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Predictors of seizures in patients with posterior reversible encephalopathy syndrome
Epilepsy & Behavior 61 (2016) 97–101
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Predictors of seizures in patients with posterior reversible encephalopathy syndrome Archana Hinduja a,e,⁎, Kenneth Habetz b, Sunil Kumar Raina c, Ryan T. Fitzgerald d, Kinshuk Sahaya a a
Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR, USA Department of Pediatric Neurology, Arkansas Children Hospital, Little Rock, AR, USA Department of Community Medicine, Dr. RP Government Medical College, Tanda, India d Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA e Department of Neurology, Ohio State University Wexner Medical Center, Columbus, OH, USA b c
a r t i c l e
i n f o
Article history: Received 14 March 2016 Revised 12 April 2016 Accepted 3 May 2016 Available online xxxx Keywords: Posterior reversible encephalopathy syndrome Hypertensive encephalopathy Seizures
a b s t r a c t Purpose: Although seizures are common in patients with posterior reversible encephalopathy syndrome (PRES), epilepsy is rare. Our objective was to identify predictors and impact of seizures in patients with PRES. Methods: A retrospective review of the clinical and radiological parameters of all patients diagnosed with PRES from 2007 to 2014 was performed. Patients were divided into two groups based on the occurrence of PRESrelated seizures at presentation or during their hospital course. Univariate and multivariate analyses were performed to determine factors associated with the occurrence of PRES-related seizures. Results: Of 100 patients, 70% experienced at least one seizure from PRES. On univariate analysis, the factors associated with seizures were the following: high Charlson comorbidity index (4.16 ± 2.89 vs. 2.87 ± 2.20, p = 0.03), systemic malignancy (41.4% vs. 16.7%, p = 0.02), occipital lobe involvement (97.1% vs. 83.3%, p = 0.02), more lobes involved (4.6 ± 1.48 vs. 3.9 ± 1.32, p = 0.03) but less likely in patients with visual disturbances (15.7% vs. 46.7%, p = 0.005), and facial droop (12.9% vs. 16.7%, p = 0.002). On multivariate analysis, only occipital lobe involvement was significantly (odds ratio: 9.63, 95% CI: 1.45–64.10, p = 0.02) associated with the occurrence of PRES-related seizures. Despite the occurrence of seizures, they were less likely to require a nursing home placement upon hospital discharge (odds ratio: 0.17, 95% CI: 0.03–0.91, p = 0.04). Conclusion: We conclude that seizures are common in patients with occipital lobe involvement from PRES. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Posterior reversible encephalopathy syndrome (PRES) is a wellrecognized acute neurotoxic syndrome characterized by a combination of clinical and neuroimaging findings. The spectrum of neurological features includes headache, impaired level of consciousness, seizures, visual disturbances, nausea/vomiting, and focal neurological deficits [1,2] in variable combinations. On neuroimaging, PRES is characterized by bilateral, cortical/subcortical vasogenic edema commonly involving the parietal and occipital regions, followed by the frontal, inferioroccipital, and cerebellar regions [3–5]. Commonly reported triggering factors include acute hypertension, preeclampsia or eclampsia, renal disease, sepsis, autoimmune diseases, and exposure to chemotherapeutic agents and immunosuppressants [6,7]. Seizures are a common manifestation and have been reported in 70–80% of PRES cases [6,7]; on occasion, status epilepticus may be the presenting symptom [8]. Despite these, epilepsy following PRES ⁎ Corresponding author at: Department of Neurology, Ohio State University Wexner Medical Center, Columbus, OH, USA. Tel.: +1 614 688 9434; fax: +1 614 366 7004. E-mail address: [email protected] (A. Hinduja).
http://dx.doi.org/10.1016/j.yebeh.2016.05.001 1525-5050/© 2016 Elsevier Inc. All rights reserved.
is rare [9]. Patients with seizures are frequently treated with antiseizure drugs (ASDs) for a short course. The pathophysiology of PRES is highly controversial. Various proposed hypotheses include vasoconstriction from hypertension with autoregulatory compensation, leading to ischemia and cerebral edema [10]; severe hypertension exceeding the autoregulatory limit, leading to hyperperfusion and cerebral edema [2,11]; and endothelial dysfunction [5,12]. Although initially thought to be reversible, recent literature has reported severe functional impairments in 44% of patients admitted to the intensive care unit [13], and the mortality is about 3–6% [6,14]. Besides, various clinical and experimental studies have reported neuronal damage from status epilepticus, although its extent following a single seizure or repeated brief seizures is controversial [15–18]. Thus, an improved understanding of the frequency and risk factors of seizures in patients with PRES would help us identify patients at risk of developing seizures and those who may benefit from continuous electroencephalographic (EEG) monitoring and prophylactic treatment in order to improve their functional outcome. The primary aim was to determine the frequency, risk factors, and discharge outcome of seizures in patients with PRES. The secondary aim was to determine the rates of recurrent seizures and epilepsy following PRES.
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2. Methods
2.4. Outcome
2.1. Subjects
Outcome was assessed using the modified Rankin Score (mRS), Glasgow Outcome Scale (GOS) at discharge, discharge disposition (home, rehabilitation facility, long-term nursing home), and in-hospital mortality. Information on neurological events, especially seizures and epilepsy, was evaluated if available upon follow-up.
