Posterior reversible encephalopathy syndrome in children with kidney disease

Introduction

Posterior reversible encephalopathy syndrome (PRES) was first reported as reversible posterior leucoencephalopathy syndrome in 1996.[1] Initially, it was described in acutely ill patients who had a reversible syndrome of headache, altered mental function, seizure, and loss of vision associated with findings indicating predominantly posterior leucoencephalopathy on imaging studies.[1] Literature consists of few case reports or few small series of patients in different clinical settings.[1234567] All age groups are susceptible to the syndrome. The setting in which it was described included patients with hypertensive encephathalopathies, patients who were receiving immunosuppressive medicines after organ transplantation or other malignancies, patients with renal failure, and patients with eclampsia. Other comorbid conditions later described included children with nephrotic syndrome, acute nephritis, hemolytic uremic syndrome, systemic lupus erythematosus, and patients with volume and electrolyte disturbances. Pathogenetic mechanism is believed to be vasogenic edema and hyperperfusion of cerebral white matter affecting commonly occipito-parietal region due to autoregulatory failure or endothelial dysfunction.[18] Predilection for posterior brain regions could be due to pial and intracerebral vessels in anterior circulation which have higher concentration of adrenergic nerves when compared with posterior hemisphere.[910] Diagnosis was made in appropriate clinical setting with neurological symptoms supported by neurological imaging by computed tomography (CT) scan brain, magnetic resonance imaging (MRI), and diffusion weighted images. We describe a series of children with kidney disease who developed PRES and describe their clinical and laboratory features.

Materials and Methods

Out of total 660 pediatric renal patients including renal transplant patients admitted at our institute during September 2010 to February 2012 (18 months), we identified 11 patients with characteristic neurological symptom complex in association with typical neurological images suggesting PRES as described in Introduction. All patients had undergone thorough evaluation clinically, neurologically, and biochemically to search for likely contributory factors with special attention to blood pressure, volume status, severity of anemia, presence or absence of hemolysis, and its severity by following peripheral smear, platelet count, LDH, level of renal function, electrolyte and acid base balance, severity of hypoproteinemia, character of underlying renal disease, and blood level of immunosuppressive medications. Hypertension was staged according to fourth Task Force report on high blood pressure in children and adolescents[11] by comparing patients BP reading to BP level for boys and girls by age and height percentile in BP table prepared by National Heart Lung and Blood Institute (NHLBI).[11] Grade 1 hypertension is defined as systolic or diastolic BP from 95 percentile to 99 percentile, +5 mm Hg for age and height for individual gender. Grade 2 hypertension is designated to BP levels that are more than 5 mmHg above 99 percentile for age and height for individual gender. Severity of acute renal failure was staged according to RIFLE criteria.[12]

Possibility of other neurological disorders like cerebral venous thrombosis, meningeal infection, intracranial hemorrhage or space occupying lesion were ruled out in each case with help of appropriate investigations. Initially, all patients were evaluated by in-house cranial CT scan without contrast. MRI with or without contrast was obtained in patients where CT brain alone was inconclusive. MR venography was performed where the possibility of cerebral venous thrombosis was considered. Imaging was studied in collaboration with hospital radiologists involved in the study. Lumbar puncture and CSF study was performed in selected cases.

All patients received appropriate treatment for renal disease, adequate dialysis for renal failure, timely correction of fluid electrolyte and acid base balance, Nitroglycerine drip and other anti-hypertensives for hypertension, IV albumin for hypoalbuminemia, plasma exchanges in cases of HUS, and dose adjustment of the medication was made. Record of Treatment received for renal disease and prevailing abnormal parameters and time frame of clinical and biochemical improvement was made and follow-up radio-images were compared (usually taken at 4 week interval and more frequently in selected cases) with original images.

