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Kathryn Hazel C. Trinidad M.D. First Year Medical Resident

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1 Kathryn Hazel C. Trinidad M.D. First Year Medical Resident
Medical grandrounds Kathryn Hazel C. Trinidad M.D. First Year Medical Resident

2 Objectives To be able to present a known case of SLE who developed seizure during the course of illness To be able to know the diagnosis, treatment, and prognosis of NPSLE To be able to know the latest updates with regards to NPSLE

3 The case H.M 35 year old G3P2 (1112) female right-handed
known case of SLE maintained on Prednisone 20mg 2x/day known case of APAS, maintained on ASA 80mg OD housewife

4 Seizure Chief Complaint

5 Interval History May 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-up c Nov 2007  (+) miscarriage; OPD follow-up for clearance prior to dilatation and curettage

6 Interval History Feb 2008  diagnosed with APAS based on history and lab results: Test Results N.V. Kaolin Clotting Time 79 sec 50 – 90 sec APTT 32 sec 25 – 40 sec DRVVT 37 sec 31 – 44 sec ACA IgG 18.8 GPL units/mL up to 15.0 GPL units/mL ACA IgM 11.72 MPL units/mL up to 12.5MPL units/mL c She was started on ASA 80mg OD

7 Monthly prenatal check-up with both Rheumatology and OB-GYN services
Interval History 9 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. c Monthly prenatal check-up with both Rheumatology and OB-GYN services

8 Interval History 2 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 resumed c

9 History 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.

10 History 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 requests 3 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 BID c

11 History of Present Illness
7 hrs PTA  severe headache (10/10)slightly relieved by Paracetamol. (-) vomiting nor blurring of vision 30 mins PTA tonic-clonic seizure ~ 30 minutes c MMC ER  Admission

12 Past Medical History Non-hypertensive Non-diabetic s/p CS (2001)
s/p dilation and curettage November 2007 No history of travel outside of Metro Manila.

13 Family History: No hypertension No diabetes No connective tissue disease. Personal and Social History: Non-smoker Non-alcoholic beverage drinker Worked as a bank teller prior to being diagnosed with SLE Currently stays at home and takes care of her children; can do light household chores

14 Physical Exam Gen. Survey: Drowsy, not in cardio-respiratory distress
Vital signs: BP = 200/100  170/ HR RR Temp 36.7C Skin: raised macules on the face and both upper extremities HEENT: Anicteric sclerae, pink palpebral conjunctivae, (+) subconjunctival effusion, no tonsillopharyngeal discharge, no cervical lymphadenopathy Chest: Symmetrical chest expansion, no retractions, clear breath sounds

15 Physical Examination Heart: Adynamic precordium, distinct S1 and S2, normal rate and rhythm, no murmurs Abdomen: Flabby abdomen, soft, non-tender, normoactive bowel sounds Extremities: Full and equal pulses, no cyanosis and no edema

16 Neurological Exam MSE: Drowsy, opens eyes to verbal stimulation but non-sustained, does not follow commands Cranial Nerves: Pupils 3mm EBRTL; Full EOMS; (+) visual threat on all planes; (-) facial asymmetry; (+) gag Sensory: Withdraws to pain in all extremities MMT: Moves all extremities non-purposely Reflexes: +2 in all reflexes Pathologic Reflexes: No Babinski Meninges: Supple neck

17 Salient Features 35 year old G3P2 (1112) female
known case of SLE on Oral steroids Steroids on hold for 1 month; resumed ~ 1 week prior to onset of symptoms known case of APAS, maintained on ASA 80mg OD Came in for tonic-clonic seizure History of fever, headache, rashes, and joint pains few days prior to seizure

18 Salient Features Proteinuria, pyuria on urinalysis sample done few days PTA On PE: Drowsy, does not follow commands, opens eyes to verbal stimulation (GCS ~ 9 – 10) Elevated BP upon admission Raised macules on the face and both upper extremities Withdraws to pain on stimulation Moves extremities non-purposely Intact reflexes Supple neck

19 Admitting Impression Neuropsychiatric SLE R/O CNS infection
Lupus nephritis Hypertension, secondary UTI APAS

20 Course in the ward

21 UPON admission CBC, Urinalysis, C3, 24hour urine, ESR, antiSmith, antidsDNA Complete Blood Count revealed improvement in pancytopenia Hydrocortisone 100mg IV q8 Referral to neurology service NGT feeding started

