integrity of the blood-brain-barrier might be an important requisite for disease activity in the brain. • Blood-brain-barrier damage has also been suggested to be a risk factor for corticosteroid-induced psychiatric disorders in SLE

14. proliferation-inducing ligand CCL2( Monocyte chemoattractant protein-1) (regulated on activation, normal T-cell expressed and secreted)

15. NPSLE CLINICAL MANIFESTATIONS

17. Fatigue • Chronic fatigue is a common symptom in SLE and usually does not relate to objective muscular effort (i.e., walking up stairs may seem no harder than walking on level ground). • Fatigue may contribute to both self-perceived and to measurable cognitive impairment, chiefly by impairing frontal lobe attentional functions. This may relate to metabolic dysfunction of brain parenchyma. • Depression, myopathy, excessive daytime fatigue due to nocturnal sleep disorder, and systemic conditions (e.g., electrolyte disturbance, fluid overload, pulmonary insufficiency) remain in the differential diagnosis. Many patients with mild orthostatic hypotension present with symptoms resembling chronic fatigue and may not complain of the usual presyncopal symptoms

18. CNS CRITERIA FOR SLE

19. REVISED CRITERIA FOR THE CLASSIFICATION OF SYSTEMIC LUPUS ERYTHEMATOSUS,1982 • Malar rash: red flat or raised over the cheeks, sparing the nasolabial folds • Discoid rash: red raise patches with keratotic scales, atrophy & scarring may occur in older lesions. • Photosensitivity: skin rash as a result of exposure to sunlight. • Oral ulcers: painless ulcers in the mouth or nasopharyngeal areas • Arthritis: nonerosive arthritis (pain,swelling or effusion) in =>2 peripheral joints. • Serositis: pleuritis (pleuritic pain or rub or pleural effusion) OR pericarditis (ECG or rub or evidence of effusion) • Renal: proteinuria (> 500 mg daily) persistent OR Cellular casts (RBC, granular, tubular or mixed) • CNS: seizures OR psychosis in absence of alternative explanation (eg drugs or metabolic disorders such as electrolyte abnormality or uremia) • Hematologic: hemolytic anemia (with reticulocytosis) OR leucopenia (< 4000/mm) on 2 or more occasions OR lymphopenia (< 1500/mm) on 2 or more occasions OR thrombocytopenia (<100,000) in absence of medications know to decrease platelets. • Immunologic: antiphospholipid antibodies present based on either an abnormal serum level of IgG or IgManticardiolipin antibodies or a positive test result for lupus anticoagulant OR Anti-DNA antibody OR Anti-Sm antibody OR false positive VDRL (or RPR). • Antinuclear antibodies: elevated level of ANA at any time, in absence of drugs known to cause "drug-induced lupus"

20. CNS LUPUS • TYPES OF PSYCHOSIS

21. PSYCHOSIS TYPES OF PSYCHOSIS TYPES OF PSYCHOSIS Schizophrenia izophreniform disorder Schizoaffective disorder Delusional disorder Substance-induced psychosis Dementia Bipolar disorder (manic depression) Major Depressive Disorder Postpartum psychosis Delirium Brief psychotic episode Psychosis due to a general medical condition Paraphrenia

22. Nervous system events included in the American College of Rheumatology (ACR),1990

23. Nervous system events included in the American College of Rheumatology (ACR) case definitions for 12 central nervous system (CNS) manifestations and 7 peripheral nervous system (PNS) manifestations in systemic lupus erythematosus (SLE).

26. In SLE patients, the majority of these NP events are attributed to non‐SLE causes, but regardless of attribution all NP events are associated with a negative impact on health‐related quality of life either mobidity or mortality

28. NPSLE, SLICC • Seizures, psychosis, mononeuritis multiplex • (in the absence of other known causes such as primary vasculitis) • Myelitis, peripheral or cranial neuropathy (in the absence of other known causes such as primary vasculitis, infection, and diabetes mellitus) • Acute confusional state • (in the absence of other causes, including toxic/metabolic, uremia, drugs)

29. Proposed Draft ACR/EULAR Criteria aim for high sensitivity & specificity ,2017 •  proposed ACR/EULAR Classification Criteria for SLE with scores in parentheses • Entry Criterion: History of a positive ANA BY Hep-2 immunofluorescence >1:80. • Opening Statements • For each criterion, do not score if a more likely cause for the symptom exists. • Occurrence of a criterion on at least one occasion is sufficient. • Criteria need not occur simultaneously. • At least one clinical criterion must be present. • Within each domain, only the highest weighted criterion is counted toward the total score.

