Introduction

Posterior reversible encephalopathy syndrome (PRES) is a well-recognized, clinical neuroradiological entity characterized by transitory neurological disturbances including altered mental status, seizures, headache and blurred vision, with acute or subacute onset [1]. PRES is more often associated with acute hypertension or immunosuppression [2]. Neuroradiological findings are mainly represented by bilateral involvement of the white and gray matter in posterior regions of the cerebral hemispheres [3]. PRES is usually considered to be a reversible condition if promptly recognized and correctly treated [1]. Otherwise, a delayed or incorrect diagnosis may lead to irreversible damage [4]. Here, we report four cases of PRES, which developed in critically ill obstetric patients admitted to our intensive care unit (ICU).

Case reports

Case 1

A 27-year-old right-handed, eclamptic woman, at the 28th week of her first gestation, was admitted to ICU after a cesarean section performed in emergency for convulsive status epilepticus (SE). A few days earlier she had presented with increased blood pressure (BP, 160/110 mmHg) and progressive edema with mild proteinuria. At admission, BP was 140/100 mmHg and proteinuria +3. Hypertension was initially controlled with nitroglycerine and then with nimodipine. Due to seizure persistence, i.v. sodium valproate (ivVPA; loading dose: 15 mg/kg; maintenance: 1.5 mg/kg per h) was administered. Non-contrast CT scan revealed diffuse reduced density in the frontoparietal lobes bilaterally, which also involved the subcortical white matter and extended up to the cortical surface (Fig. 1a). Magnetic resonance imaging (MRI) showed multiple cortical-subcortical lesions with few T1 and increased DP/T2 in the temporo-occipital and frontoparietal regions, also with bilateral involvement of basal ganglia (Fig. 1b); in addition, similar, bilateral, small cerebellar lesions were observed. With ivVPA complete remission of the seizures was achieved. The patient was ventilated for 36 h and then discharged to the ward. Brain MRI, repeated a week later, showed the almost complete remission of signal abnormalities (Fig. 1c).

Fig. 1.
figure 1

Patient 1. a Day 1: non-contrast CT scan shows diffuse hypodensity in frontoparietal lobes bilaterally, involving the subcortical white matter and also extending up to the cortical surface; b Day 1: T2-weighted MRI showing increased white/gray matter mainly in parieto-occipital lobes; c Day 8: MRI obtained after normalization of blood pressure, showing the almost complete resolution of MRI lesions

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Case 2

A 27-year-old, at the 38th week of her first gestation, developed severe hypertension (190/110 mmHg), headache, seizures and altered mental status 4 days postpartum. Biochemical and hematological investigations were within normal ranges. MRI showed extensive, mainly posterior, cortico-subcortical, abnormalities with few T1 and increased DP/T2. In addition, subtentorial lesions were also observed. Despite initial treatment with clonidine and magnesium sulfate, and successively with nimodipine and nitroprusside, hypertension persisted. The patient developed a subarachnoid hemorrhage; MRI showed the persistence of brain abnormalities but failed to detect aneurysmal lesions. The patient died 2 weeks later.

Case 3

A 24-year-old, 38 weeks gestation, eclamptic, primigravida was admitted to ICU with hypertension (170/100 mmHg), confusion, cortical blindness and SE in the immediate postpartum. MRI disclosed bilateral temporo-occipital, nucleo-capsular and pontine lesions with few T1 and increased DT/T2. Nimodipine and ivVPA (administered as in case 1) achieved normalization of BP (125–90 mmHg) and cessation of seizures. The patient rapidly improved and MRI, repeated 7 days later, was normalized.

Case 4

A 29-year-old primigravida, 35 weeks pregnant, developed confusion, mild hyperreflexia of all four limbs, blurred vision and seizures 6 days postpartum. At admission to ICU, her BP was 180/100 mmHg and heart frequency 150 bpm. MRI disclosed bilateral multiple cortico-subcortical abnormalities with few T1 and increased DP/T2 in the temporo-parieto-occipital areas; similar lesions were also observed in the centrum semiovale, left pons and left cerebellar peduncle. Nimodipine and magnesium sulfate treatment was started, with clinical and neuroradiological normalization in about 1 week.

Discussion

Posterior reversible encephalopathy syndrome is a clinical-neuroradiological entity usually presenting with headache, altered mental status, vomiting, seizures and occipital lobe-related symptoms. Patients have an acute to subacute neurological presentation, often heralded by convulsions. Seizures may be initially focal but usually become generalized, frequently recurring or realizing a true SE. Alertness and behavior disturbances range from somnolence and lethargy to stupor and coma; restlessness and agitation may alternate with lethargy. Visual disturbances range from hemianopia and blurred vision up to cortical blindness. Tendon reflexes may be brisk and some patients can also experience weakness and incoordination of the limbs [1, 2]. PRES has been reported in association with many pathological conditions, such as acute hypertension, pregnancy or puerperium, immunosuppression (HIV infection, cisplatin, tacrolimus, cyclosporin A, steroids), hemolytic uremic syndrome, acute glomerulonephritis, blood transfusion, intravenous globulin or erythropoietin administration, acute intermittent porphyria, intra-abdominal neurogenic tumors and severe hypercalcemia [1, 2, 5, 6, 7].

