ReviewAdvances in the development of biomarkers for epilepsy
Introduction
More than 50 million people worldwide have epilepsy and an estimated 2·4 million people are newly diagnosed with epilepsy each year.1 However, despite over 20 antiepileptic drugs being available, seizures remain uncontrolled in about 30% of patients. The research community has focused substantial attention on developing antiepileptic drugs with increased efficacy and fewer adverse effects.2 Additionally, awareness of the need to identify individuals at risk of developing epilepsy and to develop preventive or disease-modifying treatments is increasing.
One of the major impediments to improving epilepsy treatment options is the heterogeneity of epilepsies. Many different genetic and pathophysiological factors, alone or in combination, can underlie an increased risk of developing a seizure disorder. Among these are different forms of brain injuries such as stroke, traumatic brain injury (TBI), or perinatal and prenatal injury, and CNS malformations or tumours. This broad variety of disease entities implies that a large range of mechanisms can lead to establishment of an epileptogenic focus, and that potentially diverse mechanisms of functional impairment and seizure generation exist. Moreover, even in the comparatively homogeneous groups of patients in whom an initial injury can be identified, such as those with stroke or TBI, on average, less than 20% of patients will develop epilepsy within 1–2 years,3 implying further complexity and potentially intra-syndrome heterogeneity. Accordingly, awareness is increasing that both anti-seizure (ie, drugs used to treat epileptic seizures) and antiepileptogenic (ie, drugs used to prevent the development of epilepsy or its progression) treatments need to be developed and prescribed on an individualised basis. This is particularly relevant for antiepileptogenic drugs that would ideally be tailored to the cause for developing epilepsy (eg, a brain injury or genetic mutation). Consequently, identification of biomarkers that can help to guide diagnosis and treatment has been at the centre of research efforts in the past decade. A result of these efforts is that the medical assessment of patients with first-time seizures or initial injuries is often comprehensive, and thus detailed clinicopathological data are available.
Pitkänen and Engel4 defined a biomarker for epileptogenesis as “an objectively measurable characteristic of a biological process that reliably identifies the development, presence, severity, progression, or localization of an epileptogenic abnormality”. An epileptogenic abnormality is the pathophysiological substrate responsible for the start or continuation of epilepsy, or both. This definition captures the important features of the epilepsies that would benefit from the availability of diagnostic and prognostic biomarkers. An ideal diagnostic biomarker should provide information about clinical status, such as the extent and localisation of the epileptogenic area or the severity of the epilepsy. They might also provide information about sensitivity of clinical symptoms to specific treatments. Prognostic biomarkers, similarly, are of potentially high clinical relevance, but are more difficult to identify than diagnostic markers. They are defined as biomarkers that allow prediction of future clinical features, such as the speed of progression or severity of epilepsy, or the prediction of remission or cure, and could be used to identify features of the development of epilepsy, a process termed epileptogenesis.4, 5, 6 This term refers to a process whereby CNS tissue acquires the capability to generate the abnormal and spontaneous electrical activity that underlies seizures. In addition to unprovoked seizures, epilepsy is often associated with somatic, cognitive, psychiatric, and behavioural comorbidities, such as memory impairments.7, 8, 9 The development of these comorbidities is an important feature of epileptogenesis. Thus, a further relevant category of biomarkers could be those that can be used to predict the occurrence of comorbidities or sudden unexpected death. In the discovery of prognostic biomarkers, a crucial additional challenge is that these biomarkers are dependent on disease stage. Thus, even in a cross-section of clinically well-defined people with epilepsy, the stage of epileptogenesis (ie, time after the initial precipitating event) is likely to differ. Hence, the expected proportion of the population who are positive for a given biomarker might depend on the timing of sampling relative to disease progression. Perhaps more importantly, as a consequence, the use of combinatorial biomarkers is also likely to vary depending on the stage of the epileptogenic process. Epilepsy specialists might argue that the surrogate endpoints (eg, number of epileptic seizures) often used in clinical trials can be regarded as biomarkers and can be used to predict the effect of the treatment.10 However, in our view, surrogate endpoints do not strictly fall within the definition of biomarker and will not be discussed in this Review.
