Prophylactic Use Of Antiepileptic Drugs Research Articles

Overview of studies to prevent posttraumatic epilepsy.

Prevention of posttraumatic epilepsy (PTE) is of primary importance to reduce the degree of functional morbidity following traumatic brain injury (TBI). However, the effects of antiepileptic drugs (AEDs) in patients with TBI must be assessed separately in terms of prevention and control of provoked seizures (which include immediate and early posttraumatic seizures) and prevention of subsequent unprovoked seizures (late posttraumatic seizures or PTE). Potential mechanisms for prevention of epileptogenesis as well as reports and systematic reviews were evaluated to determine strategies and results of attempts to reduce or prevent the development of epilepsy following TBI. In observational studies, after a period ranging from 6 months to 13 years, the proportion of cases developing seizures was 0-10% in patients receiving treatment compared to 2-50% in those who were left untreated. In randomized clinical trials, the difference between active treatment [phenytoin (PHT), phenobarbital, or carbamazepine (CBZ)] and placebo was less remarkable after a follow-up ranging from 3 to 60 months and was virtually lacking for the prevention of PTE. In a Cochrane systematic review of 890 patients from 10 RCTs assessing PHT or CBZ, the pooled relative risk (RR) for prevention of early seizures was 0.33 (95% CI 0.21-0.52). By contrast, the RR for prevention of late seizures was 1.28 (95% CI 0.90-1.81). Mortality and neurological disability were similar in the two treatment groups. The use of PHT was followed by an increased (nonsignificant) risk of skin rashes. In addition, cognitive performance was significantly affected by PHT in severely injured patients at 1 month and treatment withdrawal was followed by improvement in cognitive function. The failure to influence the risk of PTE in studies of patients with TBI are similar to findings of meta-analysis of randomized clinical trials on seizure prevention in other conditions, such as febrile seizures, cerebral malaria, craniotomy, and excessive alcohol intake. For these reasons, the prophylactic use of AEDs should be short-lasting and limited to the prevention of immediate and early seizures. Chronic treatment should be considered only after a diagnosis of PTE.

Teaching evidence-based medicine to surgical subspecialty residents.

Curricula for the teaching of evidence-based medicine to residents have been the subject of reports, analyses, and commentary. Specific programs for teaching evidence-based medicine principles to surgical subspecialty residents have not been identified by the authors. The objective of this article is to report our experience in establishing a teaching program in the principles of evidence-based medicine to surgical subspecialty residents. We established a teaching program in the principles of evidence-based medicine for neurosurgical residents in a busy neurosurgical training program. Two hours were set aside every other week, replacing traditional professors' rounds with sessions led jointly by a neurosurgeon and an epidemiologist, but based on case presentations from patients currently being treated. From these presentations, searchable clinical questions were developed, and the literature was searched, critically analyzed, and summarized. Results of several cycles on this process are reported. The group developed a repository of Internet-based resources for evidence-based education and practice. Using these resources, the group analyzed six topics in the first 2 years of the program. These included the "best" way to clinically grade patients after subarachnoid hemmorhage, considerations in the biopsy and treatment of enhancing intracerebral mass lesions in patients with acquired immunodeficiency syndrome, the use of prophylactic anticonvulsants in patients with primary brain tumors, the identification of cervical spine injuries in the emergency department, the grading of the fractures of the odontoid process, and the value of removing retained bullets from the spinal canal. The outcomes ranged from finding insufficient evidence to reach a conclusion, through the identification of well-conducted and well-reported critical syntheses of the topic already available in literature, to the development of the detailed algorithm for cervical spine clearance that was accepted by the institution's emergency department. By dedicating some specific time and using resources readily available in most academic health centers, it is possible to incorporate the teaching of the principles of evidence-based practice into the ongoing education of residents on a busy surgical subspecialty service.

