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Treatment of
Neuropsychiatric lupus
Dr HAJIALILO
Treatment strategy
Diagnosis TreatmentPathogenesis
Signs
symptoms
Treatment Strategy
Before NP-SLE
Treatment strategy
Diagnosis TreatmentPathogenesis
Signs
symptoms
Treatment Strategy
Before NP-SLE
Treatment strategy
HLA-DRB104 genotype and STAT4 rs10181656 were
associated with ischemic CVD
Mutations in TREX1
On of expression quantitative trait loci (eQTL) was IRF5
cis-SNP rs4728142 with cognitive dysfunction
Prediction of NPSLE
1- Ann Rheum Dis 2010; 69:1886–1887. 2-Genes Immun 2011; 12:270–279.
3-PLoS Genet 2012; 8:e1002707
.
Treatment strategy
Arthritis Rheum 2001; 45:419–423
Include : generalized (nonneurological) SLE activity
or damage, history of previous or concurrent other
major NPSLE, aPL antibodies (persistently positive
moderate-to-high aCL or anti ß2 GPI Ig titers, LAC)
Assessment for risk factors for SLE-related events
Treatment strategy
Arthritis Rheum 2001; 45:419–423
Include: Increasing age, atherosclerotic risk factors
(hypertension, diabetes, dyslipidemia), heart ((valvular
disease, chronic atrial fibrillation), High cumulative dose
of glucocorticoids
Assessment for risk factors for SLE-unrelated events
Treatment strategy
Diagnosis TreatmentPathogenesis
Signs
symptoms
Treatment Strategy
Before NP-SLE
Treatment strategy
Arthritis Rheum 2001; 45:419–423
Most (50–60%) SLE-related events occur at disease
onset or within the first 1–2 years after diagnosis;
events occurring >6 months before the onset of
SLE are less likely to be attributed to SLE
Timing of event
Treatment strategy
40–50% of NPSLE are primary and remaining are
secondary
Exclusion of infection, hormonal/metabolic
disturbances, vitamin deficiencies, drug effects,
and association factors reported in the ACR
nomenclature and case definitions for NPSLE
Exclusion of secondary causes
1-Rheumatology (Oxford) 2012; 51:157–168 2-Ann Rheum Dis 2010; 69:2074–2082.
Treatment strategy
Arthritis Rheum 2001; 45:419–423
Minor events : (headache, anxiety, mild forms of depression
, and cognitive dysfunction, polyneuropathy without
electrophysiological confirmation ) are less likely to be
attributed to SLE
Major events : seizures, cerebrovascular disease (CVD)
myelopathy, optic neuritis, aseptic meningitis, and
psychosis, acute confusional state
Type of event: Minor versus Major
Treatment strategy
Pathogenesis of the underlying process
Antiphospholipid antibodies
Accelerated atherosclerosis
Antineuronal antibodies.Antiribosomal-P
Anti-N-methyl-D-aspartate receptor (NMDA)
Anti-RO
Antiphospholipid antibodies
Vasculopathy- Thrombotic
Inflammatory/neurotoxic
Treatment strategy
Pathogenesis of the underlying process
Vasculopathy-Thrombotic Inflammatory/neurotoxic
Can we separate these process definitely ?
