Posterior Leukoencephalopathy and Nephrotic Syndrome: Just a Coincidence

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ABSTRACT: Posterior leukoencephalopathy syndrome (PLES) is an acute neurological disorder. The most plausible hypothesis for the pathophysiology of PLES is the loss of autoregulation and consequent vasogenic edema. PLES is mostly attributed to severe or sudden elevations of arterial blood pressure. A number of reports, however, describe patients with PLES without severe hypertension. This report presents two patients with nephrotic syndrome who developed PLES without customarily severe hypertension. Proteinuria, low levels of serum albumin, or generalized increase in capillary permeability

in nephrotic syndrome can initiate PLES with moderately high arterial blood pressure levels. PLES is increasingly recognized by neurologists, but it should also be remembered by internists when confronted with patients with nephrotic syndrome who present with neurological symptoms, whether or not they have severe hypertension. KEY INDEXING TERMS: Posterior leukoencephalopathy syndrome; Nephrotic syndrome; Hypoalbuminemia; Hypertension. [Am J Med Sci 2004;327(3):156–159.]

Case Reports


Patient 1.

From the Departments of Internal Medicine (DYA, MD), Nephrology (MA, AAK, BA, YE, UY, CT, SC), Neurology (GS), and Pathology (DEB), Hacettepe University Faculty of Medicine, Ankara, Turkey. Submitted December 18, 2002; accepted August 26, 2003. Correspondence: Duygu Yazgan Aksoy, M.D., Angora Evleri Ruyalar Cad.Masal Sok., E-2 Bl No: 31 06530 Beysukent, Ankara, Turkey (E-mail: [email protected]).

A 61-year-old female patient with a 4-year history of hypertension was admitted to the emergency department with throbbing headache, dyspnea, nausea, and vomiting. She was not taking her medications regularly. On admission, her temperature was 36.2°C, pulse was 80 beats/min, and blood pressure was 180/110 mm Hg. The physical examination revealed puffy eyes, pretibial edema, and bilateral crepitations on the chest. Results of funduscopic and neurological examination were unremarkable. Her laboratory examination was notable for anemia and elevated serum urea nitrogen and creatinine values (25 and 2.4 mg/dL, respectively). She had marked hypoalbuminemia (1.8 g/dL), with a daily protein excretion of 3.5 g. Her blood pressure was controlled in 6 to 8 hours with oral captopril administration and ranged between 150/100 and 130/90 mm Hg. She was admitted to the hospital with the diagnosis of nephrotic syndrome. On her second day of hospitalization, she suddenly became drowsy and less responsive to verbal stimuli. Her blood pressure was 130/90 mm Hg and the highest blood pressure of the preceding 24 hours was 140/95 mm Hg. She also complained of blurred vision. Neurological examination showed bilateral decrease in visual acuity and dysarthria. The cranial computed tomography was normal, but fluid-attenuated inversion recovery pulse (FLAIR) images showed edema in the posterior part of the brain (Figure 1, A and B). Diffusion-weighed magnetic resonance imaging was performed the day after but revealed no abnormality in previously edematous parts of the brain (Figure 1, C and D). This was consistent with PLES, and her clinical status had spontaneously improved. She had a renal biopsy after results of serological and immunological tests were unexceptional. The light microscopic and immunofluorescent examination of the biopsy showed membranous glomerulopathy with minimal interstitial inflammation (Figure 2). She was treated conservatively because of the favorable prognosis of her renal disease, and her renal function tests

osterior leukoencephalopathy syndrome (PLES) is an acute neurological condition characterized by headache, nausea, vomiting, visual disturbances, altered mental status, decreased alertness, seizures, and occasionally, focal neurological signs. It is mostly attributed to severe or acute elevations of arterial blood pressure.1 A number of reports, however, describe PLES without severe hypertension or mild to moderate elevations in blood pressure, especially in the setting of immunosuppression or chemotherapy.2– 4 PLES was also reported in patients with renal diseases. All of these patients, however, either had severely elevated arterial pressures or had been on immunosuppressive therapy.1,5–9 We present here 2 cases of PLES that developed in patients with nephrotic syndrome who were neither severely hypertensive nor immunosuppressed. We also discuss possible factors linking nephrotic syndrome with development of PLES.


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Figure 1. FLAIR images (A and B) showing patchy hyperintense areas in the right parietal, occipital, and left occipital regions. Diffusion-weighed images (C and D) reveal no abnormality



Posterior Leukoencephalopathy and Nephrotic Syndrome

Figure 2. Diffuse and coarse granular deposits following the outline of glomerular basement membranes (fluorescein-conjugated antihuman IgG, 400⫻).

had improved afterward (serum urea nitrogen, 24 mg/dL; creatinine, 0.9 mg/dL).

