Presentation on theme: "Kathryn Hazel C. Trinidad M.D. First Year Medical Resident"— Presentation transcript:
1Kathryn Hazel C. Trinidad M.D. First Year Medical Resident Medical grandroundsKathryn Hazel C. Trinidad M.D.First Year Medical Resident
2ObjectivesTo be able to present a known case of SLE who developed seizure during the course of illnessTo be able to know the diagnosis, treatment, and prognosis of NPSLETo be able to know the latest updates with regards to NPSLE
3The case H.M 35 year old G3P2 (1112) female right-handed known case of SLE maintained on Prednisone 20mg 2x/dayknown case of APAS, maintained on ASA 80mg ODhousewife
5Interval HistoryMay 2002 experienced on-off fever (Tmax 40C), malar rash, joint pains, vomiting, photosensitivity, and oral ulcers. diagnosed with SLE; started on Prednisone 5mg OD; regular OPD follow-upcNov 2007 (+) miscarriage; OPD follow-up for clearance prior to dilatation and curettage
6Interval HistoryFeb 2008 diagnosed with APAS based on history and lab results:TestResultsN.V.Kaolin Clotting Time79 sec50 – 90 secAPTT32 sec25 – 40 secDRVVT37 sec31 – 44 secACA IgG18.8 GPL units/mLup to 15.0 GPL units/mLACA IgM11.72 MPL units/mLup to 12.5MPL units/mLcShe was started on ASA 80mg OD
7Monthly prenatal check-up with both Rheumatology and OB-GYN services Interval History9 months PTA(July 2008) 1st prenatal check-up at 7wks AOG. No rashes, joint pains, and oral ulcers; Started on Heparin 5,000 IU SQ OD Prednisone 5mg OD and ASA 80mg OD continued.cMonthly prenatal check-up with both Rheumatology and OB-GYN services
8Interval History2 months PTA(March 2009) gave birth to a live preterm male via LTCS; Discharged with ASA 80mg OD and Heparin 5,000 IU/mL; Prednisone was not resumedc
9History of present illness 11days PTA, OPD ff up with(+)occasional upper back pain, grade I bipedal edema, raised macules on both face and upper extremities.Prednisone 5mg OD was resumed. CBC, urinalysis and ESR were requested.
10History of Present Illness 4 days PTA (+) diffuse headache & joint pains; (+) fever; inc. rashes in face & extremities; consult done Prednisone inc. to 20mg BID; Advised ff up of lab requests3 days PTA pancytopenia: (Hgb-9.5 hct-30.1 wbc-2,640 plt-120,000) and proteinuria(+4) hematuria(1171/hpf), pyuria(335/hpf) bacteriuria(404); ESR was elevated at 111. Ciprofloxacin 500mg BIDc
11History of Present Illness 7 hrs PTA severe headache (10/10)slightly relieved by Paracetamol. (-) vomiting nor blurring of vision30 mins PTA tonic-clonic seizure ~ 30 minutescMMC ER Admission
12Past Medical History Non-hypertensive Non-diabetic s/p CS (2001) s/p dilation and curettage November 2007No history of travel outside of Metro Manila.
