Posterior reversible encephalopathy syndrome in the pediatric population: a pictorial essay

Posterior reversible encephalopathy syndrome (PRES) is a rare disease attributed to an increase in blood pressure that exceeds the autoregulatory capabilities of the cerebral vasculature, resulting in brain edema. Although PRES primarily affects adults, the pediatric population is also at risk. Radiologists must be aware of that risk because the imaging features on brain MRI are often atypical, especially in pediatric patients. Over a 6-year period, nine pediatric patients were diagnosed with PRES at our institution. Here, those patients are evaluated retrospectively regarding demographic characteristics, clinical profiles, imaging aspects, and outcomes. In this pictorial essay, we review the typical and atypical imaging findings of PRES in pediatric patients, demonstrating that it should be considered in patients with a clinical profile suggestive of the diagnosis, given that prompt, effective treatment is important for full recovery, thus avoiding major morbidity and mortality in such patients.


INTRODUCTION
Posterior reversible encephalopathy syndrome (PRES), first described in adults in 1996 (1) , is a rare, controversial syndrome whose pathophysiology is not fully understood. One of the main mechanisms of PRES is the failure of cerebral vascular regulatory mechanisms in the context of sudden blood pressure changes. To date, three etiological hypotheses have been proposed (2) : vasoconstriction leading to infarction; failure of vascular autoregulation, resulting in vasogenic edema; and endothelial damage with disruption of the blood-brain barrier, leading to transudation of fluid and proteins. Although PRES has been reported to be more common in adults, the pediatric population is also at risk for the syndrome. However, data in the literature regarding PRES in the pediatric population are scarce and pediatricians seem to have little experience with this syndrome (4) . Clinically, PRES is characterized by various neurological signs and symptoms, such as headaches, visual disturbance, seizures, and even altered mental status, although it can be overlooked by clinicians (4) .
Neuroimaging evaluation plays an important role in the definite diagnosis of PRES, and MRI, which can show even small lesions, is considered the gold standard (6) . Classical brain MRI findings in PRES include reversible bilateral, symmetric white matter lesions, cortical signal changes in the parietal and occipital regions on T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences, together with atypical imaging findings such as asymmetric or unilateral lesions, as well as posterior fossa lesions, contrast-enhancing lesions, and lesions that are hemorrhagic or show restricted diffusion on diffusion-weighted imaging (DWI), contributing to the controversy surrounding the syndrome. Such alterations are usually reversible, and a DWI study might help in differentiating between reversible vasogenic edema and cytotoxic edema/ischemic lesions. According to the literature, these atypical findings are more common among pediatric patients, although they do not always correlate with the severity of symptoms. That can create a diagnostic dilemma, resulting in delayed diagnosis and treatment, which can lead to poor outcomes (7) .
In this pictorial essay, we review typical and atypical imaging findings of PRES in children and adolescents treated in the intensive care unit of our hospital, demonstrating that it should be considered in patients with a clinical profile suggestive of the diagnosis, given that prompt, effective treatment is important for full recovery, thus avoiding major morbidity and mortality in this population. The main demographic, clinical, and imaging data are detailed in Table 1.
Over a 6-year period, nine pediatric patients were diagnosed with PRES. Five (60%) of those patients were female. The mean age was 10.33 years, the majority of the patients being teenagers. The primary underlying diseases were type 1 diabetes mellitus, anemia, Burkitt's lymphoma, acute lymphoblastic leukemia, seminoma, nephrotic syndrome, and supraventricular tachycardia. One patient had no relevant personal medical history. Four patients had oncologic disease and were under chemotherapy. The clinical presentations of PRES included seizures, status epilepticus, reduced level of consciousness, headache, and visual disturbance. In addition, most of the patients developed high blood pressure. Three patients were lost to follow-up: two died, and one was transferred to another facility. At 90 days of follow-up, three of the six remaining patients were asymptomatic and the other three developed gait abnormality, headaches plus dysfunctional behavior, and epilepsy, respectively. In most cases, brain MRI revealed at least one atypical imaging feature. In the T2-weighted FLAIR sequence, areas of signal hyperintensity were identified in  Table 1-Demographic characteristics, clinical profiles, outcomes, and imaging findings of pediatric patients diagnosed with PRES.  the biparietal region, occipital region, frontal lobe, temporal lobe, basal ganglia, and cerebellum. In one case, DWI showed slightly restricted diffusion in those same areas.
In two other cases, hemorrhages were identified in T2*weighted sequences. By 90 days of follow-up, the imaging abnormalities had reversed in most of the patients.

IMAGING CHARACTERISTICS OF PRES IN THE PEDIATRIC POPULATION
All brain MRIs were performed in 1.5-T scanner, with the following sequences: sagittal T1-weighted sequences with multiplanar three-dimensional reconstruction; axial proton density, T2-weighted sequences; T2-weighted FLAIR sequences; T2*-weighted sequences; DWI with apparent diffusion coefficient mapping; and coronal T2weighted sequences. The majority of the patients had impaired renal function and therefore underwent unenhanced MRI. The images were analyzed by neuroradiologists and discussed with the pediatric team when appropriate. The MRI examinations were repeated if warranted by the clinical profile of the patient and at the discretion of the clinician.

