Elsevier

Epilepsy & Behavior

Volume 24, Issue 3, July 2012, Pages 304-310
Epilepsy & Behavior

Review
Seizure diaries for clinical research and practice: Limitations and future prospects

https://doi.org/10.1016/j.yebeh.2012.04.128Get rights and content

Abstract

Purpose

An NINDS-sponsored conference in April of 2011 reviewed issues in epilepsy clinical trials. One goal was to clarify new electronic methods for recording seizure information and other data in clinical trials.

Methods

This selective literature review and compilation of expert opinion considers advantages and limitations of traditional paper-based seizure diaries in comparison to electronic diaries.

Key findings

Seizure diaries are a type of patient-reported outcome. All seizure diaries depend first on accurate recognition and recording of seizures, which is a problem since about half of seizures recorded during video-EEG monitoring are not known to the patient. Reliability of recording is another key issue. Diaries may not be at hand after a seizure, lost or not brought to clinic visits. On-line electronic diaries have several potential advantages over paper diaries. Smartphones are increasingly accessible as data entry gateways. Data are not easily lost and are accessible from clinic. Entries can be time-stamped and provide immediate feedback, validation or reminders. Data can also can be graphed and pasted into an EMR. Disadvantages include need for digital sophistication, higher cost, increased setup time, and requiring attention to potential privacy issues. The Epilepsy Diary by epilepsy.com and Irody, Inc. has over 13,000 registrants and SeizureTracker over 10,000, and both are used for clinical and research purposes. Some studies have documented patient preference and increased compliance for electronic versus paper diaries.

Seizure diaries can be challenging in the pediatric population. Children often have multiple seizure types and limited reporting of subjective symptoms. Multiple caregivers during the day require more training to produce reliable and consistent data.

Diary-based observational studies have the advantages of low cost, allowing locus-of-control by the patient and testing in a “real-world” environment. Diary-based studies can also be useful as descriptive “snapshots” of a population. However, the type of information available is very different from that obtained by prospective controlled studies. The act of self-recording observations may itself influence the observation, for example, by causing the subject to attend more vigilantly to seizures after changing medication.

Pivotal anti-seizure drug or device trials still mostly rely on paper-based seizure diaries. Industry is aware of the potential advantages of electronic diaries, particularly, the promise of real-time transmission of data, time-stamping of entries, reminders to subjects, and potentially automatic interfaces to other devices. However, until diaries are validated as research tools and the regulatory environment becomes clearer, adoption of new types of diaries as markers for a primary study outcome will be cautious.

Significance

Recommendations from the conference included: further studies of validity of epilepsy diaries and how they can be used to improve adherence; use and further development of core data sets, such as the one recently developed by NINDS; encouraging links of diaries to electronic sensors; development of diary privacy and legal policies; examination of special pediatric diary issues; development of principles for observational research from diaries; and work with the FDA to make electronic diaries more useful in industry-sponsored clinical trials.

Highlights

► Clinical care and most epilepsy trials depend upon seizure counts in diaries. ► Diaries are potentially flawed by inaccurate seizure counts. ► Electronic or on-line diaries can improve accuracy of information collection. ► Analysis of disadvantages and validation are yet to be done.

Introduction

Most clinical trials of epilepsy therapies include seizure frequency, as documented on calendar diaries, as a primary outcome variable. This places self-reported diaries at a pinnacle of importance in the development of new treatments for epilepsy, but little information exists on the accuracy or validity of these tools. On April 30, 2011, the National Institutes of Neurological Diseases and Stroke (NINDS) of the United States National Institutes of Health sponsored a conference on clinical trials in the field of epilepsy, at which seizure diaries were discussed. This article reviews seizure diaries as they now exist and possible directions for the near future.

Diaries are a form of so-called patient‐reported outcomes [33]. The Food and Drug Administration (FDA) has provided guidance, in general, on the development of PROs [13]. A review of patient‐reported outcomes (PROs) in epilepsy [35] listed 61 articles involving design and validation of PROs, including scales for Quality of Life, Seizure Severity and Psychosocial Inventories but none analyzing diaries, which is perhaps the most fundamental PRO. Under ideal circumstances, diaries developed for research and clinical trials would also be useful for direct patient care [15]. Seizure diaries have already been found to be useful for patient-based prediction of subsequent seizures [19]. However, diaries designed primarily for clinical care or seizure prediction are not the subject of this review.

Section snippets

What information should be recorded in a seizure diary?