We retrospectively reviewed all electronic medical records using the International Classification of Diseases version 9 codes for encephalopathy and PRES in patients ≥ 18 years of age, admitted to our tertiary care medical center from 2007 to 2014. All consecutive records were screened for the inclusion of PRES. A diagnosis of PRES was based on the clinical and radiological features consistent with PRES [3–5]. Magnetic resonance imaging (MRI) studies were reviewed by two independent, certified, experienced staff neuroradiologists blinded to the clinical findings, and in case of disagreement, consensus was reached. Electroencephalographic (EEG) patterns were interpreted by an experienced epileptologist blinded to clinical information and outcomes. 2.2. Definitions Diagnostic criteria of PRES were an acute neurotoxic syndrome with features of headache, impaired consciousness, seizures, visual abnormalities, nausea/vomiting, focal neurological deficits in variable combinations [1,2], and imaging findings consistent with PRES on MRI [5]. Visual disturbances included blurred vision, visual hallucinations, homonymous hemianopsia, visual neglect, and cortical blindness. Status epilepticus was defined as continuous seizures ≥5 min or two or more discrete seizures between which there was incomplete recovery of consciousness [19]. Posterior reversible encephalopathy syndrome-related epilepsy was defined as at least two unprovoked seizures occurring N24 h apart more than one month after the inciting episode with complete or near complete resolution of imaging abnormalities [20,21]. Additionally, patients with prior history of epilepsy were excluded. This time frame was selected since, although clinical recovery occurs in a few days in the majority of cases, it may occasionally take a month in certain cases [6,22,23]. A provoked seizure was defined as a seizure that occurred in the context of a precipitating cause that could lower the seizure threshold [20,21]. Hypertension was defined as a systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg [24]. 2.3. Data collection Patients were dichotomized into two groups based on the occurrence of seizures either at presentation or during hospitalization. Comparison of their baseline demographics, medical comorbidities, neurological symptoms, predisposing conditions, vital signs, Glasgow Coma Score (GCS), length of hospitalization, laboratory values, and imaging was performed. In cases with more than one predisposing condition, the clinically dominant etiology was used for analysis. Comorbidities were quantified using the Charlson comorbidity index [25]. Imaging features evaluated included the distribution of vasogenic edema (parietal, occipital, frontal, temporal, cerebellar, thalamus, midbrain, pons, medulla, lentiform nucleus, caudate, putamen, corpus callosum), number of lobes involved, severity of vasogenic edema (grading scheme by McKinney et al.), cortical or subcortical involvement, typical and atypical features, presence of restricted diffusion, hemorrhage, contrast enhancement, and degree of resolution on follow-up imaging if available. Atypical features were defined as involvement of the frontal lobes, basal ganglia, brain stem, and deep cerebral white matter; contrast enhancement; hemorrhage; restricted diffusion; and minimal involvement of the parieto-occipital regions [26]. The EEG findings analyzed were the following: background activity (normal, focal, and generalized slowing), the presence of epileptiform discharges, electrographic seizures, and periodic lateralized epileptiform discharges. Mild slowing was referred to background frequencies in the alpha–theta range, moderate slowing for frequencies in the theta range, and severe slowing for frequencies in the delta range.
2.5. Statistical analysis For all statistical analyses, SPSS version 21 software was used, and a p value of b 0.05 was considered significant. Univariate analysis was performed using Student's t-test for continuous variables and ‘z’ score for categorical variables to identify factors associated with clinical seizures. Multivariate logistic regression analysis of all significant variables (p b 0.05) on univariate analysis was performed to identify predictors associated with seizures in patients with PRES. 3. Results 3.1. Characteristics and comparison between groups with and without seizures Based on the inclusion criteria, 100 patients with PRES were identified, of which 70% experienced at least one PRES-related seizure either upon presentation or during hospitalization. Details of the cohort are described in Table 1. On MRI studies, vasogenic edema was commonly observed in the occipital lobe (93%) and parietal lobe (93%) followed by the frontal lobe (89%), cerebellum (57%), temporal lobe (39%), and thalamus (32%). On univariate analysis (Tables 2 and 3), the factors associated with the occurrence of seizures following PRES were a high Charlson comorbidity index (4.16 ± 2.89 vs. 2.87 ± 2.2, p = 0.03); systemic malignancy (41.4% vs. 16.7%, p = 0.02); occipital lobe involvement (97.1% vs. 83.3%, p = 0.02); greater number of lobes involved (4.6 ± 1.48 vs. 3.9 ± 1.32, p = 0.03), with decreased probability in patients with visual disturbances (15.7% vs. 43.3, p = 0.005); and facial droop (15.7% vs. 46.7%, p = 0.002). On multivariate analysis (Table 4), only occipital lobe involvement was associated with the occurrence of seizures in patients with PRES (odds ratio: 9.63, 95% CI: 1.45–64.10, p = 0.02). Further occurrence of a seizure on initial presentation or hospitalization did not significantly increase the risk of subsequent seizures (21.2% vs. 21.4%, p = 1.00) upon follow-up (median: 14.5 months, IQR: 4.7 months to 30.3 months). Despite the lack of a significant difference in mortality or poor functional outcome at discharge (based on mRS and GOS) between both cohorts, patients with PRES-related seizures were less likely to be discharged to a nursing home (4.3% vs. 20%, p = 0.01). Table 1 Demographics of 100 patients with PRES. Clinical characteristics
Number of patients
Age (years, median, interquartile range) Gender (males, %) Precipitating cause Hypertension Eclampsia Renal failure Malignancy Chemotherapy Seizures Generalized tonic–clonic seizures Status epilepticus Focal seizures Charlson comorbidity index (median ± SD) Glasgow Coma Score (median ± SD) Length of hospital stay (median ± SD) Length of intensive care unit stay (median ± SD) Mortality at hospital discharge
50 (33–61) 27 49 13 9 18 11 70 52 7 11 4 (2–5) 15 (10–15) 9 (4–22) 2 (0–5) 8
A. Hinduja et al. / Epilepsy & Behavior 61 (2016) 97–101 Table 2 Predictors of seizures in patients with PRES.
Age (years, mean ± SD) Male (n, %) Race (Caucasian) (n, %) Past medical history (n, %) Hypertension Diabetes mellitus Hyperlipidemia Atrial fibrillation Smoking Alcohol Past history of seizures Clinical features (n, %) Headache Nausea/vomiting Encephalopathy Coma Vision change Cranial nerve involvement Weakness Sensory loss Hospital characteristics Charlson CI (mean ± SD) GCS at insult (mean ± SD) Admitted to ICU (mean ± SD) LOH stay (days) (mean ± SD) LO ICU stay (days) (mean ± SD) Precipitating cause (n, %) Hypertension Eclampsia Renal failure Multiorgan failure Malignancy Chemotherapy Autoimmune condition Admission labs (mean ± SD) Hemoglobin, g/dL Hematocrit, % White cell count, K/μL Platelet count, K/μL Blood urea nitrogen, mg/dL Creatinine, mg/dL Serum glucose, mg/dL Serum sodium, mmol/L Serum calcium, mg/dL Serum magnesium, mg/dL Imaging (n, %) Parietal lobe Occipital lobe Frontal lobe Temporal lobe Cerebellum Thalamus Midbrain Pons Medulla Lentiform nucleus/caudate Putamen Corpus callosum No. of lobes involved (mean ± SD) Typical/atypical Cortical Restricted diffusion Contrast enhancement Hemorrhage Grade of PRES based on MRI (n, %) Mild Moderate Severe
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Table 3 Outcomes of patients with PRES who developed seizures.
