Diagnosis, Treatment and Management of Seizures
MANAGEMENT OF EPILEPSY IN ADULTS:
The management of patients with epilepsy is focused on three main goals: controlling seizures, avoiding treatment side effects, and maintaining or restoring quality of life. Physicians should assist in empowering patients with epilepsy to lead lifestyles consistent with their capabilities.
It is usually appropriate to refer the patient to a neurologist, when establishing a diagnosis and formulating a course of treatment. Referral to an epilepsy specialist may be necessary if there is doubt about the diagnosis and/or if the patient continues to have seizures.
ANTIEPILEPTIC DRUG THERAPY
When to start AED therapy — Immediate antiepileptic drug (AED) therapy is usually not necessary in individuals after a single seizure, particularly if a first seizure is provoked by factors that resolve. AED therapy should be started in patients who are at significant risk for recurrent seizures, such as those with remote symptomatic seizures. AED treatment is generally started after two or more unprovoked seizures, because the recurrence proves that the patient has a substantially increased risk for repeated seizures, well above 50 percent.
Choosing an AED — About half of patients with a new diagnosis of epilepsy will become seizure free with the first AED prescribed [39,40]. Tolerability of side effects is as important as efficacy in determining the overall effectiveness of treatment. No single AED is optimal for every patient or even most patients. The selection of a specific AED for treating seizures must be individualized considering:
- Drug effectiveness for the seizure type or types
- Potential adverse effects of the drug
- Interactions with other medications
- Comorbid medical conditions, especially but not limited to hepatic and renal disease
- Age and gender, including childbearing plans
- Lifestyle and patient preferences
In general, enzyme-inducing AEDs (eg, phenytoin, carbamazepine, phenobarbital, primidone; and less so, oxcarbazepine and topiramate) are the most problematic for drug interactions with warfarin and oral contraceptive therapy, as well as certain anti-cancer and anti-infective drugs
Combination therapy — When possible, it is preferable to maintain a patient on a single AED. This increases the probability of compliance, provides a wider therapeutic index, and is more cost-effective than combination drug treatment. Monotherapy is also associated with fewer idiosyncratic reactions and a lower incidence of teratogenic effects. Combination therapy can be associated with drug interactions between AEDs, making it difficult to dose and monitor patients.
Seizure remission is achieved with combination therapy in only a small percentage (10 to 15 percent) of patients who have failed monotherapy. While the chances of treatment success diminish incrementally with each successive drug trial, two studies suggest a value in pursuing further drug trials.
Side effects of therapy — During the first six months of treatment, systemic toxicity and neurotoxicity cause AED failure to the same degree as lack of efficacy against seizures. Serum levels that are associated with neurotoxicity vary from patient to patient, and toxicity can occur even when measured levels are considered to be within the appropriate therapeutic range.
The usual strategy in patients experiencing peak-level side effects from a specific drug is to alter the medication regimen or treatment schedule to minimize side effects; one alteration may be to spread the medication over more doses throughout the day. The physician should attempt to correlate serum drug concentrations with the patient’s side effects before abandoning that medication. Specifically, levels should be obtained when a patient is experiencing side effects compared with levels when the patient is free from symptoms can be helpful in the management of some patients.
Specific adverse reactions — Many side effects of AEDs specific to individual medications are reviewed in detail separately. Some severe reactions that are common to more than one medication include the following:
- Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) are rare but severe idiosyncratic reactions, characterized by fever and mucocutaneous lesions that have been associated with the use of carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, zonisamide, lamotrigine, and (less commonly) other AEDs.
- Reduced vitamin levels have also been described in patients taking AEDs. In one study, subnormal folate levels were reported in 16 percent of patients on AEDs (primarily in patients taking carbamazepine,gabapentin, phenytoin, or primidone). While vitamin B12 levels were lower on average in patients taking AEDs (particularly in patients taking phenobarbital, pregabalin, primidone, or topiramate), the frequency of subnormal B12 levels was not significantly different in patients compared with controls. Vitamin supplementation yielded normal levels in patients with subnormal levels within three months.
- Bone loss has also been described in patients receiving long-term AEDs.
Patient education — Before treatment is initiated, the physician needs to begin a dialogue with the patient and family to increase their understanding of epilepsy and their ability to report necessary and relevant information. Epilepsy affects each patient in a unique way, and patients differ in their capacity to understand various aspects of the disorder. As a result, physicians must tailor discussions to clarify the impact of the condition on the specific patient’s quality of life and expectations of the treatment plan. These discussions will improve the likelihood that the patient will comply with the plan of treatment.
Seizure calendar — Patients and family members should be asked to record seizures and AED doses on a calendar or diary, which can then be brought or sent to the physician for review. Seizure triggers should be indicated. The patient and family should note on the calendar the hour at which any symptoms occur. Electronic seizure diaries are also available.