Prophylactic Anticonvulsants After Neurosurgery

Six prospective, controlled trials have examined the effects of antiepileptic drugs (AEDs) given to prevent the occurrence of seizures following neurosurgery. Some studies have concentrated on specific reasons for the neurosurgery (brain tumor) while others have included people with a variety of indications for surgery. Phenytoin (PHT) has been studied most, but carbamazepine (CBZ) and phenobarbital (PB) have also been evaluated to some extent. Studies of people with traumatic brain injury (some of whom were operated on) provide some, but less direct, evidence of the prophylactic effects of AEDs after neurosurgery. Despite considerable variation in reasons for the neurosurgery, AEDs given, and study design, the overall conclusions are remarkably consistent. The seizure risk is reduced about 40%-50% for the first week after neurosurgery in those given the older AEDs compared with those given placebo or no treatment. After the first few weeks, none of the drugs has been proven to reduce the incidence of seizures and in most situations the best estimate is essentially no effect, but effects on the order of a 25%-50% reduction in late (epileptic) seizures cannot be ruled out. The new generation of AEDs have not been tested as prophylactic agents after neurosurgery. Although there are no guidelines for prophylaxis following neurosurgery in general, these results are consistent with the guidelines of professional organizations for subsets of neurosurgery cases. Those guidelines consider prophylaxis, especially using PHT, to be an option for the first week after surgery but that the routine use of prophylactic anticonvulsants after the first week is not warranted.

Prophylactic Anticonvulsants After Neurosurgery.

Six prospective, controlled trials have examined the effects of antiepileptic drugs (AEDs) given to prevent the occurrence of seizures following neurosurgery. Some studies have concentrated on specific reasons for the neurosurgery (brain tumor) while others have included people with a variety of indications for surgery. Phenytoin (PHT) has been studied most, but carbamazepine (CBZ) and phenobarbital (PB) have also been evaluated to some extent. Studies of people with traumatic brain injury (some of whom were operated on) provide some, but less direct, evidence of the prophylactic effects of AEDs after neurosurgery. Despite considerable variation in reasons for the neurosurgery, AEDs given, and study design, the overall conclusions are remarkably consistent. The seizure risk is reduced about 40%-50% for the first week after neurosurgery in those given the older AEDs compared with those given placebo or no treatment. After the first few weeks, none of the drugs has been proven to reduce the incidence of seizures and in most situations the best estimate is essentially no effect, but effects on the order of a 25%-50% reduction in late (epileptic) seizures cannot be ruled out. The new generation of AEDs have not been tested as prophylactic agents after neurosurgery. Although there are no guidelines for prophylaxis following neurosurgery in general, these results are consistent with the guidelines of professional organizations for subsets of neurosurgery cases. Those guidelines consider prophylaxis, especially using PHT, to be an option for the first week after surgery but that the routine use of prophylactic anticonvulsants after the first week is not warranted.

Tratamiento antiepiléptico profiláctico de las agresiones cerebrales

On the occasion of the First Congress of the Spanish Anti Epilepsy League we had reviewed the use of antiepileptic drugs for preventing postoperative and posttraumatic seizures.Two specific causes of epilepsy are particularly relevant to neurosurgical practice; postoperative and posttraumatic epilepsy. After reviewing the seizures arising after craniotomy for supratentorial conditions such as vascular malformations (aneurysms and arteriovenous malformations), cerebral tumours and supratentorial abscesses and empyemas, we discuss the different types of posttraumatic epilepsy and the risk factors. The pathogenesis of tumour associated epilepsy and the pathophysiological events initiating posttraumatic epilepsy are described. The use of prophylactic antiepileptic drugs is only justified in cases with several risk factors capable to develop seizures.As no treatments have yet been shown to be effective in preventing the development of epileptic seizures, additional trials are likely to be necessary.

Brain metastases: treatment options to improve outcomes.

In recent years, a broader base of treatment options has evolved to improve the outcome for patients with brain metastases. The selection of the most appropriate intervention for the individual patient is dependent on a careful evaluation of the extent of intracranial tumour, as well as an understanding of patient and tumour characteristics that are important determinants of prognosis. Recent analyses have confirmed good performance status, control of the primary tumour, absence of extracranial metastases and age less than 65 years to be predictors for longer survival. Medical therapy typically includes the use of corticosteroids, and some advances have been made in optimising the use of these agents. Prophylactic use of antiepileptic drugs in patients with brain metastases is generally discouraged. Chemotherapy was previously not considered to have a role in treating brain metastases, but has increasingly become an accepted treatment option. Recent clinical studies have evaluated the integration of chemotherapy with conventional treatments such as radiotherapy and the addition of biological response modifiers. In the past, radiotherapy has been the mainstay of treatment for brain metastases. A number of randomised controlled trials have explored external beam radiation therapy, radiation sensitisers, postoperative whole brain irradiation and prophylactic cranial irradiation. Significant improvements in survival have been demonstrated as a result of prophylactic cranial irradiation in patients with small-cell lung cancer, and improved local control of brain metastases has been achieved with postoperative whole brain irradiation. A number of studies have helped define a more efficient use of external beam irradiation. Radiosurgery in particular has been identified as an important advance in radiation treatment delivery and may provide an acceptable alternative to surgical resection in many patients. Conventional surgery has long had a role to play in establishing the diagnosis, guiding the choice of subsequent therapies and reversing life-threatening complications from brain metastases. The risks of surgery have been reduced with recent improvements in anaesthesia and intraoperative tumour localisation. Recent clinical studies have addressed the role of surgical resection in the management of patients with a single brain metastasis. Survival benefits have been demonstrated in patients undergoing surgical resection in addition to external beam radiation therapy. Despite the improvements achieved in the treatment of patients with brain metastases at first diagnosis, the question of retreatment may arise in due course. The therapeutic options available in this situation include re-operation, radiosurgery and brachytherapy.