Seizures (N = 70)
No seizures (N = 30)
p value
47.60 ± 16.52 15 (21.4%) 48 (68.6%)
46.97 ± 15.62 12 (40%) 24 (80%)
0.86 0.08 0.33
30 (57.1%) 11 (15.7%) 10 (14.3%) 2 (2.9%) 21 (30%) 9 (12.9%) 4 (5.7%)
19 (63.3%) 4 (13.3%) 4 (13.3%) 1 (3.3) 11 (36.7%) 4 (13.3%) 3 (10%)
0.66 1.00 1.00 1.00 0.64 1.00 0.43
27 (38.6%) 24 (34.3%) 58 (82.9%) 4 (5.7%) 11 (15.7%) 11 (15.7%) 9 (12.9%) 0 (0%)
12 (40%) 10 (33.3%) 24 (80%) 1 (3.3%) 13 (43.3%) 14 (46.7%) 5 (16.7%) 1 (3.3%)
1.00 1.00 0.78 1.00 0.005 0.002 0.75 0.30
4.16 ± 2.89 12.16 ± 3.77 47 (67%) 20.04 ± 34.60 4.33 ± 9.90
2.87 ± 2.20 12.93 ± 3.30 20 (66.7%) 14.97 ± 12.64 6.53 ± 10.74
0.03 0.33 1.00 0.44 0.32
56 (80%) 7 (10%) 33 (47.1%) 34 (48.6%) 29 (41.4%) 26 (37.1%) 13 (18.6%)
27 (90%) 3 (10%) 15 (50%) 16 (53.3%) 5 (16.7%) 6 (20%) 4 (13.3%)
0.26 1.00 0.83 0.83 0.02 0.11 0.77
11.55 ± 2.28 34.74 ± 6.47 10.09 ± 6.89 201.83 ± 150.34 22.20 ± 16.96 2.60 ± 3.41 133.09 ± 56.95 137.43 ± 4.83 8.70 ± 1.06 2.10 ± 0.65
11.18 ± 2.00 33.67 ± 6.14 12.16 ± 5.68 188.07 ± 113.04 28.20 ± 23.99 2.15 ± 1.72 125.40 ± 41.02 136.60 ± 5.47 8.54 ± 0.92 2.11 ± 0.69
0.44 0.44 0.15 0.65 0.16 0.50 0.51 0.45 0.45 0.95
66 (94.3%) 68 (97.1%) 64 (91.4%) 32 (45.7%) 39 (55.7%) 26 (37.1%) 6 (8.6%) 20 (28.6%) 3 (4.3%) 14 (20%) 11 (15.7%) 14 (20%) 4.6 ± 1.48 68 (97.1%) 59 (84.3%) 12 (17.1%) 5 (7.1%) 19 (27.1%)
27 (90%) 25 (83.3%) 25 (83.3%) 7 (23.3%) 18 (60%) 6 (20%) 2 (6.7%) 8 (26.7%) 2 (6.7%) 2 (6.7%) 4 (13.3%) 6 (20%) 3.9 ± 1.32 28 (93.3%) 25 (83.3%) 6 (20%) 3 (10%) 7 (23.3%)
0.43 0.02 0.30 0.05 0.83 0.11 1.00 1.00 0.64 0.14 1.00 1.00 0.03 0.58 1.00 0.77 0.10 0.81
40 (57.1%) 24 (34.3%) 6 (8.6%)
17 (56.7%) 12 (40%) 1 (3.3%)
0.97 0.59 0.3
SD, standard deviation; Charlson CI, Charlson comorbidity index; GCS, Glasgow Coma Score; ICU, intensive care unit; LOH stay, length of hospital stay; LO ICU stay, length of intensive care unit stay; No., number; MRI, magnetic resonance imaging.
Seizures (70) Outcome at discharge mRS (modified Rankin Score) (mean ± SD) GOS (Glasgow Coma Score) (mean ± SD) Discharge disposition (n, %) Home Rehab Nursing home Death Seizures on follow-up (n, %) Recurrent PRES on follow-up (n, %) Follow-up imaging (n, %) Resolution on follow-up imaging (n, %) Complete Incomplete Progression Relapse Remitting/relapsing
No seizures (30)
p value
1.83 ± 1.98 2.17 ± 1.93 0.43 4.20 ± 1.22 4.03 ± 1.07 0.52 56 (80%) 5 (7.1%) 3 (4.3%) 6 (8.6%) 11 (21.2%) 5 (9.6%) 29 (41.4%)
19 (63.3%) 4 (13.3%) 6 (20%) 1 (3.3%) 3 (21.2%) 1 (7.1%) 12 (40%)
0.07 0.32 0.01 0.34 1.00 1.00 1.00
14 (20%) 8 (11.4%) 2 (2.9%) 4 (5.7%) 1 (1.4%)
5 (16.7%) 4 (13.3%) 2 (6.7%) 1 (3.3%) 0 (0%)
0.70 0.79 0.38 0.61 0.51
Based on the clinical semiology, the most common seizure type was generalized seizures (57 patients, of which 5 patients had generalized convulsive status epilepticus), followed by focal seizures (13 patients, which progressed to generalized status epilepticus in two patients). 3.2. EEG interpretation Among 70 patients with PRES-related seizures, EEG was performed in 60 patients during their hospital course (Table 5). The most common EEG pattern was generalized slowing with a majority being in the theta–delta range, followed by normal EEG patterns and generalized with additional focal slowing. In 10 patients, besides generalized slowing, other EEG abnormalities identified were the following: epileptiform discharges, electrographic seizures, and periodic lateralized epileptiform discharges (PLEDS). In the majority of patients, the epileptogenic foci were the posterior head regions followed by the temporal and frontal regions. None of our patients had electrographic status epilepticus. Among patients without seizures, although generalized slowing was the most common pattern, none had epileptiform discharges. The most common antiseizure drugs (ASDs) used during hospitalization were fosphenytoin (39 patients) and benzodiazepines (38 patients) and upon discharge levetiracetam (39 patients) and fosphenytoin (26 patients). Antiseizure drugs were discontinued upon discharge in 8 patients who developed PRES from nonpregnancy-related etiologies. The majority of patients (54 patients) required only one ASD upon discharge that was discontinued in 21 patients at follow-up. Upon follow-up, recurrence of seizures (after exclusion of patients with prior epilepsy) occurred in 11 patients, of which 9 patients had provoked seizures, and 2 had unprovoked seizures. Of the two patients with unprovoked seizures, one developed epilepsy, and the second patient had serial focal seizures (less than 24 h apart) 3 months following PRES that did not recur during a follow-up course of one year. Although the patient with serial focal seizures (less than 24 h apart) 3 months following PRES had a normal EEG, there was encephalomalacia of bilateral parieto-occipital regions and left parahippocampal gyrus with petechial hemorrhages of the parieto-occipital regions on imaging. Only 1% (1 patient) from our cohort developed PRES-related epilepsy. This patient had generalized status epilepticus followed by complex partial seizures Table 4 Binary logistic regression analysis of predictors of seizures among patients with PRES. Variables
Odds ratio (95% CI)
p value
Disposition to nursing home Occipital lobe involvement
0.17 (0.03–0.91) 9.63 (1.45–64.10)
0.04 0.02
CI, confidence interval.