Alcohol intake — Alcohol consumption in small amounts (one to two drinks per day) may not affect seizure frequency or serum levels of AEDs in patients with well-controlled epilepsy.
In an effort to enable people with epilepsy to live as normal a life as possible, it may be reasonable to advise that limited alcohol intake is acceptable, provided there is no history of alcohol or substance abuse or a history of alcoholrelated seizures. However, patients should be aware that the data are not definitive at this time. Driving or other high-risk activities should be avoided for 24 to 48 hours after heavy alcohol intake due to the higher risk of seizures.
Noncompliance with AED therapy —Up to 50 percent of patients with epilepsy may fail to take their medications as directed; over one-half of those evaluated in emergency departments for recurrent seizures have been noncompliant.
Initiation of therapy
Choice of drug — There is an evergrowing list of newer antiepileptic drugs (AEDs) and nonpharmacologic therapies available to manage childhood epilepsy. Traditionally, the medications have been separated into “older” and “newer” groups based upon their historic regulatory approval and availability. Typically, when a medication is first approved for epilepsy, it receives an “onlabel indication” for add-on (adjunctive) therapy for partial-onset seizures in adults. Then, as experience grows and other studies are done, the use of the drug may expand to other seizure types and younger age groups.
Drug dose — The AED dose should be increased until seizures stop, unremitting adverse effects occur, or serum levels reach a high or supratherapeutic range without a significant impact upon seizure frequency. The recommended upper therapeutic serum levels of most of the AEDs can be exceeded if side effects are absent. This should be done with particular caution with phenytoin because of its nonlinear pharmacokinetics and with valproate because of dose-related thrombocytopenia. If side effects appear but are tolerable, the dose should remain stable for several weeks to determine if the symptoms remit. Dose increases can continue at a slower rate if side effects remit and seizures continue.
Drug-drug interactions — Many commonly used drugs can alter the metabolism of AEDs and vice versa. Hepatic enzyme inducers will lower the levels of drugs metabolized in the liver, and liver enzyme inhibitors will slow the metabolism of the same drugs. Cimetidine, propoxyphene, erythromycin, fluoxetine, and clarithromycin are examples of enzyme inhibitors used in children that may elevate the serum levels of some AEDs.
Serum levels — Serum levels should be used only as guides to therapy. The therapeutic range is different for each patient. Many will achieve seizure control at levels below the recommended range; others require higher levels. There is no reason to increase the dose if seizures stop when the serum level is “low” or “subtherapeutic.” If the level reaches the “therapeutic range,” yet seizures continue, the level should be increased as long as there are no adverse effects.
Compliance — Rates of non-adherence to prescribed AED therapy are difficult to measure, but are probably higher than is generally appreciated. One prospective observational study in 124 children (2 to 12 years old) with newly diagnosed epilepsy found that 58 percent demonstrated nonadherence during the first six months of treatment.
Adding a second AED — The first AED fails in 20 to 40 percent of children with epilepsy; lack of efficacy and side effects contribute roughly equally to treatment failure. A second AED is added when seizures are resistant to the initial drug. If the initial drug was partially effective, it should be continued until reasonable levels of the new AED are achieved. Tapering the first drug can then be attempted if seizures are controlled. If the initial AED is ineffective, it can be tapered earlier, as the dose of the second drug is increased.
Monotherapy versus polytherapy — Single-drug therapy is the goal of epilepsy treatment. Monotherapy is associated with better compliance, fewer adverse effects, less potential for teratogenicity, and lower cost than is polytherapy. Drug interactions are avoided and pharmacokinetics are simplified. A second AED may also be considered in children with several different seizure types when monotherapy is not effective. In one practice, the clinicians found that children with status epilepticus, developmental disabilities, and multiple seizure types were more likely to require polytherapy than those without these features.
DRUGS THAT AFFECT VOLTAGEDEPENDENT SODIUM CHANNELS — Depolarization of neuronal membranes (such as by excitatory neurotransmitters at postsynaptic receptor sites) produces an influx of sodium ions from the extracellular space into the neuron through sodium channels along the neuronal membrane.
Carbamazepine — Carbamazepine (CBZ) has been used to treat partial and generalized seizures since being introduced in Switzerland and the United Kingdom over 35 years ago. It is also effective for the treatment of affective illnesses such as bipolar disorder and chronic pain syndromes such as trigeminal neuralgia.
Adverse events — Common systemic side effects of CBZ include nausea, vomiting, diarrhea, hyponatremia, rash, pruritus, and fluid retention.
