Artigo Revisado por pares

Posterior Reversible Encephalopathy Syndrome in Children: Its High Prevalence and More Extensive Imaging Findings

2006; Elsevier BV; Volume: 48; Issue: 2 Linguagem: Inglês

10.1053/j.ajkd.2006.04.076

ISSN

1523-6838

Autores

Kenji Ishikura, Masahiro Ikeda, Yuko Hamasaki, Hiroshi Hataya, Seiichirou Shishido, Hiroshi Asanuma, Gen Nishimura, Ryugo Hiramoto, Masataka Honda,

Tópico(s)

Neurological and metabolic disorders

Resumo

Background: Posterior reversible encephalopathy syndrome is a distinctive clinicoradiological entity observed in a variety of clinical settings, including pediatric patients. A greater prevalence of this syndrome has been suggested in kidney transplant recipients and patients with kidney disease. Although usually considered benign and reversible, characteristics of this syndrome in pediatric patients remain obscure. The objective of the present study involved disclosing details of imaging findings, as well as the clinical course and prevalence of the syndrome in this field. Methods: We investigated kidney transplant recipients and pediatric patients with kidney disease in our institution from 1990 to 2004. For these patients, clinical course, imaging findings, blood pressure, concurrent medical illnesses, and administrative condition of calcineurin inhibitors were analyzed. Results: Twenty cases of posterior reversible encephalopathy syndrome were investigated in patients ranging in age from 1.9 to 18.3 years. In most patients, radiological abnormalities extended to the gray matter (17 of 20 patients), frontal and temporal lobes, and even the cerebellum (16 patients). Of 177 kidney transplant recipients (cyclosporine, 127 patients; tacrolimus, 50 patients), 6 patients administered cyclosporine (4.7%) and 4 patients administered tacrolimus (8.0%) developed the syndrome after transplantation. Conclusion: Posterior reversible encephalopathy syndrome should be suspected in pediatric kidney transplant recipients and patients with kidney disease if they have a sudden episode of neurological symptoms, even if imaging findings are not restricted to the subcortical white matter of the occipital region. Background: Posterior reversible encephalopathy syndrome is a distinctive clinicoradiological entity observed in a variety of clinical settings, including pediatric patients. A greater prevalence of this syndrome has been suggested in kidney transplant recipients and patients with kidney disease. Although usually considered benign and reversible, characteristics of this syndrome in pediatric patients remain obscure. The objective of the present study involved disclosing details of imaging findings, as well as the clinical course and prevalence of the syndrome in this field. Methods: We investigated kidney transplant recipients and pediatric patients with kidney disease in our institution from 1990 to 2004. For these patients, clinical course, imaging findings, blood pressure, concurrent medical illnesses, and administrative condition of calcineurin inhibitors were analyzed. Results: Twenty cases of posterior reversible encephalopathy syndrome were investigated in patients ranging in age from 1.9 to 18.3 years. In most patients, radiological abnormalities extended to the gray matter (17 of 20 patients), frontal and temporal lobes, and even the cerebellum (16 patients). Of 177 kidney transplant recipients (cyclosporine, 127 patients; tacrolimus, 50 patients), 6 patients administered cyclosporine (4.7%) and 4 patients administered tacrolimus (8.0%) developed the syndrome after transplantation. Conclusion: Posterior reversible encephalopathy syndrome should be suspected in pediatric kidney transplant recipients and patients with kidney disease if they have a sudden episode of neurological symptoms, even if imaging findings are not restricted to the subcortical white matter of the occipital region. POSTERIOR REVERSIBLE encephalopathy syndrome is a relatively new clinicoradiological entity first described as reversible posterior leukoencephalopathy syndrome in 1996.1Hinchey J. Chaves C. Appignani B. et al.A reversible posterior leukoencephalopathy syndrome.N Engl J Med. 1996; 334: 494-500Crossref PubMed Scopus (2647) Google Scholar Originally, it denoted a reversible predominantly posterior leukoencephalopathy in patients who had renal insufficiency or hypertension or were immunosuppressed. Since then, there have been various reports on this syndrome in a variety of clinical settings, including pediatric patients.2Ikeda M. Ito S. Hataya H. Honda M. Anbo K. Reversible posterior leukoencephalopathy in a patient with minimal-change nephrotic syndrome.Am J Kidney Dis. 2001; 37 (available www.ajkd.org): E30Abstract Full Text PDF PubMed Google Scholar, 3Ikeda M. Yata N. Kamei K. et al.Posterior leukoencephalopathy syndrome in pediatric patients with kidney disease.Pediatr Nephrol. 