1. James Thomas Houston, MD
Management of Epilepsy Following Initial Diagnosis: Current Best Practices
James Thomas Houston, MD
University of Alabama at Birmingham, Birmingham, Alabama
A REPORT FROM THE 69th ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY
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2. Confirmation of Epilepsy
Confirmation of epilepsy is the most important step to take before prescribing any antiepileptic drug (AED); an accurate diagnosis of epilepsy can be achieved using any of the following criteria:
One unprovoked seizure and a high probability of more seizures occurring over the following 10 years, as evidenced by the finding of structural abnormalities on magnetic resonance imaging;
Two unprovoked seizures occurring  24 hours apart; or
Diagnosis of an epilepsy syndrome.
Fisher RS et al. Epilepsia. 2014;55:475
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3. Timing of Treatment Initiation
Timing of treatment initiation, while essential to prevent seizure recurrence in high-risk patients, does not reduce the long-term probability of seizure freedom.
Results of the FIRST trial showed that delaying treatment until occurrence of a second seizure did not lower the probability of seizure freedom 1–4 years later.
Given these data, monitoring of low-risk patients for development of epilepsy without starting treatment may prevent possible adverse reactions from unnecessary therapy.
Musicco M et al; First Seizure Trial Group (FIRST Group). Neurology. 1997;49:991
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4. Selection of an Appropriate AED
Appropriate treatment of newly diagnosed epilepsy is a key component of long-term seizure outcomes.
Approximately 50% of patients achieve seizure freedom using the first AED prescribed:
Kwan P, Brodie MH. N Engl J Med. 2000;342:314
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5. Selection of an Appropriate AED continued
Individualizing both drug choice and dosing schemes helps provide maximal patient benefit and limits development of disabling side effects.
Selection of an appropriate initial AED involves consideration of its:
Spectrum of efficacy
Mechanism of action
Side-effect profile
Ease of administration
Cost
Potential drug interactions
Potential impact on existing comorbidities
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6. Selection of an Appropriate AED continued
There is considerable overlap in the efficacy spectrum of many currently approved AEDs:
Perucca E. Epilepsia. 2005:46(Suppl 4):31
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7. Selection of an Appropriate AED continued
Generally, most AEDs designed and approved for focal epilepsies provide additional protection against generalized tonic-clonic seizures, but their use may exacerbate absence and myoclonic seizures.
Among AEDs approved for initial treatment of focal epilepsies, similar efficacy profiles have been found among carbamazepine, phenytoin, oxcarbazepine, lamotrigine, levetiracetam, and zonisamide.
Lamotrigine, while effective in treating multiple types of epilepsy, may worsen seizures in infants with severe myoclonic epilepsy.
Perucca E. Epilepsia. 2005:46(Suppl 4):31
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8. Selection of an Appropriate AED continued
For treating new-onset focal epilepsy, newer generation AEDs generally have not been shown to be more effective than older AEDs, such as carbamazepine, valproate, or phenytoin.
Gabapentin and vigabatrin have been shown to be the least effective of the drugs evaluated in this situation.
Phenobarbital and primidone are effective against most seizure types, but they are ineffective for treating absence seizures and are less effective than carbamazepine, phenytoin, or valproic acid for treating local epilepsies.
Marson AG et al. Lancet. 2007:369:1000; Marson AG et al. Lancet. 2007;369:1016; Mattson RH et al. N Engl J Med. 1985;313:145–151.
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9. Selection of an Appropriate AED continued
Valproate is the most effective AED for treatment of idiopathic generalized epilepsy, juvenile myoclonic epilepsy, and unclassified epilepsy, even when compared with lamotrigine and topiramate.
Whereas valproate and ethosuximide therapy have similar success rates in treating childhood absence seizures, ethosuximide remains the preferred treatment.
Valproate has more potential for causing adverse effects, and ethosuximide has a greater potential to modify the properties of epilepsy.
Glauser T et al. Epilepsia. 2013;54:551
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10. Other Considerstions in Selecting an AED
Genotype, previous adverse drug reactions, age, gender, comorbidities, and concomitantly administered medications all are potential risk factors for adverse reactions.
For example, aromatic AEDs should be used cautiously in patients with a history of significant drug hypersensitivities.
AEDs with a higher occurrence of cognitive side effects should be avoided or used sparingly in patients of advanced age, and school-aged children and adolescents should be followed closely.