13Family History:No hypertensionNo diabetesNo connective tissue disease.Personal and Social History:Non-smokerNon-alcoholic beverage drinkerWorked as a bank teller prior to being diagnosed with SLECurrently stays at home and takes care of her children; can do light household chores
14Physical Exam Gen. Survey: Drowsy, not in cardio-respiratory distress Vital signs: BP = 200/100 170/ HR RR Temp 36.7CSkin: raised macules on the face and both upper extremitiesHEENT: Anicteric sclerae, pink palpebral conjunctivae, (+) subconjunctival effusion, no tonsillopharyngeal discharge, no cervical lymphadenopathyChest: Symmetrical chest expansion, no retractions, clear breath sounds
15Physical ExaminationHeart: Adynamic precordium, distinct S1 and S2, normal rate and rhythm, no murmursAbdomen: Flabby abdomen, soft, non-tender, normoactive bowel soundsExtremities: Full and equal pulses, no cyanosis and no edema
16Neurological ExamMSE: Drowsy, opens eyes to verbal stimulation but non-sustained, does not follow commandsCranial Nerves: Pupils 3mm EBRTL; Full EOMS; (+) visual threat on all planes; (-) facial asymmetry; (+) gagSensory: Withdraws to pain in all extremitiesMMT: Moves all extremities non-purposelyReflexes: +2 in all reflexesPathologic Reflexes: No BabinskiMeninges: Supple neck
17Salient Features 35 year old G3P2 (1112) female known case of SLE on Oral steroidsSteroids on hold for 1 month; resumed ~ 1 week prior to onset of symptomsknown case of APAS, maintained on ASA 80mg ODCame in for tonic-clonic seizureHistory of fever, headache, rashes, and joint pains few days prior to seizure
18Salient FeaturesProteinuria, pyuria on urinalysis sample done few days PTAOn PE:Drowsy, does not follow commands, opens eyes to verbal stimulation (GCS ~ 9 – 10)Elevated BP upon admissionRaised macules on the face and both upper extremitiesWithdraws to pain on stimulationMoves extremities non-purposelyIntact reflexesSupple neck
21UPON admissionCBC, Urinalysis, C3, 24hour urine, ESR, antiSmith, antidsDNAComplete Blood Count revealed improvement in pancytopeniaHydrocortisone 100mg IV q8Referral to neurology serviceNGT feeding started
22UPON admission…. 3 episodes of seizures at ER – Midazolam 5mg IV Loading dose Phenytoin 300mg IV x 2 doses 1 hour apartPhenytoin 100mg IV q8 Citicholine 1g IV q12 Mannitol 20% 75ml IV q6
23Upon admissionUrinalysisCo- amoxiclav 1.2 g IV every 8 hours
24Upon admission Lumbar tap done CT Scan revealed normal EEG Methylprednisolone 1 g IV in D5W 500mL x 4hours for 3 days
25Upon admission… BP 180-200/100 Cardiology referral Nicardipine drip startedECG, CXR, 2Decho were normal
262nd hospital day (-)seizures (-)headachestill drowsy but opens eyes to verbal stimuli, moves all extremities spontaneouslyBP was /100mmHgPhenytoin was shifted to Leviteracetam(Keppra) 500mg ½ tablet BIDNicardipine overlapped w/ Amlodipine 5mg OD
273rd hospital day (-) seizures/headache Awake, conversant Mannitol was tapered down to 50mL Q8 then later D/CLast dose Methylprednisolone pulse therapyHydrocortisone 100mg IV q8
283rd hospital day24 hr urine collection proteinuria with a creatinine clearance of 83.5mL/min.Serum complement C3, anti-SM and anti-dsDNA were requested which showed low C3 levels and positive anti-SM and anti-dsDNAUrine culture – no growthNephrology referralImidapril 5mg ODUTZ guided kidney biopsy contemplated
294th hospital day (-) seizures/headache Awake, conscious, coherent Tolerated soft diet, NGT removedPlaced on full dietHydrocortisone shifted to Prednisone 25mg BID
305th hospital dayCo- Amoxiclav IV was shifted to oral Co- Amoxiclav 625mg BIDASA discontinued anticipating kidney biopsyLeviteracetam continuedNo recurrence of seizures, headache, no fever
316th hospital day No recurrence of seizures, headache, no fever Decrease in raised macules on face and UECBC showed decrease in platelet to 80,000Prednisone increased to 30mg BIDKidney biopsy to be done as outpatient
327th hospital dayPatient cleared for discharge from all servicesNo recurrence of seizures, headache, no fever, significant decrease in malar rash and macules on upper extremities
338th hospital dayPatient discharged improved and stable
36Background Systemic lupus erythematosus (SLE) multisystem autoimmune connective tissue disorder with various clinical presentationsAffects many organ systems, including the central and peripheral nervous systems and muscles.90% of patients are women of childbearing ageIncidence is cases per 100,000 peopleWith full access to medical care, overall survival for SLE is 85% at 5 years and 63% at 15 yearsHarrison’s Principles of Internal Medicine 17th Ed.
