|THE THERAPEUTIC BOX
|Year : 2018 | Volume
| Issue : 1 | Page : 74-80
The antiepileptics: Drug choice in newly diagnosed epilepsy
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA
|Date of Web Publication||28-Jan-2019|
Department of Neurology, University of Massachusetts Medical School, 55 Lake Ave, North Worcester, MA 01655
Source of Support: None, Conflict of Interest: None
Numerous anti-epileptic drugs now exist worldwide for the treatment of epilepsy. With the availability of second- and third-generation antiepileptic medications, many factors may need to be considered in choosing the most appropriate treatment for an individual based on the tolerability, efficacy, and cost. This review highlights the treatment options and provides insights into how to choose among the various medications available.
Keywords: Antiepileptic therapy, appropriate, epilepsy
|How to cite this article:|
Chu F. The antiepileptics: Drug choice in newly diagnosed epilepsy. Astrocyte 2018;5:74-80
| Defining Epilepsy|| |
Originally characterized by the occurrence of two unprovoked seizures, the definition of epilepsy was most recently updated by the ILAE in 2014 that also include individuals with one unprovoked seizure, along with evidence from the clinical history, electroencephalogram (EEG), or neuroimaging studies that would increase the probability of having another seizure to the 10-year recurrence risk observed after two unprovoked seizures (≥60%)., Epileptiform activity on EEG and the presence of an epileptogenic focus on neuroimaging (e.g. mesial temporal sclerosis, focal cortical dysplasia, cavernoma) prompt most neurologists to initiate therapy after the first unprovoked seizure. Etiologies such as cortical stroke, brain injury, or central nervous system infection have been shown in the literature to increase the risk of seizure recurrence, and initiation of treatment would also be appropriate by the new definition. Learning disabilities and neurologic dysfunction have also been shown to be predictors of seizure recurrence in population studies.,,,,, In the PRO-LONG study, Beretta et al. found the long-term recurrence of seizures in patients diagnosed with the new definition to be 83.6% at 10 years. An abnormal neurologic examination and the occurrence of focal seizures were more common in the group diagnosed with the new definition. The outcome of early seizure remission as defined by seizure freedom for one year or more within 2 years of diagnosis was unchanged between those patients diagnosed using the new versus old definition. Upon further gathering of clinical history, some individuals have already had a seizure before the initial presentation. The new definition of epilepsy still considers two unprovoked seizures (at least 24 h apart) or an epileptic syndrome as sufficient for a diagnosis.
Not all individuals with epilepsy require initiation of treatment, as etiology may influence the decision to start medication or not. Metabolic factors and exposure to drug or toxins may be eliminated first, and the likelihood of seizure recurrence may be reassessed, before initiation of medication. On the contrary, severe injuries resulting from a new-onset unprovoked seizure (e.g. basal skull fracture with subarachnoid hemorrhage, humerus fracture secondary to shoulder dislocation) may prompt the clinician to treat with an antiepileptic drug even in the absence of a definite diagnosis of epilepsy to prevent further injury or complication of the current injury. Depending on the severity of the seizure, a patient who has less than one seizure per year, especially if it is nocturnal, may opt not to take medication. For the patient to make an informed decision regarding their treatment, state-dependent driving laws prohibiting driving for a duration after a breakthrough seizure or even license suspension after an accident associated with seizure should be thoroughly reviewed with the patient. Patient and family should also be informed of the rare but potential risk of sudden unexpected death in epilepsy (SUDEP), as a major risk factor for SUDEP is continued generalized tonic-clonic seizures. In the absence of absolute risk values for the individual factors associated with seizure recurrence or a way to assess the cumulative risk, individualized assessment by the clinician alongside the patient's wishes remains the mainstay of making treatment decisions.
