Posterior leukoencephalopathy without severe hypertension

Posterior leukoencephalopathy syndrome (PLES) is a rapidly evolving neurologic condition characterized by headache, nausea and vomiting, visual disturbances, altered mental status, decreased alertness, seizures, and, occasionally, focal neurologic signs.^1,2 PLES is associated with an abrupt and severe increase in blood pressure in most cases, including patients with eclampsia or renal disease with hypertension. However, it is also seen in patients treated with immunosuppressive drugs such as cyclosporin A, tacrolimus, and interferon alpha.² The main finding in neuroimaging and autopsy studies is posterior white matter edema, particularly involving the parietal and occipital lobes, which may spread to basal ganglia, brainstem, and cerebellum.^3,4 It is currently not known with certainty whether the primary cause of the edema is an ischemic process triggered by vasospasm in response to severe increases in blood pressure, or fluid extravasation through white matter arterioles and capillaries caused by a pressure-driven hyperpermeable state. In either case, complete clinical and radiologic recovery often, but not always, occurs with prompt antihypertensive treatment or withdrawal of the immunosuppressive drug. Occasionally, the clinical features and CT or standard MRI findings may be indistinguishable from a bilateral posterior cerebral artery stroke syndrome. Thus, early recognition of PLES is essential.

Echo-planar diffusion-weighted imaging (DWI) is a relatively new technique by which images sensitive predominantly to the microscopic random motion (diffusion) of water molecules are obtained.^5-7 Diffusion of water molecules decreases as cytotoxic edema develops in the early phase of cerebral ischemia.^5,7-10 On diffusion-weighted images, which contain both diffusion and T2 components, this phenomenon appears as signal that is markedly hyperintense to the normal brain tissue. On apparent diffusion coefficient (ADC) maps, which display the diffusion component only, ischemic tissue is hypointense to normal brain tissue. In patients with acute stroke-like deficits, DWI helps differentiate between early ischemic tissue injury and clinically similar nonischemic conditions when routine MR images are normal.¹¹ Furthermore, vasogenic edema is characterized by a relative increase in the diffusion of water molecules^12,13 and appears hyperintense compared with normal brain on ADC maps; a variable, weak change in signal intensity can be seen on DWI. Consequently, current data suggest that ADC maps and DWI enable a differentiation between clinical conditions associated with vasogenic or cytotoxic edema (table). We describe three patients with the clinical syndrome of PLES who had only mild elevations in blood pressure. Serial imaging studies were obtained; these included CT, standard MRI, DWI, ADC maps, and in one instance, perfusion-weighted imaging. This report has important implications concerning the early diagnosis, pathophysiology, and reversibility of PLES.

Methods. MR imaging was performed on a 1.5-tesla whole-body scanner (GE Signa, Waukesha, WI) with echo-planar capabilities (Advanced NMR Systems, Wilmington, MA). Diffusion-weighted images and ADC maps were obtained as previously described in detail.¹⁴ We used single shot, echo-planar imaging with a repetition time (TR) of 6,000 msec, time to echo (TE) of 118 msec, field of view (FOV) of 40 × 20 cm, image matrix of 256 × 128, slice thickness 6 mm with a 1-mm gap, and 20 axial slices. The effective gradient strength was 14 mT/m, b-values were 1,221 sec/mm² and 47 sec/mm² with six gradient directions and three signal averages. Quantitative maps of isotropic ADC could be computed. These trace ADC maps could be viewed directly or after conversion to isotropic diffusion-weighted images, which improved lesion conspicuity. Other routine MR sequences included sagittal T1-weighted images with TR 650 msec, TE 16 msec, FOV 20 × 20 cm, acquisition matrix of 256 × 192 pixels, slice thickness of 5 mm with a 1-mm gap, and 1 signal average. Fast fluid-attenuated inversion recovery (fFLAIR) images were acquired with TR 10,002 msec, TE 141 msec, inversion time of 2,200 msec, FOV 24 cm, acquisition matrix of 256 × 192 pixels, slice thickness 5 mm with a 1-mm gap, and 1 signal average. Fast spin-echo T2-weighted images were acquired with TR 4,200 msec, TE 102 msec, FOV 20 cm, acquisition matrix of 256 × 256 pixels, slice thickness 5 mm with a 1-mm gap, and 1 signal average. Contrast-enhanced dynamic susceptibility perfusion imaging was performed according to standard methodology previously described.¹⁴ Parameters were TR 1,499 msec, TE 50 msec, flip angle 90°C, FOV 40 × 20 cm, image matrix of 256 × 128, and slice thickness 6 mm with a 1-mm gap. Head CT was performed on a GE Advantage helical scanner (Waukesha, WI) with 5-mm contiguous axial slices with 140 kVp and 340 mAs.

