FULL-LENGTH ORIGINAL RESEARCH
Long-term risk of seizures and epilepsy in patients with posterior reversible encephalopathy syndrome *Sudhir Datar, †Tarun Singh, †Alejandro A. Rabinstein, †Jennifer E. Fugate, and †Sara Hocker Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12933
SUMMARY
Dr. Sudhir Datar is, Assistant Professor Neurocritical Care, Wake Forest University, North Carolina, U.S.A.
Objective: Seizures are common in patients with posterior reversible encephalopathy syndrome (PRES), which is reported in up to 70% of cases, and antiepileptic drugs (AEDs) are commonly prescribed. There is a paucity of data regarding the risk of subsequent seizures following resolution of PRES, and therefore the optimal duration of treatment with AEDs is currently unknown. The objective of this study was to identify the frequency of recurrent seizures and epilepsy following recovery from PRES. Methods: We performed a retrospective review of consecutive adults diagnosed with PRES between 2000 and 2010. Results: One hundred twenty-seven patients, median age 53 years (interquartile range [IQR] 37–64), were included in the analysis. The most common causes of PRES were hypertension (72%) and immunosuppression (20%). Renal failure was present in 47%. Eighty-four patients (66%) had seizures at presentation (39 focal, 45 generalized), and 13 (15%) of them presented with status epilepticus. Median duration of follow-up was 3.2 years (IQR 4 months to 6.9 years). Patients with seizures were treated with AEDs for a median of 3 months (IQR 2–7). Fifteen patients (12%) had provoked seizures during the follow-up period; in eight (53%) patients seizures were caused by recurrent PRES. Only three patients had subsequent unprovoked seizures, one of whom was considered to have developed epilepsy. Significance: We conclude that unprovoked seizures and epilepsy are uncommon in patients who have recovered from PRES. Discontinuation of AEDs following resolution of PRES should be considered, provided there is adequate control of risk factors, and absence of factors that could substantially lower the seizure threshold. KEY WORDS: Seizures, Posterior reversible encephalopathy syndrome, Hypertensive emergency, Hypertensive encephalopathy.
Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic diagnosis characterized by rapid onset headache, confusion or depression in level of consciousness, seizures, visual abnormalities, and posterior-predominant vasogenic brain edema.1,2 Conditions commonly associated with PRES include severe hypertension or wide blood pressure (BP) fluctuations, autoimmune disorders,
eclampsia, immunosuppressed state in patients with organ transplantation, and renal insufficiency.2–5 Magnetic resonance imaging (MRI) studies typically reveal predominantly posterior subcortical vasogenic edema.6,7 Clinical and radiographic findings are generally reversible. An example of a brain MRI showing characteristic vasogenic edema is presented in Figure 1. Seizures are common early in the disease course,2,4,8 and status epilepticus may be a presenting symptom.9,10 Patients who present with seizures are often started on antiepileptic drugs (AEDs) in the hospital, and these drugs may be continued on an outpatient basis after discharge. Due to the reversible nature of this disease, it is generally accepted that treatment with AEDs should be for a finite period. However, there is a lack of data regarding long-term risk of recurrent
Accepted January 5, 2015. *Department of Neurology, Division of Critical Care Neurology, Wake Forest Baptist Health, Winston Salem, North Carolina, U.S.A.; and †Department of Neurology, Division of Critical Care Neurology, Mayo Clinic, Rochester, Minnesota, U.S.A. Address correspondence to Sudhir Datar, Department of Neurology, Wake Forest Baptist Health, Medical Center Blvd, Winston Salem, NC 27157, U.S.A. E-mail: [email protected] Wiley Periodicals, Inc. © 2015 International League Against Epilepsy
1
2 S. Datar et al.
Figure 1. Example of vasogenic edema on brain MRI in a patient with PRES. Brain MRI scan, fluid-attenuated inversion recovery (FLAIR) sequences showing characteristic, posterior predominant and symmetrically distributed, vasogenic edema with involvement of U fibers. Epilepsia ILAE
seizures and epilepsy, leading to uncertainty about the optimal duration of treatment. Prolonged use of AEDs not only exposes patients to adverse effects11,12 but also adds to the cost of care. This is a common dilemma faced in clinical practice. The purpose of this study was to determine the frequency of recurrent seizures following recovery from PRES, and the factors affecting seizure recurrence and the development of epilepsy.