Glauser T et al. Epilepsia. 2013;54:551
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11. Use of AEDs During Pregnancy
Valproate is associated with the highest rate of major malformations (9.3%), followed by phenobarbital (5.5%) and topiramate (4.2%), during pregnancy.
Taking clonazepam, carbamazepine, or phenytoin during pregnancy result in a similar risk (3%).
Treatment with levetiracetam, lamotrigine, oxcarbazepine, gabapentin, or zonisamide during pregnancy is associated with the smallest risk, ranging from 2.4% to as little as 0%.
The risk of malformations in pregnant women taking carbamazepine, lamotrigine, phenobarbital, or valproate rises significantly with increasing doses.
Hernández-Díaz S et al. Neurology. 2012;78:1692; Tomson T et al. Lancet Neurol. 2011;10:609
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12. Use of AEDs During Pregnancy continued
Major malformation rates associated with treatment with AEDs during pregnancy:
Hernández-Díaz S et al. Neurology. 2012;78:1692
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13. Therapeutic Titration
After an appropriate AED has been selected, determining the initial target dose and titration schedule are essential to maximize early seizure control and minimize the risk of dose-related adverse effects.
Moderate doses of carbamazepine (400–600 mg/d), valproate (600–1,000 mg/d), and lamotrigine (125–200 mg/d) are the most effective in achieving seizure freedom.
Low-dose therapy provides minimal efficacy, whereas high-dose therapy results in decreasing efficacy with successive upward dose titrations.
Kwan P, Brodie MJ. Epilepsia. 2001;42:1255
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14. Therapeutic Titration continued
In a study comparing levetiracetam and carbamazepine monotherapy, 89% of patients taking carbamazepine were seizure free for 1 year only on 400 mg/d of the drug.
Similarly, of those patients achieving 1-year seizure freedom on levetiracetam, 86% did so on only by taking 1,000 mg/d.
Although a small percentage of patients will achieve an improvement in seizure control on doses above the recommended therapeutic range, low-dose titration should be the goal when starting AED therapy.
Brodie MJ et al. Neurology. 2007;68:402
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15. Drug-Resistant Epilepsy
Drug-resistant epilepsy, or pharmacoresistant epilepsy, can be defined as the failure of an adequate clinical trial of two or more AEDs that were tolerated and appropriately chosen and used.
Approximately 36% of newly diagnosed epilepsy patients become pharmacoresistant.
Of patients with epilepsy who meet these criteria, < 20% can be expected to become seizure-free with additional medications, and a significant number relapse after 1 year of seizure freedom.
Kwan P, Brodie MJ. Epilepsia. 2001;42:1255; Kwan P et al. Epilepsia. 2010;51:1069
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16. Pseudoresistance
Pseudoresistance may result from misdiagnosis, an inappropriate drug choice, inadequate dosing, a multitude of lifestyle issues, and other factors.
Subtherapeutic dosing is one of the most significant and easily preventable causes of pseudoresistance.
Studies of initial monotherapy with carbamazepine, lamotrigine, valproate, and levetiracetam have shown that the majority of patients (~ 80%) who achieved seizure freedom did so on the defined daily dose (DDD) or less, whereas other patients became seizure-free on increasingly larger doses.
Kwan P, Brodie MJ. Epilepsia. 2001;42:1255; Kwan P et al. Epilepsia. 2010;51:1069
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17. Pseudoresistance continued
Unfortunately, in clinical practice, a second agent often is added to an uncontrolled patient’s regimen before a dose escalation above the DDD is attempted.
Subsequent failure of this second agent may lead to an incorrect diagnosis of drug-resistant epilepsy and unnecessary evaluation of additional therapies.
Therefore, unless dose escalation above the DDD is contraindicated due to intolerability, it should be considered for all newly diagnosed patients with drug-resistant epilepsy, especially those who continue to have seizures on lower doses of the initial AED tried.
Kwan P, Brodie MJ. Epilepsia. 2001;42:1255; Kwan P et al. Epilepsia. 2010;51:1069
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18. Pseudoresistance continued
Poor patient compliance and drug/alcohol abuse are among the most important modifiable lifestyle factors contributing to pseudoresistance.
Patients who are highly suspected of noncompliance or substance abuse may need to be evaluated for untreated psychiatric illness, closer monitoring of AED blood levels, and determination of adequate financial support.
Failure to recognize these contributing factors may lead to inappropriate treatment decisions and poor long-term seizure outcomes.
