NPSLE

Systemic lupus erythematosus with neuropsychiatric manifestrations

(NPSLE)

9/12/2553

content

• What is NPSLE?• Incidence• Risk factors• Pathogenesis• Diagnosis• Management

What is NPSLE

• Neuropsychiatric events in patients with SLE– Primary NPSLE-directly attribute to active disease less

than 40%– Secondary NPSLE- complication of disease or its

therapy

• Wide variety of neurologic and psychiatric features– Involve both CNS and PNS/focal and diffuse– Range from overt manifestrations – stroke, seizure,

psychosis to subtle- cognitive impairment

What is NPSLE?

• Diagnostic and therapeutic challenge• Diagnostic work up remain unclear• Prognosis after NPSLE difficult to determine

Conclusion-1Encephalopathy in Lupus

Metabolic?

Active Lupus? Co-morbid: • Vascolopathy from premature • atherosclerosis• Sinus thrombosis• Antiphospholipid syndrome

Infection-induced? (meningitis, encephalitis, brain abscess, or

systemic infection with a secondary toxic encephalopathy)

Drug-induced?• NSAIDs (esp. aseptic meningitis)• Immunosuppressive Drugs (posterior

reversible encephalopathy syndrome)

• Steroids• Antibiotics (Betalactams, Quinolones,

metronodazole, etc)• Antiepileptics

Steroid Psychosis

• Uncommon • Dose-response

Prednisolone <40, 41-80, and >80 mg/day

Incidence 1.3%, 4.6%, 18.4%• hypoalbumienia increase risk of steroid psychosis

(serum albumin < 2.5 g/dL, and > 2.5 g/dL - adverse drug reaction prednisolone 37% และ 15% ตามล�าดับ)

The neuropsychiatric syndromes in systemic lupus erythematosus according to the American College of Rheumatology nomenclature and case definition

Central nervous system

•Aseptic meningitis•Cerebrovascular disease•Demyelinating syndrome•Headache•Movement disorder (chorea)•Myelopathy•Seizure disorders•Acute confusional state•Anxiety disorder•Cognitive dysfunction•Mood disorder•Psychosis

Peripheral nervous system• Acute inflammatory

demyelinating polyradiculo-neuropathy

• Autonomic disorder• Mononeuropathy,

single/multiplex• Myasthenia gravis• Neuropathy, cranial• Plexopathy• Polyneuropathy

Classification of NPSLE manifestations

Focal NPSLE Diffuse NPSLE• Aseptic meningitis• Demyelinating syndrome• Headache• Acute confusional state• Anxiety disorder• Cognitive dysfunction• Mood disorder• Psychosis

• Cerebrovascular disease

• Seizures

• Movement disorder

• Myelopathy

• Cranial neuropathy

• Polyneuropathy

• Mononeuropathy

• Myasthenia gravis

• Autonomic neuropathy

• Plexopathy

• Guillain-Barré syndrome

Incidence

• Events occur in 30–40% of patients with SLE• At disease onset or within the first 2 years

after diagnosis, commonly in the present of generalized disease

Estimated cumulative incidences of NPSLE syndromes

• Common (>5%)• Headache (20–40% in whites, 3–5% in Asians)

• Cognitive dysfunction (10–20% in whites, 1–2% in Asians); severe forms uncommon (3–5%)

• Mood disorders (10–20% in Caucasians, 1–2% in Asians)

• Seizure disorders (7–10%); recurrent (i.e. ≥2) episodes (epilepsy) in 12–22%

• Cerebrovascular disease (7–10% in whites/African Americans, 4–8% in Hispanics,2–5% in Asians); – ischemic stroke/TIA is the most common manifestation (>80%)

• Anxiety disorder (4–8% in whites, 0.5–1% in Asians)

Estimated cumulative incidences of NPSLE syndromes

• uncommon (1–5%)• Acute confusional state (3.0–

4.5%)• Psychosis (2.5–3.5%)• Polyneuropathy (2.0–3.0%)

• Rare (<1%)• Cranial neuropathy (0.5–1.0%)• Mononeuropathy (single,

multiplex) (0.5–1.0%)• Aseptic meningitis (0.5–1.0%)• Movement disorders (0.6%)• Demyelinating syndrome (0.3%)• Acute inflammatory

demyelinating polyradiculoneuropathy (also known as

• Guillain–Barre syndrome) (0.1%)• Autonomic disorder (0.1%)• Myasthenia gravis (0.1%)• Plexopathy (<0.1%)

