PRES in the Setting of Mycophenolate Use for Lupus Nephritis: A Diagnostic Challenge With Therapeutic Implications

PRES in the Setting of Mycophenolate Use for Lupus Nephritis: A Diagnostic Challenge With Therapeutic Implications | 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 PRES in the Setting of Mycophenolate Use for Lupus Nephritis: A Diagnostic Challenge With Therapeutic Implications Alyssa Breazeale, Mark Megaly, Pamraj Sharma This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7843447/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Jan, 2026 Read the published version in SN Comprehensive Clinical Medicine → Version 1 posted 11 You are reading this latest preprint version Abstract Posterior reversible encephalopathy syndrome (PRES) is a rare condition causing posterior brain edema, seizures, visual changes, and altered mental status. It is associated with autoimmune disease, immunosuppressants, eclampsia, renal disease, and malignancy. PRES may cause injury through either hypertension-induced hyperperfusion, causing edema, or endothelial dysfunction due to inflammation or cytotoxic injury. Prompt recognition, blood pressure control, and addressing triggers typically lead to full recovery. Here we discuss the case of a 27-year-old woman who initially presented with debilitating arthralgia and a vasculitic rash on both lower extremities. She was hospitalized while an autoimmune workup was conducted. The investigation revealed autoimmune disease, and outpatient rheumatology later confirmed systemic lupus erythematosus complicated by class IV lupus nephritis. She was initiated on therapy with mycophenolate, however, within one week she returned to the hospital with seizures and marked hypertension. MRI findings and clinical features were consistent with PRES. Given the close timing with therapy initiation, mycophenolate was suspected as the cause. With withdrawal of immunotherapy and strict blood pressure control, she improved significantly. Follow-up imaging at 3 months demonstrated almost complete resolution of PRES. This case aims to elucidate a potential novel cause of PRES associated with mycophenolate use. We propose that mycophenolate may dysregulate vascular adhesion molecules, impairing endothelial response to hypertension-induced damage. Our goal is to raise awareness and guide clinicians managing patients on mycophenolate. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Posterior Reversible Encephalopathy Syndrome (PRES) is a clinicoradiological syndrome elucidated in 1996 in the landmark study Hinchey et al. that demonstrated a pattern of acute to subacute headaches, altered mental status, seizures, and visual deficits in 15 hospitalized patients at New England Medical Center in Boston and Hospital Sainte Anne in Paris from 1988 to 1994. Many of these patients developed pathology secondary to acute hypertensive episodes (73%) superimposed in the setting of immunosuppressive therapy (53%), eclampsia (20%), or renal disease (26%). Notably, these patients shared radiological abnormalities of vasogenic white matter edema in the posterior parietal, temporal, or occipital regions of the brain which were reversed with antihypertensive medications and withdrawal or reduction of immunosuppressive therapy [ 1 ]. Further studies identified a wider range of etiologies than originally believed including additional associations to sepsis with 85% prevalence of gram-positive infection [ 2 ], autoimmune diseases [ 3 , 4 ], and autonomic dysregulation [ 3 ]. The pathophysiology of PRES is still largely debated as no randomized controlled studies have been conducted to gather strong epidemiological data. There are two main hypotheses on the pathophysiology underlying this syndrome. The first model relies on the notion of hypertension induced hyperperfusion [ 3 ]. There are autoregulatory mechanisms in place in order to maintain adequate blood flow to the brain and avoid hyper or hypoperfusion. In the case of an acute rise of blood pressure, vasoconstriction is triggered to reduce blood flow and achieve constant cerebral blood flow. However, at 160 mmHg systolic pressure or greater, this autoregulatory vasoconstriction is overcome and cerebral blood flow continues to rise with rising blood pressures [ 5 ]. Increased hydrostatic pressure can then lead to the breakdown of the blood-brain barrier causing extravasation of fluid from the cerebral blood vessels leading to vasogenic edema. This theory's explanation for why PRES mostly affects the posterior circulation is due to the belief that it has fewer adaptive mechanisms to regulate the extent of extravasation and breakdown of the blood-brain barrier. This explanation stems from the finding of significantly less adrenergic perivascular fibrosis innervating the posterior cerebral circulation compared to the anterior cerebral circulation [ 6 ]. The occurrence of hypertension in the majority of PRES patients at onset and the resulting affected edematous zones are characteristics that would seem to support this theory [ 7 ]. However, this fails to account for the 30% of PRES patients who do not present with blood pressures in a hypertensive range [ 4 ]. An alternative theory proposes that PRES is as the result of endothelial dysfunction caused by either an inflammatory state or direct cytotoxicity. This theory is supported by the observation that PRES is usually associated with a systemic inflammatory process such as sepsis, eclampsia, transplantation, autoimmune disease or exposure to certain cytotoxins. Angiographic studies in PRES demonstrated reversible focal and diffuse abnormalities thought to demonstrate endothelial dysfunction [ 6 ]. In the context of elevated blood pressures, resultant vasoconstriction that occurs through autoregulation worsens endothelial dysfunction in the context of pre-existing inflammatory versus cytotoxic injury. This could also explain the reversibility of the condition with hypertension management [ 2 ]. This case will seek to demonstrate a unique cause of PRES while extrapolating the described physiological theories to the role of Mycophenolate in syndrome development. Though immunosuppressive therapy has been recognized as a keystone etiology of PRES much of the medical literature supports the relationship between PRES development and the administration of calcineurin inhibitors. Mycophenolate is a rarely identified cause of PRES and has been largely underrepresented with only five prior case studies. Patients involved in these cases share many similarities in presentation and demographic background as highlighted in Table 1 [ 8 – 12 ]. We seek to expand upon this limited literature base and demonstrate one such case to further the recognition of the role of Mycophenolate in the development of PRES. Table 1 Summation of case