Lennox \200\223Gastaut syndrome Lennox \200\223Gastaut syndrome (LGS) is classified as an e pileptic encephalopathy. The age of onset is usually before age 8 with a peak age of onset between 3 \200\2235 years of age. The syndrome is char- acterized by a triad of multiple se izure types (tonic and atypical absence are the most common), slow spike and wave on EEG (1 \200\2232.5 Hz), and some degree of mental retardation. The etiology can be symptomatic or cryptogenic, and is often a sequelae of infants diagnosed with infantile spasms or West sy ndrome. Tonic seizures are considered a prerequisite for the diagnosis. The interictal EEG is characterized by slow spike and wave complexes (<2.5 Hz) and activation of generalized p aroxysmal fast activity during sleep. The seizures in LGS are typically refractory to medic al treatment ( 40 ). The North American study ( 11 ) found only one of 19 children (5 % ) d iagnosed with LGS achieved a 2-year remission (Table 24.2 ). That subject went on to relaps e on later follow-up. None of the \201 ve children with LGS in the Dutch study ( 23 ) ach ieved remission. Mesial temporal lobe epilepsy with hippocampal sclerosis Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a symptomatic focal epilepsy and subcategorized as a li mbic epilepsy. The age of onset is typically between late child- hood to mid adolescence. M ost patients report an aura, which con- sists of an epigastric sensation (a rising sensatio n, butter \202 ies, nausea), fear, olfactory hallucinations, lightheadedness, or d j vu ( 41 ). Seizure semiology often involve impairment of cognition and awareness as well as i psilateral upper extremity automatisms, con- tralateral dystonic posturing, Todd \200\231s paralysis, and late forced head turning prior to secondary generalization. Prognostic factors for seizure remission Different studies have used different methodologie s, and prognos- tic factors which were analyzed varied between studies, making strong concl usions untenable. In addition, there are only a few papers with multivariate analysis, and the potential interaction between prognostic factors is not well studied. Nevertheless, a f ew consistent factors emerge for both positive and negative prognosis for seizure remission . Positive predictors for seizure remission include the diagnosis of one of the benign idio pathic epilepsies such as BECTS, CAE, and JAE. Young age of seizure onset, a normal MTLE-HS is often refractory to anticonvulsant drug treatment and one of the most common typ es of epilepsy referred for epilepsy surgery. Kim et al. ( 42 ) followed 104 patients with MRI evidence of mesial temporal sclerosis for more than 2 years. Only 25 % of this cohort e ntered into a 1-year seizure remission period. In a large hospital-based survey of over 220 0 adult patients with varying CHAPTER 24 epilepsy in remission 265 Table 24.2 Remission rates by syndromes ( 11 ) Syndrome grouping a No. total after 2-year reassessment of syndromes and etiology No. ( % ) achieving 2-year remission No. ( % ) relapse Total 594 441 (74) 107 ( 24 ) Partial epilepsies 354 274 (77) 65 ( 24 ) Idiopathic partial: 62 55 (93) 4 ( 7 ) Benign rolandic 59 52 (88) 3 ( 6 ) Benign occipital 3 3 (100) 1 ( 33 ) Symptomatic partial: 205 147 (72) 44 ( 30 ) Cryptogenic partial 87 72 (83) 7 ( 24 ) Generalized epilepsies 191 132 (69) 32 ( 24 ) Idiopathic generalized (IGE): 133 111 (83) 28 ( 25 ) Benign myoclonic epilepsy in infancy 2 2 (100) 0 (0) Childhood absence 75 66 (88) 15 ( 23 ) Juvenile absence 17 14 (82) 3 ( 21 ) Juvenile myoclonic 15 8 ( 53 ) 5 (63) With generalized tonic \200\223clonic seizure on awakening 2 1 ( 50 ) 1 (100) Other IGE/unclassi \201 ed IGE 18 17 (94) 3 ( 19 ) With speci \201 c modes of precipitation 4 3 (75) 1 ( 33 ) Symptomatic/cryptogenic generalized: 49 20 ( 41 ) 4 ( 20 ) Not further classi \201 ed 3 1 ( 33 ) \200\224 West 17 9 ( 53 ) 1 ( 11 ) Lennox \200\223Gastaut 19 1 ( 5 ) 1 (100) Doose 8 7 (88) 1 ( 14 ) With myoclonic absence 2 2 (100) 1 ( 50 ) Symptomatic generalized: 9 1 ( 11 ) 0 (0) With non-speci \201 c etiology 3 0 (0) \200\224 With speci \201 c etiology 6 1 ( 17 ) 0 (0) Epilepsies of undetermined onset 49 36 (73) 10 ( 28 ) Undetermined with both focal and generalized features 2 1 ( 50 ) 1 (100) Undetermined without unequivocal focal or generalized features 47 35 (74) 9 ( 26 ) a A few syndromes with only a single individual were not