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Original Research |
1 Department of Radiology and Neuroradiology, University of Minnesota Medical
Center, Minneapolis, MN.
2 Department of Radiology, Hennepin County Medical Center, 701 Park Ave. S,
Minneapolis, MN 55415.
Received February 7, 2007;
revised May 18, 2007;
Address correspondence to A. M. McKinney
(mckinrad{at}umn.edu).
Abstract
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MATERIALS AND METHODS. Seventy-six patients were eventually included as having confirmed PRES from 111 initially suspected cases, per imaging and clinical follow-up. Two neuroradiologists retrospectively reviewed each MR image. Standard sequences were unenhanced FLAIR and T1- and T2-weighted images in all patients, with diffusion-weighted imaging (n = 75) and contrast-enhanced T1-weighted imaging (n = 69) in most. The regions involved were recorded on the basis of FLAIR findings, and the presence of atypical imaging findings (contrast enhancement, restricted diffusion, hemorrhage) was correlated with the severity (extent) of hyperintensity or mass effect on FLAIR.
RESULTS. The incidence of regions of involvement was parietooccipital, 98.7%; posterior frontal, 78.9%; temporal, 68.4%; thalamus, 30.3%; cerebellum, 34.2%; brainstem, 18.4%; and basal ganglia, 11.8%. The incidence of less common manifestations was enhancement, 37.7%; restricted diffusion, 17.3%; hemorrhage, 17.1%; and a newly described unilateral variant, 2.6%. Poor correlation was found between edema severity and enhancement (r = 0.072), restricted diffusion (r = 0.271), hemorrhage (r = 0.267), blood pressure (systolic, r = 0.13; diastolic, r = 0.02). Potentially new PRES causes included contrast-related anaphylaxis and alcohol withdrawal.
CONCLUSION. This large series of PRES cases shows that atypical distributions and imaging manifestations of PRES have a higher incidence than commonly perceived, and atypical manifestations do not correlate well with the edema severity.
Keywords: CNS • contrast enhancement • diffusion • hemorrhage • MRI • posterior reversible encephalopathy syndrome
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The typical imaging findings of PRES are most apparent as hyperintensity on FLAIR images in the parietooccipital and posterior frontal cortical and subcortical white matter; less commonly, the brainstem, basal ganglia, and cerebellum are involved [7, 8, 16–18]. Atypical imaging appearances include contrast enhancement, hemorrhage, and restricted diffusion on MRI [1–6, 9, 19–27].
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Technique
The MRI examinations were performed on multiple units over a number of
years; hence, the imaging sequence parameters varied over time. However, the
standard protocol included unenhanced axial FLAIR, T1-weighted, and
T2-weighted images in all 76 cases eventually confirmed as PRES, with
diffusion-weighted imaging (DWI) (n = 75) and gadolinium-enhanced
T1-weighted imaging (n = 69) in most. Typically, between 10 and 15 mL
of IV gadolinium-based contrast material was administered for the
contrast-enhanced examinations. When available, CT and gradient-echo MR images
were also reviewed. Sixty of the 76 patients underwent repeat imaging.
Inclusion Criteria
Two staff neuroradiologists jointly and retrospectively reviewed the 111
cases, determining via consensus which cases were truly consistent with PRES
and eventually confirming 76 cases as PRES. Inclusion as a confirmed case of
PRES was based primarily on regression of the findings of suspected PRES on
subsequent imaging, when available (n = 60), or on clinical symptom
resolution (when repeat imaging was unavailable) via extensive chart reviews
(n = 16). Specifically, criteria for inclusion consisted of one of
the following: First, initial MRI showed cortical or subcortical FLAIR and
T2-weighted hyperintensity with posterior predominance that resolved or
significantly improved on follow-up MRI or CT. Second, initial MRI showed
cortical or subcortical FLAIR or T2-weighted hyperintensity with posterior
predominance in a parietooccipital distribution typical of PRES but lacking
repeat imaging; these cases without repeat imaging were considered to be
confirmed PRES only if the patient had a complete return to baseline
neurologic status. In addition, it was mandatory for inclusion that such
patients had received a medication or experienced a condition known to cause
PRES that was treated or removed before complete symptom resolution and that
the clinician concurred that the symptoms were related to PRES (such agents
and conditions are listed in the introduction)
[1–9].
