Prevention renders a process impossible by an advanced provision.39 Prophylaxis is the process of guarding against the development of a specific disease by an action or treatment that affects pathogenesis.
One example of prevention is administration of anticonvulsants to patients with severe head trauma to prevent seizures that could cause the complications of hypertension and hypoxia. Such use of antiepileptic medications is intended to prevent the complications that are associated with tonic-clonic seizures, for patients considered at risk for such seizures. Prophylactic use of antiepileptic drugs, on the other hand, has the intention to interfere with epileptogenesis in patients with head trauma or patients undergoing neurosurgical procedures requiring incision of the neocortex.40 Although prevention of acute seizures that occur after head injury is a practical goal,40 such treatment is not likely to have a prophylactic effect against later development of epilepsy.
Clinical observations suggesting the efficacy of antiepileptic drugs as prophylactic against the development of post-traumatic epilepsy (PTE) appeared within a few years of the availability of phenytoin.40 Young et al.41 compared the observed 6% epilepsy occurrence in their treated head-injured patients to historic controls developing post-traumatic seizures. They concluded that early administration of antiepileptic drugs prevented the development of PTE and recommended prophylactic administration of phenytoin to patients with a 15% or greater risk of developing PTE.
Rish and Caveness42 did not detect a difference in early seizure occurrence between phenytoin-treated and untreated patients. However, Wohns and Wyler43 reviewed patients selected with critical trauma indicators, including depressed skull fracture, dural or cortical laceration, or a prolonged period of post-traumatic amnesia. Although the authors acknowledged the selection bias introduced in their study, they concluded that antiepileptic drug (AED) administration prevented the development of PTE.
Because the uncontrolled studies suggested that AEDs might have a prophylactic effect, prospective placebo-controlled assessments were undertaken. Penry and colleagues44 administered phenytoin and phenobarbital to head-injured patients in a double-blind fashion with placebo control. Seizure occurrence in the treated group was 21%, versus 13% in controls. The lack of significant difference between the treatment and control groups suggested that anticonvulsant administration had no effect on the development of PTE in the treated patients.
Young et al.45 used a double-blind prospective study of 179 head-injured patients, of which 85 were treated with phenytoin for 18 months and 74 were placebo controls. Seizures occurred in 12.9% of the treated patients and in 10.8% of the control patients.
Temkin et al.2 reported their experience with 404 patients treated in a prospective fashion. Patients with severe head trauma were assigned to receive either phenytoin or placebo, starting with an intravenous loading dose in the first 24 hours after injury. Serum levels were measured at regular intervals, blood levels of drug were maintained in the therapeutic range, and efforts were made to assure that evaluations were blinded. At 1 year, no difference in incidence of PTE was found between the treatment and control groups. By 2 years, PTE had occurred in 27.5% of phenytoin-treated patients and in 21.1% of controls. (They did observe that phenytoin was effective in preventing seizures during the acute period immediately after injury. Thus, early post-traumatic seizures can be prevented with administration of phenytoin for 1 or 2 weeks, but this result was not associated with a reduction of mortality.46)
Valproic acid had an effect on kindling in animals47 and was evaluated in humans as well.48 Valproic acid was given for 1 month or 6 months, or patients were treated for 1 week with phenytoin as control; 379 patients were enrolled in this study. Patients were followed for 2 years after entry into the study. Phenytoin and valproic acid were effective in preventing early seizures, with 1.5% in the phenytoin arm and 4.5% in the valproic acid arm developing seizures within the first week of injury. Valproic acid failed to prevent the development of post-traumatic seizures, with late seizures developing in 15% in the phenytoin group, 16% in the 1-month valproate group, and 24% in the 6-month valproate group. A trend to higher mortality in the valproate treatment group was noted; no specific cause was reported.48
Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.
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