Annals of the Rheumatic Diseases | A EULAR & BMJ ...



SUPPLEMENTARY MATERIAL

Table S1. Classification of NPSLE manifestations 1-2

|Central NPSLE |Peripheral NPSLE |Focal NPSLE |Diffuse NPSLE |

|Aseptic meningitis |Guillain Barré syndrome |Cerebrovascular disease |Aseptic meningitis |

|Cerebrovascular disease |Autonomic neuropathy |Seizures |Demyelinating syndrome |

|Demyelinating syndrome |Mononeuropathy |Movement disorder |Headache |

|Headache |Myasthenia gravis |Myelopathy |Acute confusional state |

|Movement disorder |Cranial neuropathy |Cranial neuropathy |Anxiety disorder |

|Myelopathy |Plexopathy |Polyneuropathy |Cognitive dysfunction |

|Seizure disorders |Polyneuropathy |Mononeuropathy |Mood disorder |

|Acute confusional state | |Myasthenia gravis |Psychosis |

|Anxiety disorder | |Autonomic neuropathy | |

|Cognitive dysfunction | |Plexopathy | |

|Mood disorder | |Guillain-Barré syndrome | |

|Psychosis | | | |

Table S2. Frequency of neuropsychiatric syndromes in SLE cohorts 3-14

|NP syndrome |CI |Comments |References |

|Cerebrovascular disease |5–10% |7–10% in Caucasians/African-Americans, 4–8% in Hispanics, 2–5% in Asians |5-6, 15-29 |

| | |Type: ischemic stroke/TIA (>80%), multifocal disease (7–12%), intra-cerebral hemorrhage (3–5%), sinus thrombosis (2%) | |

| | |Increased risk compared to general population (RR for stroke 7.9; PMR 1.8 in individuals aged 4 spinal cord segments affected, continuous or separate) | |

| | | | |

|Cranial neuropathy |1% |Most common: optic neuropathy (≤1%); cranial nerve VIII and oculo-motor nerves (III, IV, VI) palsy |33, 58-61 |

| | |Co-exist with other NPSLE syndromes (especially ischemic CVD and peripheral neuropathy) | |

| | |Optic neuropathy is often (50–60%) bilateral and may co-exist with transverse myelitis and/or seizure disorder | |

| | | | |

|Peripheral nervous system |2–3% |Higher rates when EMG studies performed (16–28% versus 6–11% in healthy individuals) |30, 33, 62-67 |

|disorders | |Often co-exists with other NPSLE syndromes | |

| | |Type: polyneuropathy (2–3%), mononeuropathy (single, multiplex) (0.5–1%), acute or chronic inflammatory demyelinating polyradiculoneuropathy | |

| | |(0.1%), myasthenia gravis (0.1%), plexopathy (15 associated with OR 3.2; 95% CI 1.1–11.2 for epilepsy; ACR |1 |30-31, 107-110 |

| | |manifestations (serositis [HR 1.8], hemolytic anemia [OR 3.0], nephritis [HRs 2.1–4.2]); increased dose of | | |

| | |corticosteroids or immunosuppressive therapy (cyclophosphamide use associated with HR 2.5–5.3) | | |

| |SLE damage |SDI ≥1.5 associated with OR 10.2; 95% CI 2.5–39.2 |1 |110 |

| |aPL antibodies1 |ORs 3.7–6.1 (aCL-IgG), 2.9; 95% CI 1.0–8.5 (aCL-IgM), 6.2; 95% CI 1.7–22.5 (LAC) |1 |6, 30-31, 35, 108,|

| | | | |110-111 |

| |Major NPSLE3 |Seizure disorder (ORs 8.3–11.0), CVD (ORs 3.0–5.6), psychosis (ORs 3.3–7.7) |1 |22, 30 , 31, 93, |

| | | | |109-110 |

| |Anti-Sm antibodies |ORs ranging 3.3–7.5 |2 |110, 112 |

| |Younger age |HR 1.04 per 1-year |2 |30, 109 |

| |Ethnicity |African-American (HR 5.4; 95% CI 1.3–22.9), Hispanic (HR 2.6; 95% CI 1.3–5.1) versus White/Caucasian |2 |30, 109 |

|Cognitive dysfunction |SLE specific | | | |

| |SLE disease activity |OR for severe cognitive dysfunction 13.4; 95% CI 4.0-36.6 for baseline SLEDAI ≥16 |2 |22, 42, 46, |

| | | | |113-114 |

| |SLE damage |OR for severe cognitive dysfunction 6.8; 95% CI 2.0–23.6 for baseline SLICC Damage Index ≥1.0 |2 |12, 47 |