Methods Retrospective chart review of 127 consecutive adults with a diagnosis of PRES between 2000 and 2010 was performed. This study was approved by the Mayo Clinic Institutional Review Board. Patients were identified by means of a text-retrieval system that searches the final diagnosis in electronic clinical notes and charts were then manually reviewed. The diagnosis of PRES was based on (1) clinical presentation (headache, encephalopathy, seizures, visual disturbances), (2) radiologic changes (vasogenic edema), and (3) documented clinical and, when available, radiographic reversibility. The basic clinical and radiographic Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12933
characteristics of the majority of these patients (n = 113) have been reported previously.2 Patients who (1) had a history of seizures prior to the onset of PRES, (2) were initially treated at another hospital and had inadequate data available for review, or (3) had other acute central nervous system (CNS) lesions that can be causally related to the seizures, were excluded. Data regarding demographic information, date of diagnosis, precipitating factors, and treatment provided were collected. Electroencephalography (EEG) reports of patients were reviewed to identify the following abnormalities with their location and severity: focal or generalized slowing, periodic lateralized epileptiform discharges (PLEDS), generalized periodic epileptiform discharges (GPEDS), focal sharps, focal spikes, other epileptiform activity such as spike and slow wave or sharp and slow wave discharges, and electrographic seizures. When available, follow-up EEG reports prior to the discontinuation of AEDs were reviewed. Types of AEDs used and the total duration of treatment prior to discontinuation were noted. The frequency of seizure recurrence following recovery from PRES was recorded. Recurrent seizures were classified as either
3 Risk of Seizures Following PRES provoked or unprovoked, based on the presence or absence of any precipitating factor that would lower the seizure threshold or cause seizures, such as recurrent PRES, systemic infection/sepsis, withdrawal from CNS suppressants, acute CNS lesion, or electrolyte disturbances. Patients who had two or more unprovoked seizures were considered to have developed epilepsy.
Results One hundred twenty-seven patients were included in the final analysis (Fig. 2). The clinical characteristics of these patients are outlined in Table 1. Median age at presentation was 53 years, and most were women (69%). The most com-
Table 1. Clinical characteristics of 127 patients with PRES Clinical Characteristics Age (years), median (IQR) Females, n (%) Precipitating factor, n (%) Hypertension Immunosuppression Sepsis Preeclampsia/eclampsia Thrombotic thrombocytopenic purpura Renal failure at presentation, n (%) Seizures at presentation, n (%) Focal Generalized tonic–clonic Status epilepticus a Duration of treatment with AEDs (months), median (IQR)
N = 127 53 (37–64) 87 (69) 92 (72) 25 (20) 14 (11) 14 (11) 6 (5) 60 (47) 84 (66) 39 (31) 45 (35) 13 (10) 3 (2–7)
IQR, interquartile range; AEDs, antiepileptic drugs. a Numbers correspond to the 84 patients who presented with seizures at the time of diagnosis of PRES.
Figure 2. Patient flow diagram. aPatients were treated elsewhere or had inadequate data available for review. bPatients had additional cerebral lesions causing the seizures, namely temporal lobe oligoastrocytoma and cerebral infarction in the setting of subarachnoid hemorrhage, respectively. cThree patients had subsequent unprovoked seizures about 3 years following the initial episode of PRES. One of these three patients did not have seizures at the time of PRES. Epilepsia ILAE
mon cause of PRES was hypertension (72%), followed by immunosuppression (20%) (Table 1). Several patients had a combination of two, and occasionally three, precipitating causes. Sixty patients (47%) had renal failure, of whom 32 (53%) had acute kidney injury, 11 (18%) had acute on chronic kidney injury, and 17 (28%) had chronic kidney disease (Table 1). Mean creatinine standard deviation (SD) at presentation in patients with renal failure was 3.1 2.3 mg/dl. Eighty-four patients (66%) had seizures at presentation (Table 1). Of these, 13 patients (15%) presented with status epilepticus, including three patients with electrographic status epilepticus. EEG recordings were obtained in 14 (33%) of 43 patients without seizures and 65 (77%) of 84 patients with seizures, 6 of whom underwent continuous EEG monitoring. EEG findings are summarized in Table 2. Generalized slowing of the EEG background in the theta-delta frequency was the most common abnormality. The bulk of focal epileptiform activity was present in the posterior head region, whereas in some cases, activity in the frontoparietal region and along the midline was noted. PLEDs occurred in five patients (6%), one of whom developed epilepsy. The median duration of follow-up was 3.2 years (interquartile range [IQR] 4 months to 6.9 years). Sixty-five of 127 patients were followed for a minimum duration of 3 years. The median duration of treatment with AEDs was 3 months (IQR 2–7 months). Levetiracetam and phenytoin were the most commonly used drugs, both during the hospital admission and in the outpatient setting. AEDs were never discontinued in 17 patients for the following reasons: seven patients died within a mean period of 3.6 months from PRES diagnosis and six patients were lost to follow-up within 1–2 months of diagnosis. Of the remaining four patients (none of whom had recurrent seizures), two were continued indefinitely on AED treatment due to patient Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12933
4 S. Datar et al. Table 2. EEG findings in 79 of 127 patients with PRES EEG finding
N = 79
EEG in patients with seizures at presentation Generalized slowing Other epileptiform abnormalitiesa Focal slowing Periodic lateralized epileptiform discharges Frontal Multifocal but maximal in the frontal region Posterior head region Electrographic status epilepticus EEG in patients without seizures at presentation Generalized slowing Focal slowing Periodic lateralized epileptiform discharges Multifocal but maximal over posterior head region Focal sharp waves Normal EEG prior to discontinuation of AEDs Normal Generalized slowing Focal slowing
65 57 11 9 4 1 1 2 3 14 11 4 1 1 1 16 5 10 3
AEDs, antiepileptic drugs. a Generalized periodic epileptiform discharges, focal/multifocal sharps, spikes, spike and wave discharges, and temporal intermittent rhythmic delta activity.
