Key words : Acute lymphoblastic leukemia, Children, Magnetic resonance imaging, Neurological complication

Introduction

Hematopoietic stem cell transplant (HSCT) is increasingly being used as a curative therapeutic option for patients with hematologic malignancies and nonmalignant diseases. Use of HSCT has been important in the treatment of numerous childhood diseases, such as immune deficiencies, hemoglo-binopathies, hematologic malignancies, and bone marrow failures.¹ However, patients undergoing HSCT are at increased risk for developing transplant-related complications that may have an effect on outcomes. One of these complications is posterior reversible encephalopathy syndrome (PRES), which may contribute to the morbidity and mortality in patients undergoing HSCT. Therefore, our goal was to determine the frequency and features of typical (classical) and atypical central variants of PRES in children who had undergone allogeneic HSCT procedures for any indication at a single center.

Materials and Methods

Patient characteristics
We retrospectively analyzed 101 pediatric patients aged between 6 months and 18 years who underwent HSCT for any indication between 2010 and 2023 in our pediatric HSCT center located in southern Turkey. We evaluated morbidity and mortality rates and several risk factors, therapies, and outcomes associated with PRES in our transplant patients. The diagnosis of PRES was made by a pediatric neurologist and a radiologist based on neurological symptoms and radiologic features and clinical characteristics. Medical data were obtained from patients’ electronic health records in our hospital. This study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Clinical Research Ethics Committee of Acibadem University (decision No. 2023-17/584; date 02/11/2023). Parental informed consent was obtained before allogeneic HSCT was performed.

Statistical analyses
We used IBM SPSS software, version 28.0, for data analyses. We summarized data by using descriptive statistics, including mean, standard deviation, median, minimum, maximum, frequencies, and percentages. We used Kolmogorov-Smirnov tests to check the distribution of variables. We used the chi-square test for comparisons of qualitative data. We used the Mann-Whitney U test for comparisons of nonnormally distributed quantitative data between paired groups. Cox regression (univariate-multivariate) and Kaplan Meier analyses were used for survival analysis. We performed univariate analyses with adjustments for age and significant risk factors. We analyzed results with 95% CI. P < .05 was considered statistically significant.

Results

During the 13-year study period, 650 patients underwent HSCT in our center; incidence of PRES was 15.5% (101 patients). Tables 1, 2, and 3 show details on patient and transplant characteristics. Among the 101 pediatric patients, 52 male and 49 female patients with mean age of 9.4 ± 4.9 years developed PRES following HSCT. In the 101 patients who underwent HSCT, the most common diagnosis was acute lymphoblastic leukemia (ALL) (n = 46, 45.5%), followed by thalassemia major (22.8%), acute myeloblastic leukemia (15.8%), Fanconi aplastic anemia (10.9%), and immunodeficiency (5%). In 52 of 101 patients (51.5%), the peripheral blood was the most common source of stem cells, whereas the most common donor was an HLA-matched family member (n = 65; 64.4%). Of 101 patients, 78 (77.2%) received cyclosporin A (CsA) and 23 (22.8%) received mycophenolate mofetil (MMF) in addition to CsA. The mean calcineurin inhibitor level was 136.8 ± 31.3 ng/mL, with range from 101.0 to 267.0 ng/mL. Study patients used prophylactic antibiotics, antivirals, and gastroprotective agents at rates ranging from 8.9% to 58.4%. Most patients had a history of steroid use (n = 77, 76.2%). Median time from HSCT procedure date to PRES onset was 20 days (range, 10-108 days). Most cases of PRES were typical, with 16 patients (15.8%) who had the central variant. Headache was the most common clinical symptom (79.2%), followed by nausea/vomiting (52.5%), elevated blood pressure (51.5%), altered mental status (27.7%) and seizures (23.8%) (Table 4).