| Types of Seizure Disorder|| |
Seizure type, as determined by focal versus generalized onset or unknown onset is worth a brief discussion as it has relevance to initial treatment selection and eventual workup of medically refractory epilepsy. The significant challenge is determining the epilepsy type based on the initial seizure presentation, and also distinguishing between a primary generalized tonic-clonic seizure versus secondarily generalized tonic-clonic seizure (focal to bilateral tonic-clonic). In a large consecutive case series of first-onset seizure, almost one-third of the 257 patients who presented with generalized tonic-clonic seizures had preceding epileptic manifestations including myoclonus which would be suggestive of a juvenile myoclonic generalized epilepsy or simple partial seizures which would be indicative of focal epilepsy. Broad-spectrum antiseizure medications that effectively prevent focal and generalized seizures – such as clobazam, lamotrigine, levetiracetam, valproic acid, and zonisamide – are recommended for initial treatment unless the patient or witnesses can confirm clear focal onset, the patient reports a preceding history of focal onset seizures, or absence and myoclonic generalized epilepsies have been excluded. Narrow-spectrum agents, traditional sodium channel blockers (carbamazepine, oxcarbazepine, and phenytoin), as well as gabapentin and pregabalin may exacerbate generalized absence and myoclonic seizures and should be avoided in idiopathic (genetic) generalized epileptics [Table 1].
| Review of the Antiepileptic Drugs (AEDs)|| |
For this review, the broad-spectrum agents and the newer generation agents will be highlighted in the context of reproductive health, comorbid conditions, drug–drug interactions, age, and psychiatric history [Table 2].
Broad spectrum AEDs
Valproate is effective against all focal and generalized seizures, including generalized absence and myoclonic seizures. Valproate should be avoided in women with epilepsy of childbearing age and who are pregnant due to the risk of teratogenicity and negative cognitive effects to the baby. For those women who require valproate to remain seizure free, minimizing the dosage to no more than 500–600 mg/day and/or supplementing with a second AED may help offset the risk of major congenital malformations (MCMs)., In the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, Meador et al. evaluated 224 children at 6 years follow-up and found lower IQ scores for those exposed to valproate compared with carbamazepine, lamotrigine, or phenytoin., The other potential adverse effects of valproate include thrombocytopenia and hyperammonemia, the latter most notably seen in patients treated with polytherapy (particularly topiramate or zonisamide). Tremor and weight gain may be intolerable side effects to the patient. In the elderly and chronic psychiatric patients on antipsychotic medication, Parkinsonism More Details and gait disorder is observed with chronic use, and symptoms may improve with discontinuation of valproate. In the pediatric population, platelet dysfunction and increased bleeding risk postop, idiosyncratic hepatotoxicity, and pancreatitis are noted. With regards to drug–drug interactions, valproate will compete with phenytoin for protein binding and has a higher free fraction when the medications are co-administered. Valproate is also a potent inhibitor of the P450 enzyme system and reduces the clearance of phenobarbital, lamotrigine, rufinamide, and carbamazepine epoxide. Caution should be taken when adding valproate to lamotrigine or vice versa to avoid a rapid rise in lamotrigine levels, increasing the risk of Stevens-Johnson syndrome More Details (SJS) and toxic epidermal necrolysis.
A broad-spectrum AED alternative for childbearing age women is lamotrigine. It is useful for prevention of focal seizures, generalized tonic-clonic seizures, and absence seizures. It may be effective against myoclonic seizures in some patients; however, in others may worsen myoclonus. Data from pregnancy registries have shown a dose-dependent and low risk of fetal malformation. While compatible with oral contraception, there may be an increased clearance of lamotrigine. The common side effects include blurred or double vision, dizziness, unsteadiness, and headache or worsened migraines. Rare but serious idiosyncratic adverse reactions include SJS, toxic epidermal necrolysis, or hypersensitivity syndrome. To help avoid such serious reactions, lamotrigine is initially uptitrated slowly at low doses and even slower with concurrent use of VPA. In April 2018, the Food and Drug Administration (FDA) posted a new safety alert regarding lamotrigine causing a rare but serious immune system reaction called hemophagocytic lymphohistiocytosis (HLH). Signs and symptoms of HLH include persistent fever, usually >101°F, rash, cytopenias, enlarged spleen, elevated triglyceride, low fibrinogen level, and high blood ferritin. HLH may be difficult to distinguish from other serious immune-related adverse reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). To improve outcome and prevent mortality of this condition, prompt identification and discontinuation of lamotrigine are essential.