shown but included in the more gen eral category under which they fell. From Berg AT et al. Epilepsia 2001; 42:1553 \200\22362 , with permission. neurological examination, and generalized onset seizures all por- tend a higher likelihood for seizure remission ( 8 , 51 , 52 ). As shown earlier in this chapter, continued seizure activity after adequate trials of two to three \201 rst-line anticonvulsant drugs portend s a lower possibility of sustained seizure remission. In addition, the duration of active s eizure activity is inversely correlated to the chances of becoming seizure free. Annegers e t al. ( 4 ) demonstrated that only around 10 % of their initial cohort entered remission if the period of active epilepsy was greater than 4 years, with less than 5 % achieving seizu re freedom if their seizures were uncontrolled for greater than 10 years. Frequent generali zed tonic \200\223clonic sei- zures, the presence of multiple seizure types, epileptiform a bnor- malities on the EEG, structural abnormalities on brain imaging, and the presence of m ental retardation also are poor prognostic factors for seizure remission ( 51 , 53 \200\22357 ). Frequent seizures ( \200\230high dens ity \200\231) after initial diagnosis was also found to be a negative predictor ( 58 ). Conclusion The prognosis for persons with epilepsy to enter remission is gen- erally favora ble. Data from resource-poor countries indicate that even some untreated or undertreated pa tients will spontaneously become seizure free. With appropriate treatment, about two-thirds of people will achieve seizure remission. Certain syndromes such as BECTS, CAE, and JAE ar e associated with a high likelihood of seizure control. Other syndromes such as LGS and MTL E-HS are associated with a poor overall prognosis (LGS) or poor prognosis oxford textbook of epilepsy and epileptic seizures 266 with medication treatment (MTLE-HS). Clearly, there is a minor- ity of epilepsy patients wh o become medically refractory, and cur- rently are unlikely to achieve any prolonged period of seizure remission. It is for this population of patients that newer treatment options c an make the most dramatic impact. scoring system for those treated with medication . J Pediatr 1993 ; 122 ( 6 ): 861 \200 \223 8 . 22. Sillanpaa M , Schmidt D . Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study . Brain 2006 ; 129 (Pt 3 ): 617 \200\223 24 . 23. Geerts A , Arts WF , Stroink H , Peeters E , Brouwer O , Peters B , et al . Course and outcome of childhood epilepsy: a 15-year follow-up of the Dutch Study of Epileps y in Childhood . Epilepsia 2010 ; 51 ( 7 ): 1189 \200\223 97 . 24. Elwes RD , Johnson AL , Shorvon SD , Reynolds EH . The prognosis for seizure control in newly diagnosed epilepsy . N Engl J Med 1984 ; 311 ( 15 ): 944 \200\223 7 . References 1. Tellez-Zenteno JF , Dhar R , Wiebe S . Long-term seizure outcomes following epilepsy sur gery: a systematic review and meta-analysis . Brain 2005 ; 128 (Pt 5 ): 1188 \200\223 98 . 2. Spencer SS , Berg AT , Vickrey BG , Sperling MR , Bazil CW , Haut S , et al . Health-rel ated quality of life over time since resective epilepsy surgery . Ann Neurol 2007 ; 62 ( 4 ): 327 \200\223 34 . 25. Lindsten H , Stenlund H , Forsgren L . Remission of seizures in a population-based adult cohort with a newly diagnosed unprovoked epileptic seizure . Epileps ia 2001 ; 42 ( 8 ): 1025 \200\223 30 . 3. Shih JJ , Ochoa JG . A systematic review of antiepileptic drug initiation 26. Engel J , Jr . A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classi \201 cation and Terminology . Epilepsia 2001 ; 42 ( 6 ): 796 \200\223 803 . and withdrawal . Neurologist. 2009 ; 15 ( 3 ): 122 \200\223 31 . 4. Annegers JF , Hauser WA , Elveback LR . Remission of seizures and relapse in patients wi th epilepsy . Epilepsia 1979 ; 20 ( 6 ): 729 \200\223 37 . 27. Proposal for revised classi \201 cation of epilepsies and epileptic 5. Placencia M , Sander JW , Roman M , Madera A , Crespo F , Cascante S , syndromes . Commission on Classi \201 cation and Terminology of the International League A gainst Epilepsy . Epilepsia 1989 ; 30 ( 4 ): 389 \200\223 99 . 28. Bouma PA , Westendorp R G , van Dijk JG , Peters AC , Brouwer OF . The et al . The characteristics of epilepsy in a largely untreated population in rural Ecuador . J Neurol Neurosurg Psychiatry 1994 ; 57 ( 3 ): 320 \200\223 5 . 