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A. Hinduja et al. / Epilepsy & Behavior 61 (2016) 97–101
Table 5 EEG findings in 78 of 100 patients with PRES. EEG findings
N = 78
EEG in patients with seizures Generalized slowinga Mild slowing Mild to moderate slowing Moderate slowing Moderate to severe slowing Severe slowing Generalized with additional focal slowing Generalized slowing with additional EEG abnormalities Epileptiform discharges Electrographic seizures Periodic lateralized epileptiform discharges Focal slowing Focal slowing with epileptiform discharges Normal EEG in patients without seizures Generalized slowing Generalized with additional focal slowing Normal
60 33 3 2 2 25 1 6 10 10 4 3 1 1 9 18 12 2 4
Slowing in all subgroups were in the moderate to severe range (except in a as mentioned above).
during the acute phase but had recurrent generalized seizures during the 2 years of follow-up. The initial EEG of this patient showed epileptiform discharges with electrographic seizures in the left posterior quadrant but on follow-up showed left temporal focal slowing only. The 3month follow-up MRI showed complete resolution of the vasogenic edema of the left cerebellum and left hippocampus but with development of bilateral hippocampal sclerosis. 4. Discussion In this single-center retrospective study of 100 patients, 70% developed PRES-related seizures, which is congruent with the results from prior studies [7,21]. The majority of patients had a generalized type of seizure semiology and generalized slowing on EEG, which are consistent with other studies [9,21]. In our cohort, the only factor associated with PRES-related seizures was involvement of the occipital lobe on imaging. This is a unique finding since there is limited information on factors associated with PRES-related seizures. This is different when compared to seizures from other vascular etiologies like acute ischemic stroke and hemorrhagic strokes, where locations like the parietal, temporal, and frontal lobes have a high propensity of seizures as opposed to occipital lobe involvement from PRES as in our cohort [27,28]. Besides, there was no significant correlation between the number of lobes involved from PRES and the occurrence of seizures, which is also unique when compared to patients with ischemic and hemorrhagic strokes [29,30]. Posterior reversible encephalopathy syndrome is a complex disease of heterogeneous etiology, with particular involvement of the parieto-occipital regions likely from relatively sparse sympathetic innervation of the vertebrobasilar circulation [31]. Cerebral blood flow studies have revealed both cerebral hypoperfusion and hyperperfusion [2,32] with evidence of angiographic vasospasm and vasculopathy predominantly affecting the posterior circulation and watershed regions [33]. In our cohort, although both the parietal and occipital lobes were involved with equal frequency, there was a greater proportion of seizures from occipital lobe involvement likely from its inherent “selective vulnerability” coupled with hypoperfusion from PRES resulting in hypoxia, a well-known mechanism of seizures [34,35]. Besides the location, the occurrence of PRES-related seizures was independent of involvement of the cerebral cortex and the presence of hemorrhage and number of affected lobes, which is also different when compared to seizures from other vascular etiologies [28,29]. Biopsies in patients with PRES have revealed edematous white matter with inflammatory response from macrophages, lymphocytes, and astrocytes, which could
alternatively explain the mechanism of seizures in these patients [36, 37]. Epilepsy and unprovoked seizures related to PRES occurred in 1–2% of our cohort, which is similar to prior studies [9,21]. The only patient who developed PRES-related epilepsy had imaging evidence of hippocampal sclerosis that may have developed as a sequel of generalized convulsive status epilepticus during PRES, which is a rare phenomenon following PRES [38]. Although both normal and abnormal MRIs have been reported on follow-up in patients who developed epilepsy, both our patients who developed unprovoked seizures had structural damage on imaging which may explain its recurrence beyond the acute phase [21]. In our cohort, although occipital lobe involvement was a predictor of PRES-related seizures in the acute phase, given a very small percentage of epilepsy following PRES, the correlation could not be fully determined. Similar to other studies, 54% of patients (22 of 41 patients) in our cohort who underwent follow-up MRI either had incomplete resolution, progression, relapse, or other imaging abnormalities like infarction, atrophy, and laminar necrosis, which is consistent with prior studies [39]. Despite a very high percentage of residual abnormalities, only 1% developed PRES-related epilepsy. Thus, besides structural abnormalities, other factors play a contributing role in the development of epilepsy which will need to be evaluated in future studies. In our cohort, the occurrence of PRES-related seizures did not influence the admission to the intensive care unit, length of hospital stay, length of intensive care utilization, or the discharge outcome based on the mRS and GOS. Besides, there was no significant correlation between PRES-related seizures and mortality, which is similar to seizures following cerebrovascular disease [40]. Interestingly, in our cohort, patients who developed seizures from PRES were less likely to be discharged to a nursing home, which may either imply that factors other than seizures played a major role in the discharge disposition or prompt identification and aggressive care were provided in the subset of patients with seizures. Some of the major drawbacks of our study include the retrospective, single-institution study design; lack of information on time intervals between causative-factor exposure and development of PRES; lack of a standardized treatment protocol for management of PRES; use of ASDs during hospitalization or upon follow-up; and lack of consistency in data on long-term clinical, imaging, EEG, and cognitive outcomes. Another pitfall of our study was that ASDs were discontinued only in a third of patients (21 patients) upon follow-up, which may have impacted the development of recurrent seizures and epilepsy. We evaluated patients who had clinical seizures or those where there was a high clinical suspicion of seizures and thus there may have been a selection bias in obtaining EEG and we may have missed electrographic seizures.
5. Conclusion Posterior reversible encephalopathy syndrome is a neurological emergency condition that requires prompt recognition and aggressive management to achieve reversibility and favorable long-term outcomes. Although seizures during the acute phase are common, unprovoked seizures or epilepsy is rare. The only identifiable predictor of seizures in our cohort was the involvement of the occipital lobe. Although incomplete resolution and residual structural lesions are common, factors beyond structural damage may play a contributing role in the occurrence of PRES-related epilepsy and will need to be evaluated in the future. Larger prospective randomized studies using advanced imaging techniques such as diffusion tensor imaging and functional MRI are required to validate this finding and help identify patients at high risk of seizures. A future direction, besides obtaining an early MRI and prompt management, is to evaluate the benefit of a short course of empiric ASDs especially in patients with cortical occipital lobe involvement or epileptiform discharges on EEG until the etiology is controlled and to assess their outcomes.