22 UPON admission…. 3 episodes of seizures at ER – Midazolam 5mg IV
Loading dose Phenytoin 300mg IV x 2 doses 1 hour apart Phenytoin 100mg IV q8 Citicholine 1g IV q12 Mannitol 20% 75ml IV q6

23 Upon admission Urinalysis Co- amoxiclav 1.2 g IV every 8 hours

24 Upon admission Lumbar tap done CT Scan revealed normal EEG
Methylprednisolone 1 g IV in D5W 500mL x 4hours for 3 days

25 Upon admission… BP 180-200/100 Cardiology referral
Nicardipine drip started ECG, CXR, 2Decho were normal

26 2nd hospital day (-)seizures
(-)headache still drowsy but opens eyes to verbal stimuli, moves all extremities spontaneously BP was /100mmHg Phenytoin was shifted to Leviteracetam(Keppra) 500mg ½ tablet BID Nicardipine overlapped w/ Amlodipine 5mg OD

27 3rd hospital day (-) seizures/headache Awake, conversant
Mannitol was tapered down to 50mL Q8 then later D/C Last dose Methylprednisolone pulse therapy Hydrocortisone 100mg IV q8

28 3rd hospital day 24 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-dsDNA Urine culture – no growth Nephrology referral Imidapril 5mg OD UTZ guided kidney biopsy contemplated

29 4th hospital day (-) seizures/headache Awake, conscious, coherent
Tolerated soft diet, NGT removed Placed on full diet Hydrocortisone shifted to Prednisone 25mg BID

30 5th hospital day Co- Amoxiclav IV was shifted to oral Co- Amoxiclav 625mg BID ASA discontinued anticipating kidney biopsy Leviteracetam continued No recurrence of seizures, headache, no fever

31 6th hospital day No recurrence of seizures, headache, no fever
Decrease in raised macules on face and UE CBC showed decrease in platelet to 80,000 Prednisone increased to 30mg BID Kidney biopsy to be done as outpatient

32 7th hospital day Patient cleared for discharge from all services No recurrence of seizures, headache, no fever, significant decrease in malar rash and macules on upper extremities

33 8th hospital day Patient discharged improved and stable

34 Final Diagnosis NPSLE Lupus Nephritis Hypertension, secondary
Urinary Tract Infection, resolved APAS

35 DISCUSSION

36 Background Systemic lupus erythematosus (SLE)
multisystem autoimmune connective tissue disorder with various clinical presentations Affects many organ systems, including the central and peripheral nervous systems and muscles. 90% of patients are women of childbearing age Incidence is cases per 100,000 people With full access to medical care, overall survival for SLE is 85% at 5 years and 63% at 15 years Harrison’s Principles of Internal Medicine 17th Ed.

37 PATHOPHYSIOLOGY SLE is caused by interactions between susceptible genes and environmental factor resulting in abnormal immune response Hyper-reactivity and hypersensitivity of T and B lymphocytes Ineffective regulation of antigen availability and ongoing antibody response Harrison’s Principles of Internal Medicine 17th Ed.

38 PATHOPHYSIOLOGY End 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 cells Fixation and cleaving of complement proteins Release of chemotaxins, vasoactive peptides, and destructive enzymes into tissues

39 ARA Criteria for diagnosis:
Malar rash Fixed erythema, flat or raised, over malar eminence Discoid rash Erythematous circular raised patches with adherent keratotic scaling and follicular plugging; atropic scarring may occur Photosensitivity Exposure to UV light causes rashes Oral ulcers Oral or nasopharyngeal Arthritis Nonerosive, involving 2 or more joints Serositis Pleuritis: + pleuritic pain or rub, OR pleural effusion, OR pericardial effusion Renal disorder Persistent proteinuria OR cellular casts Neurologic disorder Seizures or psychosis Hematologic disorder Hemolytic anemia with reticulocytosis OR Leukopenia < 4000 OR lymphopenia < 1,500 OR thrombocytopenia < 100,000 ANA Positive; if negative, check for anti-SSA (Ro) antibodies Anti-dsDNA or anti-smith antibody Positive; highly specific for SLE 4 out of 11 needed over any span of time of diagnosis Harrison’s Principles of Internal Medicine 17th Ed.