2002; 17: 71Crossref PubMed Scopus (8) Google Scholar, 4Parvex P. Pinsk M. Bell L.E. O'Gorman A.M. Patenaude Y.G. Gupta I.R. Reversible encephalopathy associated with tacrolimus in pediatric renal transplants.Pediatr Nephrol. 2001; 16: 537-542Crossref PubMed Scopus (46) Google Scholar, 5Prasad N. Gulati S. Gupta R.K. Kumar R. Sharma K. Sharma R.K. Is reversible posterior leukoencephalopathy with severe hypertension completely reversible in all patients?.Pediatr Nephrol. 2003; 18: 1161-1166Crossref PubMed Scopus (81) Google Scholar, 6Casey S.O. Truwit C.L. Pontine reversible edema A newly recognized imaging variant of hypertensive encephalopathy?.AJNR Am J Neuroradiol. 2000; 21: 243-245PubMed Google Scholar, 7Singh N. Bonham A. Fukui M. Immunosuppressive-associated leukoencephalopathy in organ transplant recipients.Transplantation. 2000; 69: 467-472Crossref PubMed Scopus (161) Google Scholar, 8Kwon S. Koo J. Lee S. Clinical spectrum of reversible posterior leukoencephalopathy syndrome.Pediatr Neurol. 2001; 24: 361-364Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 9Nakahara C. Hasegawa N. Izumi I. Kanemoto K. Iwasaki N. The use of cyclosporine in a boy with a prior episode of posterior encephalopathy.Pediatr Nephrol. 2005; 20: 657-661Crossref PubMed Scopus (8) Google Scholar, 10Aksoy D.Y. Arici M. Kiykim A.A. et al.Posterior leukoencephalopathy and nephrotic syndrome Just a coincidence?.Am J Med Sci. 2004; 327: 156-159Crossref PubMed Scopus (11) Google Scholar, 11Ozcakar Z.B. Ekim M. Fitoz S. et al.Hypertension induced reversible posterior leukoencephalopathy syndrome A report of two cases.Eur J Pediatr. 2004; 163: 728-730Crossref PubMed Scopus (42) Google Scholar Classic neuroimaging applied to patients shows edema involving the white matter in the posterior portions of the cerebral hemispheres, especially bilaterally in the parieto-occipital regions.1Hinchey J. Chaves C. Appignani B. et al.A reversible posterior leukoencephalopathy syndrome.N Engl J Med. 1996; 334: 494-500Crossref PubMed Scopus (2647) Google Scholar Although its clinical and radiological courses have been reported as benign and reversible,1Hinchey J. Chaves C. Appignani B. et al.A reversible posterior leukoencephalopathy syndrome.N Engl J Med. 1996; 334: 494-500Crossref PubMed Scopus (2647) Google Scholar a significant effect of early management on the prognosis of neurological function was suggested.12Lamy C. Oppenheim C. Meder J.F. Mas J.L. Neuroimaging in posterior reversible encephalopathy syndrome.J Neuroimaging. 2004; 14: 89-96Crossref PubMed Scopus (299) Google Scholar However, in the field of pediatric nephrology, characteristics of this syndrome remain obscure, and it still is poorly understood by pediatric nephrologists. Hence, there are occasional misdiagnoses within this field. The objective of the present study is to disclose characteristics of imaging findings, as well as the clinical course and prevalence of this syndrome, in these patients. We investigated pediatric patients with kidney disease and kidney transplant recipients (age < 20 years) in our institution from 1990 to 2004. Posterior reversible encephalopathy syndrome was diagnosed when patients had neurological symptoms (altered consciousness, seizures, visual disturbances, or headaches) and positive radiological findings and other neurological disorders were ruled out. Radiological diagnosis was made by the same pediatric radiologist (G.N.). In some patients who developed posterior reversible encephalopathy syndrome before 1999, the diagnosis was made retrospectively based on their medical records and radiological images. We analyzed clinical course, imaging findings, blood pressure, concurrent medical illnesses, and administrative condition of calcineurin inhibitors. Blood cyclosporine and tacrolimus concentrations were analyzed by using fluorescence polarization and microparticle enzyme immunoassays, respectively. Blood cyclosporine was measured as a trough level; hence, blood samples were obtained just before the next administration. Cyclosporine was administered to patients with nephrotic syndrome based on the following protocols. For patients with steroid-resistant nephrotic syndrome, cyclosporine was administered for 12 months with prednisolone (1 mg/kg every other