NP syndrome CI NP syndrome

Cerebrovascular disease

5-10% 7–10% in Caucasians/African-Americans, 4–8% in Hispanics, 2–5% in Asians

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 <45 years) not explained by traditional cardiovascular risk factors

50–60% occur within 2–4 years after diagnosis in presence of high disease activity or damage

Seizure disorder 7-10% Increased risk compared to general population (OR4.0) Type: generalized tonic-clonic (67–88%),

partial (complex) Most single seizures; recurrent (≥2) episodes (epilepsy)

in 12–22% 54–63% within the first year after diagnosis in

presence of generalized disease activity (60–75%)

NP syndrome CI commentCognitive dysfunction

10-20% More common in Caucasians (10–20%) than in Asians (1–2%)

Most cases mild-to-moderate degree; severe cognitive dysfunction uncommon (3–5%)

Higher rates (average 36%) when neuropsychological tests are used (42% moderate-to-severe)

Increased risk compared to matched healthy individuals and RA patients (39–46% versus 16–18%)

Affected domains: attention, visual/verbal memory, psychomotor speed

Movement disorder 0.6% Often (60–70%) the earliest signs of CNS involvement; mean age of presentation 20–30 years

Chorea is the most frequent; hemiballism and parkinsonian disorders rare

Most commonly (55–65%) bilateral and symmetricalACS 2.9% Rates ranging 1.8–4.7% (including ‘organic brain

syndrome’ cases) Often in presence of generalized disease activityType: hypo- or hyper-aroused states, ranging from delirium to coma

NP syndrome CI NP syndromepsychosis 2.5-3.5% 60–80% of episodes at onset or within the first

Characteristics: delusions (false beliefs refuted by objective evidence), hallucinations (perceptions in the absence of external stimuli)

Mood disorder 6-12% More frequent in Caucasians (10–20%) than in Asians (1-2%) Higher rates reported in some case-control studies (25–40%

versus 0–22% in healthy individuals or RA patients) Type: major depression–like episodes, mood disorder with

depressive and/or manic featuresAnxiety disorder

4-6% More frequent in Caucasians (4–8%) than in Asians (0.5–1%)

Headache 10-20% Increased frequency in Caucasians (20–40%) than in Asians (3–5%)

Higher rates (32–95%) reported in studies specifically studying headache

Increased frequency compared to healthy individuals or RA patients (32–61% versus 17–44%) reported by some studies; not confirmed by a meta-analysis

Type: migraine, tension, cluster, associated with intracranial hypertension, non-specific intractable headache

NP syndrome CI NP syndromeMyelopathy 1-1.5% • 40–50% as initial presentation or within the first 2–4

years after diagnosis• Type: acute transverse myelopathy (most common),

longitudinal myelopathy (>4 spinal cord segments affected, continuous or separate)

Cranial neuropathy(ischemic/thrombosis)

1% Most common: optic neuropathy (≤1%); CNVIII and (III, IV, VI) palsy

Co-exist with other NPSLE syndromes (especially ischemic CVD and peripheral neuropathytransverse myelitis and/or seizure disorder)

Bilateral and may co-exist with

PNS disorder 2-3% Higher rates when EMG studies performed (16–28% versus 6–11% in healthy individuals)

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 (<0.1%)

Risk factors for NPSLE eventsNPSLEsyndrome

Risk factor Effect size

CVD SLE specific• SLE disease activity• aPL antibodies• Heart valve disease• Previous CVD Non-SLE specific• HT• DLP• Age• Male gender• Hyperhomocysteinemia

Baseline SLEDAI ≥6 associated with HR 2.1(95% CI 1.0-4.6)ORs ranging 4.3–22.2 (aCL IgG/IgM), 3.3–12.9 (LAC)ORs ranging 7.1–8.3; associated with aPLOR 16.3

HR 3.2; 95% CI 1.4–7.3 for severe strokeHR 1.09 per 10 mg/dL increase in serum total cholesterolHR 1.07 per 1-yearOR 3.8; 95% CI 1.4–10.3 (versus female gender)ORs ranging 1.1–4.8

seizure SLE disease activity • HR 1.10 per 1-unit SLAM-R; SLEDAI >15 associated with OR 3.2; 95% CI 1.1–11.2 for epilepsy;

• ACR 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)