Levetiracetam and brivaracetam
Levetiracetam is a broad-spectrum agent that is metabolized by the kidney, and which has a low risk of MCM in pregnancy, as well as fewer drug–drug interactions, which make it compatible with oral contraceptive medication, chemotherapeutic agents, antiretroviral therapy, and anticoagulation. Irritability, somnolence, depression, and anxiety are potential adverse effects. Mood worsening may not be apparent early on. In the setting of kidney dysfunction, levetiracetam should be renally dosed. A new related therapy is brivaracetam (Briviact), a novel high-affinity synaptic vesicle protein 2A (SV2A) ligand. Like levetiracetam but with a >30-fold higher affinity for SV2A in the brain, brivaracetam could potentially exhibit increased anticonvulsant potency. Brivaracetam comes in IV and oral formulations, and is well-tolerated when initiated at a goal dose ranging from 20 to 100 mg/day divided into two doses. Gradual dose escalation is not needed. Unlike levetiracetam, brivaracetam is metabolized by the liver and is thus susceptible to drug–drug interactions via the P450 system. For instance, brivaracetam may increase exposure to the active carbamazepine-epoxide when co-administered with carbamazepine and increase plasma concentrations of phenytoin when co-administered with phenytoin. Side effects include irritability, fatigue, somnolence, and dizziness. Additional studies will need to clarify whether brivaracetam is as effective for non-levetiracetam-naïve individuals, and to evaluate its long-term side effects.
Clobazam became available in the US in 2011 and is the only 1,5-benzodiazepine acting on the gamma-aminobutyric acid-A (GABA-A) receptor. Outside the US, the drug has been used for the treatment of anxiety and epilepsy since the 1970s. The liver metabolizes clobazam to an active metabolite N-desmethylclobazam with a long half-life (71–82 h, compared with 36–42 h for clobazam). No clinically meaningful drug–drug interactions between clobazam and drugs metabolized by CYP3A4, CYP2C19, CYP1A2, or CYP2C9 have been found, but concomitant use of drugs metabolized by CYP2D6 may require dosage adjustment. Refer to the below-mentioned clobazam's reaction with cannabinoids. Withdrawal seizures may occur with abrupt discontinuation, and there is a risk of tolerance to the therapeutic effect, but this is less likely compared with traditional 1,4-benzodiazepines such as clonazepam. Side effects include drowsiness, unsteadiness, and rarely SJS. It is mainly used adjunctively and is considered a broad-spectrum AED.
Zonisamide is structurally related to sulfonamides and acts as a broad-spectrum AED by blocking T-type calcium channels, sodium channels, and carbonic anhydrase activity. Like topiramate, it may cause cognitive slowing, the development of kidney stones, and low birth weight; however, children of pregnant women treated with zonisamide exhibit lower rates of MCMs such as oral clefts. Common side effects include weight loss and worsening depression, while rare side effects can include the development of serious rash such as SJS, oligohydrosis, hyperthermia, and metabolic acidosis, with the last three being more common in the pediatric population. The long half-life of zonisamide (60 h), with once-daily dosing, may help prevent breakthrough seizures in patients who may miss their doses. No clinically significant interaction with oral contraceptives has been shown.
Topiramate and perampanel are effective in preventing generalized tonic-clonic seizures, but either is ineffective or have unknown efficacy for generalized absence and generalized myoclonic seizures. The latter two seizure types often co-occur with generalized tonic-clonic seizures, and so these medications should be used with caution and likely avoided as an initial treatment option. Topiramate is a sulfa-containing drug, which can be an effective monotherapy for focal seizures and generalized tonic-clonic seizures. In addition to inhibiting carbonic anhydrase activity, which can cause side effects of kidney stones and metabolic acidosis, its mechanisms of action include antagonism of amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA)/kainate receptors, augmentation of GABA activity, blocking of voltage-gated sodium channels, and increased potassium conductance. Topiramate has been used in several other contexts, as it is FDA-approved for a weight loss preparation in combination with phentermine and has been used off-label for mood stabilization. Topiramate can be effective at lower doses (≤100 mg daily) for migraine control, but therapeutic doses for seizure prevention are closer to 200–400 mg/day. Pregnancy on the lower doses leads to a risk ratio of 1.64 for the congenital malformation of oral cleft, compared with 5.16 on the higher doses used in people with epilepsy. It is a mild inducer of CYP3A4 and is therefore incompatible with oral contraceptive medication. Cognitive slowing, kidney stones, rare vision changes including acute myopia and secondary angle-closure glaucoma may limit its use. Common side effects of paresthesias in the distal extremities may be dose-dependent and resolve after a few weeks.