day). Cyclosporine trough levels were limited to 120 to 150 ng/mL during the first 3 months and 80 to 100 ng/mL from month 4 to the end. For patients with pathologically proven focal segmental mesangial sclerosis, methylprednisolone pulse therapy (30 mg/kg/d for 3 consecutive days) was added during weeks 1, 2, 5, 9, and 13. For patients with steroid-dependent and frequently relapsing nephrotic syndrome, cyclosporine was administered for 24 months. For these patients, trough levels were limited to 80 to 100 ng/mL during the first 6 months and 60 to 80 ng/mL from month 7 to the end. For kidney transplant recipients, each patient received either a cyclosporine- or tacrolimus-based immunosuppressive regimen for posttransplantation immunosuppression. Cyclosporine starting dose was 140 mg/m2/d intravenously, subsequently converted to an oral dose of 350 mg/m2/d, aiming at a target area under the concentration-time curve during the first 4-hour postdosing level of 4,000 to 5,000 ng·h/mL for the first month after transplantation, 2,700 to 3,500 ng·h/mL for the next 2 months, and 2,500 ng·h/mL thereafter. At the same time, cyclosporine trough level was monitored. Tacrolimus was administered at 0.15 to 0.3 mg/kg/d divided twice. In the initial protocol, target trough levels for tacrolimus were 15 to 20 ng/mL for postoperative month 1, 10 to 15 ng/mL for month 2, 7 to 10 ng/mL for month 3, and 5 to 7 ng/mL thereafter. Because of the relatively high incidence of adverse events, from October 2001, target trough levels were decreased to 10 to 15 ng/mL for month 1, 6 to 9 ng/mL for months 2 and 3, and 5 to 6 ng/mL thereafter. Mycophenolate mofetil was administered in a daily dose of 800 to 1,000 mg/m2. In addition, methylprednisolone was administered at 40 mg/m2/d with tapering, with administration switched to alternate days at month 6 after transplantation. Sandimmune (Novartis, Basel, Switzerland) was used as cyclosporine before 2000. At that time, trough level was applied predominantly to control the drug dosage. After 2000, Neoral (Novartis) was used, in accordance with the aforementioned protocol. This study was conducted on 20 patients (13 boys, 7 girls) ranging in age from 1.9 to 18.3 years (median, 8.7 years). Table 1 lists clinical characteristics and cranial imaging findings. Ten patients were kidney transplant recipients (patients 11 to 20), 7 patients had idiopathic nephrotic syndrome (patients 4 to 10), 2 patients had acute poststreptococcal glomerulonephritis (patients 2 and 3), and 1 patient had diffuse mesangial sclerosis (patient 1).Table 1Details of Clinical Course and Imaging Findings of 20 Patients With Posterior Reversible Encephalopathy SyndromePatient No.Age (y)/SexDiagnosis or Clinical StatePrescribed ImmunosuppressantsCyA and Tac Blood Concentration (ng/mL)Blood Pressure at Onset (mm Hg)Lesions on CT or MRIClinical Findings11.9/MDMS140/80O, F/GComa, status epilepticus, paralysis28.6/FAPSGN150/100O, P, T, F/W, GComa, seizures, cortical blindness312.1/MAPSGN225/120O/W, GComa, status epilepticus, headache, vomiting, cortical blindness48.4/FSRNSCyA79156/107O, P, T, F/W, GLethargy, seizures, headache, visual blurring510.0/FSRNSCyA152157/93O, P, F/W, GLethargy, seizures, headache611.2/FSRNSCyA97144/109O, T/W, GComa, seizures, vomiting, cortical blindness718.3/MSRNS172/104O/W, GLethargy, headache, vomiting, visual blurring815.1/FSRNSCyA140150/90O, F, Ce/WLethargy, recurrent seizures, headache97.6/MSSNSCyA71121/64O, Ce/W, GHeadache, vomiting, visual blurring109.4/MSSNS145/85O, P, F/W, GLethargy, seizures, headache, vomiting, visual blurring118.3/MTxCyA55198/118O, P, F, Ce/W, GComa, recurrent seizures, paralysis128.8/MTxCyA62142/92O, P, T, F/W, GStupor, seizures, vomiting135.9/MTxCyA194156/96P/WLethargy, seizures, headache146.3/MTxCyA380160/60O/W, GComa, status epilepticus, cortical blindness156.9/MTxCyA171140/90O, F/W, GConfusion, headache, cortical blindness1611.0/FTxCyA291162/82F/GLethargy, seizures178.5/MTxTac26.2152/100O, P, T, F/W, GLethargy, seizures, headache182.8/MTxTac19.2128/88O, P, F/W, GLethargy, seizures, vomiting1910.7/MTxTac15.7137/88O, F/W, GConfusion, seizures, headache2013.8/FTxTac28.3190/107F/WConfusion, recurrent seizuresAbbreviations: DMS, diffuse mesangial sclerosis; SSNS, steroid-sensitive nephrotic syndrome; SRNS, steroid-resistant nephrotic syndrome; APSGN, acute poststreptococcal glomerulonephritis; Tx, kidney transplantation; CyA, cyclosporine; Tac, tacrolimus; F, frontal region; P, posterior region; T, temporal region; O, occipital region; Ce, cerebellar region; G, gray matter; W, white