A. Hinduja et al. / Epilepsy & Behavior 61 (2016) 97–101
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Predictors of seizures in patients with posterior reversible encephalopathy syndrome Archana Hinduja a,e,⁎, Kenneth Habetz b, Sunil Kumar Raina c, Ryan T. Fitzgerald d, Kinshuk Sahaya a a
Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR, USA Department of Pediatric Neurology, Arkansas Children Hospital, Little Rock, AR, USA Department of Community Medicine, Dr. RP Government Medical College, Tanda, India d Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA e Department of Neurology, Ohio State University Wexner Medical Center, Columbus, OH, USA b c
a r t i c l e
i n f o
Article history: Received 14 March 2016 Revised 12 April 2016 Accepted 3 May 2016 Available online xxxx Keywords: Posterior reversible encephalopathy syndrome Hypertensive encephalopathy Seizures
a b s t r a c t Purpose: Although seizures are common in patients with posterior reversible encephalopathy syndrome (PRES), epilepsy is rare. Our objective was to identify predictors and impact of seizures in patients with PRES. Methods: A retrospective review of the clinical and radiological parameters of all patients diagnosed with PRES from 2007 to 2014 was performed. Patients were divided into two groups based on the occurrence of PRESrelated seizures at presentation or during their hospital course. Univariate and multivariate analyses were performed to determine factors associated with the occurrence of PRES-related seizures. Results: Of 100 patients, 70% experienced at least one seizure from PRES. On univariate analysis, the factors associated with seizures were the following: high Charlson comorbidity index (4.16 ± 2.89 vs. 2.87 ± 2.20, p = 0.03), systemic malignancy (41.4% vs. 16.7%, p = 0.02), occipital lobe involvement (97.1% vs. 83.3%, p = 0.02), more lobes involved (4.6 ± 1.48 vs. 3.9 ± 1.32, p = 0.03) but less likely in patients with visual disturbances (15.7% vs. 46.7%, p = 0.005), and facial droop (12.9% vs. 16.7%, p = 0.002). On multivariate analysis, only occipital lobe involvement was significantly (odds ratio: 9.63, 95% CI: 1.45–64.10, p = 0.02) associated with the occurrence of PRES-related seizures. Despite the occurrence of seizures, they were less likely to require a nursing home placement upon hospital discharge (odds ratio: 0.17, 95% CI: 0.03–0.91, p = 0.04). Conclusion: We conclude that seizures are common in patients with occipital lobe involvement from PRES. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Posterior reversible encephalopathy syndrome (PRES) is a wellrecognized acute neurotoxic syndrome characterized by a combination of clinical and neuroimaging findings. The spectrum of neurological features includes headache, impaired level of consciousness, seizures, visual disturbances, nausea/vomiting, and focal neurological deficits [1,2] in variable combinations. On neuroimaging, PRES is characterized by bilateral, cortical/subcortical vasogenic edema commonly involving the parietal and occipital regions, followed by the frontal, inferioroccipital, and cerebellar regions [3–5]. Commonly reported triggering factors include acute hypertension, preeclampsia or eclampsia, renal disease, sepsis, autoimmune diseases, and exposure to chemotherapeutic agents and immunosuppressants [6,7]. Seizures are a common manifestation and have been reported in 70–80% of PRES cases [6,7]; on occasion, status epilepticus may be the presenting symptom [8]. Despite these, epilepsy following PRES ⁎ Corresponding author at: Department of Neurology, Ohio State University Wexner Medical Center, Columbus, OH, USA. Tel.: +1 614 688 9434; fax: +1 614 366 7004. E-mail address: [email protected] (A. Hinduja).
http://dx.doi.org/10.1016/j.yebeh.2016.05.001 1525-5050/© 2016 Elsevier Inc. All rights reserved.
is rare [9]. Patients with seizures are frequently treated with antiseizure drugs (ASDs) for a short course. The pathophysiology of PRES is highly controversial. Various proposed hypotheses include vasoconstriction from hypertension with autoregulatory compensation, leading to ischemia and cerebral edema [10]; severe hypertension exceeding the autoregulatory limit, leading to hyperperfusion and cerebral edema [2,11]; and endothelial dysfunction [5,12]. Although initially thought to be reversible, recent literature has reported severe functional impairments in 44% of patients admitted to the intensive care unit [13], and the mortality is about 3–6% [6,14]. Besides, various clinical and experimental studies have reported neuronal damage from status epilepticus, although its extent following a single seizure or repeated brief seizures is controversial [15–18]. Thus, an improved understanding of the frequency and risk factors of seizures in patients with PRES would help us identify patients at risk of developing seizures and those who may benefit from continuous electroencephalographic (EEG) monitoring and prophylactic treatment in order to improve their functional outcome. The primary aim was to determine the frequency, risk factors, and discharge outcome of seizures in patients with PRES. The secondary aim was to determine the rates of recurrent seizures and epilepsy following PRES.
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2. Methods
2.4. Outcome
2.1. Subjects
Outcome was assessed using the modified Rankin Score (mRS), Glasgow Outcome Scale (GOS) at discharge, discharge disposition (home, rehabilitation facility, long-term nursing home), and in-hospital mortality. Information on neurological events, especially seizures and epilepsy, was evaluated if available upon follow-up.
