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Posterior Reversible Encephalopathy Syndrome: An Emerging

Disease Manifestation in Systemic Lupus Erythematosus


Claire E. Barber, MD, FRCPC,* Rene Leclerc, MD, FRCPC,

Dafna D. Gladman, MD, FRCPC,*


,
Murray B. Urowitz, MD, FRCPC,*
,
and
Paul R. Fortin, MD, MPH, FRCPC*
,
Objectives: Posterior reversible encephalopathy syndrome (PRES) is a rare feature of systemic
lupus erythematosus (SLE) that can present with seizures, visual disturbance, and/or hypertension.
We describe 7 new cases of PRES in SLE patients that highlight some of the diagnostic and
treatment dilemmas of this condition.
Methods: We obtained informed consent from patients for the review of their cases. A compre-
hensive literature search was done to nd all published cases of PRES in SLE and these were
compared with our cohort.
Results: Including our series, there are 66 cases of PRES in SLE patients published in the English
literature to date. Our series had 2 main distinguishing features when compared with the available
literature: only 43% of our patients presented with seizures compared with 83 to 95% in the
reported literature and over 50% of our cases of PRES occurred in newly diagnosed SLE.
Conclusions: PRES is a more frequent feature of SLE than previously thought and may be 1 of the
presenting manifestations of SLE. Whether PRES is a manifestation of SLE disease activity and of
its treatment or whether it represents a neuropsychiatric manifestation of SLE remain to be
determined. Consequently there continues to be controversy as to whether immunosuppression
should be used in addition to supportive measures in the treatment of PRES in SLE.
2011 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:353-363
Keywords: posterior reversible encephalopathy syndrome, reversible posterior leucoencephalopathy syn-
drome, systemic lupus erythematosus, hypertensive encephalopathy
T
he posterior reversible encephalopathy syn-
drome or PRES was described by Hinchey and
coworkers in 1996 (1). PRES is characterized by
unique brain imaging ndings consistent with vasogenic
edema on computed tomography (CT) or magnetic res-
onance imaging (MRI) classically in the occipital and pa-
rietal regions in watershed areas of the brain (2). It is
associated with various clinical features such as hyperten-
sion, seizures, and cognitive changes (as summarized in
Table 1). It has been associated with a variety of clinical
conditions including malignant hypertension, ecclamp-
sia/preeclampsia, and allogeneic bone marrow transplant
(as reviewed by (2)). Two of the 15 patients in the initial
case series had PRES related to systemic lupus erythema-
tosus (SLE). Despite several additional case reports and
series published of PRES in patients with a variety of other
underlying conditions, few additional cases in SLE were
reported. In the last 2 years, 5 larger case series have con-
*Division of Rheumatology, Department of Medicine, University Health Network,
University of Toronto, Toronto, Ontario, Canada.
Division of Internal Medicine, Department of Medicine, Universit Laval, Qubec
City, Qubec, Canada.
Division of Health Care and Outcome Research, Toronto Western Research Insti-
tute, University of Toronto, Toronto, Ontario, Canada.
Dr Rene Leclercs work was supported by Dr Paul R. Fortins Kirkland Scholar
Awards. The Kirkland Scholar Award Program at the Hospital for Special Surgery in
New York City is funded exclusively by Rheuminations Inc, a nonprot foundation
dedicated to supporting research leading to the treatment and cure of lupus. Dr Claire
Barber was a Rheumatology fellow with the University of Toronto and is now an
internist in Quebec City. Dr Paul R. Fortin is a Distinguished Senior Investigator of
The Arthritis Society with additional support from the Arthritis Centre of Excellence,
University of Toronto. This study has also been funded by an operating grant from the
Canadian Institutes of Health Research (QNT 78341).
Address reprint requests to Paul R. Fortin, MD, MPH, FRCPC, University of
Toronto, Division of Rheumatology, Department of Medicine, Toronto Western
Research Institute, 399 Bathurst Street, MP 10-304, Toronto, Ontario, Canada M5T
2S8. E-mail: pfortin@uhnresearch.ca.
SLE
353 0049-0172/11/$-see front matter 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.semarthrit.2011.07.001
tributed to this growing body of literature (3-7). In addi-
tion, a comprehensive review on pathophysiology, radio-
logic presentation, differential diagnosis, and treatment
has been published (8). Treatment of PRES is generally
supportive and aimed at blood pressure lowering (9)
(summarized in Table 2). The treatment of PRES in the
context of SLE is more complex and is further discussed
here. With appropriate treatment, the majority of patients
have neurologic recovery and reversibility of the brain
lesions on imaging (9).
We describe in this new case series 7 lupus patients
diagnosed with PRES who were admitted to our institu-
tions. We have also reviewed the existing literature and
identied 59 additional adult cases and compared themto
our population.
METHODS
We retrospectively reviewed the charts and MRI ndings
of 7 SLE patients admitted in 3 institutions (Toronto
Western Hospital, Toronto General Hospital, and
Mount Sinai Hospital) from August 2007 to January
2010 with a discharge diagnosis of PRES. We reviewed
the English language literature using PubMed database
from 1996 to January 2011 with keywords of posterior
reversible encephalopathy syndrome, reversible poste-
rior leucoencephalopathy syndrome, systemic lupus er-
ythematosus, and lupus. We also included pertinent
articles obtained from searching references in the articles
found in the primary search.