matter. Open table in a new tab Abbreviations: DMS, diffuse mesangial sclerosis; SSNS, steroid-sensitive nephrotic syndrome; SRNS, steroid-resistant nephrotic syndrome; APSGN, acute poststreptococcal glomerulonephritis; Tx, kidney transplantation; CyA, cyclosporine; Tac, tacrolimus; F, frontal region; P, posterior region; T, temporal region; O, occipital region; Ce, cerebellar region; G, gray matter; W, white matter. Calcineurin inhibitors were administered to 15 patients: cyclosporine to 6 kidney transplant recipients (patients 11 to 16), cyclosporine to 5 patients with nephrotic syndrome (patients 4 to 6, 8, and 9), and tacrolimus to 4 kidney transplant recipients (patients 17 to 20). With the exception of 1 patient (no. 9), all had significant hypertension around the time of these episodes. Average cyclosporine trough level for kidney transplant recipients was 192.2 ng/mL (range, 55 to 380 ng/mL), that for patients with nephrotic syndrome was 107.8 ng/mL (range, 71 to 152 ng/mL), and average blood tacrolimus concentration (as continuous intravenous administration) was 22.4 ng/mL (range, 15.7 to 28.3 ng/mL) for kidney transplant recipients. Clinical symptoms at the episode were as follows: altered consciousness (coma, stupor, lethargy, and confusion) in 19 patients, seizures in 17 patients, headaches in 11 patients, visual disturbance in 9 patients, vomiting in 7 patients, and paralysis in 3 patients. Nine patients underwent both computed tomography (CT) and magnetic resonance imaging (MRI; patients 1 to 6 and 8 to 10), whereas the remaining patients were studied by using only CT. Radiological abnormalities were confined to the white matter in 3 patients (nos. 8, 13, and 20) and occipital and posterior parietal areas in 4 patients (nos. 3, 7, 13, and 14). In other patients, lesions extended to the gray matter, frontal and temporal lobes, and cerebellum. There was no difference in distribution between lesions detected by using CT and MRI. Typical images (patient 2), images with cerebellar lesions (patient 9), and images including diffusion-weighted magnetic resonance images (DWIs; patient 4) are shown in Fig 1, Fig 2, Fig 3, respectively. With the exception of a patient with delayed diagnosis (patient 1) and a patient with pretransplantation developmental delay (patient 11), all recovered both clinically and radiologically within 10 weeks, with optimal control of hypertension and seizures, as well as temporal cessations of calcineurin-inhibitor therapy.Fig 2Imaging findings of patient 9 (steroid-sensitive nephrotic syndrome). (A) Based on the coronal view, a high-intensity area was distributed mainly in the left lobe of the cerebellar hemisphere on day 13 (MRI T2 weighted). (B) Bilateral symmetrical low-density areas were apparent in the cerebellar hemisphere on the 22nd day (CT). (C) Abnormalities were found to be completely resolved by day 71 without any sequelae (MRI T2 weighted).View Large Image Figure ViewerDownload (PPT)Fig 3Imaging findings of patient 4 (steroid-resistant nephrotic syndrome). (A) Bilateral symmetrical high-intensity areas were apparent in the occipital and frontal regions on day 2. These lesions were evident in both the white and gray matter (MRI fluid-attenuated inversion recovery). (B) When diffusion-weighted magnetic resonance imaging was applied, high-intensity areas were evident in approximately the equivalent region, compared with Fig 3A on the same day. (C) Imaging abnormalities, as well as neurological symptoms, were found to be completely resolved by day 14 without any sequelae (MRI fluid-attenuated inversion recovery).View Large Image Figure ViewerDownload (PPT) Between 1990 and 2004, of 177 kidney transplant recipients administered calcineurin inhibitors (cyclosporine, 127 patients; tacrolimus, 50 patients) in our institution, 6 patients administered cyclosporine (4.7%) and 4 patients administered tacrolimus (8.0%) developed posterior reversible encephalopathy syndrome after transplantation. In addition, posterior reversible encephalopathy syndrome was diagnosed in 77% of transplant recipients (10 of 13 patients) who manifested altered consciousness and seizures during the observation. Correspondingly, of 87 patients who had nephrotic syndrome and were administered cyclosporine, 5 patients (5.7%) developed this syndrome. Of patients with acute poststreptococcal glomerulonephritis who had to be managed as inpatients and those with diffuse mesangial sclerosis, relevant figures were 2 of 56 patients (3.6%) and 1 of 13 patients (7.7%), respectively. We only experienced a few patients with