Neurology India
Open access journal indexed with Index Medicus
  Users online: 2072  
 Home | Login 
  About Current Issue Archive Ahead of print Search Instructions Online Submission Subscribe Etcetera Contact  
  Navigate Here 
 Search
 
  
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (535 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

 
  In this Article
 »  Abstract
 » Conclusions
 »  References
 »  Article Tables

 Article Access Statistics
    Viewed314    
    Printed11    
    Emailed0    
    PDF Downloaded32    
    Comments [Add]    

Recommend this journal

 


 
Table of Contents    
NI FEATURE: CENTS (CONCEPTS, ERGONOMICS, NUANCES, THERBLIGS, SHORTCOMINGS) - COMMENTARY
Year : 2017  |  Volume : 65  |  Issue : 7  |  Page : 78-82

New-onset focal epilepsy in adults: Antiepileptic drug treatment


Department of Neurology, Care Hospital, Banjara Hills, Hyderabad, Telangana, India

Date of Web Publication8-Mar-2017

Correspondence Address:
J M K Murthy
Department of Neurology, Care Hospital, Banjara Hills, Hyderabad, Telangana
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/neuroindia.NI_69_17

Rights and Permissions

 » Abstract 

Focal epilepsy, non-syndromic, is by far the most prevalent epilepsy in adults. Antiepileptic drug (AED) prescription in patients with new-onset focal epilepsy is often challenging. The factors that determine AED of choice depends both on the patient-specific and AED-specific variables. Monotherapy should the initial strategy. Failure to monotherapy can be due to lack of efficacy, severe adverse events, or a hypersensitivity reaction. In such patients, the next strategy should be alternate monotherapy trials. In patients who fail up to three monotherapy trials, duotherapy with drugs having different primary mechanisms of action should be the next step. Multiple duotherapy should be tried before considering adding polytherapy. In spite of such pragmatic strategies, about 25% of patients may never become seizure free for any complete year throughout follow-up. Patients in this group should be evaluated for non-pharmacological treatment options, particularly epilepsy surgery.


Keywords: Antiepileptic drugs, duotherapy, focal epilepsy, monotherapy, rational polytherapy
Key Messages: The sequential therapeutic strategy in managing new-onset, non-syndromic focal epilepsy is discussed. In case of failure to monotherapy, three monotherapy trials, then duotherapy with drugs with differing mechanisms of action, then multiple duotherapy, and finally polytherapy, may be successively tried. Epilepsy surgery may be a treatment option when focal seizures are also resistant to polytherapy.


How to cite this article:
Murthy J M. New-onset focal epilepsy in adults: Antiepileptic drug treatment. Neurol India 2017;65, Suppl S1:78-82

How to cite this URL:
Murthy J M. New-onset focal epilepsy in adults: Antiepileptic drug treatment. Neurol India [serial online] 2017 [cited 2017 Apr 24];65, Suppl S1:78-82. Available from: http://www.neurologyindia.com/text.asp?2017/65/7/78/201674


Epilepsy is a common chronic brain disease, affecting about 60 million people worldwide with 34–76 per 100,000 new cases being added annually.[1] Circumstantial evidence, mostly from resource poor countries suggests that about two-thirds of newly diagnosed cases of epilepsy achieve remission with or without antiepileptic drug (AED) treatment and about a third persist to have seizures.[2] Epilepsy is a potentially treatable condition and with the currently available AEDs, about 70 – 80% of patients with newly diagnosed epilepsy will enter seizure remission while on drug treatment.[3],[4] About 60% of patients remain seizure free even after AEDs have been withdrawn.[5] Focal epilepsy is by far the most prevalent epilepsy in adults. Recent International League Against Epilepsy (ILAE) Commission on Classification and Terminology classifies the aetiology of epilepsies into genetic (electro-clinical syndromes), structural/metabolic, and unknown causes. Epilepsies due to the latter two aetiologies are considered under non-syndromic epilepsies.[6] This review discusses AED treatment of new-onset, non-syndromic (structural/metabolic and unknown cause) focal epilepsy in adults.[6]

AEDs: When to start

Based upon the new definition of epilepsy by the Task Force of ILAE, AED treatment should be started in patients with (1) at least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome.[7] Risk factors for enduring recurrence of seizures include: prior brain insult (Level A); an EEG with epileptiform abnormalities (Level A); significant brain-imaging abnormality (Level B); and the occurrence of a nocturnal seizure (Level B).[8] Other important considerations before the initiation of AED in patients with newly diagnosed epilepsy should be the type and natural course of epilepsy and epilepsy syndrome.