Why is it so important to identify diagnostic and prognostic biomarkers for epilepsy? One of the major objectives in the discovery of diagnostic biomarkers is to individualise and optimise treatment. Over 30 preclinical proof-of-concept studies using animal models of genetic epilepsies, cortical malformations, status epilepticus, or TBI have either shown favourable antiepileptogenic or comorbidity-modifying effects, or both.4 However, none of these experimental studies have led to a clinical trial of an antiepileptogenic drug. Designing appropriately powered clinical trials is not possible even in well-defined groups of patients with epilepsy, because of the heterogeneity of epileptogenesis and the endogenous recovery mechanisms of the brain after injury. As a consequence, adequately powered antiepileptogenic trials will only be possible after the identification of biomarkers that allow stratification of participants on the basis of the predicted risk of epileptogenesis.
In this Review, we describe the proof-of-concept preclinical studies and the first clinical studies of biomarker discovery in epilepsy (table). So far, most studies examining the validity of biomarkers, in particular prognostic biomarkers, have relied on animal models with clearly defined initial injury, such as experimental temporal lobe epilepsy (TLE) models caused by an initial status epilepticus, or stroke or TBI models; in human beings, a large portion of the data have been obtained from patients with TLE. Thus, most of the biomarker data available are from a subset of epilepsies, and might not be generalisable across the whole spectrum of the epilepsies.
Section snippets
Genetic biomarkers
Genetic mutations can cause epilepsy, make the brain more vulnerable to develop epilepsy after an acquired brain injury, such as ischaemic stroke or TBI, and influence a patient's response to a given treatment.3, 18 Genetic markers have great potential because DNA is readily available from patients at risk admitted to hospital after potentially epileptogenic injuries such as TBI, new-onset status epilepticus, or stroke. Several genetic variants have been linked to the modulation of seizure
microRNAs
MicroRNAs (miRNAs) are small non-coding RNAs that regulate post-transcriptional gene expression.49 They are differentially expressed in the brain under pathological conditions and might therefore represent both therapeutic targets and diagnostic or prognostic biomarkers for neurological diseases, including epilepsy.12, 50 Several studies have assessed the potential of miRNAs as biomarkers for different aspects of the epileptogenic process.51, 52, 53 Zucchini and colleagues54 examined the
Structural biomarkers
Structural changes are a notable feature of many epilepsies, particularly in patients with chronic TLE with hippocampal sclerosis, which shows characteristic patterns of damage, with segmental neuronal loss, gliosis, and axonal reorganisation. Whether more subtle forms of structural damage can be detected early in the course of disease and predict the future characteristics of epilepsy is unclear. T2-weighted MRI of the amygdala and thalamus has shown promise in the search for biomarkers for
Functional and electrophysiological biomarkers
Electrophysiological parameters have been explored as both diagnostic and prognostic biomarkers. In established epilepsy, recurrent seizures constitute the defining disease symptom.64 An epileptic seizure is a transient occurrence of signs or symptoms, or both, caused by abnormal excessive or synchronous neuronal activity in the brain.64, 65 In the context of epileptogenesis, the conceptual questions remaining to be answered are how networks transform from a healthy state to generate unprovoked
Biomarkers of neuroinflammation
Neuroinflammation is a prominent feature of most types of epilepsies. Neuroinflammation is characterised by the synthesis of cytokines, chemokines, danger signals mediated by endogenous molecules that are released upon tissue damage, and downstream effector molecules from microglia, astrocytes, neurons, and the microvessel endothelium, as a result of activation of the innate immune system.97 Clinical evidence has shown that neuroinflammation is a hallmark of the epileptic focus in
Microvascular injury biomarkers
Another functional system that is interlinked with neuronal function and is altered in many forms of epilepsy is the brain microvasculature. Microvascular injury can mediate delayed and long-lasting changes in the local neurovascular network (figure 3B–D). Specifically, blood–brain barrier dysfunction, and the associated leakage of serum proteins (eg, albumin), that occurs after epileptogenic injuries initiates glial activation and an inflammatory response, which are hallmark pathological
Current challenges
In the past 10 years, promising developments have been made in the biomarker specialty, but key challenges remain in the design of epilepsy biomarker studies.
Conclusions and future directions
What, then, is the way forward? Valuable lessons can be learned from other specialties. Probably the specialty most advanced in terms of biomarker discovery and their clinical use is oncology. This specialty has been driven by both technological advances in so-called omics technologies, which enable identification of molecular pathways, and by the wide availability of tumour tissue after resective surgery. As a consequence, molecular platforms for stratification of treatment of people with
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