Cause of death in patients with poststroke epilepsy ...uu.diva- 1096086/  · Cause of

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.

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