Patients with ALL were diagnosed based on clinical and magnetic resonance imaging (MRI) findings. The MRI assessments were mainly performed using T2-weighted fluid-attenuated inversion recovery images. Rates of thalamic and basal ganglia involvement were significantly higher (P < .05) in the central variant PRES group than in the typical variant PRES group, and parietal, temporal, and occipital involvement rates were significantly (P < .05) lower in the central variant PRES group than in the typical variant PRES group (Figure 1). None of the patients had a history of hypertension before HSCT. Of 101 HSCT recipients, 52 (51.5%) experienced hypertension, with all needing antihypertensive medications. No significant difference was observed between the central variant (n = 6, 37.5%) and typical variant (n = 46, 54.1%) PRES groups in the incidence of hypertension (P = .222).

Imaging studies revealed intracranial hemor-rhages or vasogenic edema in 36 patients (35.6%) (Figure 2). Sixteen patients (15.8%) needed mechanical ventilation and inotropic support in the intensive care unit (ICU) due to PRES-associated respiratory failure. All patients diagnosed with PRES had to start on antihypertensive therapy.

When we compared the typical and central variants of PRES, we found that mean age of patients with the central variant was significantly higher than age among patients with the typical variant (P < .05) (Table 5). A similar relationship was also seen with the use of calcineurin inhibitors. Rate of CsA+MMF use as a calcineurin inhibitor was significantly higher in patients with the central variant compared with the typical variant (P < .05). Furthermore, rates of steroid use and complete remission in the central variant PRES group were significantly (P < .05) lower than in the typical variant PRES group. Patients with the central variant PRES had significantly higher (P < .05) rate of hand tremor compared with patients with the typical variant PRES. Patients with central variant PRES had significantly higher (P < .05) rate of ICU admission than patients with typical variant PRES.

We analyzed cases of graft-versus-host disease (GVHD), which revealed that 9 patients in the typical variant PRES group had grade I-II acute GVHD, whereas no cases of grade 1-II GVHD were shown in the central variant PRES group. Nine patients in the typical variant and 4 patients in the central variant PRES group developed grade III-IV acute GVHD, which was not significantly different (P = .115). Moreover, we found that the incidence of grade III-IV acute GVHD was significantly (P < .05) higher among those who died of PRES.

The rate of use of proton pump inhibitor (PPI) was significantly higher among the study patients who died of PRES compared with the rest of the study population (P = .018). Furthermore, the rate of steroid use was significantly lower and time from HSCT to onset of PRES was significantly shorter among patients who died of PRES compared with the rest of the PRES population (P = .024 and P = .019, respectively). Ongoing use of CsA+MMF in patients with PRES was significantly lower in patients who died of PRES compared with the remaining study patients (P = .019).

In PRES, hand tremor, thalamic involvement, and acute GVHD were more likely to occur in patients who died of PRES compared with patients who did not die of PRES (P < .000). Of 101 study patients, 15 (14.9%) died of PRES. The PRES-related mortality rate was significantly higher in patients with the central variant (n = 10, 62.5%) compared with those with the typical variant (n = 5, 5.9%) (P < .001).

Follow-up duration was shorter in the group of patients with the central variant of PRES (P < .001) compared with those with the typical variant (mean ± SD and median of 7.8 ± 15.3 and 3.1 mo vs 21.4 ± 21.9 and 12.3 mo, respectively). Rate of complete remission was significantly lower (P < .05) in the central variant PRES group versus the typical PRES group (Figure 3). Time to onset of PRES post-HSCT was shorter in patients who died of PRES compared with those who did not die (mean ± SD and median of 26.6 ± 17.0 and 20 days vs 32.5 ± 12.5 and 26 days; P = .019). The predicted survival time in the central variant PRES group (2.9 months) was significantly (P < .05) lower than the typical PRES group (19.2 months) (Table 6). None of the other risk factors in the multivariate model were statistically significant (P > .050). When we compared PRES-related death frequencies according to diagnoses, no statistically significant results were found (Table 7).

Discussion

Posterior reversible encephalopathy syndrome has been considered an important treatment-related neurologic complication following HSCT in pediatric patients.² The most commonly prescribed drugs for preventing GVHD are calcineurin inhibitors, such as tacrolimus and CsA. Furthermore, steroids, which have also been commonly used immunosuppressive drugs in HSCT, are known to increase blood pressure and may thus cause PRES.³ Nevertheless, both of these immunosuppressive treatments have side effects, with neurotoxicity being one of the most common. Headaches and seizures are common neurological manifestations. With MRIs now widely available, the underlying etiology has been more clearly understood in most cases.

