When Reversible Becomes Fatal: Posterior Reversible Encephalopathy Syndrome as a Precursor to Catastrophic Hemorrhage Post-Liver Transplant

When Reversible Becomes Fatal: Posterior Reversible Encephalopathy Syndrome as a Precursor to Catastrophic Hemorrhage Post-Liver Transplant | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article When Reversible Becomes Fatal: Posterior Reversible Encephalopathy Syndrome as a Precursor to Catastrophic Hemorrhage Post-Liver Transplant Yao Xu, Pen Jing, Yinfeng Wang, Mingming Fei This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7151936/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract A case report of posterior reversible encephalopathy syndrome as a precursor to catastrophic hemorrhage post-liver transplant. Figures Figure 1 The Beginning: A Confusing Clinical Scenario A 47-year-old male with end-stage liver disease was readmitted for fever one month post-liver transplantation. He was receiving tacrolimus for immunosuppression, with a target trough concentration of 5–10 ng/mL. On admission, the patient was fully conscious (Glasgow Coma Scale [GCS] score of 15), with stable vital signs and no focal neurological deficits. Laboratory tests revealed a decreased platelet count (44×10⁹/L), a mildly prolonged activated partial thromboplastin time (aPTT), and a tacrolimus level of 6.88 ng/mL, which was within the therapeutic window. To determine the cause of the fever, cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) was performed, which indicated a central nervous system (CNS) viral infection. A brain magnetic resonance imaging (MRI) showed patchy hyperintensities on T2-weighted/fluid attenuated inversion recovery (FLAIR) sequences in the right frontal cortex and bilateral periventricular white matter, characteristic of vasogenic edema (Figure 1A). The Diagnostic Crossroads: A Clinician's Dilemma This clinical picture presented a critical diagnostic challenge. The patient's clear history of tacrolimus use and the classic vasogenic edema on MRI made posterior reversible encephalopathy syndrome (PRES) the primary consideration. First reported in 1996, PRES is an acute or subacute syndrome characterized by vasogenic edema, typically manifesting as headache, encephalopathy, seizures, visual disturbances, and altered consciousness 1, 2 . The incidence of PRES in solid organ transplant recipients is approximately 0.5%. As a rare neurological complication of liver transplantation, its cerebral lesions are usually reversible with a generally favorable prognosis 3, 4 . Common causes of PRES include cytotoxic drugs like immunosuppressants, as well as pathological states such as acute hypertension, eclampsia, acute kidney injury, sepsis, and hypomagnesemia 5 . Neuroimaging is central to the diagnosis of PRES and must be interpreted in conjunction with clinical symptoms and potential triggers 6 . However, given the patient's complex background of transplantation and immunosuppression, other possibilities required prudent consideration. First, with a confirmed viral infection from CSF mNGS, could the imaging changes represent infection-related demyelination? Second, tacrolimus and hypomagnesemia (which this patient later developed) are known triggers for reversible cerebral vasoconstriction syndrome (RCVS). RCVS is an encephalopathy that can present with "thunderclap" headaches, focal neurological deficits, and segmental vasoconstriction accompanied by cerebral edema 7, 8 . Although our patient lacked the typical headache, including RCVS in the differential diagnosis was essential. Furthermore, the patient had no history of cerebrovascular disease and was hemodynamically stable without focal deficits upon admission. Due to his critical and rapidly progressing condition, we were unable to perform cerebral angiography (computed tomography angiography [CTA]/magnetic resonance angiography [MRA]). Therefore, we could not definitively rule out underlying structural vascular pathologies, such as a ruptured aneurysm, arteriovenous malformation, or dural venous sinus thrombosis, which could also lead to edema and hemorrhage. This diagnostic junction was crucial because it directly informed our assessment of the patient's hemorrhage risk. A diagnosis of "typical" PRES might have suggested a good prognosis and a reversible course. However, if the underlying cause was RCVS or infectious demyelination, the treatment strategies and prognostic evaluation would be entirely different. This underscores a critical lesson: in transplant patients, where the pathological