Canadian Association of Radiologists Journal 68 (2017) 147e153

www.carjonline.org

Neuroradiology / Neuroradiologie

Posterior Reversible Encephalopathy Syndrome: A Review

Jai Shankar, DM, MSc*, Jillian Banfield, PhD
Department of Diagnostic Imaging, QE II Health Sciences Centre, Halifax, Nova Scotia, Canada

Abstract
Radiologists may be the first to suggest the diagnosis of posterior reversible encephalopathy syndrome (PRES). PRES is associated with
many diverse clinical entities, the most common of which are eclampsia, hypertension, and immunosuppressive treatment. Radiologists
should be aware of the spectrum of imaging findings in PRES. When promptly recognized and treated, the symptoms and radiological
abnormalities can be completely reversed. When unrecognized, patients can progress to ischemia, massive infarction, and death. In this
review, we present an overview of the unique signs observed on computed tomography and magnetic resonance images in PRES that can help
in the early diagnosis and treatment that is highly effective in this syndrome.

R
esum
e
Les radiologistes peuvent ^etre les premiers a lancer la piste du diagnostic de syndrome d’enc
ephalopathie post
erieure r
eversible (SEPR).
Le SEPR est associ
e a tout un
eventail d’entit
es cliniques, les plus courantes
etant l’
eclampsie, l’hypertension et la th
erapie immunosup-
pressive. Les radiologistes doivent ^etre au fait de toute la gamme de r
esultats d’imagerie associ
es au SEPR. Lorsqu’ils sont d
etect
es et trait
es
rapidement, les sympt^omes et les anomalies radiologiques peuvent dispara^ıtre completement. S’ils ne sont pas d
etect
es, ils peuvent
evoluer
vers une isch
emie, un infarctus massif et le d
eces du patient. La pr
esente revue fait le survol des signes uniques observ
es sur des images
obtenues par tomodensitom
etrie et r
esonance magn
etique en pr
esence du SEPR et qui peuvent faciliter le diagnostic et le traitement pr
ecoces,
tres efficaces pour ce syndrome.
Ó 2016 Canadian Association of Radiologists. All rights reserved.

Key Words: Eclampsia; Hypertension; Immunosuppression; Posterior reversible encephalopathy syndrome

Patients with acute symptoms of headache, altered mental
functions, seizures, and loss of vision associated with findings
indicating predominantly posterior leukoencephalopathy on
imaging studies are not uncommon. This syndrome was called
reversible posterior leukoencephalopathy in 1996 by Hinchey
et al [1], as it was thought that only white matter is involved in
this syndrome. However, later it was seen that the grey matter
is involved in this syndrome and the term posterior reversible
encephalopathy syndrome (PRES) was coined [2].
The syndrome has myriad imaging findings that are typical
in many cases, but also can be confused with other entities. The
prompt diagnosis of the cause is critical for the immediate
initiation of the appropriate therapy, which varies with the
etiology. PRES is associated with a multitude of diverse
clinical entities, the most common of which are eclampsia,
hypertension, and immunosuppressive treatment [1,3,4].
PRES is infrequently suspected by clinicians, so radiologists
may be the first to suggest the diagnosis. As this diagnosis has
important therapeutic and prognostic implications, radiolo-
gists should be aware of the spectrum of imaging findings in
PRES. When promptly recognized and treated, the symptoms
and radiological abnormalities can be completely reversed.
When unrecognized, patients’ condition can progress to
ischemia, massive infarction, and death. In this review, we
present an overview of the unique signs observed on computed
tomography (CT) and magnetic resonance (MR) images in
PRES that can help in the early diagnosis and treatment that is
highly effective in this syndrome.
Etiopathogenesis of PRES

The diseases and conditions associated with PRES are

* Address for correspondence: Jai Shankar, DM, MSc, Department of
Diagnostic Imaging, QEII Health Sciences Centre, 1796 Summer St, Room listed in Table 1. Most common of these are hypertensive
3305A, Halifax, Nova Scotia B3H 3A7, Canada. encephalopathy, eclampsia, and use of immunosuppressive
E-mail address: shivajai1@gmail.com (J. Shankar). drugs.

