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. 2015 Dec;28(6):638–643. doi: 10.1177/1971400915609338

Childhood posterior reversible encephalopathy syndrome: Magnetic resonance imaging findings with emphasis on increased leptomeningeal FLAIR signal

Ajay Agarwal 1,, Gaurav Kapur 2, Deniz Altinok 3
PMCID: PMC4757130  PMID: 26515749

Abstract

Purpose

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiologic syndrome characterized clinically by headache, seizures, and altered sensorium and radiological changes which are usually reversible. The purpose of this study was to describe the spectrum of magnetic resonance imaging (MRI) findings in childhood PRES, to determine the common etiologies for childhood PRES, and to have an insight into the pathophysiology of PRES.

Methods

The MRI results of 20 clinically diagnosed cases of PRES between July 2011 and June 2013 were reviewed. The final diagnosis of PRES was based on the clinical presentation and the MRI features at the time of presentation, which resolved on the follow-up imaging. The medical records of the patients were reviewed to determine the underlying medical disease.

Results

Eight out of the 20 patients included in the study were on cyclosporine or tacrolimus based immunosuppressant therapy for kidney transplant. Four patients had severe hypertension at presentation. The most common MRI finding was high T2-fluid-attenuated inversion recovery (FLAIR) signal in the cortex and subcortical white matter of both cerebral hemispheres, particularly in the parietal and occipital lobes (n = 16). The second most common MRI finding was increased leptomeningeal FLAIR signal (n = 7). Out of seven patients with leptomeningeal signal, five demonstrated leptomeningeal enhancement as well. Four out of these seven patients had no other parenchymal findings.

Conclusion

Childhood PRES is commonly seen in the setting of immunosuppressant therapy for kidney transplant, severe hypertension and cancer treatment. There was high incidence of increased leptomeningeal FLAIR signal and leptomeningeal enhancement in our study. It supports the current theory of endothelial injury with increased microvascular permeability as the potential pathophysiology of PRES. Also, absence of elevated blood pressure in majority of the patients in our study supports the theory of direct endothelial injury by some agents leading to vasogenic edema.

Keywords: Magnetic resonance imaging, posterior reversible encephalopathy syndrome, encephalopathy, childhood

Introduction

Posterior reversible encephalopathy syndrome (PRES) is an acute clinico-radiological syndrome which is well described in the literature, particularly in adults. It is commonly seen in the setting of eclampsia, hypertension, and post-transplant patients on cyclosporine or tacrolimus (FK-506). It has also been reported in patients with other systemic conditions such as sepsis, Wegener granulomatosis, systemic lupus erythematosus (SLE), glomerulonephritis, and post chemotherapy.15 Despite the universal awareness of this entity in the adult population, it appears that the pediatricians are less familiar with this entity. PRES is an increasingly recognized complication of pediatric cancer treatment, mainly in leukemic patients, but also in patients with solid tumors.6 Also, higher prevalence of this syndrome has been reported in pediatric kidney transplant patients and pediatric patients with kidney disease.7 Early diagnosis and proper management of these patients may decrease the morbidity. Patients usually presents with a combination of neurological symptoms like headache, seizures, altered sensorium and visual disturbances. The most common magnetic resonance imaging (MRI) feature described is cortical and subcortical vasogenic edema, particularly in the parietal and occipital lobes. However, other areas of involvement are also well described in the literature including involvement the frontal lobes, deep gray matter and brain stem.5 In this study, we retrospectively evaluated the MRI features in 20 pediatric patients diagnosed with PRES. The underlying medical conditions of the patients were also reviewed to determine the common etiologies for childhood PRES.

Material and methods

We obtained approval from the Institutional Review Board for this retrospective study. MRI of consecutive 20 children diagnosed with PRES between July 2011 and June 2013 based on clinical and imaging follow-up were reviewed. All the MRI findings were reviewed by two pediatric neuroradiologists, certificate of added qualification (CAQ) certified in neuroradiology and pediatric radiology. The medical records were reviewed to find the underlying medical conditions of the patients included in the study. The final diagnosis of PRES was made based on the clinical presentation of neurotoxic syndrome and the MRI features which resolved on the follow-up imaging (3–6 months after initial presentation).