Case reports. Patient 1. A 66-year-old right-handed woman was operated on for an ovarian tumor 4 days before developing a mild bioccipital headache. She had a history of hypertension, and her postoperative blood pressure hovered in the 160-170/60-70 mm Hg range. Her perioperative course was notable only for a few brief episodes of hypotension lasting less than 5 minutes. She did well immediately postoperatively, remained afebrile, and received taxol 235 mg and carboplatin 470 mg. Her blood pressure increased to 180-190/90-100 mm Hg on the morning her headache started; she was treated with atenolol, but her blood pressure decreased only temporarily and increased again to 184/97 mm Hg in the late evening of the same day. Then she abruptly noted a visual blurring while reading a newspaper, which she described as being like "looking through a white cloud that was becoming thicker." The following morning, she awoke with only light perception; the headache had resolved completely. Neurologic examination was normal except for cortical blindness. Blood tests were notable only for hyponatremia, with serum sodium of 123 mmol/L (normal 135 to 145) and elevated white cell count of 12.2 × 10³/mm³. Her serum sodium had decreased from 138 to 131 mmol/L after the surgery. A noncontrast-enhanced CT obtained that day showed bilateral occipital hypodense regions involving the white matter with some involvement of the overlying gray matter (figure 1A). A diagnosis was made of bilateral posterior cerebral artery territory infarctions, possibly caused by "top of the basilar embolus." Brain MRI 2 days after onset of blindness showed T2 and fFLAIR hyperintensity (figure 1, B and C) in the regions demonstrating hypodensity on CT. These regions appeared slightly hyperintense to gray and white matter on diffusion-weighted images (figure 1D). ADC maps demonstrated hyperintensity, consistent with vasogenic edema, in these regions (figure 1E). She responded well to additional atenolol treatment; blood pressure returned to normal. Her visual field examination was normal the next morning, with visual acuity of 20/25 bilaterally. A follow-up MRI on day 4 showed nearly complete interval resolution of the lesions (figure 1F).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1. Patient 1. (A) Noncontrast-enhanced axial CT demonstrates hypodensity in the posterior temporal and parietal lobes bilaterally. (B) Axial T2-weighted and (C) axial fast fluid-attenuated inversion recovery (fFLAIR) weighted MR images, obtained 2 days later, demonstrate hyperintensity in the posterior parietal and occipital lobe white matter with some involvement of the overlying cortex. (D) Diffusion-weighted MR image demonstrates these regions to have signal slightly hyperintense to normal gray and white matter. (E) Apparent diffusion coefficient MR image demonstrates these regions to have signal subtly hyperintense to normal gray and white matter, consistent with increased diffusion and vasogenic edema. No definite areas of decreased diffusion to suggest infarction are identified. (F) fFLAIR MR image obtained 2 days later demonstrates nearly complete interval resolution of the previously seen hyperintense abnormalities, consistent with reversible vasogenic edema.