0846-5371/$ - see front matter Ó 2016 Canadian Association of Radiologists. All rights reserved.
http://dx.doi.org/10.1016/j.carj.2016.08.005
148 J. Shankar, J. Banfield / Canadian Association of Radiologists Journal 68 (2017) 147e153

The pathogenesis of PRES is not precisely known. Two brain perfusion caused by endothelial dysfunction from
diametrically opposed hypotheses have been proposed. The systemic toxic effects. However, this theory would not
original hypothesis that severe hypertension leads to cerebral explain the pattern of hypertension usually preceding the
autoregulatory vasoconstriction, cerebral ischemia, and sub- development of symptoms of PRES [8].
sequent cytotoxic brain oedema [5e7]. has largely fallen out The current, more popular theory suggests that severe
of favor because of the reversibility of the pathologic hypertension leads to cerebral autoregulatory failure and
changes. Moreover, 15%-20% of patients with PRES are breakthrough vasodilatation with interstitial extravasation of
normotensive or hypotensive [8]. Even among hypertensive fluid and subsequent vasogenic brain oedema and petechial
patients, less than half have a mean arterial pressure above hemorrhage [4,12e14]. These findings resolve rapidly when
the typical upper limit of cerebral blood flow autoregulation blood pressure is lowered [13,15e18].
(
140-150 mm Hg) [9,10]. In some susceptible patients, In pre-eclampsia, the cause of PRES is considered to be
acute hypertension could cause endothelial dysfunction and endothelial activation and injury [19]. However, renal
breakdown of the bloodebrain barrier, even if hypertension decompensation may play a role, especially in eclampsia
is not greater than the typical autoregulation range [11]. associated with puerperium [1]. Altered vascular reactivity
Alternatively, hypertension could result from insufficient from an increased sensitivity to normally circulating pressure
agents, a deficiency of vasodilating prostaglandins, and
Table 1 endothelial cell dysfunction have also been proposed [20,21].
Diseases and conditions associated with posterior reversible encephalopathy
The proposed mechanisms of PRES associated with
syndrome
immunosuppressive therapy, especially for cyclosporine, are
Hypertensive encephalopathy
hypercholesterolemia, hypomagnesaemia, aluminum
Eclampsia overload, and drug levels above the therapeutic range
Pregnancy
[14,22e26]. Other possible mechanisms include direct toxic
Puerperium
Renal failure effects on vascular endothelial cells causing release of
Hemolytic-uremic syndrome endothelin, prostacyclin, and thromboxane A2 [27e29].
Immunosuppressive drugs Nephrotoxicity from cyclosporine may lead to fluid overload,
Cyclosporin A ultimately exacerbating hypertension and the altered blood-
Tacrolimus/FK-506
brain barrier [12]. The mechanism for tacrolimus and inter-
IFN-alpha
Cisplatin feron alpha is likely similar to that of cyclosporine [1].
IVIg Up to 75% of patients present with seizures [30]. How-
Erythropoietin ever, seizures are likely a manifestation, rather than a cause,
Interleukin of PRES [2].
Antiretroviral therapy in HIV
Relative lack of sympathetic supply to the posterior cir-
Granulocytic stimulating factor
Drug withdrawal: clonidine culation is thought to be responsible for dominant involve-
Other rare causes ment of the posterior circulation and therefore inefficient
Collagen vascular disorders autoregulation [3].
SLE The controversy regarding the pathophysiology of vaso-
PAN
genic oedema is due to findings such as PRES in normo-
Behcet’s disease
TTP tensives and less brain oedema in severe hypertensives [19].
Acute porphyria Additionally, hyperperfusion has not been conclusively
Post organ transplantation demonstrated in patients [19].
Post carotid endarterctomy with reperfusion syndrome-unilateral
hemispheric
GBS with autonomic hyperactivity
Endocrine disorders Imaging Features
Acute porphyria
Pheochromocytoma PRES has been described as having focal or confluent
Pheochromocytoma vasogenic oedema with classic posterior parietal and occip-
Primary aldosteronism
ital lobe involvement [31]. Calcarine and paramedian oc-
Thermal injury
Scorpion envenomation cipital lobe is spared. Subcortical white matter is usually
Hypercalcemia involved, but even cortical grey matter can be involved,
Blood transfusion depending upon the severity of the disease.
Stimulant drugs Three distinct imaging patterns of PRES have been
Phenylpropanolamine
described [31]: dominant parietal-occipital pattern
Ephedrine
Pseudoephedrine (Figure 1A); superior frontal sulcus pattern, with more iso-
lated involvement of mid and posterior aspect of superior
GBS ¼ Guillain-Barr
e syndrome; HIV ¼ human immunodeficiency virus;
IFN ¼ interferon; IVIg ¼ intravenous immunoglobulin; PAN ¼ polyarteritis frontal sulcus (Figure 1B), and holohemispheric watershed
nodosa; SLE ¼ systemic lupus erythematosus; TTP ¼ thrombotic throm- pattern, a linear pattern of involvement of frontal, parietal,
bocytopenic purpura. and occipital lobes at the watershed zone between medial
 PRES review / Canadian Association of Radiologists Journal 68 (2017) 147e153 149