AEDs: What to start

The AED selected in an individual patient with new-onset focal epilepsy ideally should fully control the seizures, be well-tolerated with no long-term safety issues particularly teratogenicity, be easy to administer, have no drug interactions, have favourable pharmacokinetics, may not need serum monitoring, and have a low cost.[9] No single AED meets these criteria. The choice of AED depends on multiple factors [Table 1].[10],[11]
Table 1: Choice of antiepileptic drugs - factors

Click here to view


Since the 1980s, several new AEDs with different mechanism(s) of action and safety profile have been introduced, providing more choice for the individual patients with focal epilepsy.[9],[12] Most of the standard and newer AEDs have been shown to have efficacy in the presence of new-onset focal epilepsy in adults in randomized, comparative, long-term monotherapy trials [Table 2] and [Table 3].[13] However, most of these trials failed to identify major differences in seizure freedom rates among the drugs being compared.
Table 2: Antiepileptic drugs effective against focal seizures

Click here to view
Table 3: Antiepileptic drugs approved as monotherapy in focal seizures

Click here to view


The SANAD trial of AED monotherapy in adults with focal epilepsy showed similar efficacy of carbamazepine, lamotrigine, and oxcarbazepine, but a lower comparative efficacy of gabapentin and. topiramate.[14],[15] In an unblended randomized study, levetiracetam monotherapy was as effective as controlled-release carbamazepine for patients with focal epilepsy.[16] A randomized, double-blind trial comparing levetiracetam and controlled-release carbamazepine in adults with focal seizures, produced equivalent seizure freedom rates.[17] In the phase III randomized, double-blind, parallel-group, non-inferiority trial in adults with focal epilepsy, zonisamide was non-inferior to controlled-release carbamazepine.[18] Updated ILAE evidence review of antiepileptic efficacy and effectiveness as initial monotherapy showed Level A evidence for carbamazepine, phenytoin, levetiracetam, and zonisamide for focal seizures in adults.[13] All the trials discussed above show carbamazepine having similar efficacy as the newer AEDs for focal seizures.

Among the standard AEDs, valproate is less efficacious than carbamazepine in reducing the frequency of dyscognitive seizures (complex partial seizures).[19] The major concerns for phenytoin are its complicated pharmacokinetics and spectrum of adverse effects.[20] Phenobarbital has a broad spectrum of activity. A meta-analysis of randomized trials suggests that few differences exist between phenobarbital and other standard AEDs.[21] Phenobarbital has been shown to be less effective than carbamazepine or phenytoin for focal seizures in mostly newly diagnosed focal epilepsy.[19]

A meta-analysis of the newer AEDs – placebo controlled studies in focal epilepsy, using sustained freedom from seizures as the outcome measure, showed the overall weighted pooled-risk difference in favour of newer AEDs compared with placebo for seizure freedom as being only 6% (94% CI 4 – 6) and the number needed to treat in terms of freedom from seizure was sixteen.[22],[23]

The preferential use of standard AEDs is recommended as monotherapy in patients with new-onset epilepsy, particularly in resource poor countries, unless there are specific reasons for doing otherwise. Based on the available evidence, the initial monotherapy-of-choice in adult patients with new-onset focal epilepsy is carbamazepine among the standard AEDs, and levetiracetam among the newer AEDs. Other AEDs may be reasonable alternatives if carbamazepine or levetiracetam are unsuitable, not tolerated, or lack efficacy [Table 2] and [Table 3].[23],[24],[25],[26]

AEDs: How to initiate

The gold standard strategy of initial treatment of new-onset focal epilepsy is monotherapy. The advantages of monotherapy include: It permits evaluation of the efficacy and adverse effects of the selected AED; reduces the toxicity; eliminates the risk of pharmacological interaction between AEDs; improves drug adherence; and minimizes the costs.[12] The AED treatment is generally started with a low dose, which is then increased with time to the optimal dose. A gradual titration can improve central nervous system tolerability, reduce the risk of idiosyncratic adverse events, or both.[27] Most patients achieving seizure freedom on the first AED do so at a lower dose.[28]

