PRES in Children Undergoing Hematopoietic Stem Cell or Solid Organ Transplantation

Pathophysiology and Risk Factors

The pathophysiology of PRES remains unclear and is still debated. Two competing theories exist, both of which entail blood-brain barrier dysfunction and leakage of fluid into the interstitium, leading to the development of cerebral vasogenic edema.¹⁴ The first theory identifies hypertension as the “primum movens.” Specifically, a rapid increase in blood pressure overcomes the cerebral vessels’ autoregulatory mechanism with cerebral hyperperfusion, causing injury to the capillary bed and vasogenic edema.¹⁴ On the basis of this theory, the predominant involvement of the posterior cerebral area in PRES might occur because sympathetic innervation, which has the ability to increase the upper limit of autoregulation, is less represented in the vertebrobasilar circulation compared with the carotid system.¹⁵

Approximately 20% to 30% of patients with PRES have normal or only slightly high blood pressure.¹⁶ In fact, whereas the hypertension/hyperperfusion theory has been the most popular, a second pathogenetic theory of PRES speculates on T-cell/endothelial cell activation, resulting in leukocyte trafficking and systemic/cerebral vasoconstriction and cerebral hypoperfusion (Fig 1).¹⁴ In these cases, endothelial dysfunction and subsequent cerebral edema could be induced by the cytotoxicity of immunosuppressive therapy, infections, and autoimmune diseases. Hypoxia increases endothelial permeability through the activation of the vascular endothelial growth factor, causing vasogenic edema. Several imaging studies have supported this hypothesis, revealing brain hypoperfusion in patients with PRES.^17,18 Neuroimaging studies have documented vasospasm, hypoperfusion, and ischemia¹⁹ and autopsy studies have confirmed a predominance of ischemic microinfarcts or cerebral vasculitis.^19,20 As a consequence, some authors have hypothesized that systemic hypertension could be a reactive and protective response rather than a cause of PRES because of the ability to improve perfusion and reduce cerebral edema.^14,15 In contrast, increasing hypertension could stimulate cerebral autoregulatory vasoconstriction; and this stimulation, together with toxicity-induced vasoconstriction, might result in further brain hypoperfusion, inducing ischemia.^14,21 Finally, vasospasm might also play a role in the genesis of local ischemia and cerebral edema.²² This second theory might be relevant in the transplantation setting, in which the putative involvement of the vasculature and endothelial damage to it seem to play critical roles in the pathophysiology of many transplant-associated complications, namely microangiopathy, veno-occlusive disease, and graft-versus-host disease (GvHD).²³

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FIGURE 1

The figure summarizes the 2 competing theories on pathophysiology of PRES, both of which entail blood-brain barrier dysfunction, leading to the development of cerebral vasogenic edema. The first theory identifies as the “primum movens” a rapid increase in blood pressure that overcomes the cerebral vessels’ autoregulatory mechanism with cerebral hyperperfusion, causing injury to the capillary bed and vasogenic edema. The second theory speculates on T-cell/endothelial cell activation, resulting in leukocyte trafficking and systemic/cerebral vasoconstriction and cerebral hypoperfusion. It is reasonable to hypothesize that many of the crucial events described in both the 2 theories could occur concomitantly in a transplantation setting, suggesting a multifactorial hypothesis of pathogenesis. APC, antigen presenting cell; CTL, cytotoxic T lymphocyte; ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; TNF-a, tumor necrosis factor α; VCAM, vascular cell adhesion molecule;

Peculiarities in the pathophysiology of PRES are certainly present across different transplantation settings. These differences are evident between HSCT and SOT, in both of which endothelial damage and activation, cytokine release, and T-cell recruitment can occur through various mechanisms (ie, chemotherapy-induced damage before HSCT, onset of acute GvHD, graft rejection, etc). Moreover, it seems that even in SOT, particularly kidney and liver transplantation, the pathophysiology of PRES could present different peculiarities, possibly influencing the respective time of onset.^21,24

