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  • RESEARCH ARTICLE

    Cause of death in patients with poststroke

    epilepsy: Results from a nationwide cohort

    study

    Julia Hansen1, Signildsberg2, Eva Kumlien3, Johan Zelano1*

    1 Department of neurology, Sahlgrenska university hospital and Sahlgrenska Academy, University of

    Gothenburg, Gothenburg, Sweden, 2 Department of Medical Sciences, Uppsala University, Uppsala,

    Sweden, 3 Department of Neuroscience, Uppsala University, Uppsala, Sweden

    * johan.zelano@neuro.gu.se

    Abstract

    The risk of death is increased for persons with epilepsy. The literature on causes of death in

    epilepsy is based mainly on cohorts with epilepsy of mixed aetiologies. For clinical purposes

    and improved understanding of mortality in different epilepsies, more information is needed

    on mortality in epilepsies of specific causes. In poststroke epilepsy (PSE), seizures occur in

    a setting of vascular disease and high mortality rates. The extent to which epilepsy contrib-

    utes to mortality in this patient group is poorly understood. We therefore aimed to describe

    causes of death (COD) in PSE on a national scale. A previously identified cohort of 7740

    patients with epilepsy or seizures after a stroke in 20052010 was investigated. A total of

    4167 deaths occurred before the end of 2014. The standardized mortality ratio for the study

    cohort was 3.56 (95% CI: 3.453.67). The main underlying causes of death were disorders

    of the circulatory system (60%) followed by neoplasms (12%). Diseases of the nervous sys-

    tem were the sixth leading underlying COD (3%), and epilepsy or status epilepticus was

    considered the underlying COD in approximately a similar proportion of cases as neurode-

    generative disorders (0.9% and 1.1%, respectively). Epilepsy was considered a contributing

    COD in 14% of cases. Our findings highlight the importance of optimal management of

    vascular morbidity in patients with PSE. The large proportion of patients with epilepsy as a

    contributing COD indicate the need of high ambitions also regarding the management of sei-

    zures in patients with PSE.

    Introduction

    Persons with epilepsy have an increased risk of death compared to the standard population;

    previous work has demonstrated that the standardized mortality ratio (SMR) for patients with

    epilepsy in general is 1.53 [1, 2]. The cause of death (COD) is often linked to the underlying

    aetiology of epilepsy, and more so if death occurs within the first few years of the epilepsy diag-

    nosis [3]. The current literature is most often based on relatively small cohorts with rather few

    deaths occurring in each aetiological category [37]. Exceptions exist, but the focus of these

    larger studies was mortality associated with epilepsy in general [8, 9]. Such studies are of great

    PLOS ONE | https://doi.org/10.1371/journal.pone.0174659 April 5, 2017 1 / 11

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    OPENACCESS

    Citation: Hansen J, sberg S, Kumlien E, Zelano J(2017) Cause of death in patients with poststroke

    epilepsy: Results from a nationwide cohort study.

    PLoS ONE 12(4): e0174659. https://doi.org/

    10.1371/journal.pone.0174659

    Editor: Stefan Kiechl, Medizinische Universitat

    Innsbruck, AUSTRIA

    Received: December 5, 2016

    Accepted: March 13, 2017

    Published: April 5, 2017

    Copyright: 2017 Hansen et al. This is an openaccess article distributed under the terms of the

    Creative Commons Attribution License, which

    permits unrestricted use, distribution, and

    reproduction in any medium, provided the original

    author and source are credited.

    Data Availability Statement: All relevant data are

    within the paper and its Supporting Information

    files. The underlying registries are not readily

    available, but protected by Swedish laws on privacy

    and health care confidentiality.

    Funding: This project was funded by Swedish

    Society of Medicine, Jeanssons foundation, The

    Goteborg Medical Society, and Sahlgrenska

    university hospital. The funders had no role in

    study design, data collection and analysis, decision

    to publish or preparation of the manuscript.

