Abstract
Traumatic brain injury (TBI) is a major risk factor for the development of epilepsy, accounting for around 5% of all epilepsy cases. The risk is greatest within the first year of injury but persists for many years afterwards. Severity of injury is the biggest predictor of future risk of epilepsy, with evidence of intracerebral and sub-dural haemorrhage being important clinical indicators. Individual characteristics including medical co-morbidities and genetic predisposition also influence this risk.
TBI-related seizures are separated into those arising within the first week of injury (early post-traumatic seizures) and those happening later (late post-traumatic seizures). This distinction is useful because early post-traumatic seizures do not appear to be an independent risk factor for the future development of epilepsy. However, the risk of further seizures after a single late post-traumatic seizure is as high as 80%. Therefore, one late post-traumatic seizure signals an increased predisposition to generate future epileptic seizures. This fulfils the criteria for diagnosing epilepsy and the individual should be counselled and treated accordingly.
In this chapter, we discuss the classification of epilepsy and TBI severity before summarising the largest epidemiological studies that have attempted to ascertain the incidence and prevalence of post-traumatic epilepsy and the major risk factors.
Introduction
Epileptic seizures are common following a traumatic brain injury (TBI)1 and are associated with a worse clinical outcome.2, 3 They frequently occur at the time of an injury (or very soon after) due to an acute disruption to normal brain structure and physiology, but they can also develop many years later.1 Early seizures (defined as those occurring within a week of injury) are not an independent risk factor for the development of future seizures,1 whereas the risk of further seizures after a single late post-traumatic seizure (occurring more than a week after injury) can be as high as 80%.4
TBI is very common, with an estimated 50 million people worldwide suffering a TBI each year.5 Given its high prevalence and its risk for the development of epilepsy, TBI is a major cause of acquired epilepsy, with population-based studies estimating it to be the basis of around 6% of all cases of epilepsy.6
Epilepsy, more properly termed ‘the epilepsies’ encompassing hundreds of different types and causes, similarly affects over 50 million people worldwide.7 Up to 5% of people will have a seizure at some point in their life,8 with an estimated 1 in 26 people developing epilepsy during their lifetime.9 An epileptic seizure is defined as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Having seizures does not, however, constitute a diagnosis of epilepsy. Almost any brain might generate a seizure at the time of a sufficiently severe insult (e.g. metabolic, toxic, inflammatory or traumatic), and this is termed an acute symptomatic or provoked seizure.10 The risk of recurrence after acute symptomatic seizures is low (1–3%), other than in individuals repeatedly exposed to the same trigger (e.g. alcohol withdrawal). Epilepsy is defined as the enduring predisposition to generate unprovoked epileptic seizures.11 From a practical perspective, the occurrence of two unprovoked seizures more than 24 hours apart has long been recognized to indicate a diagnosis of epilepsy as the risk of further seizures is high (60–90%) in this context.12 However, as we shall go on to discuss, it is now accepted that if other evidence supports a high (>60%) probability of recurrent seizures occurring after one seizure, a diagnosis of epilepsy should be made rather than waiting for a second seizure to occur. Evidence of increased risk of future seizures includes epileptic abnormalities on EEG, structural changes on brain imaging known to be highly predictive of increased risk and epidemiological evidence in relation to individual aetiologies. The risk of a recurrent seizure after a first unprovoked event in an individual can vary from <10% to >90% depending on these and other variables.13 Traumatic brain injury can precipitate acute symptomatic seizures but can also cause long-lasting structural and physiological changes in the brain that can predispose to epileptic seizures. Understanding the risks of seizures and accurately diagnosing epilepsy after a TBI is important to facilitate counselling and aid treatment decisions whilst avoiding unnecessary medication use.