processes of multiple CNS complications have similarities and overlaps, a presentation that appears consistent with PRES must undergo rigorous differential diagnosis. Fatal Clinical Evolution Given that tacrolimus is one of the most common drug-related causes of PRES, and the distribution of vasogenic edema on MRI, while not classically posterior-dominant, is still a common presentation of PRES 9, 10 , our clinical reasoning initially favored PRES. Moreover, the patient lacked the typical thunderclap headache of RCVS. Based on this, we highly suspected that tacrolimus-induced endothelial dysfunction was the core pathophysiological mechanism. However, the clinical course was anything but "reversible." On the seventh day of admission, the patient developed malignant hypertension (systolic pressure surged to 212 mmHg) and rapidly progressed into a deep coma (GCS 4+T). An emergency head Computed Tomography (CT) confirmed our most feared complication: multiple intraparenchymal hemorrhages in the right cerebral hemisphere with significant midline shift (Figure 1B-a). Despite maximal rescue interventions—including discontinuing tacrolimus, an emergency decompressive craniectomy with hematoma evacuation, and transfusion of blood products to correct coagulopathy (platelets had dropped to 26×10⁹/L)—a follow-up CT showed new hemorrhages in the right frontoparietal lobe, left ventricle, and infratentorial space (Figure 1B-b, 1B-c). Ultimately, the patient died from irreversible brain failure due to multifocal cerebral hemorrhage. Re-examining PRES: A Catalyst for Cerebral Hemorrhage The tragic and irreversible outcome of this case offers a profound lesson. In high-risk contexts such as liver transplantation, PRES should not be viewed as an isolated, benign syndrome but rather as a critical pathophysiological pathway to fatal intracerebral hemorrhage. Cerebral hemorrhage is a significant neurological complication of liver transplantation, with several case series reporting an incidence of around 10% and a mortality rate as high as 80% 11 . The current treatment for PRES is mainly supportive, focusing on blood pressure control, anti-epileptic drugs, maintaining electrolyte balance, and reducing cytotoxic drug exposure 2 . While the neurological symptoms in most patients are typically reversible, the development of intracranial hemorrhage, especially intraventricular hemorrhage, can lead to fatal consequences 12 . Clinical studies have found that approximately 10% to 25% of PRES patients have concomitant intracranial hemorrhage. Among these, intraventricular hemorrhage is one of the most severe complications, associated with an extremely poor prognosis and a significantly increased risk of death 2, 13 , shattering the traditional impression of PRES as "reversible." Reviewing this case, the common risk factors for post-transplant cerebral hemorrhage (e.g., history of chronic hypertension, severe coagulopathy) were not prominent before the bleeding occurred. The patient's blood pressure was well-controlled before the surge, and the coagulopathy was only mild. We deduce that the real "culprit" behind the rapid deterioration was the core pathology of PRES: widespread endothelial cell damage and blood-brain barrier (BBB) disruption induced by tacrolimus. This process not only caused vasogenic edema but also involved the activation of endothelial cells, which increased vascular permeability and disrupted cerebral blood flow autoregulation 9, 14, 15 . When the patient encountered any stressor—such as the infection, blood pressure fluctuations, and electrolyte disturbances seen in this case—the fragile vascular network could not compensate, leading to acute hyperperfusion injury. Finally, under the "final blow" of the hypertensive crisis, multifocal, irreversible hemorrhage occurred. Therefore, PRES did not merely "coincide" with the ICH; the pathophysiology of PRES was likely the direct mechanism causing ICH in the transplant setting. To consider it merely a "reversible" encephalopathy is to severely underestimate its hemorrhagic propensity and potential for malignant progression. Lessons Learned 1. In high-risk patients, such as transplant recipients maintained on immunosuppressive therapy with calcineurin inhibitors like tacrolimus, a high index of suspicion for PRES is warranted. Given that tacrolimus is a proven independent risk factor, any unexplained neurological symptoms or nonspecific imaging changes like white matter edema should be taken seriously and carefully evaluated for a clinical diagnosis of PRES. 2. The