Patient 2. A 39-year-old female patient with no history of hypertension presented with anorexia, nausea, and vomiting at a local hospital. Physical and neurological examinations, including arterial blood pressure were unremarkable except for mild right upper quadrant tenderness. Abdominal ultrasonography showed cholelithiasis, and she was hospitalized for an elective surgery. The night before the operation, she developed nausea, complete loss of vision in both eyes, and a generalized tonic-clonic convulsion. Her blood pressure was 190/100 mm Hg. She was confused and had 2 more generalized convulsions in the subsequent 6 hours. Antiepileptic and antihypertensive therapy was started, and she was referred to our hospital. Her blood chemistry was found to be normal except for elevated serum urea nitrogen (43.4 mg/dL) and serum creatinine (1.6 mg/dL) with low albumin (2.0 g/dL) levels. She had 4 g/day proteinuria. Cranial computed tomography just after the seizure had shown edema in the posterior part of the right hemisphere, later confirmed with T2-weighted magnetic resonance images showing regressing edema in the posterior brain regions. The diagnosis was PLES. After antiepileptic and antihypertensive treatment, all her symptoms regressed, with total recovery of vision, and she had no more convulsions. Although the measured blood pressure was very high just before her first convulsion, her blood pressure never exceeded 130/80 mm Hg under single drug treatment during her stay. Several investigations, including renal ultrasonography and renal arterial and venous doppler ultrasonography were performed, but the results were unremarkable. Renal biopsy showed type 1 membranoproliferative glomerulonephritis (Figure 3). She was put on corticosteroids and complete remission was achieved in 3 months.

Discussion PLES is a rapidly evolving neurological disorder characterized by headache, nausea, vomiting, visual disturbances, altered mental status, decreased alertness, seizures, and occasionally, focal neurological signs. It is associated with predominantly white matter edema in the posterior parietal, temporal, and occipital brain regions. It usually occurs because of severe or acute blood pressure elevations,1,2 and 158

Figure 3. Lobular accentuation caused by mesangial expansion, and capillary wall thickening with mesangial interposition and basement membrane duplication (Jones’ methenamine silver, 200⫻).

hypertensive encephalopathy is the most common cause of PLES.1,10 Patients with hypertensive encephalopathy have the same clinical signs as those with potentially reversible PLES, and they also have rapid resolution of clinical and imaging abnormalities when blood pressure is lowered. In parallel with the clinical presentation, magnetic resonance neuroimaging shows a characteristic posterior leukoencephalopathy that predominantly, but not exclusively, affects the white matter of the parietooccipital regions.10,11 Studies with diffusionweighted magnetic resonance imaging show that leukoencephalopathy is caused primarily by vasogenic rather than cytotoxic edema.10,12 Prompt antihypertensive treatment leads to complete clinical recovery, with total reversal of the brain lesions in some but not all cases. If left untreated, however, this relatively benign syndrome can cause permanent neurological deficits or even death as a result of brain edema, cerebral infarctions, and hemorrhages.11,13,14 The pathophysiology of the cerebral lesions in PLES associated with severe hypertension is attributed mainly to the failure of the autoregulatory capabilities of the cerebral vessels. This leads to dilation of cerebral arterioles, hyperperfusion breakdown of blood-brain barrier, and consequent vasogenic edema. In animals, arteriolar resistance increases proportionately as blood pressure rises until a threshold (mean arterial pressure ⵑ180 mm Hg) is reached, at which point autoregulation fails segmentally and the mechanical effect of the elevated pressure causes passive vasodilation and extravasation.15 Breakthrough vasodilation has also been demonstrated in humans with constant cerebral blood flow between mean arterial pressures of 60 and 120 mm Hg in normotensive subjects and beyond 180 mm Hg in subjects with chronic hypertenMarch 2004 Volume 327 Number 3

