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Posterior Reversible Encephalopathy Syndrome Dimitre Staykov and Stefan Schwab J Intensive Care Med 2012 27: 11 originally published online 21 January 2011 DOI: 10.1177/0885066610393634 The online version of this article can be found at: http://jic.sagepub.com/content/27/1/11

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Journal of Intensive Care Medicine 27(1) 11-24 ª The Author(s) 2012 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0885066610393634 http://jicm.sagepub.com

Posterior Reversible Encephalopathy Syndrome Dimitre Staykov, MD1, and Stefan Schwab, MD, PhD1

Abstract Posterior reversible encephalopathy syndrome (PRES) is characterized by headache, altered mental status, visual disturbances, and seizures. Radiological features typically include edema of the posterior cerebral regions, especially of the parietooccipital lobes. Atypical imaging features, such as involvement of anterior cerebral regions, deep white matter, and the brain stem are also frequently seen. Vasoconstriction is common in vascular imaging. Different conditions have been associated with PRES, but toxemia of pregnancy, solid organ or bone marrow transplantation, immunosuppressive treatment, cancer chemotherapy, autoimmune diseases, and hypertension are most commonly described. The pathophysiology of PRES is unclear and different hypotheses are being discussed. Posterior reversible encephalopathy syndrome is best managed by monitoring and treatment in the setting of a neurointensive care unit. The prognosis is usually benign with complete reversal of clinical symptoms within several days, when adequate treatment is immediately initiated. Treatment of severe hypertension, seizures, and withdrawal of causative agents represent the hallmarks of specific therapy in PRES. Delay in diagnosis and treatment may lead to permanent neurological sequelae. Therefore, awareness of PRES is of crucial importance for the intensivist. Keywords posterior reversible encephalopathy syndrome, reversible posterior leukoencephalopathy syndrome, hypertensive encephalopathy, eclampsia Received February 4, 2010. Received Revised April 30, 2010. Accepted June 4, 2010.

Introduction The term reversible posterior leukoencephalopathy syndrome (RPLS) was first used in 1996 by Hinchey et al1 to describe a condition characterized by transient headache, altered mental functioning, seizures, and loss of vision associated with findings of predominantly posterior leukoencephalopathy on imaging studies. In this case series of 15 patients, RPLS was associated with immunosuppressive or interferon therapy, eclampsia, renal disease, or autoimmune diseases.1 The newly coined term RPLS, however, basically described an already known condition. The same clinical picture with findings of elevated mean arterial pressure (MAP) and similar radiological features was known as the hypertensive encephalopathy syndrome (HTE).2-4 Meanwhile the association of hypertension with RPLS is well documented, but hypertension is not always present in such patients, as the case series of Hinchey et al already demonstrates—3 of the 15 cases did not show episodes of elevated blood pressure. Particularly in patients treated with immunosuppressive therapy hypertension may be absent.1 Therefore, the older term HTE seems indeed too restrictive for an appropriate naming. The newly introduced name RPLS has, however, also begun to cause controversy immediately after its publication.5 By now, an extensive body of literature on the

syndrome has accumulated, and the term, including its ‘‘R,’’ ‘‘P,’’ and ‘‘L’’ parts, has been increasingly considered misleading for different reasons. First, as cases with nonreversible lesions and neurological deficits have been reported, names like ‘‘occipitalparietal encephalopathy,’’6 or ‘‘potentially reversible encephalopathy syndrome’’7,8 have been suggested to be more appropriate. The term ‘‘reversible’’ is still accepted by majority of authors as a part of the name of the condition, provided that it is supposed to suggest the reversibility of symptoms with adequate therapy, and should not imply, that lesions and clinical deficits must always resolve completely. Second, although the posterior localization of the lesions on imaging is most often seen, brain regions other than the occipitoparietal lobes are reported to be very frequently affected.9 Third, it has been shown, that the lesions on neuroimaging are not restricted to the white matter, as indicated by

1

Neurology Department, University of Erlangen–Nuremberg, Germany

Corresponding Author: Dimitre Staykov, Neurology Department, University of Erlangen–Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany Email: [email protected]

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Figure 1. Computed tomography (CT) of a patient with posterior reversible encephalopathy syndrome showing bilateral occipital hypodensity. Kindly provided by Dr Marios Psychogios and Prof Michael Knauth, Neuroradiology Department, University of Go¨ttingen, Germany.

‘‘leukoencephalopathy’’. Although the linguistic debate surrounding the name of the syndrome has not been closed yet and different alternatives are still being used, over the last years the name RPLS has been increasingly replaced by ‘‘posterior reversible encephalopathy syndrome’’ (PRES).10 As the latter term better reflects the meanwhile increased knowledge about this condition and is widely accepted to be most appropriate, it will be further used in the present review.