differential diagnosis for PRES should include posterior circulation or watershed cerebral infarction, CNS infections, demyelinating diseases, RCVS, and structural vascular lesions such as ruptured aneurysm, arteriovenous malformation, or dural venous sinus thrombosis. When conditions permit, etiological diagnosis, especially CSF analysis, and vascular imaging such as CTA/MRA should be performed early to confirm or exclude vascular structural abnormalities and the presence of RCVS. 3. The hemorrhagic risk of PRES should be given serious clinical attention, and it should not be considered an absolutely benign syndrome. Patients with a high clinical suspicion of PRES should undergo dynamic risk assessment. This involves stratifying patients' hemorrhage risk by combining their immunosuppressive regimen, physiological parameters (blood pressure fluctuations, coagulation status, electrolyte disturbances), and imaging markers (such as microbleeds). 4. For PRES patients at high risk of hemorrhage, proactive blood pressure control, decisive adjustment of the immunosuppressive regimen, active management of endothelial function to stabilize the BBB, and enhanced neurocritical care with individualized monitoring and treatment strategies are necessary. Declarations Details Page 1. Confirm that manuscript complies with all instructions to authors We confirm that the submitted manuscript meticulously adheres to all instructions provided to authors, encompassing formatting, stylistic requirements, and submission guidelines. 2. Detailed description of individual author contributions X.Y. conceived the study, designed the structure, performed literature review, drafted the initial manuscript, and provided critical revisions. J.P. collected and interpreted patient data, contributed to the discussion section, prepared figures, and reviewed the manuscript. W.Y.F. provided expert neurological interpretation of imaging, and extensively revised the manuscript for intellectual content. F.M.M. ensured accuracy of clinical management details, and approved the final version. X.Y. and J.P. are co-first authors, and F.M.M. is corresponding author. 3. Confirm that authorship requirements have been met and the final manuscript was approved by all authors We confirm that all authorship requirements as stipulated by Neurocritical Care have been met. Each listed author has made substantial contributions to the conception, design, acquisition, analysis, or interpretation of the data, drafted or critically revised the manuscript for important intellectual content, and has given final approval of the version to be published. All authors agree to be accountable for all aspects of the work. 4. Confirm that this manuscript has not been published elsewhere and is not under consideration by another journal We confirm that this manuscript is an original work, has not been published elsewhere, and is not currently under consideration for publication by any other journal or publication. 5. Confirm adherence to ethical guidelines and indicate ethical approvals (IRB) and use of informed consent, as appropriate. Retrospective studies require a statement regarding IRB approval We confirm strict adherence to all ethical guidelines pertinent to submissions. As a retrospective study, IRB approval was obtained from the Biomedical Ethics Committee of the University of Science and Technology of China (USTC) . Written informed consent was obtained from the patient for the publication and any accompanying images. 6. Disclose Conflicts of Interest for all authors All authors declare no conflicts of interest related to this manuscript. 7. Confirm the use of reporting checklist, if appropriate A specific reporting checklist was not applicable. 8. List sources of funding for the study This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334(8):494–500. Geocadin RG. Posterior Reversible Encephalopathy Syndrome. N Engl J Med. 2023;388(23):2171–8. Bartynski WS, Tan HP, Boardman JF, Shapiro R, Marsh JW. Posterior reversible encephalopathy syndrome after solid organ transplantation. AJNR Am J Neuroradiol. 2008;29(5):924–30. Zeeman GG, Cunningham FG. Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia. Am J Obstet Gynecol. 2014;210(4):378–9. Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol. 2015;14(9):914–25. Bartynski WS, Boardman JF. Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol. 2007;28(7):1320–7. Liberman AL, Zhang C, Parikh NS, Salehi Omran S, Navi BB, Lappin RI, et al. Misdiagnosis of Posterior Reversible Encephalopathy Syndrome and Reversible Cerebral Vasoconstriction Syndrome in the Emergency Department. J Am Heart Association. 