Treatment of Neuropsychiatric lupus. Dr HAJIALILO

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1 Treatment of Neuropsychiatric lupus Dr HAJIALILO

2 Treatment strategy Treatment Strategy Before NP-SLE Pathogenesis Signs symptoms Diagnosis Treatment

3 Treatment strategy Treatment Strategy Before NP-SLE Pathogenesis Signs symptoms Diagnosis Treatment

4 Treatment strategy Prediction of NPSLE HLA-DRB104 genotype and STAT4 rs were associated with ischemic CVD Mutations in TREX1 On of expression quantitative trait loci (eqtl) was IRF5 cis-snp rs with cognitive dysfunction 1- Ann Rheum Dis 2010; 69: Genes Immun 2011; 12: PLoS Genet 2012; 8:e

5 Treatment strategy Assessment for risk factors for SLE-related events 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) Arthritis Rheum 2001; 45:

6 Treatment strategy Assessment for risk factors for SLE-unrelated events Include: Increasing age, atherosclerotic risk factors (hypertension, diabetes, dyslipidemia), heart ((valvular disease, chronic atrial fibrillation), High cumulative dose of glucocorticoids Arthritis Rheum 2001; 45:

7 Treatment strategy Treatment Strategy Before NP-SLE Pathogenesis Signs symptoms Diagnosis Treatment

8 Treatment strategy Timing of event 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 Arthritis Rheum 2001; 45:

9 Treatment strategy 40 50% of NPSLE are primary and remaining are secondary Exclusion of secondary causes Exclusion of infection, hormonal/metabolic disturbances, vitamin deficiencies, drug effects, and association factors reported in the ACR nomenclature and case definitions for NPSLE 1-Rheumatology (Oxford) 2012; 51: Ann Rheum Dis 2010; 69:

10 Treatment strategy Type of event: Minor versus Major 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 Arthritis Rheum 2001; 45:

11 Treatment strategy Pathogenesis of the underlying process Vasculopathy- Thrombotic Antiphospholipid antibodies Accelerated atherosclerosis Inflammatory/neurotoxic Antineuronal antibodies.antiribosomal-p NMDA)(aspartate receptor -D-methyl-N-Anti Anti-RO Antiphospholipid antibodies

12 Treatment strategy Pathogenesis of the underlying process Can we separate these process definitely? Vasculopathy-Thrombotic Inflammatory/neurotoxic

13 Treatment strategy Pathogenesis of the underlying process Some times it is difficult and impossible Vasculopathy-Thrombotic Inflammatory/neurotoxic

14 Treatment strategy Pathogenesis of the underlying process Vasculopathy- Thrombotic Antiplatelet/anticoagulation Thrombotic CVD, has also been used in antiphospholipid-associated ischaemic optic neuropathy and chorea, as well as in myelopathy refractory to immunosuppressive therapy Inflammatory/neurotoxic Glucocorticoids alone or in combination CTX or AZA Plasmapheresis,Rituximab,IVIg Aseptic meningitis, optic neuritis, transverse myelitis, peripheral neuropathy, refractory seizures, psychosis, acute confusional state; ACS

15 Novel target therapy in LUPUS Innate Immunity Adaptive Immunity

16 Novel target therapy in LUPUS Innate Immunity Targeting IFN pathway Sifalimumab Rontalizumab TNF a signaling Infliximab Adaptive Immunity

17 Novel target therapy in LUPUS Adaptive immunity B cell pathway B cell depletion Inhibition f Bcell activation Plasma cell depltion Induction of B-Cell tolerance T Cell pathway Co-stimulatory blockaed Cytokine blockade Kinase Inhibitor

18 New therapies in SLE Current opinion 2013 Target Drug Study Phase Status AntiCD20 Ocrezulimab Phase 3 RCT,multicenter This study on going but not recuritment participant Anti-CD22 Epratuzumab Phase IIb RCT,multicenter This study has been completed BAFF Inhibitor Belimumab Phase III,belimumab versus placebo in treatment SLE located northeast Asia This study currently recruiting participants IgG 1 k monoclonal antibody that binds to IgG E Omalizumab Phase Ib RCT This study currently recruiting participants Retinobanzoic acid Tamibarotene Phase 2 open label This study currently recruiting participants Antiinerfron a monoclonal antibody Rontalizumab Phase II RCT This study on going but not recuritment participant Antioxidant N-Acetylsystein Phase II RCT This study currently recruiting participants

19 Treatment strategy Treatment Strategy Before NP-SLE Pathogenesis Signs symptoms Diagnosis Treatment

20 Treatment strategy Diagnostic Approach 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, Arthritis Rheum 2001; 45:

21 Treatment strategy Treatment Strategy Before NP-SLE Pathogenesis Signs symptoms Diagnosis Treatment

22 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, (2004).