RESULTS
Case Reports
Case 1
A 22-year-old Chinese woman with a 20-month his-
tory of SLE on the basis of hypocomplementemia, rash,
and biopsy-proven lupus nephritis was brought to the
emergency room after having been found screaming by
a neighbor and witnessed to have a tonic-clonic seizure.
She had a history of class IV lupus nephritis treated
with induction intravenous cyclophosphamide and in-
travenous methylprednisolone 18 months previously
followed by maintenance azathioprine. Around that
time she had been diagnosed with a possible episode of
PRES at a peripheral hospital, where she had presented
with headache, visual disturbance, and tonic-clonic sei-
zure; however, she did not have MRI ndings of PRES
at that time. Two months before her current admis-
sion, she had a are of her renal disease and her main-
tenance treatment was switched to mycophenolate
mofetil. Unfortunately she progressed to renal failure
requiring hemodialysis. Medications on presentation
included mycophenolate mofetil 1 g twice a day, pred-
Table 1 Clinical and Radiologic Features of PRES
Clinical Features Neuroimaging
Associated underlying clinical syndromes
Allogeneic BMT
Eclampsia/pre-eclampsia
Connective tissue disease (eg, SLE)
Malignant hypertension
Solid organ transplant
Thrombotic thrombocytopenic purpura
Infection/shock/sepsis
Medications (eg, cyclosporine and others)
Headache
Cortical blindness, visual disturbance, hemianopsia
Altered mental state
Generalized seizures
Hypertension (PRES may also occur in the absence
of hypertension)
Laboratory abnormalities have been reported but
not consistently (see (2,9)).
Typically symmetric vasogenic edema seen in watershed
areas of the brain
Most commonly parietal and occipital regions as well as
frontal regions but other patterns have been described
(2,9)
CT may be minimally abnormal and MRI is more sensitive
Cortical involvement most common and seen on MRI uid
attenuated inversion recovery imaging
Hemorrhage has been described
BMT, bone marrow transplant.
Table 2 Treatment Principles in Patients with PRES
Removal of any inciting medications
Identication and treatment of the underlying disorder
Antihypertensive agents and close monitoring of blood
pressure (usually requires invasive monitoring with
arterial line). Intravenous medications are generally
required and nitroglycerin should be avoided. Goal is
to lower blood pressure to premorbid levels (for a
complete discussion, see (9))
Antiseizure medications (if seizures are present)
Treatment of concomitant electrolyte abnormalities and
coagulopathy. Monitor glucose
Supportive therapy including mechanical ventilation if
required
354 Posterior reversible encephalopathy syndrome
nisone 15 mg 4 times a day, labetalol, amlodipine, and
furosemide. She was intubated for airway protection
because of postictal agitation and admitted to the in-
tensive care unit (ICU). Her initial blood pressure was
175/120 mm Hg and increased to 200/120 mm Hg.
Following intubation, she became briey hypotensive
and required a short course of levophed to maintain her
blood pressure. Her temperature was 38.6C. She had
no focal neurologic ndings on physical examination.
Her blood work showed a creatinine elevation at 275
mol/L and low platelets at 78 bil/L. A lumbar punc-
ture (LP) was done showing 18 white blood cells and 9
red blood cells (consistent with peripheral blood count
on microscopy) and protein 0.77 g/L (normal range
0.15-0.45 g/L). Her anti-dsDNA was 7 (by Farr assay)
and her C3 was 0.62 g/L (normal range 0.9-1.8 g/L),
C4 was 0.19 g/L (normal range 0.1-0.4 g/L). She was
also found to have alveolar hemorrhage and a collapsed
right lung. Her electroencephalogram was negative for
epileptiform activity. A CT scan of the head revealed
bilateral posterior and frontal lobe white-matter hy-
poattenuation. An MRI scan revealed extensive area of
T2 signal alteration involving predominantly the sub-
cortical white matter of the parietal, occipital, and
frontal lobes with subtle areas in keeping with micro-
hemorrhages. Her initial treatment was intravenous
methylprednisolone 100 mg every 8 hours, intravenous
phenytoin, and broad-spectrum empiric antibiotics.
Mycophenolate mofetil was discontinued because of
concerns about meningitis. No specic treatment was
needed to control her blood pressure while intubated.
She was extubated 3 days later and had a prolonged
hospitalization with difcult-to-control hypertension
afterward and multifactorial weakness. She had a
marked improvement on her MRI after 14 days, reveal-
ing ongoing ill-dened areas of subcortical signal
within the white matter of both cerebral hemispheres,
particularly posteriorly. No further imaging was done
as she achieved a complete neurologic recovery. She has
not experienced a recurrence to date in over 3 years of
follow-up.
Case 2
A 44-year-old Chinese woman with past medical his-
tory of hypothyroidism was admitted with pedal
edema, facial pufness, malar rash, photosensitivity,
acute renal failure, and accelerated hypertension. She
had a history of proteinuria for the preceding 4 months
and was awaiting nephrology evaluation. One week
before admission, she was started on valsartan for ele-
vated blood pressure. She presented to the emergency
room with a 24-hour history of nausea, vomiting, and
diarrhea. Her blood pressure was 230/120 mm Hg.