NPSLEsyndrome

Risk factor Effect size

seizure • SLE damage• aPL antibody

• Major NPSLE

• Anti-Sm Ab• Younger age• Ethicity

• SDI ≥1.5 associated with OR 10.2; 95% CI 2.5–39.2• 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)• Seizure disorder (ORs 8.3–11.0), CVD (ORs 3.0–5.6),

psychosis (ORs 3.3–7.7)• ORs ranging 3.3–7.5• HR 1.04 per 1-year• African-American (HR 5.4; 95% CI 1.3–22.9), Hispanic (HR

2.6; 95% CI 1.3–5.1) versus White/Caucasian

cognitive SLE specific• SLE disease

activity• SLE damage

• Major NPSLE• aPL Ab• Heart valve

diasese

• OR for severe cognitive dysfunction 13.4; 95% CI 4.0-36.6 for baseline SLEDAI ≥16

• OR for severe cognitive dysfunction 6.8; 95% CI 2.0–23.6 for baseline SLICC Damage Index ≥1.0

• 52% of NPSLE versus 27% of non-NPSLE• ORs ranging 1.9–4.9 (for severe cognitive dysfunction)• OR 8.3; 95% CI 1.3–52 (mitral valve vegetations)

NPSLEsyndrome

Risk factor Effect size

cognitive Non-SLE specific

Age Education HT Psychiatric

disease

• Correlation coefficient ( r ) ranging 0.31–0.38 for various neuropsychological tests

• r ranging –0.28 to –0.39 for various neuropsychological tests• OR 4.7; 95% CI 1.3–17.1 for severe cognitive dysfunction• Depression (r = –0.24), psychological distress (r = –0.27)

Movement disorder

aPL Ab • OR 10.5; 95% CI 1.1–102 (aCL-IgG); also associated with APS/APS–related features

ACS SLE diasese activity

Major NPSLE

• OR 1.2; 95% CI 1.0–1.4 per 1-unit non-neuro–SLEDAI

• CVD prevalence 43% versus 10% in SLE with normal alertness

SLE diasese activity

Major NPSLE Psychologic

distress Anti-ENA

• Most associations with patient–perceived disease activity; baseline SLEDAI ≥16 associated with psychosis with adjusted OR 9.7; 95% CI 3.5-26.3

• OR for major depression 3.4; 95% CI 1.8–6.4• r = 0.30 with psychiatric manifestations, esp, depression

• Anti-Sm [RR 11.3], anti-RNP [RR 5.5], anti-Ro (association with psychosis)

Risk factors for NPSLE eventsNPSLEsyndrome

Risk factor Effect size

Myelopathy • aPL Ab • OR 9.6; 95% CI 1.8–50.7 (LAC)

Cranial neurpathy

• aPL Ab • OR 1.07; 95% CI 1.00–1.14 (aCL-IgG)

PNS • Anti-ENA• Major NPSLE

• Anti-dsDNA (OR 2.3; 95% CI 1.0–5.6), anti-Sm (33% versus 3%), anti-RNP (OR 4.6)

• 8% in patients with seizure disorder versus 3% in non-seizure SLE

Pathogenesis

• Autoantibodies-Antiribosomal P Ab, Antineuronal Ab Antiphospholipid Ab

• Vascular abnormality-– Non-inflammtory vasculopathy(accerated

artheroclerosis), – Vasculitis, – Thrombosis

• Inflammtory mediator IL-2 IL-6 IL-8 IL-10 interferon, matrix metalloproteinase 9

vascularInflammatory

mediaterAntibody to neuron

aPL

Focal Diffuse

NPSLE

Diagnosis

• W/U as non-SLE• Exclude non-SLE relate conditions• Investigation

– H&P– Routine lab– Serologic testing– CSF profile– Electrodiagnosis EEG, EMG, visual evoked potential– Imaging

Special considerationInvestigation Diagnostic W/U and interpretationSerological test Anti-ribosomal P Ab

Anti-neuronal AbAnti-ganglioside Ab not confirm utilitySerum S100

CSF exam IL-6 in active NPSLE-IgG index spec100% for diffuse/complexOligoclonal bands Anti-neuronal Ab no confirm utility Anti-ribosomal P Ab

Brain imaging Diagnostic W/U and interpretation

Conventional MRI

Recommended protocol T1/T2, FLAIR, DW1 Gd-enhanced T1 sequence

Advanced MRIMR spectroscopy

More sensitive NAA/Cho ratio in major NPSLE Cho/Cr ratio in active NPSLE

Special consideration

Management

• CS and immunosuppressive therapy in reflect inflammatory process

• Antiplatelet/anticoagulant in antiphospholipid Ab • Symptomatic therapies• Identify and treat aggravating factors