Patient 2. A 33-year-old left-handed woman was admitted for pneumococcal pneumonia, sepsis, and acute respiratory distress syndrome that developed on her sixth postpartum day after a normal spontaneous vaginal delivery. She was placed on extracorporeal mechanical oxygenation for 7 days for severe hypoxemia. She improved progressively without any serious complications. Her blood pressures did not exceed 150/80 mm Hg. On the 26th hospital day she became agitated and had a fever of 40 °C. Her blood pressure remained high for the next 2 days, between 170-190/80-100 mm Hg. The morning after the onset of hypertension and fever she experienced complex partial seizures lasting 10 minutes and was treated with Dilantin. EEG showed posterior periodic lateralizing epileptiform discharges over the left hemisphere. On neurologic examination she was lethargic; quadriparetic, weaker on the left; and cortically blind. Serum sodium was 137 mmol/L. Urinalysis was notable for 3+ albumin with hyalin and tubular casts. Blood leukocytes were elevated to 21 × 10³/mm³. Urine culture demonstrated vancomycin-resistant enterococcus. She was started on IV dexamethasone, mannitol, chloramphenicol, and magnesium. Blood chemistry and other CSF and blood tests for CNS infectious disease, collagen tissue disease, and demyelinating disease, as well as MR venography for venous sinus thrombosis were all normal. An urgent head CT showed extensive regions of low attenuation with sulcal effacement involving the subcortical white matter, with some involvement of the overlying cortex in all lobes, predominantly in the posterior temporal, occipital, and parietal lobes (figure 2, A and F). The diagnosis of bilateral posterior watershed infarcts was made. Her blood pressure subsequently decreased to 150/80 mm Hg with labetalol treatment. Later the same day, a first MRI demonstrated hyperintensity on fFLAIR weighted sequences (not shown for economy of space, but identical to figure 2, B and G); this hyperintensity corresponded to the region hypodense on CT (figure 2, A and F). The second MRI was obtained 3 days later, when, except for mild left hemiparesis, her neurologic examination was otherwise normal. fFLAIR images were unchanged (figure 2, B and G). On DWI, the same regions were mostly characterized by signal hypo- or isointense to normal gray and white matter (figure 2, C and H) and by increased signal on ADC maps, consistent with vasogenic edema. However, in both scans small areas of cortex were hyperintense on DWI, consistent with patchy regions of cytotoxic edema (figure 2, C and H). Relative cerebral blood flow maps demonstrated decreased signal intensity in the cortex characterized by hyperintensity on the DW images (figure 2, D and I). The posterior white matter abnormality improved substantially on a third MRI a week later (not shown). The patient returned to independent function but had palinopsia, visual misperception, and intermittent visual displays suggestive of persistent visual-system abnormalities. Repeat MRI 6 months later showed complete resolution of the white matter abnormality but T2 hyperintensity and tissue loss in the regions initially hyperintense on DWI (figure 2, E and J).

• Download figure
• Open in new tab
• Download powerpoint

Figure 2. Patient 2. (A and F) Noncontrast-enhanced axial CT images demonstrate hypodensity in the posterior temporal and occipital lobes bilaterally as well as in the frontal and parietal lobes. The hypodensity predominantly involves white matter, but there is some involvement of the overlying cortex. (B and G) Fast fluid-attenuated inversion recovery (fFLAIR) weighted MR images obtained 4 days later demonstrate hyperintensity in similar regions. (C and H) Diffusion-weighted (DW) images at similar levels demonstrate hypodensity and isointensity, consistent with vasogenic edema, in the affected white matter. There is hyperintensity, consistent with cytotoxic edema, in some affected cortex. (D and I) Relative cerebral blood flow maps demonstrate decreased signal intensity, consistent with decreased flow, in the cortex, which is hyperintense on DW images. (E and J) fFLAIR weighted images obtained 9 days later demonstrate persistent hyperintensity in the cortex, which was hyperintense on DW images; this is consistent with infarcted tissue. The T2 hyperintensities characterized by increased diffusion (relatively decreased signal) on the earlier images have completely resolved.