Before using a seizure diary, subjects need to prospectively describe and codify their various seizure types, in conjunction with study organizers. Patients have the capability of naming their own seizures as they perceive them. For example, seizure type “A” might be described as a feeling of déjà vu; type “B” would be representative of déjà vu followed by confusion, lip-smacking and fumbling; and type “C” would reflect an event of loss of consciousness with falling and shaking. Subjects will

Potential problems with seizure diaries

Table 1 lists the potential problems with interpretation of seizure diaries.

Entering information in diaries requires at least moderate intellectual capability and literacy, which is not present in all patients with epilepsy. However, the increasing penetration of smartphones indicates that most people will have usable input platform in the near future. Studies restricted to those capable of using paper or electronic diaries may introduce selection bias into the trials. Caregivers can assist

Electronic diaries

Electronic diaries provide an alternative to the traditional paper-based seizure diaries. These may be implemented on dedicated handheld devices or as software loaded on a standard smartphone or another commercially available device. Such devices potentially allow programming to improve data validity, real-time transmission of data, reminders to subjects, and other features. However, handheld devices and smartphones may also be lost, although some allow uploads of data when patients are

Seizure diaries in pediatric populations

Use of seizure diaries can be challenging in the pediatric population. First, children with epilepsy may be more likely than adults to have multiple seizure types. Accurate description, categorization and labeling of each seizure type (as described above) are especially crucial for children. Since younger children may not have the cognitive capacity to recognize and report seizures, the data collection must be done by caregiver's observation. Children often have multiple caregivers (parents,

Epilepsy diaries for clinical practice

Two web-based diaries have recently come into clinical use for people with epilepsy, My Epilepsy Diary by Irody, Inc. at epilepsy.com and Seizure Tracker at SeizureTracker.com. Both of these diaries are free, nonprofit services for the epilepsy community. As of March, 2012, My Epilepsy Diary had 13,052 user accounts, two-thirds of which were in the United States, 571,504 logged transactions, 86,840 seizure events, 41,070 reported side effects, and 169,513 medication-related (compliance) events.

Epilepsy diaries for research

Communication and data storage in modern times increasingly involves electronic rather than written data entry and preservation. Computer databases for tracking clinical trials have been available for decades, although not necessarily with primary data entry by the study participants. Electronic data entry is now beginning to be used without concurrent paper diaries, since translation of paper to electronic diaries increases work and introduces translation errors.

Potential advantages and

View from industry

FDA approval of a new medication or high-risk therapeutic device requires at least one adequately controlled randomized clinical trial. The manufacturers of drugs and devices are very aware of the use of medical diaries for PROs that may provide key outcome data for pivotal trials. Advisors to industry will consider whether a diary has been validated against conventional standards and whether it provides accurate as well as precise information. A diary with missing or inaccurate information,

Future directions

Predicting can be hazardous. In 1949, Popular Mechanics asserted that “Computers in the future may weigh no more than 1.5 tons.” (Wikipedia). Speculation about the use of on-line information systems in medicine will likely be as wide of the mark as was the Popular Mechanics prediction. Two trends, however, are likely for the near future: links to biosensors and electronic diaries for clinical trials.

Biosensors can be linked to on-line diaries, in order to automatically collect information about

Recommendations for clinical research

The diary subgroup attending the NINDS conference on epilepsy clinical trials offered several recommendations pertaining to seizure diaries for clinical research. These are listed below.

  • 1.

    Develop studies to validate current and new uses of epilepsy diaries as clinical and research tools.

  • 2.

    Develop a core of data sets useful for all epilepsy diary users, taking into account existing diaries and the NIH Common Data Element material.

  • 3.

    Develop a method to have core common diary information and

Disclosure of conflicts of interest

Dr. Fisher consults for Neuro-Vista, Cyberonics, ICVRx, Irody, SmartMonitor. Stanford University has received research support from Medtronic with Dr. Fisher as principle investigator. Dr. French serves as the president of The Epilepsy Study Consortium, a non-profit organization. NYU receives a fixed amount from the Epilepsy Study Consortium towards Dr. French’s salary. The money is for work performed by Dr. French on behalf of The Epilepsy Study Consortium, for consulting and clinical trial

Acknowledgments

Funding for the April 30, 2011 workshop, from which this manuscript emerged, was provided by the NINDS and the Epilepsy Study Consortium. The first author (RSF) is supported by the Maslah Saul MD Chair, the James and Carrie Anderson Fund for Epilepsy Research and the Susan E. Horngren Fund. We gratefully acknowledge Eyal Bartfeld of Irody, Inc. for a helpful review and critique.

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