2023;12(19):e030009. Ducros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol. 2012;11(10):906–17. Velilla Aparicio E, Fernández Yunquera A, Miranda Bautista J, Salcedo M. Posterior reversible encephalopathy syndrome (PRES) in post liver transplantation. Rev Esp Enferm Dig. 2023;115(3):138–40. Tetsuka S, Ogawa T. Posterior reversible encephalopathy syndrome: A review with emphasis on neuroimaging characteristics. J Neurol Sci. 2019;404:72–9. Wang WL, Yang ZF, Lo CM, Liu CL, Fan ST. Intracerebral hemorrhage after liver transplantation. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver. Transplantation Soc. 2000;6(3):345–8. Chen Z, Shen GQ, Lerner A, Gao B. Immune system activation in the pathogenesis of posterior reversible encephalopathy syndrome. Brain Res Bull. 2017;131:93–9. Hefzy HM, Bartynski WS, Boardman JF, Lacomis D. Hemorrhage in posterior reversible encephalopathy syndrome: imaging and clinical features. AJNR Am J Neuroradiol. 2009;30(7):1371–9. Verona P, Edwards J, Hubert K, Avorio F, Re VL, Di Stefano R, et al. Tacrolimus-Induced Neurotox After Transplant: Literature Rev Drug Saf. 2024;47(5):419–38. Barbas AS, Rege AS, Castleberry AW, Gommer J, Ellis MJ, Brennan TV, et al. Posterior reversible encephalopathy syndrome independently associated with tacrolimus and sirolimus after multivisceral transplantation. Am J transplantation: official J Am Soc Transplantation Am Soc Transpl Surg. 2013;13(3):808–10. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7151936","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":489395146,"identity":"e59c1051-556c-4d57-b8eb-64a89d67b7e4","order_by":0,"name":"Yao Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYBACNmbmA8Z//9nI2TczHyBOCx87W0IBD1uasQF7WwJxWuT4eRQ+8LAdStzAc8aAWIfxMG6Q4DnAuF0i5+ONNwx2croNBLXwHjYwkLjDbDkjd7PlHIZkY7MDBLXwpRkkGDxjY7iRu02ah+FA4jbCWnjMfxxIOMzDcCPnGdFaDAwbDhyWMDhzho1YLWwJxowNaQaS7W3GlnMMiPCLfP/hA0AtNvX9zMwPb7ypsJMjqAUFSPAQGTXIWkjVMQpGwSgYBSMCAAAWlz3Cb1Hl4wAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0002-5511-5801","institution":"The First Affiliated Hospital of USTC: Anhui Provincial Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yao","middleName":"","lastName":"Xu","suffix":""},{"id":489395147,"identity":"b3d93969-7c6c-4d0c-aeb9-d5effc93b87c","order_by":1,"name":"Pen Jing","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC: Anhui Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Pen","middleName":"","lastName":"Jing","suffix":""},{"id":489395148,"identity":"22158fc0-e8fc-47f4-9aa7-3d1859e0d5c7","order_by":2,"name":"Yinfeng Wang","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC: Anhui Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yinfeng","middleName":"","lastName":"Wang","suffix":""},{"id":489395149,"identity":"7d6e06c4-e809-4a5b-8b37-06169a520bc8","order_by":3,"name":"Mingming Fei","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC: Anhui Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mingming","middleName":"","lastName":"Fei","suffix":""}],"badges":[],"createdAt":"2025-07-17 19:40:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7151936/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7151936/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87975263,"identity":"0e83d81f-7ded-493d-b2ed-e82ba9f2bb18","added_by":"auto","created_at":"2025-07-31 04:03:44","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":732452,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003epresents the MRI (magnetic resonance imaging) findings approximately one month post-transplant surgery. The T2/fluid attenuated inversion recovery (FLAIR) sequence images demonstrated hyperintense signals in the right frontal cortex and periventricular white matter regions bilaterally. For \u003cstrong\u003eB\u003c/strong\u003e, \u003cstrong\u003ea\u003c/strong\u003edisplays the emergency computed tomography (CT) results obtained during the patient's acute intracerebral hemorrhage episode, revealing multiple hyperdense images in the right cerebral hemisphere along with midline shift caused by compression. \u003cstrong\u003eb\u003c/strong\u003e shows the follow-up CT scan performed after the patient underwent hematoma evacuation surgery, where postsurgical morphological changes were evident. \u003cstrong\u003ec\u003c/strong\u003e further illustrates the dynamic imaging evolution of the intracerebral hemorrhage at the 24-hour postoperative mark.