6. Nicoletti A , So \201 a V , Vitale G , Bonelli SI , Bejarano V , Bartalesi F , et al . Natural history and mortality of chronic epilepsy in an untreated population of rural Boliv ia: a follow-up after 10 years . Epilepsia 2009 ; 50 ( 10 ): 2199 \200\223 206 . outcome of absence epilepsy: a meta-analysis . Neurology 1996 ; 47 ( 3 ): 802 \200\223 8 . 29. Wirrell EC , Cam \201 eld CS , Cam \201 eld PR , Gordon KE , Dooley JM . Long- term p rognosis of typical childhood absence epilepsy: remission or progression to juvenile myoclo nic epilepsy . Neurology 1996 ; 47 ( 4 ): 912 \200\2231 8 . 7. Kwan P , Sander JW . The natural history of epilepsy: an epidemiological view . J Neurol Neurosurg Psychiatry 2004 ; 75 ( 10 ): 1376 \200\223 81 . 30. Grosso S , Galimberti D , Vezzosi P , Farnetani M , Di Bartolo RM , 8. Goodridge DM , Shorvon SD . Epileptic seizures in a population of 6000. II: Treatment an d prognosis . Br Med J (Clin Res Ed) 1983 ; 287 ( 6393 ): 645 \200\223 7 . Bazzotti S , et al . Childhood absence epilepsy: evolution and prognostic factors . Epileps ia 2005 ; 46 ( 11 ): 1796 \200\223 801 . 31. Callenbach PM , Bouma PA , Geerts AT , Arts WF , Stroink H , Peeters EA , et al . Long- term outcome of childhood absence epilepsy: Dutch Study of Epilepsy in Childhood . Epilepsy Res 2009 ; 83 ( 2-3 ): 249 \200\223 56 . 32. Panayiotopoulos CP , Obeid T , Waheed G . Di fferentiation of typical 9. Sillanpaa M , Jalava M , Kaleva O , Shinnar S . Long-term prognosis of seizures with onset in childhood . N Engl J Med 1998 ; 338 ( 24 ): 1715 \200\223 22 . 10. Semah F , Picot MC , Adam C , Broglin D , Arzimanoglou A , Bazin B , et al . Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neuro logy 1998 ; 51 ( 5 ): 1256 \200\223 62 . absence seizures in epileptic syndromes. A video EEG study of 224 seizures in 20 patients . Brain 1989 ; 112 (Pt 4 ): 1039 \200\223 56 . 11. Berg AT , Shinnar S , Levy SR , Testa FM , Smith-Rapaport S , Beckerman B , et al . Two -year remission and subsequent relapse in children with newly diagnosed epilepsy . Epilepsi a 2001 ; 42 ( 12 ): 1553 \200\223 62 . 33. Beghi M , Beghi E , Cornaggia CM , Gobbi G . Idiopathic generalized epilepsies of adole scence . Epilepsia 2006 ; 47(Suppl 2) : 107 \200\223 10 . 34. Grunewald RA , Panayiotopoul os CP . Juvenile myoclonic epilepsy. 12. Hauser WA , Kurland LT . The epidemiology of epilepsy in Rochester, A review . Arch Neurol 1993 ; 50 ( 6 ): 594 \200\223 8 . Minnesota, 1935 through 1967 . Epilepsia 1975 ; 16 ( 1 ): 1 \200\223 66 . 13. Juul-Jensen P , Foldspang A . Natural history of epileptic seizures . 35. Penry JK , Dean JC , Riela AR . Juvenile myoclonic epilepsy: long-term response to therapy . Epilepsia 1989 ; 30(Suppl 4) : S19 \200\223 23; discussion S4 \200 \223 7 . 36. Panayiotopoulos CP , Michael M , Sanders S , Valeta T , Koutroumanidis M . Ben ign childhood focal epilepsies: assessment of established and newly recognized syndromes . Brain 2008 ; 131 (Pt 9 ): 2264 \200\223 86 . 37. Medeiros LL , Yasuda C , Schmutzler KM , Guerreiro MM . Rolandic Epilepsia 1983 ; 24 ( 3 ): 297 \200\223 312 . 14. Hauser WA , Rich SS , Annegers JF , Anderson VE . Seizure recurrence after a 1st unprovoked seizure: an extended follow-up . Neurology 1990 ; 40 ( 8 ): 1163 \200\223 70 . 15. Shinnar S , Berg AT , Moshe SL , Petix M , Maytal J , Kang H , et al . Risk of seizure recurrence following a \201 rst unprovoked seizure in childhood: a prospective study . Pe diatrics 1990 ; 85 ( 6 ): 1076 \200\223 85 . discharges: clinico-neurophysiological correlation . Clin Neurophysiol 2010 ; 121 ( 10 ): 1 740 \200\223 3 . 38. Callenbach PM , Bouma PA , Geerts AT , Arts WF , Stroink H , Peeters EA , et al . Long term outcome of benign childhood epilepsy with centrotemporal spikes: Dutch Study of Epilep sy in Childhood . Seizure 2010 ; 19 ( 8 ): 501 \200\223 6 . 16. Berg AT , Shinnar S . The risk of seizure recurrence following a \201 rst unprovoked seizure: a quantitative review . Neurology 1991 ; 41 ( 7 ): 965 \200\223 72 . 17. Cockerell OC , Johnson AL , Sander JW , Hart YM , Shorvon SD . 39. Bouma PA , Bovenkerk AC , Westendorp RG , Brouwer OF . The course of benign partial epi lepsy of childhood with centrotemporal spikes: a meta-analysis . Neurology 1997 ; 48 ( 2 ): 430 \200\223 7 . Remission of epilepsy: results from the National General Practice Study of Epilepsy . Lance t 1995 ; 346 ( 8968 ): 140 \200\223 4 . 