Paucity of published controlled studies in NPSLE to guide therapeutic decision

Management

• Corticosteroid alone or combined with immunosuppressive drug in NPSLE manifestration that reflect and immune or inflammatory process

ACS Aseptic meningitis Myelitis Optic neuritis Refractory seizure Severe psychosis AIDP

NPSLE

• Headache• Confusion• Cognitive dysfunction• Seizure• Myelopathy• Peripheral nervous system disease• Optic neuritis

HEADACHE

• Migraine and tension-type headache• High risk features require additional investigation• Explosive onset• Severe headache• Age>50 years• Fever• Concious change• focal neurological signs• Overt SLE activity

Acute confusional state

• Frightening experience by disoreintation, decrease level of concious, and hullucination

• Overaroused or underaroused• precipitating conditions

– Infection– metabolic

ConfusionNPSLE:ACS

• Acute• Visual hullucination• Fluctuating level of

conciousness with decrease attention

Psychiaric disease• Insidious or slow• Chronic with intermittent

exacerbation• Auditory hullucination• Deficit in reality testing

ConfusionGeneral management Specific management• Supportive measures • Correct underlying cause or

exacerbating factors• Control agitation

• Combination of CS with immunosuppressive agents (azathioprine, cyclophosphamide)

• In refractory or relapse• rituximab (anti-CD20 mAb) or plasma

exchange therapy (synchronized with IV CY) could be considered

Cognitive dysfunction

• Severe cognitive dysfunction is uncommom• Confirmed by neuropsychological test

Cognitive dysfunction

• MRI abnormailties• Cerebral atrophy, number and size of T2weighted

lesions and cerebral infarcts– correlated with severity and progression of SLE related

cognitive dysfunction

• Volumetric MRI protocols• detect increased intracranial CSF space and decreased

cerebral ,corpus callosum and hippocampus volume—– findings that correlate with the degree of cognitive decline

Cognitive dysfunctionGeneral management Specific management• Treat exacerbating factors

• Physical exercise • Aggressive control CVS risks

factors

• Psychosocial intervention

• Donepezil and memantine for mild cognitive dysfunction and dementia

• Psychoeducational support

• Corticosteroids w/wo immunosuppressive therapy for control concurrent SLE / major NPSLE activity.

• Aspirin in aPL positive patients

• Anticoagulant therapy in APS

Seizure• Single seizures are common in SLE and relate to disease activity• DX W/U to exclude

– structural brain disease– Metabolic condition

• EEG– part of the routine evaluation– Typical epileptiform EEG patterns, such as

spikes and sharp waves, are only present in 24–50% cases, and can be normal

• Brain MRI identify structural lesions

• Normal MRI without abnormalities on EEG can withold APD drugs

General management Specific management

• Anti-epileptic therapy : • second seizure (>24 hours after

first event), • serious brain injury, • brain structural abnormalities

(MRI), • focal neurological signs, • partial seizure as the first seizure epileptic-form EEG discharges

• Consider anti-epileptic : uncontrolled disease activity, aPL antibodies, prior or concurrent CVD, severe renal involvement

• CS (≤1 mg/kg/day) alone or in combination with immunosuppressive therapy

• Anticoagulant aPL-positive patients with persistent seizure activity despite adequate control of disease activity with immunosuppressive therapy-

(azathioprine, cyclophosphamide)

Stroke

• Atherosclerosis/thrombotic/embolic is common

• Hemorrhage is rare.• Stroke caused by vasculitis is very

rare.

Stroke

• Brain imaging exclude – hemorrhage, brain injury, and vascular lesion responsible for the neurological deficit– MRI, Non-contrast CT

• Conventional Brain MRI • MRA, CTA, DSA identified vascular lesion or vasculature

aneurysms.