Results

Out of the 20 patients, 12 were girls and 8 were boys with an average age of 9 years (range 5–13 years). The most common underlying medical condition was immunosuppressant therapy for kidney transplant (n = 8). The other medical conditions were severe hypertension (n = 4), neurofibromatosis-1 (n = 3), autoimmune disorders (n = 2), chemotherapy for leukemia (n = 2), acute on chronic renal failure (n = 1), and Henoch–Schönlein purpura (n = 1). The most common presenting symptom was seizure (85%).The other common presenting symptoms were headache, vision problem and altered sensorium. Kidney transplant recipients received either a cyclosporine or tacrolimus based immunosuppressive regimen. Elevated blood pressure was present in a total of nine patients (45%). It was severe in four patients with mean systolic blood pressure (SBP) >210 mmHg. The cause of the high blood pressure in these patients was not known. Some degree of hypertension (SBP in the range 160–170 mmHg) was present in patients on immunosuppressant therapy for kidney transplant (n = 3) and on chemotherapy for leukemia (n = 2). Two patients on chemotherapy for leukemia developed PRES during the induction phase of treatment. The most common MRI finding was symmetrical or asymmetrical cortical and subcortical vasogenic edema in the cerebral hemispheres, particularly involving the parieto-occipital lobes (n = 16) (Figure 1).Other areas of involvement were frontal lobe, temporal lobe, cerebellum, brain stem, basal ganglia, thalami, corpus callosum, and deep white matter (Figures 2 and 3). The distributions of the lesions are reviewed in Table 1.

Figure 1.

Figure 1.

Axial T2W FLAIR MR image shows asymmetric increased cortical and subcortical signal in bilateral occipital and temporal lobes.

Figure 2.

Figure 2.

Axial T2W FLAIR MR image shows symmetric increased cortical and subcortical signal in bilateral fronto-parietal lobes.

Figure 3.

Figure 3.

Axial T2W FLAIR MR image shows symmetric increased signal in bilateral cerebellar hemispheres.

Table 1.

Locations of brain lesions.

Location % Patients
Occipital/parietal lobes 80
Frontal lobe 50
Temporal lobe 40
Cerebellum 25
Brain stem 15
Basal ganglia 20
Thalamus 15
Corpus callosum 5
Corona radiata 5

The second most common MRI finding was increased leptomeningeal signal on fluid-attenuated inversion recovery (FLAIR) sequence (n = 7, 35% (Figure 4)). Four out of these seven patients had no other parenchymal findings. Five out of seven patients with leptomeningeal FLAIR signal demonstrated leptomeningeal enhancement as well (Figure 5). Some of the other imaging findings were diffusion restriction (n = 3) (Figure 6), focal parenchymal hemorrhage (n = 2), and focal parenchymal enhancement (n = 3). There was isolated involvement of the corona radiata in one patient (5%).

Figure 4.

Figure 4.

Axial T2W FLAIR MR image shows symmetric increased leptomeningeal signal in bilateral fronto-parietal lobes.

Figure 5.

Figure 5.

Axial T1W post gadolinium MR image shows leptomeningeal and parenchymal enhancement in bilateral frontal lobes.

Figure 6.

Figure 6.

Axial diffusion weighted MR image shows restricted diffusion in bilateral middle cerebellar peduncles.

Discussion

PRES was initially described in the setting of eclampsia and severe hypertension. Since its initial description, a number of other medical conditions have been found to be associated with PRES, such as cyclosporine or tacrolimus treatment after organ transplant, sepsis, systemic inflammation like Wegener’s granulomatosis, collagen vascular disease, renal failure, etc.14

In this study we made an attempt to determine the common underlying medical conditions in pediatric population at risk for PRES and also to demonstrate the common MRI findings. In a study by Ishikura et al.,8 kidney transplant recipients and pediatric patients with kidney disease were investigated over a period of five years. Of 177 kidney transplant recipients (cyclosporine, 127 patients; tacrolimus, 50 patients), six patients on cyclosporine (4.7%) and four patients on tacrolimus (8.0%) developed PRES after transplantation.7,8 They concluded that PRES should be suspected in pediatric kidney transplant recipients and patients with kidney disease if they have a sudden episode of neurological symptoms, even if imaging findings are not typical. In our study, 40 % of the patients were on cyclosporine or tacrolimus based immunosuppressive regimen for kidney transplant. PRES is an also increasingly recognized complication of pediatric cancer treatment. So far, the syndrome has been mainly described in leukemic patients but can also occur in pediatric patients with solid tumors like osteosarcoma, Ewing sarcoma, neuroblastoma, etc. Risk factors for PRES in pediatric cancer patients include hypertension, chemotherapy, and administration of tacrolimus.6,9 Such patients usually present with PRES during the induction phase of treatment. The reason for this timing is not known. We had two leukemic patients on chemotherapy presenting with PRES during the induction phase.