23 Headache Cases of acute occurrence or modification of an existing chronic headache associated with high-risk factors : 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 must be viewed cautiously, and must be managed and treated accordingly.

24 Headache Headache in SLE often responds to the same interventions as non-sle headache. Migraine headache Acute : Metoclopramide IV(10 mg)or Prochlorperazine IV(10mg) or Dihydroergotamine plus diphenhydramine IV ( mg) Preventation : TCA, Valoproate,Topiromate,Calcium channel blockers type -Tension headache Cluster headache Acute : ASA, NSAIDS(Naproxen,ibuprofen,..) Acetaminophen Triptans, muscle relaxants, Preventation: TCA,Tizanidin, some time anticonvulsant agents Sumatriptan (6mg), Inhaled oxygen, Octerotide,Intra nasal lidocaine,oral Ergotamine

25 Seizure Some points Most seizures in SLE represent single isolated events; recurrent seizures (epilepsy) are less common (12 22%) Isolated seizures are most often associated with active SLE and respond to therapy for SLE. Epilepsy typically is not associated with current active SLE and responds to anticonvulsants

26 Seizure Management Control acute phase like as other patients Be sure to be open airway IV line and taking blood sample Drug for acute attack (diazepam)

27 Seizure Management The diagnostic work-up aims to exclude : Structural brain disease, metabolic disturbances infections, hypoxemia, hypertension, uremia, medication effects,tumor,

28 Seizure Management The diagnostic work-up aims to exclude : Structural brain disease, metabolic disturbances infections, hypoxemia, hypertension, uremia, medication effects,tumor, and Evaluation of disease activity

29 Seizure Management The diagnostic work-up Brain MRI EEG LP (if suspicious to infection) Blood sample(bs,na,ca,,and lab date for lupus activity)

30 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

31 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 Mean number of seizures/ month in (A) MP group; (B) Cy group A B Mean Mean 1 1 Basal 6 th month 12 th month Basal 6 th month 12 th month Ann Rheum Dis 2005;64:

32 Seizure Management 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

33 Seizure Management 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.

34 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:

35 Diagnosis : Myelitis 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

36 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. Gray matter signs have more disability (2) Transverse or longitudinal (more than three sections) myelitis 1-Arthritis& Rheumatism. Vol. 60, No. 11, November 2009, pp Arthritis Rheum Vol. 60, No. 11, November 2009, pp

37 Myelitis Longitudinal Myelitis Transverse Myelitis

38 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 : Lupus 2007; 16 :

39 Anticoagulant : Myelitis 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 Clinical Rheumatology 2011 volume

40 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

41 Rituximab in SLE EXPLORARE LUNAR LESIMAB BIOGAS registry Arthritis Rheum : LUPUS 2012, 21: Autoimmunity REV : Arthritis Rheum 2012,64:

42 Management Psychosis Consult with psychiatric R/O Other etiologies for psychosis

43 Management Psychosis Consult with psychiatric R/O Other etiologies for psychosis (Infections, Neoplasms,..):Neurologic problems Endocrine and metabolic dysfunctions (Thyroid, Parathyroid, or Adrenal abnormalities, Hypoxia, Hypoglycemia,..) Hepatic and Renal disorders Drug( corticosteroid, anti-malaria) Toxin

44 Treatment Psychosis organic involvement by SLE usually responds to steroids. )active(psychosis due to 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 eg, pulse cyclophosphamide) (trial of cytotoxic therapy is warranted followed by maintenance with azathioprine )is recommended 1-Ann Rheum Dis 64, (2005) 2-Rheumatology (Oxford) 47, (2008).

45 Treatment Psychosis 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, (2003) 2- Ann Rheum Dis 66, (2007) 3- J ECT 2013 Sep;29(3):243-6.

