Neuropsychiatric Lupus

Dr. Md. Nazrul IslamAssociate Professor of Rheumatology

BSMMU

Blood-Brain-Barrier (BBB)

Historical Perspective

Initially described by Mortiz

Kaposi in 1870s (delirium)

Prior to this, lupus thought to be

primarily cutaneous disease

The term “lupus” used as early as

the 13th century to describe a

wolf-like rash

Epidemiology of NPSLE

25-50% have some NP involvement

About 28-40% of NPSLE findings arise before or

around time of diagnosis

Most (50–60%) NPSLE events occur at disease onset

or within first year after SLE onset

Commonly (40–50%) in presence of generalised

disease activity

Neuropsychiatric Features of SLE

Only seizure and psychosis included in diagnostic criteria

Seizures may be generalized/partial, may precipitate

status

Psychosis may manifest as paranoia or hallucinations

Delirium represents a fluctuating altered consciousness

characteristic of SLE

Delirium may be caused by-

CNS vasculitis

Encephalopathy

Cerebritis (previously called organic brain syndrome)

CNSAseptic meningitis

PNSAcute inflammatory demyelinating

polyradiculo-neuropathyCerebrovascular disease

Demyelinating syndromeAutonomic disorder

Movement disorder (chorea) Mononeuropathy, single/multiplex

MyelopathyMyasthenia gravis

Seizure disorders Neuropathy, cranialAcute confusional state PlexopathyCognitive dysfunction (moderate or severe) Polyneuropathy (with

ENMG confirmation)Severe depressionPsychosis

Table 4. The modified criteria for neuropsychiatric systemic lupus erythematosus

Common Clinical Manifestations of NPSLE

Cognitive dysfunction (55-80%)

Headache (24-72%)

Mood disorders and psychosis (14-57%)

Cerebrovascular disease

Acute confusional state

Peripheral nervous system involvement

Secondary Causes of NP Symptoms

Cryptococcal

Tubercular

Meningococcal

Listeria meningitis

Herpes encephalitis

Neurosyphilis

CNS nocardiosis

Toxoplasmosis

Brain abscesses

Progressive multifocal

leukoencephalopathy

Uremia

Hypertensive

encephalopathy

Cerebral lymphoma

Medication side effects

Reversible leukoencephalopathy

Pathogenesis of NPSLE

Increased permeability of blood brain barrier

Pro-inflammatory cytokine mediated disruption of

global function

Vascular injury of small and large caliber vessels

Microangiopathic

APL antibodies, immune complexes and

leukoagglutination

May cause focal or global events

Disease Mechanism

Cognition

“…. act that involves the processing of

sensory information and includes

perception, awareness and judgment”

(Longman’s New Universal Dictionary)

Cognition

“….. refers to information processing, an

approach to the goal of understanding

human thinking. The essence of the

approach is to see cognition as being

essentially computational in nature, with

mind being the software and the brain being

the hardware.”

(Wikipedia, 2008)

Identifying Cognitive Dysfunction

Screening : Clinical judgment

Self-report questionnaires

Confirmation : Neuropsychological assessment

“Short and long batteries”

Global and domain specific impairment

Quantitative and qualitative analysis

Cognitive Dysfunction in SLEACR Guidelines for Diagnosis

Impairment in 1 of the following domains - 1)Simple

attention 2) Complex attention

3) Memory 4) Visual-spatial processing

5) Language 6) Reasoning/problem solving

7) Psychomotor speed 8) Executive function

Significant decline in cognitive function

Impact on function: social, education, occupation

Indications for Brain MRILess than 60 years

Rapid unexplained or moderate-to-severe cognitive decline

Recent and significant head trauma

New onset other neurological symptoms or signs

Development of cognitive dysfunction during

immunosuppressive or antiplatelet /anticoagulation therapy

Cerebral atrophy

The number and size of WM lesions

Cerebral infarcts correlated with severity of cognitive dysfunction

SLE related Cognitive Dysfunction

Mild cognitive impairment estimated about 80%

Variable presentation-

Overall cognitive slowing

Decreased attention

Impaired working memory

Executive dysfunction (e.g. difficulty multitasking)

SLE related Cognitive Dysfunction (Cont.)