    https://doi.org/10.1371/journal.pone.0174659http://crossmark.crossref.org/dialog/?doi=10.1371/journal.pone.0174659&domain=pdf&date_stamp=2017-04-05http://crossmark.crossref.org/dialog/?doi=10.1371/journal.pone.0174659&domain=pdf&date_stamp=2017-04-05http://crossmark.crossref.org/dialog/?doi=10.1371/journal.pone.0174659&domain=pdf&date_stamp=2017-04-05http://crossmark.crossref.org/dialog/?doi=10.1371/journal.pone.0174659&domain=pdf&date_stamp=2017-04-05http://crossmark.crossref.org/dialog/?doi=10.1371/journal.pone.0174659&domain=pdf&date_stamp=2017-04-05http://crossmark.crossref.org/dialog/?doi=10.1371/journal.pone.0174659&domain=pdf&date_stamp=2017-04-05https://doi.org/10.1371/journal.pone.0174659https://doi.org/10.1371/journal.pone.0174659http://creativecommons.org/licenses/by/4.0/
  • importance for an understanding of the burden of epilepsy, proper resource allocation in

    healthcare, and public health initiatives. However, the epilepsy classifications often used (for

    instance remote symptomatic) are too broad to easily inform clinical practice and patho-

    physiological understanding. A need for larger studies on epilepsies of different causes has

    been identified in a recent review[2].

    Cerebrovascular disease is the most common cause of epilepsy after middle age, and post-

    stroke epilepsy (PSE) complicates 68% of stroke according to fairly large and well-designed

    contemporary investigations [10, 11]. We have recently undertaken a nationwide registry-

    based cohort study on PSE in Sweden, and identified 7740 patients that suffered a first epilepsy

    or seizure diagnosis following a stroke in 20052010, resulting in a cumulative incidence of

    7,3% [12]. Mortality in the cohort was high, and PSE was associated with an increased hazard

    ratio of 1.36 (95% CI 1.201.55) for death after adjustments for stroke severity. In order to

    improve survival for patients with PSE, a better understanding of COD is required. Since PSE

    occurs in a setting of vascular disease and seizures often are focal and non-life threatening, it is

    likely that COD data from general epilepsy populations are not readily generalizable to PSE.

    We therefore wanted to investigate COD in patients with PSE.

    Some data exist. In a recent UK community-based cohort study noncerebral neoplasms,

    cardiovascular disease, and cerebrovascular disease were the most common COD, accounting

    for 59% of fatalities, as assessed by proportionate mortality ratios [3]. Epilepsy was the underly-

    ing COD in 3% of cases. Other studies have demonstrated high risks of dying in cerebrovascu-

    lar disease for patients with epilepsy in general [8]. Based on these findings, vascular disease is

    likely to be a major COD among PSE patients. However, the contribution of epilepsy to mor-

    tality in PSE is not known. Similarly, there is limited knowledge on what proportion of deaths

    in patients with PSE result from external causes that are increased in general epilepsy popula-

    tions, like suicide, transport accidents or drowning [2].

    In the present study, we aimed to describe causes of deaths in a previously identified cohort

    of 7740 patients that developed epilepsy following a stroke in 20052010.

    Materials and methods

    Study population

    An incident cohort with a first ever seizure, status epilepticus or epilepsy diagnosis following

    stroke in 20052010 was identified through cross-referencing of the Swedish Stroke Register

    and the National Patient Register (NPR) and Cause of Death (COD) Register, as previously

    described [12]. Patients with epilepsy, seizure or status epilepticus diagnosis prior to the stroke

    were excluded, as were patients that died within two months of the index stroke in order to

    reduce the influence of acute case fatality. The study years were chosen to reflect current prac-

    tice, but also allow development of PSE and sufficient follow-up time. From a total of 106455

    stroke patients fulfilling these criteria, 7740 patients had at least one seizure, epilepsy or status

    epilepticus diagnosis, more than one week after the index stroke, until the end of 2014. The

    average follow-up time was 4.8 years (SD 2.7 years). Inclusion is described in Fig 1.

    Registers and classification of COD

    The NPR and COD registers are nation-wide, with mandatory annual reporting from all

    healthcare providers in Sweden. The NPR was originally a hospital discharge register with

    complete coverage from 1987, and from 2001 hospital-based outpatient care is also reported.

    Diagnoses are registered for ICD-10 codes. For the purpose of this study, patients with occur-

    rence of any of ICD-10-codes G40, G41, or R56.8 more than 7 days after the stroke index date

    were classified as PSE. The positive predictive value of the epilepsy diagnosis in the NPR is not

    Causes of death in poststroke epilepsy

    PLOS ONE | https://doi.org/10.1371/journal.pone.0174659 April 5, 2017 2 / 11

    Competing interests: JZ has research grants from

    the funders of this study. For other projects, EK has

    research grants from The Selander and Thureus

    foundations. S has research grants from TheSwedish Stroke Register, The National Association

    for Stroke Patients in Sweden, The Swedish

    Research Council, and (institutional research