Nephrology 20 (2015) 849–854
Reversible posterior encephalopathy syndrome in children with nephrotic syndrome JUAN ZHOU, HELIN ZHENG, XUEFEI ZHONG, DAOQI WU, MO WANG, XUEMEI TANG and QIU LI Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
KEY WORDS: hypertension; magnetic resonance imaging; nephrotic syndrome; reversible posterior encephalopathy syndrome. Correspondence: Dr Juan Zhou, Department of Nephrology and Immunology, Children’s Hospital of Chongqing Medical University, NO.136, Zhongshan 2nd Road, Yuzhong District, Chongqing, China. Email: [email protected]
Accepted for publication 19 May 2015. Accepted manuscript online 25 May 2015. doi:10.1111/nep.12518
SUMMARY AT A GLANCE Reversible posterior encephalopathy (PRES) is one of the severe complications in children with nephrotic syndrome. This manuscript examines the clinical features in this condition. The results found in this study provide useful information in the setting of paediatric nephrology.
ABSTRACT: Aim: To investigate the clinical features and prognoses of children who develop reversible posterior encephalopathy syndrome (RPES) during treatment for nephrotic syndrome (NS). Methods: The clinicoradiological characteristics and prognoses of 51 patients with NS, including 21 with RPES and 30 without, were analyzed. Results: Compared with the controls, the RPES patients exhibited a higher rate of tacrolimus (P = 0.01) and cyclosporine (P = 0.02) treatment; higherdose prednisolone (P = 0.01) treatment; higher systolic blood pressure (P = 0.04), serum cholesterol (P = 0.03), and proteinuria (P < 0.01); and lower serum albumin levels (P = 0.03). Hypertension was present in 85.7% of RPES patients. The clinical manifestations of RPES included an altered mental status, seizures, headaches, nausea and vomiting, and visual impairment. Electroencephalography findings included slow waves and focal sharp or/and spiked waves; magnetic resonance imaging showed lesions localized in the occipital, parietal, frontal, temporal lobes and the cerebellum and brainstem; and magnetic resonance angiography revealed vertebral artery narrowing. All RPES patients recovered completely with timely and appropriate therapy. Conclusion: Hypertension, calcineurin inhibitor and high-dose steroid treatments, high serum cholesterol and proteinuria levels, and low serum albumin levels can predispose children with NS to RPES, although both the clinical and imaging outcomes are satisfactory.
Reversible posterior encephalopathy syndrome (RPES) is a clinical–radiological syndrome with various aetiologies that was first described in patients with renal insufficiency and/or hypertension and those receiving immunosuppressants in 1996.1 RPES is clinically characterized by headaches, an altered mental status, and seizures with classic imaging findings of subcortical vasogenic oedema (leukoencephalopathy) in the posterior brain. This condition is frequently reported in patients with a predisposing clinical condition, such as episodes of abrupt hypertension, history of cytotoxic chemotherapy, history of transplantation, and autoimmune diseases.2,3 In particular, children with kidney diseases requiring critical care develop this condition.4 Paediatric patients are more vulnerable to RPES, and paediatric and adult patients with RPES show differences in clinical and radiological findings.5,6 To date, no case-control studies except some case reports7–10 with specific focus on RPES in children with © 2015 Asian Paciﬁc Society of Nephrology
nephrotic syndrome (NS) have been published. In this study, we analyzed the clinical and radiological features and prognoses of children who did and did not develop RPES during treatment for NS.
METHODS Patients and controls From patients with primary or secondary NS who were hospitalized at the Children’s Hospital of Chongqing Medical University between 1 November 2006 and 30 November 2014, 21 with a clinical diagnosis of RPES and 30 age- and gender-matched controls without RPES were included in this study. The RPES patients included in this study exhibited clinical findings and neuroimaging abnormalities consistent with those for RPES, with documented recovery as confirmed by clinical examinations and subsequent repeated neuroimaging. 849
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Data collection We collected data on demographics, predisposing conditions, presenting symptoms, treatments, time to clinical recovery, time to neuroimaging, and subsequent imaging sessions. The documented data of blood pressure of the RPES group were measured as soon as the first clinical manifestation of RPES presented, and those of the control group were evaluated when the patients were enrolled in this study. In addition, we gathered the results of routine urine and blood laboratory investigations, including blood electrolyte and glucose, serum albumin, total cholesterol and serum creatinine levels and 24-h urinary excretion of protein. Cerebrospinal fluid was examined in patients with a fever or clinically suspected meningitis. The blood levels of cyclosporine and tacrolimus were analyzed using fluorescence polarization within 3 days of RPES onset, with blood sample collection just before the next administration. The plasma renin and aldosterone were assayed by radioimmunoassay within 5 days of RPES occurring, and the blood sample were collected when the patients with clinostatism in the morning. Electroencephalography (EEG) and brain magnetic resonance imaging (MRI) were performed routinely for all RPES patients as either the first or subsequent examination. Fundus examination was performed for four RPES patients with visual impairment, while magnetic resonance angiography (MRA) was performed for six RPES patients. Brain computed tomography (CT) was performed for seven RPES patients with clinically suspected intracranial haemorrhage. All brain CT, MRI and MRA findings were reviewed for the identification of RPES features by the same paediatric radiologist (Helin Zheng) blinded to the clinical diagnoses. Patients with no brain imaging findings available for review were not included.
