Hospital Practice ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20 Intracranial hemorrhage in the setting of posterior reversible encephalopathy syndrome: two case reports and a review Manveer Garcha, Keithan Sivakumar, Mohammed El-Hunjul, Shweta Varade & Hussam A. Yacoub To cite this article: Manveer Garcha, Keithan Sivakumar, Mohammed El-Hunjul, Shweta Varade & Hussam A. Yacoub (2018): Intracranial hemorrhage in the setting of posterior reversible encephalopathy syndrome: two case reports and a review, Hospital Practice, DOI: 10.1080/21548331.2018.1451204 To link to this article: https://doi.org/10.1080/21548331.2018.1451204 Accepted author version posted online: 08 Mar 2018. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 1 Publisher: Taylor & Francis Journal: Hospital Practice DOI: 10.1080/21548331.2018.1451204 ip t Intracranial hemorrhage in the setting of posterior reversible encephalopathy syndrome: cr two case reports and a review us Manveer Garcha1, Keithan Sivakumar2, Mohammed El-Hunjul2, Shweta Varade2, Hussam A. an Yacoub2,3 1 M USF Health Morsani College of Medicine SELECT Program, Lehigh Valley Health Network, Allentown, PA 2 ed Lehigh Valley Physicians Group – Neurology, Lehigh Valley Health Network, Allentown, PA 3 Morsani College of Medicine, University of South Florida, Tampa, FL ce pt Corresponding author: Hussam A. Yacoub, DO, MS Lehigh Valley Physician Group—Neurology Ac Lehigh Valley Health Network 1250 S. Cedar Crest Blvd., Suite 405 Allentown, PA 18103 Phone: 610-597-6873 Fax: 610-402-1689 Email: hyacoub123@yahoo.com 1 2 Abstract Posterior reversible encephalopathy syndrome (PRES) is clinically characterized by seizures, ip t changes in vision, altered mental status, and headache, with associated radiologic changes on cr brain imaging. Intraparenchymal hemorrhage is a rare complication of PRES and an atypical initial presentation of this condition. In this report, we discuss two patients who presented with us multifocal cerebral hemorrhages that were later attributed to PRES. We further expand on the pathophysiology, management, and prognosis on patients with hemorrhagic PRES. Increased M an awareness of this complication of PRES is important in guiding prognostication and treatment. Ac ce pt encephalopathy ed Keywords: Posterior reversible encephalopathy syndrome; intracranial hemorrhage; edema; 2 3 Introduction Posterior reversible encephalopathy syndrome (PRES) is clinically characterized by seizures, visual disturbance, altered mental status, and headache. The diagnosis is made when symptoms ip t occur in conjunction with radiologic evidence of reversible subcortical vasogenic edema, classically in a posterior vascular territory distribution, but has been reported in other supra- and cr infratentorial regions [1]. PRES is thought to be associated with autoimmune disorders, us uncontrolled hypertension, cytotoxic medications, sepsis, and organ failure [2]. PRES was described in 1996 by Hinchey et al. [1] in a report of 15 patients whose symptoms an included the constellation of seizures, altered mental status, visual loss, and white matter edema seen on neuroimaging, specifically in the parietal and occipital subcortical white matter. In their M initial report, these authors did not describe any patients with intraparenchymal hemorrhage associated with PRES [1]. However, the investigators selected only patients with white-matter ed abnormalities who had resolution of clinical symptoms. These criteria may have excluded patients with atypical radiological findings such as intracranial hemorrhage. All 15 patients had ce pt resolution of their symptoms; thus, the condition was referred to as “posterior leukoencephalopathy syndrome.” Due to the presence of vasogenic edema in the parietal and occipital lobes, the syndrome became more popularly known as PRES [3]. Ac In 1992, Schwartz et al. [4] analyzed imaging findings in 14 patients with PRES and reported a small hemorrhage in one patient with thrombocytopenia. Another case of PRES with extensive vasogenic edema and petechial hemorrhages in the basal ganglia was also reported, in 2005, in a patient with Guillain-Barre syndrome treated with intravenous immunoglobulin [5]. PRES with intracranial hemorrhage (ICH) was also described in 2009 by Aranas