studies into Mycophenolate associated PRES. Patients demonstrated similarities in Gender (100% female), Age with mean age of 23.2 y/o, and renal pathology (80% Lupus Nephritis IV); patients varied in duration of treatment with a mean treatment duration of 36.8 days and median of 5 days. Blood pressure data is inconclusive due to inconsistent reporting. [ 8 – 12 ] Patient Demographics Renal pathology Duration of Mycophenolate use Blood Pressure on Presentation Author and Publication year 16F Lupus Nephritis IV 20 days 135/84 mmHg Dai et. al, 2023 21F Lupus Nephritis IV 5 days Unreported Chaves et Al, 2021 29F Lupus Nephritis IV 4 days Unreported Khajuria et. al, 2016 22F Lupus Nephritis IV 5 days 190/110 mmHg Zang et. al, 2018 28F IGA Nephropathy 5 months Unreported Khanal et. al, 2021 Report of Case A 27-year-old African American female had initially presented for care with a chief complaint of persistent swelling in the bilateral lower extremities of a 2-week duration. She also reported a new onset rash of her lower extremities and diffuse arthralgias throughout. Her arthralgias were severe with the highest intensity in the lower extremities rendering the patient non-weight bearing. On physical exam, the patient was noted to have a non-blanchable, erythematous, maculopapular rash with central areas of purpura (Image 1). The patient was admitted to the hospital, and an autoimmune investigation was initiated. Autoimmune studies were remarkable for the presence of elevated Anti- Nuclear Antibodies, Anti-DsDNA, Anti-Smith, Antihistone, and Antichromatin antibodies. Subsequent studies also demonstrated hypocomplementemia, elevated CPK, and elevated IGE. During her hospitalization she received Solu Medrol and Toradol with marked improvement. She was then transitioned to oral Prednisone prior to discharge and scheduled for rheumatology follow up. In the outpatient setting she was formally diagnosed with Systemic Lupus Erythematosus by Rheumatology and started on immunosuppressive therapy with Mycophenolate and Prednisone. Six days following initiation of treatment the patient again presented to the emergency department with generalized seizures. The patient's mother provided history at that time, stating that the patient had developed a migraine headache the night prior, which proceeded into the next day. Soon after waking up, she had a witnessed generalized seizure for which EMS was called. The patient had an additional witnessed generalized seizure en route to the hospital aborted with IM versed. The patient was postictal on arrival. She was hemodynamically stable though notably hypertensive with a blood pressure of 166/60 mmHg. Her baseline blood pressure ran in the 110–120 mmHg range according to prior chart review. She was of normal body habitus with a BMI of 26.82 kg/m2. On physical exam the patient did not demonstrate any general or focalizing neurological deficits. Initial lab work was unremarkable. These results are listed below in Tables 2 and 3 . Table 2 CSF panel results taken prior to patient’s presentation with neurological involvement. Her values were all within a normal range including CSF protein important later in differential diagnosis distinction. CSF value Patient’s values Reference values Glucose 60 mg/dl 40–90 mg/dl Protein 20.4 mg/dl 15–45 mg/dl Culture and stain No growth at 4 days, no organisms seen on staining No growth with no organisms seen on staining Olgioclonal banding 0 bands < 4 bands Myelin basic protein 1.2 ng/ml 0-2.9 ng/ml Table 3 CSF cell count with differential. Our patient had an elevation in TNCs and RBCs with an elevated percentage of neutrophils in WBCs differentiation. CSF Cell count with Differential Patient Value Reference Value Appearance Clear/ Colorless Clear/ Colorless Total nucleated Cells (TNCs) 8/mm3 < 5/mm3 Red Blood Cells (RBCs) 25/mm3 < 9/mm3 Percentage of White blood cells (WBCs) that are segmented neutrophils 90% 0–6% Percent of White blood Cells that are Lymphocytes 7% 40–80% Percentage of White blood cells that are Monocytes 3% 15–45% Xanthochromia Absent Absent Initial head CT revealed hypodensities in the right posterior parietal lobes. Further evaluation with MRI revealed FLAIR hypodensity in the cortical and subcortical hemisphere’s bilaterally (Image 2). No hemorrhage or infarct was appreciable. The patient was admitted for further evaluation and lumbar puncture. In the 24 hours that followed the patient's mental status fluctuated from lethargy to confusion induced agitation requiring Ativan. Lumbar puncture results were notable for elevated white blood cell count with a predominance of nucleated cells. Meningitis and encephalitis panels were negative. The patient was noted on urinalysis to have nephrotic range proteinuria and nephrology was consulted. Kidney biopsy was obtained over the course of her hospitalization and revealed Lupus nephritis class IV. Lupus cerebritis was initially considered for this patient as it can present somewhat similar to PRES, but this was ultimately reduced in clinical suspicion as initial CSF studies were unsupportive of this diagnosis. Most importantly, CSF protein was measured at 20.4mg/dl, well within the reference range of 15–45 mg/dl, which would be highly unlikely in a patient with Lupus cerebritis. However, the patient was treated with a 3-day course of high-dose steroids for her nephrotic range proteinuria, which would also be the treatment of acute lupus cerebritis. With a high suspicion of PRES, the treatment goals for this patient were aggressive blood pressure management and discontinuation of Mycophenolate as though rare it has been linked to prior instances of PRES in medical literature. The patient had marked improvement in mental status with improvement of her blood pressure and discontinuation of Mycophenolate alone. Neurology strongly recommended avoidance of Mycophenolate in the future. The patient was maintained on Keppra for seizure prevention and a follow up MRI was scheduled for assessment of interval improvement which ultimately revealed resolution of her imaging pathology. Discussion This case serves to support the precedence of Mycophenolate induced PRES syndrome. Identifying the inducing factor for the development of PRES in many patients is complex due to multiple confounding variables making it difficult to definitively delineate an iatrogenic, autoimmune, or hypertensive source. It is most likely to be a combination of these factors that promotes a physiological environment conducive to PRES development. The hyperperfusion theory has garnered broader support over the cytotoxin theory and appears to be applicable in this case [ 13 ]. Mycophenolate relies on the inhibition of inosine-5'-monophosphate dehydrogenase to deplete T cell and B cell lines by impairing the synthesis of guanosine nucleotides