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sion.16 Although hypertensive encephalopathy is the most common cause, a number of patients developed PLES in the absence of customarily severe hypertension. Immunosuppressive therapy, interferon, sepsis, ischemic bowel disease, renal disease, erythropoietin, porphyria, and chemotherapy are some other causes of PLES.1–5 Ay et al2 reported 3 PLES patients who had severe illnesses, and they raised the question of whether infectious and metabolic abnormalities disturb the integrity of the distal brain vasculature and lead to edema formation with otherwise tolerable increases of systemic blood pressure. PLES is also an increasingly recognized neurologic disorder in patients with renal diseases. In most reported cases so far, the patients either had severely elevated arterial pressures or had been on immunosuppressive treatment.1,5–9 In this report, we present 2 female patients who had nephrotic syndrome with biopsy-documented glomerulopathies and severe hypoalbuminemia (1.8 and 2.0 g/dL). Neither of them received immunosuppressive drugs when they developed PLES. Their blood pressure readings have also not risen above the theoretical upper limits for defining hypertensive encephalopathy, but the second patient in particular had only one measurement, which prevents a clear-cut exclusion of severe hypertension-related PLES. Hypoalbuminemia with heavy proteinuria results in decreased plasma oncotic pressure, and this makes vascular fluid extravasation more likely at lower blood pressures, increasing the risk of PLES in these patients. There is also increasing evidence that nephrotic patients had severe alteration in capillary permeability that contributes to the pathophysiology of nephrotic edema.17 An increase in the permeability of cerebral arterioles and capillaries may explain the tendency of patients with nephrotic syndrome to develop PLES within limits of acceptable arterial blood pressure readings. Both patients in this report had characteristically severe hypoalbuminemia. Kim et al6 reported a patient with nephrotic syndrome whose serum albumin was 1.6 g/dL and who developed PLES with a blood pressure of 120/80 mm Hg. A possible link has also been proposed between hypertensive encephalopathy and nephrotic syndrome because of easy fluid extravasation from intracerebral capillaries.18 Another characteristic of the patients in this report is their gender. Including the first report of Hinchey (13 females among 15 patients), most reported PLES cases were women. It may be interesting to determine whether women have a greater tendency to develop PLES because of hypertension, nephrotic syndrome, or some other metabolic disturbances.2 In conclusion, PLES is a multifactorial syndrome. Hypoalbuminemia, edema, systemic capillary hy-


perpermeability, or nephrotic syndrome itself may create a tendency for PLES. PLES is very well known by neurologists, but internists should also be aware of it. PLES should be kept in mind as a diagnostic alternative when patients with nephrotic syndrome present with sudden occurrence of neurological symptoms, regardless of their arterial blood pressure readings. References 1. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494 –500. 2. Ay H, Buananno FS, Schaeffer PW, et al. Posterior leukoencephalopathy without severe hypertension: utility of diffusion-weighted MRI. Neurology 1998;51:1369 –76. 3. Ito Y, Arahata Y, Goto Y, et al. Cisplatin neurotoxicity presenting as reversible posterior leukoencephalopathy syndrome Am J Neuroradiol 1998;19:415–7. 4. Shin RK, Stern JW, Janss AJ, et al. Reversible posterior leukoencephalopathy during the treatment of acute lymphoblastic leukemia. Neurology 2001;56:388 –91. 5. Shimuzu C, Kimura S, Yoshida Y, et al. Acute leukoencephalopathy during cyclosporine A therapy in a patient with nephrotic syndrome. Pediatr Neurol 1994;8:483–5. 6. Kim BS, Lee SH, Lee JE, et al. Posterior leukoencephalopathy syndrome during steroid therapy in a Down syndrome patient with nephrotic syndrome. Nephron 2001;87:289 –90. 7. Kamar N, Kany M, Bories P, et al. Reversible posterior leukoencephalopathy syndrome in hepatitis C virus-positive long-term hemodialysis patients. Am J Kidney Dis 2001;37: E29. 8. Ikeda M, Ito S, Hataya H, et al. Reversible posterior leukoencephalopathy in a patient with minimal change nephrotic syndrome. Am J Kidney Dis 2001;37:E30. 9. Soylu A, Kavukcu S, Turkmen M, et al. Posterior leukoencephalopathy syndrome in poststreptococcal acute glomerulonephritis. Pediatr Nephrol 2001;16:601–3. 10. Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet 2000;356:411–7. 11. Schwartz RB, Jones KM, Kalina P, et al. Hypertensive encephalopathy: findings on CT, MR imaging, and SPECT imaging in 14 cases. AJR Am J Roentgenol 1992;159:379 – 83. 12. Schwartz RB, Mulkern RV, Gudbjartsson H, et al. Diffusion-weighted MR imaging in hypertensive encephalopathy: clues to pathogenesis. AJNR Am J Neuroradiol 1998;19: 859 – 62. 13. Weingarten K, Barbut D, Filippi C, et al. Acute hypertensive encephalopathy: findings on spin-echo and gradientecho MR imaging. Am J Roentgenol 1994;162:665–70. 14. Pullicino P, Zimmer W, Kwen PL. Posterior leukoencephalopathy syndrome [letter]. Lancet 1996;347:1557. 15. MacKenzie ET, Stransgaard S, Graham DI, et al. Effects of acutely induced hypertension in cats on pial arteriolar caliber, local cerebral blood flow, and the blood-brain barrier. Circ Res 1976;39:33– 41. 16. Strandgaard S, Olesen J, Skinhoj E, et al. Autoregulation of brain circulation in severe arterial hypertension. Br Med J 1973;1:507–10. 17. Rostoker G, Behar A, Lagrue G. Vascular hyperpermeability in nephrotic edema. Nephron 2000;85:194 –200. 18. Pearson ER, D’Souza RJ, Hamilton-Wood C, et al. Hypertensive encephalopathy and nephrotic syndrome: a possible link? Nephrol Dial Transplant 1999:14:1750 –2.


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