et al. [6] as a more severe variant associated with a greater risk of permanent cerebral insult. In their study, 3 4 only 28% of patients with PRES-ICH had a favorable outcome, which was defined as a modified Rankin scale of 1 or less. Whether hemorrhage in PRES is an independent causative factor for negative long-term sequelae or is simply a corollary to severe forms of PRES is unclear. ip t Additionally, it remains under debate as to whether PRES and PRES-ICH share the same pathophysiology or, instead, represent two distinct processes [7]. The overall incidence of ICH cr associated with a reversible encephalopathy such as PRES has been reported as approximately us 15% [7]. The mechanism of PRES and its variants is still not very well-described. The most widely an accepted theory is failed autoregulation of cerebral vascular tone [8, 9]. Under normal conditions cerebral blood vessels dilate when the blood pressure (BP) drops and constrict when BP M increases up to a mean of 150 mmHg. Beyond this limit, autoregulation is lost due to vascular endothelial injury with resultant hyperperfusion, vasogenic edema, passive arteriolar dilatation ed and, in the case of hemorrhagic PRES, petechial hemorrhages [10-14]. While eclampsia and hypertension are both well-known as independent risk factors for ICH, there also are reports in ce pt the literature of non-hypertensive risk factors for hemorrhagic PRES [7, 15]. In some case reports, the rate of hemorrhagic PRES associated with infection varied between 11.5% and 28%, which is on par with the rates of ICH in PRES associated with eclampsia [7, 15]. This finding Ac supports the notion that there are multiple underlying pathophysiologic mechanisms that can cause ICH in patients with PRES. Herein, we present two cases of multifocal ICH associated with PRES. While both patients possessed some risk factors for PRES, the exact factors disposing them to hemorrhage remain uncertain and are discussed further. Hemorrhagic PRES is a rare variant with a paucity of literature to describe it. We include a review of the available literature describing risk factors, 4 5 pathophysiology, and functional outcome of ICH associated with PRES, which may aid providers in the management of this patient population. Case Presentation 1 ip t A 63-year-old woman with a medical history significant for hypertension, hyperlipidemia, and diabetes mellitus type II was found obtunded in her acute rehabilitation facility. Duration of cr symptoms was unclear. The patient was not on any antiplatelet agents or anticoagulants. us Computed tomography (CT) of the head without contrast performed at an outside hospital revealed a large left frontoparietal acute hematoma with mass effect and minimal subarachnoid an hemorrhage (SAH) (Figure 1). Also noted were multiple chronic infarctions in the cerebellum and periventricular chronic small vessel ischemic disease. M Complete blood count revealed a hemoglobin of 7.5 g/dl, platelet count of 348,000/ml, and a white blood cell count of 11,300/mm3. A basic metabolic panel revealed a glucose of 125 mg/dl, ed sodium 137 mmol/L, and elevated creatinine of 2.65 mg/dl. Protime was 14.7 seconds. The patient was intubated for airway protection, given intravenous labetalol for blood ce pt pressure control, and transferred to the neuroscience intensive care unit in our facility for further management. Upon arrival, her Glasgow coma scale (GCS) score was 8T (eye, 3; verbal, 1, intubated; motor, 4) and ICH score was 2 based on the GCS and intraparenchymal hemorrhage Ac volume. The patient was unresponsive to commands but withdrew from noxious stimuli in all four extremities with no focal neurologic deficits. Electroencephalogram revealed significant muscle artifact but no clear epileptiform discharges. The patient was administered a loading dose of prophylactic fosphenytoin for seizure prophylaxis. Magnetic resonance imaging (MRI) of the brain obtained the next day revealed extension of the hematoma with intraventricular hemorrhage. Also noted were T2-weighted hyperintensities 5 6 in bilateral cerebellar hemispheres (Figure 2a) and medial parietal lobes (images not shown), the appearance of which were suggestive of PRES, in addition to a left parietal hematoma (Figure 2b). ip t The patient’s blood