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Posterior Reversible Encephalopathy Syndrome: A Review
Canadian Association of Radiologists Journal xx (2016) 1e7 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. Resume Les radiologistes peuvent ^etre les premiers a lancer la piste du diagnostic de syndrome d’encephalopathie posterieure reversible (SEPR). Le SEPR est associe a tout un eventail d’entites cliniques, les plus courantes etant l’eclampsie, l’hypertension et la therapie immunosuppressive. Les radiologistes doivent ^etre au fait de toute la gamme de resultats d’imagerie associes au SEPR. Lorsqu’ils sont detectes et traites rapidement, les sympt^omes et les anomalies radiologiques peuvent dispara^ıtre completement. S’ils ne sont pas detectes, ils peuvent evoluer vers une ischemie, un infarctus massif et le deces du patient. La presente revue fait le survol des signes uniques observes sur des images obtenues par tomodensitometrie et resonance magnetique en presence du SEPR et qui peuvent faciliter le diagnostic et le traitement precoces, 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, * Address for correspondence: Jai Shankar, DM, MSc, Department of Diagnostic Imaging, QEII Health Sciences Centre, 1796 Summer St, Room 3305A, Halifax, Nova Scotia B3H 3A7, Canada. E-mail address: [email protected] (J. Shankar).
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, 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’ 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 listed in Table 1. Most common of these are hypertensive encephalopathy, eclampsia, and use of immunosuppressive 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
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The pathogenesis of PRES is not precisely known. Two diametrically opposed hypotheses have been proposed. The original hypothesis that severe hypertension leads to cerebral autoregulatory vasoconstriction, cerebral ischemia, and subsequent cytotoxic brain oedema [5e7]. has largely fallen out of favor because of the reversibility of the pathologic changes. Moreover, 15%-20% of patients with PRES are normotensive or hypotensive [8]. Even among hypertensive patients, less than half have a mean arterial pressure above the typical upper limit of cerebral blood flow autoregulation (140-150 mm Hg) [9,10]. In some susceptible patients, acute hypertension could cause endothelial dysfunction and breakdown of the bloodebrain barrier, even if hypertension is not greater than the typical autoregulation range [11]. Alternatively, hypertension could result from insufficient Table 1 Diseases and conditions associated with posterior reversible encephalopathy syndrome Hypertensive encephalopathy Eclampsia Pregnancy Puerperium Renal failure Hemolytic-uremic syndrome Immunosuppressive drugs Cyclosporin A Tacrolimus/FK-506 IFN-alpha Cisplatin IVIg Erythropoietin Interleukin Antiretroviral therapy in HIV Granulocytic stimulating factor Drug withdrawal: clonidine Other rare causes Collagen vascular disorders SLE PAN Behcet’s disease TTP Acute porphyria Post organ transplantation Post carotid endarterctomy with reperfusion syndrome-unilateral hemispheric GBS with autonomic hyperactivity Endocrine disorders Acute porphyria Pheochromocytoma Pheochromocytoma Primary aldosteronism Thermal injury Scorpion envenomation Hypercalcemia Blood transfusion Stimulant drugs Phenylpropanolamine Ephedrine Pseudoephedrine GBS ¼ Guillain-Barre syndrome; HIV ¼ human immunodeficiency virus; IFN ¼ interferon; IVIg ¼ intravenous immunoglobulin; PAN ¼ polyarteritis nodosa; SLE ¼ systemic lupus erythematosus; TTP ¼ thrombotic thrombocytopenic purpura.