A neuroimaging study usually shows transient edema primarily in the cortex and subcortical white matter of the parieto-occipital lobes and other cerebral structures, such as basal ganglia, frontal lobes, cerebellum and brainstem, can also be involved [1, 8, 9]. At MRI, brain abnormalities usually appear increased on both echoes of a dual-echo T2-weighted sequence and either normal or decreased on T1-weighted images [3, 8]. However, fluid attenuated inversion recovery (FLAIR) imaging was judged superior to proton density and T2-weighted spin-echo for detection of supratentorial brain lesions. Furthermore, FLAIR sequences allow better characterization of the lesion location [8]. Diffusion-weighted MRI, that is more sensitive to changes in distribution of water in the brain, can better detect white matter edema as well as reliably differentiate between vasogenic and cytotoxic edema [9]. Some authors have also suggested a possible role of MR spectroscopy as having prognostic value during the acute phase [7]. Due to the widespread utilization of MRI, this syndrome is becoming more frequently diagnosed. Nevertheless, PRES remains a relatively unfamiliar condition to clinicians [1, 10].

Our patients met diagnostic criteria for this syndrome: all of them had altered consciousness, seizures and two of them also presented cortical blindness and headache. Interestingly, two patients experienced these symptoms in late postpartum without the classical pre-eclamptic signs, which is not frequently reported in the literature [11, 12]. SE occurred in two cases. In all patients, neurological examination revealed mild hyperreflexia in all four limbs and EEGs were diffusely slowed. MRI examinations revealed edema localized, mainly to the temporo-parieto-occipital areas. However, basal ganglia, frontal lobes, pons and cerebellum were also often involved. Unfortunately, we could not acquire FLAIR sequences, due to the limits of our MR instrumentation. In all patients but one, neurological and neuroimaging abnormalities completely, or almost completely, resolved on follow-up MRI. In patient 2, the unfavorable outcome was due to persistence of hypertension. In light of the absence of aneurysmal lesions at angio-MRI, it seems very likely that this condition led to a fatal subarachnoid hemorrhage.

The pathophysiology of PRES is so far not very clear. In particular, the controversial question whether a vasogenic or cytotoxic edema is involved, is frequently discussed. In conditions accompanied by high BP, e.g. hypertensive encephalopathy, it is likely that the increased systemic pressure exceeds the autoregulatory mechanisms of the cerebral vasculature [6, 10], thus resulting in a blood-brain barrier (BBB) breakdown and, hence, in fluid and blood extravasation into the brain with consequent hydrostatic edema [1, 2, 10]. The relatively selective involvement of posterior cerebral areas could reflect a major susceptibility of these regions ("watershed zone"), likely due also to a lesser degree of adrenergic innervation supporting circulatory autoregulation mechanisms [13, 14]. However, other cerebral structures, such as basal ganglia, frontal lobes, cerebellum and brainstem, can also be involved [1, 8]. Interestingly, the presence of brainstem lesions has been considered more frequently in hypertensive encephalopathy [15]. The clinical and radiological findings are identical in PRES and in hypertensive encephalopathy, thus suggesting common pathophysiological changes for these conditions [8, 16]. Concerning the mechanisms by which immunosuppression or immunosuppressive drugs can cause posterior encephalopathy, a primary or secondary breakdown of BBB has been hypothesized [1]. However, further research is needed for a better comprehension of the pathophysiology of this complex condition as well as for an appropriate therapeutical approach.

Posterior reversible encephalopathy syndrome is usually supposed to be a reversible condition; however, due to late recognition and/or to incorrect treatment, irreversible brain damage can sometimes occur [4, 8, 10]. For this reason, it should be promptly recognized and treated, by monitoring BP and/or discontinuing eventually provocative immunosuppressive drugs and adequately treating seizures. Lowering BP is mandatory; the mean arterial BP should be maintained between 105–125 mmHg. Parenterally administered calcium antagonists or labetalol and nifedipine given orally are usually preferred [17]. All our patients were also treated with i.v. nimodipine, a cerebral selective calcium-channel blocker, potentially useful in preventing cerebral vasospasm. Indeed, this additional pathophysiological mechanism has been suggested on the basis of neuroradiological studies demonstrating its occurrence on conventional or MR angiography in pregnant patients with hypertensive leukoencephalopathy [16]. A putative neuro-protective effect, supported by animal studies, has also been suggested [18, 19].

It should be kept in mind that, when PRES occurs during pregnancy, ACE inhibitors should be avoided because of their toxic effect on the fetal kidney [17]. Treatment of seizures deserves particular attention. A recent international study confirmed the efficacy of magnesium sulfate, a drug used for the prevention and treatment of eclampsia, without substantial harmful effects [20]. Traditional anti-epileptic drugs, such as phenytoin, benzodiazepines and phenobarbital, may induce severe adverse effects. Preliminary observations report ivVPA efficacy and safety in SE, also in patients with cardiovascular failure, in the elderly and in ICU, with no effects on consciousness [21, 22]. We tried ivVPA in two patients with SE, severe disturbance of vigilance and autonomic involvement; seizure remission without adverse effects was promptly obtained. However, the value of this observation is obviously anecdotal and further research is needed to assess the usefulness of ivVPA in this condition.