Neurologic examination was normal. She required
temporary hemodialysis for 1 week and IV labetalol
with rapid control of her blood pressure. She was found
to have a positive antinuclear antibody (ANA) at a titer
of 1:640 with a homogeneous pattern, C3 0.50 g/L, C4
0.07 g/L, anti-dsDNA 43 (by Farr assay), positive anti-
Ro, and anti-La antibodies, an elevated creatinine of
238 mol/L, and a proteinuria of 2.5 g per day. A head
CT scan was done because she had unexplained confu-
sion and it revealed regions of hypoattenuation with
loss of gray-white matter differentiation involving the
posterior parietal lobes bilaterally and the occipital
lobes, predominantly on the right side. A MRI per-
formed 5 days later revealed residual changes of PRES
with small areas of cortical/subcortical high uid atten-
uated inversion recovery signal in the parietal lobes and
the occipital lobe, with right-sided predominance. A
renal biopsy revealed class IV and V lupus nephritis.
She was diagnosed with SLE on the basis of a positive
ANA, positive serology, and a positive renal biopsy and
treated initially with monthly intravenous cyclophos-
phamide 0.5 g/m
2
for 3 doses and intravenous methyl-
prenisolone 50 mg every 8 hours. She was then given
mycophenolate mofetil and tapering doses of predni-
sone. Her hospital course was complicated by a right
leg deep vein thrombosis, erosive esophagitis and gas-
tritis, and multifactorial weakness. She was discharged
to a rehabilitation center after 5 weeks with a creatinine
of 68 mol/L. She had a protracted recovery to im-
prove her strength but was left with no focal decits
and no further neuroimaging was done. She has not
had a recurrence to date in over 3 years of follow-up.
Case 3
A 26-year-old Indian woman with antiphospholipid
syndrome diagnosed 7 years previously on the basis of a
left leg deep vein thrombosis and persistently positive
anticardiolipin antibody was admitted to the internal
medicine ward for investigation and treatment of a
hemoglobin of 76 g/L and an elevated creatinine at 216
mol/L. On admission, the physical examination was
unremarkable except for peripheral edema. Blood pres-
sure was 124/80 mm Hg. Her blood work revealed
hemolytic anemia with elevated lactate dehydrogenase
(LDH) at 345 U/L (190), low haptoglobin at 0.3
g/L (0.3-2.0), and a positive direct Coombs test. She
had 7 g of protein in a 24-hour urine collection and the
urinary sediment was positive for protein, red blood
cells, white blood cells, and waxy and granular casts.
She was hypocomplementemic (C3 0.2 g/L, C4 0.03
g/L) and had a positive ANA at a titer of 1:320 with
a homogeneous pattern and positive anti-dsDNA anti-
body (titer 1/320). She was diagnosed with lupus on
the basis of a positive ANA, positive serology, renal
involvement, and hemolytic anemia and was initially
treated with intravenous methylprednisolone pulses
500 mg daily for 3 days and then prednisone 20 mg
every 8 hours. Over the next few days, she developed
high blood pressure uctuating from 144 to 191/93 to
C.E. Barber et al. 355
112 mm Hg. She was started on clonidine, amlodipine,
and furosemide. Despite treatment, her blood pressure
elevation persisted. On the sixth day of hospitalization,
she had a tonic-clonic seizure. The blood pressure was
191/107 mm Hg. She was transferred to ICU and tem-
porarily intubated for airway protection. CT scan of
the head revealed nonspecic white matter changes in
the right parietal lobe, but the MRI revealed multiple
regions of cortical/subcortical signal alteration dis-
persed symmetrically involving all lobes including the
cerebellum and the left midbrain, suggestive of PRES.
Her blood pressure was controlled with intravenous
labetalol and then oral antihypertensive medications.
She was started on phenytoin and mycophenolate
mofetil was subsequently added for treatment of her
presumed lupus nephritis. Slow taper of her prednisone
was started. She had a prolonged hospitalization and
difcult-to-control hypertension despite multiple
medications (amlodipine, clonidine, hydralazine, la-
betalol, ramipril), but had no recurrence in 3 years of
follow-up. Repeat brain MRI showed near complete
resolution of previously reported changes at 2 weeks
and she had no lasting neurologic sequelae.
Case 4
A 23-year-old Chinese woman with a 5-year history of
SLE diagnosed on the basis of arthritis, alopecia, malar
rash, cytopenias, positive ANA, positive dsDNA, and low
complements presented to her rheumatologist 2 weeks
before admission with fever, chills, polyarthralgias, myal-
gias, and punctate vasculitic-like lesions on the pulp of her
ngers and toes. At this point, she refused to be admitted
to the hospital for further investigation. Her prednisone
dose was increased from 10 mg to 20 mg once a day. She
had a longstanding history of noncompliance to treat-
ment and was on no steroid-sparing agent for this reason.
She was brought to the emergency room 2 weeks later
with increasing fever and cough over the previous 2 days.
She was found to have a right lower lobe inltrate and low
blood pressure compatible with septic shock in the con-
text of pneumonia. She was intubated, admitted to the
ICU, and treated with broad-spectrum antibiotics as well
as stress-dose intravenous hydrocortisone 100 mg every 8
hours, vasopressors, and recombinant human-activated
protein C. Her sputum culture was positive for Strepto-
coccus pneumoniae. Her hospital course was complicated
by acute tubular necrosis requiring hemoltration, acute
respiratory distress syndrome requiring
oscillator ventilation, coagulopathy, Clostridium difcile
colitis, and difculty weaning from sedation with agita-
tion and increased blood pressure 150 to 204/90 to 122
mm Hg. On physical examination, she was sedated and
intubated but had asymmetrical left-sided clonus and
spasticity. Head CT and MRI were done showing bilat-
eral parasagittal hematomas in the parietal and occipital
lobes greater than 2 cm in diameter with extensive vaso-
genic edema. She was treated with intravenous labetalol
for blood pressure control and continued intravenous
methylprednisolone. A follow-up MRI 1 week later
showed a mild decrease in white-matter edema and stable
hematomas with less amelioration than expected for
PRES. She was successfully extubated and then trans-
ferred to another hospital for the rest of her hospitaliza-
tion but has had no neurologic decit and no relapse after
5 months but was lost to further follow-up.