• The acute management of SLE patients with cerebrovascular disease is similar to that in nonSLE patients

StrokeGeneral management Specific management• Thombolytic (ischemic stroke) or surgical

(hemorrhagic stroke) therapy according to indications

• In ischemic stroke/TIA-A• Anti-platelet agents within 24–48 hours

• Anticoagulation therapy when AF or cardio-embolic source is present

• Consider endarterectomy if ipsilateral severe (≥70%) carotid artery stenosis

• Secondary prevention

• Persistent aPL antibodies -oral anticoagulant

• Fulfill the criteria for APS– INR 3.1−4.0may be preferred over target

INR 2.0−3.0 but increased risk for minor bleeding events

– Long-term anti-coagulation therapy is recommended

• corticosteroids alone or in combination with immunosuppressive agents (azathioprine, cyclophosphamide)-Generalized disease activity

Myelopathy• Present with signs of gray matter dysfunction (flaccidity and

hyporeflexia) white matter dysfunction (spasticity and hyperreflexia) and neuromyelitis optica

• Relapses are common (50–60%) during corticosteroid dose reduction, highlighting the need for less intensive immunosuppressive maintenance therapy.

• The diagnostic workup– Contrast enhanced spinal cord MRI.– CSF analysis, primarily to exclude infectious causes of

myelitis• .

Myelopathy• Factors associated with severe neurological deficit

include– extensive spinal cord lesions on MRI, – reduced muscle strength at presentation– presence of aPL – delayed(>2 weeks) initiation of therapy

MyelopathySpecific management

Induction The combination of pulse MP+IVCY

Maintainance Less intensive immunosuppressive regimen

Not response to standard treatment

rituximab

aPL positive or APS not responese to immunosuppressive

Anticoagulant therapy

Peripheral nervous system

• manifestations of SLE include

• peripheral nerve injury, • myopathy• disturbances of neuromuscular junctions, which might clinically

resemble myasthenic syndromes. • mononeuritis multiplex or a more confluent polyneuropathy, result

from vasculitic insult to the vasa nervorum,• chronic sensory or sensori motor polyneuropathy results in or from a

demyelinating process• acute motor presentation resembling acute inflammatory

demyelinating polyradiculoneuropathy.

Peripheral nervous system

• Nerve conduction studies • CSF analysis is useful for identifying inflammatory

demyelinating polyradiculoneuropathy • Nerve biopsy is rarely needed

• Treatment with corticosteroids alone or in combination with immunosuppressive therapy, – has a 60–75% response rate.– For severe cases, intravenous immunoglobulin, plasma exchange

and rituximab are alternative treatment options.

Optic neuritis

• The diagnostic work-up should include a – complete ophthalmological evaluation (including funduscopy and fl

uoroangiography),– MRI – Visual evoked potentials

• Distinguished from ischaemic optic neuropathy, – unilateral, especially in patients with antiphospholipid antibodies

• Glucocorticoids (intravenous methylprednisolone) alone or in combination with immunosuppressive

• Poor clinical outcome

Conclusion 1Before give an Diagnostic for NPSLEExclude non-SLE relate conditions1. Complication from treatment

1. Steroid induced psychosis2. Immunosuppressive drug-posterior

leukoencephalopathy3. CNS infection

2 Metabolic disorder3 Drug side effect – sedative drugs, antipsychotic

drugs

Conclusion-1Encephalopathy in Lupus

Metabolic?

Active Lupus? Co-morbid: • Vascolopathy from premature • atherosclerosis• Sinus thrombosis• Antiphospholipid syndrome

Infection-induced? (meningitis, encephalitis, brain abscess, or

systemic infection with a secondary toxic encephalopathy)

Drug-induced?• NSAIDs (esp. aseptic meningitis)• Immunosuppressive Drugs (posterior

reversible encephalopathy syndrome)

• Steroids• Antibiotics (Betalactams, Quinolones,

metronodazole, etc)• Antiepileptics

Conclusion 2-clinical presentation

ANATOMICAL

CNS

PNS

DISTRIBUTION

FOCAL

DIFFUSE

Thrombosisvasculitis

Conclusion 3- management

Use corticosteroid and immunosuppressive drug• Optic neuritis• Transverse myelitis• Peripheral neuropathy• Refractory seizure• Psychosis• ACS• Presence of generalized lupus activity

Antiplatelet/anticoagulant-APS

Prognosis

Thank you for your attention

Case 1

• SLE Pred 10 mg/day• Fever 3 days• Concious change 1 day

• DDx• 1.CNS infection• 2.Meatabolic - uremia• 3.NPSLE

– ACS– HT encephalopathy

• Look for evidence of active active

• Cannot R/O infection

Case 2

• SLE on pred 30 mg/day• Visual hullucination

• Concious clear but hullucination

• DDxNPSLESteroid induce psychosis

• Psychosis+visual hullucination alone

• stop steroid