kidney diseases who manifested apparent neurological symptoms during the observation; and except for those with posterior reversible encephalopathy syndrome, patients with hemolytic uremic syndrome and neuropsychiatric systemic lupus erythematosus have been listed. In this study, we show imaging findings of posterior reversible encephalopathy syndrome in pediatric patients. At the same time, we evaluate the prevalence of this syndrome in pediatric patients with kidney disease and kidney transplant recipients. The nomenclature of this clinicoradiological entity is inaccurate and confusing.12Lamy C. Oppenheim C. Meder J.F. Mas J.L. Neuroimaging in posterior reversible encephalopathy syndrome.J Neuroimaging. 2004; 14: 89-96Crossref PubMed Scopus (299) Google Scholar, 13Stott V.L. Hurrell M.A. Anderson T.J. Reversible posterior leukoencephalopathy syndrome A misnomer reviewed.Intern Med J. 2005; 35: 83-90Crossref PubMed Scopus (246) Google Scholar Because imaging abnormalities of the syndrome are not necessarily confined to the white matter, the term "reversible posterior leukoencephalopathy syndrome," originally used for this clinicoradiological entity, is inaccurate, and "posterior reversible encephalopathy syndrome" was proposed instead.14Casey S.O. Sampaio R.C. Michel E. Truwit C.L. Posterior reversible encephalopathy syndrome Utility of fluid-attenuated inversion recovery MR imaging in the detection of cortical and subcortical lesions.AJNR Am J Neuroradiol. 2000; 21: 1199-1206PubMed Google Scholar Other candidates are immunosuppressive-associated leukoencephalopathy, hyperperfusion encephalopathies, reversible posterior cerebral edema syndrome, and so on.7Singh N. Bonham A. Fukui M. Immunosuppressive-associated leukoencephalopathy in organ transplant recipients.Transplantation. 2000; 69: 467-472Crossref PubMed Scopus (161) Google Scholar, 15Schwartz R.B. Hyperperfusion encephalopathies Hypertensive encephalopathy and related conditions.Neurologist. 2002; 8: 22-34Crossref PubMed Scopus (131) Google Scholar, 16Dillon W.P. Rowley H. The reversible posterior cerebral edema syndrome.AJNR Am J Neuroradiol. 1998; 19: 591PubMed Google Scholar Furthermore, hypertensive encephalopathy, diagnosed mainly based on the clinical settings, is considered to be a similar disease entity based on its clinical course and imaging findings.15Schwartz R.B. Hyperperfusion encephalopathies Hypertensive encephalopathy and related conditions.Neurologist. 2002; 8: 22-34Crossref PubMed Scopus (131) Google Scholar, 17Vaughan C.J. Delanty N. Hypertensive emergencies.Lancet. 2000; 356: 411-417Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar, 18Wright R.R. Mathews K.D. Hypertensive encephalopathy in childhood.J Child Neurol. 1996; 11: 193-196Crossref PubMed Scopus (40) Google Scholar Although some inaccuracy remains, we chose the term "posterior reversible encephalopathy syndrome" in this article because it has been used most frequently, particularly in the field of radiology. Few reports regarding the prevalence of posterior reversible encephalopathy syndrome have been published to date; most observed the incidence of neurological complications of calcineurin inhibitors, including milder symptoms. Among them, some studies showed the incidence of severe neurological symptoms as follows: up to 5% of patients administered cyclosporine developed severe symptoms19Bechstein W.O. Neurotoxicity of calcineurin inhibitors Impact and clinical management.Transpl Int. 2000; 13: 313-326Crossref PubMed Scopus (453) Google Scholar; 21.3% of orthotopic liver transplant recipients administered tacrolimus developed moderate or severe neurotoxicity in the early postoperative period, as did 11.7% of transplant recipients administered cyclosporine20Mueller A.R. Platz K.P. Bechstein W.O. et al.Neurotoxicity after orthotopic liver transplantation. A comparison between cyclosporine and FK506.Transplantation. 1994; 58: 155-170PubMed Google Scholar; and 20% of pediatric recipients of allogeneic stem cell transplants administered tacrolimus developed encephalopathy.21Kanekiyo T. Hara J. Matsuda-Hashii Y. et al.Tacrolimus-related encephalopathy following allogeneic stem cell transplantation in children.Int J Hematol. 