Results

A total of 11 patients (eight boys and three girls, ranging in age from 3 years to 15 years) with PRES, were evaluated and studied. Clinical and biochemical characteristics and cranial imaging findings is shown in Table 1. Presenting symptoms were seizures in ten cases (91%), headache in eight cases (72%), altered mental status in five cases (45%), and dimness of vision or cortical blindness in three cases (27%) in different combinations. So far as underlying renal disease and setting of syndrome complex is considered among these patients, six patients (55%) had acute renal failure (four had HUS, one had pauci-immune crescentic GN, one had solitary functioning kidney obstructed by a stone who developed PRES in setting of post-obstructive diuresis and associated persistent hypocalcemia), four patients (36%) had normal renal function [one patient with diffuse proliferative Lupus nephritis and uncontrolled hypertension, one patient of focal segmental glomerulosclerosis (FSGS) with high trough level of cyclosporine 300 ng/ml, one patient with MPGN who developed hypertensive encephalopathy due to non-compliance to medication, one with morbid nephrotic state with scrotal skin necrosis and severe hypoproteinemia (serum albumin 1.1 gm/dL)]. One patient of chronic renal failure (CRF) who was on continuous ambulatory peritoneal dialysis (CAPD) developed PRES after receiving inadvertent blood transfusion due to misjudged anemia and his Hb at the time of PRES was 12.5 gm/dL.

Table 1 Data of our study

Significant comorbid contributory factors found in these patients at the time of PRES were uncontrolled hypertension in all 11 patients (100%), renal failure (55%), CNI toxicity (9%), hypoproteinemia (9%), high hematocrit (9%), hypocalcemia (9%), steroid toxicity (9%), HUS (36%), and lupus nephritis (9%) [Figure 1]. A few illustrative cases are described below.

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Figure 1

Case no. 5 showing morbid nephrotic state with scrotal skin necrosis

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Case 2

An 8-year-old child, weighing 15 kg (CRF on CAPD) was found to have PRES with history of blood transfusion by private pediatrician. His Hb was 12.5 g% with grade 2 HT (BP 120/80 mm Hg) when he presented to us with PRES. Initially, we also intensified PD with 2.5% dextrose CAPD fluid, used diuretics, and controlled HT with oral medication for two days. His urine output was also more than 400 ml. Child was on CAPD for 1.5 year without any neurological complaint. During his intensive PD with hypertonic fluid, child lost 300 g weight after 1^st day and further 150 g on 2^nd day after admission. Child was euvolemic with normal X-ray chest and was not improving neurologically for two days. So, observing the temporal relationship of blood transfusion and development of PRES, we tapped 100 ml of blood on 3^rd day by femoral route and PD was switched to 1.5% Dextrose solution again. Temporal relationship of improvement with phlebotomy left no doubt about the fact that blood transfusion was causally related to PRES in this child who was habituated to low hematocrit. Sudden rise in hematocrit might have resulted in increased viscosity of blood and rise in vascular resistance, superimposed on possibly sensitive cerebral vasculature, may have resulted in hypertensive encephalopathy like picture. There are case reports in literature also about PRES after blood transfusion.[14] KDOQI clinical practice recommendation for anemia in CKD also have set target of Hb in the range of 11-12 g/dl.[15]

Initial cranial imaging revealed fairly symmetrical areas of edema not only involving occipito-parietal white matter regions in majority of cases but also extended to cortical gray matter in nine cases (81%) and extended to fronto-temporal area in five cases (45%), involved basal ganglia also in two patients (case 4 and 11) whereas cerebellum and medulla were also involved in one patient (case 11) [Figure 2].

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Figure 2

Computed tomography/Magnetic resonance imaging images of brain showing positive findings

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All patients had neurological recovery within 5-7 days except one patient of HUS (case four) who persisted to have altered mentation even after a month of follow up, though his renal function and cranial imaging had recovered completely after a month. This was the patient who had neurological symptoms for six days before getting admitted in our hospital where specific management of peritoneal dialysis and plasma exchange was started.

Follow-up cranial images were normal after four to five weeks in all cases. All patients had normal renal function after four weeks except in two cases, one with HUS who was put on CAPD and one patient with obstructed solitary functioning kidney who had serum creatinine of 1.9 mg/dl at the end of one month when he was stone free.

Discussion

With easy availability of radio-imaging technique, MRI in particular, there is increasing number of reports of PRES in all age groups including pediatric patients over last ten years.[1617] With an objective of studying predisposing factors, clinical spectrum, cranial imaging, and course of PRES in pediatric renal patients, present study was conducted. Renal patients are at particular risk of PRES because renal disease and hypertension go hand in hand. Higher chances of volume perturbation, electrolyte disturbances and mechanism of renal disease itself, its treatment-associated drug toxicities, and other complications of management put these patients at special risk for PRES.