Kwan P, Brodie MJ. Epilepsia. 2001;42:1255; Kwan P et al. Epilepsia. 2010;51:1069
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19. Pseudoresistance continued
If the failure of using two AEDs is confirmed with any degree of confidence, diagnosis of true drug-resistant epilepsy also requires a complete diagnostic review and reevaluation of seizure type/localization before adding another drug is considered.
Misdiagnosis of psychogenic nonepileptic seizures, failure to recognize cardiac disorders, or incorrect classification of underlying seizure types can lead to inappropriate AED selection and increased seizure frequency.
Referral to a tertiary epilepsy center may be needed for proper secondary evaluation.
Kwan P, Brodie MJ. Epilepsia. 2001;42:1255; Kwan P et al. Epilepsia. 2010;51:1069
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20. Rational Polypharmacy
Current evidence favors the use of “rational” polypharmacy—including combinations of both newer- and older-generation drugs—for patients with true drug-resistant epilepsy or those who have experienced treatment failure after taking adequate doses of multiple single-agent therapies.
For such patients, a combination of AEDs whose therapeutic effects are additive and adverse effects are limited when used together is most effective.
In addition, patient quality of life (QOL) and underlying condition should show improvement overall to justify polytherapy.
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21. Rational Polypharmacy continued
Polytherapies based on mechanisms of action may enhance antiseizure effects.
Certain combinations appear to offer increased effectiveness, whereas others may have limited synergistic effects; for example, combing two sodium-channel blockers with a g-aminobutyric acid (GABA) inhibitor may be more beneficial than combining two different sodium-channel agents.
Some laboratory studies have suggested that the most successful drug combinations involve the use of a single-mechanism drug and an agent possessing multiple mechanisms of action.
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22. Partial + Generalized Epilepsy
Adding lamotrigine to valproate in patients with both partial and idiopathic generalized epilepsy (IGE) produced a significantly higher response rate (64%) than that produced by adding lamotrigine to either phenobarbital or carbamazepine (41%) or to phenytoin (38%).
When lamotrigine was substituted as monotherapy for responders, IGE patients had a higher responder rate than did patients with partial-onset epilepsy.
Long-term follow-up studies revealed that coadministration of lamotrigine and valproate was superior in efficacy to use of either drug alone.
Brodie MJ, Yuen AW. Epilepsy Res. 1997;26:423
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23. Partial + Generalized Epilepsy continued
In a retrospective review of both partial and primary generalized epilepsy, ~ 80% of patients were controlled on two AEDs, with a combination of valproate and lamotrigine being the most effective.
A significant percentage of the remaining patients were controlled on three AEDs, with the most successful combinations being valprate and lamotrigine plus either topiramate or levetiracetam.
Stephen LJ et al. Epilepsia. 2001;42:357
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24. Severe Myoclonic Epilepsy of Infancy
Combining valproic acid with clobazam has been shown to be effective in treating patients with SMEI, whereas combing vigabatrin, lamotrigine, and carbamazepine could potentially worsen seizures.
Adding the investigational agent stiripentol to valproate and clobazam provided a significant synergistic effect and increased responder rate in SMEI patients.
Adding topiramate to either valproate or valproate plus clobazam and stiripentol may reduce the frequency of generalized tonic-clonic seizures and the risk of status epilepticus.
Chiron C et al. Lancet. 2000;356:1638
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25. Lennox-Gastaut Syndrome (LGS)
Lamotrigine and felbamate (and, to a lesser extent, topiramate) may be beneficial adjunctive therapies, especially when treating atonic seizures in LGS.
Lamotrigine and felbamate are more effective than topiramate in decreasing generalized tonic-clonic seizures in patients with LGS.
Adding rufinamide to AED regimens that do not contain carbamazepine may reduce the frequency of all types of seizures in LGS.
A ketogenic or other diet combined with vagal-nerve stimulation may have additional benefit.
Brodie MJ et al. Epilepsia. 2009;50:1899
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26. Other Beneficial Combination Therapies
Adding valproate to ethosuximide may be synergistic in treating childhood absence seizures.
The addition of either vigabatrin or valproate to carbamazepine may provide a greater reduction in seizure frequency in patients with partial epilepsies.
Coadministration of vigabatrin with tiagabine may have synergistic effects in treating partial seizures.
Valproate plus levetiracetam is an effective choice for reducing the frequency of myoclonic seizures.
Combining lamotrigine with topiramate or valproate may be useful in treating juvenile myoclonic epilepsy.
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27. Dietary Modification
The ketogenic diet, but not the Atkins diet, typically requires hospital admission, a period of fasting, intensive education, and involvement of a dietician.