involved in cellular proliferation [13.] It has been suggested that Mycophenolate may induce off target dysregulation of adhesion molecules such as intercellular adhesion molecule-1(ICAM-1) and vascular cell adhesion molecule 1(VCAM-1) with an additional destabilization of E selection expression in in-vitro studies utilizing human umbilical vein endothelial cells [ 11 , 13 ]. This could lead to impaired regulation of cerebral hypertension due to a reduction in vascular smooth muscle cell proliferation and impaired remodeling of the vascular wall resulting in decreased resistance to hydrostatic pressure and subsequent extravasation [ 14 ]. It is worth considering the impact this may have on patients with Lupus nephritis as they are shown at baseline to have elevated levels of VCAM and ICAM and therefore may have a greater preponderance to rely on this mechanism of action for vascular repair [ 15 ]. Further studies of serum adhesion molecules throughout the course of treatment in patients with PRES is required to reach further conclusions. A principal differential diagnosis considered for this patient was Lupus cerebritis. Lupus cerebritis is a rare neurological condition with a nondescript clinical schema. It can present with a primary or mixed effect on the central nervous system, peripheral nervous system, or the autonomic nervous system. It most commonly presents at the time of SLE diagnosis or within the first year of disease during times of active flare with patients most often demonstrating features of cognitive impairment at time of diagnosis. That being said, Lupus cerebritis should not be excluded in patients with an absence of systemic disease or evidence of disease flare at the time of presentation as it can occur independently of immunological indicators [ 16 ]. The American College of Rheumatology (ACR) diagnostic criteria rely heavily on rheumatological features of disease with the only neurological symptoms attributable to diagnostic criteria being seizure or psychosis [ 17 ]. Diagnostic approach relies on exclusion of other pathology and practitioner discretion with no gold standard workup outlined in current medical guidelines. The initial testing should exclude vascular, infectious, and iatrogenic causes and consist of a neurological assessment and psychiatric evaluation with diagnostic test appropriate to the presenting complaint in patients without SLE. Rheumatological evaluation should be considered [ 17 ]. MRI is the diagnostic imaging of choice and structurally presents with discrete periventricular lesions as the most common finding [ 17 ]. Lumbar puncture may reveal elevated protein levels, but the specific measurements of cytokines and antibodies are not recommended at this time due to lack of specificity [ 17 ]. As previously stated, our patient was determined to be at low probability for this due to the nature of her imaging and CSF results, but practitioners should remain vigilant as these clinical syndromes can overlap in presentation. Conclusion It is imperative that practitioners remain vigilant for unbeknownst iatrogenic causes of PRES as the condition is highly amenable to improvement with proper management. Among such causes Mycophenolate should be considered in medication review of patients with suspected PRES and discontinued indefinitely if identified as a causative agent. If indicated, clinicians can opt for the substitution of Mycophenolate for Cyclophosphamide at their clinical discretion. Declarations Consent to participate: The Patient Central to This Study Provided Written Informed Consent Prior to Participation Written Consent for publication: The Patient Central to This Study Provided Written Informed Consent For publication of this work Ethics approval: Obtained through our Institution’s ERB Author Contributions: Alyssa Breazeale drafted the article and furnished supporting studies for context and framing, Dr. Megaly oversaw the drafting and editing of this article’s intellectual content; Dr. Sharma oversaw patient diagnosis and treatment course and provided approval for final article publication. Funding: The authors received no financial support for the research, authorship, and/or publication of this article. Code availability: Not Applicable Conflicts of interest: Not Applicable Availability of data and material: Not Applicable Code availability: Not Applicable References Hinchey J, Chaves C, Appignani B, et al. A Reversible Posterior Leukoencephalopathy Syndrome. New England Journal of Medicine . 1996;334(8):494-500. doi:https://doi.org/10.1056/nejm199602223340803 Bartynski W, Boardman J, Zeigler Z, Shadduck R, Lister J. Posterior Reversible Encephalopathy Syndrome in Infection, Sepsis, and Shock . Accessed November 23, 2024. https://pmc.ncbi.nlm.nih.gov/articles/PMC7977225/pdf/0244.pdf Pereira PR, Pinho J, Rodrigues M, et al. Clinical, imagiological and etiological spectrum of posterior reversible encephalopathy syndrome. Arquivos de Neuro-Psiquiatria . 2015;73(1):36-40. doi:https://doi.org/10.1590/0004-282x20140176 Fischer M, Schmutzhard E. Posterior reversible encephalopathy syndrome. Journal of Neurology . 2017;264(8):1608-1616. doi:https://doi.org/10.1007/s00415-016-8377-8 Armstead WM. Cerebral Blood Flow Autoregulation and Dysautoregulation. Anesthesiol Clin. 2016 Sep;34(3):465-77. doi: 10.1016/j.anclin.2016.04.002. PMID: 27521192; PMCID: PMC4988341 Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. The Lancet Neurology . 2015;14(9):914-925. doi:https://doi.org/10.1016/s1474-4422(15)00111-8 Lee VH, Wijdicks EFM, Manno EM, Rabinstein AA. Clinical Spectrum of Reversible Posterior Leukoencephalopathy Syndrome. Archives of Neurology . 2008;65(2). doi:https://doi.org/10.1001/archneurol.2007.46 Zhang L, Xu J. Posterior reversible encephalopathy syndrome (PRES) attributed to mycophenolate mofetil during the management of SLE: a case report and review. Am J Clin Exp Immunol. 2018 Feb 5;7(1):1-7. PMID: 29531864; PMCID: PMC5840284. Khajuria B, Khajuria M, Agrawal Y. Mycophenolate-Induced Posterior Reversible Encephalopathy Syndrome. Am J Ther. 2016 Jul-Aug;23(4):e1072-3. doi: 10.1097/MJT.0000000000000270. PMID: 25933141. Khanal S, Chaudhary RK, Kc K, Lamichhane S, Kathayat S, Acharya SP. 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Clinical & ExperimentalImmunology .2003;134(2):238-245//doi.org/10.1046/j.1365-2249.2003.090.x Milošević N, Rütter M, David A. Endothelial Cell Adhesion Molecules- (un)Attainable Targets for Nanomedicines. Frontiers in Medical Technology . 2022;4. doi:https://doi.org/10.3389/fmedt.2022.846065 Yu KY, Yung S, Chau MK, et al. Clinico-pathological associations of serum VCAM-1 and ICAM-1 levels in patients with lupus nephritis. Lupus . 