Failure of initial monotherapy: Substitution versus add-on

In a clinic-based study, about 62% of patients with new-onset epilepsy achieved seizure remission on either initial or alternate monotherapy.[24] Failure to the first appropriate AED may be due to the lack of efficacy or the occurrence of adverse events, including an idiosyncratic reaction.[28],[29] Options in such patients are two: An alternate monotherapy (substitution) or a combination therapy (add-on).[30] However, the evidence for either of the options is lacking. The arguments for the alternate appropriate monotherapy include: It permits evaluation of the efficacy and adverse effects of the selected AED; reduces the toxicity associated with combination therapy; eliminates the risk of pharmacological interaction between AEDs; and, improves drug adherence.[12] The argument against add-on therapy in patients who fail to the first appropriate AED has been its propensity to cause greater toxicity without substantial improvement in outcome.[31]

The earlier randomized trials with a small sample size [32],[33] and the Italian prospective observational study [29] did not provide clear evidence for the strategy that should be preferred. The Italian study suggests that the preferred use of alternate monotherapy when the initial monotherapy fails, does not necessarily lead to a better outcome, in terms of seizure recurrence and adverse treatment effects. An open, cluster-randomized, prospective, controlled trial in patients with persistent focal seizures, despite treatment with one AED, compared efficacy of alternate monotherapy versus an early add-on treatment. The efficacy and incidence of adverse events were similar in both the groups.[34] In a prospective observational study of patients in whom the first AED was unsuccessful, there was no significant difference in seizure-free rates and the incidence of intolerable side effects between the substitution group and the add-on group.[35]

In the absence of a high level of evidence in favor of either alternative monotherapy or add-on therapy, one of the suggested options is to evaluate the combination therapy and then attempt to withdraw the first drug in the case of success (transitional combination therapy). Such an approach may prevent the substitution of a partially efficacious drug by a non-efficacious drug.[36] The data from the clinic-based study, of the 1,098 patients with newly diagnosed epilepsy, suggested that 543 (49.4%) patients were seizure-free with the first appropriate AED used as monotherapy; 136 (12.4%) patients were seizure-free with alternate monotherapy (second to seventh drug regime); and, after three monotherapy trials, the chance of seizure freedom was seen in less than 1% of patients.[24]

After failure of three sequential monotherapy trials, duotherapy may be an option. With the availability of modern non-enzyme inducing drugs, it has become easier to implement and maintain add-on treatment when it is a necessity.[20],[37] In the Western Infirmary, Glasgow clinic-based study, of the 70 patients with newly diagnosed epilepsy who remained seizure free on more than 1 drug, 67 (96%) patients were on duotherapy.[24] Testing of several duotherapy combinations sequentially before trying polytherapy has been suggested.[24],[38] In the Western Infirmary, Glasgow clinic data, of the 2379 seizure-free patients, 486 (20.4%) remained controlled on combination therapy for one or more years: 395 (81.1%) on duotherapy; 85 (17.5%) on three AEDs; and, 6 (1.2%) on four AEDs. Of the 486 seizure-free patients on polytherapy, 309 (63.6%) had focal epilepsy.[25]

Rational polytherapy

Add-on therapy can be a rational combination of AEDs. Conceptually “rational polytherapy” assumes that AED combinations with differing mechanisms of action are more effective than polytherapy with similar mechanisms of action.[39] The availability of non-enzyme inducing AEDs and AEDs with multiple and novel mechanisms of action allows clinicians to practice rational polytherapy. The ideal AED combination should possess additive, supra-additive, or synergistic effects in terms of efficacy with fewer non-serious adverse effects [Table 4].[40] A rational choice of drug combinations is currently based more on avoidance of pharmacodynamics or pharmacokinetic side effects than on evidence for supra-additive or synergic effects.[41] The proposed guidelines for combining AEDs by Brodie and Sills include: (1) Optimize the dose of baseline AED; (2) add AEDs with multiple mechanisms; (3) avoid combining AEDs with similar modes of action; (4) titrate the new AED slowly and carefully; (5) be prepared to reduce the dose of the original AED; (6) replace less effective drug if response is still poor; (6) try the range of different duotherapies; and, (7) add a third drug if there is still sub-optimal control.[38]
Table 4: Commonly used antiepileptic drugs in focal epilepsy: Mechanism(s) of action

