Does glucocorticoid administration prevent late seizures after head injury?
Watson NF, Barber JK, Doherty MJ, Miller JW and Temkin NR;
Commented by , 28 Jul 2004
Background
Glucocorticoids were often used in the past in patients with traumatic brain injury (TBI). Whether these agents impact on the probability of developing postraumatic epilepsy (PTE) is not known.
Aim
To assess the impact of glucocorticoids given in the first week after TBI on the risk of developing late posttraumatic seizures.
Methods
A seizure prevention trial dabatase of 404 patients with severe TBI was used to compare the odds of developing first and second late postraumatic seizures between 125 patients that received glucocorticoids and the remaining patients that did not.
Results
Patients exposed to glucocorticoids within 1 day of TBI were more likely to develop first late seizures than those not exposed (hazard ratio 1.74, 95% CI 1.01-2.98). After controlling for other risk factors, patients receiving corticosteroids > 2 days after injury did not show an increased risk of developing a first late seizure (hazard ratio 0.77, 95% CI 0.23-2.56).
Comment
The rationale for using glucocorticoids in TBI patients was the hope that they could reduce cerebral edema and improve survival and functional recovery. Randomized trials, however, have demonstrated that glucocorticoids do not improve outcome in moderate and severe TBI (ref. 1), and these agents no longer represent the standard of care in TBI patients (ref. 2).
Experimental data on the impact of glucocorticoids on epileptogenesis are conflicting. Glucocorticoids attenuate posttraumatic ischemia (ref. 3) and reduce epileptiform abnormalities after trauma in animal models (ref. 4), and they are efficacious against infantile spasms (ref. 5). However, they may also exacerbate excitotoxicity and oxidative injury in hippocampal neurons (ref. 6), accelerate epileptogenesis in the amygdala kindling model (ref. 7) and induce atrophic changes and depress neurogenesis in the hippocampus (ref. 8).
This study provides the only available trial data about the impact of glucocorticoids on human epileptogenesis after TBI. Contrary to the hypothesis that these agents may protect against PTE, the only significant finding was that patients with early exposure to steroids had a greater risk of having a late seizure.
This study has many strengths:
- the inclusion of a relatively large cohort of severe TBI patients recruited under the stringent criteria of a clinical trial
- the conduction of the study at a single centre
- the availability of a prospective follow-up for 2 years
There are, however, also major weaknesses:
- The trial was not aimed at assessing the effects of glucocorticoids, and therefore assignment to steroid treatment was not randomized. Although the authors controlled for risk factors in their analysis, and although mortality and injury characteristics were comparable in the two groups, it cannot be excluded that glucocorticoids were given to patients at higher risk for PTE
- Choice, dosages and duration of steroid treatment were not standardized.
Despite these limitations, it is unlikely that better evidence on the impact of glucocorticoids on posttraumatic epiletogenesis will become available in the foreseable future.
It is frustrating that all studies on interventions potentially reducing the risk of posttraumatic epilepsy, including trials of anticonvulsant drugs, have yielded negative results (ref. 9). Clinically efficacious antiepileptogenic agents, therefore, continues to represent a Holy Grail in ongoing epilepsy research (ref. 10 & ref. 11).
References
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5. Mackay M, Weiss S, Snead OC III. Treatment of infantile spasms: An evidence-based approach. Int Rev Neurobiol 2002;49:157-84
6. Goodman Y, Bruce AJ, Cheng B, et al. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J Neurochem 1996;66:1836-44
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9.Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia 2001;42:515-524
10.Loscher W. Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy. Epilepsy Res. 2002;50:105-123
11. Benardo LS. Prevention of epilepsy after head trauma: do we need new drugs or a new approach? Epilepsia 2003;44 Suppl 10:27-33