Case 5
A 34-year-old Vietnamese woman with a 12-year history
of SLE on the basis of rash, arthritis, proliferative glomer-
ulonephritis, and lupus cerebritis was seen 2 months be-
fore her presentation as an outpatient for a are with facial
rash, arthralgias, low complements, and increase in anti-
dsDNA antibody. Her prednisone was increased from 5
to 50 mg with no improvement and her azathioprine was
continued at 125 mg daily. She came to the emergency
room 1 week before admission and was found to have a
blood pressure of 210/100 mm Hg and creatinine of 200
mol/L. She was treated with enalapril 20 mg and then
discharged home on atenolol 25 mg daily with directions
to decrease salt intake and follow-up with her family doc-
tor in 3 to 5 days. She came back 1 week later with wors-
ening headache, blurred vision, lower extremities edema,
nausea, vomiting, and confusion and her blood pressure
was 216/130 mm Hg. Her blood work showed that her
creatinine had risen to 326 mol/L but with a bland
urinary sediment; her C3 was 0.04, C4 0.09, and anti-
dsDNA was elevated at 43 (by Farr assay). CT scan of the
head showed no acute changes but her MRI showed sub-
tle areas of subcortical hyperintensity in the right parietal
lobe compatible with early PRES associated with pete-
chial hemorrhage. She was admitted to the ICU for hy-
pertensive emergency and treated with intravenous la-
betalol. A renal biopsy showed 50% sclerosed glomeruli
and 50% of the remaining glomeruli had crescents com-
patible with class IV glomerulonephritis. She was treated
with intravenous cyclophosphamide 500 mg every 2
weeks for 6 doses and high-dose prednisone and then
switched to mycophenolate mofetil for maintenance. De-
spite treatment, she required regular hemodialysis starting
1 month later. She has had no further recurrence of PRES
to date after 2 years and 9 months of follow-up and she
has no lasting neurologic decits. Interestingly, she previ-
ously was diagnosed with lupus cerebritis in November
1996 when she presented with systolic blood pressure
200 mm Hg, tonic-clonic seizure, and hypodensity ar-
eas in the occipital cortex. In retrospective, this was prob-
ably her rst episode of PRES.
Case 6
A 37-year-old black woman from the Caribbean pre-
sented to a peripheral hospital with a history of nausea,
vomiting and abdominal pain, arthralgias, and facial rash
356 Posterior reversible encephalopathy syndrome
and was found to have acute renal failure (serum creati-
nine of 636 mol/L) 4 protein, and 4 blood on uri-
nalysis and acute pancreatitis with elevated amylase 1133
U/L (normal range 38-128 U/L) and lipase 318 U/L (nor-
mal range 22-51 U/L). She had hemolytic anemia
(Coombs test was positive; LDH was elevated, and she
had an undetectable haptoglobin). She had leucopenia
with white blood cell count of 1.5 bil/L (4-11 bil/L) with
lymphopenia (0.1 bil/L) and anti-dsDNA was positive at
132 (55 positive by ELISA). She had hypocomple-
mentemia (C3 0.29, C4 0.05). ANA was weakly posi-
tive (1:40 speckled-pattern), and she had a high titer an-
ticardiolipin IgM antibody at 70 IgM phospholipid units
(MPL) (normal range 0-10 MPL). Adiagnosis of SLE was
made and she was treated with intravenous methylpred-
nisolone initially 80 mg 3 times a day; then she received
additional solumedrol at a dose of 500 mg intravenously
twice a day for 3 days for worsening pancreatitis presumed
to be lupus-related. She became confused, agitated, and
paranoid and 17 days after her initial presentation she
developed acute blindness. MRI revealed bilateral sym-
metric extensive acute occipital hyperintensities and cyto-
toxic edema with some frontal lobe involvement. A pre-
sumptive diagnosis of lupus vasculitis was made and she
was treated with an additional 1 g intravenous methyl-
prednisolone daily for 3 days and 1 dose of 750 mg of
intravenous cyclophosphamide and transferred to our in-
stitution for evaluation. On arrival she became obtunded
with a Glasgow Coma Score of 3. An urgent CT scan
revealed no acute bleed. Her blood pressure was 167/99
mm Hg. MRI showed ndings in keeping with PRES
with some resolution compared with the previous MRI
images 8 days earlier. Electroencephalogram showed
some periodic epileptiform discharges in the occipital re-
gions bilaterally but no evidence of seizure. She had pro-
found electrolyte abnormalities with hypomagnesemia,
hypophosphatemia, and hypokalemia. A LP was normal.
She was transferred to the ICU with a diagnosis of PRES
for aggressive management of her blood pressure with
intravenous labetalol. Her solumedrol was tapered to 20
mg 3 times a day and the electrolyte imbalances were
corrected. She did not require intubation and her level of
consciousness improved dramatically with blood pressure
lowering. Her vision improved over the ensuing weeks
but did not completely normalize and she has been left
with a residual visual decit. She was found to have ne-
phrotic range proteinuria at 4 g/d with a normal urine
sediment and creatinine and membranous lupus nephritis
was suspected but no renal biopsy was done. Hydroxy-
chloroquine and mycophenolic acid were started to treat
her lupus. She has had no recurrence in over 1 year of
follow-up.
