Elsevier

The Lancet Neurology

Volume 7, Issue 2, February 2008, Pages 151-160
The Lancet Neurology

Review
The neurobehavioural comorbidities of epilepsy: can a natural history be developed?

https://doi.org/10.1016/S1474-4422(08)70018-8Get rights and content

Summary

Epilepsy is a common neurological disorder that can be complicated by neurobehavioral comorbidities, which include cognitive impairment, psychiatric disorders, and social problems. Although such comorbidities are traditionally thought to arise predominantly from the effects of recurrent seizures, iatrogenic effects of medications, and adverse social reactions to epilepsy (eg, stigma), there is a growing body of evidence that other factors are involved. These influences include altered neurodevelopment of the brain, cognition, and behaviour; exacerbation of the comorbidities due to decades of medically intractable epilepsy; and possible acceleration of common age-associated changes, leading to uncertain and understudied outcome in old age. This Review summarises, from a lifespan perspective, the evidence for the neurodevelopmental origins of these comorbidities, how they develop over time, and their endpoints, with an emphasis on future clinical and research challenges.

Introduction

Epilepsy is a prevalent neurological disorder that affects an estimated 50 million people worldwide.1 Although defined by the presence of recurrent seizures, epilepsy can be so much more and might include abnormalities in cognition, psychiatric status, and social adaptive behaviour; these problems are grouped under the term neurobehavioural comorbidities in this Review.

Although increasing clinical and research attention has been directed at these complications, the neurobehavioural comorbidities of epilepsy have a long and at times dispiriting history. Problems in cognition, emotional–behavioural status, and social function, which were variously referred to as the psychosocial complications or the burden of epilepsy, were investigated empirically from the start of the 20th century, when people with epilepsy were frequently segregated in colonies.2 Epileptologists subsequently sought to provide a more representative picture of the consequences of epilepsy in people who lived in the community,3 and patients with epilepsy have been the ongoing concern of national commissions,4 public health agencies,5 and special action groups of national and international health organisations, including the International League Against Epilepsy, World Health Organization, Centers for Disease Control, and Epilepsy Foundation. Recently, at the National Institutes of Health conference Curing Epilepsy 2007: Translating Discoveries into Therapies, the prevention and reversal of the comorbidities of epilepsy were identified as a major new benchmark area for research.

Although undeniably a potentially crucial complication of the epilepsies, the aetiology and course of the neurobehavioural comorbidities—or their natural history—need to be fully characterised. In this Review, we discuss the current knowledge with regard to these complications of epilepsy from a lifespan perspective. First, we give a brief overview of the prevalence of neurobehavioural comorbidities in population-based and other non-selected studies; we then turn to the question of whether the neurobehavioural comorbidities and their course are progressive; finally we discuss neurodevelopmental studies and focus on their onset and development. Although this is an atypical lifespan order, it is one that investigators have pursued to understand the neurobehavioural comorbidities of epilepsy. Because epilepsy is a family of disorders with various aetiologies, age dependence, severity, and other features, we will anchor our presentation throughout this Review to a particularly common form of epilepsy—temporal lobe epilepsy—to emphasise the core points.

Section snippets

The nature of the problem

The term comorbidity refers to the greater than coincidental presence of two conditions in the same individual.6 Comorbidity does not imply direction or causation, and the disorders might co-occur by chance or they could share genetic, environmental, or other mechanisms.7 The association or comorbidity of cognitive, psychiatric, and social problems in patients with epilepsy have frequently been investigated in selected populations; these populations typically comprise patients cared for at

Do comorbidities progress or worsen over time?

Concerns about whether cognition, psychiatric status, or social function deteriorate over time (so-called progression) in the face of chronic epilepsy or markers of epilepsy severity have been voiced for decades. Many cross-sectional studies have investigated the association among cognition and the duration and severity of epilepsy. Although indirect, these studies can be used to examine patterns of cognition or behaviour in patients who have had epilepsy for decades. The outcomes have been

Comorbidities in older patients with epilepsy

The ultimate course of neurobehavioural comorbidities in patients with chronic epilepsy is poorly understood. Research into ageing and epilepsy has focused on new-onset epilepsy in older patients and there are few data on older patients who have lived with epilepsy for decades. We are aware of only four published studies that have objectively assessed cognitive status in older patients with chronic epilepsy.95, 97, 99, 100 Compared with healthy controls (n=27), community-dwelling older patients

When do comorbidities start?

Owing to the nature and severity of the neurobehavioural comorbidities associated with chronic active epilepsy, interest in finding the origin and development of these problems has grown, and at least three sets of evidence suggest a substantial neurodevelopmental contribution.

First is the indirect investigation of the risk of comorbidities as a function of age of epilepsy onset. The results of neuropsychological studies in adults with chronic epilepsy have shown, repeatedly, that earlier age

Children and adolescents with new-onset epilepsy

The cognitive and behavioural status of patients close to the onset of recurrent seizures has been investigated, and abnormalities have been reported by some but not all investigators.137, 138, 139, 140, 141 The results of tests in children with newly diagnosed epilepsy who had not started antiseizure medications showed significantly worse behavioural adjustment and significantly poorer performance in attention, reaction time, and visual memory, with a trend for academic achievement (figure 7).

Before the onset of epilepsy

The findings that suggest that psychiatric, cognitive, and academic problems might even antedate the diagnosis of epilepsy and recognition of the first seizure are interesting and provocative.

Austin and collaborators144, 145 investigated behavioural problems in children with new-onset epilepsy compared with sibling controls and found that parents and teachers reported elevated rates of behavioural disturbances in children with epilepsy during the 6 months before the first recognised seizure. In

A lifespan perspective

Evidence shows that the onset of epilepsy in childhood might be associated with altered patterns of neural and cognitive development, an effect that might affect short-term (educational) and long-term occupational, social, and behavioural development.115 We need to determine whether this early effect increases the risk that subsequent lifetime insults, either related to epilepsy (eg, status epilepticus or number of lifetime generalised tonic–clonic seizures) or not (eg, closed head injury or

Conclusions

This Review suggests clinical and research opportunities to advance the knowledge, treatment, and prevention of the neurobehavioural comorbidities of the epilepsies throughout the lifespan. Although neurobehavioural comorbidities that antedate seizure onset have been identified by several research groups, the aetiology that underlies these comorbidities is unknown. Furthermore, because neurobehavioral comorbidities are present at the time of seizure onset in a proportion of children or

Search strategy and selection criteria

A search was carried out using PubMED for articles published up to December 2007. Search terms comprised key words related to epilepsy, including “seizure” and “seizure disorder” combined with terms to reflect neurobehavioural comorbidities, such as “depression”, “anxiety”, “cognition”, “social”, and “MRI volumetrics”, to identify potentially relevant studies. Further articles were identified from the reference lists of these papers. Only articles published in English were included. All

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