40 Neuropsychiatric SLE

41 Historical background
Hebra and Kaposi (1875)  Noted first neurologic involvement in SLE Over the last 3 decades, appreciation of Clinical significance of antineuronal, antiribosomal P, and antiphospholipid antibodies as well as advances in brain Imaging have again altered our concept of NP-SLE Baum (1904)  Related active delirium, aphasia and hemiparesis to probable disseminated LE Daly (1945)  conducted 1st modern study of NP-SLE Lewis (1954)  1st to focus on importance of EEG findings and psychometric testing in patients with NP-SLE Joseph FG, Lammie AG, Scolding NG. CNS lupus: A study of 41 patients. Neurology. 2007

42 Classification 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

43 Pathologic Classification of CNS changes observed in SLE
Vasculopathy Hyalinization Peripheral inflammation w/o infection Endothelial proliferation w/o infection Thrombosis Vasculitis Infarction Microinfarcts Large infarcts Hemorrhage Subarachnoid Microhemorrhages Subdural Intracerebral Infection Meningitis Perivascular inflammation with infection Septic hemorrhages Focal cerebritis Vasculitis with infection Joseph FG, Lammie AG, Scolding NG. CNS lupus: A study of 41 patients. Neurology. 2007

44 PATHOPHYSIOLOGY OF NERVOUS SYSTEM INVOLVEMENT
Vasculopathy Auto-antibodies Others Schur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus.

45 1. Vasculopathy characterized by small to moderate perivascular accumulation of mononuclear cells, without destruction of the blood vessel. May have small infarcts Pathogenesis not known Antiphospholipid antibodies may play a role Accelerated atherosclerosis may contribute to the risk of stroke in patients with SLE Schur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus. Joseph FG, Lammie AG, Scolding NG. CNS lupus: A study of 41 patients. Neurology. 2007

46 2. Auto-antibodies (+) Antineuronal antibodies found in one report in 45 percent of patients with CNS lupus Cognitive dysfunction associated with lymphocytotoxic antibodies Antiphospholipid antibodies  increase the risk of stroke syndromes, recurrent seizures and abnormal findings on MRI Schur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus.

47 Antiribosomal P protein antibodies  associated with lupus psychosis and depression but not with cognitive dysfunction or psychologic distress High 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 involvement Antiribosomal-P autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosis Soledad Matus,1,2,4 Patricia V. Burgos,1,2,4 Marcela Bravo-Zehnder,1,2,4 Regine Kraft,6 Omar H. Porras,5

48 3. Others Cytokines Neuropeptides Oxidative stress Nitric oxide
Interference with neurotransmission Genetic heterogeneity Schur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus.

49 Pathogenic Mechanisms causing Neuropsychiatric Symptoms in SLE
Primary Vascular occlusion/hemorrhage Auto-antibody-mediated Choroid Plexus dysfunction Cytokine effects Other mechanisms Secondary Infection Medications TTP Hypertension Uremia Electrolyte imbalances Fever Thyroid disease Atherosclerotic strokes Subdural hematoma Cerebral lymphoma Reactive depression Schur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus.

50 Diagnostic approach to manifestations of neuropsychiatric lupus
Confirm diagnosis of lupus according to ARA criteria Careful history and PE Diagnostics Monitoring: If patient improves: monitor history and PE If patient gets worse: PET scan/MRI, LP Schur PH, Khoshbin S. Diagnostic approach to the neuropsychiatric manifestations of systemic lupus erythematosus .

51 Diagnostics: Blood tests:
Complete blood cell count including platelet count and smear may demonstrate a hemolytic anemia with reticulocytosis or reductions of neutrophils, lymphocytes, or platelets Creatinine or creatinine clearance Urinalysis Liver function tests Electrolytes C3, C4, or CH50 Anti-dsDNA antibodies Erythrocyte sedimentation rate or C-reactive protein Antiphospholipid antibodies Lipid profile, glucose Ramachandran T, Grisola JS. Systemic Lupus Erythematosus.

52 Diagnostics: CSF Studies: Cell count Protein Glucose Cultures
Gram stain and other special stains VDRL IgG index Oligoclonal bands Ramachandran T, Grisola JS. Systemic Lupus Erythematosus.

53 Diagnostics: Imaging: CT Scan
indicated for suspected acute hemorrhage and in patients with contraindications to MRI (intracranial metal, pacemakers, etc.) MRI more 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 lesions Ramachandran T, Grisola JS. Systemic Lupus Erythematosus.

54 Diagnostics Positron 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

55 Diagnostics: EEG Psychologic Testing Others: 2D echo
Standard EEG indicated in seizures and encephalopathies. Evoked potentials are performed for suspected demyelinating disease. Psychologic Testing Others: 2D echo Ramachandran T, Grisola JS. Systemic Lupus Erythematosus.