Most mild-to-moderate degree of cognitive dysfunction

Overall benign course

Severe only in 3–5%

ACR proposed a 1 h battery of neuropsychological

tests for diagnosing (sensitivity 80%, specificity 81%)

Computer-based automated neuropsychological

assessment metrics system also used

SLE related Cognitive Dysfunction(Cont.)

More prevalent in active cases of SLE

Decline is not inevitable

Waxing and waning course

Difficult to distinguish from other causes of cognitive

dysfunction

Often diagnosis of exclusion due to lack of definitive

diagnostic testing

Cognitive Impairment in SLEPossible Etiologic Associations

SLE related factors

Overt CNS disease, Active disease

Medications

Corticosteroids

Non-SLE related factors

Chronic disease, Depression

Autoantibodies

Antineuronal, Anti-P, Antiphospholipid

MRI showing gray matter lesions the L posterior brain

Lupus psychosis

Delusions (false beliefs refuted by objective evidence) or

hallucinations (perceptions in the absence of external stimuli)

Anti-ribosomal-p sensitivity 25–27%, specificity 75–80%

Brain MRI sensitivity (50–70%), specificity (40–67%)

Brain SPECT identifies perfusion deficits in severe cases (80–

100%)

Residual hypoperfusion during clinical remission correlates

with future relapse

Lupus psychosis( Cont.)

Antidepressive and/or antipsychotic agents

Biofeedback-assisted cognitive behavioural treatment

Combination of glucocorticoids and cyclop, maintenance with

azathioprine (improvement 60–80%)

Relapses up to 50%

Refractory -rituximab rapid significant improvement of

psychiatric manifestations  

Most psychiatric episodes resolve within 2–4 weeks

Only 20% a chronic mild psychotic disorder

Seizure in SLE

Diffuse cerebral injury-

Diffuse APS

Diffuse vasculitis

Diffuse leukoaggregation

Anti-neuronal antibodies

Cytokines

Focal-

Focal APS

Seizure in SLE( Cont.)

Most seizures, single isolated event

Recurrent seizures less common (12–22%)

EEG abnormalities common (60–70%) (seizure

disorder)

Typical epileptiform EEG patterns only in 24–50%

 MRI can identify structural lesions

CSF examination is only useful to exclude infection

Therapy in Seizure in SLE( Cont.)

AED is not necessary single or infrequent seizures

Indications-

Unless high-risk features for recurrences present

Two or more unprovoked seizures occurring with at least 24

h interval

Serious brain injury

Brain MRI structural abnormalities

Focal neurological signs

Partial seizure

Epileptiform EEG

Therapy in Seizure in SLE( Cont.)

Quarter of SLE patients require a second AED

If seizures reflect an acute inflammatory event or if a

concomitant lupus flare -

Glucocorticoids alone or with

immunosuppressive

Pulse I/V methylprednisolone and I/V

cyclophosphamide in refractory seizures

Acute Confusional Syndrome (Delirium)

Diffuse cerebral injury-

Diffuse APS

Diffuse vasculitis

Diffuse leukoaggregation/PMN mediated

Anti-neuronal antibody

Cytokines

Acute Confusional Syndrome (Cont.)

Extensively evaluation of infections and metabolic

disturbances

CSF to exclude CNS infection

EEG help diagnose underlying seizure disorder

Brain imaging if focal neurological signs

Brain SPECT sensitive (93%) and monitor response

to treatment

Acute Confusional Syndrome (Cont.)

Haloperidol or atypical antipsychotics (other

interventions are ineffective)

Glucocorticoids with immunosuppressive in most

patients (response rates up to 70%)

 Plasma exchange therapy (synchronised with i.v

cyclophosphamide)

Rituximab in refractory cases

Cerebral Vascular Accident

Atherogenesis and thrombogenesis -

- HTN, DM, cigarettes, cholesterol,

- Sedentary, LDL, homocysteine

- Steroids, Immune complex injury

APS

Larger vessel vasculitis (Rare)

Headache in SLE

Tension

Vascular/Migraine-

Common, Complex, Ocular,

Vertebral- Basilar

SLE- immune mediated inflammatory mechanism

(Aseptic meningitis, Pseudo tumor cerebri,

etc.)

