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Risk of Unnatural Mortality in People With Epilepsy

Educational Objective
To determine the risk of cause-specific unnatural mortality in people with epilepsy and how medications contribute to this risk.
1 Credit CME
Key Points

Question  What is the risk and medication contribution to cause-specific unnatural mortality in people with epilepsy?

Findings  In this population-based cohort study, more than 50 000 people with epilepsy and 1 million matched individuals without epilepsy were identified in 2 data sets from the general populations of England and Wales. People with epilepsy had a 3-fold increased risk of any unnatural mortality and a 5-fold increased risk of unintentional medication poisoning; psychotropic and opioid, but not antiepileptic, drugs were most commonly used in poisoning.

Meaning  Clinicians should provide advice on unintentional injury and poisoning and suicide prevention and consider the toxicity of concomitant medication when prescribing drugs for people with epilepsy.


Importance  People with epilepsy are at increased risk of mortality, but, to date, the cause-specific risks of all unnatural causes have not been reported.

Objective  To estimate cause-specific unnatural mortality risks in people with epilepsy and to identify the medication types involved in poisoning deaths.

Design, Setting, and Participants  This population-based cohort study used 2 electronic primary care data sets linked to hospitalization and mortality records, the Clinical Practice Research Datalink (CPRD) in England (from January 1, 1998, to March 31, 2014) and the Secure Anonymised Information Linkage (SAIL) Databank in Wales (from January 1, 2001, to December 31, 2014). Each person with epilepsy was matched on age (within 2 years), sex, and general practice with up to 20 individuals without epilepsy. Unnatural mortality was determined using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes V01 through Y98 in the Office for National Statistics mortality records. Hazard ratios (HRs) were estimated in each data set using a stratified Cox proportional hazards model, and meta-analyses were conducted using DerSimonian and Laird random-effects models. The analysis was performed from January 5, 2016, to November 16, 2017.

Exposures  People with epilepsy were identified using primary care epilepsy diagnoses and associated antiepileptic drug prescriptions.

Main Outcomes and Measures  Hazard ratios (HRs) for unnatural mortality and the frequency of each involved medication type estimated as a percentage of all medication poisoning deaths.

Results  In total, 44 678 individuals in the CPRD and 14 051 individuals in the SAIL Databank were identified in the prevalent epilepsy cohorts, and 891 429 (CPRD) and 279 365 (SAIL) individuals were identified in the comparison cohorts. In both data sets, 51% of the epilepsy and comparison cohorts were male, and the median age at entry was 40 years (interquartile range, 25-60 years) in the CPRD cohorts and 43 years (interquartile range, 24-64 years) in the SAIL cohorts. People with epilepsy were significantly more likely to die of any unnatural cause (HR, 2.77; 95% CI, 2.43-3.16), unintentional injury or poisoning (HR, 2.97; 95% CI, 2.54-3.48) or suicide (HR, 2.15; 95% CI, 1.51-3.07) than people in the comparison cohort. Particularly large risk increases were observed in the epilepsy cohorts for unintentional medication poisoning (HR, 4.99; 95% CI, 3.22-7.74) and intentional self-poisoning with medication (HR, 3.55; 95% CI, 1.01-12.53). Opioids (56.5% [95% CI, 43.3%-69.0%]) and psychotropic medication (32.3% [95% CI, 20.9%-45.3%)] were more commonly involved than antiepileptic drugs (9.7% [95% CI, 3.6%-19.9%]) in poisoning deaths in people with epilepsy.

Conclusions and Relevance  Compared with people without epilepsy, people with epilepsy are at increased risk of unnatural death and thus should be adequately advised about unintentional injury prevention and monitored for suicidal ideation, thoughts, and behaviors. The suitability and toxicity of concomitant medication should be considered when prescribing for comorbid conditions.

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Article Information

Accepted for Publication: December 22, 2017.

Corresponding Author: Hayley C. Gorton, PhD, Centre for Pharmacoepidemiology and Drug Safety, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, 1.134 Stopford Bldg, Oxford Road, University of Manchester, Manchester M13 3PT, United Kingdom (hayley.gorton@manchester.ac.uk).

Published Online: April 9, 2018. doi:10.1001/jamaneurol.2018.0333

Author Contributions: Dr Gorton had 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.

Study concept and design: Gorton, Webb, Carr, Ashcroft.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Gorton.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Gorton, Webb, Carr, Ashcroft.

Obtained funding: John, Ashcroft.

Administrative, technical, or material support: Gorton, Carr, DelPozo-Banos.

Study supervision: Webb, John, Ashcroft.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by Greater Manchester Primary Care Patient Safety Translational Research Centre grant GMPSTRC-2012-1 (Drs Gorton, Webb, and Ashcroft) from the National Institute for Health Research. The Secure Anonymised Information Linkage (SAIL) datalink portion of the study was funded by Suicide Information Database-Cymru grant SC-14-11 and National Centre for Mental Health grant CA04 (Drs DelPozo-Banos and John) from Health and Care Research Wales.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The views expressed are those of the authors and not necessarily those of the National Health Service (NHS), National Institute for Health Research, or Department of Health.

Additional Contributions: James Lilleker, MBChB, University of Manchester, provided advice on the epilepsy Read code list. Benjamin Brown, MSc, MBChB, and Thomas Blakeman, PhD, MBChB, from the University of Manchester cross-checked the Read code lists for substance misuse, migraine, and neuropathic pain. W. Owen Pickrell, MBChB, of Swansea University provided advice on the epilepsy Read codes as compared with codes previously used in the SAIL Databank. No one received financial compensation for the stated contribution.

Additional Information: This study is based in part on data from the Clinical Practice Research Datalink (CPRD) obtained under licence from the UK Medicines and Healthcare products Regulatory Agency. The data are provided by patients and collected by the NHS as part of their care and support. The Office for National Statistics provided the linked death data within the CPRD. Data from the Office for National Statistics and from the Hospital Episode Statistics were reused with the permission of The Health & Social Care Information Centre.

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