37PATHOPHYSIOLOGYSLE is caused by interactions between susceptible genes and environmental factor resulting in abnormal immune responseHyper-reactivity and hypersensitivity of T and B lymphocytesIneffective regulation of antigen availability and ongoing antibody responseHarrison’s Principles of Internal Medicine 17th Ed.
38PATHOPHYSIOLOGYEnd result: sustained production of pathogenic auto-antibodies and formation of immune complexes that bind target tissues, resulting in:Sequestration and destruction of Ig-coated circulating cellsFixation and cleaving of complement proteinsRelease of chemotaxins, vasoactive peptides, and destructive enzymes into tissues
39ARA Criteria for diagnosis: Malar rashFixed erythema, flat or raised, over malar eminenceDiscoid rashErythematous circular raised patches with adherent keratotic scaling and follicular plugging; atropic scarring may occurPhotosensitivityExposure to UV light causes rashesOral ulcersOral or nasopharyngealArthritisNonerosive, involving 2 or more jointsSerositisPleuritis: + pleuritic pain or rub, OR pleural effusion, OR pericardial effusionRenal disorderPersistent proteinuria OR cellular castsNeurologic disorderSeizures or psychosisHematologic disorderHemolytic anemia with reticulocytosis OR Leukopenia < 4000 OR lymphopenia < 1,500 OR thrombocytopenia < 100,000ANAPositive; if negative, check for anti-SSA (Ro) antibodiesAnti-dsDNA or anti-smith antibodyPositive; highly specific for SLE4 out of 11 neededover any span oftime of diagnosisHarrison’s Principles of Internal Medicine 17th Ed.
41Historical background Hebra and Kaposi (1875) Noted first neurologic involvement in SLEOver the last 3 decades, appreciation ofClinical significance of antineuronal,antiribosomal P, and antiphospholipidantibodies as well as advances in brainImaging have again altered our concept ofNP-SLEBaum (1904) Related active delirium, aphasia and hemiparesis to probable disseminated LEDaly (1945) conducted 1st modern study of NP-SLELewis (1954) 1st to focus on importance of EEG findings and psychometric testing in patients with NP-SLEJoseph FG, Lammie AG, Scolding NG. CNS lupus: A study of 41 patients. Neurology. 2007
42Classification and Clinical Presentation Incidence of neuropsychiatric manifestations in SLE ranges from 14 – 75%Patients with NP-SLE can present with a myriad of diffuse and/or focal symptoms and signs involving the brain, spinal cord, or peripheral nervous system
43Pathologic Classification of CNS changes observed in SLE VasculopathyHyalinizationPeripheral inflammation w/o infectionEndothelial proliferation w/o infectionThrombosisVasculitisInfarctionMicroinfarctsLarge infarctsHemorrhageSubarachnoidMicrohemorrhagesSubduralIntracerebralInfectionMeningitisPerivascular inflammation with infectionSeptic hemorrhagesFocal cerebritisVasculitis with infectionJoseph FG, Lammie AG, Scolding NG. CNS lupus: A study of 41 patients. Neurology. 2007
44PATHOPHYSIOLOGY OF NERVOUS SYSTEM INVOLVEMENT VasculopathyAuto-antibodiesOthersSchur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus.
451. Vasculopathycharacterized by small to moderate perivascular accumulation of mononuclear cells, without destruction of the blood vessel.May have small infarctsPathogenesis not knownAntiphospholipid antibodies may play a roleAccelerated atherosclerosis may contribute to the risk of stroke in patients with SLESchur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus.Joseph FG, Lammie AG, Scolding NG. CNS lupus: A study of 41 patients. Neurology. 2007
462. Auto-antibodies(+) Antineuronal antibodies found in one report in 45 percent of patients with CNS lupusCognitive dysfunction associated with lymphocytotoxic antibodiesAntiphospholipid antibodies increase the risk of stroke syndromes, recurrent seizures and abnormal findings on MRISchur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus.