2021;30(7):1039-1050. doi:https://doi.org/10.1177/09612033211004727 Leitao AR, Jain MS, Luvsannyam E, Jayswal V, Tiesenga F. Lupus Cerebritis as a Rare Neuropsychiatric Manifestation of Systemic Lupus Erythematosus. Cureus . Published online May 13, 2022. doi:https://doi.org/10.7759/cureus.24973 Popescu A, H. Kao A. Neuropsychiatric Systemic Lupus Erythematosus. Current Neuropharmacology . 2011;9(3):449-457. doi:https://doi.org/10.2174/157015911796557984 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 17 Jan, 2026 Read the published version in SN Comprehensive Clinical Medicine → Version 1 posted Editorial decision: Revision requested 11 Nov, 2025 Reviews received at journal 10 Nov, 2025 Reviews received at journal 10 Nov, 2025 Reviews received at journal 08 Nov, 2025 Reviewers agreed at journal 31 Oct, 2025 Reviewers agreed at journal 31 Oct, 2025 Reviewers agreed at journal 29 Oct, 2025 Reviewers invited by journal 29 Oct, 2025 Editor assigned by journal 28 Oct, 2025 Submission checks completed at journal 28 Oct, 2025 First submitted to journal 12 Oct, 2025 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. 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08:42:51","extension":"xml","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":58151,"visible":true,"origin":"","legend":"","description":"","filename":"0b292d54fb5b449281a85bedf2d026c01structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7843447/v1/60366d91e8fda3d58528dd1f.xml"},{"id":95528695,"identity":"c4b8338b-6bb7-441b-9ba5-6e3e6114a73c","added_by":"auto","created_at":"2025-11-10 10:16:24","extension":"html","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":64775,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7843447/v1/dcec6cc337b9dbecebee1c9d.html"},{"id":95517367,"identity":"11dc2bcf-ce52-46b7-a66c-f94ba3366c1e","added_by":"auto","created_at":"2025-11-10 08:42:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":926054,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003e\u003cstrong\u003eImage 1\u003c/strong\u003e\u003c/u\u003e\u003cstrong\u003e: Depiction of the Rash present on the bilateral lower extremities at the time of presentation\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7843447/v1/2c5eec9d3ebb08598997abbd.png"},{"id":95529170,"identity":"ac8ffa1a-1da3-4499-85fe-15ee7381871b","added_by":"auto","created_at":"2025-11-10 10:16:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":215992,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003e\u003cstrong\u003eImage 2: \u003c/strong\u003e\u003c/u\u003e\u003cstrong\u003eMRI taken on 4/29/2024; Impression: Abnormal multifocal areas of FLAIR hyperintense cortical/subcortical signal abnormality (probably vasogenic edema) involving the bilateral cerebral hemispheres both posteriorly and anteriorly. Appearances would favor a nonspecific encephalopathy, potentially PRES. (Less likely considerations would include seizure activity, metabolic, or less likely infectious encephalopathy). Possible small amount of superimposed ischemia, most conspicuous on the right parasagittal parietal cortex.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7843447/v1/0c030dcb2cc326bb9c3a87cc.png"},{"id":95529909,"identity":"b40fb3d7-e209-46bb-93bd-1fff1af63063","added_by":"auto","created_at":"2025-11-10 10:17:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":84532,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003e\u003cstrong\u003eImage 3\u003c/strong\u003e\u003c/u\u003e\u003cstrong\u003e: Follow up MRI taken on 7/15/2024; Impression: Significantly improved and near completely resolved bilateral signal abnormality and vasogenic edema from brain MRI on 4/29/2024. Minimal residual signal abnormality could reflect gliosis.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7843447/v1/093a293ff8de2b1897291fdb.png"},{"id":95517369,"identity":"dbbdcea0-cc02-4c65-afaf-f8b15ea71367","added_by":"auto","created_at":"2025-11-10 08:42:51","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":192690,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cu\u003e\u003cstrong\u003eImage 4: \u003c/strong\u003e\u003c/u\u003e\u003cstrong\u003eSide by Side comparison of the same MRI slice from initial imaging on 4/29/2024 (right) to subsequent imaging on 7/15/2024 (left).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7843447/v1/8980cf75f6f842d7b2e6199b.png"},{"id":100619157,"identity":"e78179c7-0cd4-4f71-80e1-93547f1a44e5","added_by":"auto","created_at":"2026-01-19 18:07:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3193716,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7843447/v1/d43423af-6f5d-4332-bbf4-01c3becb1eab.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"PRES in the Setting of Mycophenolate Use for Lupus Nephritis: A Diagnostic Challenge With Therapeutic Implications","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePosterior Reversible Encephalopathy Syndrome (PRES) is a clinicoradiological syndrome elucidated in 1996 in the landmark study Hinchey et al. that demonstrated a pattern of acute to subacute headaches, altered mental status, seizures, and visual deficits in 15 hospitalized patients at New England Medical Center in Boston and Hospital Sainte Anne in Paris from 1988 to 1994. Many of these patients developed pathology secondary to acute hypertensive episodes (73%) superimposed in the setting of immunosuppressive therapy (53%), eclampsia (20%), or renal disease (26%). Notably, these patients shared radiological abnormalities of vasogenic white matter edema in the posterior parietal, temporal, or occipital regions of the brain which were reversed with antihypertensive medications and withdrawal or reduction of immunosuppressive therapy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Further studies identified a wider range of etiologies than originally believed including additional associations to sepsis with 85% prevalence of gram-positive infection [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], autoimmune diseases [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], and autonomic dysregulation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The pathophysiology of PRES is still largely debated as no randomized controlled studies have been conducted to gather strong epidemiological data.