Seizure prevalence and characteristics.
The overall prevalence of PTE in the group with head injuries was 43.7% (87 of 199 subjects). This compares with 53% in the cohort reported in PH2.13
The mean duration of the last seizure period (time from first to last reported seizure) was 33 months. In the most recent year of reported seizures, the most common frequency was 2 to 10 seizures per year. Complex partial seizures occurred in 31%, and simple partial seizures evolving to generalized seizures occurred in 25%. In contrast, the most commonly reported first seizure type was simple partial seizures evolving to generalized seizures (33.3%), followed by generalized (20.7%; as diagnosis was based solely on subject history, we could not determine whether these were primary or secondary). As at PH2, there was an association between the duration and frequency of seizures during the first reported seizure period (r
= 0.320, p
Eleven patients (12.6% of those with PTE; 5.5% overall) reported onset of seizures since PH2 (). There was no association between onset latency and history of cardiovascular disease, preinjury intelligence, change in intelligence, presence of bone or metal fragments, or lesion size.
Figure Prevalence of posttraumatic epilepsy in years after traumatic brain injury
For those with onset of PTE before PH3, 73.8% described no change in seizure type, 3.2% reported a change from simple partial to generalized seizures, and 4.7% changed from generalized to simple partial or complex partial seizures. Two control subjects also reported a history of seizures, both in the 13 years before PH3.
Of the 520 patients assessed at PH2, 336 did not attend PH3. When we examined the subjects with head injuries who attended both P2 and P3, the prevalence of PTE at PH3 was 45.1% (82 of 182 subjects), compared with 39.6% at PH2. 19.2% reported having a seizure in the year before P3. As in the whole sample with PTE, in the most recent year of subject-reported seizures the most common seizure frequency was 2 to 10 seizures per year, and complex partial seizures were the most common type, occurring in 15.1%. In the 17 subjects who attended P3 but not P2, the prevalence of PTE was 29.4%. Three subjects reported onset of seizures since P2, and 4 had had a seizure in the year before P3. Veterans who did not attend PH3 had significantly lower preinjury and PH2 intelligence scores (), and also a tendency to greater brain volume loss, whereas there were no significant differences in terms of seizure type or frequency. Of those subjects with head injuries who attended PH2 but not PH3, 43.9% had a positive seizure history at PH2. At the time of PH2, 28.0% of these subjects had generalized seizures, compared with 21.7% of those who went on to attend at PH3, indicating that there was no difference in terms of seizure type in PH3 attendees and nonattendees (p = 0.486).
Table 2 Differences between phase 3 attendees and nonattendees
Treatment of PTE.
More than 88% (n = 77) of the subjects with a history of PTE at PH3 were using medication at the time of their last seizure. Seventy percent were prescribed phenytoin, the second most common medication being phenobarbital (14.5%). Less common therapeutic choices were carbamazepine (4.5%) and sodium valproate (4.5%). Newer anticonvulsants were prescribed less frequently. However, 53% of the subjects (n = 41) reported having seizures in the year before PH3, which may represent a high level of refractoriness or noncompliance, but we were unable to assess which factor was responsible in this study.
Associations with brain lesions.
As in PH2, brain volume loss at PH3 was associated with PTE (t = 3.758, df = 186, p = 0.000). There was a correlation between size of lesion and seizure frequency in the first year (r = −0.203, p = 0.005) and last year of recorded seizures (r = −0.274, p = 0.000), as well as in duration of seizure history (r = −0.179, p = 0.014). However, in contrast to the results from PH2, we found that those with parietal lesions (χ2 = 13.603, df = 2, p = 0.001) and left insula involvement (χ2 = 12.845, df = 2, p = 0.002) were more likely to report a history of seizures. There were no other significant associations between lesion location and seizures. However, there was a correlation between number of lobes involved and PTE (r = 0.196, p = 0.006), and complex partial seizures were more common in those with multiple lobe involvement. There was no significant association between atrophy and PTE.
Associations with genetic markers.
We looked for association between several candidate genes and PTE (table e-3). There was an association between the presence of GRIN
2A rs11074504 and seizures present at PH3 (χ2
= 14.126, df
= 4, p
= 0.007) and GAD
2 rs1330582 and PTE at PH2 (χ2
= 11.779, df
= 4, p
= 0.019). There was also a marginal association between GAD
1 rs769395 and seizures at PH2 (χ2
= 9.351, df
= 4, p
= 0.053), but no association between PTE and the presence of the APOE
4 allele. However, when the p
values were corrected for multiple comparisons, these values did not reach significance.
Associations with intelligence.
There was no significant difference in preinjury AFQT scores between subjects with and without PTE (), whereas there were significant differences between these groups in their PH2 and PH3 AFQT scores and change in scores from PH2 to PH3 (with those with PTE showing a greater level of decline).
Table 3 Characteristics of patients with and without posttraumatic epilepsy
There was an association between the frequency of last reported seizures and PH3 AFQT score (F = 5.876, df = 6, p = 0.000), and change in AFQT scores from preinjury to PH3 (F = 4.140, df = 6, p = 0.001), with those with more frequent seizures having lower AFQT scores and greater decline in intelligence. Similarly, there was also an association between the type of last seizure and PH3 AFQT score (F = 6.010, df = 5, p = 0.000), and change in AFQT scores from preinjury to PH3 (F = 4.140, df = 6, p = 0.000). Those with partial seizures evolving to generalized seizures had the lowest AFQT scores at PH3 and the greatest level of decline from preinjury to PH3, whereas those with simple partial seizures had the highest AFQT scores at PH3 and the least level of decline.
Using a linear regression model, we examined seizure history, duration, frequency, and type vs change in and current intelligence. Unlike at PH2, PTE was predictive of current intelligence, even when allowances for brain volume loss and preinjury intelligence were introduced into the model (F = 4.102, df = 2, p = 0.018). Presence of PTE was also predictive of decline in AFQT score from preinjury to PH3 (F = 4.102, df = 2, p = 0.018). Duration of PTE was a predictor of decline in full-scale IQ from PH2 to PH3 (F = 4.559, df = 1, p = 0.034), as well as decline in intelligence from preinjury to PH2 (F = 6.883, df = 1, p = 0.010).
Overall possible predictors of PTE.
We performed a linear logistic regression analysis to assess the predictability of PTE occurrence and frequency at PH3 by total volume loss, lesion location, wound characteristics, and the 3 genetic markers that had been found to be associated with PTE. PTE was predicted by both presence of GRIN2A rs11074504 (F = 3.944, df = 2, p = 0.021) and left parietal involvement (F = 5.931, df = 1, p = 0.041). As at PH2, the presence of metal fragments was predictive of PTE (F = 5.522, df = 1, p = 0.020), and its inclusion in the analysis reduced the impact of both GRIN2A rs11074504 (F = 8.091, df = 2, p = 0.059) and left parietal involvement (F = 0.737 df = 1, p = 0.609). Total lesion volume loss (F = 7.230, df = 1, p = 0.008) was the only predictor of frequency of seizures. None of these predictors remained significant when the analysis was repeated for very late-onset PTE (>14 years after injury) only. However, given the small numbers involved, this analysis can only be viewed as exploratory.