Patient 3. A 54-year-old right-handed woman presented to the hospital with nausea and vomiting, fever, and bloody diarrhea with abdominal cramping 13 days before admission. She had a history of hypertension, coronary heart disease, resected cervical carcinoma, and hypothyroidism. Admission diagnoses included acute renal failure, liver failure, and subendocardial myocardial infarction, and she was treated with IV fluids, dopamine, ceftriaxone, gentamycin, and metronidazole. Colonoscopy revealed ischemic colitis, and she underwent immediate colectomy. Except for the fever, which persisted and the origin of which could not be found, her metabolic abnormalities stabilized after surgery. Her blood pressure was approximately 110-140/50-60 mm Hg during this period. On the 35th hospital day, her blood pressure was 151/76 mm Hg, and she became less conversant and more somnolent. Head CT on the same day was normal. The blood pressure oscillated around 140-170/60-80 mm Hg starting from a day before the onset of confusion and lasted for 2 days. It then increased to 200/85 mm Hg and, hours later, she experienced generalized tonic-clonic seizures lasting 30 minutes that were terminated with IV Valium and Dilantin. A subsequent EEG showed diffuse theta and delta showing but no epileptiform activity. On examination she was stuporous, performed only one-step commands, and had cortical blindness and right hemiparesis. An urgent CT showed left frontal as well as bilateral parietal and occipital hypodensities involving predominantly the white matter with some involvement of overlying cortex (figure 3A). A diagnosis of bilateral posterior cerebral-middle cerebral artery and left anterior cerebral-middle cerebral artery watershed infarctions was made. Her leukocyte count was 19.1 × 10³/mm³. Blood chemistries were normal except for a new increase in liver enzymes. Urinalysis was remarkable for 2+ proteinuria. She was started on IV dexamethasone. Her blood pressure decreased spontaneously to 160/60 mm Hg in a couple of hours after the seizures. One day later there was no change on clinical examination, and T2-weighted MR images demonstrated hyperintensity in the regions characterized by hypodensity on CT (figure 3B). These regions were characterized by signal isointense to hypointense to normal gray and white matter on DWI (figure 3C) and hyperintense on ADC maps (figure 3D), a vasogenic pattern. CSF and blood tests for infectious, autoimmune, and demyelinating diseases were normal. Over the following week she progressively improved to the level that she was visually tracking objects and recognizing her relatives, counting fingers, and moving all four extremities, albeit less on the right arm. Another MRI at this time revealed partial interval resolution of the lesions on fFLAIR (figure 3E), T2 (figure 3F), and DWI (figure 3G). The day after this MRI her blood pressure increased to 191/87 mm Hg from her baseline of 140-170/60-70 mm Hg, and she again became less responsive. Notwithstanding IV nitroprusside, her blood pressure increased intermittently to 220/91 mm Hg. Over the following 3 days she grew progressively more stuporous and became unresponsive to painful stimuli. MRI at this time showed new development of extensive, confluent fFLAIR (figure 3H), T2 (figure 3I), and DWI (figure 3J) hyperintense signal abnormality that was now hypointense on ADC maps (figure 3K) throughout the occipital, posterior temporal, and posterior parietal cortex, as well as subcortical white matter; this was consistent with cytotoxic edema. The patient died 3 days later; the family declined permission for autopsy.

• Download figure
• Open in new tab
• Download powerpoint

Figure 3. Patient 3. (A) Noncontrast-enhanced axial CT demonstrates hypodensity in the occipital lobes bilaterally. (B) Axial T2-weighted MR image, obtained one day later, demonstrates hyperintensity in the occipital lobe white matter bilaterally with some involvement of the overlying cortex. (C) Axial diffusion-weighted (DW) image demonstrates hypointensity and (D) axial apparent diffusion coefficient (ADC) map demonstrates hyperintensity in these regions; these findings are consistent with vasogenic edema. (E) Axial fast fluid-attenuated inversion recovery (fFLAIR) weighted, (F) axial T2-weighted, and (G) axial DW images obtained 9 days later demonstrate partial resolution of the previously seen abnormalities. (H) Axial fFLAIR and (I) axial T2-weighted images obtained 2 weeks later demonstrate an increase in the hyperintensities with extension to involve the posterior temporal lobes and most of the adjacent cortex. (J) Axial DW images demonstrate homogeneous hyperintensity and (K) axial ADC map demonstrates homogeneous hypointensity; these findings are consistent with decreased diffusion and cytotoxic edema.

Discussion. PLES is an acute, progressive neurologic syndrome associated with predominantly white matter edema in the posterior parietal-temporal and occipital brain regions. It is most commonly attributed to severe blood pressure elevations,¹ usually above limits customarily defining malignant hypertension (diastolic pressure >130 mm Hg). T2-weighted MR images at the height of symptoms show diffuse hyperintensity selectively in the parieto-occipital white matter, basal ganglia, brainstem, and cerebellum^4,15-17; these lesions likely represent extracellular edema, may produce mass effect on surrounding structures, and are usually asymmetric. PLES is not restricted to white matter tracts, occasionally also involving parieto-occipital gray matter.¹⁶ Prompt initiation of antihypertensive treatment or discontinuation of immunosuppressive drugs, if being used, can lead to complete clinical recovery with reversal of MRI lesions in some cases.^2,15,18,19 However, if untreated, permanent neurologic deficit, or even death, may occur as a result of the ensuing cerebral infarctions or hemorrhages.¹⁶

The clinical findings in PLES are not sufficiently specific to readily establish the diagnosis and may be seen in various neurologic conditions, including stroke, cerebral venous sinus thrombosis, demyelinating disorders, or encephalitis.²⁰ In cases with sudden onset of neurologic deficits, whether or not symptoms are progressive, clinical presentation may be indistinguishable from simultaneous bilateral posterior cerebral artery territory infarction, usually caused by top of the basilar embolism. Furthermore, clinical presentations characterized by decreased alertness and coexisting brainstem symptoms strongly suggest the possibility of an impending basilar artery thrombosis. Neither conventional CT nor routine MRI reliably differentiate ischemic processes (such as bilateral occipital and parietal infarctions or border zone infarctions) from reversible white matter edema. In the case of ischemic stroke, most guidelines recommend that mild to moderate hypertension should not be treated.²¹ In contrast, the treatment of hypertension in patients with PLES may be necessary to reverse the edematous process before it progresses to cause permanent brain injury (Patients 2 and 3).