Hinchey and colleagues classified PRES as a category of patients who had characteristic MRI findings and a reversible neurological condition.⁴ Primary pathophysiological mechanisms underlying PRES may include endothelial and blood-brain barrier dysfunction, hypertension, and the cytotoxic effects of pharmaceutical therapies.⁵ A broad range of potentially reversible neurologic symptoms, such as headache, visual abnormalities, altered mental status, seizures, and coma, are suggestive of a clinical and neuroradiologic entity known as PRES. The incidence of PRES following solid-organ transplantation or HSCT is approximately 10% in pediatric patients.⁶

Posterior reversible encephalopathy syndrome can be divided into 2 groups based on the distribution of lesions: typical and central (atypical) variants.⁷ Typical PRES is characterized by a widespread vasogenic edema, primarily affecting the brain’s subcortical white matter in the occipital and parietal lobes, and it mostly shows a symmetrical and bilateral pattern. Central variant (atypical) PRES affects the basal ganglia, brain stem, spinal cord, deep white matter, and splenium of the corpus callosum of the brain and usually occurs unilaterally. Hemorrhages, gyral enhancement, and cytotoxic edema are not commonly seen in complicated cases of PRES.^7-9 Although vasogenic edema is more common in the typical variant and hemorrhage is more common in the central variant, they can be seen in both PRES types. These heterogeneous, atypical imaging patterns, including permanent damage, hemorrhage, ischemic or hemorrhagic shift, and vasogenic edema in unfavorable locations present major challenges for the diagnosis and treatment of PRES.¹⁰ A PRES diagnosis also carries a higher risk of morbidity and mortality because patients frequ-ently require ICU admission and the reduction or discontinuation of immunosuppressive or anticancer therapies.

Data from previous studies have indicated that exposure to calcineurin inhibitors during early life may lead to a greater degree of neurotoxicity because of the increased permeability of the immature blood-brain barrier.¹¹ Widely recognized theories have focused on the disruption of the blood-brain barrier as a result of endothelial damage or elevated intracranial pressure.^12,13 Although most patients recover, PRES is not always curable and may be linked to significant morbidity and even mortality. Early recognition and assessment of risk factors are essential since the success of the treatment of this complication depends on timely control of the relevant precipitating factor.⁹ The exact rate of PRES following HSCT is yet unknown. Although the exact rate depends on the underlying disease, a number of studies have found that rates of incidence range from 1% to 10% following bone marrow or solid-organ transplant procedures in pediatric patients.^6,14,15 The 10% incidence of PRES in children following HSCT in the present study was com-parable to previous studies in the literature. The T2-weighted and fluid-attenuated inversion recovery hyperintensities shown in the parietal, occipital, and posterior frontal cortical and subcortical white matter are the MRI characteristics of typical PRES. Furthermore, because this knowledge is crucial for the timely identification of the disease and administration of appropriate treatment, it is important to consider that PRES may potentially manifest with an unusual presentation.¹⁶

To the best of our knowledge, publications that have reported on the characteristics of typical and central variants of PRES after HSCT in children are not available. The main aim of our study was to provide an overview of the features of PRES, including risk factors, treatment, morbidity, and mortality asso-ciated with typical and atypical central variants of PRES in children undergoing allogeneic HSCT for any indication.

In the literature, studies that have included patients experiencing PRES after HSCT in childhood have been limited.^1,2,17 Moreover, patients with atypical variant PRES have been presented as case reports.^18,19 In our study, of 101 patients diagnosed with PRES, 16 (15.8%) who had the central variant were evaluated. The value of this study is further increased by the higher number of cases evaluated with the same standard approach for both types of PRES in a single center.

