Prevention Of Recurrent Seizures Research Articles

Update on the newer antiepileptic drugs in child neurology: Advances in treatment of pediatric epilepsy

The goal of epilepsy treatment is the prevention of recurrent seizures, and antiepileptic drugs (AEDs) are the mainstay. Uncontrolled seizures may cause medical, developmental, and psychologic disturbances. Treatment advances include 1) identification of the basic mechanisms of epilepsy and action of AEDs, 2) the introduction of many new AEDs, and 3) the use of neurostimulation, starting with vagus nerve stimulation. We must balance the efficacy of an AED versus its side effects, which if persistent, lead to patient discontinuation of the AED. Although all AEDs have a proven efficacy, they are differentiated by their efficacy for a given seizure type or epilepsy syndrome versus the side effects or tolerability. The many new AEDs give us a larger armamentarium for epilepsy treatment. We refer to studies and expert opinion consensus.

Single Unprovoked Seizures.

Unprovoked seizures are common, affecting approximately 4% of the population by age 80. Only approximately 30% to 40% of patients with a first seizure will have a second unprovoked seizure (ie, epilepsy). Treatment with antiepileptic drugs (AEDs) should not be initiated unless the diagnosis of a seizure is firm. Decisions regarding treatment of single unprovoked seizures must balance seizure recurrence risk, the potential impact of a recurrent seizure, the likelihood of adverse effects of treatment, and patient preference. Risk factors for seizure recurrence include a history of remote neurologic insult, epileptiform abnormalities on electroencephalogram, focal structural lesion on neuroimaging, and family history of epilepsy. Adult patients with these risk factors have a recurrence risk of 60% to 70% and usually should be treated with an AED to prevent seizure recurrence. Without risk factors, the recurrence risk is 20% to 30%, and treatment depends on individual risk-to-benefit ratios and patient preference. Treatment of a first unprovoked seizure is often not necessary in childhood, especially if the seizure is part of a benign self-limited syndrome, such as benign Rolandic epilepsy of childhood. Treatment with an AED reduces the risk of seizure recurrence after a single unprovoked seizure. This must be balanced against the risk of adverse effects of AEDs. Treatment of the first seizure does not appear to affect the long-term prognosis of epilepsy. The choice of an AED should be guided by the seizure type and likely epilepsy syndrome diagnosis. Monotherapy is preferable. Standard AED options include phenytoin, carbamazepine, valproate, and phenobarbital. The newer AED, including gabapentin, lamotrigine, topiramate, oxcarbazepine, levetiracetam, and zonisamide, have good efficacy, favorable pharmacokinetic profiles, and often fewer adverse effects, supporting their use early in treatment. Not all of the newer AEDs are approved for use as monotherapy. Patients with single seizures should be counseled about seizure first aid and general safety measures, including precautions regarding swimming alone, engaging in high-risk activities, driving, possible seizure precipitation by photic stimuli (in generalized epilepsy), sleep deprivation, and alcohol.

Pharmacology Review

Immediate management of seizures includes stabilization, identification of the cause and specific treatment, and if needed, administration of an antiepileptic drug (AED) to prevent seizure recurrence. AED therapy is divided into standard (traditional) and alternative therapies. Alternative therapies include vitamins or cofactors specific for certain inborn errors of metabolism. Part 1 of this two-part Pharmacology Review examines some basic neonatal seizure concepts and the standard therapies (phenobarbital, phenytoin, fosphenytoin, and benzodiazepines); Part 2 reveiws alternative therapies and when to stop treatment. Seizures represent the most specific indication of neonatal neurologic insults. (1)(2) The incidence of neonatal seizures ranges from 1 to 5:1,000 live births. (2) It is vital to recognize neonatal seizures, determine their cause, and treat them because if they continue, they could interfere with supportive functions, such as respirations and feeding, and cause brain damage. (1)(2) Although seizures in an older child may be idiopathic or genetic, most neonatal seizures have a specific cause. In the series by Mizrahi and Kellaway, (3) the most common cause was hypoxic-ischemic encephalopathy (32%), followed by intracranial hemorrhage (17%), central nervous system infection (14%), infarction (7%), metabolic abnormalities (6%), inborn errors of metabolism (3%), and unknown (10%). The clinical manifestations of seizures may differ in the neonate compared with the older child and may not be as obvious. Volpe classified neonatal seizures as subtle or fragmentary seizures (more common in the preterm infant), clonic (focal or multifocal), tonic (focal or generalized), and myoclonic (focal, multifocal, or generalized). (1)(2) The generalized tonic-clonic seizure is unusual in the newborn, but it may be seen in genetic epilepsies. Electroencephalography (EEG) may be useful for confirming neonatal seizures when they are suspected. However, not all seizures have an EEG correlate, which makes diagnosis difficult. Mizrahi and Kellaway categorized seizures as …

