Risk Factors and Prognostic Markers for Posterior Reversible Encephalopathy Syndrome in Patients With Thalassemia Major After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Meiru Bu, Kemei Deng, Meiqing Wu, Lingling Shi, Yuhong Qin, Muliang Jiang, Bihong T. Chen
Journal: American Journal of Hematology (2024)

Posterior reversible encephalopathy syndrome (PRES) has been known as a neurological complication in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). PRES is an acute or subacute syndrome with various neurological symptoms such as headache, encephalopathy, visual disturbance and seizures [1]. Neuroimaging may show subcortical white matter vasogenic edema typically in bilateral parieto-occipital lobes [1]. The etiology of PRES is not clear, which has been speculated as cerebrovascular dysregulation associated with exposure to toxic agents such as chemotherapeutic drugs and immunosuppressive agents [1]. Several studies have indicated that severe hypertension, Pesaro class III, and acute graft-versus-host disease (aGVHD) are potential risk factors for PRES in patients with transfusion-dependent thalassemia (TDT) after allo-HSCT [2, 3]. Severity of brain magnetic resonance imaging (MRI) findings and the length of in-hospital stay were independent risk factors related to adverse outcomes from PRES in patients with TDT after allo-HSCT [4]. We enrolled consecutive patients with TDT after allo-HSCT from October 2010 and May 2023 and assessed their clinical factors and brain MRI findings. Univariate and multivariate binary logistic regression were used to identify the risk factors for the occurrence and the prognosis of PRES. Receiver operating characteristic (ROC) curve analysis was performed to obtain the area under the curve (AUC) values for assessing the prediction efficacy. The study methods are detailed in the Supporting Information. A total of 770 patients diagnosed with TDT underwent allo-HSCT during the study interval (Table S1). All patients underwent one allo-HSCT, with the mean age at 7.36 years. Among them, 64 patients had PRES with an incidence of 8.3%. The median time of onset for PRES from the start of allo-HSCT was 77 days (ranging from 12 to 441 days). Ten patients who developed PRES had poor prognosis, with a score of 3–6 on the modified Rankin Scale (mRS) clinical outcome scale (Supporting Information: Methods). Three of the 64 patients with PRES died, resulting in a mortality rate of 4.69%. Among the cohort of 64 cases with PRES, 45 cases showed mild brain MRI findings, 16 cases showed moderate MRI findings, and 3 cases exhibited severe MRI abnormalities. We found 6 patients showing hyperintensity on diffusion-weighted images (DWI b values = 1000s/mm2) and hypointensity in apparent diffusion coefficient (ADC). A summary of MRI findings of PRES is presented in Figure 1. The median duration for complete resolution of lesions during follow-up was 14 days (range 6–99 days). The median interval for lesion improvement was 21 days (range 3–66 days), with the earliest documented improvement observed at 3 days post-diagnosis. Regarding the development of PRES, univariate analysis showed that age, serum ferritin, hypertension, pneumonia after allo-HSCT, cytomegalovirus (CMV) infection, electrolyte disturbance, aGVHD, chronic GVHD (cGVHD), and tacrolimus (TAC) were significantly associated with the occurrence of PRES (Table S2). Multivariate logistic regression analysis showed that age (OR, 4.75; 95% confidence interval [95% CI]: 2.23–10.15; p < 0.001), serum ferritin (OR, 5.30; 95% CI: 2.23–12.62; p < 0.001), hypertension (OR, 6.50; 95% CI: 4.37–9.66; p < 0.001), CMV infection (OR, 4.45; 95% CI: 1.90–10.44; p = 0.001), and aGVHD (OR, 2.68; 95% CI: 1.56–4.59; p < 0.001) were associated with the occurrence of PRES (Table S3). Three predictors for PRES including hypertension (stage 1 and 2), age (> 10 years) and serum ferritin (> 5000 ng/mL) were extracted from the five variables from multivariate analysis through ROC curve analysis (Figure 1). The area under the curve (AUC) values from the ROC curve analysis for hypertension, age and serum ferritin were 0.87 (95% CI: 0.81–0.93), 0.71 (95% CI: 0.65–0.77), and 0.70 (95% CI: 0.63–0.77) respectively. The AUC values for aGVHD and CMV infection were 0.69 (95% CI: 0.61–0.77) and 0.68 (95% CI: 0.61–0.76), respectively. The cut-off points for the risk factors identified were as follows: hypertension (1.5, sensitivity: 0.695, specificity: 0.960), age (2.5, sensitivity: 0.452, specificity: 0.826), serum ferritin (0.5, sensitivity: 0.678, specificity: 0.727), acute GVHD (aGVHD) (0.5, sensitivity: 0.492, specificity: 0.856), and CMV infection (0.5, sensitivity: 0.542, specificity: 0.840). Regarding prognosis of PRES, univariate