Clinical and Laboratory Characteristics of PRES The clinical picture of PRES includes several typical features: seizures, an acute encephalopathy syndrome, and visual disturbances. Seizures commonly represent the first clinical manifestation of the syndrome and are the most frequently seen symptoms in PRES.11,12 Seizures are generalized in the majority of cases but may also have a focal onset with following secondary generalization. Multiple seizures are even more frequent and status epilepticus (SE) may also occur.11-13 The acute encephalopathy syndrome manifests with confusion, headache, vomiting, and altered consciousness from somnolence and lethargy to stupor and coma.1,6,10,11 Episodes of agitation may alternate with lethargic conditions. Severe disturbances of consciousness, especially after seizures, may result in intubation and

Journal of Intensive Care Medicine 27(1) mechanical ventilation, which was necessary in 39% of PRES cases in a recently reported larger case series.11 Visual disturbance in PRES varies from blurred vision to hemianopsia and complete cortical blindness.11,13 In such cases, denial of cortical blindness (Anton syndrome) may be observed.1 Other focal neurological signs such as paresis or sensory deficits have also been reported.14 Symptoms may develop acutely, or gradually over a period of several days.14 Blood pressure is normal or only minimally elevated on symptom onset in 20% to 30% of the patients.14 In the remaining 70% to 80%, hypertension is present on manifestation of PRES, the upper limits of autoregulation are however usually not reached.14 Lee et al report a mean peak systolic blood pressure of 187 mm Hg, range 80 to 240 mm Hg, within the day before presentation in 36 patients with PRES.11 As PRES is seen within a wide palette of associated conditions, laboratory characteristics may vary considerably, depending on specific pathophysiology and organ involvement. However, laboratory evidence of endothelial injury, as indicated by thrombocytopenia, cell fragmentation with elevated schistocyte counts, and increase in lactate dehydrogenase, seems to be more frequently found across conditions associated with PRES.14-18 Cerebrospinal fluid findings are usually normal, rarely a mild protein elevation has been reported, however there are few studies available in patients with PRES.11,19 Lee et al report electroencephalographic findings of slowing in 22 of 28 examined patients, focal sharp waves are less frequently seen (3 of 28 patients), and in 3 of 28 patients electroencephalography was normal.11

Imaging Characteristics of PRES Lesion Characteristics and Localization Magnetic resonance imaging (MRI) allows more precise characterization and recognition of PRES than computed tomography (CT) (Figures 1 and 2).3,9 The lesions in PRES usually show increased signal on T2- (Figure 2A) and fluid-attenuated inversion recovery (FLAIR) imaging with increased apparent diffusion coefficient (ADC) values (Figure 2C), indicating the presence of vasogenic edema.20-23 On diffusion-weighted imaging (DWI), majority of cases show no change in intensity in the corresponding areas with high T2 signal.9,24-26 A T2 shine-through effect with a slight hyperintensity on DWI is less commonly present (Figure 2B).24 Areas of restricted diffusion and hyperintensity on DWI are rarely observed.9,24 Such lesions with restricted diffusion may show ADC values, which appear normal and are surrounded by regions of vasogenic edema.25 Covarrubias et al describe this phenomenon as ‘‘pseudonormalized’’ ADC, because those changes have been observed by the authors to progress to infarction in 6 patients with PRES.25 Elevated DWI signal combined with decreased ADC usually indicates ischemic areas.26 There are, however, also reports of diffusion restriction with ADC decrease in PRES, with subsequent complete reversibility of imaging changes.24,27 Single voxel proton MR spectroscopy of the lesions may also

Staykov and Schwab

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Figure 2. Magnetic resonance images (MRI) of a patient with posterior reversible encephalopathy syndrome. Hyperintensive alterations in the occipital and frontal lobes on T2 imaging (A). A slight hyperintensity (T2-shine through effect) on diffusion imaging (B). Increased apparent diffusion coefficient (ADC) values in the corresponding areas indicate vasogenic edema (C). Kindly provided by Dr Marios Psychogios and Prof Michael Knauth, Neuroradiology Department, University of Go¨ttingen, Germany.