brain perfusion caused by endothelial dysfunction from systemic toxic effects. However, this theory would not explain the pattern of hypertension usually preceding the development of symptoms of PRES [8]. The current, more popular theory suggests that severe hypertension leads to cerebral autoregulatory failure and breakthrough vasodilatation with interstitial extravasation of fluid and subsequent vasogenic brain oedema and petechial hemorrhage [4,12e14]. These findings resolve rapidly when blood pressure is lowered [13,15e18]. In pre-eclampsia, the cause of PRES is considered to be endothelial activation and injury [19]. However, renal decompensation may play a role, especially in eclampsia associated with puerperium [1]. Altered vascular reactivity from an increased sensitivity to normally circulating pressure agents, a deficiency of vasodilating prostaglandins, and endothelial cell dysfunction have also been proposed [20,21]. The proposed mechanisms of PRES associated with immunosuppressive therapy, especially for cyclosporine, are hypercholesterolemia, hypomagnesaemia, aluminum overload, and drug levels above the therapeutic range [14,22e26]. Other possible mechanisms include direct toxic effects on vascular endothelial cells causing release of endothelin, prostacyclin, and thromboxane A2 [27e29]. Nephrotoxicity from cyclosporine may lead to fluid overload, ultimately exacerbating hypertension and the altered bloodbrain barrier [12]. The mechanism for tacrolimus and interferon alpha is likely similar to that of cyclosporine [1]. Up to 75% of patients present with seizures [30]. However, seizures are likely a manifestation, rather than a cause, of PRES [2]. Relative lack of sympathetic supply to the posterior circulation is thought to be responsible for dominant involvement of the posterior circulation and therefore inefficient autoregulation [3]. The controversy regarding the pathophysiology of vasogenic oedema is due to findings such as PRES in normotensives and less brain oedema in severe hypertensives [19]. Additionally, hyperperfusion has not been conclusively demonstrated in patients [19].
Imaging Features PRES has been described as having focal or confluent vasogenic oedema with classic posterior parietal and occipital lobe involvement [31]. Calcarine and paramedian occipital lobe is spared. Subcortical white matter is usually involved, but even cortical grey matter can be involved, depending upon the severity of the disease. Three distinct imaging patterns of PRES have been described [31]: dominant parietal-occipital pattern (Figure 1A); superior frontal sulcus pattern, with more isolated involvement of mid and posterior aspect of superior frontal sulcus (Figure 1B), and holohemispheric watershed pattern, a linear pattern of involvement of frontal, parietal, and occipital lobes at the watershed zone between medial
PRES review / Canadian Association of Radiologists Journal xx (2016) 1e7
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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 (combination 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.
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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].
detecting subcortical and cortical lesions in PRES, as compared with proton density and T2-weighted spin echo images (Figure 3) [2].
MRI Diffusion-Weighted Images MRI shows small, focal abnormalities beyond what is visible on CT [1]. Among the routine MRI sequences, fluidattenuated inversion recovery is the most sensitive in
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 xx (2016) 1e7
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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 assessment 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 associated 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
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
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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 involvement, 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 leukoencephalopathy 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 recovery 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