Click here to view


The clinical evidence in support of rational polytherapy is very limited.[38],[39],[40],[41] Data from the observational studies suggest that combining two sodium channel blockers is less effective than combination of drugs with different primary mechanisms of action.[41] Combination of valproate and lamotrigine has the best clinical evidence of synergy.[42] Valproate increases the serum level of lamotrigine through metabolic inhibition.[43] Clinical trials studying the efficacy of lacosamide in patients with focal epilepsy suggest that the combination of lacosamide and levetiracetam has possible additive efficacy.[44],[45] Pooled analysis of three phase II/III clinical trials examining the clinical use of lacosamide in patients with focal epilepsy showed a high 50% responder rate in the subgroup treated with lacosamide and concomitant levetiracetam use.[44] Another clinical study conducted in patients with focal epilepsy showed the highest seizure freedom and 50% responder rate in the subgroup treated with lacosamide and levetiracetam compared to other AEDs.[45] In the Western Infirmary, Glasgow clinic-based data, of the 486 patients (63.6% with focal epilepsy) who remained controlled on combination therapy for one or more years, most were on AEDs with different mechanisms of action.[25] In the absence of evidence-based guidelines on how and when to combine AEDs, the current practice recommendations are largely empirical.[38]

Drug resistant epilepsy

Failure to achieve sustained seizure remission with two trials of adequately dosed AEDs should signal drug-resistant epilepsy.[30] The ILAE Task Force defines drug resistant epilepsy as failure of adequate trials of two tolerated, appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve a sustained seizure-freedom. Seizure freedom is defined as freedom from seizures for a minimum of three times the longest pre-intervention inter-seizure interval (determined from seizures occurring within the past 12 months) or 12 months, whichever is longer.[46] However, there is considerable heterogeneity in the long-term seizure patterns in people who do not enter long-term remission in the early years after diagnosis.[47] Several studies have shown that some of these patients achieve seizure-freedom after several years of continuous activity and after multiple trials of more than two AEDs.[48],[49],[50],[51] In an analysis of outcome of seizures over time in the study by Brodie et al.,[24] 25% of patients never become seizure-free for any complete year throughout follow-up. Non-pharmacological treatment options, particularly epilepsy surgery, should be explored in this group of patients with drug resistant focal epilepsy.


 » Conclusions Top


Focal epilepsy is by far the most prevalent epilepsy in adults. The aetiology of focal epilepsy include genetic, structural/metabolic, and unknown causes. The natural course of genetic focal epilepsy is predictable and most often these focal epilepsies respond to the appropriate monotherapy. AED prescription in patients with new-onset focal epilepsy is often challenging. Monotherapy should the initial strategy. Failure to monotherapy can be due to lack of efficacy, severe adverse events, or hypersensitivity reaction. In such patients, the next strategy should be alternate monotherapy trials. In patients who fail to three monotherapy trials, duotherapy with drugs having different primary mechanisms of action should be tried. Multiple duotherapy should be tried before considering adding a third or fourth drug. In spite such pragmatic strategies, about 25% of patients may never become seizure free for any complete year throughout follow-up. Patients in this group should be evaluated for non-pharmacological treatment options, particularly epilepsy surgery.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest

 
 » References Top

1.
Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence of epilepsy: A systematic review and meta-analysis. Neurology 2011;77:1005-12.  Back to cited text no. 1
    
2.
Kwan P, Sander JW. The natural history of epilepsy: An epidemiological view. J Neurol Neurosurg Psychiatry 2004;75:1376-81.  Back to cited text no. 2
    
3.
Cockerell OC, Johnson AL, Sander JW, Shorvon SD. Prognosis of epilepsy: A review and further analysis of the first nine years of the British National General Practice Study of Epilepsy, a prospective population-based study. Epilepsia 1997;38:31-46.  Back to cited text no. 3
    
4.
Sillanpää M, Schmidt D. Natural history of treated childhood-onset epilepsy: Prospective, long-term population-based study. Brain 2006;129:617-24.  Back to cited text no. 4
    
5.
Sillanpaa M, Schimidt D. Epilepsy: Long-term rates of childhood-onset epilepsy remission confirmed. Nat Rev Neurol 2015;11:130-1  Back to cited text no. 5
    
6.
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51:676-85.  Back to cited text no. 6
    
7.
Fisher RS, Acvedo C, Arzimangolou A, Bogacz A, Cross JH, Elger CE, et al. A practical clinical definition of epilepsy. Epilepsia 2014;55:475-82.  Back to cited text no. 7
    