help differentiate between infarction and reversible changes in PRES. N-acetylaspartate decrease has been reported in PRES lesions, whereas lactate increase, a typical finding in ischemic areas, is usually absent.28-31 The most common location of white matter abnormalities in PRES is the posterior regions of the cerebral hemispheres, that is, the occipital lobe, the posterior parietal lobe, and the posterior temporal lobe.1,9,10,24 The frontal lobes are also very frequently involved (Figure 2).9,24 Atypical locations such as the cerebellum, the brain stem, the basal ganglia, the deep white matter, or the splenium of the corpus callosum are seen in approximately 10% to 30% of the cases.1,9,10,20,24 Cortex involvement is frequent (up to approximately 90%) and best recognizable by FLAIR imaging.10 Symmetrical edema is most commonly observed in PRES, asymmetrical or even strictly unilateral manifestations have, however, also been described.9,24 McKinney et al define 3 levels of severity of PRES distribution in

a series of 76 patients, based on FLAIR imaging: mild, moderate, and severe.24 In their analysis, there was no significant correlation between edema severity and the occurrence of restricted diffusion, hemorrhage, contrast enhancement, or maximum systolic or diastolic blood pressure. Bartynski et al, however, did find a correlation. The authors suggest a 5-level grading scale for severity of edema in PRES, in which confluence and extension of the lesions to the ventricular system, as well as involvement of the cortex, the subcortical and deep white matter, and spaceoccupying effects of the lesions are taken into account.15 Among 25 patients with PRES associated with infection, sepsis, and shock, the authors found a significant correlation between the edema severity grade and blood pressure at the time of neurotoxicity. Interestingly, more severe edema was associated with a ‘‘normotensive’’ blood pressure. In contrast, ‘‘severely hypertensive’’ patients showed lower edema grades.15 Similar findings were reported by Bartynski et al for

14 patients with kidney transplants and PRES.16 The differing results of McKinney et al and Bartynski et al are probably best explained by the use of different edema grading scales with a better sensitivity of the 5-level grading scale. Although various brain regions may be affected, certain patterns of lesion distribution appear to be more common. Bartynski et al9 have made an attempt to classify PRES lesion distribution and found 3 major patterns analyzing a large series of 136 patients with PRES: the first is a holohemispheric watershed pattern consisting of a linear distribution of edema spanning the frontal, parietal, and occipital lobes, with lesser involvement of the temporal lobes. This linear distribution of the lesions seems to be consistent with the anastomotic border zone between medial (posterior cerebral artery [PCA]; anterior cerebral artery [ACA]) and lateral (medial cerebral artery [MCA]) vessel branches. The severity of manifestation ranges from extensive to mild, with a ‘‘string of pearls’’ appearance of nonconfluent white matter lesions. The other 2 major patterns are a superior frontal sulcus pattern with predominant involvement of the mid-to-posterior aspect of the superior frontal sulcus with varying degrees of parietooccipital abnormality and a dominant parietooccipital pattern with involvement of the parietal and occipital lobes and variable temporal lobe manifestations. Each of those patterns was observed in approximately one fourth of the patients. The remaining patients showed incomplete or asymmetrical expression of the described lesion distribution patterns, partially with strictly unilateral abnormality. The imaging distribution patterns did not correlate with clinical features of the syndrome in that study. Analyzing lesion distribution in 24 patients with PRES, another work group found a significantly higher number of lesions and a trend for increased basal ganglia involvement in patients with PRES in the setting of preeclampsiaeclampsia, as compared to other causes.32 Contrast enhancement on post-gadolinium MRI, although rarely addressed in literature, is present in up to 38% of patients with PRES.24 A gyriform pattern of distribution has most commonly been described.3,21,33,34 Contrast enhancement possibly results from endothelial injury and subsequent blood–brain barrier breakdown.35 Because of the different etiology of endothelial damage, for example, by immunosuppressive drugs such as cyclosporine after solid organ transplantation, or hypoperfusion in eclampsia, there may be discrepancies in the extent of contrast enhancement dependent on the underlying cause of PRES.24

Cerebral Hemorrhage in PRES Cerebral hemorrhage is known to occur in PRES, and case series report it in 5% to 17% of patients.11,24,25,36,37 In a recently published study on 151 patients with PRES, Hefzy et al report 3 different types of hemorrhage: minute (punctual) hemorrhage, sulcal (subarachnoid) hemorrhage, and focal hematoma.36 In this largest analysis focusing on hemorrhage in PRES, a borderline significant statistical trend (P ¼ .07) for an association between the occurrence of hemorrhage and underlying etiology of PRES was found. When looking at

Journal of Intensive Care Medicine 27(1) allogenic bone marrow transplantation (allo-BMT; hemorrhage rate of 46.6%) and solid organ transplantation (hemorrhage rate of 11.7%), the authors identified a statistically significant difference. Focal hemorrhage rates were also significantly greater in allo-BMT patients. Patients with therapeutic anticoagulation or those taking aspirin were significantly more likely to develop PRES-associated hemorrhage, in contrast to patients with intrinsic coagulopathy. There was no association between hemorrhage occurrence and blood pressure. Even excluding the subset of allo-BMT patients, severe hypertension was less frequently associated with hemorrhage.36 This finding may indicate that hemorrhage in PRES is not directly caused by severe hypertension but rather a consequence of initial hypoperfusion and subsequent reperfusion injury.