Many triggers and risk factors for PRES after SOT and HSCT have been described. GvHD prophylaxis with calcineurin inhibitors (CNIs), such as tacrolimus and cyclosporine A (CSA), has been recognized as a major trigger of PRES in patients who underwent HSCT.²⁵ The use of lower doses of the same drugs for immunosuppressive treatment after SOT has been credited with lowering the incidence of PRES in these patients.²¹ Medication withdrawal often results in the alleviation of toxicity, despite a frequent lack of correlation in the literature between circulating blood levels of CNIs and the occurrence of PRES.¹⁴ In fact, CSA and FK-506 levels have been found to be in the therapeutic ranges at the onset of many cases of PRES.^14,26,27 CNIs could cause direct endothelial dysfunction mediated by enhanced systemic endothelial activation, leukocyte trafficking, and vasoconstriction or demyelinization in patients with PRES.

CNI administration was associated with chronic hypomagnesemia,²⁵ and magnesium is a competitive antagonist of calcium that has vasodilatatory effects on cerebral vasculature, as well as a blood-brain barrier protective effect. Thus, it has been suggested that hypomagnesemia might be associated with PRES because it enhances CNI neurotoxicity.^25,28 There have been fewer reports of PRES development in association with other immunosuppressive agents used mainly in SOT, particularly sirolimus.²⁹

Because a high incidence of GvHD has been noted in patients with PRES after allo-HSCT, acute GvHD has been suggested to contribute to the pathophysiology of PRES.^25,30 The administration of fludarabine during the conditioning regimen was also recognized to be a risk factor for the development of PRES in adult recipients after HSCT.³¹ In a cohort of allo-grafted children, we demonstrated significant relationships of the use of steroids and the use of cord blood as a stem cell source with the development of PRES.³²

With regard to SOT, transplant rejection, cytomegalovirus, and bacterial infections have all been identified as being associated with PRES.^6,9,10,21 Moreover, the few studies available in the literature on the risk factors significantly predisposing children who undergo SOT to the development of PRES have recognized risk factors similar to those of HSCT, mainly hypertension and the use of CNI and other immunosuppressive drugs such as sirolimus.^10,21,29

Clinical Manifestations, Diagnosis, and Complications

Neuroimaging

MRI is the gold standard for the diagnosis of PRES. The typical lesion in PRES consists of vasogenic edema, located predominantly in the subcortical white matter with frequent involvement of the cortex (Fig 2A). These lesions show a high signal on T2-weighted images and fluid attenuated inversion recovery(FLAIR) sequences: the latter sequences are more sensitive for the detection of subcortical and cortical lesions.³⁹ Diffusion-weighted imaging is required to differentiate PRES from ischemic stroke. In the majority of patients the administration of gadolinium chelates does not reveal any contrast enhancement of the brain tissue; nevertheless, in some cases, it may show mild signs of disruption of the blood-brain barrier. Although gadolinium can be helpful to exclude possible differential diagnosis (progressive multifocal leukoencephalopathy, opportunistic infections), its administration has to be carefully evaluated in transplanted children at high risk of acute and/or chronic renal failure.

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FIGURE 2

A, FLAIR T2-weighted MRI image of typical bilateral posterior vasogenic edema during the acute phase of PRES. B, Complete resolution of the vasogenic edema. C, CT scan showing a hemorrhagic complication of PRES in the right hemisphere. D, T2-weighted MRI image of cerebellar swelling and herniation during PRES.

Most patients show involvement of both hemispheres,^1,39–41 sometimes asymmetrically. Predominantly parieto-occipital involvement is usually observed (from 50% to 99% of cases), whereas the frontal and temporal lobes are affected in half of cases.^1,39,42 The cerebellum, basal ganglia, and brainstem are involved in approximately one-third of cases.

