Neuropsychiatric SLE (NPSLE) Dr. MTL NYO FCP(SA), Cert Rheum (Phys) Division of Rheumatology Department of Internal Medicine DGMAH / SMU

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1 Neuropsychiatric SLE (NPSLE) Dr. MTL NYO FCP(SA), Cert Rheum (Phys) Division of Rheumatology Department of Internal Medicine DGMAH / SMU

2 NPSLE represents a diagnostic and therapeutic challenge Wide range of presentations Different pathogenic mechanisms Lack of diagnostic tests with adequate sensitivity and specificity Limited controlled evidence for selection of optimal treatment

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4 Pathogenesis of NPSLE : 3 primary immunopathogenic mechanisms 1. Vasculopathy 2. Autoantibodies 3. Intracranial inflammatory mediators/cytokines

5 JG Hanly et al. Best Pract Res Clin Rheumatol Oct;19(5):

6 Epidemiology : The overall prevalence NP events is 37-95%. Headaches Mood disorders Seizures Cognitive dysfunction Cerebrovascular disease Polyneuropathy Anxiety Only 19-38% attributable to SLE

7 ACR nomenclature and case definitions for NPSLE syndromes Arthritis Rheum Apr;42(4):

8 NPSLE Syndromes Prevalence 95% Confidence Interval Total 56.3% (42.5%-74.7%) Headache 28.3% (18.2%-44.1%) Mood Disorders 20.7% (11.5%-37.4%) Cognitive dysfunction 19.7% (10.7%-36%) Seizures 9.9% (4.8%-20.5%) cerebrovascular disease 8.0% (4.5%-14.3%) Anxiety disorders 6.0% ( %) Psychosis 4.6% ( %) Acute confusional state 3.4% ( %) Polyneuropathy 2.3% ( %) Cranial neuropathy 2.2% ( %) A Unterman et al. A Meta-Analysis. Semin Arthritis Rheum Aug; 41(1): 1-11 [1439 NPSLE patients, with 2709 NPSLE syndromes]

9 1999 ACR criteria did not differentiate SLE patients from controls 1. All headaches 2. Anxiety 3. Mild depression 4. Mild cognitive impairment 5. Polyneuropathy without EPS confirmation Specificity improves from 46% to 93% by excluding minor events : ARTHRITIS CARE & RESEARCH 45: , 2001

10 The prevalence of all headache types (TTH & migraine also) does not differ between SLE patients and controls. Not enough evidence regarding the term `lupus headache. No scientific evidence to support a particular pathogenetic mechanism for lupus headache Headache is not related to SLE activity.

11 Attributing a neuropsychiatric event to SLE 1. Exclusion of 2 causes (infections, metabolic, drugs, lipids) 2. Type of event (minor Vs major) 3. Timing of event 4. Risk factors for SLE-related events (SLEDAI, Concurrent NPSLE, apls) 5. Risk factors for SLE-unrelated events (Atherosclerosis risk, AF, VHD, Age) 6. Neuroimaging studies 7. CSF & EEG 8. Clinical response to treatment Fanouriakis A et al. Curr Opin Rheumatol Sep; 25(5):

12 NP events Due to SLE (Model A) Headache 477 (52%) 0 Mood disorders 132 (14.4%) 23 Seizure disorder 53 (5.8%) 32 Anxiety disorder 52 (5.7%) 0 Cerebrovascular disease 47 (5.1%) 22 Cognitive dysfunction 41 (4.5%) 10 Polyneuropathy 23 (2.5) 7 Acute confusional state 21 (2.3%) 10 Mononeuropathy 16 (1.7%) 6 Psychosis 16 (1.7%) 9 % of 917 NPSLE events 100% 15.4% JG Hanly et al. Ann Rheum Dis Oct; 70(10): (Canada)

13 16/370 (4.3%) patients presented with a total of 23 major CNS events Seizures 2.2% Strokes 1.6% Myelopathy 1.4% Optic neuritis 0.5% Aseptic meningitis and 0.3% Acute psychosis) 0.3% Incidence was 7.8/100 person years. EI Kampylafka et al. PLoS One. 2013; 8(2): e55843 (Greece)

14 Diagnostic approach NPSLE : Confirm diagnosis of SLE (SLICC classification criteria) Assess SLE activity and damage Exclude metabolic abnormalities, infection and medications as confounding variables Investigations for Neuropsychiatric Events in SLE EEG JG Hanly et al. Best Pract Res Clin Rheumatol Oct;19(5):