We retrospectively reviewed all electronic medical records using the International Classification of Diseases version 9 codes for encephalopathy and PRES in patients ≥ 18 years of age, admitted to our tertiary care medical center from 2007 to 2014. All consecutive records were screened for the inclusion of PRES. A diagnosis of PRES was based on the clinical and radiological features consistent with PRES [3–5]. Magnetic resonance imaging (MRI) studies were reviewed by two independent, certified, experienced staff neuroradiologists blinded to the clinical findings, and in case of disagreement, consensus was reached. Electroencephalographic (EEG) patterns were interpreted by an experienced epileptologist blinded to clinical information and outcomes. 2.2. Definitions Diagnostic criteria of PRES were an acute neurotoxic syndrome with features of headache, impaired consciousness, seizures, visual abnormalities, nausea/vomiting, focal neurological deficits in variable combinations [1,2], and imaging findings consistent with PRES on MRI [5]. Visual disturbances included blurred vision, visual hallucinations, homonymous hemianopsia, visual neglect, and cortical blindness. Status epilepticus was defined as continuous seizures ≥5 min or two or more discrete seizures between which there was incomplete recovery of consciousness [19]. Posterior reversible encephalopathy syndrome-related epilepsy was defined as at least two unprovoked seizures occurring N24 h apart more than one month after the inciting episode with complete or near complete resolution of imaging abnormalities [20,21]. Additionally, patients with prior history of epilepsy were excluded. This time frame was selected since, although clinical recovery occurs in a few days in the majority of cases, it may occasionally take a month in certain cases [6,22,23]. A provoked seizure was defined as a seizure that occurred in the context of a precipitating cause that could lower the seizure threshold [20,21]. Hypertension was defined as a systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg [24]. 2.3. Data collection Patients were dichotomized into two groups based on the occurrence of seizures either at presentation or during hospitalization. Comparison of their baseline demographics, medical comorbidities, neurological symptoms, predisposing conditions, vital signs, Glasgow Coma Score (GCS), length of hospitalization, laboratory values, and imaging was performed. In cases with more than one predisposing condition, the clinically dominant etiology was used for analysis. Comorbidities were quantified using the Charlson comorbidity index [25]. Imaging features evaluated included the distribution of vasogenic edema (parietal, occipital, frontal, temporal, cerebellar, thalamus, midbrain, pons, medulla, lentiform nucleus, caudate, putamen, corpus callosum), number of lobes involved, severity of vasogenic edema (grading scheme by McKinney et al.), cortical or subcortical involvement, typical and atypical features, presence of restricted diffusion, hemorrhage, contrast enhancement, and degree of resolution on follow-up imaging if available. Atypical features were defined as involvement of the frontal lobes, basal ganglia, brain stem, and deep cerebral white matter; contrast enhancement; hemorrhage; restricted diffusion; and minimal involvement of the parieto-occipital regions [26]. The EEG findings analyzed were the following: background activity (normal, focal, and generalized slowing), the presence of epileptiform discharges, electrographic seizures, and periodic lateralized epileptiform discharges. Mild slowing was referred to background frequencies in the alpha–theta range, moderate slowing for frequencies in the theta range, and severe slowing for frequencies in the delta range.
2.5. Statistical analysis For all statistical analyses, SPSS version 21 software was used, and a p value of b 0.05 was considered significant. Univariate analysis was performed using Student's t-test for continuous variables and ‘z’ score for categorical variables to identify factors associated with clinical seizures. Multivariate logistic regression analysis of all significant variables (p b 0.05) on univariate analysis was performed to identify predictors associated with seizures in patients with PRES. 3. Results 3.1. Characteristics and comparison between groups with and without seizures Based on the inclusion criteria, 100 patients with PRES were identified, of which 70% experienced at least one PRES-related seizure either upon presentation or during hospitalization. Details of the cohort are described in Table 1. On MRI studies, vasogenic edema was commonly observed in the occipital lobe (93%) and parietal lobe (93%) followed by the frontal lobe (89%), cerebellum (57%), temporal lobe (39%), and thalamus (32%). On univariate analysis (Tables 2 and 3), the factors associated with the occurrence of seizures following PRES were a high Charlson comorbidity index (4.16 ± 2.89 vs. 2.87 ± 2.2, p = 0.03); systemic malignancy (41.4% vs. 16.7%, p = 0.02); occipital lobe involvement (97.1% vs. 83.3%, p = 0.02); greater number of lobes involved (4.6 ± 1.48 vs. 3.9 ± 1.32, p = 0.03), with decreased probability in patients with visual disturbances (15.7% vs. 43.3, p = 0.005); and facial droop (15.7% vs. 46.7%, p = 0.002). On multivariate analysis (Table 4), only occipital lobe involvement was associated with the occurrence of seizures in patients with PRES (odds ratio: 9.63, 95% CI: 1.45–64.10, p = 0.02). Further occurrence of a seizure on initial presentation or hospitalization did not significantly increase the risk of subsequent seizures (21.2% vs. 21.4%, p = 1.00) upon follow-up (median: 14.5 months, IQR: 4.7 months to 30.3 months). Despite the lack of a significant difference in mortality or poor functional outcome at discharge (based on mRS and GOS) between both cohorts, patients with PRES-related seizures were less likely to be discharged to a nursing home (4.3% vs. 20%, p = 0.01). Table 1 Demographics of 100 patients with PRES. Clinical characteristics
Number of patients
Age (years, median, interquartile range) Gender (males, %) Precipitating cause Hypertension Eclampsia Renal failure Malignancy Chemotherapy Seizures Generalized tonic–clonic seizures Status epilepticus Focal seizures Charlson comorbidity index (median ± SD) Glasgow Coma Score (median ± SD) Length of hospital stay (median ± SD) Length of intensive care unit stay (median ± SD) Mortality at hospital discharge
50 (33–61) 27 49 13 9 18 11 70 52 7 11 4 (2–5) 15 (10–15) 9 (4–22) 2 (0–5) 8
A. Hinduja et al. / Epilepsy & Behavior 61 (2016) 97–101 Table 2 Predictors of seizures in patients with PRES.
Age (years, mean ± SD) Male (n, %) Race (Caucasian) (n, %) Past medical history (n, %) Hypertension Diabetes mellitus Hyperlipidemia Atrial fibrillation Smoking Alcohol Past history of seizures Clinical features (n, %) Headache Nausea/vomiting Encephalopathy Coma Vision change Cranial nerve involvement Weakness Sensory loss Hospital characteristics Charlson CI (mean ± SD) GCS at insult (mean ± SD) Admitted to ICU (mean ± SD) LOH stay (days) (mean ± SD) LO ICU stay (days) (mean ± SD) Precipitating cause (n, %) Hypertension Eclampsia Renal failure Multiorgan failure Malignancy Chemotherapy Autoimmune condition Admission labs (mean ± SD) Hemoglobin, g/dL Hematocrit, % White cell count, K/μL Platelet count, K/μL Blood urea nitrogen, mg/dL Creatinine, mg/dL Serum glucose, mg/dL Serum sodium, mmol/L Serum calcium, mg/dL Serum magnesium, mg/dL Imaging (n, %) Parietal lobe Occipital lobe Frontal lobe Temporal lobe Cerebellum Thalamus Midbrain Pons Medulla Lentiform nucleus/caudate Putamen Corpus callosum No. of lobes involved (mean ± SD) Typical/atypical Cortical Restricted diffusion Contrast enhancement Hemorrhage Grade of PRES based on MRI (n, %) Mild Moderate Severe
99
Table 3 Outcomes of patients with PRES who developed seizures.