Figure 1. The different patterns of involvement in posterior reversible encephalopathy syndrome: (A) dominant parietal-occipital pattern and (B) superior
frontal sulcus pattern. Holohemispheric watershed pattern has a combination of panels A and B.

hemispheric and lateral hemispheric arterial supply (combi-
nation of Figure 1, A and B).
Other atypical distributions are temporal lobes, cerebellar
hemispheres, brainstem, basal ganglia, deep white matter,
and splenium [31]. Knowledge of the variation in patterns is
important for recognizing PRES.
The most important feature is the reversibility of the
imaging findings, which may take days to weeks following
initiation of treatment. If treatment is not promptly initiated,
PRES may progress to infarction or hemorrhage. Brainstem
involvement and intracranial hemorrhage are associated with
poor prognosis [3,4].
CT
CT is less sensitive than MR imaging (MRI) in detecting
the initial findings. Initial CT was normal in up to 22% of
cases in 1 study (Figure 2) [31]. Even in cases when initial

Figure 2. Computed tomography (A) done 5 hours before the magnetic resonance imaging. (B) The computed tomography scan appears normal, whereas the
fluid-attenuated inversion recovery images show extensive parieto-occiptal lobe hyperintensity, as well as some in the frontal and temporal lobes bilaterally.
150 J. Shankar, J. Banfield / Canadian Association of Radiologists Journal 68 (2017) 147e153

Figure 3. (A) The T2-weighted image and (B) fluid-attenuated inversion recovery axial image of the same patient. The hyperintense signal on fluid-attenuated
inversion recovery is not very obvious on T2-weighted images.

CT scan showed the lesion, the subsequent MRI has shown
more lesions [31].
MRI
MRI shows small, focal abnormalities beyond what is
visible on CT [1]. Among the routine MRI sequences, fluid-
attenuated inversion recovery is the most sensitive in
detecting subcortical and cortical lesions in PRES, as
compared with proton density and T2-weighted spin echo
images (Figure 3) [2].
Diffusion-Weighted Images
Diffusion-weighted (DWI) MRI reliably distinguishes
vasogenic oedema in PRES from cytotoxic oedema in the