18. Kwan P , Brodie MJ . Early identi \201 cation of refractory epilepsy . 40. Arzimanoglou A , French J , Blume WT , Cross JH , Ernst JP , Feucht M , et al . Lennox- Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial meth odology . Lancet Neurol 2009 ; 8 ( 1 ): 82 \200\223 93 . N Engl J Med 2000 ; 342 ( 5 ): 314 \200\2231 9 . 19. 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 th e ILAE Commission on Classi \201 cation and Terminology, 2005-2009 . Epilepsia 2010 ; 51 ( 4 ): 676 \200\223 85 . 41. French JA , Williamson PD , Thadani VM , Darcey TM , Mattson RH , Spencer SS , et al . Characteristics of medial temporal lobe epilepsy: I. Results of histor y and physical examination . Ann Neurol 1993 ; 34 ( 6 ): 774 \200\223 80 . 20. Keranen T , Riekkinen PJ . Remission of seizures in untreated epilepsy . BMJ 1993 ; 307 ( 6902 ): 483 . 42. Kim WJ , Park SC , Lee SJ , Lee JH , Kim JY , Lee BI , et al . The prognosis for contro l of seizures with medications in patients with MRI evidence for mesial temporal sclerosis . Epilepsia 1999 ; 40 ( 3 ): 290 \200\223 3 . 21. Cam \201 eld C , Cam \201 eld P , Gordon K , Smith B , Dooley J . Outcome of childhood epilepsy: a population-based study with a simple predictive CHAPTER 24 epilepsy in remission 267 51. Annegers JF , Shirts SB , Hauser WA , Kurland LT . Risk of recurrence after an initial unprovoked seizure . Epilepsia 1986 ; 27 ( 1 ): 43 \200\223 50 . 52. Arts WF , Geerts AT , Brouwer OF , Boudewyn Peters AC , Stroink H , van Donselaar CA . The early prognosis of ep ilepsy in childhood: the prediction of a poor outcome. The Dutch study of epilepsy in child hood . Epilepsia 1999 ; 40 ( 6 ): 726 \200\223 34 . 43. Wiebe S , Blume WT , Girvin JP , Eliasziw M . A randomized, controlled trial of surgery for temporal-lobe epilepsy . N Engl J Med 2001 ; 345 ( 5 ): 311 \200\2231 8 . 44. Thom M , Mathern GW , Cross JH , Bertram EH . Mesial temporal lobe epilepsy: How do we improve surgical outcome? Ann Neurol 2010 ; 68 ( 4 ): 424 \200\223 34 . 53. Cam \201 eld PR , Cam \201 eld CS , Gordon K , Dooley JM . If a \201 rst 45. Ozkara C , Uzan M , Benbir G , Yeni N , Oz B , Hanoglu L , et al . Surgical outcome of patients with mesial temporal lobe epilepsy related to hippocampal sclerosis . Epilepsia 20 08 ; 49 ( 4 ): 696 \200\223 9 . antiepileptic drug fails to control a child \200\231s epilepsy, what are the chances of suc cess with the next drug? J Pediatr 1997 ; 131 ( 6 ): 821 \200\223 4 . 46. Callaghan B , Schlesinger M , Rodemer W , Pollard J , Hesdorffer D , 54. Reynolds EH . The prevention of chronic epilepsy . Epilepsia 1988 ; Allen Hauser W , et al . Remission and relapse in a drug-resistant epilepsy population foll owed prospectively . Epilepsia 2011 ; 52 ( 3 ): 619 \200\223 26 . 29(Suppl 1) : S25 \200\223 8 . 55. Schmidt D , Tsai JJ , Janz D . Generalized tonic-clonic seizures in patients with complex-partial seizures: natural history and prognostic relevance . Epilepsi a 1983 ; 24 ( 1 ): 43 \200\223 8 . 47. Callaghan BC , Anand K , Hesdorffer D , Hauser WA , French JA . Likelihood of seizure remission in an adult population with refractory epilepsy . Ann Neuro l 2007 ; 62 ( 4 ): 382 \200\223 9 . 56. Liimatainen SP , Raitanen JA , Ylinen AM , Peltola MA , Peltola JT . The bene \201 t of active drug trials is dependent on etiology in refractory focal epilepsy . J Neurol Neurosurg Psychiatry 2008 ; 79 ( 7 ): 808 \200\223 12 . 48. Choi H , Heiman GA , Munger Clary H , Etienne M , Resor SR , Hauser WA . Seizure remiss ion in adults with long-standing intractable epilepsy: an extended follow-up . Epilepsy Res 2011 ; 93 ( 2-3 ): 115 \200\2231 9 . 49. Choi H , Heiman G , Pandis D , Cantero J , Resor SR , Gilliam FG , et al . Seizure remission and relapse in adults with intractable epileps y: a cohort study . Epilepsia 2008 ; 49 ( 8 ): 1440 \200\223 5 . 57. Wirrell EC . Prognostic signi \201 cance of interictal epileptiform discharges in newly diagnosed seizure disorders . J Clin Neurophysiol 2010 ; 27 ( 4 ): 239 \200\223 4 8 . 58. MacDonald BK , Johnson AL , Goodridge DM , Cockerell OC , Sander JW , Shorvon SD . Fact ors predicting prognosis of epilepsy after presentation with seizures . Ann Neurol 2000 ; 4 8 ( 6 ): 833 \200\223 41 . 