Cyclosporin-induced posterior reversible encephalopathy syndrome

By C. Frank Gould, MD; James D. Lowe, MD; Justin Q. Ly, MD; Scot E. Campbell, MD; Brian J. Fortman, MD; Douglas P. Beall, MD

Findings
Magnetic resonance imaging (MRI) showed areas of increased T2 signal within the medial portion of the occipital lobes bilaterally (Figures 1 through 3). These regions of increased signal appear to be cytotoxic (involving both the gray matter and white matter) but there is no evidence of restricted diffusion (increased signal) on the diffusion-weighted images (Figure 2). The increased signal is seen on the fluid-attenuated inversion recovery (FLAIR) (Figure 1A), apparent diffusion coefficient (ADC) map (Figure 1B), and T2-weighted (Figure 3) sequences. These findings indicate the low likelihood of cytotoxic brain injury from a cerebrovascular event and raise the possibility of early reversible edema. It should also be noted that the primary findings are seen within the posterior portions of the cerebrum, a territory supplied by the posterior cerebral artery.

Discussion
Posterior reversible encephalopathy is a heterogenous collection of disorders associated with a breakdown in cerebral perfusion autoregulatory mechanisms.1-3 It can be seen in eclampsia,4,5 hypertensive encephalopathy,2,6 hemolytic uremic syndrome,7,3 cryoglobulinemia,4 and systemic lupus erythematosus.7 In the posttransplant population, it is a well-known complication of antirejection therapy with cyclosporin A8-10 and tacrolimus.7 It has also been reported in association with chemotherapeutic agents, such as cisplatin11 and interferon alpha.7

The distribution of T2 abnormalities in cyclosporin-induced PRES is thought to be related to the sparse sympathetic innervation in the posterior circulation. Pathologic studies have shown that the relative density of sympathetic innervation is greatest in the internal carotid and anterior cerebral territories and least in the basilar artery and its branches.1,2 For this reason, breakdown of autoregulatory mechanisms would occur first in the more poorly innervated vessels of the posterior circulation.

The clinical presentation is nonspecific and includes headache, nausea, vomiting, visual changes, decreased alertness, and seizures.7 When recognized promptly, the symptoms and radiologic abnormalities can be reversed by rapid control of blood pressure or withdrawal of the offending drug.7,2,6 When undiagnosed, the patient can progress to ischemia, massive infarction, and death.1,6

The changes in T2-weighted MR images result from fluid extravasation into the interstitium, which is called vasogenic edema.2In the hypertensive encephalopathy model, increases in blood pressure lead to vasoconstriction in order to maintain constant perfusion to the brain. Once a certain threshold is reached, the autoregulatory mechanisms fail, the cerebral vasculature dilates passively from the mechanical effects of increased pressure within the vessel, and fluid leaks across the blood-brain barrier.1,2 In contradistinction, cytotoxic edema in the setting of acute stroke results from decreased activity of the Na-K pump across the glial cell membrane.1,5 When this happens, water becomes trapped inside the cell, leading to cell death.

Diffusion-weighted imaging (DWI) reliably distinguishes between vasogenic edema and cytotoxic edema.1,2,5 Restricted diffusion in cytotoxic edema yields marked hyperintensity on DWI, with hypointensity on ADC maps.1,2 Vasogenic edema, on the other hand, results in increased motion of water molecules in the interstitium, so it yields hyperintense ADC values and hypo- to isointense signal on DWI.1,2 The "classic" PRES case, therefore, presents with areas of abnormal T2 signal that are normal on DWI but have increased ADC values that reflect vasogenic edema.

Increased DWI signal is usually associated with low ADC values. This combination most often represents cytotoxic edema that is associated with stroke. In some cases of PRES, the initially high ADC values may be lower on follow-up scans. These cases have been shown to have a worse clinical outcome (ie, cerebral infarction and death) when this signal pattern is accompanied by increased signal on the DWI images.12 Cases of PRES have also been shown to have regions of normal T2 signal, high DWI signal, and normal ADC signal (a pattern suggestive of stroke) and also have co-existing regions of high T2 and ADC signal (findings consistent with vasogenic edema).12 This phenomenon is likely related to ischemic changes that are superimposed upon the severe edema. Resolution of the areas of increased DWI signal may occur on follow-up MRI examinations. This likely represents the resolution of ischemic regions in the posterior circulation location rather than the normalization of small areas of infarction.

CONCLUSION

The resolution of the increased DWI signal combined with the prototypical vasogenic edema appearance of PRES supports the theory that the MRI signal changes seen in PRES may often indicate a combination of edema and early infarction. The fact that some patients with PRES eventually progress to frank cerebral infarction and even death further emphasizes the need for prompt recognition and subsequent treatment of the underlying cause of this disorder.

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Cyclosporin-induced posterior reversible encephalopathy syndrome.  Appl Radiol. 

September 05, 2006
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