Figure 4. Three different cases of posterior reversible encephalopathy syndrome showing (A, B) predominately free diffusion with small area of restricted
diffusion, T2 shine-through effect (C, D), and (E, F) predominantly restricted diffusion with peripherally free diffusion. (Arrows) point to the areas of
hyperintensity on diffusion-weighted images.
 PRES review / Canadian Association of Radiologists Journal 68 (2017) 147e153
Figure 5. Reversibility of the lesions. (A, B) Complete reversibility of the lesion in 1 week and (C, D) no reversibility of the lesion even after 4 weeks.
setting of cerebral ischemia [3,32e34]. DWI can be used to
monitor for ischemia as a complication of PRES [3]. On DWI,
the hallmark of PRES lesions is a pattern of vasogenic oedema
(Figure 4, A and B), but it may show T2 shine-through effect or
pattern of ischemia (Figure 4, C and D). Quantitative assess-
ment of apparent diffusion coefficient (ADC) maps may show
subtle involvement with PRES, which may go unnoticed on
conventional MRI [3]. Foci of high signal intensity in the
cortex suggest that either it is undergoing infarction or already
infarcted (Figure 4, A, B, E, and F).
The extent of involvement has prognostic implications
[3], and helps identify patients who need more aggressive
treatment. Patient outcome correlates with the extent of
combined T2 and DWI signal abnormalities [3]. High DWI
signal intensity and low or normal ADC values are associ-
ated with cerebral infarction and may give the earliest
warning of nonreversibility as vasogenic oedema progresses
to cytotoxic oedema (Figure 4, E and F) [3].
The mechanism for progression of severe vasogenic
oedema to cytotoxic oedema is unclear [3,35]. According to
151
Ay et al [32], increased tissue pressure may impair the
microcirculation in areas of massive oedema, eventually
leading to ischemia. DWI can help predict conversion to
infarction and irreversible tissue damage.
Angiography
Both conventional catheter and MR angiograms have been
reported to show focal vasoconstriction, focal vasodilatation,
and string of bead appearance of medium and small arteries
[36]. These findings are reversible on follow up. However,
angiograms may show normal appearance of the vessels and
is important in differentiating PRES from arterial infarcts.
Perfusion Studies
MR perfusion has been reported to show decreased cerebral
blood volume and cerebral blood flow in PRES [37]. This
pattern supports the autoregulatory arterial vasoconstriction
hypothesis. However, no change in permeability has been
152 J. Shankar, J. Banfield / Canadian Association of Radiologists Journal 68 (2017) 147e153
reported [37]. Thus, interstitial oedema in PRES might be
caused by elevation of capillary hydrostatic pressure mediated
by venous constriction [37]. However, MR perfusion and CT
perfusion have shown both increased and decreased perfusion
in PRES [12]. Thus, PRES may be a dynamic process, with
perfusion changing over time [12]. Perfusion findings are not
very helpful in the diagnosis of PRES.
Reversibility
Reversibility of the lesions is the most important feature of
PRES when present (Figure 5). As discussed previously, the
reversibility of the lesions is also associated with good
prognosis of these patients. The imaging features associated
with poor prognosis and thus irreversibility of these lesions
are 1) low ADC values in the lesions, 2) brainstem involve-
ment, and 3) evidence of hemorrhage on initial imaging.
Differential Diagnoses
Differential diagnoses for imaging findings of PRES are
mainly based on the distribution of the lesions. Important
differential diagnoses are basilar top syndrome, venous