8.
Krumholz A, Wiebe S, Gronseth GS, Gloss DS, Sanchez AM, Kabir AA, et al. Evidence-based guideline: Management of an unprovoked first seizure in adults (Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society). Epilepsy Currents 2015;15:144-52.  Back to cited text no. 8
    
9.
Schmidt D, Schachter SC. Drug treatment of epilepsy in adults. BMJ 2014;348:g2546  Back to cited text no. 9
    
10.
Glauser G, Ben Menachem E, Bourgeois B, Cnaan A, Chadwick D, Guerreiro C, et al. ILAE treatment guidelines: Evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006;47:1094-120  Back to cited text no. 10
    
11.
Moshe SL, Perucca E, Ryvlin P, Tomson T. Epilepsy: New advances. Lancet 2015;884-8.  Back to cited text no. 11
    
12.
Santulli L, Coppola A, Balestrini S, Striano S. The challenges of treating epilepsy with 25 antiepileptic drugs. Pharmacological Research 2016;107;211-9.  Back to cited text no. 12
    
13.
Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kälviäinen R, et al., and the ILAE Subcommission on AED Guidelines. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013;54:551-63.  Back to cited text no. 13
    
14.
Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: An unblinded randomised controlled trial. Lancet 2007;369:1000-15.  Back to cited text no. 14
    
15.
Bonnett L, Smith CT, Smith D, Williamson P, Chadwick D, Marson AG. Prognostic factors for time to treatment failure and time to 12 months of remission for patients with focal epilepsy: Post-hoc, subgroup analysis of data from the SANAD trial. Lancet Neurol 2012;11:331-40.  Back to cited text no. 15
    
16.
Trinka E, Manson AG, Van Paesschen W, Kälviäinen R, Marovac J, Duncan B, et al. KOMET: An uninhibited, randomized, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended sodium valproate as monotherapy with newly diagnosed epilepsy. J Neurol Neurosurg Psychiatry 2013;84:1138-47.  Back to cited text no. 16
    
17.
Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ, and the Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007;68:402-8.  Back to cited text no. 17
    
18.
Baulac M, Brodie MJ, Patten A, Segieth J, Giorgi L. Effcacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: A phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol 2012;11:579-88.  Back to cited text no. 18
    
19.
Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, et al. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313:145-51.  Back to cited text no. 19
    
20.
Schmidt D. Starting, choosing, changing, and discontinuing drug treatment for epilepsy patients. Neurol Clin 2016;34:363-81.  Back to cited text no. 20
    
21.
Kwan P, Brodie MJ. Phenobarbital for the treatment of epilepsy in the 21st century: A critical review. Epilepsia 2004;45:1141-9.  Back to cited text no. 21
    
22.
Beyenburg S, Stavem K, Schmidt D. Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: Systematic review and meta-analysis. Epilepsia 2010;51:7-26.  Back to cited text no. 22
    
23.
Brodie MJ, Kwan P. Newer drugs for focal epilepsy in adults. BMJ 2012;344:e345.  Back to cited text no. 23
    
24.
Brodie MJ, Barry SJE, Bamagous GA, Norrei JD, Kwan P. Pattern of treatment response in newly diagnosed epilepsy. Neurology 2012;78:1548-54.  Back to cited text no. 24
    
25.
Stephen LJ, Forsyth M, Kelly K, Brodie MJ. Antiepileptic drug combinations – Have newer agents altered clinical outcomes? Epilepsy Res 2012;98:194-8.  Back to cited text no. 25
    
26.
Brodie MJ, Kelly K, Stephen LJ. Prospective audits with newer antiepileptic drugs in focal epilepsy: Insights into population responses? Epilepsy Behav 2014;31:73-6.  Back to cited text no. 26
    
27.
Perucca E, Dulac O, Shorvon S, Tomson T. Harnessing the clinical potential of antiepileptic drug therapy: Dosage optimisation. CNS Drugs 2001;15:609-21.  Back to cited text no. 27
    
28.
Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia 2001;42:1255-60.  Back to cited text no. 28
    
29.
Millul A, Ludice A, Adami M, Porzio R, Mattana F, Beghi E. The THEOREM Study Group. Alternative monotherapy or add-on therapy in patients with epilepsy whose seizures do not respond to the first monotherapy: An Italian multicentre prospective observational study. Epilepsy Res 2013;28:494-500.  Back to cited text no. 29
    
30.
Kwan P, Brodie M J. Early identification of refractory epilepsy. N Engl J Med 2000;342:314-9  Back to cited text no. 30
    