To support clinical decision-making, several large epidemiological studies have attempted to quantify the risks of seizures after TBI. In this chapter, we outline and summarize the results from the largest studies. These studies have provided valuable information on the incidence of post-traumatic epilepsy (PTE). In particular, they highlight the significant increased risk of epilepsy conferred by a TBI and show, perhaps surprisingly, that this risk persists for many years after the injury (over 20 years for a severe TBI1). Severity of injury, presence of intracranial haemorrhage, length of post-traumatic amnesia, length of loss of consciousness and time after injury are all clear predictors of seizure risk. In addition, other factors, including the presence of additional medical comorbidities, depression and a family history of epilepsy, may also increase the risk of the development of PTE.14, 15 These factors highlight that the development of epilepsy is likely to be a multifactorial process, dependent on the characteristics of the individual as well as the injury itself.
Definitions and Terminology for Post-traumatic Epilepsy
In order to understand the potential risks of PTE and the relationship to TBI severity, it is important to appreciate how epilepsy, PTE and TBI severity are defined and classified.
A Practical Definition for Epilepsy
The current conceptual definitions of epilepsy and epileptic seizures were formulated in 2005 by the International League Against Epilepsy (ILAE)16:
Epileptic seizure: A transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Epilepsy: A disorder of the brain characterized by an enduring predisposition to generate epileptic seizures, and by the neurobiological, psychological and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure.
At the time these definitions were proposed, the diagnosis of epilepsy required the occurrence of two unprovoked seizures at least 24 hours apart. The rationale for this requirement was based on epidemiological data showing the risk of recurrence after a single unprovoked seizure is 30–50%.17 Following a second unprovoked seizure, this risk rises to 60–90%.12 Exposing an individual to the potential harm of treatment therefore seems reasonable after two but probably not one seizure. However, despite the value of this working definition, it became increasingly apparent that it was inadequate in certain situations. In particular, it did not address situations where there was a high risk of future seizures after a single unprovoked seizure. For example, individuals who have suffered a remote brain insult (e.g. stroke or traumatic injury) have a comparable risk of a second unprovoked seizure to those suffering two unprovoked seizures.18
This is now articulated in the practical, operational clinical definition of epilepsy put forward in 2014,11 which states:
Epilepsy is a disease of the brain defined by any of the following conditions:
1. At least two unprovoked (or reflex) seizures occurring >24 h apart
2. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years
Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years.
This update in the working definition is important as the treatment goal in the management of epilepsy is reducing the mortality and morbidity associated with seizures. Therefore, it is logical that the decision to initiate treatment should be based on future risk of seizures rather than necessarily waiting for a second seizure to occur. It is difficult to provide a specific risk threshold at which an individual is considered to have ‘epilepsy’ rather than an isolated unprovoked seizure, but it seems reasonable to assume that an individual with a predisposition for further seizures comparable to that following two unprovoked seizures should also be considered to have epilepsy and managed as such.
The classification and terminology relating to seizures19 and epilepsies20 were also updated in 2017. Previous classification systems, particularly in relation to focal onset (previously termed partial) seizures, did not adequately capture the range of different seizure types. In addition, some felt the term ‘partial’ inferred these were less important or incomplete seizures/epilepsies, whereas in reality they are often the most disabling and difficult to control. Currently recommended terms and mapping to prior terminology is summarized in Table 2.1.
Table 2.1 Summary of common terminology for types of seizures used by lay people and how this maps to the previous and current classification
| Lay term | Previous terminology | Current terminology (ILAE 2017) |
|---|---|---|
| Convulsion, Grand Mal, seizure | Generalized tonic-clonic seizure, secondary generalized tonic-clonic seizure | Generalized tonic-clonic seizure focal to bilateral tonic-clonic seizure |
| Absence, blank, petit mal | Complex partial seizure Absence seizure | Focal impaired awareness absence seizure |
| Funnies, turns, déjà vu, aura, warning, partial, small seizure | Partial seizures (multiple types) | Focal seizures (multiple types) |
| Drop attack | Atonic seizure, tonic seizure, partial seizure | Atonic seizure, tonic seizure, focal seizure, nonepileptic |
| Jerk, twitch | Myoclonic seizure, simple partial seizure | Myoclonic seizure, focal motor seizure |
The new classification comprises three levels of classification and six aetiological groups as summarized in Figure 2.1. The starting point of this framework is to define the seizure onset as focal, generalized or unknown. The second level is epilepsy type, including focal, generalized, combined generalized and focal and unknown. Some individuals may have both. For example, a patient with a generalized epilepsy syndrome, such as juvenile myoclonic epilepsy, may also suffer a TBI and acquire post-traumatic focal epilepsy. The third level is of an epilepsy syndrome diagnosis where one exists. An epilepsy syndrome refers to a collection of qualities including seizure type, EEG and imaging features. Typical examples of well-recognized epilepsy syndromes include Dravet syndrome and childhood absence epilepsy.