Echo-planar DWI is sensitive to the molecular diffusion of water. Water diffusion decreases in cytotoxic edema.^5,7-10 In acute ischemia, depletion of high-energy phosphates leads to cessation of Na⁺-K⁺ ATPase activity; water becomes trapped intracellularly, its motion restricted. The decreased water diffusion is characterized by marked hyperintensity on DWI and hypointensity on ADC maps. Conversely, regions with vasogenic edema have markedly increased ADCs compared with normal tissue^12,13 and are visualized as hypo- or isointense signal on DWI.

Notwithstanding symptoms suggestive of posterior circulation or watershed infarctions and "confirmatory" early changes on CT and T2-weighted images, the extensive lesions in our three patients were predominantly characterized by hypo- to isointense DWI signal, suggestive of increased water diffusion, i.e., extracellular edema. ADC maps of the large regions of T2 abnormality were hyperintense, not hypointense, as in ischemic lesions. Likewise, Schaefer et al.²² recently reported an eclamptic patient with extensive T2 hyperintensities whose DWI demonstrated increased diffusion.

In considering these techniques for use in ischemic stroke, diffusion imaging is not entirely specific because cytosolic edema can occur from causes other than ischemia. Decreased ADC values have been described in status epilepticus in humans and animals as well as in spreading depression in animals^23-26; in both of these nonischemic conditions there is movement of ions and water into neural tissue, i.e., cytosolic edema. In addition, we have observed decreased ADC values in some regions of intracerebral hemorrhage or abscess. In the earliest stages, diffusion imaging may be normal (with normal T2) in occasional patients with symptomatic brain ischemia.²⁷ In the diagnosis of hyperacute stroke, coupling DWI with perfusion imaging increases the sensitivity and specificity of MRI.¹⁴ An increase in T2 signal caused by increased water within regions of vasogenic edema can also cause slight DWI hyperintensity, so-called T2 shine-through. However, ADC maps, which lack the T2 component, show normal or elevated signal intensity in vasogenic edema, in contrast to the decreased signal intensity in acute ischemic lesions.

There are two proposed hypotheses regarding the pathophysiology of the cerebral lesions in PLES associated with severe hypertension. The first suggests that vasospasm in response to sudden and severe increases in systemic blood pressure causes ischemia, first with cytotoxic then with extracellular edema. Animal experiments have demonstrated sausage-like arteriolar vasoconstriction in response to induced hypertension,²⁸ and human angiographic studies reported vasospasm during hypertensive crises.^29,30 However, against the vasospasm/ischemia hypothesis is the reversibility of the radiologic lesions with abrupt treatment. Moreover, ischemic edema associated with vasospasm is usually seen in the context of clear infarctions. In addition, increased perfusion was noted in one symptomatic patient examined with ^99mTc-HMPAO SPECT by Schwartz et al.¹⁵

The second proposed mechanism suggests loss of autoregulation, resulting in dilatation of cerebral arterioles and disruption of the blood-brain barrier (BBB).^31-34 In animals, arteriolar resistance increases proportionately as blood pressure rises until a threshold is reached at which autoregulation fails segmentally, and the mechanical effect of elevated pressure causes passive vasodilation and extravasation.^34-36 Tamaki et al.³⁷ measured regional cerebral blood flow (rCBF) and permeability of the BBB in stroke-prone, spontaneously hypertensive rats when the animals developed signs of encephalopathy. In regions with increased permeability, rCBF was initially either normal or increased. Our data are consistent with this proposed mechanism of PLES, occurrence of extracellular edema (increased T2 and ADC) not associated with ischemic changes.