infarction, trauma, vasculitis, encephalitis, and demyelinating
disorders. Sparing of the medial occipital lobe and thalamus,
as well as MR angiography findings, rule out the possibility of
basilar top syndrome. Venous infarction can be ruled out by
showing normal venous structures. Trauma can be ruled out
by the clinical history and absence of any other radiological
signs of trauma. Vasculitis is a difficult differential diagnosis
to rule out. The typical pattern of distribution of PRES lesions
can help. However, in atypical distribution of the lesions,
vasculitis continues to be an important differential diagnosis.
In these cases, reversibility of the lesions, if demonstrated, is
important. The predominant involvement of white matter
rules out encephalitis. The involvement of grey matter does
not favor the diagnosis of demyelinating disorders.
Conclusion
The cause of PRES is multifactorial. Because PRES is
reversible and readily treated by controlling blood pressure
and discontinuing the offending immunosuppressive agent or
decreasing the dose, it should be promptly recognized. The
imaging findings are quite typical but can be confused with
other diseases, so radiologists must know the spectrum of
findings on imaging in cases of PRES.
References
[1] Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leu-
koencephalopathy syndrome. N Engl J Med 1996;334:494e500.
[2] Casey SO, Sampaio RC, Michel E, Truwit CL. Posterior reversible
encephalopathy syndrome: Utility of fluid-attenuated inversion recov-
ery MR imaging in the detection of cortical and subcortical lesions.
AJNR Am J Neuroradiol 2000;21:1199e206.
[3] Covarrubias DJ, Luetmer PH, Campeau NG. Posterior reversible
encephalopathy syndrome: Prognostic utility of quantitative
diffusion-weighted MR images. AJNR Am J Neuroradiol 2002;23:
1038e48.
[4] Karia SJ, Rykken JB, McKinney ZJ, Zhang L, McKinney AM. Utility
and significance of gadolinium-based contrast enhancement in poste-
rior reversible encephalopathy syndrome. AJNR Am J Neuroradiol
2016;37:415e22.
[5] Horn EH, Filshie M, Kerslake RW, Jaspan T, Worthington BS,
Rubin PC. Widespread cerebral ischaemia treated with nimodipine in a
patient with eclampsia. BMJ 1990;301:794.
[6] Ito T, Sakai T, Inagawa S, Utsu M, Bun T. MR angiography of
cerebral vasospasm in preeclampsia. AJNR Am J Neuroradiol 1995;
16:1344e6.
[7] Port JD, Beauchamp Jr NJ. Reversible intracerebral pathologic entities
mediated by vascular autoregulatory dysfunction. Radiographics 1998;
18:353e67.
[8] Rabinstein AA, Mandrekar J, Merrell R, Kozak OS, Durosaro O,
Fugate JE. Blood pressure fluctuations in posterior reversible enceph-
alopathy syndrome. J Stroke Cerebrovasc Dis 2012;21:254e8.
[9] Mueller-Mang C, Mang T, Pirker A, Klein K, Prchla C, Prayer D.
Posterior reversible encephalopathy syndrome: Do predisposing risk
factors make a difference in MRI appearance? Neuroradiology 2009;
51:373e83.
[10] Li Y, Gor D, Walicki D, et al. Spectrum and potential pathogenesis of
reversible posterior leukoencephalopathy syndrome. J Stroke Cere-
brovasc Dis 2012;21:873e82.
[11] Hefzy HM, Bartynski WS, Boardman JF, Lacomis D. Hemorrhage in
posterior reversible encephalopathy syndrome: Imaging and clinical
features. AJNR Am J Neuroradiol 2009;30:1371e9.
[12] Rykken JB, McKinney AM. Posterior reversible encephalopathy
syndrome. Semin Ultrasound CT MR 2014;35:118e35.
[13] Dinsdale HB, Robertson DM, Haas RA. Cerebral blood flow in acute
hypertension. Arch Neurol 1974;31:80e7.
[14] Truwit CL, Denaro CP, Lake JR, DeMarco T. MR imaging of reversible
cyclosporin A-induced neurotoxicity. AJNR Am J Neuroradiol 1991;
12:651e9.
[15] Dinsdale H, Robertson D, Chiang T, Mukherjee S. Hypertensive ce-
