Background: Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiographic syndrome of multiple etiologies. Still, the exact pathophysiology of PRES is not clear. Aims and Objectives: To study demographic, etiological, and clinic-radiological profiles of patients presenting with PRES and their outcome at the tertiary care teaching hospital. Materials and Methods: A retrospective observational and non-interventional study was conducted at tertiary care center in from January 2009 to December 2013 at Krishna Institute of Medical Sciences, Karad. Inclusion Criteria: The clinical history of acute neurologic change including headache, encephalopathy, seizure, visual disturbance, or focal deficit with magnetic resonance imaging (MRI) brain imaging findings of focal vasogenic edema with clinical or radiologic proof of reversibility. Results: Of a total 43 patients with suspected diagnosis of PRES, 29 patients were included fulfilling all inclusion criteria of PRES. Of total the 29 patients with confirmed diagnosis of PRES, 22 (75.86%) were female and 7 (24.13%) were male patients, predominated by female population (relative risk [RR]: 3.14; odds ration [OR]: 9.87; ‘P‘ < 0.001). The overall mean age was 33.65 years (±15.26) and mean duration of stay was 10.13 days (±4.98). The most common clinical presentation was generalized tonic-clonic seizures, seen in 23 (79.31%) patients, headache in 21 (72.41%) patients, and visual disturbances 13 (44.82%) patients. A total of 18 (62.06%) patients were hypertensive and 11 (37.93%) were normotensive [RR: 1.63]. A total of 6 (27.27%) females and 5 (71.42%) males were normotensive and total 16 (72.72%) females and 2 (28.57%) males were hypertensive (RR: 1.12). Of a total of 22 female patients with PRES, 19 (86.36%) were in a postpartum state, one (4.45%) had systemic lupus erythematous (SLE), one (4.54%) had community-acquired pneumonia (CAP) with acute respiratory distress syndrome (ARDS) with septicemia and one (4.54%) had chronic hypertension in accelerated phase. Postpartum state was significantly associated with PRES (‘P‘ < 0.001). A total of 15 (68.18%) female patients had pregnancy-induced hypertension (PIH)/eclampsia. Of a total of 7 male patients with a diagnosis of PRES. two (28.57%) were had chronic kidney disease (CKD), two (28.57%) had chronic hypertension, one (14.28%) had alcohol intoxication, one (14.28%) had rheumatoid arthritis (RA), and one (14.28%) had septicemia with septicemic shock. Of a total three (10.34%) deaths, two were females (6.89%) and one (3.44%) was male. Total 26 (89.65%) patients were discharged after successful treatment. A total of three patients succumbed during treatment with case fatality rate of 10.34% (RR: 1.06). The most commonly involved location was the parieto-occipital and cerebellum brain region, which was seen in 23 (79.31%) patients and the lesions were asymmetric in 27 (93.10%) and symmetric in 2 (6.89%) cases. All 29 (100%) patients had bilateral affection. Conclusion: The present study revealed the significant numbers of patients in postpartum state with PRES syndrome with good prognosis. The present study highlighted affection of young, female population with history of hypertension with predominant affection of parieto-occipital and cerebellar involvement in PRES. Autoimmune disease, infection, alcohol intoxication, and CKD were less common factors associated with PRES. The history of hypertension in clinical scenario with neuro-imaging, we should consider the possibility of PRES and aggressively treat based on the clinical presentation. Brain imaging plays an important role in diagnosis of PRES. The early diagnosis, prompt treatment including maintenance of hydration control of blood pressure and seizure and removal of precipitating factors is mandatory for a good outcome of PRES with minimal or no residual neuro-deficit. Keywords: Posterior reversible encephalopathy syndrome, PRES, postpartum, seizures
Posterior reversible encephalopathy syndrome (PRES) is a clinical radiographic syndrome of heterogeneous etiologies. PRES is of various neurologic signs and symptoms that include headache, nausea, vomiting, altered mental status, seizure, visual disturbance, focal neurologic deficits, stupor, and coma. Many causes of PRES have been reported, including hypertensive encephalopathy, preeclampsia, eclampsia, renal failure, immunosuppressants, acute intermittent porphyria, thrombotic thrombocytopenic purpura, and systemic lupus erythematosus (SLE). Seizures in the early postpartum period are a diagnostic dilemma. Convulsions in the puerperium should be treated as eclampsia until proven otherwise. The other causes of convulsions should be vigorously pursued like cerebral venous