Mayoclinproc 85-5-004
Mayoclinproc 85-5-004
Mayoclinproc 85-5-004
Jennifer E. Fugate, DO; Daniel O. Claassen, MD; Harry J. Cloft, MD, PhD; David F. Kallmes, MD;
Osman S. Kozak, MD; and Alejandro A. Rabinstein, MD
Objective: To identify and define clinical associations and radio- sia, renal disease, sepsis, and exposure to immunosuppres-
logic findings of posterior reversible encephalopathy syndrome
(PRES).
sants.2-8 It has been less commonly described in the setting of
autoimmune disease.9-13 The distinctive role of autoimmune
Patients and Methods: Patients prospectively diagnosed as
having PRES from October 1, 2005, through April 30, 2009, were disease in the pathophysiology of PRES is often clouded
pooled with retrospectively identified patients admitted from by concurrent hypertension, renal disease, and/or the use of
August 1, 1999, through September 30, 2005. We performed a immunosuppressants.
detailed review of clinical information, including demographics,
presenting symptoms, medical history, and risk factors. All pa- Despite the syndrome’s name, radiographic lesions in
tients underwent computed tomography of the brain or magnetic PRES are rarely isolated to the “posterior” parieto-occipi-
resonance imaging. Findings on magnetic resonance imaging tal white matter and instead often involve the cortex, fron-
were analyzed independently by 2 neuroradiologists.
tal lobes, basal ganglia, and brainstem.14,15 No conclusive
Results: We identified 120 cases of PRES in 113 patients (mean evidence supports a clear relationship between clinical
age, 48 years). Mean peak systolic blood pressure was 199 mm
Hg (minimum-maximum, 160-268 mm Hg), and mean peak diastol- conditions and specific imaging findings of severity or lo-
ic blood pressure was 109 mm Hg (minimum-maximum, 60-144 cation of edema,16 although some studies have suggested
mm Hg). Etiologies of PRES included hypertension (n=69 [61%]), correlations such as greater vasogenic edema in normoten-
cytotoxic medications (n=21 [19%]), sepsis (n=8 [7%]), preec-
lampsia or eclampsia (n=7 [6%]), and multiple organ dysfunction sive patients5 and a trend for basal ganglia involvement in
(n=1 [1%]). Autoimmune disease was present in 51 patients patients with preeclampsia or eclampsia.16
(45%). Clinical presentations included seizures (n=84 [74%]), The underlying pathophysiology of PRES remains elu-
encephalopathy (n=32 [28%]), headache (n=29 [26%]), and vi-
sual disturbances (n=23 [20%]). In the 115 cases (109 patients) sive. Several theories have been proposed, the most widely
for which magnetic resonance imaging findings were available, accepted of which states that rapidly developing hyper-
the parieto-occipital regions were the most commonly involved tension leads to a breakdown in cerebral autoregulation,
(n=108 [94%]), followed by the frontal lobe (n=88 [77%]), tempo-
ral lobe (n=74 [64%]), and cerebellum (n=61 [53%]). Cerebellar particularly in the posterior head region (where there is a
involvement was significantly more frequent in patients with a relative lack of sympathetic innervation). Hyperperfusion
history of autoimmunity (P=.008), and patients with sepsis were ensues with protein and fluid extravasation, producing fo-
more likely to have cortical involvement (P<.001).
cal vasogenic edema.1,10,17 An alternative theory, which has
Conclusion: A substantial proportion of patients with PRES have
underlying autoimmune conditions that may support endothelial
been best characterized in preeclampsia, eclampsia, and
dysfunction as a pathophysiologic mechanism. On brain imaging, sepsis, implicates endothelial dysfunction.18,19 A third theory
the location and severity of vasogenic edema were mostly similar proposes that vasospasm with subsequent ischemia may be
for the different clinical subgroups.
responsible.20-22
Mayo Clin Proc. 2010;85(5):427-432 Early recognition of PRES is important for timely insti-
tution of therapy, which typically consists of gradual blood
CT = computed tomography; min-max = minimum-maximum; MRI = mag- pressure control and withdrawal of potentially offending
netic resonance imaging; PRES = posterior reversible encephalopathy
syndrome; SE = status epilepticus
agents. Although reversible by definition, secondary com-
plications, such as status epilepticus (SE), intracranial
hemorrhage, and massive ischemic infarction, can cause
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a Clinic Proceedings.