Vascular and Cerebral Perfusion Imaging The state of cerebral perfusion in PRES is still a subject of controversy because of contradictory findings reported in different studies. Animal studies suggest that experimentally induced hypertension above the autoregulatory limit leads to breakdown of the blood–brain barrier, hyperperfusion, and leakage of fluid into the brain, with subsequent vasogenic edema.38 The evidence of hyperperfusion in the clinical setting of PRES is, however, not convincing. Single reports of hyperperfusion in PRES detected either by single-photon emission computed tomography (SPECT)2,39 or by MR-perfusion imaging40 have been published. There is, however, controversy on the interpretation of those findings.14,40 The majority of studies on cerebral perfusion imaging in PRES reports hypoperfusion in the affected areas with vasogenic edema.15,28,41-43 In studies using MR-perfusion imaging, a reduction of relative cerebral blood volume (rCBV) in the affected areas of the brain has been reported.41,43 Reductions in rCBV measured in edematous areas range from one third up to two thirds of reference normal cortical rCBV.41,43,44 In a large case series of women with eclampsia, brain perfusion assessed by SPECT has also demonstrated perfusion deficits in the predominantly affected watershed areas, in which PRES lesions occur.45 Hypoperfusion has also been reported using CT-perfusion imaging in a patient with PRES.46 These findings are usually coupled with vessel irregularities and vasospasm shown on vascular imaging.15,28,41,42 Catheter angiography41,47-51 and MR angiography studies15,28,41,42,52-54 in patients with PRES have demonstrated vascular abnormalities as focal vasoconstriction, focal vasodilation, ‘‘string-of-bead,’’ or ‘‘string-of-sausages’’ appearance. Follow-up MR angiography usually demonstrates reversal of vasculopathy.41

Conditions Associated With PRES PRES has been associated with a variety of conditions and predisposing factors, which are summarized in Table 1. Moderate-to-severe hypertension, commonly present in PRES, is reported in approximately 75% of cases.14 Hypertension has been recognized as a major factor in the setting of PRES,

Staykov and Schwab Table 1. Conditions and Predisposing Factors Associated With PRESa Frequent associations Hypertension preeclampsia–eclampsia Posttransplantation/immune suppression Cyclosporine, tacrolimus Cytotoxic treatment Autoimmune diseases Systemic lupus erythematodes, Wegener granulomatosis, scleroderma, polyarteriitis nodosa, psoriasis, Graves disease, rheumatoid factor positive arthropathy Infection/sepsis Rare associations Hypomagnesemia Hypercalcemia Hypercholesterolemia Intravenous immunoglobulin Linezolid treatment Guillain-Barre syndrome Ephedra overdose Triple H therapy Tumor lysis syndrome Hydrogen peroxide Dimethyl sulfoxide stem cells Contrast media exposure Corticosteroid treatment Lysergic acid diethylamide Scorpion poison Averrhoa carambola ingestion Abbreviation: PRES, posterior reversible encephalopathy syndrome. a For references see text.

which has contributed to the implementation of the earlier term ‘‘hypertensive encephalopathy.’’ Various patterns of lesion distribution have been associated with HTE,3,4,34,55-60 including hemispheric distribution of lesions or brain stem and cerebellar edema, in 1 case resulting in obstructive hydrocephalus.58 The differentiation between deep white matter lesions and chronic changes due to hypertension (lacunar disease) may be difficult. The association of preeclampsiaeclampsia and PRES is well documented.32,47,61-73 Preeclampsia is responsible for the world’s largest maternal death rates of approximately 60 000 per year.74 Acute cerebral complications, such as eclampsia, cerebral edema, and intracerebral hemorrhage, account for the majority of fatalities.75,76 PRES is hypothesized to be the primary injury in eclampsia. Following the general trend, hypertension is absent in approximately one fourth of the women who develop PRES.77 The placenta is thought to be the primary cause of toxemia, and placenta removal is considered curative.78 Delayed eclampsia, with PRES within several weeks after delivery may also occur.48,50 In a recently reported case of delayed postpartum PRES occurrence, retained placental fragments were suggested as the underlying cause.79 No specific lesion distribution patterns have been associated with this condition, however, a trend toward more frequent involvement of the basal ganglia and a significantly higher number of involved brain regions have been observed in PRES in the setting of preeclampsia–eclampsia, as compared to other underlying conditions.32