2005; 81: 264-268Crossref PubMed Scopus (31) Google Scholar However, most of these complications were not necessarily diagnosed as posterior reversible encephalopathy syndrome or related conditions by neuroimaging. During our observation, we experienced 20 patients with posterior reversible encephalopathy syndrome. Of 177 kidney transplant recipients, 10 patients (5.6%) developed this syndrome: 6 patients (4.7%) administered cyclosporine and 4 patients (8.0%) administered tacrolimus. Taking into consideration the severe symptoms at the onset of this syndrome and potential sequelae, these figures must be noteworthy. Of 87 patients with nephrotic syndrome administered cyclosporine, 5 patients (5.7%) developed this syndrome. This result might be exaggerated because exclusively severe and refractory patients with nephrotic syndrome were referred to our hospital; despite this, we must remain cautious of posterior reversible encephalopathy syndrome when managing nephrotic patients with cyclosporine. At the same time, in both kidney transplant recipients and patients with nephrotic syndrome, if they experience a sudden episode of neurological symptoms, they should be suspected of being affected with posterior reversible encephalopathy syndrome. The key pathophysiological process of this syndrome was identified as vasogenic edema.12Lamy C. Oppenheim C. Meder J.F. Mas J.L. Neuroimaging in posterior reversible encephalopathy syndrome.J Neuroimaging. 2004; 14: 89-96Crossref PubMed Scopus (299) Google Scholar, 17Vaughan C.J. Delanty N. Hypertensive emergencies.Lancet. 2000; 356: 411-417Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar One hypothesized cause of vasogenic edema is autoregulation failure in cerebral blood flow, the regularity of which is normally controlled by sympathetic nerves. When body blood pressure exceeds a certain point, autoregulation failure occurs. This results in cerebral hyperperfusion, disruption of the blood-brain barrier, and, finally, vasogenic edema. Endothelial cell damage of vessels caused by calcineurin inhibitor administration also may result in vasogenic edema. The posterior region was shown to be vulnerable because vessels of the posterior circulation, arising from the basilar artery, have sparse sympathetic innervasion.17Vaughan C.J. Delanty N. Hypertensive emergencies.Lancet. 2000; 356: 411-417Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar Extensive distribution of the lesion, as seen in our series, may result from different patterns of innervations of sympathetic nerves in pediatric patients. At the same time, most of our patients experienced relatively severe alterations in consciousness and seizures. Compared with adult series,1Hinchey J. Chaves C. Appignani B. et al.A reversible posterior leukoencephalopathy syndrome.N Engl J Med. 1996; 334: 494-500Crossref PubMed Scopus (2647) Google Scholar, 7Singh N. Bonham A. Fukui M. Immunosuppressive-associated leukoencephalopathy in organ transplant recipients.Transplantation. 2000; 69: 467-472Crossref PubMed Scopus (161) Google Scholar these symptoms appeared to be much more severe and might be related to the extended imaging abnormalities. The diagnostic process for posterior reversible encephalopathy syndrome has improved with the application of MRI, currently considered a more sensitive diagnostic tool than CT scanning to detect the lesion of this syndrome. In particular, a fluid-attenuated inversion recovery image is suitable to detect the lesion in the superficial area of the gray matter.14Casey S.O. Sampaio R.C. Michel E. Truwit C.L. Posterior reversible encephalopathy syndrome Utility of fluid-attenuated inversion recovery MR imaging in the detection of cortical and subcortical lesions.AJNR Am J Neuroradiol. 2000; 21: 1199-1206PubMed Google Scholar The significance of contrast-enhanced MRI findings has not been established.22Ugurel M.S. Hayakawa M. Implications of post-gadolinium MRI results in 13 cases with posterior reversible encephalopathy syndrome.Eur J Radiol. 2005; 53: 441-449Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Some investigators showed the importance of DWI for this syndrome to evaluate the lesion as cytotoxic or noncytotoxic edema.23Schwartz R.B. Mulkern R.V. Gudbjartsson H. Jolesz F. Diffusion-weighted MR imaging in hypertensive encephalopathy Clues to pathogenesis.AJNR Am J Neuroradiol. 1998; 19: 859-862PubMed Google Scholar, 24Crasto S.G. Rizzo L. Sardo P. Davini O. De Lucchi R. Reversible encephalopathy syndrome Report of 12 cases with follow-up.Neuroradiology. 