Statistical analysis The numerical data are expressed as means and standard deviations (SDs) and were analyzed using Statistical Package for the Social
Sciences for Windows, version 11.0 (SPSS Chicago, IL, USA). To analyze differences between the RPES and control groups, Student’s t-test was used to compare numerical data and the χ2 test was used to compare categorical data except the number of patients who received blood purification therapy and renal biopsy, which was compared using Fisher’s exact test. A two-sided P-value of 0.05). The clinical manifestations of RPES at onset and its incidence and durations are shown in Table 2. Neurological findings for the RPES patients were unremarkable, except for neck rigidity in two patients.
Table 1 Demographic data and clinical proﬁles of patients with nephrotic syndrome with or without reversible posterior encephalopathy syndrome (RPES)
Male/female Age (years) Disease duration (years) Underlying conditions Primary nephrotic syndrome Systemic lupus erythematosus Henoch–Schönlein purpura Treatment with tacrolimus Dose of tacrolimus (mg/kg per day)† Treatment with cyclosporine Dose of cyclosporine (mg/kg per day)† Treatment with cyclophosphamide Accumulated dose of cyclophosphamide (mg/kg)† Dose of prednisolone (mg/kg per day) Blood puriﬁcation therapy Blood pressure (mmHg) Systolic Diastolic Duration of hospitalization (days)
12/9 9.64 ± 2.03 0.91 ± 0.53
16/14 8.79 ± 1.85 1.12 ± 0.16
14 (66.7%) 5 (23.8%) 2 (9.5%) 7 (33.3%)* 0.09 ± 0.02 5 (23.8%)* 5.34 ± 1.24 4 (19.1%) 84.27 ± 34.16 1.28 ± 0.41* Haemodialysis: 3(14.3%) Haemoﬁltration: 1 (4.8%)
22 (73.3%) 8 (26.8%) 0 2 (6.7%) 0.08 ± 0.02 2 (6.7%) 4.79 ± 1.87 6 (20%) 102.37 ± 27.42 0.64 ± 0.37 Haemodialysis: 4(13.3%) Haemoﬁltration: 2 (6.7%)
162.33 ± 24.06* 102.78 ± 16.32 23.57 ± 10.36
104.82 ± 20.47 81.63 ± 14.58 19.21 ± 9.83
*P < 0.05 compared with the control group. †Calculated on the number of patients treated with this drug. RPES, Reversible posterior encephalopathy syndrome.
© 2015 Asian Paciﬁc Society of Nephrology
RPES in children with NS
Table 2 Clinical manifestations of reversible posterior encephalopathy syndrome (RPES) Clinical manifestations
Altered mental status Confusion Lethargy Stupor Coma Seizures Headache Nausea/vomiting Visual impairment Visual blurring Cortical blindness Visual hallucinations
19 7 6 4 2 17 12 7 5 2 2 1
90.5 33.3 28.6 19.1 9.5 80.9 57.1 33.3 23.8 9.5 9.5 4.8
5.39 ± 3.16 8.32 ± 3.87 5.68 ± 2.14 3.27 ± 1.78 2.25 ± 0.75 1.57 ± 0.48 10.38 ± 4.26 8.67 ± 3.84 3.72 ± 2.14 5.95 ± 3.15 1.53 ± 0.37 2.67
†Calculated on the number of patients with this clinical manifestation.
Table 3 Laboratory results of patients with nephrotic syndrome with or without reversible posterior encephalopathy syndrome (RPES)
Blood glucose concentration (mmol/L) Serum sodium (mmol/L) Serum calcium (mmol/L) Serum total cholesterol (mmol/L) Serum albumin (g/L) Serum creatinine (μmol/L) Proteinuria (mg/kg per 24 h) Blood levels of tacrolimus (μg/L)† Blood levels of cyclosporine (ng/mL)† Renal biopsy Minor and minimal change Focal segmental glomerular sclerosis Mesangial proliferation
4.78 ± 1.32 138.27 ± 12.87 2.14 ± 0.35 10.86 ± 4.51* 17.23 ± 5.16* 93.17 ± 42.35 0.74 ± 0.34** 5.84 ± 1.48 94.31 ± 28.67 18*** 3 12 3
5.13 ± 1.67 147.32 ± 15.21 2.07 ± 0.42 6.76 ± 2.35 27.89 ± 8.34 72.68 ± 37.21 0.35 ± 0.23 5.13 ± 2.36 86.77 ± 29.34 11 5 4 2
*P < 0.05 compared with the control group. **P < 0.01 compared with the control group. ***P < 0.05 for difference in the constituent ratio in available renal biopsy compared with that in the control group. †Calculated on the number of patients treated by this drug.