Aseptic Meningitis

Viral

NSAIDS

- Ibuprofen

SLE - Immune mediated inflammatory

disorder (IMID) (e.g. meningeal

vasculopathy)

Transverse Myelitis in SLE

Spinal artery

- APS

- Vasculitis

- Leukoaggregation / neutrophil mediated

Movement Disorder

Chorea best documented in SLE associated with APS

Brain imaging when focal neurological signs or to

exclude secondary causes

Most (55–65%) experience a single episode subsides

within days to a few months

Treatment of Movement Disorder

Dopamine antagonists is usually effective

Glucocorticoids in combination Azathioprine /

cyclophosphamide

Antiplatelet and/or anticoagulation therapy in

antiphospholipid-positive

Differential Diagnosis of NPSLE

Sjögren’s syndrome

MCTD

Multiple sclerosis

RA

Sarcoidosis

Polyarteritis nodosa

Microscopic angiitis

Hepatitis C

Temporal arteritis

Wegener’s

granulomatosis

Behçet’s disease

Chronic fatigue

syndrome

Fibromyalgia

Somatization disorder

Biomarkers for NPSLE

Area of aggressive

investigation

Many with low

specificity

Many are

experimental

Currently with limited

clinical application

Implicated Antibodies/ Biomarkers/ Cytokines

Anti-phospholipid

Anti-ribosomal P

Anti-neuronal

Anti-glial fibrillary acidic protein (GFAP)

Anti-endothelial cell

Anti-N-methyl-D-aspartate (NMDA)

Microtubule-associated protein 2 (MAP-2)

Matrix metalloproteinase-9 (MMP-9)

Interleukins (IL) 2, 6, 8, 10

Tumor necrosis factor alpha (TNF-α)

Interferon alpha and gamma

Neuroimaging in NPSLE

Brain structure: Computed tomography (CT)

Magnetic resonance imaging (MRI)

Magnetization transfer imaging (MTI)

Diffusion weighted imaging (DWI)

Brain function: Positron emission tomography (PET), (SPECT)

Magnetic resonance angiography (MRA)

Magnetic resonance spectroscopy (MRS)

Perfusion weighted imaging (PWI)

Functional MRI (fMRI)

Supplementation with EEG

Normal study does not rule out disease

– Cerebral vasculitis not detected on MRI/MRA or even autopsy

Cognitive Impairment and Brain Imaging

Brain structure

No association between MRI abnormalities and cognitive impairment

(Kozora et al Arthritis Rheum 1998;41:41(Sabbadini el al Lupus 1999;8:11)

Brain function

Correlation between impaired memory and visual-spatial function with

hypoperfusion on SPECT (n=37) (Sabbadini et al Lupus

1999;8:11)

Correlation between fluctuating cognitive abnormalities and cerebral

glucose metabolism (n=3)(Carbotte et al J Neurol Neurosurg Psychiatry 1992;

55:1054)

No association between PET abnormalities and cognitive impairment

(n=35) (Sailer et al J Neurol 1997;244:186)

Diagnostic Testing

LP exclude infection, hemorrhage or confirm organic

process

NP testing most useful to distinguish functional from

organic etiology

Anti-ribosomal P antibodies in patients with psychosis

APL Ab useful in CVA, seizures and focal neurological

defects

Management of NPSLECurrent Approach

Establish diagnosis of NPSLE

Identify aggravating factors: HTN, infection, metabolic

Symptomatic: Anticonvulsants, psychotropics, anxiolytics

Immunsuppression: Corticosteroids, Cyclophosphamide,

Azathioprine, MMF, B cell depletion

Anticoagulation: Heparin, warfarin

Take Home Points

NP manifestations of SLE are very common

Clinical diagnosis can be elusive-

Presentations are varied

Diagnostic testing is often unreliable

Prolonged immune suppression is mainstay

of therapy

Thank You