pressure was well-controlled with intravenous nicardipine. She improved clinically and was extubated on hospital day 3. Nine days following initial presentation, a repeat cr MRI of the brain with and without gadolinium demonstrated decreased signal in the cerebellum us (Figure 2c), supporting the diagnosis of a reversible encephalopathy syndrome. An underlying mass in the left frontoparietal region was not seen on follow-up imaging. The patient continued an to improve and was discharged to an acute rehabilitation facility. The acute renal failure Case Presentation 2 M improved and creatinine returned to normal. A 58-year-old woman with a medical history significant for hypertension, hyperlipidemia, ed peripheral neuropathy, rheumatoid arthritis (RA), and chronic obstructive pulmonary disease, was found confused and minimally responsive at home on the floor. The patient was found by a ce pt family member who had last seen her, in normal condition, 9 hours prior. On arrival to an outside hospital her GCS was 9 (eye, 3; verbal, 2, intubated; motor, 4), ICH score was 1 (based on GCS). Blood pressure was elevated at 189/105. CT of the head without contrast revealed multiple areas Ac of hemorrhage including a 2.5x2.7x3.8 cm hematoma in the right frontal subcortical region with adjacent edema and small left frontal, right parietal, and parietotemporal subcortical hemorrhages (Figure 3). Bifrontal, biparietal, and bitemporal SAH were also present. Also noted were areas of low attenuation in the cerebellum consistent with age indeterminate ischemia. The patient was intubated for neurological deterioration and airway protection and was transferred to our neuroscience intensive care unit for further management. 6 7 Complete blood count revealed a hemoglobin of 9.8 g/dl, platelet count of 231,000/ml, and a white blood cell count of 10,100/mm3. A basic metabolic panel revealed a glucose of 114 mg/dl, sodium 143 mmol/L, and elevated creatinine of 0.56 mg/dl. Protime was 13.2 seconds. ip t Initial evaluation revealed that she was unresponsive to commands and poorly attentive. Motor examination was non-focal. She was started on intravenous nicardipine and labetalol for cr blood pressure control. MRI of the brain showed edema within the cerebellar hemispheres us (Figure 4a) and pons as well as large parenchymal hemorrhages in the bilateral frontal regions, (Figure 4b), which were now deemed to be unlikely secondary to malignancy or metastatic an disease. Cerebellar and pontine T2-fluid-attenuated inversion recovery (FLAIR) sequence hyperintensities were consistent with PRES. M At the time of admission, the patient was taking duloxetine and sulfasalazine. These medications were discontinued due to their potential role in the precipitation of PRES. With ed ongoing blood pressure control and seizure prophylaxis with levetiracetam, the patient improved clinically and was extubated 8 days after admission. Hospitalization was complicated by a ce pt Clostridium difficile infection, which was treated with metronidazole. The patient’s neurological examination improved gradually. Repeat MRI with and without contrast demonstrated decreased signal in the cerebellum (Figure 4c), supporting the diagnosis of Ac a reversible encephalopathy. She continued to improve and was discharged to an acute rehabilitation facility. Discussion PRES is a clinical and radiological diagnosis. It is characterized by seizures, visual disturbance, altered mental status, and headache—symptoms that occur in conjunction with radiologic evidence of reversible edema within the brain parenchyma, including the posterior 7 8 fossa. Several uncommon variants of PRES have been recently described in the literature, including pontine reversible edema, PRES with syndrome of cerebral autoregulation disturbance, and central variant PRES [16-19]. While uncommon, PRES may also present with ICH, as in the ip t cases described in this report. In a retrospective study of 263 patients diagnosed with PRES, 51 patients (19.4%) were cr found to have ICH [15]. Prior estimates on the rate of ICH in patients with PRES have ranged us from 6.4% to 17% [7, 20, 21]. The higher incidence reported in the Sharma et al. study [15] may reflect the practice of increased MRI utilization when evaluating a patient with