As transplanted children can present with a wide spectrum of acute neurologic complications, the evaluation with MRI is fundamental to obtain a secure diagnosis of PRES. However, computed tomography (CT) is usually the first investigation recommended for children with acute neurologic complications after transplantation, mainly to exclude hemorrhagic events related or not to PRES. Unfortunately, the CT findings in PRES are sometimes normal or nonspecific. A study comparing the different sensitivities of both assessment modalities after PRES found negative or nonspecific radiologic patterns on CT scans in more than half of patients, whereas MRI was able to detect typical PRES lesions in all the cases.⁴⁰

Differential Diagnosis

PRES occurring after HSCT or SOT must be distinguished from other acute neurologic complications, namely CNS infections, metabolic disturbances (electrolyte imbalances or multiple organ failure), cerebrovascular disorders, and CNS involvement by an underlying disorder (Table 1).^9,11,13 The frequency of transplant-related complications differs depending on the type of transplant. In the context of pediatric liver or combined liver and small bowel transplant,³⁸ the most frequent causes of neurologic disorders described in the literature include metabolic encephalopathy, followed by PRES, CNS infection, and cerebrovascular accident. With regard to renal transplantation, PRES assumes a major role in the onset of neurologic complications, followed by CNS infection and hypertensive encephalopathy.⁶

PRES represents the main etiology for neurologic complications after pediatric allo-HSCT.^3,11,49,50 Other causes of neurologic disturbances, in descending order of frequency, include the following: CNS infection, CNS involvement by the underlying disease, encephalopathy of unknown origin, metabolic disturbances, or neurotoxicity of certain drugs (ie, busulfan).

Instrumental, radiologic, and laboratory findings can help differentiate PRES from other common complications after transplantation. Ictal and/or postictal abnormalities on EEG (rhythmic epileptiform activity, periodic lateralized epileptiform discharges, and/or slowing) in the posterior regions of the brain are particularly suggestive of PRES.²⁷

Although cerebral images are usually normal or scarcely informative in cases of metabolic derangement or CNS involvement by hematologic disease, CNS infections are associated with heterogeneous, but suggestive, imaging findings spanning from an abscess lesion, a focal lesion surrounded by perilesional edema (ie, in the case of a cerebral Epstein-Barr Virus (EBV)-posttransplant lymphoproliferative disorders), or diffuse edema.¹¹ In bacterial meningitis, abnormal thickening and enhancement of the leptomeninges are detectable on MRI with contrast enhancement. In the case of CNS aspergillosis, CT or MRI can detect vasculopathy and multiple septic infarcts involving the basal ganglia, thalami, and the corticomedullary area, often in association with hemorrhage and abscess formation.⁵¹ In patients with clinical suspicion of CNS infection or involvement by hematologic disease, cerebrospinal fluid analysis and related blood examinations are useful in reaching a diagnosis. Diffusion-weighted imaging is required to differentiate PRES from cerebrovascular disorders, such as ischemic stroke.

Outcomes

The clinical and radiologic reversibility of PRES has been extensively described since its first description,^1,33 but over the years, the recognition of nonreversible cases has revealed the heterogeneous evolution of this syndrome.^52–54 Globally, limited and conflicting data are available on functional outcomes. Some authors have reported good outcomes in children with PRES after SOT or allo-HSCT because all of their patients recovered from symptoms and none developed neurologic abnormalities.^6,11,26 However, other studies have noted the presence of residual or late-onset neurologic sequelae or epilepsy secondary to permanent brain lesions.^4,52

The impact of PRES on survival rates is particularly difficult to define because the relative effects of PRES and other factors (baseline disease, therapies) remain unclear. Moreover, data concerning mortality rates after PRES have derived mainly from case reports or small retrospective studies, from which it is difficult to draw accurate conclusions.