sinus thrombosis (CVST), PRES, meningitis and cerebral vascular accident (CVA). PRES can present with focal neurologic deficits, mimicking a stroke and can often represent a diagnostic challenge when presenting atypically. A high degree of suspicion is required in the clinical setting in order to yield the proper diagnosis. PRES is caused by reversible ischemia most commonly of the posterior cerebral vasculature, thus affecting the parietal-occipital region. Common location of PRES are parietal-occipital most common followed by posterior frontal, temporal lobe, thalamus, cerebellum, brainstem, basal ganglia affected by other vascular territories can cause PRES. The PRES is also called as “reversible posterior leukoencephalopathy syndrome” and “reversible posterior cerebral edema syndrome.” Hypertension (HTN) is the most commonly identified cause of PRES, followed by medications, eclampsia, and systemic factors. The pathophysiology of HTN related PRES is due to a failure of cerebrovascular autoregulation, which in turn results in vasogenic edema. Nonhypertensive PRES may be due to immune response to various stimuli. The pathology usually affects the posterior brain hemisphere (parietal-occipital region), which may be a consequence of reduced sympathetic innervation in this area. Usually it is a reversible phenomenon, as indicated by the name, but if not recognized early and treated appropriately, irreversible brain injury may ensue. Cerebral computed tomography (CT) perfusion (CTP) is utilized in many institutions as the first line in acute stroke imaging and has proved to be a very sensitive measure of cerebral blood flow dynamics, most commonly employed to delineate the infracted tissue from penumbra (at-risk tissue) in ischemic strokes. However, abnormal CTP are also seen in stroke mimics such as seizures, hypoglycemia, tumors, migraines, and PRES. [1],[2],[3] In this article, we describe PRES in patients, presented with seizure with focal neurological deficits, concerning for a cerebrovascular accident. As there is inadequate data are available about PRES, the present study was conducted to correlate the demographic clinic-radiological profile of PRES.
A retrospective observational and non-interventional study was conducted at a tertiary care center in from January 2009 to December 2013 at the Krishna Institute of Medical Sciences, Karad. The medical research ethical committee of the Krishna Institute of Medical Sciences University, Karad, approved the protocol. Twenty-nine patients were eventually included as having confirmed PRES from 43 initially-suspected cases, as per imaging and clinical progress. Patient records were assessed for demographic data, clinical presentation, blood pressure measurements, laboratory parameters, co-morbid and predisposing conditions, and neuro-imaging. The primary etiology of PRES was determined for each case on the basis of the diagnosis of the attending physician. Aims and objectives To study demographic, etiological, and clinic-radiological profile of patients presenting with PRES and their outcome at a tertiary care teaching hospital. Inclusion criteria The presences of all three of the following criteria were mandatory for inclusion:
HTN was defined as a systolic blood pressure of 140 mm Hg or greater, or a diastolic blood pressure of 90 mm Hg or greater. Clinic-radiological inclusion criteria Inclusion as a confirmed case of PRES was based primarily on regression of the findings of suspected PRES on subsequent imaging, when available (n = 13), 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:
Exclusion criteria Cases lacking both clinical and imaging findings favoring PRES with an alternative diagnosis were excluded from the study. MRI Brain imaging Standard sequences were unenhanced FLAIR and T1- and T2-weighted images in all patients, with diffusion-weighted imaging and contrast-enhanced T1-weighted imaging. The regions involved were recorded on the basis of FLAIR findings, and the presence of atypical imaging findings (contrast enhancement, restricted diffusion and hemorrhage) was correlated with the severity of hyperintensity or mass effect on FLAIR. Patients with clinically and radiologically diagnosed PRES were identified retrospectively. The location was defined as frontal lobe, parieto-occipital region, temporal lobe, basal ganglia, cerebellum, brainstem, deep white matter, cortical zone, subcortical zone, and watershed zone. Statistical analysis was done by computer software SPSS-11, trial version. Categorical data were analyzed by mean, standard deviation (S.D.), percentage and Chi-square test. The level of significance was set at ‘P‘ < 0.05, and 95% confidence interval (CI) was used throughout.