| |Major NPSLE3 |52% of NPSLE versus 27% of non-NPSLE |2 |6, 43, 115-118 |

| |aPL antibodies1 |ORs ranging 1.9–4.9 (for severe cognitive dysfunction) |2 |6, 47, 119-121 |

| |Heart valve disease2 |OR 8.3; 95% CI 1.3–52 (mitral valve vegetations) |2 |27, 122 |

| |Non-SLE specific | | | |

| |Age |Correlation coefficient ( r ) ranging 0.31–0.38 for various neuropsychological tests |1 |10, 22, 39, 47, |

| | | | |123-124 |

| |Education level |r ranging –0.28 to –0.39 for various neuropsychological tests |2 |10, 120, 123 |

| |Hypertension |OR 4.7; 95% CI 1.3–17.1 for severe cognitive dysfunction |2 |47 |

| |Psychiatric disease |Depression (r = –0.24), psychological distress (r = –0.27) |2 |10, 120, 125-127 |

|Movement disorders |aPL antibodies1 |OR 10.5; 95% CI 1.1–102 (aCL-IgG); also associated with APS/APS–related features |2 |6, 48, 128-130 |

|Acute confusional state |SLE disease activity |OR 1.2; 95% CI 1.0–1.4 per 1-unit non-neuro–SLEDAI |3 |27, 93 |

| |Major NPSLE |CVD prevalence 43% versus 10% in SLE with normal alertness |3 |131 |

|Psychiatric disorders |SLE disease activity |Most associations with patient–perceived disease activity; baseline SLEDAI ≥16 associated with psychosis with|2 |22, 69-70, 74, |

| | |adjusted OR 9.7; 95% CI 3.5-26.3 | |132-133 |

| |Major NPSLE |OR for major depression 3.4; 95% CI 1.8–6.4 |2 |115, 134-135 |

| |Psychological distress4 |r = 0.30 with psychiatric manifestations, particularly depression |2 |70, 73-74, 76, 132|

| |Anti-ENA |Anti-Sm [RR 11.3], anti-RNP [RR 5.5], anti-Ro (association with psychosis) |2 |112, 136-137 |

|Myelopathy |aPL antibodies1 |OR 9.6; 95% CI 1.8–50.7 (LAC) |2 |55, 138-140 |

|Cranial neuropathy |aPL antibodies1 |OR 1.07; 95% CI 1.00–1.14 (aCL-IgG) |3 |6 |

|Peripheral neuropathy |Anti-ENA |Anti-dsDNA (OR 2.3; 95% CI 1.0–5.6), anti-Sm (33% versus 3%), anti-RNP (OR 4.6) |2 |22, 63, 112 |

| |Major NPSLE3 |8% in patients with seizure disorder versus 3% in non-seizure SLE |2 |30, 33, 93 |

CVD, cerebrovascular disease, SLEDAI, SLE disease activity index, HR, hazard ratio, 95% CI, 95% confidence interval, aPL, antiphospholipid, OR, odds ratio, SLAM, Systemic Lupus Activity Measure, SDI, SLE International Collaborating Clinics Damage Index, APS, antiphospholipid syndrome.

1 Persistently positive, moderate-to-high titers of aPL antibodies

2 Moderate-to-severe mitral valve regurgitation and/or valve vegetations

3 Refers to past or concurrent major NPSLE syndrome

4 Including also stressful life event, lack of social support

Table S4. Diagnostic work-up in SLE patients who present with neuropsychiatric signs or symptoms

|NPSLE |Diagnostic work-up and interpretation of tests |Evidence |References |

|General NPSLE | | | |

|H&P1 |Determine the neuropsychiatric syndrome(s) present and the extent of neurological deficit |– | |

| |Exclude mimicking conditions (hypertensive encephalopathy, syncope, panic attack, migraine) | | |

| |Identify secondary causes or aggravating factors: infections (including CNS infections, levodopa), hypoxia or hypercarbia, head trauma, | | |

| |adverse drug reactions (anticholinergics, narcotic analgesics), alcohol or illicit drug use, withdrawal syndromes | | |

|CBC, biochemistry2 |Exclude secondary causes: metabolic disturbances (hypo- or hyperglycemia, uremia, electrolyte abnormalities), vitamin deficiencies, |– | |

| |liver or thyroid disease | | |

|Serological tests |Anti-ribosomal P antibodies: limited utility (sensitivity 25–27%, specificity 75–80%) |1 |141-146 |

| |Anti-neuronal antibodies: limited utility (sensitivity 77%, specificity 96%, LR+ 20.7 in headache/seizure with abnormal MRI) |3 |147 |

| |Anti-ganglioside antibody: not confirmed utility (RR 3.7–4.0 for NPSLE) |3 |148 |

| |Serum S100B: not confirmed utility (levels ≥0.125 ng/mL have 78% sensitivity and 80% specificity to differentiate active NPSLE from |3 |149-150 |