2004; 46: 795-804Crossref PubMed Scopus (8) Google Scholar DWI works on the principle that sensitizing a standard magnetic resonance image to diffusion weighting identifies regions of abnormal water movement, resulting in increased signal intensity. On the other hand, based on our experience, the results were inconsistent with these reports. DWI of patients 4 (Fig 3) and 8 showed some high-intensity areas that were considered cytotoxic and irreversible. Conversely, both clinical course and imaging abnormalities were completely reversible in these cases. At the same time, DWIs were obtained in only 2 patients in our series. Taken together, we cannot conclude the significance of this imaging method when evaluating the prognosis of this syndrome. Whereas MRI may contribute to the high prevalence of the syndrome and widespread imaging alteration of the present study, CT scanning still has some advantages because of its ability to detect intracranial hemorrhage25Schwartz R.B. Bravo S.M. Klufas R.A. et al.Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy CT and MR findings in 16 cases.AJR Am J Roentgenol. 1995; 165: 627-631Crossref PubMed Scopus (287) Google Scholar and its practicality for severely ill patients, particularly in the acute phase. In addition, the superiority of MRI over CT in detecting the lesion of the syndrome could not be confirmed, and we were not able to evaluate differences in findings precisely because the 2 studies were performed at different times. Therefore, a combination of these 2 modalities currently is recommended. Differential diagnoses of posterior reversible encephalopathy syndrome have been reported as ischemic stroke, cerebral venous thrombosis, intracranial vasculitis, progressive multifocal leukoencephalopathy, X-linked adrenoleukodystrophy, and so on.12Lamy C. Oppenheim C. Meder J.F. Mas J.L. Neuroimaging in posterior reversible encephalopathy syndrome.J Neuroimaging. 2004; 14: 89-96Crossref PubMed Scopus (299) Google Scholar, 26Illner A. PRES.in: Blaser S.I. Pocket Radiologist PedsNeuro. Medical Reference, Salt Lake City, UT2003: 220-222Google Scholar Conversely, some patients were referred from other institutions with diagnoses of acute disseminated encephalomyelitis, encephalitis caused by electrolyte disturbance, and encephalopathy of unknown origin, showing the lack of awareness of this syndrome that still exists among clinicians and radiologists.6Casey S.O. Truwit C.L. Pontine reversible edema A newly recognized imaging variant of hypertensive encephalopathy?.AJNR Am J Neuroradiol. 2000; 21: 243-245PubMed Google Scholar, 10Aksoy D.Y. Arici M. Kiykim A.A. et al.Posterior leukoencephalopathy and nephrotic syndrome Just a coincidence?.Am J Med Sci. 2004; 327: 156-159Crossref PubMed Scopus (11) Google Scholar Considering the prevalence of this syndrome stated previously, a wider understanding of this syndrome in these fields is critical. Hypertension and calcineurin inhibitor administration were shown to be the chief risk factors for this syndrome,1Hinchey J. Chaves C. Appignani B. et al.A reversible posterior leukoencephalopathy syndrome.N Engl J Med. 1996; 334: 494-500Crossref PubMed Scopus (2647) Google Scholar, 8Kwon S. Koo J. Lee S. Clinical spectrum of reversible posterior leukoencephalopathy syndrome.Pediatr Neurol. 2001; 24: 361-364Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 12Lamy C. Oppenheim C. Meder J.F. Mas J.L. Neuroimaging in posterior reversible encephalopathy syndrome.J Neuroimaging. 2004; 14: 89-96Crossref PubMed Scopus (299) Google Scholar particularly if both factors coexist.25Schwartz R.B. Bravo S.M. Klufas R.A. et al.Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy CT and MR findings in 16 cases.AJR Am J Roentgenol. 1995; 165: 627-631Crossref PubMed Scopus (287) Google Scholar In our experience, 19 of 20 patients had significant hypertension at onset. To prevent this syndrome, close observation and control of blood pressure in patients with risk factors appear essential. The effect of blood calcineurin inhibitor concentration is controversial. Initially, our patients administered tacrolimus had a relatively high blood concentration, and we have adopted a new immunosuppressive regimen for posttransplantation immunosuppression since October 2001. At the same time, it was considered that fluid retention, renal failure, and alteration in vascular permeability may increase the potential for this syndrome.1Hinchey J. Chaves C. Appignani B. et al.A reversible posterior leukoencephalopathy syndrome.N Engl J Med. 1996; 334: 494-500Crossref PubMed Scopus (2647) Google Scholar, 2Ikeda M. Ito S. Hataya H. Honda M. Anbo K. Reversible posterior leukoencephalopathy in a patient with minimal-change nephrotic syndrome.Am J Kidney Dis. 2001; 37 (available www.ajkd.org): E30Abstract Full Text PDF PubMed Google Scholar, 10Aksoy D.Y. Arici M. Kiykim A.A. et al.Posterior leukoencephalopathy and nephrotic syndrome Just a coincidence?.Am J Med Sci. 2004; 327: 156-159Crossref PubMed Scopus (11) Google Scholar, 17Vaughan C.J. Delanty N. Hypertensive emergencies.Lancet. 