Antiepileptogenesis in Humans: Ways to Move Forward
Antiepileptogenesis in Humans: Ways to Move Forward
TBI represent an important and costly heath problem. The overall incidence of TBI in developed countries is 200 per 100 000 patients per year. The affected population includes mainly previously healthy young people, resulting in high mortality and morbidity rates, including lifelong disability.
Moderate and severe TBI are a leading cause of epileptic seizures, with overall risk of seizures ranging from 2 to 57% depending on the location and severity of brain injury, and the presence of neurological deficits. Seizures occurring in the early posttraumatic phase may lead to secondary brain damage as a result of increased metabolic demands and intracranial pressure, as well as excessive neurotransmitter release; this involves an increased morbidity with negative impact on the quality of life.
Differentiating between early (i.e., provoked) and late (i.e., unprovoked) seizures is of utmost importance to evaluate the indications and the efficacy of drug treatment for preventing PTE. Posttraumatic seizures occurring within 24 h of TBI (defined as immediate seizures) and those occurring within the first 7 days after TBI (early seizures) are provoked seizures, that is, reflecting the acute consequences of brain trauma, such as oedema. As a consequence, immediate and early seizures do not entail a diagnosis of epilepsy. Conversely, seizures occurring after 7 days (late seizures) are considered unprovoked seizures, provided brain lesions are not progressing at that stage. PTE is defined as the occurrence of repeated unprovoked seizures as a result of TBI.
Hence, the role of AEDs in the prevention of provoked or unprovoked posttraumatic seizures (PTE) should be assessed separately.
A Cochrane review assessed the overall efficacy and tolerability of preventing early and late seizures in patients with acute TBI of any severity. Only placebo-controlled RCTs or those using no drug as comparator were included. Based on the assessment of 1405 available patients (six trials, four with phenytoin, one with phenobarbital, one with carbamazepine or phenytoin), the pooled relative risk (RR) for early seizure prevention was 0.34 (95% confidence interval, CI 0.21–0.54), with 10 patients needed to be treated to get one seizure-free individual. However, seizure control in the acute phase did not lead to a significant reduction in late seizures, mortality, death, and neurological disability. Furthermore, the use of ASDs was associated with an increased (although not statistically significant) risk of skin rashes (pooled RR = 1.57; 95% CI 0.57–39.88).
Because the prophylactic use of ASDs seems effective only against early seizures, with a risk of adverse events, it should be brief, that is, not lasting more than 7 days. Prolonged treatment should be considered only after a diagnosis of PTE. Regarding the choice of ASD, evidence-based data support the use of phenytoin (level of evidence: class I), beginning with an intravenous loading dose initiated as soon as possible after TBI. A recent non-RCT found no difference between levetiracetam and phenytoin with respect to early posttraumatic seizure rate, adverse drug reactions, or mortality, whereas phenytoin proved to be most cost-effective (Table 1). The health economic aspects may however change dramatically with the availability of generic levetiracetam in most European countries.
Further RCTs should be performed to test whether newer ASDs could be more effective than older ASDs for preventing PTE.
Antiepileptogenic Trials in Patients With Traumatic Brain Injury
TBI represent an important and costly heath problem. The overall incidence of TBI in developed countries is 200 per 100 000 patients per year. The affected population includes mainly previously healthy young people, resulting in high mortality and morbidity rates, including lifelong disability.
Moderate and severe TBI are a leading cause of epileptic seizures, with overall risk of seizures ranging from 2 to 57% depending on the location and severity of brain injury, and the presence of neurological deficits. Seizures occurring in the early posttraumatic phase may lead to secondary brain damage as a result of increased metabolic demands and intracranial pressure, as well as excessive neurotransmitter release; this involves an increased morbidity with negative impact on the quality of life.
Differentiating between early (i.e., provoked) and late (i.e., unprovoked) seizures is of utmost importance to evaluate the indications and the efficacy of drug treatment for preventing PTE. Posttraumatic seizures occurring within 24 h of TBI (defined as immediate seizures) and those occurring within the first 7 days after TBI (early seizures) are provoked seizures, that is, reflecting the acute consequences of brain trauma, such as oedema. As a consequence, immediate and early seizures do not entail a diagnosis of epilepsy. Conversely, seizures occurring after 7 days (late seizures) are considered unprovoked seizures, provided brain lesions are not progressing at that stage. PTE is defined as the occurrence of repeated unprovoked seizures as a result of TBI.
Hence, the role of AEDs in the prevention of provoked or unprovoked posttraumatic seizures (PTE) should be assessed separately.
A Cochrane review assessed the overall efficacy and tolerability of preventing early and late seizures in patients with acute TBI of any severity. Only placebo-controlled RCTs or those using no drug as comparator were included. Based on the assessment of 1405 available patients (six trials, four with phenytoin, one with phenobarbital, one with carbamazepine or phenytoin), the pooled relative risk (RR) for early seizure prevention was 0.34 (95% confidence interval, CI 0.21–0.54), with 10 patients needed to be treated to get one seizure-free individual. However, seizure control in the acute phase did not lead to a significant reduction in late seizures, mortality, death, and neurological disability. Furthermore, the use of ASDs was associated with an increased (although not statistically significant) risk of skin rashes (pooled RR = 1.57; 95% CI 0.57–39.88).
Because the prophylactic use of ASDs seems effective only against early seizures, with a risk of adverse events, it should be brief, that is, not lasting more than 7 days. Prolonged treatment should be considered only after a diagnosis of PTE. Regarding the choice of ASD, evidence-based data support the use of phenytoin (level of evidence: class I), beginning with an intravenous loading dose initiated as soon as possible after TBI. A recent non-RCT found no difference between levetiracetam and phenytoin with respect to early posttraumatic seizure rate, adverse drug reactions, or mortality, whereas phenytoin proved to be most cost-effective (Table 1). The health economic aspects may however change dramatically with the availability of generic levetiracetam in most European countries.
Further RCTs should be performed to test whether newer ASDs could be more effective than older ASDs for preventing PTE.
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