31.
Schmidt D, Gram L. Monotherapy versus polytherapy in epilepsy. A reappraisal. CNS Drugs 1995;3:194-208.  Back to cited text no. 31
    
32.
Deckers CLP, Hekster YA, Keyser A, van Lier HJJ, Meinardi H, Renier WO. Monotherapy versus polytherapy for epilepsy: A multicenter double-blind randomized study. Epilepsia 2001;42:1387-94.  Back to cited text no. 32
    
33.
Beghi E, Gatti G, Tonini C, Ben-Menachem E, Chadwick DW, Nikanorova M, et al. Adjunctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: A multicentre, randomized, pragmatic controlled trial. Epilepsy Res 2003;57:1-13.  Back to cited text no. 33
    
34.
Semah F, Thomas P, Coulbaaut S, Derambure P. Early add-on treatment vs alternative monotherapy in patients with partial epilepsy. Epileptic Disord 2014;16:165-74.  Back to cited text no. 34
    
35.
Kwan P, Brodie MJ. Epilepsy after the first drug fails: Substitution or add-on? Seizure 2000;9:464-8.  Back to cited text no. 35
    
36.
Deckers CL, Genton P, Sills GJ, Schmidt D. Current limitations of antiepileptic drug therapy: A conference review. Epilepsy Res. 2003;53:1-17.  Back to cited text no. 36
    
37.
Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D. Enzyme induction with antiepileptic drugs: Cause for concern? Epilepsia 2013;54:11-27.  Back to cited text no. 37
    
38.
Brodie MJ, Sills GJ. Combining antiepileptic drugs-Rational polytherapy? Seizure 2011;20:369-175.  Back to cited text no. 38
    
39.
St Louis EK. Truly “rational” polytherapy: Maximizing efficacy and minimizing drug interactions, drug load, and adverse effects. Current Neuropharmacology 2009;7:96-105.  Back to cited text no. 39
    
40.
Brigo F, Ausserer H, Tezzon F, Nardone R. When one plus one makes three: The quest for rational antiepileptic polytherapy with supra-additive anticonvulsant efficacy. Epi Behavior 2013;27:439-42.  Back to cited text no. 40
    
41.
French JA, Faught E. Rational polytherapy. Epilepsia 2009;50 (Suppl 8): 63-68.  Back to cited text no. 41
    
42.
Brodie MJ, Yuen AW. Lamotrigine substitution study: Evidence for synergism with sodium valproate? Study Group. Epilepsy Res 1997;26:423-32.  Back to cited text no. 42
    
43.
Yuen AW, Land G, Weatherley BC, Peck AW. Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992;33:511.  Back to cited text no. 43
    
44.
Chung S, Ben-Menachem E, Sperling MR, Rosenfeld W, Fountain NB, Benbadis S, et al. Examining the clinical utility of lacosamide: Pooled analyses of three phaseII/III trials. CHS Drugs 2010;24:1041-54.  Back to cited text no. 44
    
45.
Stephen LJ, Brodie MJ. Pharmacotherapy of epilepsy: Newly approved and developmental agents. CNS Drugs 2011;25:89-107.  Back to cited text no. 45
    
46.
Kwan P, Arzimanoglou A, Bergnts AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:1069-1077.  Back to cited text no. 46
    
47.
Neligan A, Bell GS, Sander JW, Shorvon SD. How refractory is refractory epilepsy? Patterns of relapse and remission in people with refractory epilepsy. Epi Res 2011;96:225-30.  Back to cited text no. 47
    
48.
Luciano AL, Shorvon SD. Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Ann Neurol 2007;62:375-81.  Back to cited text no. 48
    
49.
Schiller Y. Seizure relapse and development of drug resistance following long-term seizure remission. Arch Neurol 2009;66:1233-9.  Back to cited text no. 49
    
50.
Callaghan BC, Anand K, Hesdorffer D, Hauser WA, French JA. Likelihood of seizure remission in an adult population with refractory epilepsy. Ann Neurol 2007;62:382-9.  Back to cited text no. 50
    
51.
Choi H, Heiman G, Pandis, Cantero J, Resor SR, Gilliam FG, et al. Seizure remission and relapse in adults with intractable epilepsy: A cohort study. Epilepsia 2008;49:1440-5.  Back to cited text no. 51
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
Print this article  Email this article
   
Online since 20th March '04
Published by Wolters Kluwer - Medknow