15 MRI (T1, T2, FLAIR, Gadolinium) WM hyperintensities in the frontoparietal regions Periventricular lesions Aging and hypertension also cause WM hyperintensities Difficult to distinguish active from chronic lesions A normal MRI scan is common Peterson PL et al. Best Pract Res Clin Rheumatol Oct;19(5):727-39

16 MR images of the first episode of active NPSLE in 74 patients 1. WM hyperintensities in 36 patients (49%) 2. GM hyperintensities in 18 patients (25%) 3. Small parenchymal defects in 12 patients (16%) 4. Absence of MRI abnormalities (42%) ARTHRITIS & RHEUMATISM; Vol. 63, No. 3, March 2011, pp (Netherlands)

17 133 brain MRIs of 118 patients with NPSLE 1. WM hyperintensities in 76 MRIs (57.1 %) 2. GM hyperintensities in 41 MRIs (30.8 %) - Seizures, CVDs 3. Parenchymal defects in 31 MRIs (23.3 %) - CVDs 4. Cerebral atrophy in 20 MRIs (15.0 %) 5. No abnormalities in 40 MRIs (30.1%) Rheumatology International; published online : 15 Oct 2014 (South Korea)

18 Autoantibodies : Anti-ribosomal P antibodies psychosis and depression Anti-phospholipid antibodies CVAs/TIAs (also with seizures, chorea, transverse myelitis and cognitive dysfunction) Anti-NR2 glutamate receptor antibodies conflicting results Anti lymphotoxic antibodies, anti neuronal antibodies JG Hanly et al. Ann Rheum Dis Oct; 70(10):

19 Management of NPSLE : Rule out infections Correct contributing factors (Eg. HPT, metabolic abnormalities) Assess the severity of CNS disease (Minor Vs Major) Identify the probable underlying pathogenic mechanism(s) Therapies 1. Symptomatic 2. Immunosuppressives 3. Anticoagulant

20 Symptomatic Treatment : Depression and anxiety antidepressants/ anxiolytics Mild psychosis antipsychotics Seizures anticonvulsants (lifelong if persistent EEG abnormality after 1 year) Headaches analgesics, ergotamine

21 Anticoagulation : For focal thrombotic disease associated with apl antibodies CVA/TIAs Cerebral venous sinus thrombosis Chorea (usually self limited) Myelitis (may be combined with immunosuppression) Demyelinating Syndrome (MS like) Seizures (if not responsive to anticonvulsants) Dementia/cognitive dysfunction

22 Immunosuppression : 1. Corticosteroids ± Cyclophosphamide (Azathioprine) Severe psychosis Generalized seizures Acute confusional state Aseptic meningitis Myelitis Peripheral/cranial neuropathies; Mononeuropathy multiplex Severe cognitive dysfunction Severe depression

23 2. For Refractory Disease: Rituximab Plasmapheresis IVIG Intrathecal Methotrexate

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25 After randomization (32 patients between 1998 and 1999) Methyl Pred 1g daily for 3 days Oral prednisone on the 4 th day at 1mg/kg - 3 months 2 arms Methyl prednisone (MP) arm MP 1g - monthly for 4 months - every 2 months for 6 months - every 3 months for 1 year Cyclophosphamide (CYC) arm CYC 0.75g/m2- monthly for 1 year - every 3 months for 1 year

26 Improvement/Response : 20% change from basal conditions in clinical, serological and specific neurological measures at 4 months 24/32 patients (75%) responded to treatment 18/19 patients (94.7%) in CYC arm 7/13 patients (58%) in MP arm 7/32 patients (25%) failed to respond to treatment 6/7 patients are from MP arm

27 (Refractory)

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29 35 cases of refractory NPSLE 85% patients responded - after 1 cycle of treatment Complete response(50%) Partial response (35%) A significant dose reduction of oral corticosteroids Relapse after RTX treatment was noted in 45% of cases Seminars in Arthritis and Rheumatism Aug 27

30 Conclusion : NPSLE remains a diagnostic and therapeutic challenge Less than half of NP events are attributable to SLE Management of non-sle related factors is essential Management of NPSLE depends on the severity of manifestation and possible underlying mechanism(s) Current treatment is mostly based on anecdotal data and expert opinion

31 Thank You

32 Diagnostic approach NPSLE : For specific symptoms or signs: Stroke CT scan, APLs, MRI, Echo, carotid doppler Seizures EEG Neuropathy EMG Psychosis MRI, EEG, LP Cognitive abnormalities Psychometric testing, MRI, EEG, APLs Anxiety or depression Psychometric testing Meningitis/fever LP