What route of drug administration is often used when patients are newly diagnosed with a seizure?

Page last reviewed: 18 September 2020
Next review due: 18 September 2023

This section discusses the use of anticonvulsant agents for absence, tonic or atonic, myoclonic, and tonic-clonic seizures. A discussion of treatment for focal-onset seizures, including refractory cases, also follows, with some findings from the Veterans Administration (VA) Cooperative Studies and Standard and New Antiepileptic Drugs (SANAD) trial.

If only absence seizures are present, most neurologists treat them with ethosuximide. If absence seizures are present along with other seizure types (eg, generalized tonic-clonic seizures, myoclonic seizures), the choices are valproic acid, lamotrigine, or topiramate. Do not use carbamazepine, gabapentin or tiagabine, because these drugs may exacerbate absence seizures. It is uncertain whether pregabalin, a medication related to gabapentin, may also exacerbate this type of seizure.

Investigators of a single, double-blind, randomized, controlled trial that compared the efficacy, tolerability, and neuropsychologic effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy concluded that ethosuximide was the drug of choice for this clinical scenario. [33] Valproate was equally as effective as ethosuximide in newly diagnosed childhood absence epilepsy, but it was associated with more adverse effects.

Tonic or atonic seizures are dramatic seizures. Patients with Lennox-Gastaut syndrome may have seizures, and this syndrome is best treated with broad-spectrum drugs (eg, valproic acid, lamotrigine, topiramate) or felbamate as a last resort. Other treatment modalities include the use of vagal nerve stimulation (VNS). The US Food and Drug Administration (FDA) has approved several agents—rufinamide, clobazam, [34]  extended-release topiramate, [35, 36, 37, 38] cannabidiol, [39, 40, 41]  and stiripentol [42]  —as adjunctive therapies for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex.

Myoclonic seizures have a bimodal distribution. Infants with myoclonic epilepsies usually have a poor prognosis; however, in late childhood and adolescence, the syndrome of juvenile myoclonic epilepsy (JME) is often the cause of myoclonic seizures. The seizures associated with JME are usually readily controlled with the appropriate broad-spectrum antiepileptic drug (AED), but JME has a high recurrence rate of approximately 80-90% after discontinuation of anticonvulsants.

The best medications for JME and myoclonic seizures are valproic acid, lamotrigine, and topiramate. Levetiracetam is approved by the FDA for adjunctive therapy of JME; this is the first medication approved for this syndrome. Anecdotal evidence suggests that zonisamide might be helpful in JME. Note that if partial seizure medications, such as phenytoin and carbamazepine, are used to treat JME, these agents may not only be ineffective, but in certain cases they may exacerbate the seizures.

Primary generalized tonic-clonic seizures respond to valproic acid, topiramate, or lamotrigine. Levetiracetam and perampanel are indicated as adjunctive therapy for these seizures.

The SANAD trial investigators concluded that valproate should remain the drug of first choice for many patients with generalized and unclassified epilepsies, as it is better tolerated than topiramate and more efficacious than lamotrigine. [43] However, in women of childbearing age, the known potential adverse effects of valproate during pregnancy (ie, black box warnings of severe birth defects and impaired cognitive development) must be balanced against the benefits of seizure control. Levetiracetam and zonisamide were not included in SANAD, which tested only lamotrigine, topiramate, and valproate.

A 2014 study by Shallcross et al, however, indicated that whereas in utero exposure to the AED valproate is associated with language and motor development deficits in children, the same is not true for levetiracetam. In the study, valproate exposure resulted in children having lower scores on tests of comprehension, expressive language abilities, and motor skills compared with children exposed to levetiracetam. In fact, children exposed to levetiracetam did not differ from children unexposed to any AED on tests of thinking, movement, and language when tested at age 36-54 months. [44, 45]

In focal-onset seizures, there are many AED choices with monotherapy indications, including carbamazepine, cenobamate, lacosamide, lamotrigine, oxcarbazepine, and topiramate. (see Anticonvulsants in Specific Patient Populations, below). Adjunctive therapy with levetiracetam, tiagabine, gabapentin, pregabalin, lacosamide, cenobamate, or ezogabine may be considered if the first or second monotherapy trial with first-line treatments fails. Discussing the adverse-effect profiles of anticonvulsants with patients is important, because the efficacies of anticonvulsants appear to be similar. [46]

The VA Cooperative Study I clearly demonstrated similar efficacies for carbamazepine, phenytoin, primidone, and phenobarbital. [47] However, carbamazepine and phenytoin were tolerated better by men than women. The VA Cooperative Study II findings showed that carbamazepine and valproic acid had similar efficacies. [48] However, subset analysis for complex focal seizures suggested that carbamazepine may be a better choice than valproate. [48]

In elderly subjects (patients aged ≥60 years) in the VA Cooperative Study, lamotrigine and gabapentin were better tolerated than carbamazepine and were similarly effective. [49] However, gabapentin caused more adverse effects than lamotrigine. Those results led to the recommendation of lamotrigine as first-line monotherapy in elderly patients. [49]

The focal seizures arm of the SANAD trial demonstrated that although carbamazepine is the standard drug treatment, lamotrigine is clinically better with respect to time to treatment failure. [50] This study also determined that lamotrigine is a cost-effective alternative to carbamazepine for patients with focal-onset seizures. Carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate were included for comparison. [50] However, the cost-effectiveness of medications has changed, as many new AEDs also have generic formulations.