\u003c/p\u003e\u003cp\u003eThere are two main hypotheses on the pathophysiology underlying this syndrome. The first model relies on the notion of hypertension induced hyperperfusion [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. There are autoregulatory mechanisms in place in order to maintain adequate blood flow to the brain and avoid hyper or hypoperfusion. In the case of an acute rise of blood pressure, vasoconstriction is triggered to reduce blood flow and achieve constant cerebral blood flow. However, at 160 mmHg systolic pressure or greater, this autoregulatory vasoconstriction is overcome and cerebral blood flow continues to rise with rising blood pressures [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Increased hydrostatic pressure can then lead to the breakdown of the blood-brain barrier causing extravasation of fluid from the cerebral blood vessels leading to vasogenic edema. This theory's explanation for why PRES mostly affects the posterior circulation is due to the belief that it has fewer adaptive mechanisms to regulate the extent of extravasation and breakdown of the blood-brain barrier. This explanation stems from the finding of significantly less adrenergic perivascular fibrosis innervating the posterior cerebral circulation compared to the anterior cerebral circulation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The occurrence of hypertension in the majority of PRES patients at onset and the resulting affected edematous zones are characteristics that would seem to support this theory [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, this fails to account for the 30% of PRES patients who do not present with blood pressures in a hypertensive range [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAn alternative theory proposes that PRES is as the result of endothelial dysfunction caused by either an inflammatory state or direct cytotoxicity. This theory is supported by the observation that PRES is usually associated with a systemic inflammatory process such as sepsis, eclampsia, transplantation, autoimmune disease or exposure to certain cytotoxins. Angiographic studies in PRES demonstrated reversible focal and diffuse abnormalities thought to demonstrate endothelial dysfunction [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In the context of elevated blood pressures, resultant vasoconstriction that occurs through autoregulation worsens endothelial dysfunction in the context of pre-existing inflammatory versus cytotoxic injury. This could also explain the reversibility of the condition with hypertension management [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This case will seek to demonstrate a unique cause of PRES while extrapolating the described physiological theories to the role of Mycophenolate in syndrome development.\u003c/p\u003e\u003cp\u003eThough immunosuppressive therapy has been recognized as a keystone etiology of PRES much of the medical literature supports the relationship between PRES development and the administration of calcineurin inhibitors. Mycophenolate is a rarely identified cause of PRES and has been largely underrepresented with only five prior case studies. Patients involved in these cases share many similarities in presentation and demographic background as highlighted in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e [\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. We seek to expand upon this limited literature base and demonstrate one such case to further the recognition of the role of Mycophenolate in the development of PRES.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummation of case studies into Mycophenolate associated PRES. Patients demonstrated similarities in Gender (100% female), Age with mean age of 23.2 y/o, and renal pathology (80% Lupus Nephritis IV); patients varied in duration of treatment with a mean treatment duration of 36.8 days and median of 5 days. Blood pressure data is inconclusive due to inconsistent reporting. [\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient Demographics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRenal pathology\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDuration of Mycophenolate use\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBlood Pressure on Presentation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAuthor and Publication year\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16F\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLupus Nephritis IV\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 days\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e135/84 mmHg\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDai et. al, 2023\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e21F\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLupus Nephritis IV\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 days\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnreported\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eChaves et Al, 2021\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e29F\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eLupus Nephritis IV\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e4 days\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eUnreported\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eKhajuria et. al, 2016\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e22F\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eLupus Nephritis IV\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e5 days\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e190/110 mmHg\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eZang et. al, 2018\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e28F\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eIGA Nephropathy\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e5 months\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eUnreported\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eKhanal et. al, 2021\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Report of Case","content":"\u003cp\u003eA 27-year-old African American female had initially presented for care with a chief complaint of persistent swelling in the bilateral lower extremities of a 2-week duration. She also reported a new onset rash of her lower extremities and diffuse arthralgias throughout. Her arthralgias were severe with the highest intensity in the lower extremities rendering the patient non-weight bearing. On physical exam, the patient was noted to have a non-blanchable, erythematous, maculopapular rash with central areas of purpura (Image 1). The patient was admitted to the hospital, and an autoimmune investigation was initiated.\u003c/p\u003e\u003cp\u003eAutoimmune studies were remarkable for the presence of elevated Anti- Nuclear Antibodies, Anti-DsDNA, Anti-Smith, Antihistone, and Antichromatin antibodies. Subsequent studies also demonstrated hypocomplementemia, elevated CPK, and elevated IGE. During her hospitalization she received Solu Medrol and Toradol with marked improvement. She was then transitioned to oral Prednisone prior to discharge and scheduled for rheumatology follow up. In the outpatient setting she was formally diagnosed with Systemic Lupus Erythematosus by Rheumatology and started on immunosuppressive therapy with Mycophenolate and Prednisone.