Treatment strategy
Pathogenesis of the underlying process
Vasculopathy-Thrombotic Inflammatory/neurotoxic
Some times it is difficult and impossible
Treatment strategy
Pathogenesis of the underlying process
Thrombotic CVD, has also been used in antiphospholipid-associated ischaemic
optic neuropathy and chorea , as well as in myelopathy refractory to
immunosuppressive therapy
Aseptic meningitis, optic neuritis, transverse myelitis, peripheral neuropathy,
refractory seizures, psychosis, acute confusional state; ACS
Vasculopathy- Thrombotic
Inflammatory/neurotoxic
Antiplatelet/anticoagulation
Glucocorticoids alone or in
combination CTX or AZA
Plasmapheresis,Rituximab,IVIg
Innate Immunity
Adaptive Immunity
Novel target therapy in LUPUS
Innate Immunity
Targeting IFN pathway
Sifalimumab
Rontalizumab
TNF a signaling
Infliximab
Adaptive Immunity
Novel target therapy in LUPUS
Novel target therapy in LUPUS
Adaptive immunityB cell pathwayB cell depletion
Inhibition f Bcell activation
Plasma cell depltion
Induction of B-Cell tolerance
T Cell pathwayCo-stimulatory blockaed
Cytokine blockade
Kinase Inhibitor
StatusStudy PhaseDrugTarget
This study on going but not
recuritment participant
Phase 3 RCT,multicenterOcrezulimabAntiCD20
This study has been completedPhase IIb RCT,multicenterEpratuzumabAnti-CD22
This study currently recruiting
participants
Phase III,belimumab
versus placebo in
treatment SLE located
northeast Asia
BelimumabBAFF Inhibitor
This study currently recruiting
participants
Phase Ib RCTOmalizumabIgG 1 k
monoclonal
antibody that binds
to IgG E
This study currently recruiting
participants
Phase 2 open labelTamibaroteneRetinobanzoic acid
This study on going but not
recuritment participant
Phase II RCTRontalizumabAntiinerfron a
monoclonal
antibody
This study currently recruiting
participants
Phase II RCTN-AcetylsysteinAntioxidant
New therapies in SLE Current opinion 2013
Treatment strategy
Diagnosis TreatmentPathogenesis
Signs
symptoms
Treatment Strategy
Before NP-SLE
Treatment strategy
Arthritis Rheum 2001; 45:419–423
NeuroImaging : MRI(small punctuate hyperintense T2-weighted
focal lesions in subcortical and periventricular WM, diffuse
cortical GM lesions , cerebral atrophy, infarcts)
CTScan , MRS, SPECT
CSF Analysis
EEG (Abnormalities has 50–60% sensitivity and specificity for
active Primary NPSLE)
Serology ( Anti-DsDNA,C3,C4, Anti-Ribosomal-P,aPL,…)
Echo, Doppler,
Diagnostic Approach
Treatment strategy
Diagnosis TreatmentPathogenesis
Signs
symptoms
Treatment Strategy
Before NP-SLE
Headache
In patients with lupus all headache types was not different from controls .
Usually it does not require further investigation and it should be classified according to IHS criteria and managed as a primary headache .
Headache might be the heralding symptom of a more complex CNS syndrome.
Brain127,1200–1209 (2004).
Headache
Cases of acute occurrence or modification of an existing chronic headache associated with high-risk factors :
must be viewed cautiously, and must be managed and treated accordingly.
Severe headache refractory to analgesic drugs,
sudden onset, vomiting, fever, immunosuppression ,
aPL positivity and alarm signs (sign of infection,
meningeal signs, papilledema, focal neurologic signs,
decreased level of consciousness
Headache
Acute : Metoclopramide IV(10 mg)or Prochlorperazine
IV(10mg) or Dihydroergotamine plus diphenhydramine IV
(12.5-25 mg)
Preventation : TCA, Valoproate,Topiromate,Calcium channel
blockers
Migraine
headache
Acute : ASA, NSAIDS(Naproxen,ibuprofen,..)
Acetaminophen Triptans, muscle relaxants,
Preventation: TCA,Tizanidin, some time
anticonvulsant agents
Tension-type
headache
Sumatriptan (6mg), Inhaled oxygen, Octerotide,Intra nasal
lidocaine,Oral ErgotamineCluster
headache
Headache in SLE often responds to the same
interventions as non-SLE headache.
Seizure
Most seizures in SLE represent single isolated events;
recurrent seizures (epilepsy) are less common (12–22%)
Some points
Epilepsy typically is not associated with current active
SLE and responds to anticonvulsants
Isolated seizures are most often associated with active
SLE and respond to therapy for SLE .
Seizure
Control acute phase like as other patients
Be sure to be open airway
IV line and taking blood sample
Drug for acute attack (diazepam)
Management
Seizure
The diagnostic work-up aims to exclude :
Structural brain disease , metabolic disturbances
infections, hypoxemia, hypertension, uremia,
medication effects ,tumor,…
Management
Seizure
The diagnostic work-up aims to exclude :
Structural brain disease , metabolic disturbances
infections, hypoxemia, hypertension, uremia,
medication effects ,tumor,…
Evaluation of disease activity
and
Management
Seizure
The diagnostic work-up
Brain MRI
EEG
LP (if suspicious to infection)
Blood sample(BS,Na,Ca,…,and lab date for lupus activity)
Management
Seizure
Are glucocorticoid useful of seizure in lupus
patients ?
