Posterior Reversible Encephalopathy Syndrome

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92.1 Clinical Features

and Laboratory Investigations Hypertensive encephalopathy may lead to reversible clinical symptoms including headache, nausea, vomiting, altered mental functioning, cerebral blindness, and epileptic seizures.

The syndrome can be present in a number of conditions characterized by hypertension: eclampsia, renal insufficiency, hemolytic–uremic syndrome, thrombotic thrombocytopenic purpura, and acute intermittent porphyria. In most cases the symptoms and MR abnormalities will disappear with antihyper- tensive treatment. With or without hypertension, the clinical and MR pattern may also be seen in patients undergoing anticancer therapy, bone marrow, or organ transplantation, using either anticancer medication or immunosuppressive therapy (see also Chap. 88).

Because of the first reported findings on MRI and the transient nature of the clinical symptoms, the name reversible posterior leukoencephalopathy syndrome (RPLS) was suggested. When it became clear that often gray matter was also involved, the name was changed into posterior reversible encephalopathy syndrome (PRES). This name has stuck so far, but does not cover the entire spectrum of manifestations of transient clinical symptoms and MRI abnormalities seen in relation to hypertensive and drug-related encephalopathies.

92.2 Pathology

Pathological descriptions are rare, as expected in a usually reversible disorder. Occasionally the results of a brain biopsy are mentioned, usually with vasogenic edema as the only finding. The best data have been obtained in eclampsia, because in the first half of the twentieth century the condition could be lethal. The descriptions give a varied picture of cerebral pathology, with white matter edema, most pronounced in the watershed areas, sometimes with pronounced mass effect, potentially resulting in tentorial hernia- tion. In addition, there may be microinfarctions, cortical petechiae, and pericapillary hemorrhages. Larg- er hemorrhages may occur in subcortical regions, deep white matter, and basal ganglia.

92.3 Pathogenetic Considerations

There are many theories trying to explain the nature and location of the lesions seen in PRES. The underlying problems are complex, and it is likely that mul- tiple factors play a role in the pathogenesis. This point can be illustrated by a discussion of a few different underlying disorders.

Transient symptoms of hypertensive encephalopathy were recognized clinically even in the first half of the twentieth century in pre-eclampsia and eclampsia. The clinical picture of pre-eclampsia consists of hypertension, confusion, proteinuria, and edema oc- curring in the second half of pregnancy. Symptoms vary in severity and multiorgan involvement is common. Neurological symptoms include headache, confusion, hyperreflexia, visual hallucinations, and cerebral blindness. Eclampsia is characterized by the oc- currence of an epileptic seizure or coma in a patient with a pre-eclampsia syndrome. This syndrome and the neurological implications have been studied ex- tensively. Many factors have been identified that pre- dispose to eclampsia, including an immunological maternal reaction (probably triggered by placental debris), dietary factors (such as deficiency of magnesium, calcium, and zinc, and excess of sodium) and genetic factors (such as abnormal alleles for the genes of tumor necrosis factor-a, angiotensinogen, factor V, and nitric oxide synthase). The maternal response leads to widespread cellular dysfunction with increased capillary permeability, raised fibronectin levels, and damaged endothelium. Subsequently, coagulation abnormalities develop with increased activation and consumption of platelets, low antithrombin III levels, abnormal prostaglandin levels, and in some cases diffuse intravascular coagulation. Endocrine abnormalities include activation of the renin–an- giotensin–aldosterone axis, abnormal catecholamine levels, and abnormalities of progesterone metabo- lism. This constellation leads to hypertension, edema, proteinuria, bleeding tendencies, renal dysfunction, liver damage, and neurological abnormalities. The hypertension exceeds the regulatory capacity of the vessel walls (muscular regulation), so that the local autoregulation (regulating size of the vessels and the admitted blood flow) depends solely on the sympathetic innervation of the vessels, which is relatively poor in the vertebrobasilar system. Hypertension and

Posterior Reversible Encephalopathy Syndrome

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immune-mediated endothelial dysfunction lead to extravasation of red cells and plasma proteins, resulting in cerebral edema. Vasospasm, prostaglandin deficiency, defects in the e-NOS gene coding for nitric oxide synthase, and endothelial damage play a role in the eventual progression of the lesion to ischemia and infarction. Thus, in eclampsia a varied picture of cerebral pathology, with cerebral edema, microinfarctions, cortical petechiae, and pericapillary hemorrhages, results in the clinical manifestations of headache, confusion, visual disturbances, and seizures.

Reversible leukoencephalopathies predominantly in the posterior cerebral areas also have been described in the hemolytic–uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP).

In these disorders PRES is only one of many possible manifestations. Both disorders are microangiopathic hemolytic anemias characterized by hemolytic ane- mia, thrombocytopenia, CNS dysfunction, fever, and/or renal dysfunction. HUS is usually seen in in- fants and children, whereas TTP more often presents in adults. Clinical findings include acute renal insufficiency and encephalopathy, often with seizures, hemorrhagic colitis, and upper respiratory infection. MRI and CT abnormalities develop over days, showing patchy white matter areas in the frontal, parietal, and occipital gray and white matter. In patients who died, occlusive platelet thrombi were found, primarily con- fined to the cortical gray matter. There was mild endothelial proliferation in the larger vessels. Capillar- ies showed proliferation, or “wickerwork” formation.