Table 2 shows comparison of our results with two other pediatric studies of PRES in literature. It could be seen that in all three pediatric series there were more boys than girls with PRES. Other two pediatric series, recently published, also showed more boys than girls.[1617] In adult series, females were affected more frequently than males even when eclampsia cases were excluded.[1618]

Table 2 Comparative data of PRES in pediatric patients

Seizure as a presenting symptom was most common in Ishikura's study (85%) as well as in our study (91%). All the series had different combination of four clinical characteristic symptoms as a presenting picture. So far as level of renal function was considered among these patients, we found six patients (55%) with acute renal failure. Other two studies have not specified about level of renal function. But more and more patients with hypertension and renal failure of different etiologies are reported with PRES.[16]

All three studies have associated hypertension in more than 95% of their cases. Hypertension was almost always observed in PRES but its level was not correlated to the severity of PRES and cause effect relationship is yet to be established, as in many cases other comorbid conditions like drug toxicity, vacuities, auto-immune disease, or endothelial dysfunction from any cause may be involved.[192021222728]

Nephrotic state is a special risk for PRES and may have multiple factors involved because they are often hypertensive, receive steroid and CNI, may have severe hypoproteinemia, and may have massive oedema with fluid retention and associated increased vascular permeability.[2930] Ishikura's series had seven cases (35%), Kwon series had two cases (16%) whereas our study had two cases (18%) of nephrotic syndrome.

Like our series (36% HUS), series of Kwon et al. also had two cases of HUS (16.5%) who developed PRES. Here, pathological process itself in addition to renal failure and hypertension could be involved in pathogenesis like that of pre-eclampsia.[20]

Our patient with pauci-immune crescentic GN (case 1) had developed PRES following three pulses of methylprednisolone. High dose steroid was also found associated in study by Kwon et al., in two cases (16%) of nephrotic syndrome, whereas no specific allegation to steroid high dose was made in Ishikura series.

Ishikura's Series had ten patients (50%) with kidney transplantation on CNI and Kwon et al. 33% of cases on CNI and our study had 9% (1 case) of PRES which was associated with CNI overdose. Immunosuppresive medicines and CNI in particular are more frequently reported to be associated with PRES in post-transplant scenario. After renal toxicity, vascular toxicity, and neurotoxicity are the most serious side effect of CNI, affecting 25-59% of transplant patients.[23] Reduction in drug dosage or prompt withdrawal of cytotoxic drugs is usually recommended in cases of PRES.[2425] When same agent is re-introduced, patient must be followed closely as recurrence has been reported in this setting.[26]

Recently, de Laat from Netherlands described seven childhood cancer patients with clinical radiological findings of PRES.[16] He also reviewed 49 other documented cases of PRES from literature during childhood cancer and concluded that hypertension and renal failure related to immunosuppressive treatment of leukemia and other solid tumor seems to be the most important triggers for occurrence of PRES.[16] Similarly, Faruk Inceik from Turkey in 2009 described nine cases of pediatric PRES of whom seven were receiving immunosuppressive treatment and two were hypertensive crisis patients. Four patients received intrathecal injections of immunosuppressive drugs for different reasons and developed PRES.[17]

Involvement of occipital and parietal region was almost universal in all three studies and lesions were not restricted to white matter alone but involved gray matter also in majority of cases in all three studies. Other areas like frontal lobe, temporal lobe, basal ganglia, cerebellum, and medulla were involved in lesser frequency in all series with individual incidence.

Follow-up cranial images were normal after four to five weeks in all cases in present study. One case of HUS (9%) persisted to have altered mentation even after a month of follow-up, though his renal function and cranial imaging had recovered completely. In a study by Ishikura, also 90% had complete recovery and 10% had neurological sequel. Kwon et al. also had complete neurological recovery in 92% of cases.

Conclusion

PRES is not uncommon in pediatric nephrology. Hypertension, renal disease, immunosuppression, and chemotherapy of malignancies are triggers for PRES. It is important to consider this diagnosis in children presenting with seizure, visual disturbances, headache, and altered mentation in appropriate clinical setting.