Phenytoin — Phenytoin was introduced nearly 60 years ago for use in epilepsy and is still widely prescribed for partial and generalized seizures. Similar to carbamazepine, it blocks voltagedependent neuronal sodium channels. The major systemic side effects of phenytoin are gingival hypertrophy, body hair increase, rash, and lymphadenopathy
- Phenytoin has been associated with the Stevens-Johnson syndrome and toxic epidermal necrolysis, particularly during the first eight weeks of therapy.
- Folic acid supplementation 0.5 mg/ day was associated with a reduced incidence of gingival hyperplasia (21 versus 88 percent) after six months in a randomized trial of children (ages 6 to 15 years) who were recently started on phenytoin.
Lamotrigine — The cellular mechanism of action of lamotrigine (LTG) is not completely understood, and it may have multiple effects. In rodent brain preparations, LTG blocks the repetitive firing of neurons by inactivating voltagedependent sodium channels.
Oxcarbazepine — Oxcarbazepine is a compound with a similar chemical structure to carbamazepine and likely a similar mechanism of action (table 1A-C).
Metabolism of oxcarbazepine occurs in the liver, but only minimally affects the cytochrome P450 system. This represents a major advantage over carbamazepine, particularly in patients who require polytherapy
The most common side effects of oxcarbazepine are sedation, headache, dizziness, rash, vertigo, ataxia, nausea, hyponatremia, and diplopia.
Zonisamide – Zonisamide is a sulfonamide derivative that is chemically and structurally unrelated to other anticonvulsants. Its primary mechanism of action appears to be to blocking both voltage dependent sodium and T-type calcium channels.
Lacosamide — Lacosamide selectively enhances slow inactivation of voltagedependent sodium channels; this results in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.
Rufinamide — Rufinamide is structurally unrelated to other marketed AEDs. Rufinamide modulates the activity of sodium channels, prolonging the inactive state. This action is particularly effective in depolarized neurons.
DRUGS THAT AFFECT CALCIUM CURRENTS — There are three types of calcium channels in neurons, each of which is distinguished by its rate of reactivation and voltage dependency. Low-threshold T-type calcium currents inactivate quickly and have been described in experimental preparations of thalamic relay neurons.
Ethosuximide — Ethosuximide diminishes T-type calcium currents in thalamic neurons, which are further reduced as membrane potentials become more hyperpolarized.
The recommended dose of ethosuximide is 20 to 40 mg/kg per day in one to three divided doses. Blood levels should be checked initially after one to three weeks, with a goal therapeutic concentration of 40 to 100 mcg/mL.
DRUGS THAT AFFECT GABA ACTIVITY — Gamma-aminobutyric acid (GABA) is a neurotransmitter that is widely distributed throughout the central nervous system and exerts postsynaptic inhibition. The GABA(A) receptor complex has binding sites for GABA, benzodiazepines, and phenobarbital. Picrotoxin and other similar proconvulsants bind to the GABA(A) receptor and block chloride channels, thereby preventing postsynaptic inhibition.
Phenobarbital — Phenobarbital (PBOB) is among the oldest AEDs still in use. It is effective for the treatment of generalized and partial seizures. However, its clinical utility is limited by its sedating effects
Tiagabine — Tiagabine (TGB) is a second generation AED that is indicated as adjunctive treatment for partial seizures. It is a potent enhancer of GABA action via specific inhibition of GABA reuptake into presynaptic neurons and glia in vitro.
Vigabatrin — Vigabatrin (VGB) is an irreversible inhibitor of GABA-transaminase that raises the concentration of GABA in the central nervous system.
Benzodiazepines — Benzodiazepines enhance GABA inhibition by increasing the frequency of GABA-mediated chloride channel openings.
Clobazam — Clobazam is approved by the US FDA for as an adjunctive therapy in patients >2 years of age with LennoxGastaut syndrome (LGS).
Others — Clonazepam is most often used as an adjunctive therapy for myoclonic and atonic seizures. Clorazepate, diazepam, and lorazepam are effective for those seizure types as well as for partial and generalized tonic-clonic seizures.
DRUGS THAT AFFECT GLUTAMATE RECEPTORS
Perampanel — Perampanel is an orally active, noncompetitive AMPA-type glutamate receptor antagonist. It appears to inhibit AMPA-induced increases in intracellular calcium, reducing neuronal excitability.
DRUGS WITH MULTIPLE MECHANISMS OF ACTION — A number of antiepileptic drugs (AEDs) have multiple mechanisms by which they prevent seizures.
Valproate — Valproate (valproic acid, VPA) is a broad-spectrum AED used alone and in combination for the treatment of generalized and partial seizures.
Felbamate — The mechanism of action of felbamate is not well understood. It blocks the channel at the N-methyl-Daspartate (NMDA) excitatory amino acid receptor and augments GABA function in rat hippocampal neuronal cultures.