Any diagnosis of epilepsy should also include the cause where possible and identification of any important comorbidities. For most individuals, the appropriate category will either be obvious or unknown. However, some will seem to straddle more than one group. For example, tuberous sclerosis is a known genetic condition, yet would be classified as a structural cause, as the ‘dominant’ contributor to the risk of seizures is the associated structural brain abnormality. By definition, PTE would involve focal onset seizures and be considered structural in terms of aetiology, even though there may be metabolic factors involved in triggering seizures and the development of epilepsy.
Post-traumatic Seizures and Post-traumatic Epilepsy
Seizures following trauma are classified based on their timing in relation to the injury, as this has important prognostic implications with regards to the risk of future seizures. The presence of seizures occurring within the first 7 days after a TBI is a strong risk factor for late seizures. However, this increased risk is almost entirely eliminated with adjustment for other prognostic factors such as injury severity.1 Early seizures of themselves do not confer a sufficiently high risk of subsequent recurrent seizures to warrant long-term treatment and a diagnosis of epilepsy. They are therefore considered acute symptomatic seizures. In contrast, even a single late seizure (>7 days after injury) does confer a substantial risk of future unprovoked seizures, that is, the development of PTE.18
A large epidemiological study illustrating this analysed the prognosis after a first acute symptomatic seizure (occurring within 7 days of the TBI) and after a first unprovoked seizure (>7 days after injury) in terms of short- and long-term mortality and risk of subsequent unprovoked seizures.18 Individuals with a first acute symptomatic seizure compared with a first unprovoked seizure were significantly more likely to die within the first 30 days after the seizure (11%, 95% CI (6.1–19.6%) vs. 0%) and less likely to experience a subsequent unprovoked seizure over the next 10 years (13.4% (95% CI=7.0–24.8%) vs. 46.6% (95% CI=30.4–66.3%)). There was no difference in mortality at 10 years between the two groups. From this analysis the authors concluded that early and late seizures following a TBI are different entities with different prognoses. Furthermore, early seizures are not associated with an ‘enduring predisposition to generate epileptic seizures’ and should therefore not be considered as a marker for the development of epilepsy.
Classification of Traumatic Brain Injury Severity
As detailed in the following section, different epidemiological studies employed different definitions for TBI severity. There is a clear link between TBI severity and risk of development of PTE, although there is no uniform consensus on how severity should be defined. A combination of length of post-traumatic amnesia, length of loss of consciousness, Glasgow Coma Score, presence of skull fracture and presence of structural brain injury (e.g. contusion, cerebral or extra-cerebral haematoma) are the most commonly used indicators. Differentiating between penetrating and nonpenetrating TBI is also important, as the risk of PTE after a penetrating injury is far higher (case series report around 50% risk of PTE in military personnel suffering penetrating head injuries21).
Additionally, neuroimaging has only become commonplace over the last 30–40 years and therefore the older epidemiological studies do not include it in their assessment of severity. However, neuroimaging is an important indicator of TBI severity22 and therefore a key component in more recent TBI severity classifications (e.g. the Mayo classification for TBI severity23).