Clinical and radiologic findings in PRES
Our understanding of PRES is derived primarily from the analysis and is referred to as a case throughout the ar-
small retrospective studies in which the definition of the ticle. Radiologic characteristics used for statistical analysis
syndrome varies. The range of presentations and clini- included location of edema, severity of edema, cortical vs
cal associations is still being recognized. Our study aims subcortical location, and presence of hemorrhage. Clinical
to further characterize the syndrome both clinically variables included seizures at presentation, SE, hyperten-
and radiologically in an attempt to better understand its sion, and history of autoimmunity. P<.05 was considered
pathophysiology. statistically significant.
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Clinical and radiologic findings in PRES
5-fluorouracil, sirolimus, thalidomide, gemcitabine, pacli- Table 1. Frequency of Locations Affected by Vasogenic Edema
in PRES in 115 Cases (109 Patients)
taxel, carboplatin, sorafenib, infliximab, or hydroxyurea. With Brain MRI Performed
A history of autoimmune disease was present in 51
Location No. (%) of cases
patients (45%), of whom three-fourths were women. Au-
toimmune diseases in these patients included thrombotic Parieto-occipital lobes 108 (94)
Frontal lobe 88 (77)
thrombocytopenic purpura (14 [27%]), systemic lupus ery- Temporal lobe 74 (64)
thematosus (9 [18%]), hypothyroidism (5 [10%]), sclero- Cerebellum 61 (53)
derma (3 [6%]), Crohn disease (3 [6%]), ulcerative colitis Basal ganglia 39 (34)
Brainstem 31 (27)
and/or primary sclerosing cholangitis (2 [4%]), rheumatoid Subcortical 114 (99)
arthritis (2 [4%]), diabetes mellitus type 1 (2 [4%]), and 1 Cortical 12 (10)
patient each (2%) with Grave disease, Hashimoto thyroidi- Deep white matter 46 (40)
tis, antiphospholipid syndrome, antiglomerular basement MRI = magnetic resonance imaging; PRES = posterior reversible enceph-
membrane antibody disease, autoimmune hepatitis, polyar- alopathy syndrome.
teritis nodosa, thromboangiitis obliterans, polyglandular
autoimmune syndrome, Sjögren syndrome, granulomatous and unilateral in 1 case. Restricted diffusion was present in
interstitial nephritis, and neuromyelitis optica. 30 cases (26%), and hemorrhage was present in 10 (9%).
Contrast enhancement was evident in 16 (15% of overall
Radiologic Findings population and 21% of those given contrast medium).
All 120 cases had initial neuroimaging with either MRI or When analyzed according to clinical subgroups, imag-
computed tomography (CT) of the head. Magnetic reso- ing characteristics, including lesion location and severity,
nance imaging was available for 115 of 120 cases. Mean were largely similar (Table 2). Representative images dem-
time to MRI from clinical presentation was 2 days (min- onstrating severity of edema are seen in Figure 1. Only 2
max, 1-11 days). (11%) of the 19 patients with SE had cortical involvement,
The most commonly involved location was the parieto- and only slightly over half (10 [53%]) had deep white mat-
occipital brain region, which was seen in 108 (94%) of the ter involvement. There was limited correlation with severity
115 cases. This was followed by the frontal lobe in 88 cases of edema for patients with SE, with 8 (42%) demonstrat-
(77%), the temporal lobe in 74 (64%), the cerebellum in 61 ing mild edema and 11 (58%) showing moderate to severe
(53%), the basal ganglia in 39 (34%), and the brainstem in edema. The parieto-occipital region was involved in almost
31 (27%) (Table 1). Of the cases, 114 (99%) had subcor- all of these patients (18 [95%]). Similarly, most patients with
tical involvement and 12 (10%) had cortical involvement. seizures of any type showed no cortical involvement (76
Lesions were located in the deep white matter in 46 cases [88%]). Involvement of the classic parieto-occipital brain re-
(40%), showed an external watershed pattern in 50 (43%), gion was noted in 51 (59%) of the 86 patients with seizures.