rebral microinfarction and cerebrovascular reactivity. Eur Neurol 1971;
6:29e33.
[16] Johansson BB. The blood-brain barrier and cerebral blood flow in acute
hypertension. Acta Med Scand Suppl 1983;678:107e12.
[17] Robertson DM, Dinsdale HB, Ayashi T, Tu J. Cerebral
lesions in adrenal regeneration hypertension. Am J Pathol 1970;
59:115e32.
[18] Byrom FB. The pathogenesis of hypertensive encephalopathy and
its relation to the malignant phase of hypertension; Experimental evi-
dence from the hypertensive rat. Lancet 1954;267:201e11.
[19] Bartynski WS. Posterior reversible encephalopathy syndrome, part 2:
Controversies surrounding pathophysiology of vasogenic edema. AJNR
Am J Neuroradiol 2008;29:1043e9.
[20] Donaldson JO. Invited review: The brain in eclampsia. Hypertens
Pregnancy 1994;13:115e33.
[21] Roberts JM, Redman C. Pre-eclampsia: More than pregnancy-induced
hypertension. Lancet 1993;341:1447e51.
[22] Bhatt BD, Meriano FV, Buchwald D. Cyclosporine-associated central
nervous system toxicity. N Engl J Med 1988;318:788e9.
[23] de Groen PC, Aksamit AJ, Rakela J, Forbes GS, Krom RA. Central
nervous system toxicity after liver transplantation. the role of cyclo-
sporine and cholesterol. N Engl J Med 1987;317:861e6.
[24] Hughes RL. Cyclosporine-related central nervous system toxicity in
cardiac transplantation. N Engl J Med 1990;323:420e1.
[25] Humphreys TR, Leyden JJ. Acute reversible central nervous system
toxicity associated with low-dose oral cyclosporine therapy. J Am Acad
Dermatol 1993;29:490e2.
[26] Rubin AM, Kang H. Cerebral blindness and encephalopathy with
cyclosporin A toxicity. Neurology 1987;37:1072e6.
[27] Benigni A, Morigi M, Perico N, et al. The acute effect of FK506 and
cyclosporine on endothelial cell function and renal vascular resistance.
Transplantation 1992;54:775e80.
 PRES review / Canadian Association of Radiologists Journal 68 (2017) 147e153
[28] Bunchman TE, Brookshire CA. Cyclosporine-induced synthesis of
endothelin by cultured human endothelial cells. J Clin Invest 1991;88:
310e4.
[29] Fogo A, Hakim R, Sugiura M, Inagami T, Kon V. Severe endothelial
injury in a renal transplant patient receiving cyclosporine. Trans-
plantation 1990;49:1190e1.
[30] Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syn-
drome: Clinical and radiological manifestations, pathophysiology, and
outstanding questions. Lancet Neurol 2015;14:914e25.
[31] Bartynski WS, Boardman JF. Distinct imaging patterns and lesion
distribution in posterior reversible encephalopathy syndrome. AJNR
Am J Neuroradiol 2007;28:1320e7.
[32] Ay H, Buonanno FS, Schaefer PW, et al. Posterior leukoencephalop-
athy without severe hypertension: utility of diffusion-weighted MRI.
Neurology 1998;51:1369e76.
[33] Schaefer PW, Buonanno FS, Gonzalez RG, Schwamm LH.
Diffusion-weighted imaging discriminates between cytotoxic and
153
vasogenic edema in a patient with eclampsia. Stroke 1997;28:
1082e5.
[34] Schwartz RB, Mulkern RV, Gudbjartsson H, Jolesz F. Diffusion-
weighted MR imaging in hypertensive encephalopathy: clues to path-
ogenesis. AJNR Am J Neuroradiol 1998;19:859e62.
[35] Gao B, Yu BX, Li RS, et al. Cytotoxic edema in posterior
reversible encephalopathy syndrome: Correlation of MRI features
with serum albumin levels. AJNR Am J Neuroradiol 2015;36:
1884e9.
[36] Bartynski WS, Boardman JF. Catheter angiography, MR angiography,
and MR perfusion in posterior reversible encephalopathy syndrome.
AJNR Am J Neuroradiol 2008;29:447e55.
[37] Brubaker LM, Smith JK, Lee YZ, Lin W, Castillo M. Hemo-
dynamic and permeability changes in posterior reversible en-
cephalopathy syndrome measured by dynamic susceptibility
perfusion-weighted MR imaging. AJNR Am J Neuroradiol 2005;
26:825e30.