ICH, allowing for an visualization of the parenchymal edema that characterizes PRES and differentiating it from other entities. Furthermore, it is possible that, as awareness of PRES and its hemorrhagic variant to it. ed Risk Factors M increases, providers are becoming more sensitive to the diagnosis and the factors that predispose Hypertension was recognized as a risk factor for hemorrhagic PRES in both these cases, ce pt which is consistent with what has been reported in the literature [7, 15]. Of all patients who suffer spontaneous ICH, 75% have hypertension [22], and the approximate incidence of ICH in patients with PRES is 15% [14]. These data support the notion that hypertension is not the sole Ac risk factor for developing ICH in association with PRES. While eclampsia and hypertension are both independent risk factors for ICH [13, 14], other etiologies of ICH associated with a reversible encephalopathy remain undefined. In two separate case series, the association of PRES-ICH with eclampsia ranged from 5.6% to 25.8%; for infections, the incidence varied between 11.5% and 28% [7, 15]. In some reports, ICH rates were higher in patients who had 8 9 underlying eclampsia and sepsis as compared to those with hypertension and the absence of other significant comorbidities [7, 20, 21]. PRES has been linked to the use of several medications. A recent case reported by Zappela ip t and colleagues [23] presented strong evidence that an incidence of PRES was induced by the use of duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI). The authors concluded that cr SNRIs have the potential to raise arterial blood pressure and may play a role in precipitating us hemorrhagic PRES [23], but there is a dearth of supportive literature. A central-variant PRES secondary to the use of sulfasalazine has been reported by Ocek and colleagues [24], but an literature supporting the link between this drug and hemorrhagic PRES is lacking. Both duloxetine and sulfasalazine were among the list of current medications being taken by our Case M 2 patient. The patient in Case 1 had a normal creatinine at baseline with acute renal failure upon ed presentation, and the creatinine normalized as the patient’s underlying condition was treated. In a retrospective study of 24 patients with PRES, renal failure of any etiology was found to be a ce pt precipitant factor of PRES [25]. Kidney failure affects coagulation factors and endothelial function, which may precipitate PRES [26]. Chronic kidney disease is also associated with an increased risk of hemorrhagic stroke, especially in the advanced stages, which may be related to Ac platelet dysfunction, but the role in hemorrhagic PRES is unclear. Rheumatological disorders such as RA are known to be independent risk factors for both ischemic and hemorrhagic stroke. In a recently published meta-analysis of ischemic and hemorrhagic stroke in patients with varying rheumatological disorders, 562 hemorrhagic strokes were reported among patients with RA, with a 43-118 range of incident rate per 100,000 personyears [27]. Although the incidence of PRES among patients was not reported, these data may be 9 10 relevant to our patient in Case 2 who had a history of RA. Inflammatory arthropathies and plasma markers of inflammation appear to play a role in mediating intracranial hemorrhage, and RA increases the risk of hemorrhagic stroke by 60% to 100% when compared to the general ip t population [27]. cr Pathophysiology us There are several ways in which the pathophysiologies of hypertensive hemorrhage versus those of hemorrhagic PRES are thought to differ. Hypertensive hemorrhage is thought to be an precipitated by a mechanical process of gradual pressure-induced degradation of the arteriolar wall, whereby the integrity of the cerebral arterial vasculature becomes compromised. These M mechanically damaged arterioles are pre-disposed to forming micro aneurysms, especially at arteriolar bifurcations, which are at an increased risk of rupture [28, 29]. In contrast, the ed pathophysiological mechanisms underlying hemorrhagic PRES remain unclear. Hemorrhage in PRES is thought in part to be due to the failure of autoregulation of cerebral vascular ce pt permeability [30]. Mechanical stress from hypertension, the modulatory effects of intracellular signaling molecules (e.g., inflammatory cytokines), and extrinsic molecules (e.g., toxins and chemotherapeutic agents), may induce disruption of the blood brain barrier, leading to fluid Ac extravasation and parenchymal edema. This disruption of the local cellular and regulatory milieu may predispose to arterial vasospasm, microvascular thrombosis, and ischemia, leading to bleeding into the cortical parenchyma and/or the subarachnoid space [19, 31]. The pathophysiologic differences in spontaneous ICH and hemorrhagic PRES have implications for patterns seen on radiographic presentation as well [3]. 