Risk Factors for Post-Traumatic Seizures

There are several patient and injury characteristics that increase the likelihood of developing PTS. These include increased injury severity (Glasgow Coma Scale score of less than 10, prolonged length of coma, prolonged length of post-traumatic amnesia), depressed skull fractures, cortical contusions, subdural hematomas, epidural hematomas, intracerebral hematomas, penetrating injuries and wounds with dural penetration, a seizure within the first week of injury, male gender, age, and having had multiple neurosurgical procedures (Brain Injury Special Interest Group 1998; Dikmen et al. 1991; Englander et al. 2003; Krause-Titz et al. 2016; Walker et al. 2015; Wang et al. 2013a; Yablon 1993; Yeh et al. 2013; Zhao et al. 2012). Ferguson et al. (2010) also found those who had other concomitant injuries or comorbid conditions, previous head injuries, stroke, or depression were more likely to develop LPTS, which is congruent with the findings of previous studies (Andelic et al. 2009; Annegers et al. 1998; Weiss et al. 1983). The risk of unprovoked epileptic seizures is greatest during the first six months post injury and higher for individuals with severe injuries (Mahler et al. 2015).

The first year post injury is often when post-traumatic epilepsy (PTE) develops (Di Luca & de Lacerda 2013; Lamar et al. 2014; Lucke-Wold et al. 2015), however, the risk remains high within two years of injury (Lamar et al. 2014). In a cohort study conducted by Ferguson et al. (2010), the incidence of PTE was highest in individuals 30 to 54 years of age. However, higher rates of PTE have also been reported for those 50 to 59 and 60 to 69 years of age (Zhao et al. 2012). According to a meta-analysis conducted by Xu and colleagues (2017), risk factors for PTE include: male gender, previous alcohol abuse, loss of consciousness at time of TBI, post-traumatic amnesia, and focal neurological signs. Moreover, Diamond et al. (2014) recently explored genetic variance and PTE development in 256 individuals with moderate to severe TBI. The study found that higher cerebrospinal fluid and serum IL-1β (a potential biomarker for epilepsy) ratios were associated with an increased risk of PTE (Diamond et al. 2014). Due to this study being one of the first studies exploring this gene variability, more studies are needed before firm conclusions can be made.

It is important to identify patients who are at high-risk of developing PTS since these patients may benefit from pharmacological seizure prophylaxis. According to Yablon and Dostrow (2001) the clinical characteristics of the patient, the injury, and information obtained from neuroimaging and electrophysiologic assessment techniques can be used to identify those at high risk for developing seizure disorders post injury.

 

Table: Studies of Risk Factors for Late Post-traumatic Seizures (Yablon & Dostrow 2001) (p.310)

Risk Factor

Reference

Patient Characteristics

Age

(Annegers et al. 1980; Asikainen et al. 1999; Hahn et al. 1988; Kollevold 1979)

Alcohol use

(Evans 1962; Heikkinen et al. 1990; Japan Follow-up Group for Posttraumatic Epilepsy 1991; Kollevold 1978)

Family history

(Caveness 1963; Evans 1962; Heikkinen et al. 1990; Hendrick 1968)

Injury Characteristics

Bone/metal fragments

(Ascroft 1941; Salazar et al. 1985; Walker & Yablon 1959)

Depressed skull fracture

(Hahn et al. 1988; Jennett 1975; Phillips 1954; Wiederholt et al. 1989)

Focal contusions/injury

(Da Silva et al. 1992; De Santis et al. 1992; Eide & Tysnes 1992; Glötzner et al. 1983; Heikkinen et al. 1990)

Focal neurologic deficits

(Da Silva et al. 1992; Jennett 1975; Salazar et al. 1985)

Lesion location

(Da Silva et al. 1992; Evans 1962; Grafman 1992)

Dural penetration

(Caveness & Liss 1961; Evans 1962; Salazar et al. 1985)

Intracranial hemorrhage

(Glötzner et al. 1983; Hahn et al. 1988; Japan Follow-up Group for Posttraumatic Epilepsy 1991)

Injury severity

(Evans 1962; Jennett 1975; Salazar 1985; Walker & Yablon 1961)

Other

Early post-traumatic seizures

(Heikkinen 1990; Jennett 1975; Salazar et al. 1985)

 

 

There are several patient and injury characteristics that increase the likelihood for the development of late post-traumatic seizures. Some important patient characteristics include: increasing age, premorbid alcohol abuse, and family history.

In terms of injury characteristics, markers of increasing injury severity such as penetrating injuries and depressed skull fracture increase the risk.

Seizures occurring within the first week post injury (early seizures) increase the risk of late post-traumatic seizures.

 

Onset

The risk of epilepsy is highest within the first two years following brain trauma (Dikmen et al. 1991; Englander et al. 2003; Yablon 1993). Yablon and Dostrow (2001) have noted that one-half to two-thirds of individuals who suffer PTS will experience seizure onset within the first 12 months, and 75-80% will have seizures within two years of their TBI (Caveness et al. 1979; Da Silva et al. 1992; Da Silva et al. 1990; Pohlmann-Eden & Bruckmeir 1997; Walker & Yablon 1959; Walker & Yablon 1961). Similarly, of those patients with PTE, Zhao et al. (2012) reported that 66% developed seizures within the first 6 months, 9.9% between 7 and 12 months, 11.7% between 13 and 24 months, and 8.5% between 25 and 36 months. Further, Wang et al. (2013b) examined 3039 individuals with TBI and of the 9.8% that experienced PTS within the first 2 years, occurrence rates at 6 months and 1 year were 59.9% and 78.1%, respectively. 