Third, initial MRI showed T2-weighted or FLAIR hyperintensity in the
brainstem, basal ganglia, or subcortical or cortical frontal regions without
posterior predominance (atypical distribution), and the imaging findings
resolved or significantly improved on follow-up MRI in the setting of a cause
previously attributed to PRES.
Cases lacking both clinical and imaging followup were excluded. Parietooccipital involvement was not an inclusion criterion because the intent was to detect atypical PRES.
Classification of Edema Severity Based on FLAIR Imaging
In light of previous studies indicating that potentially severe cases
involve the brainstem or basal ganglia, or have confluent vasogenic edema with
mass effect [6,
7], the reviewers classified
the eventually confirmed 76 PRES cases as either mild, moderate, or severe on
the basis of the extent of hyperintensity on FLAIR imaging and the presence of
mass effect.
Mild—Mild PRES (Fig. 1A, 1B, 1C) was defined as cortical or subcortical white matter edema without parenchymal hemorrhage, mass effect, herniation, or minimal involvement of only one of group of cerebellum, brainstem, or basal ganglia.
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Severe—Severe PRES (Fig. 3A, 3B, 3C) was defined as confluent edema extending from the cortex to the ventricle, or edema or hemorrhage causing midline shift or herniation. Alternatively, involvement of all three of the group of cerebellum, brainstem, and basal ganglia was considered severe.
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Clinical Correlation of Cause, Follow-Up, and Blood Pressure Measurements
In all 76 patients, the presenting symptom, PRES cause, and other agents
potentially causing PRES were recorded. However, 16 of these patients lacked
repeat imaging but were included on the basis of clinical and imaging findings
typical of PRES, with symptom resolution after therapy. Patients without known
causes were included only if their repeat imaging was consistent with PRES.
Average and maximum systolic and diastolic blood pressures on the day of the
MRI were recorded.
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The remaining, confirmed 76 PRES patients (40 female, 36 male) ranged from 5 to 80 years old (mean, 33.5 years). Sixty of the 76 were confirmed as having PRES on the basis of marked improvement or resolution on repeat imaging. The remaining 16 were confirmed clinically by an extensive chart review; in these, the mean time to symptom resolution based on clinical examination was 10.2 days after MRI. Seventy-three of the 76 were associated with known offending causes (Table 1), most commonly cyclosporine (n = 34), hypertension (n = 17), or eclampsia (n = 5). Regarding the other three, in one the only known medication was steroids, in another acute alcohol withdrawal occurred with no known medications, and in the third anaphylaxis occurred from iodinated contrast material; these three cases all had bilateral parietooccipital involvement on FLAIR and near-resolution of the hyperintensity on follow-up imaging without atrophy, which is typical of PRES. Regarding the edema extent and severity based on FLAIR, 32 (42.1%) were classified as mild, 27 (35.5%) as moderate, and 17 (22.3%) as severe (Figs. 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B, 3C). The most common presenting symptoms are also listed in Table 1.
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The regions of brain most commonly involved (Fig. 4) were the parietooccipital (n = 75, 98.7%), frontal (n = 60, 78.9%), and temporal (n = 52, 68.4%). Less common areas of involvement included the cerebellum (n = 26, 34.2%), thalamus (n = 23, 30.3%), brainstem (n = 14, 18.4%), and basal ganglia (lentiform or caudate, n = 9, 11.8%). No cases involved only the orbitofrontal region. Cortical or subcortical white matter edema sparing the deep white matter was present in 54 patients (71.0%), with both cortical and subcortical white matter and deep white matter edema in 22 (29.0%). Only one patient (cocaine usage with severe hypertension) lacked parietooccipital edema, but this patient had severe brainstem, thalamic, and deep white matter edema; this patient dramatically improved and symptoms nearly resolved after undergoing antihypertensive therapy. We considered this a central variant, not an ischemic manifestation of cocaine usage, because no DWI abnormalities were noted on the initial MRI, and the findings nearly resolved on repeat MRI. Another patient with malignant hypertension and predominately brainstem and thalamic involvement occurred but had minimal parietooccipital involvement outside of the brainstem, and hence was counted with the other 75 patients with parietooccipital edema. Also, two tumefactive cases were completely unilateral and simulated neoplasm (Fig. 5A, 5B), with no enhancement; in both, discontinuation of cyclosporine resulted in dramatic imaging and neurologic improvement.