50. Berg AT , Levy SR , Testa FM , D \200\231Souza R . Remission of epilepsy after two drug failures in children: a prospective study . Ann Neurol 2009 ; 65 ( 5 ): 510 \200\2231 9 . This page intentionally left blank CHAPTER 25 Drug Interactions Philip N. Patsalos Introduction Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment and the trea tment goal is seizure freedom. Indeed, monotherapy AEDs can render approximately 65 % of ne wly diagnosed patients seizure-free ( 1 ). However, for the remaining 35 % of patients it i s common practice to prescribe AEDs in combination so as to achieve optimal seizure control . When AED combinations are used there is an increased risk of pharmacokinetic and/or pharm acody- namic interactions which in turn can result in adverse clinical con- sequences. For newly licensed AEDs, which can only be prescribed as adjunctive therapy in the \201 rst i nstance, combination therapy is the only option and therefore their propensity to interact is a major consideration. Mechanisms of drug interactions There are two types of interaction, pharmacokinetic interac tions and pharmacodynamic interactions. Pharmacokinetic interactions The vast majority ( > 99 % ) of clinically signi \201 cant id enti \201 able AED interactions are the consequence of pharmacokinetic interactions and ar e associated with a change in drug plasma concentration and are therefore more readily dete ctable and quanti \201 able and their time course is often well characterized. Induction o r inhibition of drug metabolizing enzymes are the principal mechanisms of these interaction s whilst pharmacokinetic interactions at the level of absorption, protein binding, and excr etion are rare. For patients with epilepsy, AEDs are administered for prolonged periods comprising of many years and often for a lifetime and therefore increasing the probability of prescribing poly therapies, particularly for those patients that inevitably develop intercurrent or associat ed conditions which will require AEDs to be combined with non-AED drugs. Even those patient s that respond to mono- therapy may similarly experience the consequences of AED inter- act ions as AEDs are added and withdrawn during the optimization of their monotherapy drug regi men. Furthermore, polytherapy AED regimens are often required to treat patients with multip le seizure types. Drug absorption interactions AED absorption interactions are rare but include the impairmen t of absorption of carbamazepine, gabapentin, phenobarbital, and phenytoin by antacids ( 3 , 4 ). More recently it has been observed that drugs that modulate the expression of gastro intestinal drug transporters such as P-glycoprotein and multiple drug resistance proteins 2 and 3 can reduce drug absorption and it is via this mech- anism that carbamazepine reduces talinolol absorption ( 5 ). Protein binding interactions The best documented plasma protein binding displacement inter- action involving AEDs is that of phenytoin by valproic acid ( 6 ). This results, in some p atients, in a modest rise in free phenytoin concentration occurring due to a concomitant in hibition of pheny- toin metabolism by valproic acid and occasionally in phenytoin toxicity. For these displacement interactions to be signi \201 cant, pro- tein binding needs to be 90 % or higher and only phenytoin, valp- roic acid, diazepam, tiagabine, lacosamide, and st iripentol have this characteristic ( 6 \200\2238 ). However, unless additional mechanisms o ccur, although a fall in total drug concentration (as the displaced drug redistributes rapi dly into tissues and undergoes compensa- tory elimination) occurs, the free drug concentrat ion remains practically unchanged and therefore the pharmacological conse- quence of such i nteractions is negligible. Nevertheless, the inter- pretation of plasma drug concentration measurements requires the That AEDs are commonly associated with clinically relevant drug interactions can be attribu ted to their various characteristics: (1) most AEDs have a narrow therapeutic index so that even small changes in their plasma drug concentration can result in seizure exacerbation o r increased adverse effects; (2) the most widely used AEDs (carbamazepine, phenobarbital, p henytoin, and valproic acid) have a substantial ability to induce and/or inhibit hepatic me tabolism; (3) additionally these AEDs, along with some of the newer AEDs (e.g. eslicarbazep ine acetate, felbamate, lamotrigine, oxcarbazepine, retigabine, tiagabine, topiramate, and zonisamide), are susceptible to inhibition and induction of their own metabo- lism ( 2 \200 \2234 ). This chapter will review those interactions that are most fre- quently encountered clinical ly and those interactions which because of their magnitude are particularly likely to resul t in adverse clinical consequences. oxford textbook of epilepsy and epileptic seizures 270 interactions in which drug metabolism is decreased ( 10 , 11 ). AEDs that undergo metabolis m by cytochrome P450s (CYPs) (e.g. carbamazepine, phenytoin, phenobarbital, ethosuximide, p rimidone, tiagabine, topiramate, zonisamide) or uridine diphos- phate glucuronyltransferase s (UGTs) (e.g. lamotrigine, valproic acid, oxcarbazepine, eslicarbazepine acetate) are susc eptible to these types of interactions ( 12 , 13 ). In contrast, AEDs that are renally elim inated (e.g. gabapentin, levetiracetam, pregabalin, viga- batrin), or undergo non-CYP or no n-UGT metabolism (e.g. lacosamide) or whose metabolism is non-hepatic (e.g. levetira- cetam ) are devoid of such interactions ( 13 , 14 ). appreciation that therapeutic and toxic effects will occur at total drug concentrations low er than usual and that patient manage- ment may best be guided by monitoring free unbound d rug con- centrations ( 9 ). Renal excretion interactions Despite numerous AEDs undergoing primarily renal excretion (e. g. gabapentin, levetiracetam, pregabalin, and vigabatrin) there are no documented AED inter actions involving a change in renal excretion processes. Metabolic drug interactions The metabolic characteristics of the various AEDs and their pro pensity to undergo metabolic interactions is summarized in Table 25. 1 . Metabolic interact ions are subdivided into induction interactions in which drug metabolism is increased and i nhibition Inhibition mechanisms Enzyme inhibition occurs when a drug or its metabolite(s) blocks the activity of one or more drug metabolizing enzymes. This results in a decrease in the rate o f metabolism of the affected drug leading to increased plasma concentrations and, possibly, clinical toxicity. Table 25.1 Metabolic characteristics of antiepileptic drugs and their propensity to interac t AED Hepatic metabolism Enzymes involved in metabolism Elimination by renal excretion Propensity to interact Carbamazepine Substantial (98 % ) CYP1A2, CYP2C8, CYP3A4 Minimal (2 % ) Substantial Phenytoin Substantial (95 % ) CYP2C9, CYP2C19 Minimal (2 % ) Substantial Phenobarbital Substantial (80 % ) CYP2E1, CYP2C19 Minimal (20 % ) Substantial Primidone Minimal (35 % ) CYP2E1, CYP2C9, CYP2C19 Moderate (65 % ) Substantial Stiripentol Substantial (73 % ) CYP1A2, CYP2C19, CYP3A4 Minimal (27 % ) Substantial Valproic acid Substantial (97 % ) CYP2A6, CYP2C9, CYP2C19, CYP2B6, UGT1A3, UGT2B7 Minimal (3 % ) Substantial Lamotrigine Substantial (90 % ) UGT1A4, UGT1A1, UGT2B7 Minimal (10 % ) Moderate Topiramate Moderate (50 % ) Not identi \201 ed but involve CYP isoenzymes Moderate (50 % ) Moderate Clobazam Substantial (100 % ) CYP3A4 None (0 % ) Minimal Clonazepam Substantial (99 % ) CYP3A4 Minimal (1 % ) Minimal Eslicarbazepine acetate Substantial ( > 99 % ) Not identi \201 ed but UGTs are involved Minimal (1 % ) Minimal Ethosuximide Substantial (80 % ) CYP2B, CYP2E1, CYP3A4 Minimal (20 % ) Minimal Felbamate Moderate (50 % ) CYP3A4, CYP2E1 Moderate (50 % ) Minimal Retigabine Moderate (50 \200\22365 % ) UGT1A1, UGT1A3, UGT1A4, UGT1A9 Minimal (20 \200\22330 % ) Minimal Ru \201 namide Substantial (96 % ) Unknown (but not CYP-dependent) Minimal (4 % ) Minimal Oxcarbazepine Substantial ( > 99 % ) Not identi \201 ed but UGTs are involved Minimal (<1 % ) Minimal Tiagabine Substantial (98 % ) CYP3A4 Minimal (<2 % ) Minimal Zonisamide Moderate (65 % ) CYP3A4 Minimal (35 % ) Minimal Gabapentin Not metabolized None Substantial (100 % ) Insigni \201 cant/ non-interacting Lacosamide Moderate (60 % ) Demethylation Minimal (40 % ) Insigni \201 cant/ non-interacting Levetiracetam Minimal (30 % ) \200\224 non-hepatic occurs in whole blood Type-B esterase Moderate (66 % ) Insigni \201 cant/ non-interacting Pregabalin Not metabolized None Substantial (98 % ) Insigni \201 cant/ non-interacting Vigabatrin Not metabolized None Substantial (100 % ) Insigni \201 cant/ non-interacting CHAPTER 25 drug interactions 271 Interactions between AEDs Inhibition interactions resulting in increased AED concentration Of the AEDs, valproic acid, topiramate, oxcarbazepine, stiripen- tol, and felbamate are inh ibitors of