Demographic profile Of a total 43 patients with suspected diagnosis of PRES, 29 patients were included fulfilling all inclusion criteria of PRES in this retrospective observational study. Of a total 29 patients with confirmed diagnosis of PRES, 22 (75.86%) were female (mean age of 29.90 years and S.D. ± 11.33) and 7 (24.13%) were male (mean age of 45.42 years with S.D. ± 7.20) patients, predominated by female population (relative risk [RR]: 3.14; odds ratio [OR]: 9.87; ‘P‘ < 0.001). The overall mean age was 33.65 years (SD ± 15.26) and mean duration of stay was 10.13 days (SD ± 4.98). Clinical and etiological profile The most common clinical presentation was generalized tonic-clonic seizures, seen in 23 (79.31%) patients, headache in 21 (72.41%) and visual disturbances 13 (44.82%). A total of 18 (62.06%) patients were hypertensive and 11 (37.93%) were normotensive (RR: 1.63; OR: 2.67; ‘P‘ = 0.066, i.e., insignificant). A total of 6 (27.27%) females and 5 (71.42%) males were normotensive and total 16 (72.72%) females and 2 (28.57%) males were hypertensive (RR: 1.12 OR: 1.6; ‘P‘ = 0.59 insignificant). Of total 22 female patients with PRES, 19 (86.36%) were in postpartum state, one (4.45%) had systemic lupus erythematous (SLE), one (4.54%) had community-acquired pneumonia (CAP) with acute respiratory distress syndrome (ARDS) with septicemia and one (4.54%) had chronic hypertension in an accelerated phase. Postpartum state was significantly associated with PRES (RR: 6.33; OR: 40.11; ‘P‘ < 0.001). Total 15 (68.18%) female patients had pregnancy-induced hypertension (PIH)/eclampsia. Of total 7 male patients with diagnosis of PRES, two (28.57%) were had chronic kidney disease (CKD), two (28.57%) had chronic HTN, one (14.28%) had alcohol intoxication, one (14.28%) had rheumatoid arthritis (RA), and one (14.28%) had septicemia with septicemic shock. Of total three (10.34%) deaths, two were in female (6.89%) (one had HELLP syndrome and one had septicemia with CAP) and one (3.44%) was a male patient with CKD. A total of two patients had CKD (male), two had autoimmune disease (one male had RA and one female had SLE), a total of one had infectious etiology (female: CAP with septicemia), and one male had alcohol intoxication [Table 1] [Graph 1].
Imaging profile The most commonly involved location was the parieto-occipital [Figure 1] and [Figure 3] and cerebellar region, including one with brain stem [Figure 2] involvement, which was seen in 23 (79.31%) patients, followed by the frontal lobe in 3 cases (10.34%), temporal lobe in 2 (6.88%) [Figure 1] and [Figure 3], and the basal ganglia with thalamus in 1 patient (3.44%). Of the cases, 21 (72.41%) had subcortical involvement and 8 (27.58%) had cortical involvement [Figure 3]. The lesions were asymmetric in 27 (93.10%) [Figure 1] and [Figure 3] and symmetric in 2 (6.89%) cases. All 29 (100%) patients had bilateral affection on neuro-imaging [Table 2] [Figure 1], [Figure 2] and [Figure 3] [Graph 2].
Clinical outcome Total 26 (89.65%) patients were (mean age 32.46 years [±9.92] and mean duration of stay was 15.14 days [±4.92]) discharged after successful treatment (female: 20 [76.94%] and male: 6 [23.07%]). Total three patients (mean age was 44 years [±14.73] mean duration of stay was 12 days [±6.24]) succumbed during treatment with a case fatality rate of 10.34%; of them two (9.09%) were female and one (14.28%) was male (RR: 1.06; OR: 1.66; ‘P‘ = 0.6942 statistically insignificant). Of total 3 death two (66.66%) had HTN and one (33.33%) was normotensive (RR: 2; OR: 4; ‘P‘ = 0.414 insignificant) [Table 3].