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In the 75 patients with PRES on DWI, most (n = 41) had edema
isointense to normal-appearing parenchyma on DWI. Twenty-one (28.0%) showed
"T2 shine-through" hyperintensity on FLAIR and DWI. Thirteen
(17.3%) had restricted diffusion consisting of small, patchy, or punctate
areas much less extensive than the surrounding vasogenic edema. Two of the 13
had mild cortical gyral restriction, with a 10–20% ADC decrease relative
to normal areas (Fig. 2A,
2B,
2C); on follow-up imaging,
those regions lacked restricted diffusion, the edema resolved, and there was
minimal focal atrophy much smaller in size than the initial area of decreased
ADC. Only a weak correlation was present between the presence of restricted
diffusion and the FLAIR severity (r = 0.271, 
2 =
5.443, p = 0.32). Of note, restricted diffusion from PRES was
differentiated from HIE because the DWI abnormalities of HIE were more
extensive than on FLAIR (the reverse was true with PRES), cortical contrast
enhancement in HIE (when present) simulating enhancing PRES did not resolve on
repeat MRI, and there were generally poor, irreversible neurologic outcomes
with HIE. Also, the restricted diffusion in PRES was either punctate or
focally gyriform, without the multifocality of HIE.
Regarding hemorrhagic PRES, there were 13 cases (17.1%): five with
parenchymal hemorrhage and 10 with subarachnoid hemorrhage; two had both
parenchymal hemorrhage and subarachnoid hemorrhage. Of the eight cases of
subarachnoid hemorrhage (without parenchymal hemorrhage) that were initially
called subarachnoid hemorrhage on the basis of sulcal hyperintensity on FLAIR,
three were confirmed as hemorrhage on CT, T1-weighted imaging, or
gradient-echo MRI (Fig. 6A,
6B,
6C,
6D,
6E,
6F). A weak correlation
existed between the presence of hemorrhage and the edema extent or severity on
FLAIR imaging (r = 0.267, 2 = 5.415, p =
0.33).
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2 = 0.356, p
=0.99). Notably, four PRES patients had known leukodystrophies, two with metachromatic leukodystrophy and two with adrenoleukodystrophy. All four received cyclosporine after bone marrow transplantation. The cortical and subcortical white matter edema was readily discernible from the underlying deep white matter inflammation (Fig. 7A, 7B).
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Regarding blood pressure values, the maximum and average systolic and diastolic blood pressure values on the day of MRI were generally less elevated in cyclosporine-related PRES than in hypertensive or eclamptic PRES (Table 2). Two of the 34 cyclosporine-related cases had a maximum systolic blood pressure of less than 140 mm Hg and a maximum diastolic blood pressure of less than 85 mm Hg on the day of the MRI. No significant or weak correlation was noted between the edema severity and the maximum systolic (r = 0.13, p = 0.27) or diastolic (r = 0.02, p = 0.89) blood pressure on the day of MRI. In addition, considering together only the hypertensive or eclamptic patients (n = 22), only weak correlation was noted between the severity of edema and the systolic (r = 0.02, p = 0.94) or diastolic (r = 0.35, p = 0.14) blood pressure.
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PRES is not an entirely posterior phenomenon, but rather appears in a gradient-like fashion from posterior to anterior, presumably reflecting the gradient of sympathetic innervation [27, 30–32]. Accordingly, frontal lobe involvement was present in most of our cases (79%), usually in the posterior portion of the superior frontal gyrus (anterior cerebral artery distribution) and the precentral gyrus (middle cerebral); the lentiform or caudate nuclei were involved in 11.8%, usually being supplied by anterior circulation lenticulostriate branches [33]. This distribution confirms that the "posterior" in "posterior reversible encephalopathy syndrome" is a misnomer because most cases involve anterior circulation structures. However, a posterior predominance is certainly seen in each lobe; for example, the orbitofrontal region was spared in all but the most severe cases. Hence, "multifocal," "posterior dominant," or simply "reversible encephalopathy syndrome" may better apply to this reversible syndrome.