If seizures are thought to reflect an acute inflammatory
event or if a concomitant lupus flare is present,
glucocorticoids alone or in combination with
immunosuppressive therapy may be given.
The combination of pulse methylprednisolone and
cyclophosphamide has shown effectiveness in refractory
seizures in the context of generalized lupus activity.
Ann Rheum Dis 2005,64:620
Management
1
2
3
4
5
6
7
8
Basal 6 th month 12 th month Basal 6 th month 12 th month
1
2
3
4
5
6
7
8
1
2
3
4
1
2
3
4
Mean number of seizures/ month
in (A) MP group; (B) Cy group
A B
MeanMean
Ann Rheum Dis 2005;64:620–625.
Induction treatment with 3 g of IV methylprednisolone (MP) followed
by either IV monthly cyclophosphamide (Cy) versus IV MP
bimonthly every 4 months for 1 year and then IV Cy or IV MP every
3 months for another year for severe NP manifestations
Seizure
Correlation with APS :
The mechanism for seizures in SLE patients with aPL has
been related to focal cerebral ischemia or to a direct
aPL-mediated effect on neurons, and this may explain
why antiplatelet and anticoagulation therapy has been
anecdotally reported to be effective in recurrent
refractory unprovoked seizures.
Curr Pharm Des 2008,14(13) :1261-9
Management
Seizure
When we need to anticonvulsant therapy for
seizure in SLE ?
After a single episode of unprovoked seizures
prescription of chronic therapy with an
anticonvulsant should be delayed unless high-
risk features for recurrence are present.
Management
Risk features for recurrence of seizure in
SLE
Two or more unprovoked seizures occurring within 24 h
Serious brain injury
Brain MRI structural abnormalities causally linked to seizures
Focal neurological signs
Partial seizure
Epileptiform EEG
Previous stroke (HR: 2.4)
persistently positive Moderate-to-high titers of
anticardiolipin IgG (HR: 2.2)
Ann Rheum Dis 2010;69:2074–2082
Myelitis
Diagnosis :
With clinical evaluation and confirmed with contracted
enhanced MRI
Are there co-exist other NPSLE symptoms or signs
If there are perform brain MRI
R/O other causes of myelopathy :
Tumor, Abscess , Vertebral compression fracture, Anterior
spinal artery syndrome , Infection With MRI and CSF
analysis
Myelitis
Types of Myelitis:Patients may present with signs of grey matter (lower motor neuron) dysfunction (flaccidity and hyporeflexia) or withe matter (upper motor neuron) dysfunction (spasticity and hyperreflexia); the latter can be associated more with neuromyelitis optica (NMO)
and antiphospholipid and correlation with Anti-RO.
Transverse or longitudinal (more than three sections) myelitis
Gray matter signs have more disability (2)
1-Arthritis& Rheumatism. Vol. 60, No. 11, November 2009, pp 3378–3387
2-Arthritis Rheum Vol. 60, No. 11, November 2009, pp 3378–3387
Myelitis
Transverse MyelitisLongitudinal Myelitis
Myelitis
The combination of intravenous methylprednisolone and
intravenous cyclophosphamide (for 3–6 months
according to severity and clinical response) quickly
added in association with oral prednisone. Because of
the high risk of relapses cyclophosphamide therapy
should be followed by treatment with
immunosuppressants such as azathioprine. (1)
Plasma exchange therapy has been used in severe cases(2),(3)
1-Ann Rheum Dis 2000, 59,120 2-Ther Apher Dial 2003; 7 : 173 – 82
3-.Lupus 2007; 16 : 817 – 22
Myelitis
Anticoagulant :
Some dates support use of anticoagulant with
glucocorticoids in the presence of antiphospholipid
antibodies.(1) but a recent systematic review concluded
anticoagulation no additional benefit over standard
immunosuppression. (2) but may be considered in focal
myelitis and refractory cases. (3)
1- J Rheumatol 2004, 31:280 2-European Journal of Neurology April 2011
3-Clinical Rheumatology 2011 volume 30 981-986
Myelitis
Rituximab :
Recently an observational study in six SLE patients
suggested that a treatment regimen of rituximab and
methylprednisolone pulses could be beneficial in
preventing permanent neurological damage in severe
lupus myelopathy.In this study 4 of 6 patients showed
complete response within 12 months.