56 Diagnostic approach for specific signs and symptoms
Stroke - CT scan, blood tests for coagulopathy (including lupus anticoagulant), MRI, echocardiogram, carotids ultrasonography Seizures – EEG Neuropathy – EMG Psychosis - MRI, EEG, lumbar puncture Cognitive abnormalities - Psychometric testing, MRI, EEG, blood tests for coagulopathy, antibrain antibody Anxiety or depression - Psychometric testing Meningitis/fever - lumbar puncture Schur PH, Khoshbin S. Diagnostic approach to the neuropsychiatric manifestations of systemic lupus erythematosus .

57 TREATMENT: 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 recovery Various 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.

58 TREATMENT: 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.

59 CLINICAL UPDATES

60 IV 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.

61 RESULTS Of the 32 patients studied, 18/19 receiving Cy and 7/13 receiving MP responded to treatment (p,0.03) CONCLUSIONS Cy 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

62 CLINICAL UPDATES

63 Efficacy 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 antibody a chimeric antibody that directly targets B cells a 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

64 Efficacy of rituximab (anti-CD20) for refractory SLE involving CNS
Inclusion Criteria: Presence of a highly active disease CNS lesions resistant to conventional treatment. such as intravenous cyclophosphamide pulse treatment (IV-CY), cyclosporine A (CsA), PE and immunoadsorption therapy Treatment Protocol: Patients 1–5 and 10  treated with 375 mg/m2 rituximab once a week for 2 weeks Patient 9  treated with single dose of 375 mg/m2 rituximab Patients 6 and 7  treated with 500 mg rituximab once a week for 4 weeks Patient 8  treated with 1000 mg once biweekly for 4 weeks.

65 RESULTS Treatment 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.

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67 CONCLUSION Rituximab 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

68 THANK YOU

69 Complete Blood Count 4/24/09 4/28/09 5/4/09 Hgb 9.5 11.2 10.1 Hct 30.1
35.9 31.7 WBC 2,640 5,160 7,730 Seg 72 65 75 Lym 19 24 13 Mono 9 11 8 Platelet Count 120,000 140,000 80,000

70 Complete Blood Count 4/24/09 4/28/09 5/4/09 Hgb 9.5 11.2 10.1 Hct 30.1
35.9 31.7 WBC 2,640 5,160 7,730 Seg 72 65 75 Lym 19 24 13 Mono 9 11 8 Platelet Count 120,000 140,000 80,000

71 Blood Chemistries 4/24/09 4/28/09 4/29/09 4/30/09 5/4/09 ESR 111 77 Na
143 140 K 3.4 4.2 BUN 19.99 25.01 Crea 0.9 1.2 RBS 120 CRP Neg C3 30.3 Anti-SM + dsDNA Albumin 2.3

72 Urinalysis 4/24/09 4/28/09 Color Yellow Transparency Hazy pH 6.0 6.5
Spec. Grav 1.02 Sugar Negative CHON +4 +3 Ketones Nitrites Leucocyte Esterase RBC 1,171.50/uL 2,123.00/uL WBC 335.50/uL 236.50/uL Epithelial Cells 16.50/uL 11.0/uL Bacteria 404.06/uL 245.16/uL

73 No microorganism seen; Pus cells 0 – 1/OIF AFB
CSF Analysis CSF GS/CS No microorganism seen; Pus cells 0 – 1/OIF AFB No acid fast bacilli seen VDRL Non-reactive Phadebact Negative for Streptococcus Group B, Streptococcus pneumoniae, Haemophilus influenzae type B, Neisseria meningitides ABCY W135 and E. coli K1 antigens CALAS Negative India Ink KOH No fungal elements seen Color Non-xanthochromic Transparency Clear RBC 13/uL WBC Lymphocytes 1/uL 1% Protein Total CHON: 88.8 mg% (NV 15 – 45) Sugar Glucose 59 mg% (NV 40 – 75) Urine CS No growth in 48 hours

74 535.2 mg% = 8563.2 /24 hours (Ref Value: 0 – 149.1mg/24hrs)
Urine chemistry Urine Protein 535.2 mg% = /24 hours (Ref Value: 0 – 149.1mg/24hrs) Urine Creatinine 90.2 mg% = mg /24 hours (Ref Value: 600 – 2500 mgs/24hrs) Total Volume 1600mL / 24hrs

75 IMAGING STUDIES CXR normal Cranial CT Scan Normal non-contrast CT 2D Echo Normal 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. EEG Abnormal 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

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