Typical imaging findings
Although it has been reported that the lesions caused by PRES are asymmetric in 28% of cases (8) , the typical imaging aspects are focal regions of symmetric cortical and subcortical white matter lesions with signals that are hypointense on T1-weighted sequences and hyperintense on T2-weighted FLAIR sequences, likely representing vasogenic edema, in both parieto-occipital regions, without restricted diffusion or hemorrhage (6,8) , as shown in Figure  1. In the classic definition of PRES, the spontaneous disappearance of lesions is considered normal (Figure 2).

Atypical imaging findings Atypical regions and asymmetric lesions
Lesions attributed to PRES are not always posterior or symmetric, and atypical imaging could represent an early finding of the more classic radiological and clinical scenario (8) . Although the exact frequency of atypical imaging findings in pediatric PRES is unknown, it has been reported to be as high as 50% in the infratentorial region and 25-30% in the deep gray matter (7) . Other authors have reported that atypical MRI lesions occur in 61-82% of pediatric patients with PRES, compared with 10-58% of adults with the syndrome (4) . The regions most often affected, in descending order, are the parietal lobes, occipital lobes, frontal lobes, inferior temporo-occipital junction, and cerebellum; that is due to better sympathetic innervation and the consequent improvement in autoregulation of the anterior circulation (8) . On T2-weighted FLAIR sequences (Figure 3), lesions with hyperintense signals can be seen in atypical locations such as the frontal lobe, temporal lobe, deep gray matter, posterior fossa, brainstem, and cerebellum (6) . The lesions may also be asymmetric, with gadolinium enhancement, hemorrhagic changes, or restricted diffusion (4) . Some of these uncharacteristic imaging findings, especially extensive vasogenic edema, hemorrhage, and restricted diffusion, have been linked to poorer clinical outcomes (7) .
Several theories exist to explain why there are regions of restricted diffusion in some cases of PRES. The most popular theory is that hyperperfusion causes a severe mass effect from vasogenic edema with compression of the local microcirculation, resulting in acute ischemia and cytotoxic edema (4,9) . Chen et al. (10) also demonstrated that patients who present cytotoxic edema on brain MRI are more likely to have worse outcomes and neurologic sequela. Therefore,  early detection of that alteration is critical to prevent vasogenic edema from progressing to irreversibility (9) .

Hemorrhage
The presence of hemorrhage on T2*-weighted imaging or (the more sensitive) susceptibility-weighted imaging (4) is also considered atypical in PRES ( Figure 5). In PRES, hemorrhage development may be secondary to the rupture of pial vessels in the setting of severe hypertension or reperfusion injury in the setting of vasoconstriction (7) . Hemorrhage reportedly occurs in 5-30% of cases, and the possible anatomical locations for its occurrence, with a similar incidence, are the brain parenchyma (focal hematoma), gyri (petechial hemorrhages), and the subarachnoid space (8) .
In PRES, a higher rate of microhemorrhage is associated with vasculopathy (7,8,10) . Patients who present with hemorrhage on brain MRI could have worse outcomes and sequelae. Although the clinical relevance of microhemorrhage is unknown, more extensive parenchymal bleeding may develop into sequelae that worsen the prognosis (4) . Hemorrhage might also be more common in transplant recipients, due to the underlying coagulopathy, or in patients receiving anticoagulation therapy, who constitute a major proportion of patients with PRES (7) .

Enhancing lesions
Progressive disorder of the mechanisms of cerebrovascular regulation may cause damage to the blood-brain barrier. In such cases, marked contrast enhancement can be seen on T1-weighted imaging after gadolinium administration (8) , as depicted in Figure 6. The reported rates of such enhancement are approximately 37-43% (7) . However, the presence or pattern of enhancement has not been found to show a significant association with patient outcomes (7) .

Irreversible lesions
If the diagnosis is made early and treatment is applied promptly, PRES is potentially reversible, although it can also be irreversible (Figure 7). The rate of irreversible neurologic  A B C D damage related to PRES has been reported to be as high as 12%. There have been reports of recurrence (5) and permanent neurological sequelae, with a mortality rate of 16% (10) .

CONCLUSION
Although PRES is a rare diagnosis in pediatric patients, it should not be overlooked when pediatric patients present with a clinical profile suggestive of the diagnosis. In most cases, the syndrome is reversible and has a mild course, especially if diagnosed early and treated promptly with supportive care. Imaging is fundamental for the initial diagnosis of PRES, particularly in pediatric patients, in whom atypical lesions might be more common. The fact that PRES may have an atypical presentation should be borne in mind for timely recognition and treatment of the condition. Consequently, there is a need for prospective, long-term follow-up studies to elucidate which typical or atypical imaging characteristics indicate reversibility and correlate with long-term outcomes. Such studies are especially needed in the pediatric population, in whom this syndrome may have a more severe or even life-threatening course, with sequelae and possible irreversible damage.