kathryn hazel c. trinidad m.d. first year medical resident

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

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

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

Seizure

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

Nov 2007 (+) miscarriage; OPD follow-up for clearance prior to dilatation and curettage

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

• Feb 2008 diagnosed with APAS based on history and lab results:

She was started on ASA 80mg OD

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.

Monthly prenatal check-up with both Rheumatology and OB-GYN services

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

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.

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

7 hrs PTA severe headache (10/10)slightly relieved by Paracetamol. (-) vomiting nor blurring of vision

30 mins PTA tonic-clonic seizure ~ 30 minutes

MMC ER Admission

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

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

Gen. Survey: Drowsy, not in cardio-respiratory distress

Vital signs: BP = 200/100 170/100 HR 81 RR 20 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

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

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

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

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

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

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

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

Urinalysis Co- amoxiclav 1.2 g IV every 8 hours

Lumbar tap done

CT Scan revealed normal

EEG

Methylprednisolone 1 g IV in D5W 500mL x 4hours for 3 days

BP 180-200/100 Cardiology referral Nicardipine drip

started

ECG, CXR, 2Decho were normal

(-)seizures (-)headache still drowsy but

opens eyes to verbal stimuli, moves all extremities spontaneously

BP was 140-150/100mmHg

Phenytoin was shifted to Leviteracetam(Keppra) 500mg ½ tablet BID

Nicardipine overlapped w/ Amlodipine 5mg OD

(-) seizures/headache

Awake, conversant Mannitol was tapered

down to 50mL Q8 then later D/C

Last dose Methylprednisolone pulse therapy

Hydrocortisone 100mg IV q8

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

(-) seizures/headache Awake, conscious,

coherent Tolerated soft diet,

NGT removed

Placed on full diet Hydrocortisone

shifted to Prednisone 25mg BID

No recurrence of seizures, headache, no fever

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

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

No recurrence of seizures, headache, no fever, significant decrease in malar rash and macules on upper extremities

Patient cleared for discharge from all services

Patient discharged improved and stable

NPSLE Lupus Nephritis Hypertension, secondary Urinary Tract Infection, resolved APAS

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 12-39 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.

SLE is caused by interactions between susceptible genes and environmental factor resulting in abnormal immune response1. Hyper-reactivity and hypersensitivity of T

and B lymphocytes2. Ineffective regulation of antigen

availability and ongoing antibody response


End result: sustained production of pathogenic auto-antibodies and formation of immune complexes that bind target tissues, resulting in:1. Sequestration and destruction of Ig-coated

circulating cells2. Fixation and cleaving of complement

proteins3. Release of chemotaxins, vasoactive

peptides, and destructive enzymes into tissues

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


Hebra and Kaposi (1875) Noted first neurologic involvement in 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

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

Joseph FG, Lammie AG, Scolding NG. CNS lupus: A study of 41 patients. Neurology. 2007

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

Vasculopathy Hyalinization Peripheral

inflammation w/o infection

Endothelial proliferation w/o infection

Thrombosis Vasculitis

Hemorrhage Subarachnoid Microhemorrhages Subdural Intracerebral

Infarction Microinfarcts Large infarcts Infection

Meningitis Perivascular

inflammation with infection

Septic hemorrhages

Focal cerebritis Vasculitis with

infectionJoseph FG, Lammie AG, Scolding NG. CNS lupus: A study of 41 patients. Neurology. 2007

1. Vasculopathy2. Auto-antibodies3. Others

Schur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus. www.Uptodate.com

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. www.Uptodate.com

Joseph FG, Lammie AG, Scolding NG. CNS lupus: A study of 41 patients. Neurology. 2007

(+) 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


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 apoptosisSoledad Matus,1,2,4 Patricia V. Burgos,1,2,4 Marcela Bravo-Zehnder,1,2,4 Regine Kraft,6 Omar H. Porras,5

Cytokines Neuropeptides Oxidative stress Nitric oxide Interference with neurotransmission Genetic heterogeneity


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


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 . www.Uptodate.com

1. Blood tests:a. Complete blood cell count including

platelet count and smear may demonstrate a hemolytic anemia with

reticulocytosis or reductions of neutrophils, lymphocytes, or platelets

b. Creatinine or creatinine clearancec. Urinalysisd. Liver function testse. Electrolytesf. C3, C4, or CH50g. Anti-dsDNA antibodiesh. Erythrocyte sedimentation rate or

C-reactive proteini. Antiphospholipid antibodiesj. Lipid profile, glucose

Ramachandran T, Grisola JS. Systemic Lupus Erythematosus. www.e-medicine.com

2. CSF Studies:a. Cell countb. Proteinc. Glucosed. Culturese. Gram stain and other special stainsf. VDRLg. IgG indexh. Oligoclonal bands


3. Imaging:a. CT Scan

indicated for suspected acute hemorrhage and in patients with contraindications to MRI (intracranial metal, pacemakers, etc.)

b. 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


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

4. EEG Standard EEG indicated in seizures and

encephalopathies. Evoked potentials are performed for

suspected demyelinating disease.

5. Psychologic Testing

6. Others: 2D echo


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 . www.Uptodate.com

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 0.5-2 mg/kg/d, azathioprine 1-2 mg/kg/d,, permitting gradual reduction or elimination of chronic steroid therapy.


Intravenous cyclophosphamide (at an initial dose of 500 mg per square meter of body surface area) is given in the ff:1. Acute or recent onset of neurologic

symptoms such as seizures or organic brain syndromes in the absence of another cause.

2. Evidence of active inflammation in the brain such as increased cells and protein in the cerebrospinal fluid, brain swelling on MRI or CT scan.

3. 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. www.e-medicine.com

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.

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

RESULTS Of the 32 patients studied, 18/19

receiving Cy and 7/13 receiving MP responded to treatment (p,0.03)

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

Inclusion Criteria:1. Presence of a highly active disease 2. 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.

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.

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

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

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 0.9

RBS 120

CRP Neg

C3 30.3

Anti-SM +

dsDNA +

Albumin 2.3

4/24/09 4/28/09

Color Yellow Yellow

Transparency Hazy Hazy

pH 6.0 6.5

Spec. Grav 1.02 1.02

Sugar Negative Negative

CHON +4 +3

Ketones Negative Negative

Nitrites Negative Negative

Leucocyte Esterase

Negative Negative

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

CSF AnalysisCSF GS/CS No microorganism seen; Pus

cells 0 – 1/OIFAFB No acid fast bacilli seen

VDRL Non-reactive

PhadebactNegative for Streptococcus Group B, Streptococcus pneumoniae, Haemophilus influenzae type B, Neisseria meningitides ABCY W135 and E. coli K1 antigens

CALAS Negative

India Ink Negative

KOH No fungal elements seen

Color Non-xanthochromic

Transparency Clear

RBC 13/uL

WBC Lymphocytes

1/uL1%

Protein Total CHON: 88.8 mg% (NV 15 – 45)

Sugar Glucose 59 mg% (NV 40 – 75)

Urine CS No growth in 48 hours

Urine chemistry

Urine Protein 535.2 mg% = 8563.2 /24 hours (Ref Value: 0 – 149.1mg/24hrs)

Urine Creatinine 90.2 mg% = 1443.2mg /24 hours (Ref Value: 600 – 2500 mgs/24hrs)

Total Volume 1600mL / 24hrs

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

kathryn hazel c. trinidad m.d. first year medical resident

Documents

od slide

days slide

seizure slide

started slide

normal slide

curettage slide

bid slide

edema slide