Clinical profile of solitary seizures

Background: Solitary seizure is one of the controversies in neurology. This study was taken up to study the clinical profile of solitary seizure and the factors related to seizure recurrence with a view to evolve guidelines for management. Methods: We studied 150 cases of solitary seizure. All our patients were males. The age varied from 18–52 years. The diagnosis of seizure was confirmed with history. Apart from clinical neurological examination, blood counts, urinalysis and screening investigations to exclude possible underlying metabolic disorders were done. Inter-ictal EEG and contrast enhanced CT scan were done. Results: CT scan was abnormal in 28 cases. EEG was abnormal in 33; clinical abnormality was noted in 15 cases. Median follow up duration was 1.2 years. 18 patients had seizure recurrence. Type of seizure, EEG findings (normal or abnormal) and treatment with antiepileptic drugs did not have any effect on seizure recurrence. Seizure recurrence was less common in presence of CT scan abnormality though it was not significant statistically. Routine laboratory tests of blood count, blood sugar and urinalysis were normal in all cases. Conclusion: In cases of solitary seizure, type of seizure, results of EEG and CT scan findings are not likely to predict seizure recurrence. Treatment with antiepileptic drugs does not prevent seizure recurrence. Laboratory investigations like blood counts, urinalysis and blood sugar estimation are unlikely to be of value in routine work-up of these cases.

When to start drug therapy in epilepsy

Discussing the usefulness of drugs in childhood epilepsy, Dr Newton (January 2004, JRSM1) suggests that ‘After two seizures most people will have a further seizure and this is probably the pivotal point at which the decision to treat or to delay treatment should be made’. Since antiepileptic drugs do not alter the natural course or long-term remission rate of epilepsy, the primary aim of treatment is to prevent seizure recurrence. In certain patients the recurrence rate after a single episode is particularly high—for example, those with a history of brain injury;2 those who had status epilepticus;3 and those who had a partial rather than a generalized seizure.4 The risk of recurrence after a first episode of seizure is much higher in children with abnormal electroencephalograms (EEGs) than in those with normal EEGs (80% versus 31%).5 Those with an abnormal CT scan at initial seizure have a higher risk of recurrence than those with normal scans.6 Though I agree with Dr Newton that antiepileptic drugs (AEDs) are generally not required after a first episode of unprovoked seizure, these are factors that might favour early treatment. Children and parents also need education on how to avoid precipitating factors. In one study, a lower relapse rate (uninfluenced by AED therapy) was observed in a group educated to avoid such factors.7 If drugs are prescribed, many patients and caregivers need help in managing prescriptions to minimize the risk of adverse effects.8

Efficacy and Safety of Remacemide versus Carbamazepine in Newly Diagnosed Epilepsy: Comparison by Sequential Analysis

An international trial comparing remacemide hydrochloride with carbamazepine was undertaken in newly diagnosed epilepsy using a novel double-blind, parallel group, double triangular sequential design. Patients with two or more partial or generalized tonic–clonic seizures in the previous year were randomized to 600 mg daily of remacemide or carbamazepine. Subsequent dosage adjustments were allowed while maintaining the blind. The trial completed 20 months after initiation following the second interim analysis. Efficacy data on 449 patients showed carbamazepine to be significantly more effective than remacemide in preventing seizure recurrence (P = 0.003). Median time to first seizure after titration, the primary endpoint, was 112 days for remacemide and 306 days with carbamazepine. Time to second, third, and fourth seizures after randomization all significantly favored carbamazepine. Remacemide was shown unequivocally to be inferior to carbamazepine in this patient population. This study also establishes carbamazepine as a proven treatment for use in subsequent active control comparative trials.