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7151936/v1/b0da573048e8f41f5410631e.jpeg"},{"id":88825080,"identity":"4191a92e-558e-41c1-b1d2-70f68fd5ec98","added_by":"auto","created_at":"2025-08-11 18:40:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1056128,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7151936/v1/80726147-cf2f-4562-9934-40fc41ce0ac4.pdf"}],"financialInterests":"","formattedTitle":"When Reversible Becomes Fatal: Posterior Reversible Encephalopathy Syndrome as a Precursor to Catastrophic Hemorrhage Post-Liver Transplant","fulltext":[{"header":"The Beginning: A Confusing Clinical Scenario","content":"\u003cp\u003eA 47-year-old male with end-stage liver disease was readmitted for fever one month post-liver transplantation. He was receiving tacrolimus for immunosuppression, with a target trough concentration of 5–10 ng/mL. On admission, the patient was fully conscious (Glasgow Coma Scale [GCS] score of 15), with stable vital signs and no focal neurological deficits. Laboratory tests revealed a decreased platelet count (44×10⁹/L), a mildly prolonged activated partial thromboplastin time (aPTT), and a tacrolimus level of 6.88 ng/mL, which was within the therapeutic window.\u003c/p\u003e\n\u003cp\u003eTo determine the cause of the fever, cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) was performed, which indicated a central nervous system (CNS) viral infection. A brain magnetic resonance imaging (MRI) showed patchy hyperintensities on T2-weighted/fluid attenuated inversion recovery (FLAIR) sequences in the right frontal cortex and bilateral periventricular white matter, characteristic of vasogenic edema (Figure 1A).\u003c/p\u003e"},{"header":"The Diagnostic Crossroads: A Clinician's Dilemma","content":"\u003cp\u003eThis clinical picture presented a critical diagnostic challenge. The patient's clear history of tacrolimus use and the classic vasogenic edema on MRI made posterior reversible encephalopathy syndrome (PRES) the primary consideration. First reported in 1996, PRES is an acute or subacute syndrome characterized by vasogenic edema, typically manifesting as headache, encephalopathy, seizures, visual disturbances, and altered consciousness\u003csup\u003e1, 2\u003c/sup\u003e. The incidence of PRES in solid organ transplant recipients is approximately 0.5%. As a rare neurological complication of liver transplantation, its cerebral lesions are usually reversible with a generally favorable prognosis\u003csup\u003e3, 4\u003c/sup\u003e. Common causes of PRES include cytotoxic drugs like immunosuppressants, as well as pathological states such as acute hypertension, eclampsia, acute kidney injury, sepsis, and hypomagnesemia\u003csup\u003e5\u003c/sup\u003e. Neuroimaging is central to the diagnosis of PRES and must be interpreted in conjunction with clinical symptoms and potential triggers\u003csup\u003e6\u003c/sup\u003e. However, given the patient's complex background of transplantation and immunosuppression, other possibilities required prudent consideration.\u003c/p\u003e\n\u003cp\u003eFirst, with a confirmed viral infection from CSF mNGS, could the imaging changes represent infection-related demyelination? Second, tacrolimus and hypomagnesemia (which this patient later developed) are known triggers for reversible cerebral vasoconstriction syndrome (RCVS). RCVS is an encephalopathy that can present with \"thunderclap\" headaches, focal neurological deficits, and segmental vasoconstriction accompanied by cerebral edema\u003csup\u003e7, 8\u003c/sup\u003e. Although our patient lacked the typical headache, including RCVS in the differential diagnosis was essential. Furthermore, the patient had no history of cerebrovascular disease and was hemodynamically stable without focal deficits upon admission. Due to his critical and rapidly progressing condition, we were unable to perform cerebral angiography (computed tomography angiography [CTA]/magnetic resonance angiography [MRA]). Therefore, we could not definitively rule out underlying structural vascular pathologies, such as a ruptured aneurysm, arteriovenous malformation, or dural venous sinus thrombosis, which could also lead to edema and hemorrhage.\u003c/p\u003e\n\u003cp\u003eThis diagnostic junction was crucial because it directly informed our assessment of the patient's hemorrhage risk. A diagnosis of \"typical\" PRES might have suggested a good prognosis and a reversible course. However, if the underlying cause was RCVS or infectious demyelination, the treatment strategies and prognostic evaluation would be entirely different. This underscores a critical lesson: in transplant patients, where the pathological processes of multiple CNS complications have similarities and overlaps, a presentation that appears consistent with PRES must undergo rigorous differential diagnosis.