All new medications have been tested as adjunctive therapy, and head-to-head comparisons of new drugs with carbamazepine have been conducted in Europe. In general, the new drugs have similar statistical efficacies but fewer adverse effects than carbamazepine; this puts the results of the SANAD trial somewhat in doubt, as the SANAD investigators did not find any important differences or trends for scores on the Adverse Events Profile among the drugs.

Of the new anticonvulsants, lamotrigine and topiramate appear to have broad spectrum of action in many seizure types. [51, 52] The American Academy of Neurology and the American Epilepsy Society assembled a task force that reviewed the literature and provided evidence-based recommendations for monotherapy, adjunctive therapy, treatment of primary generalized seizures, treatment in children, and treatment of subgroups of new-onset and refractory epilepsy. [51, 52]

If carbamazepine fails to control the seizures, lamotrigine, topiramate, tiagabine, gabapentin, levetiracetam, oxcarbazepine, pregabalin, and zonisamide are considered for second- or third-line therapy. Several new anticonvulsants, including lamotrigine, topiramate, and oxcarbazepine, are indicated as monotherapy. Although the new anticonvulsants are considered second- or third-line therapy, they can be used as first-line therapy in some patients, especially as these medications have become generic.

In October 2013, the FDA approved labeling changes for ezogabine, including a boxed warning, emphasizing increased risks for potentially permanent adverse effects, such as retinal abnormalities, vision loss, and skin discoloration. The agency recommended that the use of ezogabine be limited to patients who have had an inadequate response to several other therapies and in whom the treatment benefits outweigh the risks. The FDA also recommended eye examinations for patients before they start on ezogabine, as well as every 6 months over the course of treatment. [53, 54, 55]

Although the term medically refractory epilepsy has been used for cases that fail to respond to three antiepileptic drugs, the International League Against Epilepsy (ILAE) has proposed defining drug-resistant epilepsy as the failure to achieve sustained seizure freedom despite adequate trials of two antiepileptic drugs, either as monotherapy or in combination. [56, 57] The drugs must have been appropriately chosen and used, and failure must have occurred because of lack of efficacy and not because of adverse effects. 

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare developmental epileptic encephalopathy caused by mutations in the CDKL5 gene. 

Ganaxolone is a GABAA receptor positive modulator. It binds specifically to GABAA receptors to enhance their inhibitory effects. It is indicated for seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients aged 2 years or older. CDD, a rare developmental epileptic encephalopathy, is largely a disease of pediatric and young adult patients. 

Approval was based on the phase 3 MARIGOLD trial. Patients treated with ganaxolone (n = 49) showed a median 30.7% reduction in 28-day major motor seizure frequency, compared with 6.9% reduction for those receiving placebo (n = 51) (p = 0.0036). In the open label extension study, patients treated with ganaxolone for at least 12 months (n = 48) experienced a median 49.6% reduction in major motor seizure frequency. [58]  

A study of the ILAE criteria in pediatric epilepsy patients found that the probability of achieving seizure freedom was 65%, 29%, 27% and 21%, respectively, with trials of successive therapeutic regimens. [56, 57] Patients with medically refractory epilepsy should be referred to an epileptologist.

Immunotherapy may be a viable treatment strategy in a subset of epileptic patients whose seizures are refractory to management with conventional AEDs and whose poor seizure control may result from the presence of neural-specific antibodies. [59, 60] Iorio et al found autoantibodies specific to neural antigen in 2 of 29 patients with epilepsy and other neurologic symptoms and/or autoimmune diseases (group 1) and in 9 of 30 patients with AED-resistant epilepsy (group 2).

Of the patients in group 2 who received (1) immunotherapy with intravenous (IV) steroids and IV immunoglobulin for 6 months, (2) IV methylprednisolone, IV immunoglobulin, and rituximab, or (3) IV steroids, 5 cycles of plasmapheresis, and oral steroids, 75% had a reduction in seizure frequency of 50% or greater. [60] The remaining patients in group 2 who received immunotherapy were evenly distributed between those who had a reduction in seizure frequency of 20-50% and those with a reduction of less than 20%. [60]  

Future advances in AEDs will involve agents that alter the natural history of epilepsy and modify disease as opposed to providing primarily symptomatic treatment.