47Antiribosomal P protein antibodies associated with lupus psychosis and depression but not with cognitive dysfunction or psychologic distressHigh levels of autoantibodies to a 50 kDa antigen located in the plasma membrane of brain synaptic terminals in 19 of 20 patients with SLE who had CNS involvementAntiribosomal-P autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosisSoledad Matus,1,2,4 Patricia V. Burgos,1,2,4 Marcela Bravo-Zehnder,1,2,4 Regine Kraft,6 Omar H. Porras,5
483. Others Cytokines Neuropeptides Oxidative stress Nitric oxide Interference with neurotransmissionGenetic heterogeneitySchur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus.
49Pathogenic Mechanisms causing Neuropsychiatric Symptoms in SLE PrimaryVascular occlusion/hemorrhageAuto-antibody-mediatedChoroid Plexus dysfunctionCytokine effectsOther mechanismsSecondaryInfectionMedicationsTTPHypertensionUremiaElectrolyte imbalancesFeverThyroid diseaseAtherosclerotic strokesSubdural hematomaCerebral lymphomaReactive depressionSchur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus.
50Diagnostic approach to manifestations of neuropsychiatric lupus Confirm diagnosis of lupus according to ARA criteria Careful history and PE DiagnosticsMonitoring:If patient improves: monitor history and PEIf patient gets worse: PET scan/MRI, LPSchur PH, Khoshbin S. Diagnostic approach to the neuropsychiatric manifestations of systemic lupus erythematosus .
51Diagnostics: Blood tests: Complete blood cell count including platelet count and smearmay demonstrate a hemolytic anemia with reticulocytosis or reductions of neutrophils, lymphocytes, or plateletsCreatinine or creatinine clearanceUrinalysisLiver function testsElectrolytesC3, C4, or CH50Anti-dsDNA antibodiesErythrocyte sedimentation rate or C-reactive proteinAntiphospholipid antibodiesLipid profile, glucoseRamachandran T, Grisola JS. Systemic Lupus Erythematosus.
52Diagnostics: CSF Studies: Cell count Protein Glucose Cultures Gram stain and other special stainsVDRLIgG indexOligoclonal bandsRamachandran T, Grisola JS. Systemic Lupus Erythematosus.
53Diagnostics: Imaging: CT Scan indicated for suspected acute hemorrhage and in patients with contraindications to MRI (intracranial metal, pacemakers, etc.)MRImore sensitive and used to define site and extent of lesions.A negative MRI result does not rule out CNS lupus, and MRI abnormalities may not be diagnostic of NPSLE.Follow-up MRIs may be indicated to document progression, improvement, or significance of lesionsRamachandran T, Grisola JS. Systemic Lupus Erythematosus.
54DiagnosticsPositron emission tomography (PET) and single photon emission computed tomography (SPECT) have also been explored as functional imaging tools in lupus and both appear to be more sensitive in detecting subtle brain changes in NPSLE
55Diagnostics: EEG Psychologic Testing Others: 2D echo Standard EEG indicated in seizures and encephalopathies.Evoked potentials are performed for suspected demyelinating disease.Psychologic TestingOthers: 2D echoRamachandran T, Grisola JS. Systemic Lupus Erythematosus.
56Diagnostic approach for specific signs and symptoms Stroke - CT scan, blood tests for coagulopathy (including lupus anticoagulant), MRI, echocardiogram, carotids ultrasonographySeizures – EEGNeuropathy – EMGPsychosis - MRI, EEG, lumbar punctureCognitive abnormalities - Psychometric testing, MRI, EEG, blood tests for coagulopathy, antibrain antibodyAnxiety or depression - Psychometric testing Meningitis/fever - lumbar punctureSchur PH, Khoshbin S. Diagnostic approach to the neuropsychiatric manifestations of systemic lupus erythematosus .