\u003c/p\u003e"},{"header":"Fatal Clinical Evolution","content":"\u003cp\u003eGiven that tacrolimus is one of the most common drug-related causes of PRES, and the distribution of vasogenic edema on MRI, while not classically posterior-dominant, is still a common presentation of PRES\u003csup\u003e9, 10\u003c/sup\u003e, our clinical reasoning initially favored PRES. Moreover, the patient lacked the typical thunderclap headache of RCVS. Based on this, we highly suspected that tacrolimus-induced endothelial dysfunction was the core pathophysiological mechanism.\u003c/p\u003e\n\u003cp\u003eHowever, the clinical course was anything but \"reversible.\" On the seventh day of admission, the patient developed malignant hypertension (systolic pressure surged to 212 mmHg) and rapidly progressed into a deep coma (GCS 4+T). An emergency head Computed Tomography (CT) confirmed our most feared complication: multiple intraparenchymal hemorrhages in the right cerebral hemisphere with significant midline shift (Figure 1B-a). Despite maximal rescue interventions—including discontinuing tacrolimus, an emergency decompressive craniectomy with hematoma evacuation, and transfusion of blood products to correct coagulopathy (platelets had dropped to 26×10⁹/L)—a follow-up CT showed new hemorrhages in the right frontoparietal lobe, left ventricle, and infratentorial space (Figure 1B-b, 1B-c). Ultimately, the patient died from irreversible brain failure due to multifocal cerebral hemorrhage.\u003c/p\u003e"},{"header":"Re-examining PRES: A Catalyst for Cerebral Hemorrhage","content":"\u003cp\u003eThe tragic and irreversible outcome of this case offers a profound lesson. In high-risk contexts such as liver transplantation, PRES should not be viewed as an isolated, benign syndrome but rather as a critical pathophysiological pathway to fatal intracerebral hemorrhage.\u003c/p\u003e\n\u003cp\u003eCerebral hemorrhage is a significant neurological complication of liver transplantation, with several case series reporting an incidence of around 10% and a mortality rate as high as 80%\u003csup\u003e11\u003c/sup\u003e. The current treatment for PRES is mainly supportive, focusing on blood pressure control, anti-epileptic drugs, maintaining electrolyte balance, and reducing cytotoxic drug exposure\u003csup\u003e2\u003c/sup\u003e. While the neurological symptoms in most patients are typically reversible, the development of intracranial hemorrhage, especially intraventricular hemorrhage, can lead to fatal consequences\u003csup\u003e12\u003c/sup\u003e. Clinical studies have found that approximately 10% to 25% of PRES patients have concomitant intracranial hemorrhage. Among these, intraventricular hemorrhage is one of the most severe complications, associated with an extremely poor prognosis and a significantly increased risk of death\u003csup\u003e2, 13\u003c/sup\u003e, shattering the traditional impression of PRES as \"reversible.\"\u003c/p\u003e\n\u003cp\u003eReviewing this case, the common risk factors for post-transplant cerebral hemorrhage (e.g., history of chronic hypertension, severe coagulopathy) were not prominent before the bleeding occurred. The patient's blood pressure was well-controlled before the surge, and the coagulopathy was only mild. We deduce that the real \"culprit\" behind the rapid deterioration was the core pathology of PRES: widespread endothelial cell damage and blood-brain barrier (BBB) disruption induced by tacrolimus. This process not only caused vasogenic edema but also involved the activation of endothelial cells, which increased vascular permeability and disrupted cerebral blood flow autoregulation\u003csup\u003e9, 14, 15\u003c/sup\u003e. When the patient encountered any stressor—such as the infection, blood pressure fluctuations, and electrolyte disturbances seen in this case—the fragile vascular network could not compensate, leading to acute hyperperfusion injury. Finally, under the \"final blow\" of the hypertensive crisis, multifocal, irreversible hemorrhage occurred. Therefore, PRES did not merely \"coincide\" with the ICH; the pathophysiology of PRES was likely the direct mechanism causing ICH in the transplant setting. To consider it merely a \"reversible\" encephalopathy is to severely underestimate its hemorrhagic propensity and potential for malignant progression.