46 Cerebrovascular Disease(CVD) Strokes have been reported in up to 19 percent of patients with SLE and a cause of increased mortality and disability. Ischemic stroke TIA Types of CVD Multifocal disease ICH Sinus Thrombosis Vasculitis

47 Cerebrovascular Disease Work up 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 SLEDAI >6 has HR: 2.1 for CVD 1-Nat. Rev. Rheumatol.6, (2010) 2-Rheumatology (Oxford)43, (2004)

48 Cerebrovascular Disease Treatment 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.

49 Criteria for treating acute stroke with tpa Inclusion criteria 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 Exclusion criteria Significant stroke or head trauma in the previous three months Previous intracranial hemorrhageintracranial neoplasm, arteriovenous malformation, or aneurysm, Recent intracranial or intraspinal surgery systolic (Persistent blood pressure elevation 185 mmhg or diastolic 110 mmhg mm/platelet count <100,000 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 Strok 2013, 44 :870

50 Cerebrovascular Disease Treatment 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. What are recommendations?

51 Cerebrovascular Disease Treatment Recommendations for anticoagulation 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 Low dose Asprin 81mg Ann. Rheum. Dis.69, (2010).

52 Cerebrovascular Disease Treatment Recommendations for anticoagulation For the patient with SLE and ischemic stroke and moderate or high levels of apl, Warfarin with INR 2-3 or 3-4? The level of anticoagulation is still debated

53 Cerebrovascular Disease Treatment Recommendations for anticoagulation It has been suggested that the international normalized ratio should be titrated to in the absence of risk factors previous arterial thrombosis, including ischemic stroke, severe venous or recurrent thrombosis. and 3.0 and 4.0 in patients with risk factors. (1),(2) 1-J. Autoimmun.33,92 98 (2009). 2-J. Thromb. Haemost.3, (2005).

54 Cerebrovascular Disease Treatment 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.

55 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.

56 Acute confusional state Management 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 1-Ther Apher Dial 2003; 7 : Lupus 2007; 16 : J Neurol Neurosurg Psychiatr 1992; 55 :

57 Management 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) Arthritis Rheum.37, (1994).

58 Management 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, (1999) 2- Neurology64, (2005).

59 Peripheral polyneuropathies Treatment 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.

60 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: ,2001

61 Peripheral polyneuropathies Treatment 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

62 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); :)3(Rev Neurol 2003 Mar;159

63 Peripheral polyneuropathies Chronic demyelinating polyradiculopathy like chronic inflammatory demyelinating polyneuropathy(cipd) Therapy with glucocorticoids and intravenous gamma globulin If there is evidence of.or plasmapheresis may be indicated axonal damage on electrodiagnostic studies or vasculitis on nerve biopsy, then more potent immunosuppressive therapy is indicated(cyclophosphamide) :)10(Lupus 2012 Sep;21

64 Optic neuropathy Cranial Neuropathies R/O other neurological conditions, such as brainstem stroke and meningitis, Funduscopy Fluoroangiography Contrast-enhanced MRI

65 Optic neuropathy Cranial Neuropathies Pulse intravenous methylprednisolone in combination with intravenous cyclophosphamide is recommended Anticoagulation may be considered in antiphospholipidpositive 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 :

66 Cranial Neuropathies 0.9 Visual acuity Prednisolon Daily dose Received cyclophosphamide Received IV methylprednisolone Hospitalised for hypotension, pneumonit British Journal of Ophthalmology 1997 Month

67 Treatment CSF analysis : Meningitis (Aseptic) WBC > 1000 microl, glucose <20 mg/dl, pr>250 mg/dl and positive Gram stain Septic meningitis Antibiotics should be initiated promptly Empiric : Vancomycin +Ampicillin + Cefepime or Meropenem

68 Treatment CSF analysis : Meningitis (Aseptic) Cell count <500/microL, >50 percent CSF lymphocytes, protein <80 to 100 mg/dl normal glucose, and negative Gram stain. R/O other etiology for aseptic meningitis especially viral etiology

69 Treatment CSF analysis : Aseptic meningitis Cell count <500/microL, >50 percent CSF lymphocytes, protein <80 to 100 mg/dl normal glucose, and negative Gram stain. R/O other etiology for aseptic meningitis especially viral etiology High dose Glucocorticoid

70 Movement disorders Chorea 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: Stroke 2000, 31:3079

71 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 : Neurology 2007; 69 : J Rheumatol 2008; 35 :

72 Thank you

73 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 ( 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 steroidsparing agents