We note that central PRES, with brainstem or basal ganglia involvement sparing the parietooccipital region, is rare but certainly occurs, consistent with the low incidence noted in previous case reports; correlation should be made with the blood pressure because these patients usually have extreme hypertension [16–18]. Five such cases were suspected at the outset of this study; one was confirmed as PRES by rapid improvement after antihypertensive therapy, whereas the other four were related to central or extrapontine myelinolysis. A similar-appearing case of PRES in this study had brainstem involvement but was not deemed a central variant because of the minimal presence of parietooccipital edema. Hence, radiologists should be aware that PRES may occasionally present with minimal or no detectable parietooccipital edema. In such cases, it is necessary to exclude other causes of acute brainstem or basal ganglia edema, such as myelinolysis or encephalomyelitis, using a combination of clinical history and follow-up imaging, when necessary.
Two cases of completely unilateral involvement occurred (2.6%), which to our knowledge has not been previously described. The MRI differential diagnosis included neoplasm, encephalitis, and inflammatory or infectious leukoencephalopathy; these entities differ in treatment, may have mass effect, and can undergo biopsy. Hence, we term this variant "tumefacient," because the severe edema, mass effect, and symptoms dramatically improved with cyclosporine cessation.
Another goal was to evaluate how often hemorrhage occurred in PRES, having previously been described in PRES from various causes [3, 4, 20, 26]. The mechanism of hemorrhage is presumed to arise from the phenomenon of breakthrough perfusion, in which the maximally constricted end arterioles cannot further respond to hyperperfusion; this failed autoregulation leads to macromolecule extravasation and possibly hemorrhage into the cortex or subarachnoid space [13]. This occurred in 17.1% of the patients (n = 13), with a weak correlation noted between the presence of hemorrhage and the extent or severity of edema on FLAIR imaging. The most common type was subarachnoid hemorrhage (13.2%); less commonly, parenchymal hemorrhage was noted (6.6%). However, one could criticize the use of FLAIR to detect subarachnoid hemorrhage because nonhemorrhagic exudates may create sulcal hyperintensity [34]. This methodology was used because FLAIR was routinely available in this retrospective study.
Regarding this potential criticism, eight (10.5%) of the 13 cases had confirmatory findings of either subarachnoid hemorrhage or parenchymal hemorrhage on CT, T1-weighted imaging, or gradient-echo MRI, regardless of the FLAIR findings. Hence, the hemorrhage frequency is likely between 10.5% and 17.1%, and FLAIR may be suitable to screen for subarachnoid hemorrhage in PRES because it is a routine MRI sequence in PRES evaluation. Also, in patients with subarachnoid hemorrhage who do not have parenchymal hemorrhage, the apparent subarachnoid hemorrhage on FLAIR resolved on repeat imaging as the edema waned. Hence, foci of high sulcal signal on FLAIR (when parenchymal hemorrhage is not present) may ultimately be of little consequence because this finding correlated poorly with extent or severity of edema on FLAIR imaging and usually resolved after removal or treatment of the offending agent.
On DWI, the most common appearances in this study were isointensity (54.7%) and DWI bright T2 shine-through (28%), as shown previously [19–22]. Diffusion restriction occurred in a minority (17.3%) of patients; it was usually punctate and surrounded by much larger areas of edema with no ensuing atrophy. The presence of this finding correlated poorly with the FLAIR extent or severity. However, two patients (2.7%) did have a focal gyral configuration of restriction, with mild ensuing atrophy and residual neurologic deficit. In this regard, significant debate has developed in recent literature regarding the various DWI phenomena of PRES. Although lesions are typically isointense related to T2 washout (a balance of T2 effects and increased water diffusibility), T2 shine-through can arise from T2 prolongation being the dominant contributor to signal intensity, noted as ADC and b = 0 DWI hyperintensity greater than the trace DWI. Hypointense lesions may also occur from further increased diffusibility [19, 22].