15 PRES has been frequently described in the setting of allo-BMT or stem cell transplantation,2,18,80-84 as well as after solid organ transplantation,85-97 mostly in connection with cyclosporine or tacrolimus neurotoxicity. PRES occurs most commonly in the first month after allo-BMT, the remaining cases usually within 1 year after transplantation.80,83,89,98 The incidence of PRES seems to vary with different preconditioning regimens and comprises approximately 7% to 9% using myeloablative marrow preconditioning and cyclosporine immune suppression.80,83,98 Even higher incidences (approximately 16%) have been reported using higher dose myeloablative regimens, in contrast to a PRES incidence of only 3% when nonmyeloablative preconditioning was used.81,98 As higher incidence of graft versus host disease (GVHD) has been identified in patients developing PRES, GVHD effects have been suggested to play a role in the pathogenesis of PRES.84,99-101 In solid organ transplantation, PRES incidence has been reported to vary between 0.4% and 6%.16,95,102 PRES seems to occur earlier in the course after liver transplantation—in most cases within 2 months—and markedly later after kidney transplantation.16,102 Systemic hypertension is more often noted after kidney transplantation compared to liver, lung, or heart transplantation, and hypertensive patients tend to develop less brain edema than normotensive patients with PRES.14,16,94,102,103 Transplant rejection and infection have been reported to often accompany PRES after solid organ transplantation.16 High-dose multidrug cytotoxic chemotherapy has also been associated with PRES, especially in children with leukemia.104-107 Additionally, several chemotherapeutic drugs have been reported in connection with PRES: cytarabine,108,109 cisplatin,110 gemcitabine,30 tiazofurin,111 and bevacizumab.112,113 In recent years, reports of PRES in patients with connective tissue diseases, the majority of them with systemic lupus erythematosus (SLE) and also Wegener granulomatosis, polyarteriitis nodosa, scleroderma, psoriasis, Graves disease, and rheumatoid factor positive arthropathy have accumulated.1,3,6,15,53,114-133 The particular role of the underlying connective tissue disease in the pathogenesis of PRES is not clear in those cases, because comorbidity like hypertension, renal involvement with renal insufficiency, infection, or recent immunosuppressive treatment with corticosteroids, cyclophosphamide, cyclosporine, mycophenolate mofetil, rituximab, and azathioprine, all factors separately associated with PRES, were present in most patients.133 Interestingly, withdrawal of putatively causative immunosuppressive drugs on one hand, and administration of high-dose corticosteroids or adjunctive immunosuppressive drugs, including cyclophosphamide or mycophenolate mofetil on the other hand have been reported to lead to successful treatment of PRES.133,134 A recent study of 106 patients identified infection and sepsis as an important, though not yet recognized cause of PRES, particularly in relation to infection with gram-positive organisms.15 Infection and sepsis have been suggested to be responsible for one fourth of the cases with PRES in this study.15 This observation has, however, yet to be confirmed in other studies.

16 Rarely or anecdotally reported associations with PRES include hypomagnesemia, hypercalcemia, hypercholesterolemia, acute pancreatitis, intravenous immunoglobulin, linezolid treatment, Guillain-Barre´ syndrome, Ephedra overdose, triple H therapy, tumor lysis syndrome, hydrogen peroxide, contrast media exposure, corticosteroid treatment, influenza A infection, lysergic acid amide, and scorpion poison.13,19,135-151

