Kathryn Hazel C. Trinidad M.D. First Year Medical Resident
Jan 08, 2016
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
Harrison’s Principles of Internal Medicine 17th Ed.
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
Harrison’s Principles of Internal Medicine 17th Ed.
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
Schur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus. www.Uptodate.com
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
Schur PH, Khoshbin S. Neurologic manifestations of systemic lupus erythematosus. www.Uptodate.com
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. www.Uptodate.com
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
Ramachandran T, Grisola JS. Systemic Lupus Erythematosus. www.e-medicine.com
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
Ramachandran T, Grisola JS. Systemic Lupus Erythematosus. www.e-medicine.com
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
Ramachandran T, Grisola JS. Systemic Lupus Erythematosus. www.e-medicine.com
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.
Ramachandran T, Grisola JS. Systemic Lupus Erythematosus. www.e-medicine.com
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 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