10 11 Hefzy and colleagues [7] conducted a retrospective analysis of 151 cases with PRES and found that 15.2% of patients developed PRES-ICH. They described several types of hemorrhage: minute, sulcal, subarachnoid, and focal hematoma, with similar incidence rates, and proposed ip t several conditions that may predispose patients to the development of PRES-ICH. For one, the use of certain immunosuppressants such as cyclosporine and tacrolimus can cause endothelial cr injury or induce vasoconstriction through endothelial cell production. Systemic vasoconstriction us caused by these medications can also cause hypertension and subsequently reduce cerebral blood flow due to autoregulatory vasoconstriction. Alternatively, they could directly decrease blood an flow due to cerebral vasoconstriction. The analysis also suggested that cerebral vasoconstriction as well as blood pressure instability could predispose one to a reperfusion injury leading to focal M brain hematomas. It was found that patients with therapeutic anticoagulation were more likely to develop PRES-related hemorrhage. The combination of these various factors could ultimately ed lead to increased risk of hemorrhage in patients diagnosed with PRES. Interestingly, the incidence of hemorrhage in patients with PRES did not positively correlate with the level and ce pt severity of arterial hypertension [7]. Table 1 summarizes case series with PRES and their reported percentages of ICH, which vary from 8% to 36%. Associated coagulopathies were not reported in all the studies, but Ac thrombocytopenia and thrombotic thrombocytopenia purpura appear to be associated risk factors. [INSERT TABLE 1 ABOUT HERE] Imaging It is important to distinguish how hemorrhagic PRES differs in radiologic presentation from isolated ICH related to high blood pressure. In a study of 76 patients with confirmed PRES, 13 11 12 patients were identified as having hemorrhagic PRES. In this sub-cohort, SAH was found to be more common than ICH; however, MRI T2 FLAIR sequencing was used to detect ICH [20]. The use of FLAIR sequencing without comparing to susceptibility weighted imaging for SAH may ip t lead to false positive results, as non-hemorrhagic exudates may mimic the signs of hemorrhage [36]. In both our patients, the hemorrhage was very evident on the CT of the head and magnetic cr resonance played no role in the diagnosis or exclusion of a bleed; rather, brain MRI was obtained reversible encephalopathy such as vascular anomalies. us in our patients to evaluate for underlying lesions and potential etiologies of the ICH other than a an In a larger study, 51 patients were identified with PRES-related hemorrhage [15]. In these, ICH occurred in approximately 90% and SAH occurred in only 27%. In the ICH cases, more M than half of the patients had multiple foci of hemorrhage, which were primarily punctuate in nature and occurred mainly within regions of edema or the corresponding vascular territories ed within the cerebral convexities. In the SAH cases, the presence of blood within the cerebral convexities (sparing the basal cisterns) supported a non-aneurysmal etiology. The degree of ce pt hemorrhage in most of these cases was reportedly mild to moderate with edema lying directly underneath the SAH or in the inferior lobar regions. Coagulopathy was present in 47% of the PRES-ICH cases [15]. However, a smaller study by Aranas et al. [6] showed coagulopathy in Ac 85% of a cohort of 7 patients with PRES-ICH. This prevalence suggests that the underlying process of PRES undoubtedly involves a large portion of the cerebral parenchyma. Treatment The current treatment of ICH associated with PRES is similar