Food sharing and the option to eat some restaurant foods and low-carbohydrate store-bought products are allowed under the modified Atkins diet, but they are not approved for the ketogenic diet.
Both diets have shown similar efficacy in reducing seizure frequency by up to 50% in about half of the patients who have tried them.
Side effects include constipation and lipid elevation.
Kossoff EH et al. Epilepsy Behav. 2013;29:437
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28. Dietary Modification continued
Differences between the ketogenic diet and the modified Atkins regimen:
Kossoff EH et al. Epilepsy Behav. 2013;29:437
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29. Vagal-Nerve Stimulation
Vagal-nerve stimulation is approved by the FDA for treatment of refractory partial seizures in patients over 12 years of age.
This open-loop feedback system may be used with magnetic stimulation for on-demand applications.
Stimulation frequency and duration are adjusted independently for each patient, and changes in settings require a qualified practitioner’s involvement.
Potential side effects include cough and hoarseness, which typically occur as the output current is increased.
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30. Vagal-Nerve Stimulation continued
Newer modifications provide automated stimulation based upon changes in heart rate (20%–70%) that accompany ictal activity.
Lowering the threshold for stimulation increases the sensitivity for recognizing ictal activity but also causes a rise in false-positive findings and unwanted stimulations that may negatively affect patient compliance and QOL.
Vagal-nerve autostimulation offers feasibility and safety comparable to those of the normal device, but its likelihood to improve clinical outcomes has not yet been determined.
VNS Therapy Programming Software, Model 250 Physician’s Manual. Houston, Tex: Cyberonics, Inc; 2015
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31. Responsive Neurostimulation
Responsive neurostimulation is FDA approved for refractory partial seizures in adults with epilepsy; it typically is used in patients with drug-resistant partial seizures who are not good surgical candidates and who have one or two identified seizure foci.
Responsive neurostimulation was studied in 191 patients who were randomized to a sham- or active-treatment group; the sham-treatment group began responsive neurostimulation 5 months after surgery.
Both groups had an initial 1-month-long period of improved seizure control without the device providing neurofeedback stimulation.
Morrell MJ; RNS System in Epilepsy Study Group. Neurology. 2011;77:1295
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32. Responsive Neurostimulation continued
Once the device was turned on, the active-treatment group experienced a steady, significant reduction in seizure frequency when compared with the sham-treatment group.
Morrell MJ; RNS System in Epilepsy Study Group. Neurology. 2011;77:1295
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33. Responsive Neurostimulation continued
Long-term follow-up over several years has shown possible continued improvement in seizure frequency and responder rates over time, suggesting that responsive neurostimulation actually may modify epilepsy.
Responsive neurostimulation holds great promise as an additional treatment option for drug-refractory patients with partial seizures.
Potential side effects are similar to other deep-brain stimulation procedures (eg, for Parkinson’s disease) and include implant-site infection and rare intracranial hemorrhage.
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34. Deep-Brain Stimulation
Deep-brain stimulation focuses on the anterior nucleus of the thalamus; it has been approved in Europe and Canada for treatment of refractory partial seizures in adults but not yet in the U.S.
Thalamic stimulation is similar in effectiveness and safety to responsive neurostimulation at 1 year.
Long-term follow-up studies of both deep-brain stimulation and responsive neurostimulation have shown a significantly greater improvement in seizure frequency and higher responder rates at 5 years than at 1 year, suggesting that both techniques may cause disease modification.
Salnova V et al. Neurology. 2015;84:1017
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35. Deep-Brain Stimulation continued
A review of seizure outcomes in patients undergoing deep-brain stimulation showed fewer seizures after battery depletion than were observed preimplantation, suggesting again that long-term thalamic stimulation may cause disease modification:
Kukiert A et al. Neuromodulation. 2015;18:439
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36. Disease Modification
Earlier initiation of antiepileptic therapy in patients with epileptic encephalopathies may be associated with improved cognitive outcomes independent of the specific treatment chosen.
Results of studies involving mouse models of epileptic encephalopathies have shown that early treatment may suppress the development of spike/wave epilepsy and further cognitive dysfunction.
Patients with severe traumatic brain injuries have a greater risk of developing seizures than do those with mild or moderate injuries—but this increased risk remains only about 15% at 30 years.
Pellock JM et al. Epilepsia. 2010;51:2175; Blumenfeld H et al. Epilepsia. 2008;49:400
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