\u003c/p\u003e\u003cp\u003eSix days following initiation of treatment the patient again presented to the emergency department with generalized seizures. The patient's mother provided history at that time, stating that the patient had developed a migraine headache the night prior, which proceeded into the next day. Soon after waking up, she had a witnessed generalized seizure for which EMS was called. The patient had an additional witnessed generalized seizure en route to the hospital aborted with IM versed. The patient was postictal on arrival. She was hemodynamically stable though notably hypertensive with a blood pressure of 166/60 mmHg. Her baseline blood pressure ran in the 110\u0026ndash;120 mmHg range according to prior chart review. She was of normal body habitus with a BMI of 26.82 kg/m2. On physical exam the patient did not demonstrate any general or focalizing neurological deficits. Initial lab work was unremarkable. These results are listed below in Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCSF panel results taken prior to patient\u0026rsquo;s presentation with neurological involvement. Her values were all within a normal range including CSF protein important later in differential diagnosis distinction.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCSF value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatient\u0026rsquo;s values\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference values\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGlucose\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60 mg/dl\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40\u0026ndash;90 mg/dl\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProtein\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20.4 mg/dl\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15\u0026ndash;45 mg/dl\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCulture and stain\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eNo growth at 4 days, no organisms seen on staining\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eNo growth with no organisms seen on staining\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOlgioclonal banding\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e0 bands\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;4 bands\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMyelin basic protein\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1.2 ng/ml\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e0-2.9 ng/ml\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCSF cell count with differential. Our patient had an elevation in TNCs and RBCs with an elevated percentage of neutrophils in WBCs differentiation.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCSF Cell count with Differential\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatient Value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eReference Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAppearance\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClear/ Colorless\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eClear/ Colorless\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal nucleated Cells (TNCs)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8/mm3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;5/mm3\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRed Blood Cells (RBCs)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e25/mm3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;9/mm3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePercentage of White blood cells (WBCs) that are segmented neutrophils\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e90%\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e0\u0026ndash;6%\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePercent of White blood Cells that are Lymphocytes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e7%\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e40\u0026ndash;80%\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePercentage of White blood cells that are Monocytes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e3%\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e15\u0026ndash;45%\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eXanthochromia\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eInitial head CT revealed hypodensities in the right posterior parietal lobes. Further evaluation with MRI revealed FLAIR hypodensity in the cortical and subcortical hemisphere\u0026rsquo;s bilaterally (Image 2). No hemorrhage or infarct was appreciable. The patient was admitted for further evaluation and lumbar puncture. In the 24 hours that followed the patient's mental status fluctuated from lethargy to confusion induced agitation requiring Ativan. Lumbar puncture results were notable for elevated white blood cell count with a predominance of nucleated cells. Meningitis and encephalitis panels were negative. The patient was noted on urinalysis to have nephrotic range proteinuria and nephrology was consulted. Kidney biopsy was obtained over the course of her hospitalization and revealed Lupus nephritis class IV.\u003c/p\u003e\u003cp\u003eLupus cerebritis was initially considered for this patient as it can present somewhat similar to PRES, but this was ultimately reduced in clinical suspicion as initial CSF studies were unsupportive of this diagnosis. Most importantly, CSF protein was measured at 20.4mg/dl, well within the reference range of 15\u0026ndash;45 mg/dl, which would be highly unlikely in a patient with Lupus cerebritis. However, the patient was treated with a 3-day course of high-dose steroids for her nephrotic range proteinuria, which would also be the treatment of acute lupus cerebritis. With a high suspicion of PRES, the treatment goals for this patient were aggressive blood pressure management and discontinuation of Mycophenolate as though rare it has been linked to prior instances of PRES in medical literature. The patient had marked improvement in mental status with improvement of her blood pressure and discontinuation of Mycophenolate alone. Neurology strongly recommended avoidance of Mycophenolate in the future. The patient was maintained on Keppra for seizure prevention and a follow up MRI was scheduled for assessment of interval improvement which ultimately revealed resolution of her imaging pathology.