Our pediatric patients who developed PRES after allo-HSCT had a higher mortality rate than patients who were free from neurologic disturbances (5-year survival: 32.3% vs 45.8%).^11,32 This finding was also emphasized in a large study of allo-HSCT in adults.¹³

Recommendations for Management and Follow-up

Supportive care is the cornerstone of treatment of patients with PRES after SOT or HSCT. The management of these patients can require an ICU or intermediate care unit admission to allow for continuous monitoring of vital and cerebral functions and, in particular, to avoid the upper airway obstruction and respiratory failure that can occur in patients with impaired consciousness or seizures (Fig 3). Antiepileptic drugs (AEDs) should be administered as early as possible to control ongoing seizures. Benzodiazepines (diazepam 0.5 mg/kg given rectally [maximum of 10 mg] or intravenous midazolam 0.1–0.2 mg/kg over 2–3 minutes followed by continuous infusion at rates of 0.5–2 μg/kg per minute, titrated to efficacy) are often used as first-line agents. In patients with refractory seizures, intravenous phenytoin (15–18 mg/kg at a rate of 1 mg/kg per minute; maintenance at 5 mg/kg per day divided twice daily) or phenobarbital (10–15 mg/kg at a rate of 1–2 mg/kg per minute; maintenance at 5 mg/kg per day divided twice daily) or an anesthetic with anticonvulsant effects, such as propofol or thiopental, might be required. We suggest obtaining an EEG as soon as possible at the onset of neurologic signs/symptoms; in addition, serial EEG recordings should be obtained during the acute phase to monitor treatment efficacy and to investigate for the presence of nonconvulsive seizures. Hereafter, EEG follow-up is not required in patients who fully recover after PRES.

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FIGURE 3

Diagnostic and management flowchart for PRES in transplanted children. BP, blood pressure; HR, heart rate; NCSE, nonconvulsive status epilepticus; PML, progressive multifocal leukoencephalopathy; PTLD, posttransplant lymphoproliferative disease.

A particularly controversial issue is the duration of antiepileptic therapy after PRES. In most studies, AEDs were discontinued after the patients were seizure-free for at least 3 to 6 months.⁴ Other studies, however, have suggested continuing AEDs on a longer-term basis.⁵² Considering the occasional or provoked nature of seizures, our practice is to administer prophylactic treatment with AEDs (benzodiazepines and/or phenytoin) only during the acute phase of the neurologic complications. We then discontinue AEDs upon MRI evidence of edema resolution.¹¹ We believe that prolonged prophylactic treatment with AEDs is unnecessary in patients with occasional or provoked seizures due to PRES, but it should be considered in cases of later development of secondary epilepsy.

Blood pressure is commonly measured at least once per day in patients undergoing transplantation, but in case of PRES the monitoring should be switched to a more intensive way and tailored according to specific clinical conditions. Little pediatric experience is available on the best pharmacologic approach for lowering blood pressure in children with PRES. In the case of severe hypertension during the acute phase of PRES, blood pressure should be lowered gradually after excluding cerebral infarction. Arterial pressure should be reduced by ∼25% within the first hour, followed by subsequently slower reduction.⁵⁵ Indeed, a sudden reduction in blood pressure is not recommended because it can worsen the cerebral perfusion pressure and promote ischemic lesions. In these cases, vasodilators (sodium nitroprusside: 0.53–10 μg/kg per minute via intravenous infusion⁵⁶) and calcium channel blockers (nicardipine: 1–3 μg/kg per minute via intravenous infusion^56,57) are commonly used antihypertensive agents.

In nonemergency cases specific classes of antihypertensive drugs should be used preferentially because transplanted children are at risk of specific comorbidities such as renal failure or being exposed to concurrent medical conditions. Examples include the use of angiotensin-converting enzyme inhibitors (enalapril: 0.08 mg/kg per day administered orally up to 5 mg/day, once or twice a day⁵⁶) in children with concomitant proteinuric renal diseases.

After the clinical recovery of PRES, patients should be treated for hypertension until predisposing risk factors are present. In any case the efficacy of antihypertensive prophylaxis to prevent PRES recurrence is not documented.