Case 7
A 31-year-old female from the Philippines with a past
history of migraines and on no regular medication pre-
sented with a newonset seizure. Before admission she had
a 3-week history of malaise, dry cough, headache, and
arthralgias in her hands and had been taking nonsteroidal
anti-inammatory drugs. In the emergency department
she was hypertensive 179/120 mm Hg and this increased
to 244/151 mm Hg. She had a further seizure in the
emergency department and became combative and re-
quired intubation. She was thrombocytopenic with plate-
lets of 66 bil/L (normal 150-400 bil/L); hemoglobin was
normal at 120 g/L and she had lymphopenia (0.6 bil/L,
normal 1.5-4.0 bil/L) with normal total white blood cell
count at 9.1 bil/L. There was no evidence of hemolysis
and thrombotic thrombocytopenic purpura was ex-
cluded. CT of her head revealed hypoattenuation within
the occipital lobes bilaterally and MRI conrmed bilateral
occipital vasogenic edema with a small area of cytotoxic
edema in the left occipital cortex in keeping with PRES. A
full infectious workup including LP, blood cultures, and
viral serologies was negative. Autoimmune workup re-
vealed anti-dsDNA by Farr assay of 100 U/mL (nega-
tive 7 U/mL) and by ELISA of 500 IU/mL (positive
180 IU/mL); she was hypocomplementemic (C3 0.22
g/L and C4 0.04 g/L), ANA positive at a titer of 1:640,
and anticardiolipin antibodies negative. She developed
acute renal failure with a peak serum creatinine of 242
mol/L. Urinalysis revealed heme granular casts in keep-
ing with acute tubular necrosis, and her creatinine subse-
quently declined. She was diagnosed with SLE by the
treating physician on the basis of positive ANA, positive
serology, and thrombocytopenia. Although she did not
completely fulll American College of Rheumatology cri-
teria, SLE was the most likely diagnosis and as it was felt
that her PRES was due to active SLE, she was given pulse
steroids with 500 mg solumedrol daily for 3 days and was
then changed to prednisone 20 mg 3 times a day. She was
initially treated with phenytoin but this was discontinued
after an electro-encephalogram demonstrated only peri-
odic lateralized epileptiform discharges with no epileptic
focus. She was extubated 6 days later and was profoundly
weak. Her weakness was attributed to critical illness poly-
neuropathy and myopathy and she recovered gradually.
She had no neurologic decits but required ongoing oral
antihypertensive agents. She was started on azathioprine
100 mg daily and hydroxychloroquine for treatment of
her lupus and has had no recurrence of PRES in 1 year of
follow-up and no further imaging has been done.
Literature Review
We found 59 well-described cases in the English language
literature of PRES syndrome occurring in SLE patients
and we are describing 7 more in this review. Forty-four of
the cases are detailed in Table 3. Baizabal-Carvallo and
coworkers describe the remaining 22 cases in a single co-
hort from Mexico (6).
The largest cohort of SLE patients with PRES has re-
cently been reported from a center in Mexico (6). In this
C.E. Barber et al. 357
Table 3 Summary of Characteristics of 43 SLE Patients with PRES
a,b,c
Author and Year Age/Sex
Time (mo)
from dx Clinical Findings
Highest BP
(mm Hg)
Highest
Creatinine (mol/L)
Cassano 2007 (28) 30/F 0.75 AMF, TC SZ NA CrCl 18
Ishimori 2007 (3) 47/F NA HA, VA, AMF, SZ 200/110 106
Ishimori 2007 (3) 20/F 24 HA, AMF, TC SZ 132/104 35
e
Ishimori 2007 (3) 25/M NA HA, VA 176/105 141
Ishimori 2007 (3) 24/F 72 HA, VA, AMF, TC SZ 169/108 186
Ozgencil 2007 (10) 31/F 1 HA, VA, TC SZ 186/112 tHD
Zar 2007 (25) 20/F NA HA, VA, SZ 190/110 398
Kur 2006 (4) 29/F 72 VA, TC SZ 206/135 136
Kur 2006 (4) 23/F 24 HA, VA, AMF, TC SZ 140/90 119
Kur 2006 (4) 23/F 36 HA, VA, AMF, TC SZ 194/126 227
Magnano 2006 (5) 24/F 108 HA, VA, TC SZ 210/100 460
Magnano 2006 (5) 32/F 12 HA, TC SZ 156/94 159
Magnano 2006 (5) 37/M 1 HA, VA, TC SZ 175/97 327
Magnano 2006 (5) 30/F 120 HA, VA, TC SZ 158/110 tHD
Magnano 2006 (5) 40/F 132 HA, TC SZ 180/100 265
Mitsushita 2006 (23) 32/F 15 VA, TC SZ 190/120 CrCl 22
Min 2006 (27) 22/F 24 HA, VA, AMF, TC SZ 200/110 tHD
Pasupuleti 2005 (12) 19/F NA TC SZ 180/110 cHD
Shin 2005 (24) 24/F 48 HA, TC SZ 130/80 NA
Mavragani 2004 (26) 38/F 156 HA, VA, SZ 210/120 tHD
Thaipisuttikul 2004 (29) 20/F 96 HA, SZ 220/150 194
Yong 2003 (21) 39/F NA VA, TC SZ 150/90 NA
f
Dy 2002 (30) 31/F 264 AMF 156/103 106