Many causes have been described for HUS and TTP.

In children hemorrhagic colitis is the most frequent cause; in adults, immune-mediated diseases, for ex- ample, systemic lupus erythematosus. HUS and TTP are classified as “uremic encephalopathies.” The imaging findings may be similar to those described in hypertensive encephalopathies of other origins. Most probably the encephalopathy is the result of more than one factor. In patients with severe hypertension it is assumed that acute increase of blood pressure exceeds the limits of local autoregulation. Distal vessels and capillaries are exposed to too high a pressure and to hyperperfusion. This causes damage to the endothelium so that blood plasma and, in some cases, erythrocytes can pass the blood–brain barrier.

Reversible encephalopathic clinical symptoms and lesions on MRI resembling those of PRES may also be seen in acute intermittent porphyria. Acute intermittent porphyria is a disorder with an autosomal domi- nant mode of inheritance, caused by a deficiency of porphobilinogen deaminase. More than 80% of carri- ers never develop symptoms. Symptoms are often precipitated by the influence of drugs, hormones, and nutritional factors that change the rate of heme syn- thesis in the liver. Patients with acute intermittent

porphyria present with subacute episodes of abdom- inal pain, vomiting, nausea, bowel distension or ileus, and neurovisceral and circulatory disturbances. The neurological problems are extremely variable and include autonomic neuropathy, peripheral axonal neuropathy, and CNS dysfunction. In subacute attacks, central and peripheral neurological symptoms may become prominent. Patients may have seizures, visual hallucinations, and cerebral blindness. Bilateral lesions in the parieto-occipital and posterior frontal lobes have been found in these patients. The lesions disappear after treatment. The similarity of the clinical and imaging pattern to other cases of PRES is evi- dent. Some of the patients have hypertension during these subacute episodes, but not all. It is likely that other factors play a role in the development of CNS dysfunction

Hypertension has not been found in all patients with PRES. Nocturnal registration of blood pressure in patients with PRES without hypertension has shown transient rises in blood pressure, a “riser” pattern, in some patients. It remains to be proven whether that is the case in a significant number of patients with PRES.

In eclampsia, HUS, and TTP, as well as in acute intermittent porphyria and other disorders in which PRES develops, hypertension is only one of the factors that play a role in the development of the encephalopathy. This explains why not all patients develop the syndrome under the same conditions.

Autoregulation of blood flow (velocity) and flux (vol- ume) is dependent on local vascular wall (muscular) response and neuronal, sympathetic regulation. The predominant involvement of the parieto-occipital lobes, but also the involvement of brain stem and cerebellum, may be explained by the relative poverty of the sympathetic innervation of the vertebrobasilar vascular system. Other factors mentioned as con- tributing to PRES are direct toxic influences on the endothelium, vasoconstriction due to the liberation of endothelin, and the formation of microthrombi.

What is not explained in any of these theories is the location of lesions in border zones, both parieto- occipital and frontal, suggesting temporary hypoperfusion as responsible factor.

92.4 Therapy

When hypertension is present, treatment of the hypertension and any underlying disease may lead to disappearance of clinical symptoms and MR abnormalities, usually within 14 days. This, of course, also depends on the underlying cause. In patients with eclampsia, delivery of the child when possible and, where necessary, treatment of hematological abnormalities, renal disorders, and hypertension should be

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instituted. The positive influence of magnesium sul- fate on the eclamptic condition has been recognized for many years, as has the role of pyridoxine in the past few decades. In patients in whom PRES is caused by immunosuppressive and/or chemotherapeutic drugs, the drug regimen has to be abandoned or changed. Once the treatment is stopped, further dete- rioration may occur for 1 or 2 weeks before improvement sets in. Complete disappearance of clinical and imaging symptoms and signs may occur, but residual damage is not rare.

92.5 Magnetic Resonance Imaging

In many cases of PRES and its variants CT shows hy- podensity in the affected areas, predominantly the parieto-occipital regions. In some cases hemorrhages are seen, related to extravasation of erythrocytes.

MRI is more sensitive than CT and allows better delineation of the abnormalities, such as an invento- ry of all involved areas, their location in border zones, and the involvement of gray as well as white matter.

Standard MR techniques, such as T1-weighted, proton density, T2-weighted, and FLAIR images demonstrate the lesions. FLAIR usually depicts hemorrhages fairly well. Gradient refocused images should be added to pick up microhemorrhages. Contrast enhancement may be seen in some of the lesions.

The lesions are predominantly located in the parieto-occipital region. In that location they tend to- wards symmetry, but asymmetrical presentations are not rare. The splenium of the corpus callosum may be involved. Usually the deep white matter is involved, but the overlying cortex is usually affected as well. In other cases the lesions are located in the parieto-occipital and frontal border zones (Fig. 92.1), suggesting that an episode of hypoperfusion has occurred. One must be aware of other presentations: PRES may affect solely the thalamic nuclei, the frontal border zones, the midbrain, the pons, or the cerebellum (Figs. 92.2 and 92.3). In the initial period some mass effect may be present, with secondary effects such as hydrocephalus. In some patients the lesions are extensive (Fig. 92.1); in others they are much more lim- ited (Fig. 92.4). With treatment MRI abnormalities disappear completely or nearly completely in most patients (Figs. 92.2 and 92.5).

