Epilepsy biomarkers

Abstract

A biomarker is defined as an objectively measured characteristic of a normal or pathologic biologic process. Identification and proper validation of biomarkers of epileptogenesis (the development of epilepsy) and ictogenesis (the propensity to generate spontaneous seizures) might predict the development of an epilepsy condition; identify the presence and severity of tissue capable of generating spontaneous seizures; measure progression after the condition is established; and determine pharmacoresistance. Such biomarkers could be used to create animal models for more cost-effective screening of potential antiepileptogenic and antiseizure drugs and devices, and to reduce the cost of clinical trials by enriching the trial population, and acting as surrogate markers to shorten trial duration. The objectives of the biomarker subgroup for the London Workshop were to define approaches for identifying possible biomarkers for these purposes. Research to identify reliable biomarkers may also reveal underlying mechanisms that could serve as therapeutic targets for the development of new antiepileptogenic and antiseizure compounds.

Keywords: Biomarkers; Epileptogenesis; Ictogenesis; Surrogate markers; Therapeutic intervention.

Figure 1

Multifactorial basis of epilepsy. A. The dashed line indicates seizure threshold; it is wavy to acknowledge that seizure threshold is not static. Seizure threshold or probability is defined as the propensity or likelihood for a seizure to occur; it also represents epileptogenicity, but what might more accurately be called ictogenicity. B. represents a specific epileptogenic abnormality which could be structural metabolic or genetic. Specific epileptogenic abnormalities are also not necessarily static, and the degree of epileptogenicity can change from one time to another. C. illustrates precipitating factors, which can be external, for instance for reflex seizures, or internal and usually not detectable. Precipitating factors determine when seizures occur. The subsequent panels illustrate how these three factors interact. Someone with a high threshold may have epileptogenic abnormalities and precipitating factors and never have seizures, while someone with a low threshold could have seizures due to epileptogenic abnormalities without precipitating factors, seizures due to precipitating factors without an epileptogenic abnormality (provoked seizures), or both.

Figure 2

A) This figure illustrates the role of the three factors shown in Figure 1 in the development and maintenance of an epilepsy condition. At the bottom there is a cascade of mechanisms that begin, continue, and maintain the epileptogenic process. These last for varying periods of time. Some may invariably lead to epilepsy and others not. The top line illustrates changes in threshold. A lower threshold indicates an increased propensity for seizure generation related to the epileptogenic processes illustrated on the bottom line. Once the threshold goes below a certain level (dashed line), seizures occur, either in response to precipitating factors illustrated in the middle line, or spontaneously. The threshold level could be considered ictogenicity and the bottom boxes could represent epileptogenesis. Measures taken at point A might reveal biomarkers of epileptogenic processes with a predictive value for development of epilepsy, while biomarkers of ictogenicity would have no predictive value. Measures taken at point B might reveal biomarkers of different epileptogenic mechanisms that have a different predictive value than those at A, and could permit staging of the epileptogenic process, while measures of ictogenicity could reveal a change suggestive of a developing epileptogenic process. Measures taken at point C could reveal biomarkers of epileptogenic processes which document that an epilepsy condition exists, and perhaps determine whether it was stable or progressive. Biomarkers of epileptogenicity at this point might also reveal that an epilepsy condition exists, but would provide no information regarding potential progression. Measures that are taken at point D could also yield biomarkers indicating whether epileptogenesis is persistent or progressive, while changes in biomarkers of ictogenicity from point C to point D could indicate progression or improvement, but not determine whether this reflects changes in epileptogenic processes (See also Figures 2B and 2C). Repeated measures could document reduction in epileptogenic processes as a result of antiepileptogenic interventions, and fluctuations in ictogenicity due to antiseizure drugs, or circumstances such as illness or stress that might increase the propensity for seizures to occur. Measures taken at any point in time after the development of epilepsy might reveal biomarkers of the onset of a precipitating factor, which could be used for seizure prediction. Such biomarkers would be necessary for the development of interventions that abort seizures. B) This figure illustrates progression. In this case, more of the epileptogenic processes continue after seizures begin and threshold continues to be reduced, resulting in more frequent or more severe seizures with precipitating factors. Measures at D could indicate biomarkers of epileptogenic processes which document progression as well as a further lowering of the threshold or increased ictogenicity. C) This figure illustrates remission where an intervention results in an increase in threshold and freedom from seizures but the underlying epileptogenic abnormality persists. Measures taken at D in this situation could reveal biomarkers indicating that the epileptogenic process persists, although the threshold is elevated so that ictogenicity is decreased, perhaps even to a “normal” level.

Figure 3

A) This figure illustrates cure. In this instance, the intervention after epilepsy is established eliminates the underlying epileptogenic abnormality so that a measure taken at D. would be the same as in Figure 2B, but a measure taken at E. would show that biomarkers for the underlying epileptogenic abnormality are now resolved, confirming cure. B) This figure illustrates prevention. In this case, an intervention shortly after the epileptogenic process begins results in the elimination of the underlying epileptogenic abnormality before seizures occur and the threshold returns to baseline. Measures at B would indicate loss of some biomarkers of the epileptogenic abnormality, while measures at C and D would indicate absence of biomarkers for the epileptogenic abnormality and a return of threshold, or ictogenicity, to baseline levels, confirming prevention.