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case serves to support the precedence of Mycophenolate induced PRES syndrome. Identifying the inducing factor for the development of PRES in many patients is complex due to multiple confounding variables making it difficult to definitively delineate an iatrogenic, autoimmune, or hypertensive source. It is most likely to be a combination of these factors that promotes a physiological environment conducive to PRES development. The hyperperfusion theory has garnered broader support over the cytotoxin theory and appears to be applicable in this case [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Mycophenolate relies on the inhibition of inosine-5'-monophosphate dehydrogenase to deplete T cell and B cell lines by impairing the synthesis of guanosine nucleotides involved in cellular proliferation [13.] It has been suggested that Mycophenolate may induce off target dysregulation of adhesion molecules such as intercellular adhesion molecule-1(ICAM-1) and vascular cell adhesion molecule 1(VCAM-1) with an additional destabilization of E selection expression in in-vitro studies utilizing human umbilical vein endothelial cells [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This could lead to impaired regulation of cerebral hypertension due to a reduction in vascular smooth muscle cell proliferation and impaired remodeling of the vascular wall resulting in decreased resistance to hydrostatic pressure and subsequent extravasation [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. It is worth considering the impact this may have on patients with Lupus nephritis as they are shown at baseline to have elevated levels of VCAM and ICAM and therefore may have a greater preponderance to rely on this mechanism of action for vascular repair [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Further studies of serum adhesion molecules throughout the course of treatment in patients with PRES is required to reach further conclusions.\u003c/p\u003e\u003cp\u003eA principal differential diagnosis considered for this patient was Lupus cerebritis. Lupus cerebritis is a rare neurological condition with a nondescript clinical schema. It can present with a primary or mixed effect on the central nervous system, peripheral nervous system, or the autonomic nervous system. It most commonly presents at the time of SLE diagnosis or within the first year of disease during times of active flare with patients most often demonstrating features of cognitive impairment at time of diagnosis. That being said, Lupus cerebritis should not be excluded in patients with an absence of systemic disease or evidence of disease flare at the time of presentation as it can occur independently of immunological indicators [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The American College of Rheumatology (ACR) diagnostic criteria rely heavily on rheumatological features of disease with the only neurological symptoms attributable to diagnostic criteria being seizure or psychosis [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Diagnostic approach relies on exclusion of other pathology and practitioner discretion with no gold standard workup outlined in current medical guidelines. The initial testing should exclude vascular, infectious, and iatrogenic causes and consist of a neurological assessment and psychiatric evaluation with diagnostic test appropriate to the presenting complaint in patients without SLE. Rheumatological evaluation should be considered [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. MRI is the diagnostic imaging of choice and structurally presents with discrete periventricular lesions as the most common finding [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Lumbar puncture may reveal elevated protein levels, but the specific measurements of cytokines and antibodies are not recommended at this time due to lack of specificity [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. As previously stated, our patient was determined to be at low probability for this due to the nature of her imaging and CSF results, but practitioners should remain vigilant as these clinical syndromes can overlap in presentation.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIt is imperative that practitioners remain vigilant for unbeknownst iatrogenic causes of PRES as the condition is highly amenable to improvement with proper management. Among such causes Mycophenolate should be considered in medication review of patients with suspected PRES and discontinued indefinitely if identified as a causative agent. If indicated, clinicians can opt for the substitution of Mycophenolate for Cyclophosphamide at their clinical discretion.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Patient Central to This Study Provided Written Informed Consent Prior to Participation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWritten Consent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Patient Central to This Study Provided Written Informed Consent For publication of this work\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eObtained through our Institution’s ERB\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlyssa Breazeale drafted the article and furnished supporting studies for context and framing, Dr. Megaly oversaw the drafting and editing of this article’s intellectual content; Dr. Sharma oversaw patient diagnosis and treatment course and provided approval for final article publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors received no financial support for the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHinchey J, Chaves C, Appignani B, et al. A Reversible Posterior Leukoencephalopathy Syndrome. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e. 1996;334(8):494-500. doi:https://doi.org/10.1056/nejm199602223340803\u003c/li\u003e\n\u003cli\u003eBartynski W, Boardman J, Zeigler Z, Shadduck R, Lister J. \u003cem\u003ePosterior Reversible Encephalopathy Syndrome in Infection, Sepsis, and Shock\u003c/em\u003e. Accessed November 23, 2024. https://pmc.ncbi.nlm.nih.gov/articles/PMC7977225/pdf/0244.pdf\u003c/li\u003e\n\u003cli\u003ePereira PR, Pinho J, Rodrigues M, et al. Clinical, imagiological and etiological spectrum of posterior reversible encephalopathy syndrome. \u003cem\u003eArquivos de Neuro-Psiquiatria\u003c/em\u003e. 2015;73(1):36-40. doi:https://doi.org/10.1590/0004-282x20140176\u003c/li\u003e\n\u003cli\u003eFischer M, Schmutzhard E. Posterior reversible encephalopathy syndrome. \u003cem\u003eJournal of Neurology\u003c/em\u003e. 2017;264(8):1608-1616. doi:https://doi.org/10.1007/s00415-016-8377-8\u003c/li\u003e\n\u003cli\u003eArmstead WM. Cerebral Blood Flow Autoregulation and Dysautoregulation. Anesthesiol Clin. 2016 Sep;34(3):465-77. doi: 10.1016/j.anclin.2016.04.002. PMID: 27521192; PMCID: PMC4988341\u003c/li\u003e\n\u003cli\u003eFugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. \u003cem\u003eThe Lancet Neurology\u003c/em\u003e. 2015;14(9):914-925. doi:https://doi.org/10.1016/s1474-4422(15)00111-8\u003c/li\u003e\n\u003cli\u003eLee VH, Wijdicks EFM, Manno EM, Rabinstein AA. Clinical Spectrum of Reversible Posterior Leukoencephalopathy Syndrome. \u003cem\u003eArchives of Neurology\u003c/em\u003e. 2008;65(2). doi:https://doi.org/10.1001/archneurol.2007.46\u003c/li\u003e\n\u003cli\u003eZhang L, Xu J. Posterior reversible encephalopathy syndrome (PRES) attributed to mycophenolate mofetil during the management of SLE: a case report and review. Am J Clin Exp Immunol. 