Seizures (N = 70)
No seizures (N = 30)
p value
47.60 ± 16.52 15 (21.4%) 48 (68.6%)
46.97 ± 15.62 12 (40%) 24 (80%)
0.86 0.08 0.33
30 (57.1%) 11 (15.7%) 10 (14.3%) 2 (2.9%) 21 (30%) 9 (12.9%) 4 (5.7%)
19 (63.3%) 4 (13.3%) 4 (13.3%) 1 (3.3) 11 (36.7%) 4 (13.3%) 3 (10%)
0.66 1.00 1.00 1.00 0.64 1.00 0.43
27 (38.6%) 24 (34.3%) 58 (82.9%) 4 (5.7%) 11 (15.7%) 11 (15.7%) 9 (12.9%) 0 (0%)
12 (40%) 10 (33.3%) 24 (80%) 1 (3.3%) 13 (43.3%) 14 (46.7%) 5 (16.7%) 1 (3.3%)
1.00 1.00 0.78 1.00 0.005 0.002 0.75 0.30
4.16 ± 2.89 12.16 ± 3.77 47 (67%) 20.04 ± 34.60 4.33 ± 9.90
2.87 ± 2.20 12.93 ± 3.30 20 (66.7%) 14.97 ± 12.64 6.53 ± 10.74
0.03 0.33 1.00 0.44 0.32
56 (80%) 7 (10%) 33 (47.1%) 34 (48.6%) 29 (41.4%) 26 (37.1%) 13 (18.6%)
27 (90%) 3 (10%) 15 (50%) 16 (53.3%) 5 (16.7%) 6 (20%) 4 (13.3%)
0.26 1.00 0.83 0.83 0.02 0.11 0.77
11.55 ± 2.28 34.74 ± 6.47 10.09 ± 6.89 201.83 ± 150.34 22.20 ± 16.96 2.60 ± 3.41 133.09 ± 56.95 137.43 ± 4.83 8.70 ± 1.06 2.10 ± 0.65
11.18 ± 2.00 33.67 ± 6.14 12.16 ± 5.68 188.07 ± 113.04 28.20 ± 23.99 2.15 ± 1.72 125.40 ± 41.02 136.60 ± 5.47 8.54 ± 0.92 2.11 ± 0.69
0.44 0.44 0.15 0.65 0.16 0.50 0.51 0.45 0.45 0.95
66 (94.3%) 68 (97.1%) 64 (91.4%) 32 (45.7%) 39 (55.7%) 26 (37.1%) 6 (8.6%) 20 (28.6%) 3 (4.3%) 14 (20%) 11 (15.7%) 14 (20%) 4.6 ± 1.48 68 (97.1%) 59 (84.3%) 12 (17.1%) 5 (7.1%) 19 (27.1%)
27 (90%) 25 (83.3%) 25 (83.3%) 7 (23.3%) 18 (60%) 6 (20%) 2 (6.7%) 8 (26.7%) 2 (6.7%) 2 (6.7%) 4 (13.3%) 6 (20%) 3.9 ± 1.32 28 (93.3%) 25 (83.3%) 6 (20%) 3 (10%) 7 (23.3%)
0.43 0.02 0.30 0.05 0.83 0.11 1.00 1.00 0.64 0.14 1.00 1.00 0.03 0.58 1.00 0.77 0.10 0.81
40 (57.1%) 24 (34.3%) 6 (8.6%)
17 (56.7%) 12 (40%) 1 (3.3%)
0.97 0.59 0.3
SD, standard deviation; Charlson CI, Charlson comorbidity index; GCS, Glasgow Coma Score; ICU, intensive care unit; LOH stay, length of hospital stay; LO ICU stay, length of intensive care unit stay; No., number; MRI, magnetic resonance imaging.
Seizures (70) Outcome at discharge mRS (modified Rankin Score) (mean ± SD) GOS (Glasgow Coma Score) (mean ± SD) Discharge disposition (n, %) Home Rehab Nursing home Death Seizures on follow-up (n, %) Recurrent PRES on follow-up (n, %) Follow-up imaging (n, %) Resolution on follow-up imaging (n, %) Complete Incomplete Progression Relapse Remitting/relapsing
No seizures (30)
p value
1.83 ± 1.98 2.17 ± 1.93 0.43 4.20 ± 1.22 4.03 ± 1.07 0.52 56 (80%) 5 (7.1%) 3 (4.3%) 6 (8.6%) 11 (21.2%) 5 (9.6%) 29 (41.4%)
19 (63.3%) 4 (13.3%) 6 (20%) 1 (3.3%) 3 (21.2%) 1 (7.1%) 12 (40%)
0.07 0.32 0.01 0.34 1.00 1.00 1.00
14 (20%) 8 (11.4%) 2 (2.9%) 4 (5.7%) 1 (1.4%)
5 (16.7%) 4 (13.3%) 2 (6.7%) 1 (3.3%) 0 (0%)
0.70 0.79 0.38 0.61 0.51
Based on the clinical semiology, the most common seizure type was generalized seizures (57 patients, of which 5 patients had generalized convulsive status epilepticus), followed by focal seizures (13 patients, which progressed to generalized status epilepticus in two patients). 3.2. EEG interpretation Among 70 patients with PRES-related seizures, EEG was performed in 60 patients during their hospital course (Table 5). The most common EEG pattern was generalized slowing with a majority being in the theta–delta range, followed by normal EEG patterns and generalized with additional focal slowing. In 10 patients, besides generalized slowing, other EEG abnormalities identified were the following: epileptiform discharges, electrographic seizures, and periodic lateralized epileptiform discharges (PLEDS). In the majority of patients, the epileptogenic foci were the posterior head regions followed by the temporal and frontal regions. None of our patients had electrographic status epilepticus. Among patients without seizures, although generalized slowing was the most common pattern, none had epileptiform discharges. The most common antiseizure drugs (ASDs) used during hospitalization were fosphenytoin (39 patients) and benzodiazepines (38 patients) and upon discharge levetiracetam (39 patients) and fosphenytoin (26 patients). Antiseizure drugs were discontinued upon discharge in 8 patients who developed PRES from nonpregnancy-related etiologies. The majority of patients (54 patients) required only one ASD upon discharge that was discontinued in 21 patients at follow-up. Upon follow-up, recurrence of seizures (after exclusion of patients with prior epilepsy) occurred in 11 patients, of which 9 patients had provoked seizures, and 2 had unprovoked seizures. Of the two patients with unprovoked seizures, one developed epilepsy, and the second patient had serial focal seizures (less than 24 h apart) 3 months following PRES that did not recur during a follow-up course of one year. Although the patient with serial focal seizures (less than 24 h apart) 3 months following PRES had a normal EEG, there was encephalomalacia of bilateral parieto-occipital regions and left parahippocampal gyrus with petechial hemorrhages of the parieto-occipital regions on imaging. Only 1% (1 patient) from our cohort developed PRES-related epilepsy. This patient had generalized status epilepticus followed by complex partial seizures Table 4 Binary logistic regression analysis of predictors of seizures among patients with PRES. Variables
Odds ratio (95% CI)
p value
Disposition to nursing home Occipital lobe involvement
0.17 (0.03–0.91) 9.63 (1.45–64.10)
0.04 0.02
CI, confidence interval.