and showed an internal watershed pattern in 6 (5%). Lesions Of 54 patients with autoimmune disease, 35 (65%) had
were asymmetric in nearly half of the cases (n=55 [48%]) cerebellar involvement (Figure 2), a statistically signifi-
Table 2. Radiologic Features of 115 Cases (109 Patients) With PRES, Visualized With MRI, According to Clinical Subset
Moderate Parieto- Basal Brain- Sub- Asym- Hemor-
Total Mild to severe occipital Temporal Frontal ganglia CBL stem Cortical cortical metric DWI rhage Enhanced
Status
epilepticus 19 8 (42) 11 (58) 18 (95) 14 (74) 15 (79) 6 (32) 11 (58) 5 (26) 2 (11) 19 (100) 5 (26) 4 (21) 1 (5) 2 (11)
Seizures 86 37 (43) 49 (57) 51 (59) 61 (71) 68 (79) 28 (33) 47 (55) 21 (24) 10 (12) 85 (99) 36 (42) 22 (26) 7 (8) 11 (13)
Autoimmunity 54 27 (50) 27 (50) 48 (89) 33 (61) 43 (80) 16 (30) 35 (65) 16 (30) 6 (11) 53 (98) 27 (50) 14 (26) 1 (2) 6 (11)
Immuno-
suppressed 49 24 (49) 25 (51) 45 (92) 29 (59) 38 (78) 15 (31) 27 (55) 10 (20) 19 (39) 48 (98) 23 (47) 14 (29) 5 (10) 7 (14)
Sepsis 19 11 (58) 8 (42) 19 (100) 9 (47) 15 (79) 6 (32) 6 (32) 3 (16) 11 (58) 19 (100) 9 (47) 7 (37) 1 (5) 1 (5)
Normotensive 11 8 (73) 3 (27) 10 (91) 4 (36) 7 (64) 3 (27) 3 (27) 0 (0) 4 (36) 10 (91) 5 (45) 1 (9) 0 (0) 1 (9)
Renal failure 66 28 (42) 38 (58) 61 (92) 41 (62) 50 (76) 22 (33) 22 (33) 20 (30) 17 (26) 65 (98) 24 (36) 20 (30) 6 (9) 7 (11)
Hypertension 66 28 (42) 38 (58) 62 (94) 43 (65) 47 (71) 23 (35) 33 (35) 20 (30) 16 (24) 66 (100) 28 (42) 18 (27) 4 (6) 11 (17)
Preeclampsia
or eclampsia 7 4 (57) 3 (43) 7 (100) 5 (71) 6 (86) 2 (29) 2 (29) 2 (29) 4 (57) 7 (100) 4 (57) 2 (29) 0 (0) 1 (14)
Cytotoxic
medications 27 13 (48) 14 (52) 26 (96) 17 (63) 20 (74) 7 (26) 7 (26) 6 (22) 7 (26) 27 (100) 14 (52) 5 (19) 1 (4) 2 (7)
Numbers indicate the number of patients affected followed by percentage in parentheses. Mild and moderate to severe describe the severity of edema.
CBL = cerebellum; DWI = diffusion-weighted imaging (indicates a positive result); MRI = magnetic resonance imaging; PRES = posterior reversible
encephalopathy syndrome.
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a Clinic Proceedings.
Clinical and radiologic findings in PRES
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a Clinic Proceedings.