Clinical Rheumatology 2011 volume 30 981-986
Rituximab in SLE
EXPLORARE
LUNAR
LESIMAB
BIOGAS registry
Arthritis Rheum 2010 62:222-233
LUPUS 2012 , 21:1036-1076
Autoimmunity REV 2006 11:357-364
Arthritis Rheum 2012,64:1215-1226
Psychosis
Consult with psychiatric
R/O Other etiologies for psychosis
Management
Psychosis
Consult with psychiatric
R/O Other etiologies for psychosis
Neurologic problems:(Infections, Neoplasms ,..)
Endocrine and metabolic dysfunctions (Thyroid, Parathyroid, or
Adrenal abnormalities, Hypoxia, Hypoglycemia,..)
Hepatic and Renal disorders
Toxin
Management
Drug( corticosteroid , anti-malaria)
Psychosis
Psychosis due to (active )organic involvement by SLE usually responds to steroids.
Treatment should be initiated as soon as possible to prevent permanent damage(1-2mg/kg) given for a few weeks in divided doses is usually sufficient
If no improvement is seen within two to three weeks, a trial of cytotoxic therapy (eg, pulse cyclophosphamide)
is warranted followed by maintenance with azathioprine is recommended)
1-Ann Rheum Dis 64,620-625(2005) 2-Rheumatology (Oxford) 47,1498–1502 (2008).
Treatment
PsychosisTreatment
In psychosis refractory to conventional
immunosuppressive treatment :
Plasma exchange or rituximab may be effective
options. (1),(2)
Electroconvulsive therapy (refractory cases )
Antipsychotics ( Chlorpromazine- Trifluoperazine-
Haloperidol ,..) should be prescribed according to
guidelines, especially in relapsing cases.
1-Ther .Apher. Dial 7,173-182(2003) 2- Ann Rheum Dis 66,470-475 (2007)
3- J ECT 2013 Sep;29(3):243-6.
Cerebrovascular Disease(CVD)
Ischemic stroke
TIA
Multifocal
disease
ICH
Sinus
Thrombosis Vasculitis
Types of CVD
Strokes have been reported in up to 19 percent of patients
with SLE and a cause of increased mortality and disability.
Cerebrovascular Disease
History and physical examination :
Neuro Imaging ( CTscan, MRI/DWI ,CT or MR
angiography )Assessment other sites and risk factors for
thrombosis (Echo, Doppler sonography.lipid and glucose level,hypercoagulation state,…)
Evaluation of SLE activity
Work up
SLEDAI >6 has HR: 2.1 for CVD
1-Nat. Rev. Rheumatol.6,358–367 (2010)
2-Rheumatology (Oxford)43,1555–1560 (2004)
Cerebrovascular Disease
The acute management of SLE stroke or TIA is
similar to that in the general population.
A stroke specialist consultation is necessary
to identify patients who are candidates for
thombolytic or surgical therapy; unless
contraindicated .
Treatment
Exclusion criteria Inclusion criteria
Significant stroke or head trauma in the
previous three months
Previous intracranial hemorrhageIntracranial
neoplasm, arteriovenous malformation, or
aneurysm, Recent intracranial or intraspinal
surgery
Persistent blood pressure elevation (systolic
≥185 mmHg or diastolic ≥110 mmHg
Platelet count <100,000/mm
Current anticoagulant use with an
INR>1.7 Evidence of a multilobar
infarction with hypodensity involving >33
percent of the cerebral hemisphere
Pregnancy, Age >80 years
Clinical diagnosis of ischemic stroke
causing measurable neurologic deficit
Onset of symptoms <4.5 hours before
beginning treatment; if the exact time
of stroke onset is not known, it is
defined as the last time the patient
was known to be normal
Age ≥18 years
Strok 2013 , 44 :870
Criteria for treating acute stroke with tPA
Cerebrovascular Disease
Chronic anticoagulation therapy with warfarin or
asprin is indicated in most patients with stroke
syndromes due to aPL or thrombosis if they are
stable and if there is no evidence of hemorrhage.
Treatment
What are recommendations?