Differentiation from other disorders depends on the location. When the border zones alone are affected, other disorders leading to hypoperfusion must also be considered. Isolated involvement of the pons has to be differentiated from central pontine myeli-

nolysis. Isolated thalamic involvement also occurs in deep venous thrombosis. With a protracted state of the lesions low-grade gliomas have to be ruled out.

When only the midbrain, pons, or cerebellum is affected, a correct diagnosis may be extremely difficult and depends on careful interpretation of all MR data in relationship to all the available clinical data.

Most important are the addition of diffusion- weighted imaging and the use of ADC maps (Fig.

92.6). These techniques allow differentiation of areas with low diffusivity, which may progress to infarction, and areas with high diffusivity, probably representing vasogenic edema, which may revert to normal. Unfor- tunately, results reported in the literature are contra- dictory. Some authors report decreased diffusivity;

others show increased ADC values, or “pseudo”-nor- malized ADC values, the latter, according to the authors, the result of intravoxel presence of both vasogenic and cytotoxic edema. However, most evi- dence so far suggests that lesions with a high ADC, probably representing vasogenic edema, are reversible, whereas lesions with a low ADC, representing cytotoxic edema, are irreversible.

Perfusion studies with SPECT and MRI have also shown conflicting results. Both hypo- and hyperperfusion have been reported in the involved areas, as has diffuse hypoperfusion over the entire brain. Be- cause in many cases border zones are involved, one might expect hypoperfusion to occur at some point during the development of the disorder. Perhaps the differences in results of perfusion studies may be explained by differences in the time elapsed between onset of the disorder and the time of the MR exami- nation. The severity and rate of development of the process and underlying factors may be also of impor- tance.

MRS has revealed diffuse metabolic abnormalities in PRES, even in areas that have a normal signal on imaging. Reduced ratios of N-acetylaspartate over choline and N-acetylaspartate over creatine, with high choline concentrations in the normal-appearing white matter have been reported. Quantification of the metabolites confirmed these findings: low con- centration of N-acetylaspartate and high concentra- tion of choline. After treatment MRS findings return to normal. Unfortunately there are also MRS studies reporting either no biochemical abnormalities in the affected areas during the acute stages of the disease, or no improvement of the MR spectra despite disappearance of clinical symptoms. Because most studies comprise a single observation or data on a small number of patients, it remains difficult to draw gener- al conclusions.

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Fig. 92.1. An 11-year-old girl with hypertensive encephalopa- thy.T2-weighted images (first and second row) show the typical pattern of the posterior reversible encephalopathy syndrome (PRES): nearly symmetrical lesions in the parieto-occipital lobes and the frontal border zones. The lesions involve both

gray and white matter. No abnormalities are seen in midbrain, pons, or cerebellum. On FLAIR images (third row) the lesions are more conspicuous, but FLAIR may be less good in depict- ing lesions in the posterior fossa

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Fig. 92.2. T2-weighted transverse images in a 58-year-old man with hypertensive encephalopathy (first three rows).There are diffuse mild white matter abnormalities in the cerebral hemispheres, but the more important abnormalities are seen

in the midbrain and pons. These latter lesions show some swelling. A repeat MRI was obtained a few weeks later (fourth and fifth rows) and show that with treatment all lesions have disappeared

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Fig. 92.2. (continued).

Fig. 92.3. Two coronal T2-weighted images of a 32-year-old pregnant woman with eclampsia. The left image shows extensive involvement of the parieto-occipital lobe; the right image shows involvement of the basal ganglia, predominantly on the right side, and of the mesial temporal struc- tures. After delivery and therapy an almost complete recovery followed

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Fig. 92.4. In this 7-year-old girl with reflux nephropathy and hypertensive encephalopathy the T2-weighted images show only a few lesions with an asymmetrical distribution

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Fig. 92.5. A 63-year-old woman was admitted to the intensive care unit with septic shock, respiratory infection, and diarrhea.

After recovery she complained of memory problems. The up- per row of FLAIR images shows lesions in this phase. The lower row of T2-weighted images shows complete disappearance of

the lesions on follow-up. The MRI findings are highly sugges- tive of PRES, although the causative factors in this patient are not known. Courtesy of Dr. E.P.J. Arnoldus, Department of Neu- rology, TweeSteden Hospital, Tilburg, The Netherlands

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Fig. 92.6. The first two rows contain the FLAIR images of a 52-year-old man with hypertensive encephalopathy, showing the common MR pattern of PRES lesions. The third and fourth rows show Trace diffusion-weighted images (b = 1000), with bright spots in the parieto-occipital area, more extensive on

the right side, and some tiny hyperintense spots in the frontal border zones. The fifth and sixth rows show ADC maps with a mixture of higher and lower than average values in the involved areas

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Fig. 92.6. (continued)