Clinical and radiologic findings in PRES
Table 3. Frequency of Agreement Between 2 Independent with PRES, including abrupt hypertension, immunosup-
Neuroradiologists on Radiologic Characteristic on Brain MRI in
PRES for 100 Cases (93 Patients)
pressant use, infection, preeclampsia or eclampsia, and
renal disease. In addition, we found a substantial pro-
Radiologic characteristic Agreement, % of cases
portion of patients affected by underlying autoimmune
Subcortical involvement 98 and inflammatory conditions. The most common clinical
Hemorrhage 98
Enhancement 94
presentations were new-onset seizures, encephalopathy,
Parieto-occipital location 90 headache, and visual disturbances. Status epilepticus as a
Cerebellum location 90 clinical presentation of PRES was not uncommon. Brain
Brainstem location 89
Cortical involvement 89
MRIs reviewed independently by 2 neuroradiologists re-
Basal ganglia location 87 vealed the parieto-occipital head region to be the region
Frontal lobe location 83 most consistently involved, followed by the frontal lobe,
Internal watershed pattern 81
Temporal lobe location 79
temporal lobe, and cerebellum. Unexpectedly, patients
Restricted diffusion 79 with seizures and SE rarely had involvement of corti-
Deep white matter involvement 72 cal matter. Patients with autoimmune disease were more
Edema severity 63
Asymmetry 63
likely to have cerebellar involvement, and patients with
External watershed pattern 46 sepsis or active infection were more likely to have cortical
MRI = magnetic resonance imaging; PRES = posterior reversible encepha
involvement.
lopathy syndrome. The high percentage of patients with PRES who have
autoimmune disorders may support the theory that PRES
presence of hemorrhage (in agreement for 98% of cases is in part caused by endothelial dysfunction, a process
in each). The presence of restricted diffusion was agreed in which the host autoimmune response is essential. En-
upon in 79% of cases, and edema severity and asymmetry dothelial cells become activated and damaged by an in-
were both agreed upon in 63% of cases. flammatory cytokine response stemming from monocytes
Cerebral vascular imaging with magnetic resonance an- and lymphocytes, which can lead to leakage of fluid and
giography, CT angiography, or digital subtraction catheter protein into the interstitium.18,19 Autoimmunity has been
angiography was performed in 37 cases (32 with magnetic recently implicated in PRES in association with neuromy-
resonance angiography, 1 with CT angiography, and 4 with elitis optica spectrum disorders.27 This raises the possibil-
digital subtraction catheter angiography). Vasospasm was ity of autoimmune-mediated disruption of the endothe-
noted in 4 cases, distal vasculature pruning in 1, focal pos- lial aquaporin 4 water channels, which may predispose to
terior cerebral artery stenosis in 1, vertebral artery dissec- PRES.
tion in 1, and an incidental right internal carotid aneurysm Abrupt hypertension undoubtedly contributes to the
in 1. Findings on the remaining angiographic studies were development of PRES, and the hyperperfusion theory is
unremarkable. supported by the frequent presence of substantial hyper-
Follow-up neuroimaging was performed in 74 of 120 tension in patients with PRES and subsequent resolution
cases; the overall median time to follow-up imaging was 20 of clinical symptoms and radiologic edema with prompt
days (min-max, 1-390 days). Follow-up imaging showed treatment of hypertension. Hyperperfusion has also been
evidence of radiologic improvement in 65 cases (88%), shown radiologically on single-photon emission CT in case
with complete or near-complete resolution of abnormali- reports of patients with PRES.7,17 However, this theory is
ties in 52 (70%). Median time to follow-up imaging for not comprehensive because PRES can affect normotensive
this group was 26.5 days (min-max, 4-390 days). Thirteen patients23 and does not uniformly occur in patients with hy-
(18%) had partial resolution with a median time to follow- pertensive surges above the normal upper limits of cerebral
up imaging of 7 days (min-max, 4-30 days). Nine (12%) autoregulation.