A conundrum arises in the setting of DWI hyperintensity and "pseudonormal" ADC from intravoxel averaging of focal cytotoxic edema in larger areas of vasogenic edema; these lesions can progress to infarction [6, 23–25]. Several theories address this cytotoxic effect. First, hyperperfusion may cause severe mass effect from vasogenic edema compressing the local microcirculation, with pseudonormal or slightly elevated ADC values surrounded by larger areas of vasogenic edema [6, 12, 23–25]. Second, vasoconstriction may be a response to the edema, eventually causing cytotoxicity if not reversed; accordingly, narrowed intracranial arteries have been noted in hypertensive human and animal models [14, 25, 35–37]. Third, spasm could occur in response to the subarachnoid hemorrhage that uncommonly occurs in PRES. Also, aggressive correction of hypertension may induce ischemia [38]. On the basis of this study, tiny or punctate restricted diffusion foci appear to be unlikely to lead to atrophy, but a larger (> 3 mm), gyral pattern may lead to irreversible insult. Notably, even gyral restricted diffusion partially reversed; repeat MRI in such cases excludes alternative insults such as HIE.
The incidence of contrast enhancement in PRES has not been previously well described in a large series; contrast use is only briefly mentioned in large studies of PRES [1, 4, 7, 19–20, 24]. Regarding enhancement, a gyriform pattern has been described [2, 20, 26, 27]. We found a higher frequency (37.7%) than expected from the literature [4, 20, 39]; the exception is a study noting enhancement in 33% of patients [6]. These discrepancies may relate to various factors, including contrast bolus timing, amount, and type, and may also be caused by lack of contrast use in many studies, possibly because contrast-enhanced imaging is not necessary to diagnose PRES. In addition, the degree of enhancement could relate to the cause; transplantation drugs such as cyclosporine can cause direct endothelial injury and subsequent blood–brain barrier breakdown, potentially differing in pathophysiology from classic hyperperfusion syndromes such as hypertension or eclampsia [40–43].
The lack of elevated blood pressure in several patients in our series supports the possibility that enhancement in the nonhypertensive cases may result from direct endothelial injury causing blood–brain barrier breakdown. In hypertensive cases, the elevated hydrostatic pressure could cause capillary endothelial injury, hyperpermeability, and ultimately enhancement or hemorrhage from blood–brain barrier breakdown, particularly if combined with venous congestion or constriction [4, 44–47]. We found no correlation between the extent on FLAIR and the presence of enhancement, and we conclude that although contrast material is not required to evaluate PRES, it may aid in excluding other causes.
Regarding blood pressure the day of the MRI, only weak correlations were found between blood pressure elevation and severity of edema on FLAIR. Blood pressure may even be normal in some cases of PRES, particularly in the setting of chemotherapy, immunosuppressive therapy, or sepsis [48, 49]. A potential criticism regarding our measurements is that the measurement at the time of MRI is not necessarily representative of the initial insult because the findings on MRI could persist for days after the symptom onset. Also, blood pressures can be labile, and our determination of MRI severity could relate to the timing after the symptom onset rather than the intrinsic severity. We note that our institutional standard has been to perform MRI of suspected PRES within 24 hours of admission, but given the retrospective nature of this study and the complexity of the cases, it was difficult to note the exact time of MRI after symptom onset.
Two potentially new causes of PRES were identified: anaphylaxis as a reaction to iodinated IV contrast material and alcohol withdrawal. Both lacked a hypertensive history and improved on repeat imaging. In the case of anaphylaxis, PRES is possibly related to the release of endotoxins with resultant endothelial injury; we could not formulate a plausible reason for PRES in the setting of alcohol withdrawal without hypertension. Other medications or illicit drug use could cause PRES but were not noted on laboratory testing or extensive social histories.
In conclusion, atypical distributions and imaging manifestations of PRES have a higher incidence than commonly perceived. Given the common involvement of the regions supplied by the anterior circulation, the term "multifocal," or simply removing "posterior" from the term "posterior reversible encephalopathy syndrome," may be more appropriate terminology. The atypical manifestations of contrast enhancement, restricted diffusion, and hemorrhage all correlate poorly with the edema severity on FLAIR MRI and can resolve on repeat imaging with appropriate therapy.
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