The patho-physiology of PRES remains mysterious. PRES has been described in a number of medical conditions including hypertension and postpartum state. Prompt recognition of this catastrophic condition and treatment is important in preventing the permanent damage due to cerebral ischemia. PRES is characterized by headache, seizures, confusion, and visual disturbance. Other focal neurologic deficits are uncommon. Seizures, which might begin focally, are usually generalized tonic-clonic and often multiple. It might be associated with visual phenomena such as visual loss and hallucinations to suggest occipital lobe origin. Other visual abnormalities include hemianopia, visual neglect, blurred vision, and cortical blindness. Clinical examination invariably shows normal papillary reflexes and fundoscopic findings. More serious causes of headache and seizure include meningitis, encephalitis, ischemic and hemorrhagic strokes, cerebral venous thrombosis and cerebral artery dissection should be thought for differential diagnosis. Prompt diagnosis and treatment for any of these is crucial. The pathogenesis of this syndrome appears to be related to disorder of cerebral autoregulation and endothelial dysfunction. The accompanying endothelial damage is reversible when hypertension is relieved which emphasizes the relationship between the severity of vasogenic oedema and the severity of hypertension. The various mechanisms ascribed to this condition are autoregulation, cerebral ischeamia, endothelial dysfunction, sepsis, uraemia, metabolic disturbances. We compared our results with various other studies. Alexander et al. [4] reported the incidence of regions of involvement was parieto-occipital, 98.7%; posterior frontal, 78.9%; temporal, 68.4%; thalamus, 30.3%; cerebellum, 34.2%; brainstem, 18.4%; and basal ganglia, 11.8%. Potentially new PRES causes included alcohol withdrawal. This large series of PRES cases shows that atypical distributions and imaging manifestations of PRES have a higher incidence than commonly perceived. Similarly in our study, the majority of patients had involvement of parito-occipital and cerebellar (79.31%) region. Cho et al. [1] reported PRES associated with pregnancy, in peripartum period presented with generalized tonic-clonic seizure headache, loss of vision, and short-term memory loss. Similarly in our study PRES is predominantly affected in postpartum female population. Rodrigo Pedraza et al. [5] stated PRES is most commonly associated with hypertensive encephalopathy, preeclampsia-eclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. The treatment is based in the management or withdrawal of the triggering factor. These findings are comparable with present study, in which significant number (62.06%) of patients had HTN, 86.36% females were in postpartum state, 15 (68.18%) female patients had PIH/eclampsia and one patient had HELLP syndrome who succumbed. Hypertension, postpartum state with PIH/eclampsia and were most common association and HELLP syndrome was uncommon association with PRES in our study. Panagiotis Zis et al. [6] reported a case PRES in a young woman, with a history of a miscarriage and a molar pregnancy. Ülkü Mete Ural et al. [7] reported a 33-year-old multi-gravida with a history of preeclampsia in term pregnancy complicated by PRES without seizures in postpartum period. Similarly, in our study 20.68% patients had PRES without seizure. Chhabra et al. [8] reported PRES in a 23-year-old female patient, with unremarkable antenatal period, who developed convulsions in the immediate postpartum period following elective cesarean delivery. Similarly in our stud,y 3 (15.78%) female patients out of 19 in postpartum state without history of PIH/eclampsia had PRES. Jamie et al. [9] also reported two cases with late postpartum encephalopathy (LPE) who have had a normal pregnancy and delivery and have no signs of a preeclamptic syndrome. Long et al. [10] described a case of PRES in a previously healthy parturient who presented with generalized tonic-clonic seizures. Shakuntala et al. [11] reported a case of PRES occurring in atypical areas like the caudate and lentiform nuclei of the brain following an uneventful lower segment caesarean section in a normotensive patient. Similarly in our study one (3.44%) patient had involvement of basal ganglia and thalamus. Similarly Jeong-Yeon Hong et al. [12] reported case of PRES in a 29-year-old normotensive parturient who developed headache with generalized seizures. Ay et al. [13] reported three female patients with mild elevations in blood pressure with a neurologic syndrome consistent with PLES (T2 hyperintense regions in the posterior cerebrum with vasogenic edema). However, PRES very rarely develops in pregnant women