Pathophysiology of PRES The mechanism of PRES is still poorly understood and controversial. There are 2 commonly cited opposing hypotheses on the pathogenesis of PRES. The older hypothesis states that hypertension leads to autoregulatory vasoconstriction and hypoperfusion with resulting ischemia and cerebral edema.152 This idea was supported by findings of edema in the posterior cerebral regions combined with vasospasm on vascular imaging in patients with eclampsia and hypertension.48,153 The newer hypothesis suggests that severe hypertension exceeds the autoregulatory limits of the cerebral vasculature and leads to breakthrough of the blood–brain barrier, fluid leakage, and vasogenic edema.3 This more intuitive explanation has become popular in recent years, mainly because of the frequently reported benefit of emergent hypertension treatment with subsequent recovery of symptoms and alterations in imaging.13,154 Moreover, animal studies investigating the cerebral squealae of severe hypertension have demonstrated breakthrough of the blood–brain barrier, hyperperfusion, and vasogenic edema when the upper limits of autoregulation are exceeded.38,155 However, the role of hypertension in PRES has not been sufficiently elucidated yet and continues to be the subject of controversy.152 In humans, the upper limits of autoregulation are usually reached at a mean arterial pressure (MAP) of 150 to 160 mm Hg.155,156 Due to the rich sympathetic innervation of cerebral vessels, sympathetic stimulation leads to increase of the upper limit of autoregulation by up to 30 mm Hg MAP.152 Those limits are also increased in patients with chronic hypertension.152 Given the considerable prevalence of moderate-to-severe hypertension in the setting of PRES (up to 75% of patients), it should be noted that observed blood pressure levels, although in some reported cases elevated quite severely,56,157 in the majority of cases it does not reach the upper limits of autoregulation.1,9,41,98,122 Furthermore, circumstances leading to increased levels of autoregulation are a common finding in PRES, for example, chronic hypertension, or increased sympathetic stimulation, as reported in patients treated with cyclosporine.158,159 Moreover, PRES is frequently seen without hypertension, as reported in patients with eclampsia, after allo-BMT or solid organ transplantation.9,18,77 In this subset of patients, however, ‘‘relative hypertension’’ may play a role. Women with eclampsia having borderline hypertensive blood pressure values (systolic pressure of less than 140 mm Hg) are often young primigravidas whose blood pressures have risen from markedly low baseline levels.74 The importance of this mechanism for the pathogenesis of PRES is yet still

Journal of Intensive Care Medicine 27(1) unclear. Some recent findings show that the severity of cerebral edema is inversely correlated to the blood pressure level in patients with PRES.15,16,41 Those observations have led to the speculation that increased blood pressure may represent a secondary event in the mechanism of disease, not causing edema by fluid leakage, but rather appearing as a reaction to hypoperfusion and ischemia, thus supportive for the older hypothesis of pathogenesis.152 Although animal studies underpin the hypothesis of breakthrough of the blood–brain barrier by increased MAP,38 those observations have been made on otherwise healthy animals, in contrast to the usually very complex systemic conditions associated with PRES in humans. Apart from hypertension, other common findings across underlying conditions may give further clues regarding the pathophysiology of PRES. Looking at the major conditions, in the setting of which PRES commonly occurs, namely transplantation, autoimmune disease, preeclampsiaeclampsia, cancer chemotherapy, infection, and sepsis, endothelial injury to a certain extent seems to be almost uniformly present. In allo-BMT, the combination of preconditioning regimens and following GVHD leads to release of proinflammatory cytokines and endothelial activation or injury.98,99,160 In solid organ transplantation, graft rejection related to a T-cell response is additionally associated with the development of antiendothelial antibodies, primarily against the allogenic transplant.161 On the other hand, immunologically active cells within a liver transplant may contribute to a GVHD similar mechanism of endothelial damage.98 Autoimmune diseases as SLE and Wegener granulomatosis are characterized by vasculitis.162 In toxemia of pregnancy, a placenta maternal immune reaction is considered the underlying cause of cytokine release, endothelial activation, and injury.78 Furthermore, antiendothelial antibodies are more frequently found in women with eclampsia, as compared to healthy pregnancies (50% vs 16%).78 In cancer, immunologic reaction to cancer, or direct damage of the endothelium by chemotherapeutic drugs are possible mechanisms of endothelial injury.98,152 Endothelial activation in infection, triggered by bacterial endotoxins, and endothelial injury in sepsis represent an important part of the primary infection response and secondary septic response.163 Laboratory markers of endothelial injury, namely thrombocytopenia, cell fragmentation (schistocytes), and elevated lactate dehydrogenase, are commonly found across those conditions.14 Considering the important role of the endothelium in cerebral autoregulation and its vasodilator influence,164 endothelial injury in PRES-associated conditions may lead to vascular instability and vasoconstriction, with subsequent hypoperfusion.152,164 Cerebral hypoperfusion of the regions showing abnormalities on imaging in PRES, accompanied by evidence of vasculopathy and vasoconstriction on vascular imaging, has been indeed better documented, 15,28,41-54 as compared to the sporadic reports of hyperperfusion.2,39,40 Therefore, the available evidence seems to be in better unison with the older hypothesis on the pathogenesis of PRES, which considers hypoperfusion central. In this context, the occurrence of edema patterns in the watershed areas of cerebral circulation is also better explained.