had no change, with a median time to follow-up imaging We found no correlation between clinical characteris-
of 5 days (min-max, 1-92 days); 7 of them probably had tics and the extent of vasogenic edema seen on brain imag-
follow-up imaging too early (≤11 days from symptom on- ing in PRES. This is consistent with previous findings,16
set) and the other 2 were imaged at the time of a recurrent yet contradicts other reports suggesting that the extent of
episode of PRES. vasogenic edema may be inversely related to blood pres-
sure at the time of symptom onset.5 We also found no over-
all difference in lesion location on the basis of suspected
Discussion
PRES etiology. However, we found strong associations
In this large clinical series, we found many of the classic with a history of autoimmune disease, involvement of the
etiologies and predisposing factors known to be associated cerebellum, and cortical involvement with infection. Al-
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a Clinic Proceedings.
Clinical and radiologic findings in PRES
though the relevance of the last association is uncertain, it is 5. Bartynski WS, Boardman JF, Zeigler ZR, et al. Posterior reversible en-
cephalopathy syndrome in infection, sepsis, and shock. AJNR Am J Neurora-
interesting given the tendency of patients with sepsis to have diol. 2006;27(10):2179-2190.
epileptogenic abnormalities on electroencephalography.28 6. Furukawa M, Terae S, Chu BC, et al. MRI in seven cases of tacroli-
Status epilepticus is a not uncommon presentation of mus (FK-506) encephalopathy: utility of flair and diffusion-weighted imaging.
Neuroradiology. 2001;43(8):615-621.
PRES. Its occurrence is not associated with the severity of 7. Small SL, Fukui MB, Bramblett GT, et al. Immunosuppression-induced leu-
radiologic edema, and most of these patients actually lack koencephalopathy from tacrolimus (FK506). Ann Neurol. 1996;40(4):575-580.
8. Appignani BA, Bhadelia RA, Blacklow SC, et al. Neuroimaging findings
cortical involvement. Recognition that PRES may present in patients on immunosuppressive therapy: experience with tacrolimus toxic-
with SE is important because, in addition to anticonvul- ity. AJR Am J Roentgenol. 1996;166(3):683-688.
9. Kur JK, Esdaile JM. Posterior reversible encephalopathy syndrome–an
sants, appropriate treatment requires identifying and treat- underrecognized manifestation of systemic lupus erythematosus. J Rheumatol.
ing the underlying cause of PRES. 2006;33(11):2178-2183.
This study is limited because the transplant and che- 10. Primavera A, Audenino D, Mavilio N, et al. Reversible posterior leuco-
encephalopathy syndrome in systemic lupus and vasculitis. Ann Rheum Dis.
motherapy patient population is underrepresented as a 2001;60(5):534-537.
result of the organization of our medical center. In addi- 11. Pozo-Rosich P, Villoslada P, Canton A, et al. Reversible white matter
alterations in encephalopathy associated with autoimmune thyroid disease. J
tion, the study shares the limitations of all retrospective Neurol. 2002;249(8):1063-1065.
studies, particularly in that the timing of follow-up imag- 12. Tateishi Y, Iguchi Y, Kimura K, et al. A case of autoimmune thyroid dis-
ing was not uniform. There may be a bias toward more ease presenting posterior reversible encephalopathy syndrome. J Neurol Sci.
2008;271(1-2):203-206.
benign cases because patients who died of acute critical 13. Bohnen NI, Parnell KJ, Harper CM. Reversible MRI findings in a patient
illness had to be excluded to ensure reversibility. How- with Hashimoto’s encephalopathy. Neurology. 1997;49(1):246-247.