preference in one, and use of phenytoin for hand-foot cramping in another; in the other two cases, the cause for continuation of AEDs could not be surmised from the records. Only one of these two patients had seizures at the onset of PRES; the other patient was started on levetiracetam solely because of epileptiform discharges on EEG. Three patients had subsequent unprovoked seizures approximately 3 years following recovery from PRES. Of these, two patients had a single episode of unprovoked seizures, following which one patient was restarted on AED and the other had his phenytoin dose increased. Only one of these two patients had seizures during the initial episode of PRES. The third patient had recurrent unprovoked seizures and thus was diagnosed with epilepsy. Another 15 patients had provoked seizures during the follow-up period; 8 of the patients had seizures due to recurrent PRES (of a total of 12 patients who had recurrent PRES during the follow-up). Seizures in the remaining 7 of 15 patients were attributed to various provoking factors as summarized in Table 3.
Discussion In this retrospective series of 127 patients with PRES, unprovoked seizures following resolution of PRES were very uncommon. We found that of 84 patients with seizures at presentation, only three patients ultimately had unprovoked seizures, which occurred approximately 3 years after the episode of PRES. Of these three patients, only one had recurrent seizures and was considered to have developed epilepsy. Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12933
Table 3. Subsequent seizures following the initial episode of PRES Subsequent seizures following PRES
N = 18
Unprovoked seizures Developed epilepsy Single episode of unprovoked seizures Provoked seizures Recurrent PRESa Systemic infection/sepsis Benzodiazepine withdrawal Alcohol withdrawal Subdural hemorrhage Intracerebral hemorrhage Otherb Duration until first seizure recurrence (months), median (IQR) Duration of follow up (years), median (IQR)c
3 1 2 15 8 4 2 1 1 1 3 10 (3–36) 3.2 (0.3–6.9)
IQR, interquartile range. a Total of 12 patients had recurrent PRES. b Includes electrolyte disturbances and suspected PRES due to severe hypertension and cyclophosphamide use. c Numbers reflect the follow up of all 127 patients with PRES.
Various precipitating factors as outlined in Table 3 were considered responsible for subsequent seizures in 15 patients. Recurrent PRES was the most common precipitant, while toxic, metabolic and structural causes were responsible for the rest. Eight of 12 patients with recurrent PRES developed seizures. Thus, PRES recurrence appears to be a strong risk factor for subsequent seizures in patients with a first episode of PRES. Seizures commonly occur acutely in PRES, yet there are few data on the long-term outcome of these patients with regard to the risk of developing recurrent seizures or epilepsy. One retrospective review of EEG findings in 17 patients with seizures caused by PRES found that no patient had recurrent seizures within 6 months. However, the primary goal of this study was to describe EEG findings, not risk of subsequent epilepsy, and 32 patients with PRES were excluded from the analysis (including 21 with seizures).8 There is likely a small risk of recurrent seizures in some patients after PRES, and this has been described in isolated case reports.13,14 One report described a post-liver transplantation patient with PRES who had recurrent seizures despite normalization of neuroimaging. Another patient with several episodes of recurrent PRES developed chronic epilepsy. Both of these cases experienced recurrent seizures despite maintenance AED treatment. Our series is the largest to describe recurrent seizures and epilepsy following PRES, and our results indicate that recurrent unprovoked seizures are very uncommon. PLEDs have been reported infrequently in patients with PRES.14,15 In general, they are most often seen in the setting of acute, destructive lesions, such as cerebral infarction or hemorrhage, encephalitis, abscess, or malignancy.16 In our series, PLEDs occurred in five patients (6%), and they were
5 Risk of Seizures Following PRES present in the only patient in our cohort who developed epilepsy. Whether presence of PLEDs on the acute EEG justifies a repeat EEG prior to discontinuation of AED following resolution of PRES remains unclear. In almost all of our patients, seizures associated with PRES occurred very early—within 24–48 h of presentation. However, most patients with seizures were treated with AEDs during the hospitalization, which may have prevented early recurrent seizures beyond the first 24–48 h. There were 14 patients who had seizures at the onset of PRES and yet did not receive any AEDs in the hospital. Four had eclampsia and received magnesium sulfate therapy. None of these 14 patients had any recurrence of seizures. Our study has some limitations. Patients were identified from hospitalization at a large tertiary medical center, which could result in referral bias toward unusual or severe cases. The retrospective, observational nature of the study with nonuniform follow-up evaluation does not allow us to calculate true incidence of the development of recurrent seizures or epilepsy following PRES. We also cannot know if the initial episode of PRES was causative in the development of subsequent unprovoked seizures that occurred in three patients. These patients had multiple medical comorbidities at baseline, including the need for hemodialysis in two, making it impossible to exclude the effects of other factors on the risk of recurrent seizures. Treatment with AEDs was at the discretion of the treating clinician and was not standardized. Finally, AEDs were still being used at last followup in 17 cases, of which 13 patients were either lost to follow-up within a few months or died, and only 4 patients remained on AEDs long term. Therefore, although AED use may have influenced the frequency of early seizure recurrence and may have led to an underestimation of risk of recurrent seizures or epilepsy, it is unlikely that this acted as a major confounder in the long-term assessment of these patients. Our results offer a clear clinical message. Unprovoked seizures and epilepsy are uncommon in patients who have recovered from PRES. Discontinuation of AEDs following resolution of PRES should be considered, provided there is adequate control of risk factors, and absence of factors that could substantially lower the seizure threshold.