\u003c/p\u003e"},{"header":"Lessons Learned","content":"\u003cp\u003e1. In high-risk patients, such as transplant recipients maintained on immunosuppressive therapy with calcineurin inhibitors like tacrolimus, a high index of suspicion for PRES is warranted. Given that tacrolimus is a proven independent risk factor, any unexplained neurological symptoms or nonspecific imaging changes like white matter edema should be taken seriously and carefully evaluated for a clinical diagnosis of PRES.\u003c/p\u003e\n\u003cp\u003e2. The differential diagnosis for PRES should include posterior circulation or watershed cerebral infarction, CNS infections, demyelinating diseases, RCVS, and structural vascular lesions such as ruptured aneurysm, arteriovenous malformation, or dural venous sinus thrombosis. When conditions permit, etiological diagnosis, especially CSF analysis, and vascular imaging such as CTA/MRA should be performed early to confirm or exclude vascular structural abnormalities and the presence of RCVS.\u003c/p\u003e\n\u003cp\u003e3. The hemorrhagic risk of PRES should be given serious clinical attention, and it should not be considered an absolutely benign syndrome. Patients with a high clinical suspicion of PRES should undergo dynamic risk assessment. This involves stratifying patients' hemorrhage risk by combining their immunosuppressive regimen, physiological parameters (blood pressure fluctuations, coagulation status, electrolyte disturbances), and imaging markers (such as microbleeds).\u003c/p\u003e\n\u003cp\u003e4. For PRES patients at high risk of hemorrhage, proactive blood pressure control, decisive adjustment of the immunosuppressive regimen, active management of endothelial function to stabilize the BBB, and enhanced neurocritical care with individualized monitoring and treatment strategies are necessary.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eDetails Page\u003c/h2\u003e\u003cp\u003e\u003cem\u003e1. Confirm that manuscript complies with all instructions to authors\u003c/em\u003e\u003c/p\u003e\u003cp\u003eWe confirm that the submitted manuscript meticulously adheres to all instructions provided to authors, encompassing formatting, stylistic requirements, and submission guidelines.\u003c/p\u003e\u003cp\u003e\u003cem\u003e2. Detailed description of individual author contributions\u003c/em\u003e\u003c/p\u003e\u003cp\u003eX.Y. conceived the study, designed the structure, performed literature review, drafted the initial manuscript, and provided critical revisions. J.P. collected and interpreted patient data, contributed to the discussion section, prepared figures, and reviewed the manuscript. W.Y.F. provided expert neurological interpretation of imaging, and extensively revised the manuscript for intellectual content. F.M.M. ensured accuracy of clinical management details, and approved the final version. X.Y. and J.P. are co-first authors, and F.M.M. is corresponding author.\u003c/p\u003e\u003cp\u003e\u003cem\u003e3. Confirm that authorship requirements have been met and the final manuscript was approved by all authors\u003c/em\u003e\u003c/p\u003e\u003cp\u003eWe confirm that all authorship requirements as stipulated by \u003cem\u003eNeurocritical Care\u003c/em\u003e have been met. Each listed author has made substantial contributions to the conception, design, acquisition, analysis, or interpretation of the data, drafted or critically revised the manuscript for important intellectual content, and has given final approval of the version to be published. All authors agree to be accountable for all aspects of the work.\u003c/p\u003e\u003cp\u003e\u003cem\u003e4. Confirm that this manuscript has not been published elsewhere and is not under consideration by another journal\u003c/em\u003e\u003c/p\u003e\u003cp\u003e We confirm that this manuscript is an original work, has not been published elsewhere, and is not currently under consideration for publication by any other journal or publication.\u003c/p\u003e\u003cp\u003e\u003cem\u003e5. Confirm adherence to ethical guidelines and indicate ethical approvals (IRB) and use of informed consent, as appropriate. Retrospective studies require a statement regarding IRB approval\u003c/em\u003e\u003c/p\u003e\u003cp\u003eWe confirm strict adherence to all ethical guidelines pertinent to submissions. As a retrospective study, IRB approval was obtained from the \u003cem\u003eBiomedical Ethics Committee of the University of Science and Technology of China (USTC)\u003c/em\u003e. Written informed consent was obtained from the patient for the publication and any accompanying images.