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diffusion-weighted MR images. AJNR Am J Neuroradiol 2002;23: 1038e48. Karia SJ, Rykken JB, McKinney ZJ, Zhang L, McKinney AM. Utility and significance of gadolinium-based contrast enhancement in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol 2016;37:415e22. 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. Ito T, Sakai T, Inagawa S, Utsu M, Bun T. MR angiography of cerebral vasospasm in preeclampsia. AJNR Am J Neuroradiol 1995; 16:1344e6. Port JD, Beauchamp Jr NJ. Reversible intracerebral pathologic entities mediated by vascular autoregulatory dysfunction. Radiographics 1998; 18:353e67. Rabinstein AA, Mandrekar J, Merrell R, Kozak OS, Durosaro O, Fugate JE. Blood pressure fluctuations in posterior reversible encephalopathy syndrome. J Stroke Cerebrovasc Dis 2012;21:254e8. 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. Li Y, Gor D, Walicki D, et al. Spectrum and potential pathogenesis of reversible posterior leukoencephalopathy syndrome. J Stroke Cerebrovasc Dis 2012;21:873e82. 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. Rykken JB, McKinney AM. Posterior reversible encephalopathy syndrome. Semin Ultrasound CT MR 2014;35:118e35. Dinsdale HB, Robertson DM, Haas RA. Cerebral blood flow in acute hypertension. Arch Neurol 1974;31:80e7. Truwit CL, Denaro CP, Lake JR, DeMarco T. MR imaging of reversible cyclosporin A-induced neurotoxicity. AJNR Am J Neuroradiol 1991; 12:651e9. Dinsdale H, Robertson D, Chiang T, Mukherjee S. Hypertensive cerebral microinfarction and cerebrovascular reactivity. Eur Neurol 1971; 6:29e33. Johansson BB. The blood-brain barrier and cerebral blood flow in acute hypertension. Acta Med Scand Suppl 1983;678:107e12. Robertson DM, Dinsdale HB, Ayashi T, Tu J. Cerebral lesions in adrenal regeneration hypertension. Am J Pathol 1970; 59:115e32. Byrom FB. The pathogenesis of hypertensive encephalopathy and its relation to the malignant phase of hypertension; Experimental evidence from the hypertensive rat. Lancet 1954;267:201e11. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: Controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol 2008;29:1043e9. Donaldson JO. Invited review: The brain in eclampsia. Hypertens Pregnancy 1994;13:115e33. Roberts JM, Redman C. Pre-eclampsia: More than pregnancy-induced hypertension. Lancet 1993;341:1447e51. Bhatt BD, Meriano FV, Buchwald D. Cyclosporine-associated central nervous system toxicity. N Engl J Med 1988;318:788e9. de Groen PC, Aksamit AJ, Rakela J, Forbes GS, Krom RA. Central nervous system toxicity after liver transplantation. the role of cyclosporine and cholesterol. N Engl J Med 1987;317:861e6. Hughes RL. Cyclosporine-related central nervous system toxicity in cardiac transplantation. N Engl J Med 1990;323:420e1. Humphreys TR, Leyden JJ. Acute reversible central nervous system toxicity associated with low-dose oral cyclosporine therapy. J Am Acad Dermatol 1993;29:490e2. Rubin AM, Kang H. Cerebral blindness and encephalopathy with cyclosporin A toxicity. Neurology 1987;37:1072e6. 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 xx (2016) 1e7 [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. Transplantation 1990;49:1190e1. [30] Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: 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 leukoencephalopathy 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
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vasogenic edema in a patient with eclampsia. Stroke 1997;28: 1082e5. Schwartz RB, Mulkern RV, Gudbjartsson H, Jolesz F. Diffusionweighted MR imaging in hypertensive encephalopathy: clues to pathogenesis. AJNR Am J Neuroradiol 1998;19:859e62. 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. Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol 2008;29:447e55. Brubaker LM, Smith JK, Lee YZ, Lin W, Castillo M. Hemodynamic and permeability changes in posterior reversible encephalopathy syndrome measured by dynamic susceptibility perfusion-weighted MR imaging. AJNR Am J Neuroradiol 2005; 26:825e30.
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. Resume Les radiologistes peuvent ^etre les premiers a lancer la piste du diagnostic de syndrome d’encephalopathie posterieure reversible (SEPR). Le SEPR est associe a tout un eventail d’entites cliniques, les plus courantes etant l’eclampsie, l’hypertension et la therapie immunosuppressive. Les radiologistes doivent ^etre au fait de toute la gamme de resultats d’imagerie associes au SEPR. Lorsqu’ils sont detectes et traites rapidement, les sympt^omes et les anomalies radiologiques peuvent dispara^ıtre completement. S’ils ne sont pas detectes, ils peuvent evoluer vers une ischemie, un infarctus massif et le deces du patient. La presente revue fait le survol des signes uniques observes sur des images obtenues par tomodensitometrie et resonance magnetique en presence du SEPR et qui peuvent faciliter le diagnostic et le traitement precoces, 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, * Address for correspondence: Jai Shankar, DM, MSc, Department of Diagnostic Imaging, QEII Health Sciences Centre, 1796 Summer St, Room 3305A, Halifax, Nova Scotia B3H 3A7, Canada. E-mail address: [email protected] (J. Shankar).