Acknowledgments Dr. Sudhir Datar has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. There was no industry, government, or institutional sponsorship or financial interest in this study.
Disclosure None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Additional Contributors Dr. Datar contributed to study design, acquisition of data, interpretation of data, and drafting/revising the manuscript for content. Dr. Singh contributed to acquisition of data and interpretation of data. Dr. Rabinstein contributed to study concept and design, interpretation of data, and drafting/ revising the manuscript for content. Dr. Fugate contributed to study design, acquisition of data, interpretation of data, and drafting/revising the manuscript for content. Dr. Hocker contributed to study concept and design, interpretation of data, and drafting/revising the manuscript for content.
References 1. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494–500. 2. Fugate JE, Claassen DO, Cloft HJ, et al. Posterior reversible encephalopathy syndrome: associated clinical and radiologic findings. Mayo Clin Proc 2010;85:427–432. 3. Burrus TM, Mandrekar J, Wijdicks EF, et al. Renal failure and posterior reversible encephalopathy syndrome in patients with thrombotic thrombocytopenic purpura. Arch Neurol 2010;67:831–834. 4. Lee VH, Wijdicks EF, Manno EM, et al. Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol 2008;65:205–210. 5. Rabinstein AA, Mandrekar J, Merrell R, et al. Blood pressure fluctuations in posterior reversible encephalopathy syndrome. J Stroke Cerebrovasc Dis 2012;21:254–258. 6. Bartynski WS, Boardman JF. Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol 2007;28:1320–1327. 7. Hauser RA, Lacey DM, Knight MR. Hypertensive encephalopathy. Magnetic resonance imaging demonstration of reversible cortical and white matter lesions. Arch Neurol 1988;45:1078–1083. 8. Kastrup O, Gerwig M, Frings M, et al. Posterior reversible encephalopathy syndrome (PRES): electroencephalographic findings and seizure patterns. J Neurol 2012;259:1383–1389. 9. Kozak OS, Wijdicks EF, Manno EM, et al. Status epilepticus as initial manifestation of posterior reversible encephalopathy syndrome. Neurology 2007;69:894–897. 10. Rossi R, Saddi MV, Ticca A, et al. Partial status epilepticus related to independent occipital foci in posterior reversible encephalopathy syndrome (PRES). Neurol Sci 2008;29:455–458. 11. Haruda F. Phenytoin hypersensitivity: 38 cases. Neurology 1979;29:1480–1485. 12. Mula M, Trimble MR, Yuen A, et al. Psychiatric adverse events during levetiracetam therapy. Neurology 2003;61:704–706. 13. Baldini M, Bartolini E, Gori S, et al. Epilepsy after neuroimaging normalization in a woman with tacrolimus-related posterior reversible encephalopathy syndrome. Epilepsy Behav 2010;17:558–560. 14. Skiba V, Etienne M, Miller JA. Development of chronic epilepsy after recurrent episodes of posterior reversible encephalopathy syndrome associated with periodic lateralized epileptiform discharges. Seizure 2011;20:93–95. 15. Fitzpatrick W, Lowry N. PLEDs: clinical correlates. Can J Neurol Sci 2007;34:443–450. 16. Garcia-Morales I, Garcia MT, Galan-Davila L, et al. Periodic lateralized epileptiform discharges: etiology, clinical aspects, seizures, and evolution in 130 patients. J Clin Neurophysiol 2002;19:172–177.
Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12933
Long-term risk of seizures and epilepsy in patients with posterior reversible encephalopathy syndrome *Sudhir Datar, †Tarun Singh, †Alejandro A. Rabinstein, †Jennifer E. Fugate, and †Sara Hocker Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12933
SUMMARY
Dr. Sudhir Datar is, Assistant Professor Neurocritical Care, Wake Forest University, North Carolina, U.S.A.
Objective: Seizures are common in patients with posterior reversible encephalopathy syndrome (PRES), which is reported in up to 70% of cases, and antiepileptic drugs (AEDs) are commonly prescribed. There is a paucity of data regarding the risk of subsequent seizures following resolution of PRES, and therefore the optimal duration of treatment with AEDs is currently unknown. The objective of this study was to identify the frequency of recurrent seizures and epilepsy following recovery from PRES. Methods: We performed a retrospective review of consecutive adults diagnosed with PRES between 2000 and 2010. Results: One hundred twenty-seven patients, median age 53 years (interquartile range [IQR] 37–64), were included in the analysis. The most common causes of PRES were hypertension (72%) and immunosuppression (20%). Renal failure was present in 47%. Eighty-four patients (66%) had seizures at presentation (39 focal, 45 generalized), and 13 (15%) of them presented with status epilepticus. Median duration of follow-up was 3.2 years (IQR 4 months to 6.9 years). Patients with seizures were treated with AEDs for a median of 3 months (IQR 2–7). Fifteen patients (12%) had provoked seizures during the follow-up period; in eight (53%) patients seizures were caused by recurrent PRES. Only three patients had subsequent unprovoked seizures, one of whom was considered to have developed epilepsy. Significance: We conclude that unprovoked seizures and epilepsy are uncommon in patients who have recovered from PRES. Discontinuation of AEDs following resolution of PRES should be considered, provided there is adequate control of risk factors, and absence of factors that could substantially lower the seizure threshold. KEY WORDS: Seizures, Posterior reversible encephalopathy syndrome, Hypertensive emergency, Hypertensive encephalopathy.
Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic diagnosis characterized by rapid onset headache, confusion or depression in level of consciousness, seizures, visual abnormalities, and posterior-predominant vasogenic brain edema.1,2 Conditions commonly associated with PRES include severe hypertension or wide blood pressure (BP) fluctuations, autoimmune disorders,
eclampsia, immunosuppressed state in patients with organ transplantation, and renal insufficiency.2–5 Magnetic resonance imaging (MRI) studies typically reveal predominantly posterior subcortical vasogenic edema.6,7 Clinical and radiographic findings are generally reversible. An example of a brain MRI showing characteristic vasogenic edema is presented in Figure 1. Seizures are common early in the disease course,2,4,8 and status epilepticus may be a presenting symptom.9,10 Patients who present with seizures are often started on antiepileptic drugs (AEDs) in the hospital, and these drugs may be continued on an outpatient basis after discharge. Due to the reversible nature of this disease, it is generally accepted that treatment with AEDs should be for a finite period. However, there is a lack of data regarding long-term risk of recurrent
Accepted January 5, 2015. *Department of Neurology, Division of Critical Care Neurology, Wake Forest Baptist Health, Winston Salem, North Carolina, U.S.A.; and †Department of Neurology, Division of Critical Care Neurology, Mayo Clinic, Rochester, Minnesota, U.S.A. Address correspondence to Sudhir Datar, Department of Neurology, Wake Forest Baptist Health, Medical Center Blvd, Winston Salem, NC 27157, U.S.A. E-mail: [email protected] Wiley Periodicals, Inc. © 2015 International League Against Epilepsy
1
2 S. Datar et al.
Figure 1. Example of vasogenic edema on brain MRI in a patient with PRES. Brain MRI scan, fluid-attenuated inversion recovery (FLAIR) sequences showing characteristic, posterior predominant and symmetrically distributed, vasogenic edema with involvement of U fibers. Epilepsia ILAE
seizures and epilepsy, leading to uncertainty about the optimal duration of treatment. Prolonged use of AEDs not only exposes patients to adverse effects11,12 but also adds to the cost of care. This is a common dilemma faced in clinical practice. The purpose of this study was to determine the frequency of recurrent seizures following recovery from PRES, and the factors affecting seizure recurrence and the development of epilepsy.
