Management and Clinical Outcome of Posterior Reversible Encephalopathy Syndrome in Pediatric Oncologic/Hematologic Diseases: A PRES Subgroup Analysis With a Large Sample Size

Abstract

This study investigated the management and clinical outcomes along with associated factors of posterior reversible encephalopathy syndrome (PRES) in childhood hematologic/oncologic diseases. We present data from children with hematologic/oncologic diseases who developed PRES after treatment of the primary disease with chemotherapy and hematopoietic stem cell transplantation (HSCT) at 3 medical centers in Changsha, China from 2015 to 2020, and review all previously reported cases with the aim of determining whether this neurologic manifestation affects the disease prognosis. In the clinical cohort of 58 PRES patients, hypertension [pooled odds ratio (OR) = 4.941, 95% confidence interval (CI): 1.390, 17.570; P = 0.001] and blood transfusion (OR = 14.259, 95% CI: 3.273, 62.131; P = 0.001) were significantly associated with PRES. Elevated platelet (OR = 0.988, 95% CI: 0.982, 0.995; P < 0.001), hemoglobin (OR = 0.924, 95% CI: 0.890, 0.995; P < 0.001), and blood sodium (OR = 0.905, 95% CI: 0.860, 0.953; P < 0.001), potassium (OR = 0.599, 95% CI: 0.360, 0.995; P = 0.048), and magnesium (OR = 0.093, 95% CI: 0.016, 0.539; P = 0.008) were protective factors against PRES. Data for 440 pediatric PRES patients with hematologic/oncologic diseases in 21 articles retrieved from PubMed, Web of Science, and Embase databases and the 20 PRES patients from our study were analyzed. The median age at presentation was 7.9 years. The most common primary diagnosis was leukemia (62.3%), followed by solid tumor (7.7%) and lymphoma (7.5%). Most patients (65.0%) received chemotherapy, including non-induction (55.2%) and induction (44.8%) regimens; and 86.5% used corticosteroids before the onset of PRES. Although 21.0% of patients died during follow-up, in most cases (93.2%) this was not attributable to PRES but to severe infection (27.3%), underlying disease (26.1%), graft-vs.-host disease (14.8%), multiple organ dysfunction syndrome (8.0%), and respiratory failure (3.4%). PRES was more common with HSCT compared to chemotherapy and had a nearly 2 times higher mortality rate in patients with oncologic/hematologic diseases than in those with other types of disease. Monitoring neurologic signs and symptoms in the former group is therefore critical for ensuring good clinical outcomes following treatment of the primary malignancy.

Keywords: chemotherapy; children; hematopoietic stem cell transplantation; management; neurotoxicity; oncologic/hematologic diseases; posterior reversible encephalopathy syndrome.

Figure 1

Flowchart of studies selection.

Figure 2

Forest plot for incidence of transfusion.

Figure 3

Forest plot for the comparison of mortality between Chemotherapy and HSCT.

Figure 4

Proposed pathogenic model for cerebral edema and CNS dysfunction after conducting chemotherapy, HSCT and immunosuppressive agents. Endothelial wall inflammation disrupts the tight junctions and increase the permeability of the BBB due to high levels of circulating cytokines (TNF-α, IL-1, endothelin-1) and activating leucocytes (autoreactive T-cells). Consequently, enhanced fluid and cell diapedesis, and interstitial edema formation ensues. PRES manifestation and the dysfunction of microvasculature may be driven by the presence of checkpoint inhibitors (HSCT, chemotherapy, and immunosuppressive agent), by interactions with autoantibodies and autoreactive T-cells, and via abnormal secretion of angiogenic growth factors (VEGF) and proangiogenic cytokines (IL-8) (33, 66, 67), VEGF expression is increased, leading to increased vascular permeability and interstitial cerebral edema (33). Blood transfusion triggers a rapid increase in the hemoglobin, platelet, and viscosity levels, which is thought to trigger transfusion-associated circulatory overload (TACO) (–71). Elevated blood pressure, acute hypoxia, anemia, and lactic acidosis are all risk factors for TACO (69, 72); on the other hand, acute hypoxia may decrease cerebrospinal fluid (CSF) volume, increase cerebral blood volume (CBV), and increase brain parenchyma perfusion as an early responses to hypoxia (within 40 min) (73, 74). This increase could induce acute vascular endothelium dysfunction and an elevation of vascular resistance, leading to extravasation of macromolecules into the brain. Also, the velocity of brain blood flow is shown to increase after transfusion (70, 75). Cytokines induce the expression of adhesion molecules (ICAM-1, VCAM-1), which interact with leukocytes and potentiate ROS production. ROS and ALA might cause direct endothelial cell injuries, increasing the expression of VEGF and vascular permeability. A low ATP supply impairs energy-dependent processes, such as NA⁺/K⁺ ATPase function. While an ADH excess causes ALA neurotoxicity and the effect of IL-6 in the hypothalamus might lead to an increment in ADH secretion. ADH inhibits NA⁺/K⁺ ATPase and induces NKCC2 and AQP4 in astrocytes, leading to increase ion/water influx and swelling (76). ADH excess may also lead to electrolyte disorders (hyponatremia, hypocalcemia, hypomagnesemia) (, , –79). NO deficiency: PTX3, heme deficiency and ROS might impair NOS function, thus decreasing NO synthesis and causing endothelial dysfunction. PEPT2 dysfunction: The PEPT2*2 variant has a lower affinity for ALA than PEPT2*1, which might cause a diminished ALA efflux in the choroid plexus and a more significant ALA neurotoxicity in the brain (80). Electrolyte disorders (hyponatremia, hypocalcemia, hypomagnesemia), low CSF (81), and lack of ATP might also reduce PEPT2 function. These cascades lead to vasogenic cerebral edema, and certain precipitants are probably necessary to cause PRES and CNS dysfunction. PRES, posterior reversible encephalopathy syndrome; TACO, transfusion-associated circulatory overload; ADH, Antidiuretic hormone; ALA, 5-Aminolevulinic acid; ALAS1, 5-Aminolevulinic acid synthase-1; AQP4, Aquaporin-4; BBB, Blood-brain barrier; ICAM1, Intracellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule 1; IL, Interleukin; NKCC1, Na⁺ K⁺ 2Cl⁻ Cotransporter 1; NO, Nitric oxide; NOS, Nitric oxide synthase; PEPT2, Peptide transporter-2; PTX3, Pentraxin-3; ROS, Reactive oxygen species; TCA, Tricarboxylic acid cycle; TNF-α,Tumor necrosis factor-α; VCAM1, Vascular cell adhesion protein-1; VEGF, Vascular endothelial growth factor.