Perampanel (Fycompa) is a noncompetitive AMPA receptor antagonist, and can be used as adjunctive treatment of focal onset seizures with or without secondarily generalized seizure, and of primary generalized tonic-clonic seizures in idiopathic generalized epilepsy at daily doses of 4–12 mg. Common side effects include dizziness and somnolence, while hostility and aggression may be more unusual adverse reactions. In the perampanel phase III randomized, double-blind studies, falls were found to be a potential and dose-dependent risk associated with treatment.,
Among narrow-spectrum AEDs to treat focal epilepsy, carbamazepine is an effective and affordable traditional sodium channel blocker. Carbamazepine is a potent inducer of enzymes in the P450 system and induces its own metabolism, resulting in increased clearance over the first 4 weeks of administration. The liver metabolizes carbamazepine to an active metabolite carbamazepine-10,11-epoxide, and this epoxide may be elevated and be a source of side effects, despite the total carbamazepine level being in the therapeutic range. The epoxide may also be susceptible to excessive accumulation when co-administered with inhibitors of the P450 system (e.g. valproate, select calcium channel blockers diltiazem, and verapamil). Testing for the HLA-B1502 allele in individuals of Asian descent is recommended before initiation of carbamazepine due to the increased risk of SJS and toxic epidermal necrolysis in these individuals compared with the general population. When either total or epoxide levels are supratherapeutic, individuals may have symptoms of cerebellar toxicity (e.g. ataxia, diplopia). The other potential side effects include hyponatremia and leukopenia, while aplastic anemia, DRESS syndrome, and lupus-like syndrome are potential but rare adverse events. Chronic use can result in lowering of bone. Carbamazepine now comes in an IV formulation which can be infused over 30 min every 6 h for bioequivalence to oral carbamazepine and has been found to serve as a safe and tolerable bridge therapy. Intravenous carbamazepine was reported to have no clinically significant cardiac rhythm changes since no instances of QTcF value exceeded 500 ms, but transient elevations in serum complete blood count, triglycerides, alanine aminotransferase have been observed in rare individuals undergoing IV carbamazepine treatment.
Oxcarbazepine and eslicarbazepine
In contrast to carbamazepine, oxcarbazepine – a structural analog of carbamazepine and considered a new generation sodium channel blocker – causes less P450 enzyme induction, and may be better tolerated. Licarbazepine is an active metabolite that is responsible for the antiseizure activity. Although oxcarbazepine does not exhibit a clinically significant interaction with warfarin, it still lowers the efficacy of oral contraceptive medications. Risk of hyponatremia may be slightly higher compared with carbamazepine. For childbearing women, oxcarbazepine monotherapy exposure may have decreased risk for fetal malformation comparable to low-dose lamotrigine (≤325 mg/day), and in contrast to high-dose carbamazepine. More recently, a third-generation oral sodium channel blocker and relative of carbamazepine and oxcarbazepine, eslicarbazepine acetate (Aptiom) became available with active metabolite S-licarbazepine, the active enantiomer of the monohydroxy derivative of oxcarbazepine. Eslicarbazepine may also enhance slow inactivation of the voltage-gated sodium channels. With a relatively long half-life, it is administered and tolerated as a once-daily dose. Like oxcarbazepine, it is a weak inducer and has similar risks of hyponatremia. It should not be co-administered with oxcarbazepine because of this risk. DRESS syndrome is a rare but potential adverse reaction.