to that for other forms of ICH. Blood pressure should be tightly regulated while being mindful of the risk of secondary ischemia from excessive pressure reduction [37, 38]. Intravenous blood pressure–lowering agents such as 12 13 nicardipine are preferred over oral agents, as they are titratable with a faster onset of action [39]. Provoked seizures are typically treated with an antiepileptic agent for 1 to 3 months with repeat imaging recommended after several weeks. Demonstration of improving cerebral edema with no ip t reoccurrence of seizure is sufficient to discontinue anti-epileptic medications [30]. Hyperglycemia, particularly in the first 24 hours, has been linked to a worse functional outcome cr in patients with hemorrhagic PRES [34]. Treatment of hyperglycemia in patients with PRES- us ICH or PRES-SAH and the associated influence on functional outcome have not been selectively investigated; further studies are warranted. an Prognosis PRES is usually a reversible syndrome, but irreversible cases, severe functional impairment, M and increased morbidities and mortalities have been described. There are only a few cohort studies evaluating functional outcome in patients with PRES and factors associated with worse ed outcome. In 2017, 151 cases of patients with PRES were reviewed and in-hospital mortality was analyzed [33]. Altered coagulation and subarachnoid hemorrhage, among other factors such as ce pt sepsis and altered mental status at onset, were related to in-hospital death. Similarly, in 2014, of 47 patients with PRES who were retrospectively evaluated, a fatal outcome was seen in nine patients [40]. In this study, imaging findings of hemorrhage were found to be associated with Ac increased risk of fatal outcome [40]. In another recent study, Schweitzer et al [32] retrospectively reviewed 99 cases of PRES between 2008 and 2014 and analyzed their imaging studies for vasogenic edema and hemorrhage. Imaging at initial presentation showed hemorrhage in 36% of cases with PRES and hemorrhage with mass effect in 7%. In their analysis, ICH with mass effect, vasogenic edema, and presence of restricted diffusion were associated with worse functional outcome [32]. 13 14 In 2012, a PRES study group conducted a retrospective cohort study of 70 patients with PRES [34]. The main outcome measure was a Glasgow Outcome Scale on day 90, with a score of 5 designating good recovery. Ischemic infarcts and/or ICH occurred in 14% of patients, ip t comparable to that reported by Hefzy et al. [7]. Predictors of poor functional outcome included severe hyperglycemia on initial presentation and time to causative-factor control. Hemorrhagic cr conversion of PRES and/or the presence of ICH or SAH did not seem to correlate with poor is difficult to draw a conclusion with certainty. us functional outcome. However, because hemorrhages were not separated from ischemic stroke, it an Martins et al. [41] reported a malignant case of PRES with subtle hemorrhagic conversion in a 14-year old patient, who was taking tacrolimus after renal transplant. The patient subsequently M developed rapidly progressive neurological deterioration and severe vasogenic edema with mild hemorrhage. Imaging studies supported the diagnosis of PRES, and brain death was later ed confirmed. In this malignant case, the presence of ICH in association with PRES did not appear to be the major contributing factor to poor outcome; rather, it was due to the rapid progression of ce pt cerebral edema and other existing comorbidities [41]. Overall, ICH with PRES appears to correlate with worse functional outcome. More Ac prospective studies are warranted to support this observation. Conclusion Initially, there was low suspicion for hemorrhagic PRES in the two patients reported herein. However, in our institution, MRI is a routine imaging modality utilized for evaluation of ICH initially seen on CT scans of the head. MRI is essential to rule out an underlying mass with hemorrhagic conversion or vascular anomalies such as cavernomas. This approach has allowed 14 15 us to recognize cases of PRES with ICH that would otherwise have gone undiagnosed. The changing paradigm of PRES, the presence of new variants, and our ever increasing knowledge of the unique pathophysiology and epidemiology of this