analysis showed that age, serum ferritin, MRI severity, CMV infection, pneumonia after allo-HSCT, and TAC were significantly associated with PRES prognosis (Table S4). Multivariate logistic regression analysis showed that MRI severity (OR, 6.749; 95% CI: 1.41–32.41; p = 0.017) was the independent risk factor for the prognosis of PRES (Table S5). This study identified risk factors such as hypertension, age (> 10 years), and serum ferritin being associated with the occurrence of PRES. Hypertension has been emphasized as common adverse events of calcineurin inhibitors and has been associated with PRES. Similarly, a study has shown that severe hypertension is the independent risk factor of PRES post-HSCT in TDT [2]. The mechanism for hypertension being associated with PRES is not clear. Evidence suggests that dysregulation of cerebral blood flow may play a role in the development of PRES [1]. Rapidly developing hypertension in PRES may surpass cerebral blood flow autoregulation, which may cause hyperperfusion and breakdown of blood–brain barrier, allowing the interstitial extravasation of plasma and macromolecules [1]. Notably, the cerebral blood flow autoregulation threshold is lower in children than in adults, resulting in a lower mean blood pressure for PRES symptoms in pediatric patients [1]. To mitigate neurotoxicity during the transplantation process, it is advisable to maintain blood pressure close to baseline levels or lower when using calcineurin inhibitors. We identified that older age (> 10 years) was an independent risk factor for development of PRES post allo-HSCT in pediatric patients with TDT. A previous study suggested that patients over 10 years of age suffering from pediatric hematologic diseases and PRES were likely to have a poor outcome [5]. In this study, serum ferritin level was identified as a risk factor for development of PRES in patients with TDT after allo-HSCT, which was a novel finding that had not been reported in literature. Serum ferritin is a well-known inflammatory marker. In patients with TDT, excess iron catalyzes the formation of free radicals, exacerbating oxidative stress. This oxidative stress is a significant factor in the pathophysiology of TDT, contributing to cellular damage and inflammation. The inflammatory response prompts endothelial cells to release inflammatory cytokines, which leads to increased endothelial permeability and subsequently results in vascular edema [6]. Therefore, monitoring serum ferritin levels (< 5000 ng/mL) may play an important role in preventing PRES. Our study also identified two risk factors such as MRI severity and hypointensity on ADC maps on brain MRI being predictors for poor prognosis in patients with TDT who had PRES after allo-HSCT, which was consistent with literature. Deng et al. similarly reported that MRI severity was an independent risk factor for poor prognosis from PRES [4]. Hypointensity on ADC map has been reported to be related to bad prognosis in patients with PRES [1]. High DWI signal intensity and pseudonormalized ADC values have been shown to be associated with cerebral infarction and may represent the earliest sign of non-reversibility as severe vasogenic edema progressing to cytotoxic edema [1]. The optimal timing for follow-up neuroimaging to monitor the recovery of PRES remains uncertain. In our cohort, the earliest time for the resolution of brain lesions upon follow-up was 3 days, with a median time of 14 days for complete resolution. The median time to observe lesion improvement was 21 days. Based on our findings and previous studies, we would suggest that a follow-up MRI should be acquired within 5–7 days after the initial scan, which may assist clinical decision making regarding therapeutic options. In summary, we identified three risk factors including hypertension, older age (> 10 years) and high serum ferritin level for development of PRES and two risk factors such as high MRI severity and hypointensity on ADC maps for poor prognosis of PRES in the largest cohort to date of patients with TDT and PRES after allo-HSCT. Early diagnosis and prompt management of PRES could improve the outcome of the pediatric patients with TDT. Study design: M.J., Y.Q. Data collection and analysis: M.B., K.D., L.S., M.W., B.C. Manuscript preparation: M.B., K.D., B.C. All authors revised and approved the final version. We thank our scientific writer Nancy Linford, Ph.D. for editing this manuscript. The Institutional Review Board (IRB) of the First Affiliated Hospital of Guangxi Medical University approved the study. Informed consent was obtained from all participants included in the study. The authors declare no conflicts of interest. The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.