Methods Retrospective chart review of 127 consecutive adults with a diagnosis of PRES between 2000 and 2010 was performed. This study was approved by the Mayo Clinic Institutional Review Board. Patients were identified by means of a text-retrieval system that searches the final diagnosis in electronic clinical notes and charts were then manually reviewed. The diagnosis of PRES was based on (1) clinical presentation (headache, encephalopathy, seizures, visual disturbances), (2) radiologic changes (vasogenic edema), and (3) documented clinical and, when available, radiographic reversibility. The basic clinical and radiographic Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12933
characteristics of the majority of these patients (n = 113) have been reported previously.2 Patients who (1) had a history of seizures prior to the onset of PRES, (2) were initially treated at another hospital and had inadequate data available for review, or (3) had other acute central nervous system (CNS) lesions that can be causally related to the seizures, were excluded. Data regarding demographic information, date of diagnosis, precipitating factors, and treatment provided were collected. Electroencephalography (EEG) reports of patients were reviewed to identify the following abnormalities with their location and severity: focal or generalized slowing, periodic lateralized epileptiform discharges (PLEDS), generalized periodic epileptiform discharges (GPEDS), focal sharps, focal spikes, other epileptiform activity such as spike and slow wave or sharp and slow wave discharges, and electrographic seizures. When available, follow-up EEG reports prior to the discontinuation of AEDs were reviewed. Types of AEDs used and the total duration of treatment prior to discontinuation were noted. The frequency of seizure recurrence following recovery from PRES was recorded. Recurrent seizures were classified as either
3 Risk of Seizures Following PRES provoked or unprovoked, based on the presence or absence of any precipitating factor that would lower the seizure threshold or cause seizures, such as recurrent PRES, systemic infection/sepsis, withdrawal from CNS suppressants, acute CNS lesion, or electrolyte disturbances. Patients who had two or more unprovoked seizures were considered to have developed epilepsy.
Results One hundred twenty-seven patients were included in the final analysis (Fig. 2). The clinical characteristics of these patients are outlined in Table 1. Median age at presentation was 53 years, and most were women (69%). The most com-
Table 1. Clinical characteristics of 127 patients with PRES Clinical Characteristics Age (years), median (IQR) Females, n (%) Precipitating factor, n (%) Hypertension Immunosuppression Sepsis Preeclampsia/eclampsia Thrombotic thrombocytopenic purpura Renal failure at presentation, n (%) Seizures at presentation, n (%) Focal Generalized tonic–clonic Status epilepticus a Duration of treatment with AEDs (months), median (IQR)
N = 127 53 (37–64) 87 (69) 92 (72) 25 (20) 14 (11) 14 (11) 6 (5) 60 (47) 84 (66) 39 (31) 45 (35) 13 (10) 3 (2–7)
IQR, interquartile range; AEDs, antiepileptic drugs. a Numbers correspond to the 84 patients who presented with seizures at the time of diagnosis of PRES.
Figure 2. Patient flow diagram. aPatients were treated elsewhere or had inadequate data available for review. bPatients had additional cerebral lesions causing the seizures, namely temporal lobe oligoastrocytoma and cerebral infarction in the setting of subarachnoid hemorrhage, respectively. cThree patients had subsequent unprovoked seizures about 3 years following the initial episode of PRES. One of these three patients did not have seizures at the time of PRES. Epilepsia ILAE
mon cause of PRES was hypertension (72%), followed by immunosuppression (20%) (Table 1). Several patients had a combination of two, and occasionally three, precipitating causes. Sixty patients (47%) had renal failure, of whom 32 (53%) had acute kidney injury, 11 (18%) had acute on chronic kidney injury, and 17 (28%) had chronic kidney disease (Table 1). Mean creatinine standard deviation (SD) at presentation in patients with renal failure was 3.1 2.3 mg/dl. Eighty-four patients (66%) had seizures at presentation (Table 1). Of these, 13 patients (15%) presented with status epilepticus, including three patients with electrographic status epilepticus. EEG recordings were obtained in 14 (33%) of 43 patients without seizures and 65 (77%) of 84 patients with seizures, 6 of whom underwent continuous EEG monitoring. EEG findings are summarized in Table 2. Generalized slowing of the EEG background in the theta-delta frequency was the most common abnormality. The bulk of focal epileptiform activity was present in the posterior head region, whereas in some cases, activity in the frontoparietal region and along the midline was noted. PLEDs occurred in five patients (6%), one of whom developed epilepsy. The median duration of follow-up was 3.2 years (interquartile range [IQR] 4 months to 6.9 years). Sixty-five of 127 patients were followed for a minimum duration of 3 years. The median duration of treatment with AEDs was 3 months (IQR 2–7 months). Levetiracetam and phenytoin were the most commonly used drugs, both during the hospital admission and in the outpatient setting. AEDs were never discontinued in 17 patients for the following reasons: seven patients died within a mean period of 3.6 months from PRES diagnosis and six patients were lost to follow-up within 1–2 months of diagnosis. Of the remaining four patients (none of whom had recurrent seizures), two were continued indefinitely on AED treatment due to patient Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12933
4 S. Datar et al. Table 2. EEG findings in 79 of 127 patients with PRES EEG finding
N = 79
EEG in patients with seizures at presentation Generalized slowing Other epileptiform abnormalitiesa Focal slowing Periodic lateralized epileptiform discharges Frontal Multifocal but maximal in the frontal region Posterior head region Electrographic status epilepticus EEG in patients without seizures at presentation Generalized slowing Focal slowing Periodic lateralized epileptiform discharges Multifocal but maximal over posterior head region Focal sharp waves Normal EEG prior to discontinuation of AEDs Normal Generalized slowing Focal slowing
65 57 11 9 4 1 1 2 3 14 11 4 1 1 1 16 5 10 3
AEDs, antiepileptic drugs. a Generalized periodic epileptiform discharges, focal/multifocal sharps, spikes, spike and wave discharges, and temporal intermittent rhythmic delta activity.