with mild HTN or normal blood pressure. [10],[13] Madura Adikari et al. [14] reported hypertensive encephalopathy following post-streptococcal glomerulonephritis is a known but developing PRES is rare association. Shaharir et al. [15] reported PRES is a rare neurological disorder which is increasingly recognized to occur in SLE, in our study one (3.44%) female patient had SLE who developed PRES. Jennifer E. Fugate et al. [3] reported autoimmune disease was present in 45% patients these findings are not comparable with our study, in which only one (3.44%) patient had SLE and one (3.44%) male patient had RA. Liman et al. [16] reported mortality of 4.8% in PRES. Similarly in our study, 3 patients succumbed with overall case fatality rate of 10.34%. de Laat et al. [17] found that HTN seems to be the most important trigger for the occurrence of PRES, with seizures being the most common accompanying sign. These findings are comparable with our results in which 62.06% patients had HTN and 68.18% female patients had PIH/eclampsia and generalized tonic-clonic seizures was the most common presenting feature in 79.31% patients. Jennifer E. Fugate et al. [3] reported 61% of patients with PRES had HTN and 7% had sepsis, with parieto-occipital regions were commonly involved [94%]. These findings are comparable with our results in which generalized tonic-clonic seizures was the most common presenting feature in 79.31% patients followed by headache in 72.41%, HTN was present in 62.06% and infection was present in 3.44% (CAP with septicemia) of patients. In our study the most commonly involved location in PRES was parieto-occipital and cerebellum brain region (79.31%). Jennifer E Fugate et al. [3] reported only 6% patient with preeclampsia or eclampsia, these findings are not comparable with our study were 68.18% female patients had pregnancy induced hypertension/ eclampsia. Legriel et al. [18] reported seizures in 81% patients. Cerebral imaging abnormalities were bilateral (93%) and predominated in the parietal (93%) and occipital (86%) white matter. Median number of brain areas involved was four. Total 41% had hypertensive encephalopathy. Total 16% patients died during course of treatment. These findings are comparable with our results in which generalized tonic-clonic seizures was present in 79.31% patients followed by headache in 72.41% with MRI imaging showing 100% bilateral and asymmetric involvement parieto-occipital and cerebellar region with median 3 area of brain involvement with hypertension in more than half (62.06%) of the population. Paul et al. [19] stated that the hemolysis (H), elevated liver enzymes (EL), and low platelets (LP) (HELLP) syndrome is the extended spectrum of severe preeclampsia and is associated with high mortality. Of total 108 patients, 12 patients had HELLP and eight (66%) patients had neurological complications. Neurological complications are not uncommon in patients with HELLP syndrome and a high index of suspicion is essential. Similarly in our study one (3.44%) patient had HELLP syndrome who succumbed. Trikha et al. [20] reported a 25-year-old primigravida who presented in term pregnancy with seizures and blindness, scheduled for emergency caesarean section. In our study, the most common clinical presentation was generalized tonic-clonic seizures, seen in 79.31% patients, headache in 72.41% and visual disturbances 44.82%. Gera et al. [21] case series included 11 (1.66%) patients predominated by male population of PRES out of a total 660 renal pediatric patients. Presenting symptoms were headache in 73%, dimness of vision or cortical blindness in 36%, seizures in 91%. CKD was present in 9%. The contributory factors were uncontrolled HTN (100%); brain imaging showed involvement of occipito-parietal area (100%) and other brain areas (63%). These findings, except for male gender predominance, are comparable with our results were seizure and headache were most common presenting complaints and two (6.88%) patients with CKD with hypertension as a contributory factor with predominantly parieto-occipital involvement had PRES. Jennifer E Fugate et al. [3] found that the patients with sepsis were more likely to have cortical involvemen;, similarly our patient with CAP and septicemia had cortical involvement. Alejandro A Rabinstein et al. [22] analyzed the blood pressure (BP) profiles in 25 cases of PRES and 25 controls. Although acute HTN is frequent in patients with PRES, BP fluctuations do not appear to be more common in hospitalized patients who develop PRES compared with controls matched for age and history of HTN. Other predisposing factors must therefore contribute to the development of PRES. These findings are comparable with our results in which, 37.93% patient developed