Topiramate — Topiramate (TPM) also has multiple mechanisms of action. It blocks voltage-dependent sodium channels, enhances the activity of GABA at a nonbenzodiazepine site on GABA(A) receptors, and antagonizes an NMDA– glutamate receptor. It also weakly inhibits carbonic anhydrase in the central nervous system.
DRUGS WITH OTHER MECHANISMS OF ACTION
Gabapentin — Gabapentin binds to the auxiliary alpha-2-delta subunit of a voltage-dependent calcium channel, which may inhibit inward calcium currents and attenuate neurotransmitter release.
Levetiracetam — Levetiracetam (LEV) is a broad spectrum AED and is approved as adjunctive therapy to treat partialonset seizures in patients aged 4 years or older with epilepsy, as adjunctive therapy in treating myoclonic seizures in patients aged 12 years or older with juvenile myoclonic epilepsy, and as adjunctive therapy for primary generalized tonicclonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy.
Pregabalin — Pregabalin also has multiple potential mechanisms of action. It binds to the alpha2-delta subunit of voltage-gated calcium channels and modulates calcium currents.
Ezogabine — Ezogabine or retigabine is believed to exert its antiepileptic effect by opening KCNQ2/3 voltagegated potassium channels, activating M-current, which regulates neuronal excitability and suppresses epileptic activity.
MANAGEMENT OF STATUS EPILEPTICUS:
INITIAL APPROACH — Patients with generalized motor seizures that are frequent or separated by a period of significantly impaired consciousness or who are medically unstable require immediate assessment and treatment, which usually is accomplished in the setting of the emergency department.
Initial assessment — A brief physical examination should assess respiratory and circulatory status. A rapid neurologic examination should be performed to provide a preliminary classification of the type of SE. A history obtained from a parent or caregiver may help to determine the cause of the seizures.
An adequate airway should be established immediately if there is respiratory compromise, and supportive therapy (e.g., oxygen, mechanical ventilation) should be instituted as needed. A secure intravenous catheter should be placed for sampling of blood and administration of medications. Ongoing monitoring of vital signs should be initiated.
Pharmacologic agents: — There are four main categories of drugs used to treat status epilepticus: benzodiazepines, phenytoin (or fosphenytoin), barbiturates, and propofol.
Benzodiazepines — Benzodiazepines remain the first-line treatment for status epilepticus because they can rapidly control seizures.
Diazepam — Diazepam has a high lipid solubility and therefore an ability to rapidly cross the blood-brain barrier; it is highly effective in rapidly terminating seizures when administered at doses of 0.1 to 0.3 mg/intravenously.
Lorazepam — Although lorazepam is as effective as diazepam in terminating seizures, the time from its injection to its maximum effect against seizures is as long as two minutes. The clinical advantage of lorazepam is that the effective duration of action against seizures is as long as four to six hours because of its less pronounced redistribution into adipose tissue.
Midazolam — Like lorazepam and diazepam, midazolam is very effective in acutely terminating seizures (frequently in less than one minute), but it has a short half-life in the central nervous system.
Clobazam — Clobazam has been used to treat status epilepticus outside the United States in settings where intravenous formulations are available.
Phenytoin — Phenytoin is one of the most commonly used treatments for status epilepticus, despite the trial described above which showed that initial treatment of generalized convulsive status epilepticus with lorazepamalone was more effective than treatment with diazepam and phenytoin.
Fosphenytoin — Fosphenytoin is a prodrug of phenytoin that is hydrolyzed into phenytoin by serum phosphatases. Fosphenytoin is highly water soluble and therefore unlikely to precipitate during intravenous administration.
Barbiturates — Barbiturates are similar to benzodiazepines in that they also bind to the GABA(A) receptor, amplifying the actions of GABA by extending GABAmediated chloride channel openings.
Phenobarbital — Phenobarbital is an excellent anticonvulsant, especially in the acute management of seizures.
Pentobarbital — Pentobarbital is used primarily in the treatment of refractory status epilepticus, typically with a loading dose of 10 mg/kg infused at a rate of up to 100 mg/minute.
Thiopental — Some centers use thiopental instead of pentobarbital for refractory status epilepticus, but there are a number of problems with this approach.
Propofol — Propofol is a hindered phenolic compound with anticonvulsant properties. The drug is unrelated to any of the currently used barbiturate, opioid, benzodiazepine, arylcyclohexylamine, or imidazole intravenous anesthetic agents. Hypotension and respiratory depression may complicate its use.
Valproic acid — The use of intravenous (IV) valproic acid (Depacon) is increasingly used in the treatment of status epilepticus. (FDA) approved it only for slow infusion rates (up to 20 mg/min).