preference in one, and use of phenytoin for hand-foot cramping in another; in the other two cases, the cause for continuation of AEDs could not be surmised from the records. Only one of these two patients had seizures at the onset of PRES; the other patient was started on levetiracetam solely because of epileptiform discharges on EEG. Three patients had subsequent unprovoked seizures approximately 3 years following recovery from PRES. Of these, two patients had a single episode of unprovoked seizures, following which one patient was restarted on AED and the other had his phenytoin dose increased. Only one of these two patients had seizures during the initial episode of PRES. The third patient had recurrent unprovoked seizures and thus was diagnosed with epilepsy. Another 15 patients had provoked seizures during the follow-up period; 8 of the patients had seizures due to recurrent PRES (of a total of 12 patients who had recurrent PRES during the follow-up). Seizures in the remaining 7 of 15 patients were attributed to various provoking factors as summarized in Table 3.
Discussion In this retrospective series of 127 patients with PRES, unprovoked seizures following resolution of PRES were very uncommon. We found that of 84 patients with seizures at presentation, only three patients ultimately had unprovoked seizures, which occurred approximately 3 years after the episode of PRES. Of these three patients, only one had recurrent seizures and was considered to have developed epilepsy. Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12933
Table 3. Subsequent seizures following the initial episode of PRES Subsequent seizures following PRES
N = 18
Unprovoked seizures Developed epilepsy Single episode of unprovoked seizures Provoked seizures Recurrent PRESa Systemic infection/sepsis Benzodiazepine withdrawal Alcohol withdrawal Subdural hemorrhage Intracerebral hemorrhage Otherb Duration until first seizure recurrence (months), median (IQR) Duration of follow up (years), median (IQR)c
3 1 2 15 8 4 2 1 1 1 3 10 (3–36) 3.2 (0.3–6.9)
IQR, interquartile range. a Total of 12 patients had recurrent PRES. b Includes electrolyte disturbances and suspected PRES due to severe hypertension and cyclophosphamide use. c Numbers reflect the follow up of all 127 patients with PRES.
Various precipitating factors as outlined in Table 3 were considered responsible for subsequent seizures in 15 patients. Recurrent PRES was the most common precipitant, while toxic, metabolic and structural causes were responsible for the rest. Eight of 12 patients with recurrent PRES developed seizures. Thus, PRES recurrence appears to be a strong risk factor for subsequent seizures in patients with a first episode of PRES. Seizures commonly occur acutely in PRES, yet there are few data on the long-term outcome of these patients with regard to the risk of developing recurrent seizures or epilepsy. One retrospective review of EEG findings in 17 patients with seizures caused by PRES found that no patient had recurrent seizures within 6 months. However, the primary goal of this study was to describe EEG findings, not risk of subsequent epilepsy, and 32 patients with PRES were excluded from the analysis (including 21 with seizures).8 There is likely a small risk of recurrent seizures in some patients after PRES, and this has been described in isolated case reports.13,14 One report described a post-liver transplantation patient with PRES who had recurrent seizures despite normalization of neuroimaging. Another patient with several episodes of recurrent PRES developed chronic epilepsy. Both of these cases experienced recurrent seizures despite maintenance AED treatment. Our series is the largest to describe recurrent seizures and epilepsy following PRES, and our results indicate that recurrent unprovoked seizures are very uncommon. PLEDs have been reported infrequently in patients with PRES.14,15 In general, they are most often seen in the setting of acute, destructive lesions, such as cerebral infarction or hemorrhage, encephalitis, abscess, or malignancy.16 In our series, PLEDs occurred in five patients (6%), and they were
5 Risk of Seizures Following PRES present in the only patient in our cohort who developed epilepsy. Whether presence of PLEDs on the acute EEG justifies a repeat EEG prior to discontinuation of AED following resolution of PRES remains unclear. In almost all of our patients, seizures associated with PRES occurred very early—within 24–48 h of presentation. However, most patients with seizures were treated with AEDs during the hospitalization, which may have prevented early recurrent seizures beyond the first 24–48 h. There were 14 patients who had seizures at the onset of PRES and yet did not receive any AEDs in the hospital. Four had eclampsia and received magnesium sulfate therapy. None of these 14 patients had any recurrence of seizures. Our study has some limitations. Patients were identified from hospitalization at a large tertiary medical center, which could result in referral bias toward unusual or severe cases. The retrospective, observational nature of the study with nonuniform follow-up evaluation does not allow us to calculate true incidence of the development of recurrent seizures or epilepsy following PRES. We also cannot know if the initial episode of PRES was causative in the development of subsequent unprovoked seizures that occurred in three patients. These patients had multiple medical comorbidities at baseline, including the need for hemodialysis in two, making it impossible to exclude the effects of other factors on the risk of recurrent seizures. Treatment with AEDs was at the discretion of the treating clinician and was not standardized. Finally, AEDs were still being used at last followup in 17 cases, of which 13 patients were either lost to follow-up within a few months or died, and only 4 patients remained on AEDs long term. Therefore, although AED use may have influenced the frequency of early seizure recurrence and may have led to an underestimation of risk of recurrent seizures or epilepsy, it is unlikely that this acted as a major confounder in the long-term assessment of these patients. Our results offer a clear clinical message. Unprovoked seizures and epilepsy are uncommon in patients who have recovered from PRES. Discontinuation of AEDs following resolution of PRES should be considered, provided there is adequate control of risk factors, and absence of factors that could substantially lower the seizure threshold.