Though initially termed "reversible posterior leukoencephalopathy," the process in some cases is not reversible.³⁸ In ischemic stroke patients, irreversible brain injury is characterized by increased DWI signal and decreased ADC. This pattern was not seen at all in Patient 1, it developed in small posterior cortical regions surrounding the massive edema in Patient 2, and was not seen initially, but then appeared on the subsequent study before death in Patient 3. In the study of Tamaki et al.,³⁷ concomitant with the development of marked vasogenic edema, CBF fell to levels producing infarction in the regions surrounding the edema. In Patient 2, CBF was decreased on perfusion imaging in regions with the cytotoxic pattern on DWI. These appeared permanently injured on follow-up MRI. Although the relative contributions of ischemia and persistent seizure activity to the DWI abnormality cannot be ascertained, our data are consistent with those of the animal studies of Tamaki et al. in which the microcirculation in edematous regions was impaired by elevated tissue pressure.

The preferential distribution of white matter lesions in posterior brain regions is not well understood. Topographic variation in the cerebrovascular sympathetic innervation may be important.³⁹ The blood vessels of the pia are supplied by sympathetic nerves from the superior cervical sympathetic ganglion. The density of sympathetic innervation is maximal in the internal carotid and anterior cerebral territories.^39,40 It decreases posteriorly and is the least in the basilar artery and its branches. Importantly, the superficial vessels over the cortical surface respond to changes in blood pressure and function as a pressure equalization reservoir.^39,41 Conversely, the penetrating vessels (medullary arteries), which arise from the superficial arteries, supply deep gray and white matter and receive scarce adrenergic innervation.⁴² Local metabolic products such as lactic acid and carbon dioxide affect the size and permeability of these perforating arteries.

Sympathetic mediated vasoconstriction may be more effective in protecting the perforating small arterioles in the anterior circulation from overperfusion in acute hypertension.^43-46 In cats with induced hypertension, sectioning the superior cervical chain led to greater extravasation of Evans blue in the ipsilateral hemisphere, especially in the marginal and suprasylvian gyri.⁴² Because of this anterior to posterior gradient of sympathetic innervation, in PLES a hyperperfusion state in perforating white matter arterioles might occur with a posterior to anterior gradient of edema.

Although hypertensive encephalopathy is the most common cause of PLES, there are a number of cases that occurred in the absence of severe hypertension. Only one of the 15 patients reported by Hinchey et al.² had diastolic blood pressure greater than 130 mm Hg. In all of our patients, neurologic deterioration was preceded by a recent, in-hospital elevation of blood pressure; however, they never reached levels considered to be malignant. All our patients had severe metabolic abnormalities (such as ischemic bowel disease, sepsis, leukocytosis, hyponatremia, urinary protein loss, and fever). One was taking steroids, and another received a dose of taxol/carboplatin. We raise the question whether severe infectious and metabolic abnormalities in our patients disturbed the integrity of the distal brain vasculature or interfered with the sympathetic tonus, leading to edema formation with otherwise tolerable increases of systemic blood pressure.

Postoperative hyponatremia occurred in one of our patients. A postsurgical syndrome of fatal cerebral edema in hyponatremic women has been recently described.⁴⁷ Ayus and Arieff⁴⁸ suggest that females have a greater propensity to develop cerebral edema with comparable hyponatremia than do males. All our patients were women. Likewise, 13 of 15 patients reported by Hinchey et al.² were women. However, the question of whether female sex is a greater risk factor for developing PLES remains to be solved by larger, controlled studies.

Our findings implicate four important clinical and pathophysiologic points in PLES. First, DWI and ADC maps distinguish between potentially reversible PLES and clinically similar ischemic conditions. Quick and accurate diagnosis of PLES allows the clinician to initiate the most appropriate treatment at an early time point. Second, PLES shows a specific MRI pattern, i.e., widespread lesions predominantly involving the posterior white matter, with some involvement of the overlying cortex, that are hyperintense on T2-weighted images, mostly hypo- or isointense on DWI, and hyperintense on ADC maps. Currently available data suggest that this pattern specifies vasogenic edema as opposed to the cytotoxic edema pattern commonly seen in acute ischemic stroke. Third, superimposed upon the pattern of vasogenic edema, DWI hyperintense regions with decreased ADC can occur, indicating irreversible injury. Fourth, severe hypertension is not mandatory for PLES to develop, either radiologically or clinically. Although elevation relative to baseline is the rule, PLES may develop at much lower blood pressure levels than are customarily considered malignant, especially in female patients with metabolic abnormalities or hyponatremia. However, radiologic-pathologic correlations are still needed in PLES to verify the status of small vessels, to define the extent of edema, and to characterize the tissue injury. Further physiologic studies of the interactions between metabolic abnormalities, the integrity of the BBB, and the vascular hemodynamics will be required to better understand the dramatic clinical and radiologic features of PLES.