The TBI severity classification systems used in the epidemiological studies include the head Abbreviated Injury Scale (AIS), the International Classification of Diseases (ICD) and combined clinical markers, including the Glasgow Coma Scale (GCS), length of post-traumatic amnesia, length of loss of consciousness, skull fracture, subdural haematoma, brain contusion or intracerebral haemorrhage. The GCS is commonly used to stratify severity of TBI, with a score of 13–15 considered mild, 9–12 moderate and 3–8 severe.24 However, its use can be confounded by other factors not attributable to the TBI, such as length of time between injury and assessment, early sedation and extra-cranial injuries. In addition, individuals with structural injuries present on neuroimaging but GCS 13 or greater have been shown to have outcomes more consistent with a moderate rather than mild injury, suggesting GCS alone can underestimate severity.22 The head AIS ranks anatomic injury on a scale of 1 (least severe) to 6 (most severe).25 It uses standardized terminology to stratify the severity of injury and has been shown to weakly correlate with functional outcome.26–28 Finally, the ICD has been used in some epidemiological studies to classify TBI severity.29, 30 These studies used the following ICD codes for stratification: ICD-9-CM 850 = Mild, ICD-9-CM 851–854 = Severe and ICD-9-CM 800–804 to signify the presence of a skull fracture. Mild TBI is classified as ‘concussion’ (ICD-9-CM 850) with or without loss of consciousness that can be greater than 24 hours and without a return to pre-existing conscious level. There is no consensus agreement on what constitutes a diagnosis of concussion,31 making its use problematic in classifying injury severity. In addition, most clinicians would consider a head injury with loss of consciousness greater than 24 hours and without a return to pre-existing conscious level (even without intracerebral haemorrhage or skull fracture) to be a severe brain injury. The severe TBI classification only includes patients with evidence of cerebral contusion, traumatic subarachnoid haemorrhage, extradural haemorrhage or subdural haemorrhage.
Epidemiology of Post-traumatic Epilepsy
The risk of developing PTE is dependent on injury severity and type, ranging from 2% after mild injuries to over 50% following penetrating injuries.1, 15, 21 Given the high incidence of TBI, with around 50 million people worldwide suffering a TBI each year,5 the prevalence of PTE is also very high. In addition, the prevalence of TBI as the causative factor for epilepsy varies by age group due to the varying incidence of TBI and other factors influencing risk of epilepsy (e.g. stroke) in different age groups. In one study, nearly 30% of epilepsy cases where a cause could be determined were attributed to a TBI in the 15–34-year-old age group, whereas it only accounted for 14% in younger children and 8% in adults over the age of 65 years given the increasing likelihood of other factors in this group (e.g. stroke).6
The risk of early seizures (within the first 7 days of injury) varies between 2% and 17% and is dependent on injury severity and age.32 In isolation, early seizures are a strong risk factor for the development of late seizures; however, when other factors such as injury severity are taken into account this risk is removed. Hence, early seizures do not appear to be an independent risk factor for the development of PTE.1 Seizures can develop many years after a TBI, with an enduring risk above that of the matched population even 20 years after a severe TBI.1 The risk of seizure recurrence after a single late seizure (>1 week after injury) is high (over 80%4) and therefore these individuals need counselling regarding future seizure risk and anti-epileptic treatment to reduce the risk of further seizures.
Evidence for Post-traumatic Seizure Risk
Several large epidemiological studies have attempted to determine the effect of TBI on the future risk of seizures. The results of the largest studies are summarized in Table 2.2. Due to methodological differences, it is not possible to pool the data from all studies and specific limitations for each study need to be borne in mind. In particular, not all studies use a comparison group, which given the incidence of seizures in the general population is a significant flaw. In addition, the utility of retrospective studies is dependent on the validity of the diagnoses and the generalizability of the results from the population studied. Finally, given the evidence that the risk of PTE can persist for over 30 years after the injury, the length of follow-up is an important factor and a major reason why it is difficult to conduct these studies.
Table 2.2 Largest studies investigating risk of seizures after traumatic brain injury
Related posts:
Chapter 6 – Sport-related Concussive Convulsions
Chapter 7 – Accidents and Injuries during Seizures
Chapter 8 – Cognitive Rehabilitation of Traumatic Brain Injury and Post-traumatic Epilepsy
Chapter 12 – Antiepileptogenic Therapies for Post-traumatic Epilepsy: Is There Any Evidence?
Chapter 13 – Effects of Antiepileptic Drugs on Cognition
Chapter 14 – Post-traumatic Epilepsy in Low Income Countries
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