The cause of neurotoxic syndrome and the mechanism behind the PRES imaging appearance is still controversial and debatable. PRES typically results in interstitial fluid accumulation or vasogenic edema which may be due to increasing hydrostatic pressure and/or increased microvascular permeability. There are two theories currently believed to explain the pathophysiology of vasogenic edema in PRES: (1) hyperperfusion state due to intravascular pressures exceeding their autoregulatory capabilities causing endothelial injury with blood–brain barrier breakthrough leading to extravasation of fluid and resulting cortical or subcortical edema;10 and (2) hypoperfusion and ischemia due to excessive vasoconstriction that occurs as a response to high intravascular pressures leading to endothelial injury with loss of integrity of the blood–brain barrier.5,1114

Hypertension is believed to be a key risk factor for PRES in children with cancer.6,9 The cause of hypertension is such patients are not well established but it may be related to steroid induced hypertension or renal dysfunction. In a study on pediatric cancer patients, all patients were found to have elevated blood pressure at the time of PRES. Also, PRES is more common during the induction phase of treatment. It may be related to the fact that endothelial dysfunction occurs particularly during the induction phase because of repetitive systemic and intrathecal administration of chemotherapy. In pediatric patients with renal disease, acute hypertension again seems to be the underlying mechanism.7,8 However, in a study on pediatric renal population, almost half the children had no evidence of elevated blood pressure at the time of PRES episodes. The authors felt that certain drugs like cyclosporine, tacrolimus, etc. may have direct effects on the vasculature.7 In our study the blood pressure was within normal limits in 55% of the patients, thereby supporting the fact there are factors other than hypertension which plays a role in pathophysiology of PRES. It supports the theory of direct endothelial injury by some agents like drugs leading to vasogenic edema. On imaging (computed tomography/MRI), the most typical finding described is symmetric cortical and subcortical vasogenic edema in the cerebral hemispheres. The parietal and occipital lobes are most commonly affected, followed by the frontal lobes, the infero-posterior temporal lobes, and the cerebellum. Patchy areas of vasogenic edema may also be seen in the deep gray matter, brain stem, and deep white matter.4,5,15,16 Usually, the MRI findings in PRES are completely reversible on follow up imaging with clinical improvement. MR diffusion-weighted imaging (DWI) helps to differentiate between cytotoxic and vasogenic edema.14,17 In severe cases of PRES, there may be irreversible injury of the brain parenchyma leading to infarction. However, brain infarction in the setting of PRES is rare with an incidence of approximately 11–26 % and suggests a bad prognosis.16,17 Focal intracranial hemorrhage either parenchymal or subarachnoid is also described in PRES with an incidence of approximately 15%.16 In our study, the most common MRI finding was cortical and subcortical vasogenic edema similar to as described in the literature, particularly for adults. There was no pattern for cerebral involvement specific for children. There were a few unusual areas of involvement in the brain but those are also already reported. An interesting finding which was seen in our study was abnormal increased leptomeningeal signal on FLAIR, seen in 35% of patients. This was the isolated finding in four patients. There was leptomeningeal enhancement in five out of these seven patients (25%). There have also been a few reported cases of increased leptomeningeal FLAIR signal in PRES, however, this finding has not been emphasized in the current literature of PRES. Increased leptomeningeal signal intensity on FLAIR have been described in a wide range of pathologic conditions, such as subarachnoid hemorrhage, meningitis, leptomeningeal spread of malignant disease, moyamoya disease, leptomeningeal melanosis, and supplemental oxygen.18 None of the patients in our study were suffering from any underlying conditions which are known to cause leptomeningeal high signal intensity. The presence of this finding also supports the current theory of endothelial injury with increased microvascular permeability as the potential pathophysiology of PRES.5,19 As of now, we do not have an answer to why this finding was more commonly seen in the pediatric population with PRES when compared to the adult population. It may be related to sepsis which is also a known cause of PRES. However, there was no laboratory evidence to support it.

Conclusion

Childhood PRES is commonly seen in the setting of immunosuppressant therapy for kidney transplant, severe hypertension and cancer treatment. On imaging, the most typical finding is cortical and subcortical vasogenic edema particularly in the parietal and occipital lobes. This pattern is also the most common pattern described in adults. The underlying mechanism and pathophysiology of PRES still remains unclear and controversial. Presence of abnormal increased leptomeningeal signal on FLAIR and leptomeningeal enhancement in a fairly good number of patients in our study supports the current theory of endothelial injury with increased microvascular permeability as the potential pathophysiology of PRES. Also, absence of elevated blood pressure in majority of the patients in our study supports the theory of direct endothelial injury by some agents leading to vasogenic edema.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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