14. Lee VH, Wijdicks EF, Manno EM, et al. Clinical spectrum of reversible
ever, requiring proof of reversibility is actually a strength posterior leukoencephalopathy syndrome. Arch Neurol. 2008;65(2):205-210.
of our study because it preserves the homogeneity of the 15. Bartynski WS, Boardman JF. Distinct imaging patterns and lesion distri-
population. Additional strengths of the study are that it bution in posterior reversible encephalopathy syndrome. AJNR Am J Neurora-
diol. 2007;28(7):1320-1327.
is one of the largest clinical series of PRES patients and 16. Mueller-Mang C, Mang T, Pirker A, et al. Posterior reversible enceph-
that radiologic evaluations were completed by 2 indepen- alopathy syndrome: do predisposing risk factors make a difference in MRI
appearance? Neuroradiology. 2009;51(6):373-383.
dent neuroradiologists blinded to the clinical details of 17. Schwartz RB, Jones KM, Kalina P, et al. Hypertensive encephalopathy:
the cases. findings on CT, MR imaging, and SPECT imaging in 14 cases. AJR Am J
Roentgenol. 1992;159(2):379-383.
18. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: cur-
rent concepts. Am J Obstet Gynecol. 1998;179(5):1359-1375.
Conclusion 19. Aird WC. The role of the endothelium in severe sepsis and multiple or-
gan dysfunction syndrome. Blood. 2003;101(10):3765-3777.
The most novel finding in our clinical series of PRES pa 20. Trommer BL, Homer D, Mikhael MA. Cerebral vasospasm and eclamp-
tients is the high prevalence of autoimmune disorders. sia. Stroke. 1988;19(3):326-329.
21. Ito T, Sakai T, Inagawa S, et al. MR angiography of cerebral vasospasm
Although we do not consider PRES an autoimmune con- in preeclampsia. AJNR Am J Neuroradiol. 1995;16(6):1344-1346.
dition per se, this association with autoimmune disorders 22. Lin JT, Wang SJ, Fuh JL, et al. Prolonged reversible vasospasm in cy-
suggests that endothelial dysfunction may lie at the core of closporin A-induced encephalopathy. AJNR Am J Neuroradiol. 2003;24(1):
102-104.
its pathophysiology. Further research is needed to assess 23. Ay H, Buonanno FS, Schaefer PW, et al. Posterior leukoencephalopathy
the merit of this hypothesis. without severe hypertension: utility of diffusion-weighted MRI. Neurology.
1998;51(6):1369-1376.
24. Schwartz RB. A reversible posterior leukoencephalopathy syndrome
References [letter]. N Engl J Med. 1996;334(26):1743.
1. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoen- 25. Koch S, Rabinstein A, Falcone S, et al. A. Diffusion-weighted imaging
cephalopathy syndrome. N Engl J Med. 1996;334(8):494-500. shows cytotoxic and vasogenic edema in eclampsia. AJNR Am J Neuroradiol.
2. Hauser RA, Lacey DM, Knight MR. Hypertensive encephalopathy: 2001;22(6):1068-1070.
magnetic resonance imaging demonstration of reversible cortical and white 26. Schaefer PW, Buonanno FS, Gonzalez RG, et al. Diffusion-weighted im-
matter lesions. Arch Neurol. 1988;45(10):1078-1083. aging discriminates between cytotoxic and vasogenic edema in a patient with
3. Schwaighofer BW, Hesselink JR, Healy ME. MR demonstration of eclampsia. Stroke. 1997;28(5):1082-1085.
reversible brain abnormalities in eclampsia. J Comput Assist Tomogr. 1989; 27. Magana SM, Matiello M, Pittock SJ, et al. Posterior reversible enceph-
13(2):310-312. alopathy syndrome in neuromyelitis optica spectrum disorders. Neurology.
4. Raroque HG Jr, Orrison WW, Rosenberg GA. Neurologic involvement 2009;72(8):712-717.
in toxemia of pregnancy: reversible MRI lesions. Neurology. 1990;40(1):167- 28. Oddo M, Carrera E, Claassen J, et al. Continuous electroencephalogra-
169. phy in the medical intensive care unit. Crit Care Med. 2009;37(6):2051-2056.
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a Clinic Proceedings.