PRES without HTN. Liman et al. [16] reported 24 patients with preeclampsia-eclampsia associated PRES and 72 patients with PRES of other predisposing causes were included in the study. They found major clinico-radiological differences between preeclampsia-eclampsia and other predisposing causes pointing toward a less severe course of disease in preeclampsia-eclampsia. Similarly in our study, a total 68.18% female patients had PIH/eclampsia; of them one with HELLP syndrome succumbed with mortality rate of 6.66% and one patient with CAP with septicemia succumbed 14.28%, an indication more mortality in patients without preeclampsia-eclampsia. Siebert et al. [23] studied total 18 paediatric patients with PRES with frequent predisposing causes were renal and haemato-oncologic diseases. Frontal lesions occurred as frequently as parietal lesions followed by occipital lesions. Clinical syndromes associated with PRES included seizures in 100% patients. Similarly in our adult population seizure was common presenting feature with predominant affection of parieto-coccipital and cerebellar region. Jennifer E Fugate et al. [3] observed cerebellar involvement was significantly more frequent in patients with a history of autoimmunity (‘P‘ = .008); similarly, in our study one patient with SLE and with RA had cerebellar involvement. Although many researchers believe that hypertensive encephalopathy is the cause of PRES, however, there have been reports of cases of PRES without any hypertensive complications. MRI techniques, such as echo-planar diffusion-weighted images and apparent diffusion coefficient maps, make it possible to differentiate the edema from other pathologic states. Regarding therapeutic strategies, a reduction in blood pressure and seizure control are essential. The cerebral edema usually resolves with treatment for the hypertension. However, transtentorial herniation has been reported. More aggressive measures may be warranted in the case of impending herniation. When patients present with a focal neurologic deficit, a CT scan must be performed in order to rule out a hemorrhagic or ischemic stroke. However, the CT scan is rarely abnormal and MRI is the imaging modality of choice. The T2-weighted MRI demonstrates hyperintensity spreading out from posterior brain regions. In the acute setting, diffusion-weighted imaging (DWI), but not standard MRI, can distinguish ischemic injury from those conditions known to cause vasogenic brain edema. DWI is potentially valuable in understanding the pathophysiology of PRES and in diagnosing patients who do not have previously known risk factors.
PRES is a serious and increasingly recognized disorder, but data from observational studies on outcome and mortality in PRES are scarce. The present study highlighted the significant affection of postpartum females with PRES syndrome with good outcome and prognosis, compared to other central nervous system (CNS) conditions, including cerebro-vascular accident and cerebral venous sinus thrombosis. There is wide range of differential diagnosis for the neurological catastrophic manifestation during peripatum period like cerebral venous sinus thrombosis, meningitis, PRES, and ischemic and hemorrhagic stroke. Present study highlighted affection of young, female population with history of hypertension with predominant affection of parieto-occipital and cerebellar involvement in PRES. Autoimmune disease (RA and SLE), infection, alcohol intoxication and chronic kidney disease were less common factors associated with PRES. The history of hypertension in clinical scenario with neuro-imaging, we should consider the possibility of PRES and aggressively treat based on the clinical presentation. Prompt and pertinent strategies of treatment may reverse the edematous process before it progresses to permanent brain injury. Brain imaging play an important role in diagnosis of PRES. Meticulous clinical examination, including previous history, clinical scenario, high degree of clinical suspicion, and expert brain imaging reporting, is mandatory for the diagnosis of PRES. The early diagnosis, prompt treatment including maintenance of hydration control of BP and seizure and removal of precipitating factors is mandatory for good outcome of PRES with minimal or no neuro-deficit. The importance of prompt suspicion and management in preventing short- and long-term neurological deficits in reversible condition like PRES is highlighted. PRES is an under-diagnosed entity in clinical practice with hypertension is an important trigger. Early diagnosis and treatment of co-morbid conditions is of prime importance for early reversal of syndrome.
Source of Support: None, Conflict of Interest: None
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