30. Proposed ACR/EULAR Criteria aim for high sensitivity & specificity,2017 Hematological Domain Leukopenia (3) Thrombocytopenia (4) Autoimmune hemolysis (4) Renal Domain Proteinuria >0.5g 24 hours (4) Renal biopsy with Class II or V lupus nephritis (8) Renal biopsy with Class III or IV lupus nephritis (10) Antiphospholipid Domain Present (anti-cardiolipin antibody positive with medium or high units, or anti-β2-GP1 positive or lupus anticoagulant positive) (2) Complement Proteins Domain Low C3 or Low C4 (3) Low C3 and Low C4 (4) Highly Specific Antibodies Domain Anti-dsDNA antibody (6) Anti-Smith antibody (6 • Constitutional Domain Unexplained fever >38.3 C (2) • Muco-Cutaneous Domain Non-scarring alopecia (2) Oral ulcers (2) Sub-acute cutaneous or discoid lupus (4) Acute cutaneous lupus (6) • Arthritis Domain Synovitis in two or more joints or tenderness in two or more joints or ≥30 minutes of morning stiffness (6) • Neurologic Domain Delirium (2) Psychosis (3) Seizure (5) • Serositis Domain Pleural or pericardial effusion (5) Acute pericarditis (6)

31. Delirium: is characterized by 1 2 3 4

32. Mental status changes; : Acute or subacute mental status changes but should be differentiated opportunistic infections that result in meningitis, encephalitis, brain abscess, or systemic infection with a secondary toxic encephalopathy

33. Neurologic domain: • Psychosis: characterized by (1) delusions and/or hallucinations without insight and  (2) absence of delirium • Seizure: primary generalized seizures or partial/focal seizures, with independent description by a reliable witness. If EEG is performed, abnormalities must be present • Mononeuropathy (single or multiplex) : either motor or sensory disturbance in distribution of one or more peripheral nerves on physical examination, or abnormalities on nerve conduction study or EMG • Cranial neuropathy: disorder of sensory and/or motor function of one or more cranial nerves, including optic neuritis

34. Eliminated chorea, myelitis, stroke; added mononeuropathy; broadened optic neuritis to cranial neuropathy; term “acute confusional state” changed to “delirium” per ACR 1999 nomenclature]

35. Neurologic domain: Seizures • Seizuresare already known to occur in 14-25% of patients with lupus compared with 0.5-1% in the general population. • Seizures may result from cerebral vasculitis (ischemic or hemorrhagic manifestations), cardiac embolism opportunistic infection, drug intoxication, or associated metabolic derangements. • Partial or secondarily generalized seizures are most common, but all seizure types have been reported

36. Neurologic domain: Peripheral neuropathy • Peripheral neuropathy occurs in as many as 18% of patients with SLE. • A sensory or sensorimotor predominantly distal polyneuropathy is most common; however, the patchy deficits and subacute time course of mononeuritis multiplex and the rapidly progressive course of acute demyelinating polyneuropathy have been reported. • The neuromuscular junction may be affected, mimicking the weakness patterns (and physiology) of myasthenia gravis or myasthenic syndrome.

37. Myositis :is clinically apparent as proximal weakness and myalgias in 3-5% of patients

38. Stroke • Stroke is clinically evident in 5-10% • may involve small, medium, or large vessels by a variety of mechanisms • Subacute evolution or any premonitory symptoms suggest a thrombotic or vasculiticmechanism, whereas an abrupt onset with maximum deficit initially supports an embolic mechanism • Ischemic stroke should be differentiated from brain hemorrhage, brain abscess, and other structural lesions

39. Spinal cord involvement • Spinal cord involvement is rare but devastating. Transverse myelitis, subacute-to-chronic demyelinating syndromes, and abrupt vascular occlusive events (e.g., spinal artery thrombosis) have been described. • Slowly progressive lesions may result from demyelination or compression by tumor or central disc herniation. Rapid onset suggests transverse myelitis, infarction, or compression by a rapidly expanding lesion (e.g., epidural abscess

40. Other neurologic syndromes Less common neurologic syndromes include • movement disorders (chorea, • ataxia, parkinsonism), • pseudotumorcerebri (Idiopathic • cranial hypertension ) • venous sinus thrombosis.

41. Neurologic syndromes are often present at SLE presentation, and SLE should be considered in the following individuals

42. MANAGEMENT OF NPSLE Diagnostic and treatment algorithm

43. Laboratory Evaluation • There is no single diagnostic test that is sensitive and specific for SLE-related neuropsychiatric manifestations

44. The assessment of individual patients is based on clinical neurologic and rheumatologic evaluation, immunoserologic testing, brain imaging, and psychiatric and neuropsychological assessment. • These examinations are used to support or refute the clinical diagnostic impression, exclude alternative explanations, and form the basis for prospective monitoring of clinical evolution and response to treatment interventions.

45. Activity Vs. damage

46. Summary • Nervous system disease in SLE is comm0n • The ACR case definitions: platform for characterization of SLE events • Attribution studies suggest that one third of NP events are due to SLE, but all are associated with lower self – reported HRQoL. • Separate immunopathogenetic pathways: ischemic and inflammatory • Many NP events resolve or improve with current standered of care and those attributed to SLE may have a better outcome • Research agenda: neuroimaging, biomarkers and clinical trials of optimal therapies (e.g. smptomatic , immunosuppression , anticoagulation , biologics )

47. NPSLE , commom clinical presentations in practicing are • Headache (39%–61%) • Seizures (8%–18%) • Cerebrovascular disease (2%–8%) • Psychosis (3%–5%) • Cranial neuropathy (1.5%–2.1%) • Movement disorder (1%). Fatigue 80%

49. THANKS