Laboratory and imaging ﬁndings The findings of urine and blood laboratory investigations in the RPES and control groups are summarized in Table 3. Serum sodium and calcium levels and blood glucose levels were normal in both groups, with no significant difference between groups. The RPES group patients exhibited higher serum total cholesterol levels (t = 2.25, P = 0.03), higher proteinuria (t = 2.98, P < 0.01), and lower serum albumin levels (t = 2.34, P = 0.03) compared with the control group patients. There were no significant differences in the blood levels of tacrolimus and cyclosporine between the two groups (P > 0.05). The plasma renin and aldosterone of two patients with severe hypertension in the RPES group were higher than the reference value. The results of available renal histopathology were different between groups (P = 0.03), with the RPES group showing higher ratio of focal segmental © 2015 Asian Paciﬁc Society of Nephrology
glomerular sclerosis and glomerulonephritis compared with the control group. Cerebrospinal fluid data with normal protein level of 0.31 ± 0.08 g/L and white blood cell count of 0.13 ± 0.06 × 106/L were observed from the available 12 patients with RPES. Fundus examination in the four patients with visual impairment revealed normal findings. Electroencephalography at RPES onset showed slow waves in 14 patients (66.8%), focal sharp or/and spiked waves in five (23.8%), and normal findings in two (9.5%). Abnormal electroencephalographic data of a patient with RPES are shown in Figure 1. All patients underwent repeated EEG at different time points and showed complete recovery. The earliest and latest complete recoveries were documented at 20 and 172 days respectively, with the median time of 63 days. All RPES patients underwent cerebral MRI, and the mean time interval between the onset of symptoms and neuroimaging was 3.24 ± 2.57 days (range, 0–9 days). Among the seven (33.3%) patients who underwent both CT and MRI, four (19.1%) exhibited normal CT findings but evidence of RPES on MRI, while three (14.3%) exhibited low-density areas in the occipital and/or parietal lobes on CT. In all RPES patients, cerebral MRI showed abnormal signals localized in the cortical and subcortical regions of the occipital (19 patients, 90.5%), parietal (15 patients, 71.4%), frontal (four patients, 19.1%), and temporal lobes (three patients, 14.3%); cerebellum (two patients, 9.5%); and brainstem (one patient, 4.8%). The RPES lesions observed on MRI were predominantly localized in the white matter, with extension to the gray matter in three patients (14.3%). Sixteen RPES patients (76.2%) showed bilateral cerebral lesions with symmetrical (seven patients, 33.3%) or asymmetrical (nine patients, 42.9%) abnormal signals, while the remaining five patients (23.8%) showed unilateral cerebral lesions. All patients showed a significant improvement on subsequent neuroimaging, which included 18 MRI sessions and three CT sessions. Complete resolution of RPES on MRI was observed within 17 sessions, and the earliest and latest complete resolutions were documented at 7 and 178 days, respectively, with a median of 47 days. Among the six patients examined by MRA, four showed vertebral artery narrowing to varying degrees in different positions, which completely recovered on subsequent neuroimaging (Fig. 2).
Treatment and prognosis Emergency treatment for the acute phase of RPES included the administration of anticonvulsants and antihypertensives and the withdrawal of immunosuppressants (cyclosporine or tacrolimus). Intravenous diazepam or midazolam was administered to patients immediately at convulsive seizure onset. Patients with hypertension in the RPES group received emergency antihypertensive treatment, including intravenous sodium nitroprusside and/or oral captopril and/or nifedipine administration, and their systolic blood 851
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Fig. 1 Electroencephalographic data of a 5-year-old Chinese boy with nephrotic syndrome and hypertension who developed reversible posterior encephalopathy syndrome (RPES) with seizures and confusion. Electroencephalographic images obtained on day 2 show an abnormal 1.5–3-Hz δ-rhythm in the bilateral occipital leads (indicated by arrows in a). The basic rhythm slows down slightly on day 7 images (indicated by arrows in b), while the normal 8–9-Hz α-rhythm has recovered and the slow δ-rhythm has disappeared on day 20 images (indicated by arrows in c).
Fig. 2 Brain magnetic resonance imaging (MRI) ﬁndings at the onset (a) of reversible posterior encephalopathy syndrome (RPES) and 4 weeks later (b) in a 9-year-old Chinese girl with nephrotic syndrome. The patient developed disturbed consciousness and generalized tonic clonic convulsions at RPES onset and regained full consciousness 5 days later. She was not febrile and showed no clinical or laboratory evidence of infection. The upper panels (a) show subcortical and cortical hyperintense signals in the posterior region of both parietal lobes on T2FLAIR imaging. Mild narrowing of the distal basilar artery and left vertebral artery is observed on magnetic resonance angiography (MRA). The lower panels (b) show the brain MRI ﬁndings obtained 4 weeks after RPES onset. The previously mentioned abnormalities have almost disappeared. MRA shows a considerable increase in the patency of the distal basilar and left vertebral arteries.
pressure was gradually brought under control to