Primavera 2001 (22) 22/F 60 HA, VA, AMF, SZ 200/130 390
Primavera 2001 (22) 22/F 12 HA, VA, AMF, SZ 170/110 tHD
Primavera 2001 (22) 30/F 120 HA, VA, TC SZ 210/125 tHD
Delanty 1997 (31) 28/F NA AMF, SZ 220/130 cHD
Hinchey 1996 (1) 30/F NA HA, VA, AMF 200/110 292
Hinchey 1996 (1) 39/F NA HA, VA, AMF, SZ 200/130 274
Bell 1996 (32) 22/F NA VA, TC SZ NA tHD
Bell 1996 (32) 19/F NA HA, VA, TC SZ NA NA
Leroux 2008 (7) 45/F 26 HA, AMF, SZ, VA 190/100 175
Leroux 2008 (7) 22/F 97 SZ, VA 180/120 270
Leroux 2008 (7) 23/F 27 HA, SZ, CB 220/110 275
Leroux 2008 (7) 39/F 300 HA, CB 210/120 120
Bag 2010 (17) 23/F 108 AMF 141/91 Normal
Chen 2010 (33) 31/F 5 HA, SZ, 190/130 tHD
Barber 1 22/F 20 AMF, TC SZ 200/120 cHD
Barber 2 44/F 0 AMF 230/120 tHD
Barber 3 26/F 0.25 HA, TC SZ 191/107 232
Barber 4 23/F 60 AMF 204/112 tHD
Barber 5 34/F 144 HA, VA, AMF 216/130 488
Barber 6 37/F 0.5 CB, AMF 167/99 636
Barber 7 31/F 0 HA, TCSZ 244/151 242
AHTN, anti-hypertensive; ACV, anticonvulsant; AMF, altered mental function; AZA, azathioprine; BP, blood pressure; CB, cortical blindness;
cHD, chronic hemodialysis; CrCl, creatinine clearance (cc/min); CyA, cyclosporine A; d, days; EPO, erythropoietin; F, female; HA, headache;
HD, high dose; IV CYC, IV cyclophosphamide; IV MP, IV methylprednisolone; LD, low dose; M, male; MMF, mycophenolate mofetil; NA, not
available; 6-MP, mercaptopurine; PE, plasma exchange; PO CYC, oral cyclophosphamide; PP, plasmapheresis; Pred, Prednisone; TC SZ,
tonic-clonic seizure; tHD, transient hemodialysis; VA, visual abnormalities; Vincr, vincristine.
a
For those patients with more than 1 episode, the features from the last episode are listed.
b
Two previously reported cases (1) were excluded because of the insufcient clinical information.
c
Neuroimaging description was removed from the table since our patients do not differ from the recently published review (8).
d
Only partial visual improvement. (32) Those 2 cases were included even if reported before PRES was coined because their clinical
presentation was detailed enough to retrospectively make this diagnosis.
e
Normal creatinine but proteinuria.
f
No mention of the creatinine but renal failure.
358 Posterior reversible encephalopathy syndrome
Table 3 Continued
Steroids at
Diagnosis
Immunosupressor at
Diagnosis Treatment After PRES
Clinical Recovery
(time[d])
Imaging normalization
(time[d])
IVMP No AHTN, ACV, IVMP, IVCYC, PP Yes (10) Yes (20)
HD steroid IVCYC NA Yes (7) Yes (7)
IVMP NA ACV Yes (7) Yes (7)
Yes MMF AHTN Yes (4) Yes (90)
IVMP NA AHTN, IVMP Yes (7) Yes (10)
Yes No AHTN, ACV Yes (10) Yes (10)
IVMP than HC MMF AHTN, tapering steroids Yes (2) Almost (60)
NA CyA D/C CyA, AHTN, ACV Yes (NA) Near complete (21)
Yes No ACV, IVMP, IVCYC Yes (NA) Yes (28)
Yes MMF AHTN, ACV, IVMP, IVCYC, PP Yes (NA) Yes (28)
IVMP MMF AHTN, ACV Yes (1) NA
IVMP IVCYC AHTN Yes (NA) NA
IVMP PO CYC AHTN, ACV Yes (7) Petechial hem (14)
IVMP IVCYC AHTN, pred Yes (2) Yes (35)
HD steroid NA AHTN, ACV Yes (1) Yes (30)
NA CyA AHTN, d/c CycA Yes (NA) NA
IVMP IVCYC ACV, IVMP, PP Yes (4) Near complete (30)
Yes PO CYC AHTN Yes (2) Yes (NA)
HD Pred CyA, vincr ACV, HD Pred, d/c CycA Yes (NA) Yes (30)
NA Rituximab AHTN, ACV, IVMP, IVCYC, PP Yes (1) Yes (45)
Yes No AHTN, ACV Yes (NA) Near complete (14)
NA IVCYC AHTN, MMF Yes (56) NA
PO Pred IVCYC AHTN, pred tapering, IVCYC Yes (NA) NA
IVMP IVCYC AHTN, ACV Yes (4) Yes (NA)
IVMP IVCYC AHTN, ACV Yes (10) Yes (10)
IV corticos NA AHTN, ACV Yes (14) Yes (NA)
NA NA AHTN, ACV, decrease EPO Yes (NA) NA
NA NA AHTN Yes (14) NA
NA NA AHTN Yes (14) NA
IVMP NA ACV, IVMP Yes (6) Near complete (6)
NA NA ACV, IVMP Yes (3) Yes (5)
PO HD Pred MMF AHTN, AC, IV MP, D/C MMF, Yes (15) Near complete (48)
PO HD Pred IVCYC AC, D/C IVCYC, MMF added Yes (7) Normal (15)
PO Pred NA AHTN, AC No
d
Partial (120)
Po Pred NA IV MP, IVIG, PE Yes (3) Yes (49)
Po Pred 6-MP IVMP, IVCYC Yes (6) Yes (56)
Po HD Pred IVCYC then AZA (recent) AHTN, ACV, IVMP No No (patient died)
PO HD Pred MMF ACV, IVMP Yes (2) Marked amelioration
(14)
No No AHTN, IVMP, IVCYC Yes (1) Marked amelioration
(5)
IVMP No AHTN, ACV Yes (1) Near complete (14)
PO Pred LD No AHTN, IVMP Yes (8) No, mild amelioration
(7)
PO Pred LD AZA AHTN, HD pred, IVCYC Yes (2) NA
IVMP No AHTN, IVMP, IVCYCx1, MMF No
d
NA
No No AHTN, IVMP, AZA Yes (prolonged) NA
C.E. Barber et al. 359
cohort 22 cases of PRES were identied in 21 patients.