Single Brain Metastasis.

The management of single brain metastases has evolved substantially over the last decade. The advent of triple-dose contrast-enhanced MRI scans has improved the radiologists' capacity to resolve small tumors, and, thereby, has resulted in a declining percentage of brain metastases classified as single. Only 25% to 30% of brain metastases are single; single brain metastases in the absence of systemic metastases are termed solitary. Randomized trials suggest that patients not in imminent danger of herniation are best managed initially with dexamethasone 2 to 4 mg administered orally twice daily. The routine use of prophylactic anticonvulsants is discouraged. Patients with refractory progressive systemic tumor likely to prove fatal within 3 to 6 months should receive fractionated whole brain radiotherapy. Patients with highly radiosensitive primary tumors such as small cell lung cancer, lymphoma, and germinoma should also receive whole brain radiotherapy. Patients with inactive or controllable systemic cancer and good performance status benefit from the addition of local strategies like surgery or radiosurgery to whole brain radiotherapy. Although surgery and radiosurgery have not been compared in a randomized controlled trial, data suggest that results are similar. Consequently, for most metastases that fall within the size constraints of radiosurgery (3.5 cm or smaller in diameter), radiosurgery is preferred for its relatively noninvasive nature. Patients with larger or cystic tumors, with obstructive hydrocephalus, or neurologic instability despite corticosteroids are best treated with craniotomy. Fractionated whole brain radiation following surgical or radiosurgical management of single brain metastasis appears to decrease the risk of recurrent brain metastasis, although it has not been shown to improve survival. We recommend its use in most patients, although patients with tumors likely to be highly resistant to fractionated radiotherapy or at high risk of radiation neurotoxicity may reasonably defer its use.

New therapies and changing patterns of treatment for malaria

The launch of the Roll Back Malaria initiative by the World Health Organization in the period under review confirms malaria's place as one of the great public health priorities worldwide. The period 1998-1999 has seen some advances and some disappointments in the treatment of malaria, against a backdrop of spreading drug resistance. Most encouraging is the clear demonstration that intermittent prospective treatment of asymptomatic pregnant women in endemic areas reduces morbidity. The greatest disappointment has been the result of trials with the artemether-benflumetol fixed-dose combination therapy. Questions have been raised about several widely accepted practices, including measurement of quinine levels, exchange transfusion, and the prophylactic use of anticonvulsants in children with cerebral malaria.

Is the prophylactic use of antiepileptic drugs in Sturge-Weber syndrome justified?

Sturge-Weber syndrome (SWS) is a rare neurocutaneous syndrome. Epilepsy is one of its most common features and is usually the first neurological manifestation. Adequate control of epilepsy assumes major importance in SWS as the early onset of seizures and severe seizures are associated with developmental regression and hemiparesis. Recent advances in neuroimaging have helped in making preclinical and early diagnosis in SWS. The author proposes treating newly diagnosed patients with severe SWS with antiepileptic drugs (AEDs) before the onset of epilepsy. This may help prevent the development of hemiplegia and the developmental problems that may ensue.

Palliative management of brain metastases.

The development of brain metastases in patients with advanced cancer is associated with increased morbidity and diminished longevity. Palliative treatment modalities focus predominantly on improving quality of life. Well-established beneficial treatments include the use of corticosteroids, radiotherapy, and surgery. Management issues that require further exploration and clarification include the dosages of glucocorticoids, the prophylactic use of anticonvulsants and the indications for radiosurgery.

Short-term perioperative anticonvulsant prophylaxis for the surgical treatment of low-risk patients with intracranial aneurysms.

