Type of Edema in Posterior Reversible Encephalopathy Syndrome Depends on Serum Albumin Levels: An MR Imaging Study in 28 Patients

Discussion

In a clinical report of 28 consecutive patients with PRES, we focused on the type of edema and serum albumin levels. We found that patients with vasogenic edema had significantly decreased serum albumin levels compared with edema with cytotoxic components, indicating that low serum albumin levels may be involved in the development of vasogenic edema in PRES.

Vasogenic edema in PRES has been attributed so far to the hypothesis that increased perfusion pressure overwhelms cerebral autoregulation with consecutive hyperperfusion and fluid extravasation. However, PRES has been increasingly observed in patients on immunosuppressive therapy or chemotherapy and in patients with infection, sepsis, and shock without elevation of systemic blood pressure,¹⁵ suggesting additional pathophysiologic mechanisms.² As mentioned below, many conditions prone to PRES are characterized by decreased serum albumin levels and a proinflammatory systemic process, as has been recently reviewed by Bartynski⁸: Proinflammatory cytokines such as IL-1, IL-6, interferon-γ, and tumor necrosis factor-α are elevated during sepsis and preeclampsia. The proinflammatory cytokine milieu and, in some conditions, additional T-cell activation lead to endothelial cell activation and eventually to T-cell trafficking,¹⁶ endothelial cell swelling, and production of vasoactive substances resulting in disturbed microcirculation with either increased vascular permeability or vasoconstriction.⁸ Albumin plays an integral part in this systemic process. In addition to inflammation, clinical conditions particularly prone to PRES are often associated with high oxidative stress and decreased serum albumin levels.^17,18

Serum albumin has a mean life span of 14–18 days.¹⁹ In healthy individuals, 30%–40% of serum albumin is maintained within the vascular compartment; it leaks from plasma at a rate of 5% per hour and is returned at an equivalent rate.²⁰ Albumin can be reduced as a consequence of an elevated metabolic albumin turnover, accelerated aging of the molecules through oxidative stress, or increased leakage due to immune-mediated vasculopathy.^20,21 In line with these characteristics, 71% of our patients had decreased serum albumin levels.

Serum albumin normally accounts for 75% of protein in blood plasma and, therefore, also for 75% of COP. COP affects osmotic pressure because the negative charges attract sodium, thus holding water and exerting an antagonistic effect on perfusion pressure.^12,18 In conditions with endothelial damage due to inflammatory processes, reduction of COP may facilitate fluid extravasation and development of vasogenic edema.

Albumin is one of the most important plasma antioxidants, scavenging and detoxifying ROS.²² Excessive production of ROS, as seen in conditions predisposing to PRES, can lead to damage of several molecules, including albumin, and endothelial dysfunction, and may contribute to disease progression.²¹ Low albumin levels or damage to albumin molecules themselves in the context of abundant oxidative stress (eg, in proinflammatory conditions) may blunt the antioxidative properties of albumin and promote endothelial damage.¹⁰ Moreover, albumin may directly influence vascular integrity by binding to the extracellular matrix and subendothelium and by reducing the permeability of these layers to large molecules.^13,18

In accordance, vasogenic edema in PRES was significantly more frequent in patients with decreased serum albumin levels, whereas cytotoxic components occurred more frequently in patients with normal serum albumin levels.

A possible correlation between low albumin levels and PRES is supported by Ishikura et al,²³ who reported 7 pediatric patients who developed PRES during nephrotic syndrome and low levels of serum albumin. In these patients, PRES rapidly abated after substitution of albumin, despite further treatment with cytotoxic substances. Similarly, ifosfamide-induced cerebral vasogenic edema, a condition resembling PRES, seems to occur exclusively in patients with low serum albumin levels.²⁴ In contrast, cytotoxic edema in PRES may contribute to cerebral vasospasm, with endothelial activation or injury leading to reduced cerebral blood flow with consequent hypoxia, as described in several PRES studies using MR imaging or conventional angiography.^9,25

Due to the retrospective character of our case series, we acknowledge certain limitations of our results. MR imaging protocols differed between patients, and ADC maps were not available for 9 of our patients. In those patients, the type of edema was determined by using only DWI and FLAIR sequences. Clinical data were obtained from medical reports. Therefore, it is conceded that certain minimal symptoms at presentation may have been missed due to a lack of documentation. Caution is needed in interpreting blood pressure in the context of albumin in our patient sample, because blood pressure was documented at the onset of symptoms in only 15 patients. Unfortunately, our retrospective sample size (N = 28) does not provide sufficient information to draw statistically sound conclusions on whether PRES present outside the posterior circulation is associated with decreased serum albumin levels and, second, whether the extent of vasogenic edema might be associated with reduction of serum albumin levels.

Patients developing a decrease in serum albumin levels seem to be at particular risk for the development of vasogenic edema and eventually PRES. Because PRES is not necessarily benign and reversible in all patients, more focused and accurate treatment strategies are needed. Infusion of human serum albumin at an early and reversible phase to increase oncotic pressure and restore antioxidative potential could theoretically prevent widespread oxidative and/or ischemic damage to vulnerable vascular structures in PRES and should be subjected to prospective studies.