Staykov and Schwab Speculations have been made in order to explain the predominant involvement of the posterior parts of the brain in PRES. One explanation has been proposed by Schwartz et al.3 The authors mention the evidence of a protective effect of sympathetic innervation of the cerebral vasculature against marked increases of blood pressure.165 Based on a histofluorescence study by Edvinsson et al,166 which has shown a less dense sympathetic innervation of the vertebrobasilar compared to the internal carotid system, Schwarz et al concluded that the vertebrobasilar system is more likely to be affected by increases in blood pressure and more susceptible to breakthrough of the upper limits of autoregulation. A newer study aiming at quantification of perivascular nerve fibres in human basal cerebral arteries has, however, shown exactly the opposite relation of innervation density in the circle of Willis, namely a higher perivascular sympathetic nerve density in the PCA and the posterior communicating artery (PCom), as compared to the rest of the basal cerebral arteries.167 The authors used a methodology of histologic preparation, which probably allows better representation of perivascular nerve fibers, especially of fibers within deeper layers of the vessel wall, as compared to the method used by Edvinsson et al.166 This finding allows the speculation that the higher density of sympathetic innervation of the PCA may contribute to increased vasoconstriction, hypoperfusion, and subsequent cerebral edema in the setting of endothelial injury in this part of the cerebral vasculature. This explanation would then better fit into the hypothesis of hypoperfusion as the central mechanism in the pathogenesis of PRES. The number of studies quantitatively investigating innervation density in human cerebral arteries is, however, still too small, the results controversial, and the correlation of those findings to clinical, imaging features, and hypotheses on the pathogenesis of a complex condition like PRES remains speculative. The repeated reports of different findings in the anterior and posterior parts of cerebral circulation, including in vivo functional studies using transcranial Doppler sonography,168 however, indicate the possible role of different innervation and vascular reactivity in the development of the imaging patterns in PRES.

17 to point out that reversibility of PRES is not spontaneous and delay in diagnosis and treatment may lead to permanent damage to affected areas of the brain.10,25,170,171 Ischemia represents one of the major complications of PRES, occurring typically in the posterior border zone between the territories of the middle and posterior cerebral arteries.25,46 Patients with multiple seizures in the course of PRES are at an especially high risk of developing infarction.74,169 When hemorrhage occurs in PRES, focal parenchymal bleedings most likely lead to permanent clinical symptoms, as compared to minute, or sulcal bleeding.36 Epilepsy may represent another long-term complication of PRES. Patients with hippocampal sclerosis, or permanent focal changes and temporal lobe epilepsy, which has developed months to years after an episode of PRES, have been reported.154,172,173 It appears plausible, that lesions in PRES, which evolve into permanently damaged areas, may cause seizures in the long-term course. The development of hippocampal sclerosis after PRES, however, may also be coincidental and this issue remains controversial.173 To date, no data are available on the long-term neurocognitive consequences of PRES. Theoretically, the presence of permanent cerebral lesions in a considerable part of the patients who had suffered PRES may be reflected in a certain level of cognitive dysfunction. In a study using a questionnaire for cognitive functioning, formerly eclamptic women indeed reported cognitive impairment several years after complicated pregnancy.174 Objective neurocognitive testing performed in women several months after preeclampsia has also shown presence of cognitive deficits in such patients.175 Recurrence of PRES has been infrequently documented in single-case reports. Relapsing PRES has been reported in patients after solid organ transplantation, chemotherapy, allo-BMT, autoimmune disease, sickle cell disease, and in a patient with a mitochondrial disorder.19,54,82,97,176,177 Multiple episodes of PRES in a single patient have been reported in children with renal disease178 and in a patient with SLE, for a total of 4 recurrent episodes of PRES that have been documented.53

Differential Diagnosis and Treatment Prognosis and Treatment of PRES Natural History With timely institution of adequate treatment, PRES is usually completely reversible within several days to several weeks.1,74,157 Incomplete recovery has, however, also been reported under adequate therapy.19,154,169 In a recent longterm follow-up report on patients with PRES, in approximately 25% of the cases, abnormalities on imaging did not resolve completely and clinical improvement often preceded improvement on imaging.19 Similar results have been reported in women with eclampsia within several months from the event.74 When studied 7 years postpartum, 40% of formerly eclamptic women have shown white matter lesions on imaging, as compared to 17% of patients with no eclampsia.74 It is important