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, 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’ 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 listed in Table 1. Most common of these are hypertensive encephalopathy, eclampsia, and use of immunosuppressive 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
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The pathogenesis of PRES is not precisely known. Two diametrically opposed hypotheses have been proposed. The original hypothesis that severe hypertension leads to cerebral autoregulatory vasoconstriction, cerebral ischemia, and subsequent cytotoxic brain oedema [5e7]. has largely fallen out of favor because of the reversibility of the pathologic changes. Moreover, 15%-20% of patients with PRES are normotensive or hypotensive [8]. Even among hypertensive patients, less than half have a mean arterial pressure above the typical upper limit of cerebral blood flow autoregulation (140-150 mm Hg) [9,10]. In some susceptible patients, acute hypertension could cause endothelial dysfunction and breakdown of the bloodebrain barrier, even if hypertension is not greater than the typical autoregulation range [11]. Alternatively, hypertension could result from insufficient Table 1 Diseases and conditions associated with posterior reversible encephalopathy syndrome Hypertensive encephalopathy Eclampsia Pregnancy Puerperium Renal failure Hemolytic-uremic syndrome Immunosuppressive drugs Cyclosporin A Tacrolimus/FK-506 IFN-alpha Cisplatin IVIg Erythropoietin Interleukin Antiretroviral therapy in HIV Granulocytic stimulating factor Drug withdrawal: clonidine Other rare causes Collagen vascular disorders SLE PAN Behcet’s disease TTP Acute porphyria Post organ transplantation Post carotid endarterctomy with reperfusion syndrome-unilateral hemispheric GBS with autonomic hyperactivity Endocrine disorders Acute porphyria Pheochromocytoma Pheochromocytoma Primary aldosteronism Thermal injury Scorpion envenomation Hypercalcemia Blood transfusion Stimulant drugs Phenylpropanolamine Ephedrine Pseudoephedrine GBS ¼ Guillain-Barre syndrome; HIV ¼ human immunodeficiency virus; IFN ¼ interferon; IVIg ¼ intravenous immunoglobulin; PAN ¼ polyarteritis nodosa; SLE ¼ systemic lupus erythematosus; TTP ¼ thrombotic thrombocytopenic purpura.
brain perfusion caused by endothelial dysfunction from systemic toxic effects. However, this theory would not explain the pattern of hypertension usually preceding the development of symptoms of PRES [8]. The current, more popular theory suggests that severe hypertension leads to cerebral autoregulatory failure and breakthrough vasodilatation with interstitial extravasation of fluid and subsequent vasogenic brain oedema and petechial hemorrhage [4,12e14]. These findings resolve rapidly when blood pressure is lowered [13,15e18]. In pre-eclampsia, the cause of PRES is considered to be endothelial activation and injury [19]. However, renal decompensation may play a role, especially in eclampsia associated with puerperium [1]. Altered vascular reactivity from an increased sensitivity to normally circulating pressure agents, a deficiency of vasodilating prostaglandins, and endothelial cell dysfunction have also been proposed [20,21]. The proposed mechanisms of PRES associated with immunosuppressive therapy, especially for cyclosporine, are hypercholesterolemia, hypomagnesaemia, aluminum overload, and drug levels above the therapeutic range [14,22e26]. Other possible mechanisms include direct toxic effects on vascular endothelial cells causing release of endothelin, prostacyclin, and thromboxane A2 [27e29]. Nephrotoxicity from cyclosporine may lead to fluid overload, ultimately exacerbating hypertension and the altered bloodbrain barrier [12]. The mechanism for tacrolimus and interferon alpha is likely similar to that of cyclosporine [1]. Up to 75% of patients present with seizures [30]. However, seizures are likely a manifestation, rather than a cause, of PRES [2]. Relative lack of sympathetic supply to the posterior circulation is thought to be responsible for dominant involvement of the posterior circulation and therefore inefficient autoregulation [3]. The controversy regarding the pathophysiology of vasogenic oedema is due to findings such as PRES in normotensives and less brain oedema in severe hypertensives [19]. Additionally, hyperperfusion has not been conclusively demonstrated in patients [19].
Imaging Features PRES has been described as having focal or confluent vasogenic oedema with classic posterior parietal and occipital lobe involvement [31]. Calcarine and paramedian occipital lobe is spared. Subcortical white matter is usually involved, but even cortical grey matter can be involved, depending upon the severity of the disease. Three distinct imaging patterns of PRES have been described [31]: dominant parietal-occipital pattern (Figure 1A); superior frontal sulcus pattern, with more isolated involvement of mid and posterior aspect of superior frontal sulcus (Figure 1B), and holohemispheric watershed pattern, a linear pattern of involvement of frontal, parietal, and occipital lobes at the watershed zone between medial
PRES review / Canadian Association of Radiologists Journal xx (2016) 1e7
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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 (combination 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.
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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].
detecting subcortical and cortical lesions in PRES, as compared with proton density and T2-weighted spin echo images (Figure 3) [2].
MRI Diffusion-Weighted Images MRI shows small, focal abnormalities beyond what is visible on CT [1]. Among the routine MRI sequences, fluidattenuated inversion recovery is the most sensitive in
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 xx (2016) 1e7
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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 assessment 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 associated 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
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
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J. Shankar, J. Banfield / Canadian Association of Radiologists Journal xx (2016) 1e7
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 involvement, 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 leukoencephalopathy 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 recovery 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
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