With a few minor differences, the overall clinical and radiological aspects of PRES in children are comparable to those in adults. Contrary to previous studies in adults, the mean age in our study patients with central variant PRES was higher than those with the typical variant PRES (mean ± SD and median of 12.1 ± 5.3 and 14.0 years vs 8.9 ± 4.7 and 9.0 years, respectively; P = .033).²⁰ Research has shown that PRES usually occurs within the first month posttransplant, in line with our study (mean ± SD and median of 27.5 ± 16.5 and 20 days).²¹ However, late-onset PRES was found to be associated with a higher mortality rate. This can be explained by the relationship of PRES with the use of immunosup-pressive agents and the requirement for immunosup-pressives at higher doses, as it is indicated in complicated transplant cases. Moreover, because higher doses of immunosuppressives are adminis-tered in patients undergoing HSCT compared with other diseases, recent studies have often focused on this issue. This is supported by the fact that the frequency of PRES and PRES-related deaths did not significantly differ according to diagnoses, since all of our study patients used immunosuppressives. Previous work reported that atypical MRI lesions are more common in children than in adults.³

The prevalence of hypertension did not differ between the PRES variant groups unlike previous studies (n = 6 [37.5%] vs n = 46 [54.1%]; P = .222). This finding suggested that there is no correlation between the location of involvement and the development of hypertension in PRES. In a study of 110 children and adults diagnosed with PRES, seizures were more common in children and visual disturbances were more common in adults.²² In our present study, we observed no differences between the typical and atypical variant PRES groups in symptoms except for hand tremor. This may be explained by the fact that diseases affecting the basal ganglia and thalamus may cause symptoms such as resting tremor, postural instability, and poor balance and coordination.

In line with previous studies, we found no significant correlations between the source of stem cells, patient age, or patient sex and the development of PRES.² In addition, in accordance with previous publications, our data did not show any significant association between serum CsA levels and the onset of PRES.^1,6 Patients with PRES did not relapse and/or had no acute GVHD flares when alternative immunosuppressants were administered instead of CsA, suggesting that alternative immunosup-pressants can be safely used without any concern for PRES recurrence. Furthermore, unlike other studies,^1,17,23 we found no relationship between PRES and acute GVHD grade. This may be related to the fact that many alternative immunosuppressive treatment options could be started without delay in our patients with PRES. However, ongoing use of CsA+MMF as a calcineurin inhibitor was signifi-cantly more common than in the typical PRES group. Although our series adds to the previously published list of drugs linked to PRES, we did not observe a clear correlation between PRES and prophylactic use of antibacterial, antiviral, and gastrointestinal system-protective agents. Furthermore, it was noteworthy that the use of PPIs was more common among patients who later died of PRES. Previous studies have cited an increased frequency of PRES due to the potential hypomagnesemia-inducing effect of PPI use.^24,25 Changes in magnesium levels in the blood can lead to endothelial dysfunction and cerebral edema in the posterior circulation areas, which are common findings in patients with PRES.²⁶

Similar to previous studies, all of our patients who had hypertension required antihypertensive treatment (n = 52, 51.5%). In a study from Gaziev and colleagues in 222 children with thalassemia and 59 children with sickle cell disease, all 31 patients with PRES had elevated blood pressures and required interventions.¹ However, PRES can also develop in normotensive or hypotensive patients.⁵ The fact that hypertension was seen in some but not all children with PRES supported the hypothesis of direct endothelial injury and vasospasm.

If treated appropriately and immediately, PRES has a favorable prognosis and is frequently rever-sible, with symptom improvement or resolution occurring within a few days to several weeks.²⁷ Of note, if the therapy is not started immediately, patients may experience life-threatening complications, including focal neurologic deficits and cerebellar herniation.²⁸ Our clinic is a center where an average of 50 pediatric HSCTs are performed annually and where transplant-related complications such as PRES are frequently seen. Because our team is highly experienced in the management of PRES, cases of PRES are diagnosed without delay and treatment begins within 24 hours in our center. Because MRI can identify posterior cerebral edema shortly after the onset of initial symptoms, it is considered as an essential diagnostic tool.⁵ In our clinic, we routinely perform brain MRI as an initial workup to evaluate patients with suspected PRES.