Cerebrovascular Disease
For the patient with SLE and an ischemic stroke who has no
other identifiable risk factors (eg, does not have atrial
fibrillation, has no vegetations by echocardiography, has no
significant extracranial arterial stenosis, has no aPL) and for
whom MRI suggests small vessel thrombosis
Treatment
Recommendations for anticoagulation
Low dose Asprin 81mg
Ann. Rheum. Dis.69,2074–2082 (2010).
Cerebrovascular Disease
For the patient with SLE and ischemic stroke and
moderate or high levels of aPL,
The level of anticoagulation is still debated
Treatment
Recommendations for anticoagulation
Warfarin with INR 2-3 or 3-4 ?
Cerebrovascular Disease
It has been suggested that the international
normalized ratio should be titrated to 2.0–3.0 in the
absence of risk factors
and 3.0 and 4.0 in patients with risk factors. (1),(2)
Treatment
Recommendations for anticoagulation
previous arterial thrombosis, including ischemic stroke,
severe venous or recurrent thrombosis.
1-J. Autoimmun.33,92–98 (2009).
2-J. Thromb. Haemost.3,844–845 (2005).
Cerebrovascular Disease
CVD due to vasculitits is extremely rare, therefore
immunosuppression is not recommended unless
there is an associated lupus flare .
All the modifiable risk factors must be carefully
assessed and managed according to the existing
guidelines .
Treatment
Acute confusional state
Patients should be extensively evaluated for underlying precipitating conditions, especially infections and metabolic disturbances.
CSF examination is recommended to exclude CNS infection
EEG may help diagnose underlying seizure disorder.
Brain imaging is indicated if the patient has focal neurological signs, history of head trauma or malignancy, fever, or when the initial diagnostic work-up has failed to reveal any obvious cause of the ACS.
Brain SPECT is sensitive (93%) and may help monitor response to treatment.
Acute confusional state
Addressing and correcting the underlying causes.
Drug treatment with haloperidol or atypical antipsychotics is used only when other interventions are ineffective in controlling agitation and an underlying cause of ACS has been excluded.
A combination of glucocorticoids with immunosuppressive agents is effective in most patients (response rates up to 70%).
Plasma exchange therapy (synchronised with intravenous cyclophosphamide) and rituximab have been used in refractory cases
Management
1-Ther Apher Dial 2003; 7 : 173 – 82 2-Lupus 2007; 16 : 817 – 22 .
3-J Neurol Neurosurg Psychiatr 1992; 55 : 1157 – 61
Cognitive Dysfunction
Identification and treatment of any associated (e.g., metabolic disturbances, drug abuse or withdrawal) or aggravating (e.g., hypertension or dyslipidemia anxiety and depression) causes of impairment.
Corticosteroid use must be considered only in patients with high disease activity . There has been only one double-blind, paired, placebo-controlled study published . Treatment with 0.5 mg/kg/day prednisone for 21 days, followed by steroid tapering, has been reported to improve cognition in five out of eight patients (n=8 patients)
Management
Arthritis Rheum.37,1311–1320 (1994).
Cognitive Dysfunction
Antiplatelet and anticoagulation therapy :
Might be helpful in patients with persistent positively for aPL and progressive cognitive impairment mostly in the presence of MRI abnormalities and other vascular risk factors. (1), (2)
The result of a prospective study suggests that regular use of asprin may help prevent a decline in cognitive function, particularly in older patients (2)
Symptomatic treatment and Cognitive rehabilitation is an alternative or complementary therapeutic approach
1-Arthritis Rheum.42,728–734 (1999) 2- Neurology64,297–303 (2005).
Management
Peripheral polyneuropathies
Sensory or sensory motor poly neuropathy
Patients with significant paresthesia and abnormal
Nerve Conduction Study (NCS), are treated
with prednisolon 1mg/kg with gabapentin
100mg TDS or TCA .
If either of these approaches is ineffective or
causes intolerable side effects, we would next
utilize carbamazepine .
Treatment
Peripheral polyneuropathies
Patients with mild symptoms or normal NCS or
both are treated symptomatically with
neuroleptic medications because 67% will not
deteriorate on follow-up .
Acta Neurol Scand 103:386-391,2001
Treatment
Peripheral polyneuropathies
Mononeuritis multiplex
It is typically occurs in the setting of active SLE.