Pyridoxine‐dependent seizures: A case report and a critical review of the literature

Pyridoxine-dependent seizures are a recognized, although rare, cause of intractable seizures in neonates. Patients with this autosomal recessive disorder have recurrent seizures that are resistant to conventional anticonvulsants but respond dramatically to intravenous administration of pyridoxine. Life-long supplementation with pyridoxine is required to prevent seizure recurrence. In the absence of a biological marker for the disease, clinical diagnosis is often delayed and severe neurological sequelae are common. Herein, we report on the clinical course of a neonate with pyridoxine-dependent seizures. Delayed normalization of the electroencephalogram and a normal developmental outcome (at 15 months of age) on a dose of 10 mg/kg pyridoxine are distinctive features of the present case. We also review recent clinical observations and neurochemical studies that have added to our knowledge of this disorder.

Status epilepticus.

Status epilepticus is a medical emergency that requires rapid and vigorous treatment to prevent neuronal damage and systemic complications. Failure to diagnose and treat status epilepticus accurately and effectively results in significant morbidity and mortality. Cerebral metabolic decompensation occurs after approximately 30 min of uncontrolled convulsive activity, and the window for treatment is therefore limited. Therapy should proceed simultaneously on four fronts: termination of seizures; prevention of seizure recurrence once status is controlled; management of precipitating causes of status epilepticus; management of the complications. This article reviews current opinions about the classification, aetiology and pathophysiology of adult generalised convulsive status epilepticus and details practical management strategies for treatment of this life-threatening condition.

Management approaches to prolonged seizures and status epilepticus.

Status epilepticus (SE) treatment should proceed on four fronts: termination of SE, prevention of recurrence, management of potential precipitating causes, and management of SE complications and underlying conditions. The intensity of the treatment should reflect the risk to the patient from SE, and drugs likely to depress respiration and blood pressure should initially be avoided. The Veterans Administration cooperative trial showed that when treating overt SE, first-line treatment success rates were: lorazepam 64.9%; phenobarbital 58.2%; diazepam/phenytoin 55.8%; and phenytoin alone 43.6%. The aggregate response rate to second-line agents for patients who did not respond to first-line agents was 7.0%, and it was 2.3% for third-line agents, raising the question of the efficacy of a second and third drug. The recommended treatment for generalized convulsive SE is to begin with lorazepam. As a second-line agent, phenytoin or fosphenytoin, is still recommended if SE control is not achieved within 5 to 7 min. Fosphenytoin achieves a free phenytoin level of about 2 micro/mL in 15 min, as opposed to 25 min with phenytoin itself. Moreover, fosphenytoin is safer and, despite higher cost, it may be cost-effective. High-dose barbiturates, high-dose benzodiazepines, and propofol are employed for major treatment for refractory SE. Patients at this stage should undergo continuous electroencephalogram monitoring. Once SE is controlled, prevention of seizure recurrence should be individualized to each patient. The major complications of generalized convulsive SE (GCSE), rhabdomyolysis and hyperthermia, should be watched for and treated.

The role of the middle ear and tonsil in the etiology of febrile convulsions

The middle ear and tonsil are thought to be important sources of infection in children with febrile seizures. However, these patients are rarely examined by an otolaryngologist in the acute phase and we are unaware of any previous studies where otolaryngologists have documented the presence of acute suppurative otitis media (ASOM) and tonsillitis in a series of children with febrile convulsions. We carried out a prospective study on 47 children admitted to two Dublin hospitals with a diagnosis of simple febrile convulsion. All children were examined by an otolaryngology resident within 6 h of admission. Nine children were noted to have ASOM and 18 had acute tonsillitis. The otolaryngology resident's opinion of the condition of the ears and throat often differed from that of the admitting pediatric resident, as documented in the clinical records. We review the recent literature on febrile convulsions and discuss the possible role of the otolaryngologist in the prevention of seizure recurrence.

Management of generalized tonic-clonic status epilepticus.

The steps to be taken in the management of GTC status are outlined in Table 2. Once the GTC status is brought under control, prevention of recurrent seizures must be considered. The specific etiology must be sought. Those patients who require long-term prophylactic anticonvulsant therapy include those with structural brain abnormalities, progressive neurological disorders, and patients with idiopathic epilepsy.

Treatment of Status Epilepticus

Status epilepticus, particularly the convulsive form, is a medical emergency, warranting prompt and aggressive treatment. To do this, one must have a thorough understanding of the pharmacology of the anticonvulsant agents. Therapy should be directed toward rapid termination of the status epilepticus, prevention of seizure recurrence, and treatment of any underlying cause. Most importantly, one should establish and adhere to a standard treatment protocol for best results.