57TREATMENT:High-dose IV corticosteroid regimens consist of methylprednisolone 1-2 g daily for 3-6 doses, followed by oral prednisone 60 mg daily, then tapering according to clinical recoveryVarious steroid-sparing strategies have evolved for long-term use, including cyclophosphamide mg/kg/d, azathioprine 1-2 mg/kg/d,, permitting gradual reduction or elimination of chronic steroid therapy.Ramachandran T, Grisola JS. Systemic Lupus Erythematosus.
58TREATMENT:Intravenous cyclophosphamide (at an initial dose of 500 mg per square meter of body surface area) is given in the ff:Acute or recent onset of neurologic symptoms such as seizures or organic brain syndromes in the absence of another cause.Evidence of active inflammation in the brain such as increased cells and protein in the cerebrospinal fluid, brain swelling on MRI or CT scan.Failure to respond to a one to two week course of high dose oral corticosteroids (eg, prednisone in a dose of 1 to 2 mg/kg per day) or to pulse methylprednisolone (1000 mg/day for three days). Ramachandran T, Grisola JS. Systemic Lupus Erythematosus.
60IV CYCLOPHOSPHAMIDE VS METHYLPREDNISOLONE Patients and methods:RCT at two tertiary care centres of patients with SLE with severe NP manifestations such as seizures, optic neuritis, peripheral or cranial neuropathy, coma, brainstem disease, or transverse myelitis.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.The primary end point was response to treatment: at least 20% improvement from basal conditions on clinical, laboratory, or specific neurological testing variables.
61RESULTSOf the 32 patients studied, 18/19 receiving Cy and 7/13 receiving MP responded to treatment (p,0.03)CONCLUSIONSCy was significantly more effective than MP.Cy was clearly better in patients with seizures, peripheral neuropathy, optic neuritis, and brainstem disease, while differences were not clear in coma and transverse myelitis
63Efficacy of rituximab (anti-CD20) for refractory SLE involving CNS Study describes the results of treatment of patients with NPSLE who had previously failed to respond to various immunosuppressants.Rituximab anti-CD20 antibodya chimeric antibody that directly targets B cellsa biological preparation that eliminates B cells through a variety of mechanisms such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and apoptosis.has recently been used for the treatment of a variety of SLE disease conditions and good therapeutic response has been reported
64Efficacy of rituximab (anti-CD20) for refractory SLE involving CNS Inclusion Criteria:Presence of a highly active diseaseCNS lesions resistant to conventional treatment. such as intravenous cyclophosphamide pulse treatment (IV-CY), cyclosporine A (CsA), PE and immunoadsorption therapyTreatment Protocol:Patients 1–5 and 10 treated with 375 mg/m2 rituximab once a week for 2 weeksPatient 9 treated with single dose of 375 mg/m2 rituximabPatients 6 and 7 treated with 500 mg rituximab once a week for 4 weeksPatient 8 treated with 1000 mg once biweekly for 4 weeks.
65RESULTSTreatment with rituximab resulted in rapid improvement of central nervous system-related manifestations, particularly acute confusional state.Rituximab also improved cognitive dysfunction, psychosis and seizure, and reduced the SLE Disease Activity Index Score at day 28 in all 10 patients.These effects lasted for >1 year in five patients.Flow cytometric analysis showed that rituximab down regulated CD40 and CD80 on B cells and CD40L, CD69 and inducible costimulator on CD4+ T cells.
67CONCLUSIONRituximab rapidly improved refractory NPSLE, as evident by resolution of various clinical signs and symptoms and improvement of radiographic findings.The down regulation of functional molecules on B and T cells suggests that rituximab modulates the interaction of activated B and T cells through costimulatory molecules.These results warrant further analysis of rituximab as treatment for NPSLE
75IMAGING STUDIESCXRnormalCranial CT ScanNormal non-contrast CT2D EchoNormal LV dimension with normal wall thickness, motion and contractility. Color flow and Doppler study showed trace MR and PR with mild TR. There was also a note of decreased relaxation based on prolonged IVRT.EEGAbnormal EEG due to epileptiform discharges on the right frontocentrotemporal region suggestive of a tenderncy towards localization related seizure, on top of mild diffuse slowing of background activity at 7 – 8 Hz