Twenty cases were in women (95.2%); mean age of onset
was 24.9 8.6 years, and patients had a high disease
activity as measured by the SLE disease activity index
ranging from12 to 39. Three patients were on cyclophos-
phamide at the time of PRES and the majority (82%)
were hypertensive. Antiphospholipid antibody syndrome
was identied in 8 patients (6).
Some interesting comparisons between our cases and
the other reported series can be made and are summarized
in Table 4. Our patients were similar in respect to gender,
age, presence of renal failure, or hypertension at time of
diagnosis of PRES and type of MRI changes when com-
pared with previous series. The majority of our cases (6/7)
were of Asian ethnicity. In our cohort we note a number
of distinguishing features: rst, at the time of presentation
less than 50% presented with seizures (3/7, 42.9%) com-
pared with 31/37, 84%, in the summarized case reports
(Table 4), and 95.5%in the Mexican cohort (6). None of
our patients were treated with cyclophosphamide before
presentation with PRES compared with 44.8% in the
other 59 reported cases and 13.6%in the Mexican cohort.
However 1 patient in our series was initially treated for
her symptoms with cyclophosphamide, which was associ-
ated with clinical worsening (case 6). Last, in our institu-
tion PRES was often part of the acute presentation of a
patient with newly diagnosed SLE (4/7 of ours compared
with 2/31 in the literature).
DISCUSSION
In all 7 of our cases the patients had PRES in the context
of active SLE; 3 had biopsy-proven active lupus nephritis
and 1 a presumptive diagnosis on the basis of proteinuria
but did not undergo renal biopsy. Only 4 cases were on
immunosuppressives at the time of presentation with
PRES and 4 cases occurred in newly diagnosed SLE. Six of
them received immunosuppressive treatment for active
lupus. Case 6 had PRES after high-dose pulse of methyl-
prednisolone and this was tapered after the onset of PRES
with the addition of mycophenolic acid for underlying
active renal disease. All of our patients except case 6 had
complete resolution of neurologic symptoms and decits
with no recurrence. While none of our patients was on
cyclophosphamide at the time PRES developed, 1 (case 6)
was treated for presumed CNS vasculitis and this was
associated with worsening of her PRES; 44.8% in the
other 59 reported cases and 13.6%in the Mexican cohort
(Table 3) did receive treatment with cyclophosphamide
around the time of diagnosis. Other authors have re-
ported similar association between use of cyclophosph-
amide and PRES (6). One explanation for this discrep-
ancy between the literature and our cases could be that the
previously reported association between recent cyclo-
phosphamide treatment and PRES results from the asso-
ciation with active disease, especially lupus nephritis and
its accompanying manifestations of hypertension, renal
failure, and hypoalbuminemia. This association with cy-
clophosphamide would be less apparent in our cases since
they often are recent diagnoses and primarily managed
with immunosuppressive agents other than cyclophosph-
amide. It is unclear why the majority of our patients with
PRES were of Asian ethnicity as our Toronto cohort
counts only 11.6% Asians and the majority in our cohort
are Caucasians. This discrepancy may be because Cauca-
sians have a less severe disease course and PRES may be
associated with severe disease. There could potentially be
other genetic factors and this observation bears further
study.
As previously reported (8,10,11), MRI is the recom-
mended diagnostic modality to diagnose PRES as CT
Table 4 Comparison of Features Between Previously Reported Cases of PRES in SLE and Our Cases
Our Cases
N 7
Summary of
N 37
Baizabal-Carvallo et al (6) N 21,
22 episodes
Mean age (yr) 31.0 28.4 24.9 8.6
Gender 7F:0M 35F:2M 20F:1M
HTN 6/7 25/34 18/22 episodes
Renal disease
a
6/7 33/34 16/21
Seizure 3/7 31/37 21 (95.5%)
No exposure to high dose prednisone
b
or
immunosuppressive
2/7 3/32 ?
Recent exposure to cyclophosphamide 0/7 13/29 3/22
Recent exposure to high-dose prednisone 4/7 20/23 ?
Recent exposure to other
immunosuppressive
c
2/7 22/30 7 (on AZA)
New lupus diagnosis 4/7 2/31 Mean duration of SLE at presentation
61.8 months (53.6)
F, female; M, male.
a
Dened has an abnormal creatinine or proteinuria.
b
HD: high dose dened as Prednisone 1 mg/kg or equivalent or higher.
c
Immunosuppressants other than cyclophosphamide or prednisone.