syndrome warrant a re-assessment of the ip t preferred imaging modality for suspected ICH. The presence of PRES has important implications for prognosis, as the clinical outcome in PRES is favorable in most cases, although the prognosis cr of hemorrhagic PRES is more variable [6]. us This article presents an important addition to the existing body of work surrounding this entity. The authors believe that increased awareness of this rare complication of PRES is Transparency ce pt None. ed Declaration of funding M an important in guiding prognostication and treatment. Declaration of financial/other interests Ac The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose. Acknowledgements The authors gratefully acknowledge the contributions of Jacqueline Grove, Medical Editor, in manuscript preparation and editing. 15 16 References 1. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334:494–500. ip t 2. Fugate JE, Claassen DO, Cloft HJ, et al. Posterior reversible encephalopathy syndrome: associated clinical and radiologic findings. Mayo Clin Proc. 2010;85:427–432. cr 3. 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Radiology. 1998;208:417–422. 19 20 37. Neutel JM, Smith DH, Wallin D, et al. A comparison of intravenous nicardipine and sodium nitroprusside in the immediate treatment of severe hypertension. Am J Hypertens. 1994;7:623–628. ip t 38. Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet. 2000;356:411–417. 39. Arnoldus EP, Van Laar T. A reversible posterior leukoencephalopathy syndrome. N Engl cr J Med. 1996;334:1745; author reply 1746. us 40. Alhilali LM, Reynolds AR, Fakhran S. A multi-disciplinary model of risk factors for fatal outcome in posterior reversible encephalopathy syndrome. J Neurol Sci. 2014;347:59-65. an 41. Martins WA, Marrone LC. Malignant posterior reversible encephalopathy syndrome: A Ac ce pt ed M case of posterior irreversible encephalopathy syndrome. J Clin Neurol. 2016;12:236–237. 20 21 Table 1. Case series reports of PRES with associated ICH and coagulopathy Year PRES Cases Cases PRES- Coagulopathy Reported ICH n (%) (N) n (%) 2017 99 36 (36%) NR Siebert et al.33 2016 151 52 (34%) 39 (25.8%) Datar et al.34 2015 127 1 (1%) Li et al.19 2013 2 0 (0%) Legriel et al.35 2012 70 Ni et al.25 2010 24 us 6 (4.7%) an 7 (10%) NR 0 (0%) 1 (4.2%) M TTP NR acute intermittent porphyria 51 (19%) 124 (47%) 2010 120 19 (9%) 32 (27%) 2009 7 7 (100%) 6 (85%) ce pt Aranas et al.6 263 ed Fugate et al.2 2010 cr Schweitzer et al.32 Sharma et al.15 Comments ip t Author Hefzy et al.7 2009 151 23 (15%) 8 (5.2%) Bartynski & 2007 136 11 (8%) NR McKinney et al.18 2007 76 13 (17%) NR Schwartz21 2002 110 7 (6%) 3 (2.7%) de Seze et al.17 2000 2 0 (0%) NR Hinchey et al.1 1996 15 0 (0%) NR TTP Ac Boardman3 TCP 21 22 Schwartz et al.4 1992 14 3 (21%) 3 (21%) TCP Abbreviations: ICH = intracranial hemorrhage; NR = not reported; PRES = posterior reversible encephalopathy syndrome; Ac ce pt ed M an us cr ip t PRES-ICH = PRES with intracranial hemorrhage; TCP = thrombocytopenia; TTP = thrombotic thrombocytopenia purpura 22 23 Figure Legend Figure 1. CT of the head shows a large multilobar hyperdense mass consistent with acute us cr ip t hematoma in the (a) deep posterior left frontal lobe and (b) deep anterior left parietal lobe. an Figure2. (a) Fluid-attenuated inversion recovery (FLAIR) MRI showing patchy T2hyperintensity in bilateral cerebellar hemispheres with an appearance that increases suspicion for M reversible encephalopathy syndrome; (b) FLAIR MRI showing heterogeneous intensity in the left parietal region with surrounding vasogenic edema, consistent with a known large intracranial ed hemorrhage; (c) FLAIR MRI shows decreased abnormal signal hyperintensity within the Ac ce pt bilateral cerebellar hemispheres, suggestive of a reversible encephalopathy syndrome. 23 24 Figure 3. CT of the head without contrast on admission showed multiple areas of hyperdensities us cr ip t in bilateral frontal regions, consistent with acute hematomas. Figure 4. (a) T2-FLAIR MRI showing patchy hyperintensity in bilateral cerebellar hemispheres; an (b) T2-FLAIR MRI reveals bilateral frontal intraparenchymal hemorrhages with surrounding Ac ce pt ed M edema; (c) resolution of the abnormal signal involving bilateral cerebellar hemispheres. 24