\u003c/p\u003e\u003cp\u003e\u003cem\u003e6. Disclose Conflicts of Interest for all authors\u003c/em\u003e\u003c/p\u003e\u003cp\u003eAll authors declare no conflicts of interest related to this manuscript.\u003c/p\u003e\u003cp\u003e\u003cem\u003e7. Confirm the use of reporting checklist, if appropriate\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA specific reporting checklist was not applicable.\u003c/p\u003e\u003cp\u003e\u003cem\u003e8. List sources of funding for the study\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThis study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med. 1996;334(8):494\u0026ndash;500.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGeocadin RG. Posterior Reversible Encephalopathy Syndrome. N Engl J Med. 2023;388(23):2171\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBartynski WS, Tan HP, Boardman JF, Shapiro R, Marsh JW. Posterior reversible encephalopathy syndrome after solid organ transplantation. AJNR Am J Neuroradiol. 2008;29(5):924\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZeeman GG, Cunningham FG. Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia. Am J Obstet Gynecol. 2014;210(4):378\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol. 2015;14(9):914\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBartynski WS, Boardman JF. Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol. 2007;28(7):1320\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiberman AL, Zhang C, Parikh NS, Salehi Omran S, Navi BB, Lappin RI, et al. Misdiagnosis of Posterior Reversible Encephalopathy Syndrome and Reversible Cerebral Vasoconstriction Syndrome in the Emergency Department. J Am Heart Association. 2023;12(19):e030009.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDucros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol. 2012;11(10):906\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVelilla Aparicio E, Fern\u0026aacute;ndez Yunquera A, Miranda Bautista J, Salcedo M. Posterior reversible encephalopathy syndrome (PRES) in post liver transplantation. Rev Esp Enferm Dig. 2023;115(3):138\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTetsuka S, Ogawa T. Posterior reversible encephalopathy syndrome: A review with emphasis on neuroimaging characteristics. J Neurol Sci. 2019;404:72\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang WL, Yang ZF, Lo CM, Liu CL, Fan ST. Intracerebral hemorrhage after liver transplantation. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver. Transplantation Soc. 2000;6(3):345\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen Z, Shen GQ, Lerner A, Gao B. Immune system activation in the pathogenesis of posterior reversible encephalopathy syndrome. Brain Res Bull. 2017;131:93\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHefzy HM, Bartynski WS, Boardman JF, Lacomis D. Hemorrhage in posterior reversible encephalopathy syndrome: imaging and clinical features. AJNR Am J Neuroradiol. 2009;30(7):1371\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVerona P, Edwards J, Hubert K, Avorio F, Re VL, Di Stefano R, et al. Tacrolimus-Induced Neurotox After Transplant: Literature Rev Drug Saf. 2024;47(5):419\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBarbas AS, Rege AS, Castleberry AW, Gommer J, Ellis MJ, Brennan TV, et al. Posterior reversible encephalopathy syndrome independently associated with tacrolimus and sirolimus after multivisceral transplantation. Am J transplantation: official J Am Soc Transplantation Am Soc Transpl Surg. 2013;13(3):808\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7151936/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7151936/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA case report of posterior reversible encephalopathy syndrome as a precursor to catastrophic hemorrhage post-liver transplant.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"When Reversible Becomes Fatal: Posterior Reversible Encephalopathy Syndrome as a Precursor to Catastrophic Hemorrhage Post-Liver Transplant","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-31 04:03:35","doi":"10.21203/rs.3.rs-7151936/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"014dc730-ba44-4512-ad8b-f4caec352cf7","owner":[],"postedDate":"July 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-11T18:32:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-31 04:03:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7151936","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7151936","identity":"rs-7151936","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}