The long-term use of anticonvulsant medication to prevent postoperative seizures in patients with aneurysms has been accepted medical practice for many years. The low incidence of seizures in more recent aneurysm series makes it appropriate to re-evaluate the use of prophylactic anticonvulsants to prevent postoperative epilepsy, especially in patients at low risk of seizure disorders. On the basis of preoperative presentation, we categorized 387 of the 420 craniotomies for aneurysms over a 4-year period to be at low risk of seizure. Postoperative anticonvulsant medication in this group was restricted to an average of 3 days. A retrospective analysis of the incidence of early postoperative seizures and late postoperative seizure disorders was performed in the populations of patients with ruptured aneurysms and with unruptured aneurysms with an average follow-up of 2.4 years. The overall seizure rate in the study group was 5.4%. Patients with ruptured aneurysms had an early postoperative seizure rate of 1.5% and a long-term seizure disorder rate of 3.0%. Early and long-term seizure rates for unruptured aneurysms were 2.6 and 4.4%, respectively. No patients who had early seizures went on to develop epilepsy, and all seizure disorders were well controlled once anticonvulsants were begun. These data support the idea that anticonvulsant medication may be safely restricted to the immediate perioperative period for most patients with aneurysms.

Cognitive Effects of PHT and CBZ After Brain Trauma

The effects of prophylactic anticonvulsant use of phenytoin (PHT) and carbamazepine (CBZ) on the cognitive and emotional status of a total of 80 brain trauma patients are compared and reported from the Division of Neurosurgery and Department of Neurology, St Louis University School of Medicine and School of Public Health.

Neurobehavioral Effects of Phenytoin and Carbamazepine in Patients Recovering From Brain Trauma: A Comparative Study

To compare the effects of prophylactic anticonvulsant use of phenytoin and carbamazepine on the cognitive and emotional status of the patient after brain injury. Double-blind, placebo-controlled study with assessments before and after withdrawal from drug treatment. Patients had been initially treated by neurosurgeons at a university hospital and were followed up during the study on an outpatient basis. Forty of 64 patients receiving phenytoin and 42 of 127 patients receiving carbamazepine from 6 to 44 months for seizure prophylaxis after brain injury met study criteria and were assigned to continue or discontinue treatment. Groups were balanced for age, sex, race, weight, intelligence, type of injury, duration of therapy, and drug plasma concentration at screening. A battery of neuropsychological tests was administered twice during a 4-week baseline period, at the end of a 4- to 5-week period of continued drug treatment or placebo, and after 4 weeks of not receiving medication. Attention and concentration, psychomotor speed, memory, verbal fluency, and emotional state. No significant differences were found in the performance of patients in medication and placebo groups for either drug at the end of the placebo phase. Patients in the combined groups showed significant improvement (P < .01) on several measures of motor and speeded performance following cessation of drug treatment. Multivariate analyses showed additional differences between phenytoin and carbamazepine and also suggested a significant practice effect on some measures used. Both phenytoin and carbamazepine seem to have negative effects on cognitive performance, particularly on tasks with significant motor and speed components. Practice effects were noted and may account for much of the improvement when patients stopped taking the drugs. Overall effects of the drugs were small and of limited clinical significance, but differences among subjects were noted that may affect selection of a particular drug for the individual patient.

Risk of epilepsy after aneurysm operations.

This prospective study was undertaken to evaluate the risk of epilepsy after aneurysm operations. The patients were discharged after operation without any anticonvulsant prophylactic treatment and followed-up for 12 months. Out of 128 such patients 121 were submitted for final evaluation. Epilepsy was diagnosed if two or more seizure attacks occurred during that time. Such attacks occurred in 8 patients, so the risk of epilepsy was estimated at 7% for the 12 months after operation in patients without prophylactic treatment. In another 3 patients single seizures occurred during the follow-up, they were not treated with anticonvulsant drugs; seizures did not recur for up to two years. Detailed analysis of the patients with late epilepsy revealed that most of them were pre-operatively in the 3rd clinical group according to WFNS scale. The rationale for the use of prophylactic anticonvulsants after aneurysm surgery seems to be doubtful in view of this study and data from the literature.

Early seizures following intracerebral hemorrhage: implications for therapy.