Of our study patients, 36 (35.6%) had additional radiological findings accompanied by vasogenic edema or hemorrhage. Although hemorrhage was found to be more common in our atypical variant PRES group, there was no difference between the central variant versus the typical variant PRES groups in terms of complications such as vasogenic edema and/or hemorrhagic events overall (n = 5 [31.3%] vs n = 31 [36.5%], respectively; P = .689). However, PRES-related mortality rate in our central variant PRES group was remarkably higher (n = 10 [62.5%] vs n = 5 [5.9%]; P < .001) than in our typical variant PRES group. The higher incidence of hemorrhagic events in the atypical variant PRES group, especially in progressive cases, may have contributed to the increased mortality. Previous research showed that 5% to 17% of patients with PRES developed intraparenchymal or subarachnoid hemorrhage.^7,8,29

In the literature, investigations showed that rate of mortality was higher in patients with the central variant type, in line with our study. In a study from Canpolat and colleagues on 17 patients diagnosed with PRES, atypical involvement was associated with a higher mortality rate compared with the central variant.³⁰ Siebert and colleagues studied 151 adult patients, including immunosuppressed patients, and reported that subarachnoid hemorrhage, an atypical finding, was an independent risk factor for increased mortality in patients with PRES (P = .01), with an in-hospital mortality rate of 11.2%.²² In a study of 60 adult cancer patients diagnosed with PRES, median overall survival in patients who presented with a typical MRI pattern was 3.2 months compared with 1.8 months in those with an atypical MRI pattern (P = .026).³¹ The fact that thalamic and basal ganglia involvement was more common in our patients with the central variant and occipital, parietal, and temporal involvement was more common in our patients with the typical variant indicated an association between the distribution of lesions and clinical outcomes (P < .001).

The management of PRES is primarily sup-portive. A prompt diagnosis is essential since favo-rable outcomes depend on timely elimination of precipitating factors.⁹ Antihypertensive treatment is recommended for patients with acute hypertension to minimize the risk of cerebral, coronary, and renal ischemia. The guidelines for the management of status epilepticus recommend early administration of intravenous benzodiazepines as the first line of treatment of seizures, and fosphenytoin and pheno-barbital should be given after acute intervention. Levetiracetam was our preferred antiepileptic drug in most patients because of its low side effect profile, wide spectrum of indications, and lower potential for drug interactions. Most common indications for admitting patients to the ICU include encep-halopathy, seizures, and status epilepticus. Eighteen percent of our patients (68.8% diagnosed with central variant PRES; P < .001) were admitted to the ICU for different reasons.³² This can be explained by the higher incidence of hemorrhagic complications in the central variant PRES group (4 of 5 patients with hemorrhage). Rates of ICU admission in patients with PRES in the literature have ranged from 21% to 40%.^9,33,34

Even patients who receive appropriate treatment can have residual abnormalities, so not all cases are completely resolve.³⁵ In the present study, the rate of complete remission was significantly higher in the typical PRES group than in the atypical PRES group based on follow-up MRI scans (n = 4 [25.0%] vs n = 72 [84.7%]; P < .001). This result correlates and can be associated with increased mortality in variant type PRES. Three patients (2.9%) in our study showed improved epilepsy and unprovoked seizures related to PRES, which is comparable to previous research.^36,37 Although provoked seizures are common during the acute phase of PRES, epilepsy is uncommon, and the long-term risk of unprovoked seizures is low. Imaging studies revealed structural damage in our 3 patients who experienced unprovoked seizures, which may be responsible for the persistence of epilepsy after the acute phase. Only 2.9% of patients experienced PRES-related epilepsy, despite a high rate of central nervous system involvement. Therefore, it will be necessary to assess these additional aspects in future research as they may contribute to the development of epilepsy in addition to central involvement. Two patients in the central variant PRES group and 5 patients in the typical PRES group presented with dizziness during the follow-up (P = .306).

Conclusions

Our study aimed to show that the prognosis of central variant of PRES is worse than typical PRES because of the more critical functions of the brain stem, cerebellum, and basal ganglia compared with other regions of the central nervous system. Patients with central variant PRES in our study had significantly increased risk of mortality. Because this clinical-radiological condition frequently manifests with atypical MRI findings, it is especially important to consider PRES as a potential diagnosis when the clinical presentation is consistent with PRES but radiological findings are not typical to PRES. Multicenter prospective studies are required to improve our understanding of the risk factors for this complication and its effect on transplant-related morbidity and mortality rates in pediatric patients.

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