Although the risk of developing PTS is highest within months after the injury (Temkin 2001), the risk remains high for a period of years. As brain injury severity increases, the period of time for which a survivor is at risk of developing PTS also increases. After 5 years, adults with mild TBI no longer have a significantly increased risk relative to the general population (Annegers et al. 1998), whereas those with moderate, severe TBI, or penetrating TBI remain at increased risk for more than five years post injury (Annegers et al. 1998; Da Silva et al. 1992; Pagni 1990; Salazar et al. 1985). Moreover, military personnel suffering severe penetrating missile brain injuries show an elevated risk for more than 15 years after the injury (Annegers et al. 1998; Caveness et al. 1979; Feeney & Walker 1979; Salazar et al. 1985; Weiss et al. 1983). The incidence of seizures beginning later than three years post injury is 5% (Zhao et al. 2012).

Those with penetrating trauma typically have their first unprovoked seizure sooner than those patients with non-penetrating trauma (Kazemi et al. 2012). Unprovoked seizures occurred at a median time of one year post injury in a study of 50 participants (Di Luca & de Lacerda 2013); the former was influenced by injury severity, as well as age at the time of injury (Di Luca & de Lacerda 2013). In contrast, a study by Kazemi et al. (2012) found that for those with penetrating trauma, 78% had their first seizure within 1 year and 22% after 1 year. The mean latency to epilepsy onset was found to be shorter for mesial temporal sclerosis compared to lesional neocortical trauma (Gupta et al. 2014).

Recurrence

Seizure recurrence is an important factor in the determination of disability, likelihood of employment, and quality of life, and has been associated with increased health care costs (Baker et al. 1997; Yablon & Dostrow 2001). After a brain insult, there is a latency period where epileptogenesis can begin, which may progress into unprovoked recurrent seizures. Early seizures are likely due to brain insult and the recurrent rate of seizures in this time period is low (Lamar et al. 2014). Some studies have reported that in patients who experienced early PTS, only one-half had a recurrence while another quarter experienced a total of only two to three seizures (De Santis et al. 1979; Kollevold 1979). After a latent period, epileptogenesis may occur, where a non-epileptic brain increases in excitability due to molecular and cellular alterations from a brain injury. Such alterations in the brain may eventaully lead to spontaenous recurrent seizures (Lamar et al. 2014; Lucke-Wold et al. 2015). The risk of seizure recurrence in the late stage post-injury is higher compared to the early stage and may be more representative of epilepsy (Lamar et al. 2014). In a study conducted by Zhao et al. (2012), 5.7% of patients with TBI experienced seizures more than once a week, 69.5% more than once a month, and 24.8% had a seizure frequency greater than once a year. After Vagus Nerve Stimulation, patients with PTE demonstrated a greater reduction in seizure frequency, with 50% fewer seizures occurring at three months and 7% fewer at two years than individuals with non-PTE who received Vagus Nerve Stimulation (Englot et al. 2012). 

Table: Studies of Post-Traumatic Seizure Recurrence

Authors

Recurrence Incidence

Haltiner et al. (1997)

63 adults with moderate or severe TBI and LPTS. The cumulative incidence of recurrent late seizures was 86% over 2yrs, 52% had >4 late seizures, and 37% had >9 late seizures.

Pohlmann-Eden & Bruckmeir (1997)

 

57 patients with PTE were compared to 50 age and sex-matched severe TBI controls. Of those with PTE, 35% became seizure-free over 3 years and 21% had >1 seizure per week. 

 

The following table provides a summary of the natural history for the onset and recurrence of PTS (Yablon & Dostrow 2001)

Table: Summary of Onset and Recurrence of Post-Traumatic Seizures

Feature

Reference

20 – 30 % of patients with early PTS experience a late seizure.

(Yablon & Dostrow 2001)

Seizure onset after the first week is associated with a much higher likelihood of seizure recurrence.

(Haltiner et al. 1997; Walker & Yablon 1961)

Seizure frequency within the first year post injury may predict future seizure recurrence.

(Salazar et al. 1985)

Persistent PTS may be seen more commonly with partial seizures and less commonly with generalized seizures.

(Salazar et al. 1985)

A seizure occurring within a few minutes of a head injury has not been found to increase the risk of recurrence in individuals who sustain a mild TBI. 

(Jennett 1975; McCrory et al. 1997)

A small number of patients experience frequent seizure recurrences, apparently refractory to conventional anti-seizure therapy.

(Haltiner et al. 1997; Pohlmann-Eden & Bruckmeir 1997)

Some patients may benefit from surgical intervention.

(Diaz-Arrastia et al. 2000; Marks et al. 1995)

 

 

The risk of epilepsy is highest within the first two years following brain trauma

As brain injury severity increases, the period of time for which a survivor is at risk of developing post- traumatic seizures also increases.

Individuals who develop seizures after the first week following TBI have an increased chance of experiencing seizure recurrence; seizures occurring immediately following TBI do not increase the risk of recurrence.