Acknowledgments Dr. Sudhir Datar has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. There was no industry, government, or institutional sponsorship or financial interest in this study.
Disclosure None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Additional Contributors Dr. Datar contributed to study design, acquisition of data, interpretation of data, and drafting/revising the manuscript for content. Dr. Singh contributed to acquisition of data and interpretation of data. Dr. Rabinstein contributed to study concept and design, interpretation of data, and drafting/ revising the manuscript for content. Dr. Fugate contributed to study design, acquisition of data, interpretation of data, and drafting/revising the manuscript for content. Dr. Hocker contributed to study concept and design, interpretation of data, and drafting/revising the manuscript for content.
References 1. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494–500. 2. Fugate JE, Claassen DO, Cloft HJ, et al. Posterior reversible encephalopathy syndrome: associated clinical and radiologic findings. Mayo Clin Proc 2010;85:427–432. 3. Burrus TM, Mandrekar J, Wijdicks EF, et al. Renal failure and posterior reversible encephalopathy syndrome in patients with thrombotic thrombocytopenic purpura. Arch Neurol 2010;67:831–834. 4. Lee VH, Wijdicks EF, Manno EM, et al. Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol 2008;65:205–210. 5. Rabinstein AA, Mandrekar J, Merrell R, et al. Blood pressure fluctuations in posterior reversible encephalopathy syndrome. J Stroke Cerebrovasc Dis 2012;21:254–258. 6. Bartynski WS, Boardman JF. Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol 2007;28:1320–1327. 7. Hauser RA, Lacey DM, Knight MR. Hypertensive encephalopathy. Magnetic resonance imaging demonstration of reversible cortical and white matter lesions. Arch Neurol 1988;45:1078–1083. 8. Kastrup O, Gerwig M, Frings M, et al. Posterior reversible encephalopathy syndrome (PRES): electroencephalographic findings and seizure patterns. J Neurol 2012;259:1383–1389. 9. Kozak OS, Wijdicks EF, Manno EM, et al. Status epilepticus as initial manifestation of posterior reversible encephalopathy syndrome. Neurology 2007;69:894–897. 10. Rossi R, Saddi MV, Ticca A, et al. Partial status epilepticus related to independent occipital foci in posterior reversible encephalopathy syndrome (PRES). Neurol Sci 2008;29:455–458. 11. Haruda F. Phenytoin hypersensitivity: 38 cases. Neurology 1979;29:1480–1485. 12. Mula M, Trimble MR, Yuen A, et al. Psychiatric adverse events during levetiracetam therapy. Neurology 2003;61:704–706. 13. Baldini M, Bartolini E, Gori S, et al. Epilepsy after neuroimaging normalization in a woman with tacrolimus-related posterior reversible encephalopathy syndrome. Epilepsy Behav 2010;17:558–560. 14. Skiba V, Etienne M, Miller JA. Development of chronic epilepsy after recurrent episodes of posterior reversible encephalopathy syndrome associated with periodic lateralized epileptiform discharges. Seizure 2011;20:93–95. 15. Fitzpatrick W, Lowry N. PLEDs: clinical correlates. Can J Neurol Sci 2007;34:443–450. 16. Garcia-Morales I, Garcia MT, Galan-Davila L, et al. Periodic lateralized epileptiform discharges: etiology, clinical aspects, seizures, and evolution in 130 patients. J Clin Neurophysiol 2002;19:172–177.
Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12933