2018 Feb 5;7(1):1-7. PMID: 29531864; PMCID: PMC5840284.\u003c/li\u003e\n\u003cli\u003eKhajuria B, Khajuria M, Agrawal Y. Mycophenolate-Induced Posterior Reversible Encephalopathy Syndrome. Am J Ther. 2016 Jul-Aug;23(4):e1072-3. doi: 10.1097/MJT.0000000000000270. PMID: 25933141.\u003c/li\u003e\n\u003cli\u003eKhanal S, Chaudhary RK, Kc K, Lamichhane S, Kathayat S, Acharya SP. Posterior reversible encephalopathy syndrome presenting as refractory status epilepticus in a patient taking Mycophenolate mofetil for IgA nephropathy: A case report. Ann Med Surg (Lond). 2021 Feb 5;63:102147. doi: 10.1016/j.amsu.2021.01.095. PMID: 33643649; PMCID: PMC7895702.\u003c/li\u003e\n\u003cli\u003eDai Y, Liu W, Hong F. Post reversible encephalopathy syndrome attributed to mycophenolate mofetil used in the treatment of SLE: A case report and review of literature. \u003cem\u003eJournal of International Medical Research\u003c/em\u003e. 2023;52(1). doi:https://doi.org/10.1177/03000605231218620\u003c/li\u003e\n\u003cli\u003eChaves BMR, George J, Diaz CA, Mosquera M, Amer B, Ghose R. 702: A RARE CASE OF POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME FOLLOWING MYCOPHENOLATE MOFETIL. \u003cem\u003eCritical Care Medicine\u003c/em\u003e. 2020;48(1):331-331. doi:https://doi.org/10.1097/01.ccm.0000626548.82563.ac\u003c/li\u003e\n\u003cli\u003eK LECKEL, W-D BEECKEN, JONAS D, et al. The immunosuppressive drug mycophenolate mofetil impairs the adhesion capacity of gastrointestinal tumour cells. \u003cem\u003eClinical \u0026amp; ExperimentalImmunology\u003c/em\u003e.2003;134(2):238-245//doi.org/10.1046/j.1365-2249.2003.090.x\u003c/li\u003e\n\u003cli\u003eMilo\u0026scaron;ević N, R\u0026uuml;tter M, David A. Endothelial Cell Adhesion Molecules- (un)Attainable Targets for Nanomedicines. \u003cem\u003eFrontiers in Medical Technology\u003c/em\u003e. 2022;4. doi:https://doi.org/10.3389/fmedt.2022.846065\u003c/li\u003e\n\u003cli\u003eYu KY, Yung S, Chau MK, et al. Clinico-pathological associations of serum VCAM-1 and ICAM-1 levels in patients with lupus nephritis. \u003cem\u003eLupus\u003c/em\u003e. 2021;30(7):1039-1050. doi:https://doi.org/10.1177/09612033211004727\u003c/li\u003e\n\u003cli\u003eLeitao AR, Jain MS, Luvsannyam E, Jayswal V, Tiesenga F. Lupus Cerebritis as a Rare Neuropsychiatric Manifestation of Systemic Lupus Erythematosus. \u003cem\u003eCureus\u003c/em\u003e. Published online May 13, 2022. doi:https://doi.org/10.7759/cureus.24973\u003c/li\u003e\n\u003cli\u003ePopescu A, H. Kao A. Neuropsychiatric Systemic Lupus Erythematosus. \u003cem\u003eCurrent Neuropharmacology\u003c/em\u003e. 2011;9(3):449-457. doi:https://doi.org/10.2174/157015911796557984\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7843447/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7843447/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePosterior reversible encephalopathy syndrome (PRES) is a rare condition causing posterior brain edema, seizures, visual changes, and altered mental status. It is associated with autoimmune disease, immunosuppressants, eclampsia, renal disease, and malignancy. PRES may cause injury through either hypertension-induced hyperperfusion, causing edema, or endothelial dysfunction due to inflammation or cytotoxic injury. Prompt recognition, blood pressure control, and addressing triggers typically lead to full recovery.\u003c/p\u003e\u003cp\u003eHere we discuss the case of a 27-year-old woman who initially presented with debilitating arthralgia and a vasculitic rash on both lower extremities. She was hospitalized while an autoimmune workup was conducted. The investigation revealed autoimmune disease, and outpatient rheumatology later confirmed systemic lupus erythematosus complicated by class IV lupus nephritis. She was initiated on therapy with mycophenolate, however, within one week she returned to the hospital with seizures and marked hypertension. MRI findings and clinical features were consistent with PRES. Given the close timing with therapy initiation, mycophenolate was suspected as the cause. With withdrawal of immunotherapy and strict blood pressure control, she improved significantly. Follow-up imaging at 3 months demonstrated almost complete resolution of PRES.\u003c/p\u003e\u003cp\u003eThis case aims to elucidate a potential novel cause of PRES associated with mycophenolate use. We propose that mycophenolate may dysregulate vascular adhesion molecules, impairing endothelial response to hypertension-induced damage. Our goal is to raise awareness and guide clinicians managing patients on mycophenolate.\u003c/p\u003e","manuscriptTitle":"PRES in the Setting of Mycophenolate Use for Lupus Nephritis: A Diagnostic Challenge With Therapeutic Implications","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-10 08:42:46","doi":"10.21203/rs.3.rs-7843447/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-12T01:22:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-10T22:41:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-10T14:48:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-08T16:15:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196651878718337722864641861937768380639","date":"2025-10-31T11:54:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"226287229920397590372298894302249444034","date":"2025-10-31T10:11:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"216483934367671420977424424443974210284","date":"2025-10-29T10:34:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-29T08:13:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-29T02:34:54+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-28T23:46:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"SN Comprehensive Clinical Medicine","date":"2025-10-13T01:16:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ac96dc93-affb-4e14-beeb-83b45a2db17f","owner":[],"postedDate":"November 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T17:41:36+00:00","versionOfRecord":{"articleIdentity":"rs-7843447","link":"https://doi.org/10.1007/s42399-025-02242-2","journal":{"identity":"sn-comprehensive-clinical-medicine","isVorOnly":false,"title":"SN Comprehensive Clinical Medicine"},"publishedOn":"2026-01-17 16:30:45","publishedOnDateReadable":"January 17th, 2026"},"versionCreatedAt":"2025-11-10 08:42:46","video":"","vorDoi":"10.1007/s42399-025-02242-2","vorDoiUrl":"https://doi.org/10.1007/s42399-025-02242-2","workflowStages":[]},"version":"v1","identity":"rs-7843447","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7843447","identity":"rs-7843447","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}