The differential diagnosis of PRES includes a wide variety of acute neurological disorders with different etiologies. Several important conditions with prognostic and therapeutic implications should be considered: ischemic stroke and cerebral sinus thrombosis are usually easily ruled out by MRI and MR angiography. Inflammatory diseases, such as infectious (eg, viral) encephalitis, or autoimmune diseases like acute disseminated encephalomyelitis, can be excluded by cerebrospinal fluid examinations or negative bacteriological and virological tests. Other rare diseases, like mitochondrial disorders, or cerebral autosomal dominant arteriopathy with stroke and ischemic leukoencephalopathy (CADASIL), may also mimic the clinical and radiological appearance of PRES.13 There are several important aspects in the treatment of PRES: (i) the removal or reduction of the causative drug,

18 (ii) aggressive management of blood pressure if hypertension is present, (iii) treatment of seizures and SE, and (iv) consideration of delivery by cesarean section in pregnant women with refractory symptoms.13 PRES is best managed in the setting of a neurocritical care unit with the possibility of close consultation with other specialties according to the underlying systemic condition, for example, oncology, rheumatology, obstetric critical care. Clinical and operative monitoring, that is, invasive blood pressure monitoring, monitoring of airways and oxygenation, and electroencephalographic monitoring in patients with seizures, are essential in the acute phase of PRES. Intubation and mechanic ventilation may be necessary in up to 39% of patients.11 General management also includes maintenance of homeostasis, sufficient hydration and arterial oxygenation, correction of hypoglycaemia, electrolyte disturbances, or coagulopathy. Treatment of elevated blood pressure is considered central in the management of PRES. Generally, the goal of treatment is the reduction of mean blood pressure to premorbid levels. Intravenous antihypertensive drugs should be preferably used and blood pressure should be monitored with an arterial catheter. Intravenous nicardipine (5-15 mg/h) and labetalol (2-3 mg/ min) are considered first-line medications in PRES.13 Hydralazine and diazoxide may also be used for antihypertensive treatment. As nitroglycerine has been reported to aggravate cerebral edema in PRES, it should not be primarily used in such patients.179 Too rapid correction of hypertension in pregnant women should be avoided in order to avert compromised uteroplacental blood flow.13,171 The aim of the therapy in such patients is to lower the mean arterial pressure by no more than 15% to 25%. Antihypertensive treatment is usually recommended for sustained systolic blood pressure values of more than 160 mm Hg and diastolic blood pressure of at least 110 mm Hg.180,181 Small reductions in blood pressure in the first 60 minutes with a target systolic value of approximately 140 to 155 mmHg and/ or diastolic value of 90 to 105 mmHg have been recommended.182 Both intravenous hydralazine and labetalol have been shown to be safe for the management of hypertension in women with preeclampsia–eclampsia. Angiotensin-converting enzyme inhibitors should be avoided in pregnant women, because of their toxic effects on the fetal kidney.183 Status epilepticus is a neurologic emergency, in which a single generalized epileptic seizure does not cease within 5 minutes of onset, or recurrent epileptic seizures occur without complete clinical or electroencephalographic recovery between the single events. A focal SE is considered present if a focal seizure continues for more than 30 minutes.184 Generalized SE has a mortality of up to 40% depending on the underlying condition and duration. Therefore, this condition particularly requires immediate, aggressive, and effective treatment in order to prevent neuronal damage or death.185 After initial control of cardiorespiratory function and blood glucose level, the first-line treatment of SE consists of benzodiazepines, most commonly diazepam or lorazepam.185 Lorazepam is administered intravenously in boluses of 2 mg given slowly over 2 to

Journal of Intensive Care Medicine 27(1) 5 minutes, up to a cumulative dose of 10 mg. This treatment is usually followed by administration of second-line drugs such as phenytoin (15-18 mg/kg initially, maximal injection speed 50 mg/min) if SE persists after 20 minutes. In most countries, phenytoin is approved for the first-line treatment of SE. Third-line treatment of refractory SE usually consists of coma induction using anesthetics, such as propofol, midazolam, or barbiturates.185 In pregnant women with eclampsia, magnesium sulfate has been shown to be effective in treatment and prevention of eclamptic seizures compared to traditional antiepileptic drugs, such as diazepam or phenytoin.186

Conclusion Since its description in 1996, many reports on PRES have accumulated in the literature. Although the pathophysiology of this condition has not been sufficiently elucidated yet, its clinical features and radiological appearance have been well documented. For the critical care physician, awareness of PRES is important, because immediate diagnosis and treatment initiation have the potential to result in a very good outcome, whereas delay in adequate therapy can lead to permanent neurological sequelae. Acknowledgments The authors thank Dr Marios Psychogios and Prof Michael Knauth from the Neuroradiology Department of the University of Go¨ttingen, Germany, for kindly providing the images for this article.

Declaration of Conflicting Interests The author(s) declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding The author(s) received no financial support for the research and/or authorship of this article.

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