npsle
TRANSCRIPT
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