360 Posterior reversible encephalopathy syndrome
scans may be normal or show nonspecic white-matter
changes. We note that CT was either normal or showed
only mild abnormality in 3 of our cases and similar nd-
ings have been described by other authors (3,5,12). We
feel that a MRI is required to diagnose PRES if it is clin-
ically suspected. Indeed 1 of the reasons PRES may be
underdiagnosed in some centers is the limited availability
of MRI imaging internationally. Typical ndings on MRI
include hemispheric edema that is symmetric with pari-
etal and occipital lobes affected most commonly (Fig. 1),
although variant subtypes affecting other areas of the
brain have been described (2). Additionally hemorrhage
can be a complication of PRES affecting up to 15% of
cases (as reviewed by Bartynski (2)). Our series supports
the ndings from previous reports to the effect that the
changes related to edema on MRI are mostly reversible in
less than 2 weeks, but that ischemic changes (11) and
microhemorrhages (5) take longer to disappear even if the
clinical picture of PRES is completely resolved. It is of
interest to note that most irreversible cases of PRES have
been reported in non-SLE patients (13-16).
A question raised by our case series is related to the
higher prevalence of PRES compared with what we would
extrapolate from previous reports. Indeed, our 7 cases
were observed in our institution over a period of 3 years.
This could reect a referral bias as we are a tertiary care
center for complex rheumatologic diseases. As well, in the
past, this feature may have been diagnosed and treated as
neuropsychiatric lupus and not labeling it as PRES. In
addition, increased access to MRI has allowed for better
characterization and faster diagnosis of this reversible dis-
order. Baizabal-Carvallo and coworkers also noted a high
number of cases as 1.5% of all their SLE cases seen in the
emergency department at their center had PRES (6).
Clinically our cases were similar to previously re-
ported cases in that the majority were hypertensive.
Nevertheless, as demonstrated in case 6, the blood
pressure may be normal or only mildly elevated. This
raises the question of what may be the underlying
mechanism for PRES in the absence of hypertension
and whether this could be related to the underlying
diagnosis of SLE (17). Indeed the pathophysiology of
PRES, although not fully elucidated, is felt to be po-
tentiated by elevated arterial pressure exceeding the
limits of cerebral autoregulation leading to hydrostatic
brain edema or autoregulatory vasoconstriction leading
to ischemia and subsequent brain edema (18). Other
potential pathogenic mechanisms for PRES in the con-
text of SLE may include T-cell activation leading to
inammatory cytokine production, which up-regulates
cell adhesion molecules and increased leukocyte traf-
cking leading to cerebral microcirculatory dysfunc-
tion (18). Indeed all of our cases had evidence of active
disease at the time of presentation with PRES as has
been noted by other authors using validated measures
of disease activity (6). Endothelial dysfunction caused
by an imbalance in vasodilatory and constrictive medi-
ators also likely plays a role in the pathogenesis of PRES
(18). Interestingly, some authors have found a greater
than 50% prevalence of anticardiolipin antibodies in
cases with SLE and PRES (6). As these antibodies may
cause endothelial activation (19), further study into a
pathogenic relationship in PRES is warranted. Indeed,
further study of PRES may yield insight into the patho-
genic mechanism of other CNS manifestations in SLE,
which may also be characterized by endothelial activa-
tion and or disruption of the blood-brain barrier (20).
Figure 1 CT and MRI scans from a 37-year-old woman (case
6) with systemic lupus complicated by posterior reversible
encephalopathy syndrome (PRES). Her CT scan reveals bilat-
eral low-density signals in the occipital lobes extending into
the parietal region with mass effect (A). MRI uid attenuated
inversion recovery reveals extensive hyperintensity bilaterally
extending from the parietal to the occipital lobes (B). The
pattern of posterior cortical/subcortical watershed involve-
ment is classic for PRES.
C.E. Barber et al. 361
The treatment of PRES requires treatment of hyperten-
sion, management of seizures, and general supportive care
(1,3,8,21,22). What remains controversial is whether PRES
is a feature of active SLEor whether it is a complication of its
treatment. Many authors maintain that lowering the immu-
nosuppression is integral to treatment as there is a possible
link between the induction of PRES and a number of med-
ications including cyclophosphamide (8), cyclosporine
(4,23,24), mycophenolate mofetil (3,4,25), and rituximab
(26). One of our cases occurred in the context of high-dose
steroids (case 6). Conversely, other authors maintain that
PRES is a feature of active disease and have treated it with
high doses of cyclophosphamide and intravenous meth-
ylprednisolone (17). In the largest case series to date, all of
the 21 patients (22 episodes of PRES) were treated with
corticosteroids within the rst 3 days after presentation
with prednisone at 1 to 1.5 mg/kg/d and in 15 episodes
pulse methylprednisolone at 1 g/d was employed for 3
days before switching to oral prednisone and 8 patients
received pulse cyclophosphamide (6).
In summary, PRES may be more frequent than previ-
ously thought in lupus. Physicians caring for lupus pa-
tients should be aware of this diagnosis as it is reversible
with appropriate management. As our series highlights,
PRES may be a presenting feature of lupus and may pres-
ent in the absence of seizures, previously reported as a
classic feature. A delay in diagnosis and treatment may
contribute to progressive increase in neurologic symp-
toms and progression to infarction (11,27). Further study
of patients with PRES and lupus may help us understand
the pathogenic mechanisms involved and clarify whether
PRES should be considered 1 of the neuropsychiatric
manifestations of SLE or a consequence of active disease
in other organ systems or its treatment.
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