It is belived to be a vasculitic of vasa nervorum.
Use prednisolon 1to 2mg/kg or pulse
methylprednisolone with cyclophosphamid (either
oral daily or monthly pulse) with or without plasma
exchange for a six months period.
IVIg or rituximab are others alternative.
Lupus 1996, 5:74
Treatment
Peripheral polyneuropathies
Acute polyradiculoneuropathy (Guillain-Barre like)
Such patients respond to glucocorticoids with in
weeks if there has been no neuronal damage .
but in some cases the addition of IVIg or
plasmapheresis might be necessary .
Am J Emerg 2009 sep ,27(7);900
Rev Neurol 2003 Mar;159(3:)300-6
Peripheral polyneuropathies
Chronic demyelinating polyradiculopathy like chronic
inflammatory demyelinating polyneuropathy(CIPD)
Therapy with glucocorticoids and intravenous gamma globulin
or plasmapheresis may be indicated .If there is evidence of
axonal damage on electrodiagnostic studies or vasculitis on
nerve biopsy, then more potent immunosuppressive therapy
is indicated(cyclophosphamide).
Lupus 2012 Sep;21(10:)1119-23
Cranial Neuropathies
R/O other neurological conditions,
such as brainstem stroke
and meningitis,
Funduscopy
Fluoroangiography
Contrast-enhanced MRI
Optic neuropathy
Cranial Neuropathies
Pulse intravenous methylprednisolone in combination
with intravenous cyclophosphamide is recommended
Anticoagulation may be considered in antiphospholipid-
positive patients not responding to immunosuppressive
therapy.
SLE-related optic neuritis is associated with poor visual
outcome and only 30% of patients maintain a visual
acuity greater than 20/25
Ann Rheum Dis 2005; 64 : 620 – 5 .
Optic neuropathy
Cranial Neuropathies
0.9
0.1
0.5
0 5 10 15 20
Received cyclophosphamide
Received IV methylprednisolone
Hospitalised for hypotension, pneumonit
Month
Visual
acuity
Prednisolon
Daily
dose
British Journal of Ophthalmology 1997
60
10
Meningitis (Aseptic)
CSF analysis :
WBC > 1000 microL , glucose <20 mg/dl ,
pr>250 mg/dl and positive Gram stain
Treatment
Antibiotics should be initiated promptly
Empiric : Vancomycin +Ampicillin + Cefepime or Meropenem
Septic meningitis
Meningitis (Aseptic)
CSF analysis :
Cell count <500/microL, >50 percent CSF
lymphocytes, protein <80 to 100 mg/dl
normal glucose, and negative Gram stain.
Treatment
R/O other etiology for aseptic meningitis
especially viral etiology
Aseptic meningitis
CSF analysis :
Cell count <500/microL, >50 percent CSF
lymphocytes, protein <80 to 100 mg/dl
normal glucose, and negative Gram stain.
Treatment
R/O other etiology for aseptic meningitis
especially viral etiology
High dose Glucocorticoid
Movement disorders
Most patients (55–65%) experience a single episode
of chorea that subsides within days to a few
months.
Symptomatic therapy with dopamine antagonists is
usually effective.
Glucocorticoids in combination with
immunosuppressive agents may be used to control
NPSLE disease activity.1- Ann Rheum Dis 2010, 69:2074 2- Stroke 2000, 31:3079
Chorea
Movement disorders
Chorea
Antiplatelet and/ or anticoagulation therapy is
administered in antiphospholipidpositive patients,
especially when other antiphospholipid/
APSrelated manifestations are present
1- Medicine (Baltimore) 1997; 76 : 203 – 12
2-Neurology 2007; 69 : 644 – 54
3- J Rheumatol 2008; 35 : 2165 – 70
Thank you
Demyelinating Syndrome
Reports of therapy in SLE-related demyelinating syndromes are anecdotal.
In patients with active brain MRI lesions and progressive and relapsing syndromes:
Methylprednisolone (500–1000 mg daily for 3 days), cyclophosphamide pulses (500 mg every 2 weeks for 3 months or 750 mg/m2 body surface monthly for 3–6 months) and plasma exchange, if available, followed by oral prednisone and immunosuppressants as steroid-sparing agents
Recommended