2000; 356: 411-417Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar These risk factors, frequently observed in kidney transplant recipients and patients with nephrotic syndrome, may have a role in the considerable prevalence of posterior reversible encephalopathy syndrome in these patients. Rigorous and meticulous control of blood pressure is mandatory to manage posterior reversible encephalopathy syndrome,15Schwartz R.B. Hyperperfusion encephalopathies Hypertensive encephalopathy and related conditions.Neurologist. 2002; 8: 22-34Crossref PubMed Scopus (131) Google Scholar, 17Vaughan C.J. Delanty N. Hypertensive emergencies.Lancet. 2000; 356: 411-417Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar subsequent to ruling out cerebral infarction. Various parenteral drugs are suitable, such as sodium nitroprusside, labetalol, hydralazine fenoldopam, glyceryl trinitrate enalaprilat, and nicardipine.17Vaughan C.J. Delanty N. Hypertensive emergencies.Lancet. 2000; 356: 411-417Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar Among them, in our experience in pediatric patients, intravenous administration of nicardipine is effective to limit blood pressure promptly to within the appropriate range with less fluctuation. It is infused with an initial dose of 0.5 μg/kg/min and can be increased up to 5 μg/kg/min. On the other hand, cessation of calcineurin inhibitor use remains a controversial issue, particularly for kidney transplant recipients.7Singh N. Bonham A. Fukui M. Immunosuppressive-associated leukoencephalopathy in organ transplant recipients.Transplantation. 2000; 69: 467-472Crossref PubMed Scopus (161) Google Scholar We discontinued calcineurin inhibitor therapy in most of our transplant recipients until blood pressure and other risk factors were controlled, then readministered another type of calcineurin inhibitor (cyclosporine to tacrolimus, or vice versa). Conversely, some reports showed successful control without their cessation.4Parvex P. Pinsk M. Bell L.E. O'Gorman A.M. Patenaude Y.G. Gupta I.R. Reversible encephalopathy associated with tacrolimus in pediatric renal transplants.Pediatr Nephrol. 2001; 16: 537-542Crossref PubMed Scopus (46) Google Scholar, 9Nakahara C. Hasegawa N. Izumi I. Kanemoto K. Iwasaki N. The use of cyclosporine in a boy with a prior episode of posterior encephalopathy.Pediatr Nephrol. 2005; 20: 657-661Crossref PubMed Scopus (8) Google Scholar For patients with frequently relapsing nephrotic syndrome refractory to other immunosuppressants, we are now studying the effects of cyclosporine readministration after risk factors, namely hypertension, fluid retention, and edema, have been controlled. The prognosis of posterior reversible encephalopathy syndrome generally is accepted as benign, except for patients with intracranial hemorrhage,1Hinchey J. Chaves C. Appignani B. et al.A reversible posterior leukoencephalopathy syndrome.N Engl J Med. 1996; 334: 494-500Crossref PubMed Scopus (2647) Google Scholar, 5Prasad N. Gulati S. Gupta R.K. Kumar R. Sharma K. Sharma R.K. Is reversible posterior leukoencephalopathy with severe hypertension completely reversible in all patients?.Pediatr Nephrol. 2003; 18: 1161-1166Crossref PubMed Scopus (81) Google Scholar, 25Schwartz R.B. Bravo S.M. Klufas R.A. et al.Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy CT and MR findings in 16 cases.AJR Am J Roentgenol. 1995; 165: 627-631Crossref PubMed Scopus (287) Google Scholar and this also was true for our patients. At the same time, prolonged seizures, hypertension, or both may result in permanent neurological deficit and cerebral infarction.5Prasad N. Gulati S. Gupta R.K. Kumar R. Sharma K. Sharma R.K. Is reversible posterior leukoencephalopathy with severe hypertension completely reversible in all patients?.Pediatr Nephrol. 2003; 18: 1161-1166Crossref PubMed Scopus (81) Google Scholar, 27Abe K. Reversible posterior leukoencephalopathy syndrome.Intern Med. 2004; 43: 900-901Crossref PubMed Scopus (11) Google Scholar Proper and early diagnosis of this syndrome therefore is critical. In conclusion, pediatric kidney transplant recipients and patients with kidney diseases should be suspected of being affected with posterior reversible encephalopathy syndrome if they experience a sudden episode of neurological symptoms, even if imaging findings are not restricted to within the subcortical white matter of the occipital region.

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