While less often started as first-line therapy in the outpatient setting, phenytoin, a traditional sodium channel blocker, is used in emergent and inpatient settings, and is effective for prevention of focal seizures and generalized tonic-clonic seizures. Phenytoin is a strong inducer of the P450 enzyme system, making it incompatible with oral contraceptives as well as other medications whose efficacy may be lowered when co-administered. Several commonly used medications can also inhibit phenytoin's metabolism and thereby lead to a risk of toxicity, including allopurinol, amiodarone, cimetidine, fluconazole, metronidazole, paroxetine, verapamil, and trazodone. Calcium, antacids, and tube feeding during administration may decrease bioavailability. Because phenytoin is highly protein-bound and other medications (e.g. valproate) may compete for protein binding and cause an increase in free phenytoin, it is recommended that free phenytoin levels be checked in addition to total levels when determining whether a patient has achieved therapeutic levels. At therapeutic dosages, phenytoin follows nonlinear kinetics due to a saturable metabolism, after which further uptitration should be done cautiously with lower dose increments. Supratherapeutic levels may lead to an increase in seizure activity and cerebellar toxicity. It is available in oral and IV formulations. Fosphenytoin, a phenytoin prodrug that is available for IV and IM administration, is often used in pediatric patients, the elderly, or patients with significant cardiac disease. Complications of IV phenytoin administration include local complications such as phlebitis or purple hand syndrome and more systemic reactions including bradycardia/arrhythmia and hypotension. IV fosphenytoin has a lower risk of local injury and may be infused more rapidly. IM fosphenytoin is absorbed and tolerated well.
Lacosamide (Vimpat) similar to eslicarbazepine enhances slow inactivation of sodium channels. It can be used as monotherapy or adjunctive therapy for focal seizures. It is available in oral and IV formulations and has been used in the treatment of refractory status epilepticus. When combined with other sodium channel blockers, side effects of dizziness and ataxia may be accentuated. Prolongation of PR interval can be a dose-dependent effect, and for patients with atrial arrhythmia or significant cardiac disease, EKG should be monitored, and alternative therapies considered.
Active research and clinical trials have been focused on evaluating CBD use in Dravet syndrome and for drop seizures in Lennox-Gastaut syndrome (LGS), two specific pediatric-onset epilepsy syndromes. More recent studies are also looking at broader efficacy for the general population of refractory epileptics. With the advent of state-approved use of medical marijuana for children and adults with epilepsy, more refractory epileptics and their families are exploring the use of CBD and its effect on their seizure control. We will briefly review what is known about the compound in marijuana and possible precautions that should be observed when co-administered with antiseizure drugs. Among the hundreds of phytocannabinoids in cannabis, CBD has had documented anticonvulsant effects in multiple preclinical animal models. Open-label experiences with CBD support efficacy for other refractory epilepsy conditions, including Tuberous Sclerosis, Febrile infection-related epilepsy syndrome (FIRES), and focal epilepsy., Potential drug–drug interaction with AEDs include an increase in levels of zonisamide, eslicarbazepine, topiramate, rufinamide, and the active clobazam metabolite N-desmethylclobazam. The interaction with clobazam may lead to increased sedation which could be a result of CBD's potent inhibition of CYP2C19 which metabolizes N-desmethylclobazam. A preemptive decrease in clobazam dosage may be required in anticipation of decreased metabolism of N-desmethylclobazam following addition of CBD. Finally, a significant increase in AST/ALT levels had been observed in patients treated with a combination of CBD and VPA.
| Summary|| |
In summary, once indication for treatment is established based upon likelihood and risk of further seizures, individual assessment by the clinician and ongoing collaboration with the patient is essential to finding the most effective and best-tolerated treatment regimen which may evolve throughout the natural history of their disease and various stages of life. Referral to an epilepsy center for additional evaluation and treatment is indicated if the patient fails two medication trials or if seizures are severe or frequent [Figure 1].
|Figure 1: Approach to treatment of new onset epilepsy. Antiepileptic drug (AED), Oral contraceptive pills (OCPs), Electroencephalogram (EEG)|
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[Table 1], [Table 2]