Seizures occurred in 19 of 112 patients (17%) with nontraumatic, supratentorial intracerebral hemorrhage (ICH). All seizures occurred at ICH onset; patients without seizures at hemorrhage onset remained seizure-free until the last recorded follow-up. Seizures were significantly associated with extension of blood into the cerebral cortex. We found no association between seizures and hemorrhage size or the presence of subarachnoid or intraventricular blood. These data suggest that (1) seizures, in ICH, occur at hemorrhage onset, (2) patients without seizures at hemorrhage onset are at very low risk for subsequent seizures during their hospitalization, (3) hemorrhage involving the cerebral cortex, regardless of site of origin, predisposes to seizures, and (4) the prophylactic use of anticonvulsants in the acute management of these patients appears unwarranted, especially in patients without cortical extension.

Factors Influencing Posttraumatic Seizures in Children

The ideal treatment of children with head trauma would include prevention of posttraumatic seizures. Ninety-two of 937 children with head injuries (9.8%) experienced posttraumatic seizures. In 94.5% of these patients (87 of 92), seizures developed within the first 24 hours after injury. Three children convulsed between 24 hours and 7 days, but only 2 children developed seizures after the 1st week. Factors found to influence the likelihood of seizures included severe head injury (GCS, 3 to 8), diffuse cerebral edema, and acute subdural hematoma (P less than 0.001). Seizures occurred in 35% of severely head-injured children compared to 5.1% with minor head injury (P less than 0.001). A less significant correlation (P less than 0.1) was noted between seizures and open, depressed skull fractures. We found no significant correlation between seizure occurrence and numerous other factors including age, sex, fracture location and type (other than open, depressed fractures), parenchymal injuries, fixed neurological deficits, and cranial operation. Based on our observations, we recommend the prophylactic use of anticonvulsants in children at higher risk for posttraumatic seizures: those with diffuse cerebral edema, acute subdural hematoma, open, depressed skull fracture with parenchymal damage, or severe head injury (GCS less than or equal to 8).

The prophylactic use of phenytoin during iopamidol contrast studies of the subarachnoid space.

Contrast examinations of the subarachnoid space are associated with side effects including convulsions. Attention has been given to the prophylactic use of anticonvulsants. We describe a simple oral regimen using the established anticonvulsant phenytoin that can be administered to short-stay patients and that achieves effective serum and CSF concentrations. A preliminary account of this work was presented to the British Pharmacological Society in January 1984 in London.

The nature of posttraumatic epilepsy.

✓ The development, recession, and residua of posttraumatic epilepsy follow natural laws that are imperfectly defined. However, studies from World War I, World War II, the Korean conflict, and the Vietnam War demonstrate the following patterns: 1) The onset of seizures is significantly related to local brain destruction and its location, and to diffuse brain damage, reflected by alteration in consciousness. 2) The incidence of seizures has remained the same from one war to another, in spite of marked improvement in patient transport, surgical techniques, medical management, and the prophylactic use of anticonvulsants in Vietnam. 3) After injuries incurred in combat and support activities, the onset of new cases of epilepsy rises sharply, with approximately 5% having a seizure in the first week, 10% in the first 3 months, 16% in the first 6 months, 23% in the first year, 29% in the first 2 years; after that there is a low, but protracted rate of new cases of epilepsy. 4) Those cases that occur in the first week are less influenced by the agent of injury or local brain damage, thereafter there is a sharp divergence with the more extensive injuries providing the greater number of patients with seizures. 5) In the population at risk, 65% to 75% never have a seizure. In those that do, the development varies in degree, adjudged from frequency of seizures. The latter ranges from a single seizure to a number that defies an accurate count. 6) As new patients with seizures accumulate, earlier patients cease having seizures. Within 5 to 10 years, one-half of the patients have ceased having seizures, with or without therapy. Half of the remainder, about 8% of the injured, have intractable seizures. 7) While there is a clear correlation between severity of injury and onset of seizures, there is no correlation between severity of injury and cessation of attacks. However, there is a correlation between the attack frequency and persistence of seizures. 8) From the preceding, two principal determinants are evident: the constitutional tendency toward seizures (probably a multifactorial genetic trait), and the brain damage. In onset of seizures, both play a part, the constitutional factor apparently determining severity of attacks. In cessation or persistence of seizures, the constitutional factor plays the dominant role.

Prophylaxis in alcoholics in the withdrawal period.

Attention is drawn to the occasional appearance of Korsakov's psychosis immediately after a convulsive seizure in chronic alcoholics and to the possibility that withdrawal fits may contribute to the dementia seen in some chronic alcoholics. The routine prophylactic use of anticonvulsants and B vitamins in the withdrawal period is advocated and described.