| |active non-NPSLE) | | |

| |Other tests (autoantibodies, cytokines, other biomarkers) have limited diagnostic utility | | |

|CSF examination3 |Indicated to exclude CNS infection | | |

| |Mild abnormalities: common in active NPSLE (pleocytosis: 22–36% [usually 20–100 cells/hpf], ↑ protein: 30–66% [usually 70–110 mg/dL], ↓ |2 |151-152 |

| |glucose: 8–42% [usually 30–40 mg/dL] | | |

| |Cannot accurately differentiate SLE– from non-SLE–attributed events | | |

| |Not specific to the type of NPSLE | | |

| |IL–6: increased in active NPSLE but their diagnostic utility remains to be established |2 |153-155 |

| |IgG index: sensitivity 75%, specificity 100% for diffuse/complex NPSLE |2 |156 |

| |Oligo-clonal bands: sensitivity 55%, specificity 92% for diffuse/complex NPSLE |2 |156 |

| |Anti-neuronal antibodies (high titers): limited utility (sensitivity 58%, specificity 89%, PPV 88%, NPV 61%) |2 |147, 157-158 |

|EEG |Modest sensitivity (42–84%, usually 60%) and specificity (50%) in active NPSLE; unspecific theta (slowing) activity in 50–80%, focal or |2 |8, 33, 156, 159-166 |

| |lateral abnormalities in 20–40% | | |

| |Neurometric quantitative EEG: no additional benefit | | |

| |Indicated to diagnose underlying seizure disorder (80% sensitive in the acute phase: epileptic-form discharges in 50–70% and diffuse | | |

| |slow waves in 30–50%) | | |

|Visual evoked potentials |Useful to determine optic nerve involvement |3 |167 |

| |No utility in the diagnostic work-up of other NPSLE syndromes | | |

|Transcranial doppler US |Detection of micro-embolic signals in patients with history of CVD (PPV 93%, NPV 94%) |2 |168-169 |

| |High blood flow velocities in middle cerebral arteries and/or detection of micro-embolic signals: modest correlation with acute seizures| | |

| |or stroke (sensitivity 67%, specificity 83%) | | |

|Brain MRI (conventional) |Test of choice in imaging of NPSLE; more sensitive than CT |1 |27, 47, 104, 170-177 |

| |Recommended protocol: conventional T1/T2, FLAIR, DWI, and Gd-enhanced T1 sequences | | |

| |Useful to exclude brain mass or abscess; may rule out CNS infection (meningeal enhancement) | | |

| |Moderate sensitivity (55–60%) in acute NPSLE (specificity 50–70%); increased sensitivity in major versus minor (64% versus 30%) and in | | |

| |focal versus diffuse (76% versus 51%) NPSLE | | |

| |Small punctuate hyperintense focal lesions in subcortical and periventricular WM on T2-weighted and FLAIR images, without contrast | | |

| |enhancement; T1–weighted signals are usually normal | | |

| |Sensitivity 51% for acute NPSLE (54% in major, 30% in minor NPSLE); increased in focal than diffuse major NPSLE (79% versus 48%) | | |

| |Located in the frontal-parietal regions (70–80%) and in the basal ganglia or infratentorial region (cerebellum) (8–10%); no correlation | | |

| |with the type of NP syndrome | | |

| |Moderate specificity (also present in 18–40% of non-NPSLE); improved specificity (70–90%) if multiple (≥5), medium-sized (≥6–8 mm), | | |

| |bi-hemispheric lesions | | |

| |Positive correlation with age, SLE duration, hypertension, aPL, heart valve disease | | |

| |Cerebral atrophy | | |

| |Usually mild-to-moderate (30% in major NPSLE, 30–40% in focal versus 15–20% in diffuse NPSLE) | | |

| |Low specificity (40–60%); positive correlation with age, SLE duration, cumulative dose of steroids, SLE damage, aPL | | |

| |DWI: improved sensitivity (including cases of diffuse NPSLE with normal-appearing conventional MRI) |1 |178-185 |

| |Early (first 7-10 days) detection of acute ischemic CVD lesions | | |

| |Discrimination between recent (restricted diffusion) and old (no diffusion restriction) hyperintense ischemic lesions | | |

| |Volumetric MRI: diagnostic utility not determined (↑ T2–weighted lesions, cerebral or regional (corpus callosum, hippocampus) atrophy in|2 |11, 171, 175, 186-191 |

| |patients with past NPSLE) | | |

|Advanced MRI | | | |

|Magnetization transfer imaging |Limited use in routine clinical practice due to lack of standardized normal MTR values |2 |192-198 |

| |Useful in the diagnosis of past versus acute NPSLE: ↓ MTR peak height (whole brain); ↓ MTR mean (values ................
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