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A. Hinduja et al. / Epilepsy & Behavior 61 (2016) 97–101
Table 5 EEG findings in 78 of 100 patients with PRES. EEG findings
N = 78
EEG in patients with seizures Generalized slowinga Mild slowing Mild to moderate slowing Moderate slowing Moderate to severe slowing Severe slowing Generalized with additional focal slowing Generalized slowing with additional EEG abnormalities Epileptiform discharges Electrographic seizures Periodic lateralized epileptiform discharges Focal slowing Focal slowing with epileptiform discharges Normal EEG in patients without seizures Generalized slowing Generalized with additional focal slowing Normal
60 33 3 2 2 25 1 6 10 10 4 3 1 1 9 18 12 2 4
Slowing in all subgroups were in the moderate to severe range (except in a as mentioned above).
during the acute phase but had recurrent generalized seizures during the 2 years of follow-up. The initial EEG of this patient showed epileptiform discharges with electrographic seizures in the left posterior quadrant but on follow-up showed left temporal focal slowing only. The 3month follow-up MRI showed complete resolution of the vasogenic edema of the left cerebellum and left hippocampus but with development of bilateral hippocampal sclerosis. 4. Discussion In this single-center retrospective study of 100 patients, 70% developed PRES-related seizures, which is congruent with the results from prior studies [7,21]. The majority of patients had a generalized type of seizure semiology and generalized slowing on EEG, which are consistent with other studies [9,21]. In our cohort, the only factor associated with PRES-related seizures was involvement of the occipital lobe on imaging. This is a unique finding since there is limited information on factors associated with PRES-related seizures. This is different when compared to seizures from other vascular etiologies like acute ischemic stroke and hemorrhagic strokes, where locations like the parietal, temporal, and frontal lobes have a high propensity of seizures as opposed to occipital lobe involvement from PRES as in our cohort [27,28]. Besides, there was no significant correlation between the number of lobes involved from PRES and the occurrence of seizures, which is also unique when compared to patients with ischemic and hemorrhagic strokes [29,30]. Posterior reversible encephalopathy syndrome is a complex disease of heterogeneous etiology, with particular involvement of the parieto-occipital regions likely from relatively sparse sympathetic innervation of the vertebrobasilar circulation [31]. Cerebral blood flow studies have revealed both cerebral hypoperfusion and hyperperfusion [2,32] with evidence of angiographic vasospasm and vasculopathy predominantly affecting the posterior circulation and watershed regions [33]. In our cohort, although both the parietal and occipital lobes were involved with equal frequency, there was a greater proportion of seizures from occipital lobe involvement likely from its inherent “selective vulnerability” coupled with hypoperfusion from PRES resulting in hypoxia, a well-known mechanism of seizures [34,35]. Besides the location, the occurrence of PRES-related seizures was independent of involvement of the cerebral cortex and the presence of hemorrhage and number of affected lobes, which is also different when compared to seizures from other vascular etiologies [28,29]. Biopsies in patients with PRES have revealed edematous white matter with inflammatory response from macrophages, lymphocytes, and astrocytes, which could
alternatively explain the mechanism of seizures in these patients [36, 37]. Epilepsy and unprovoked seizures related to PRES occurred in 1–2% of our cohort, which is similar to prior studies [9,21]. The only patient who developed PRES-related epilepsy had imaging evidence of hippocampal sclerosis that may have developed as a sequel of generalized convulsive status epilepticus during PRES, which is a rare phenomenon following PRES [38]. Although both normal and abnormal MRIs have been reported on follow-up in patients who developed epilepsy, both our patients who developed unprovoked seizures had structural damage on imaging which may explain its recurrence beyond the acute phase [21]. In our cohort, although occipital lobe involvement was a predictor of PRES-related seizures in the acute phase, given a very small percentage of epilepsy following PRES, the correlation could not be fully determined. Similar to other studies, 54% of patients (22 of 41 patients) in our cohort who underwent follow-up MRI either had incomplete resolution, progression, relapse, or other imaging abnormalities like infarction, atrophy, and laminar necrosis, which is consistent with prior studies [39]. Despite a very high percentage of residual abnormalities, only 1% developed PRES-related epilepsy. Thus, besides structural abnormalities, other factors play a contributing role in the development of epilepsy which will need to be evaluated in future studies. In our cohort, the occurrence of PRES-related seizures did not influence the admission to the intensive care unit, length of hospital stay, length of intensive care utilization, or the discharge outcome based on the mRS and GOS. Besides, there was no significant correlation between PRES-related seizures and mortality, which is similar to seizures following cerebrovascular disease [40]. Interestingly, in our cohort, patients who developed seizures from PRES were less likely to be discharged to a nursing home, which may either imply that factors other than seizures played a major role in the discharge disposition or prompt identification and aggressive care were provided in the subset of patients with seizures. Some of the major drawbacks of our study include the retrospective, single-institution study design; lack of information on time intervals between causative-factor exposure and development of PRES; lack of a standardized treatment protocol for management of PRES; use of ASDs during hospitalization or upon follow-up; and lack of consistency in data on long-term clinical, imaging, EEG, and cognitive outcomes. Another pitfall of our study was that ASDs were discontinued only in a third of patients (21 patients) upon follow-up, which may have impacted the development of recurrent seizures and epilepsy. We evaluated patients who had clinical seizures or those where there was a high clinical suspicion of seizures and thus there may have been a selection bias in obtaining EEG and we may have missed electrographic seizures.
5. Conclusion Posterior reversible encephalopathy syndrome is a neurological emergency condition that requires prompt recognition and aggressive management to achieve reversibility and favorable long-term outcomes. Although seizures during the acute phase are common, unprovoked seizures or epilepsy is rare. The only identifiable predictor of seizures in our cohort was the involvement of the occipital lobe. Although incomplete resolution and residual structural lesions are common, factors beyond structural damage may play a contributing role in the occurrence of PRES-related epilepsy and will need to be evaluated in the future. Larger prospective randomized studies using advanced imaging techniques such as diffusion tensor imaging and functional MRI are required to validate this finding and help identify patients at high risk of seizures. A future direction, besides obtaining an early MRI and prompt management, is to evaluate the benefit of a short course of empiric ASDs especially in patients with cortical occipital lobe involvement or epileptiform discharges on EEG until the etiology is controlled and to assess their outcomes.
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