In an attempt to remove potential promoting factors, patients should be evaluated for metabolic disturbances, particularly hypomagnesemia, and for bleeding diathesis, either of which can require prompt correction.⁴⁴ Upon the occurrence of PRES, in most studies, ongoing CNI treatment was discontinued, and a different immunosuppressant agent was introduced (CSA to tacrolimus, or vice versa), with monitoring of the drug level according to the individual GvHD and rejection risks, respectively.^13,31,58 Discontinuation of other agents potentially involved in PRES pathogenesis should be considered (Table 2).

Neuroimaging is also needed upon the appearance of symptoms to obtain a correct diagnosis. CT is usually the first investigation recommended at the onset of an acute neurologic complication after transplantation, mainly to exclude hemorrhagic events. Nevertheless, MRI must be performed to define secure diagnosis and the extent of encephalopathy. Moreover, neuroimaging must be obtained during PRES, at the appearance of new focal neurologic deficits and/or at the occurrence of neurologic deterioration, to exclude complications, such as ICH and cerebral herniation. Patient follow-up using neuroimaging studies has been controversial. Some authors have reported that in the presence of typical initial imaging findings and clinical presentation with subsequent total clinical recovery, a follow-up study is redundant because there is strong evidence in the literature of the reversible nature of cerebral lesions.⁵⁸ However, as mentioned above, PRES can lead to persistent brain damage.⁴¹ The ideal timing for repeat brain imaging to document radiologic recovery is unclear, although improvements in abnormalities have usually been reported 7 to 15 days after symptom onset.^26,31

Prospectives

Although substantial advances have been made in recent years within the transplantation community in the recognition and management of PRES, several questions remain unanswered. The risk factors predisposing one to developing PRES remain an open issue. The modification of identifiable risk factors before or during transplantation would significantly impact the outcomes. Few studies involving large series of patients and variables are available.^13,32

A significant role of hypertension in the onset of PRES has been suggested across different transplant settings, but the exact nature of this role remains unclear; clarification would have significant implications for transplant patients, who are usually exposed to drugs that promote hypertension. Other potential promoting factors, such as baseline disease, electrolyte abnormalities, concurrent infections, and plasma levels of CNIs, have not yet been elucidated. Moreover, researchers have yet to identify a circulating serologic biomarker possibly implicated in the development of PRES. Many candidates are of potential interest: inflammatory cytokines, such as tumor necrosis factor α, interleukin-1, and interferon-γ; markers of endothelial activation, such as p-selectin, e-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1; and endothelin-1 upregulation.

The role of neuroimaging in the diagnosis of PRES has been well defined; nevertheless, it would be interesting to investigate whether new functional neuroimaging methods, such as magnetic resonance (MR) perfusion, arterial spin-labeled MR, and MR spectroscopy, could play major roles in understanding the pathophysiology of PRES.

Once a diagnosis has been made, the withdrawal or modification of immunosuppressive drugs is the primary matter of concern for transplant physicians. Studies focusing on the reliable switching of immunosuppressive drugs and the identification of a safe alternative immunosuppressant regimen, although challenging to conduct, would have undisputed importance because for both HSCT and SOT the availability of relatively new drugs (ie, belatacept or mammalian target of rapamycin [mTOR] inhibitors) for allograft rejection and GvHD prophylaxis are now encouraging the development of a variety of alternative combinations of immunosuppressive schedules to be studied. Moreover, each pediatric transplant community should emphasize the development of a uniform management strategy for PRES in terms of the optimal timing for reevaluation with MRI and subsequent follow-up.

Pediatricians who care for child transplant patients have certainly become increasingly accustomed to recognizing and managing PRES over the years. Nevertheless, PRES remains an intriguing and evolving matter of interest in the field of neurologic complications after pediatric organ or hematopoietic stem cell transplantation, and new knowledge is needed.