hepatic metabolism and thus elevate the plasma concentrations of other AEDs. By far the most potent and broad ranging inhibitor of drug metabolism is valproic acid. Topira mate is a modest inhibitor and oxcarbazepine a weak inhibitor. In contrast, stiripentol and felbamate are potent inhibi- tors, resulting in clinically important interactions, but the se AEDs are rarely used in epilepsy. Felbamate can cause serious liver and bone marrow toxi city and stiripentol has a limited license for the adjunctive treatment of seizures in chil dren with severe myoclonic epilepsy in infancy (Dravet syndrome). Sulthiame is another pote nt inhibitor of hepatic metabolism (e.g. increases phenytoin and phenobarbital blood concen tration several-fold) but is rarely used clinically ( 12 ). Inhibition is usually competitive in nature and dose-dependent, and tends to begin as soon as suf \201 cient concentrations of the inhibitor are achieved, with signi \201 cant inhi bition being often observed within 24 hours after addition of the inhibitor ( 10 ). The tim e to maximal inhibition will depend on the elimination half-life of the affected drug and t he inhibiting agent which will now have a more prolonged half-life, to achieve steady-state (Table 25. 2 ). Thus, AEDs with short half-lives will achieve maximum increase in blood co ncentrations sooner than those with longer half-lives (e.g. ru \201 namide versus phenobar bital; Table 25. 2 ). The time course of de-inhibition, when the inhibitor is withdrawn, is dependent on the elimination half-life of the inhibitor. Induction mechanisms Induction of drug metabolizing enzymes in the liver results in an incr ease in enzyme activity which in turn results in an increase in the rate of metabolism of d rugs which are substrates of those enzymes, leading to a decrease in plasma concentration o f the affected drug. If the affected drug has an active metabolite, induc- tion leads to in creased metabolite concentration and a possible increase in drug toxicity. As enzyme induct ion requires synthesis of new enzymes, the time course of induction (and its reversal upon removal of the inducer) is dependent on the rate of enzyme synthesis and degradation and th e time to reach steady-state con- centrations of the inducing drug. Consequently, induction is usu- ally gradual and dose-dependent and differs between the different enzyme-inducing AEDs. For phenobarbital, induction starts after approximately 1 week, with maximal inductio n occurring after 2 \200\2233 weeks following its initiation. Phenytoin induction is maxima l by 1 \200\2232 weeks after phenytoin initiation and carbamazepine is asso- ciated with au toinduction (induces its own metabolism) which is complete within 3 \200\2235 weeks ( 11 , 15 , 16 ). In contrast to the other enzyme-inducing AEDs, the process of de-induction, upon cessa- tion of carbamazepine, is rapid with greater than 68 % de-induction occurring withi n 6 days ( 17 ). Valproic acid is a potent inhibitor of CYP2C9, UGT1A4, and epoxide hydrolase activity and a weak inhibitor of CYP2C19 and CYP3A4 activity and this results in major interactions with car- bamazepine, phenobarbital, and lamotrigine and two moderate interactions with felbamat e and ru \201 namide. Plasma concentra- tions of the pharmacologically active metabolite o f carbamazepine, carbamazepine-10,11- epoxide, are increased in patients treated with carba mazepine and valproic acid in combination. This is the consequence of inhibition of the enz yme epoxide hydrolase which is responsible for the metabolism of carbamazepine-10,11- epox- ide and can occur without any signi \201 cant changes in carbamazepine concentrations and result in toxicity ( 18 ). The interaction with phenobarbital is the result of inhibition of CYP2C9 and CYP2C19 by valproic acid and this results in a 30 \200\22350 % increase in pl asma phenobarbital concentration and a reduction in phenobarbital (or primidone) dosage by up to 80 % may be required to avoid side effects (particularly sedation and cognitive impai rment) ( 19 ). The interaction with lamotrigine is the result of inhibition of the UGT1A4 e nzyme responsible for the glucuronide conjugation of lamotrigine and results in an approxim ate 2-fold increase in plasma lamotrigine concentrations ( 20 ). Indeed this potent interac tion is already optimum at relatively low valproate doses ( \211 500mg/day in an adult) ( 21 ). Because lamotrigine administration can be associ- ated with a cutaneous rash, which is particularly prevalent when a fast increment in plasma lamotrigine concentration occurs, the introduction of lamotrigine in a patient already taking valproic acid should be undert aken with caution, using a low starting dose and a slow dose escalation rate. However, it s hould be noted that there is no risk of rash if valproic acid is introduced in a patient al ready stabilized on lamotrigine. Valproic acid may inhibit the metabolism of other AEDs inc luding ethosuximide, felbamate, phenytoin, and ru \201 namide. A particularly complex inte raction is that with phenytoin in which valproic acid inhibition occurs along with a concur rent displacement of phenytoin from plasma protein binding sites. This results in an increa se in free plasma phenytoin concentration which may not be apparent when a patient is moni- tored by use of total phenytoin concentrations and thus free pheny- toin concentrations sh ould be used to guide patient management in this situation ( 9 ). Table 25.2 Time to steady-state and therefore maximum therapeutic outcome consequent to an inhibitory interaction of those antiepileptic drugs (AEDs) which are known to be affected b y inhibitory interactions Half-life (hours) a Affected AED Steady-state (days) achieved after 5 half-lives (values are rounded up or down for clarity) Carbamazepine 8 \200\22320 2 \200\2234 2 \200\2237 (7 \200\22310) b Clobazam 10 \200\22330 Ethosuximide 40 \200\22360 8 \200\22312 Felbamate 16 \200\22322 3 \200\2235 Lamotrigine 15 \200\22335 3 \200\2237 Phenobarbitone 70 \200\223140 15 \200\22329 Phenytoin 30 \200\223100 6 \200\22321 Ru \201 namide 6 \200\22310 1 \200\2232 Valproic acid 11 \200\22320 2 \200\2234 a Values are in the absence of interacting medication (9). b Includes time to steady-state for pharmacologically active metabolite Stiripentol inhibits CYP1A2, CYP2C19, and CYP3A4 and con- sequently can decrease the cleara nce of carbamazepine, clobazam, N-desmethyl-clobazam. oxford textbook of epilepsy and epileptic seizures 272 good example of this effect is that of primidone when phenytoin or carbamazepine are co-pre scribed. Because primidone is metab- olized partly to phenobarbital, stimulation of metabol ism may actually result in enhanced production of the phenobarbital metab- olite and theref ore an increased pharmacological effect. Another example relates to valproic acid the metab olism of which is typi- cally enhanced by carbamazepine, phenytoin, and phenobarbital resul ting in decreased plasma concentrations and decreased effec- tiveness of valproic acid Howe ver, this interaction may also lead to increased formation of hepatotoxic metabolites and m ay explain why patients taking these AEDs are more susceptible to valproate- induced liver toxicity ( 25 ). phenobarbital, phenytoin, primidone, and valproic acid ( 7 ). The inhibition of clobazam me tabolism is associated with a concur- rent and even more potent inhibition of the pharmacol ogically active metabolite, N-desmethylclobazam, so that stiripentol increases clobazam pla sma levels and N-desmethylclobazam plasma levels severalfold ( 22 ). Felbamate inhibits CYP 2C19 and epoxide hydrolase so that plasma concentration of carbamazepine- 10,11-epoxide, N- desmethyl-clobazam, phenobarbital, phenytoin and valproic acid are increased. Oxcarbazepine is a weak inhibitor and topiramate is a modest inhibitor of CYP2C19. Conseque ntly, oxcarbazepine, particularly when used at high dosages ( > 1800 mg/day), can increase plasma phenytoin concentrations by up to 40 % and to a lesser extent phe- nobarbital ( 23 ) . Topiramate can increase plasma phenytoin con- centrations in a small subset of patients b y 25 % . Ru \201 namide can decrease the clearance of phenobarbital and phenytoin by less than 20 % and increase their plasma concentrations ( 24 ). Other inhibi- tory drug interact ions caused by AEDs also occur but these are less common and are usually of modest clinical signi \201 cance. An interesting interaction is that between phenytoin and the angiotensin-receptor blocker l osartan. While phenytoin increases plasma concentrations of losartan by 17 % , it decreases the plasma concentrations of the active carboxylic acid metabolite E3174 by 63 % through i nhibition of its CYP2C9-mediated formation clear- ance. Therefore, a reduced antihypertensi ve effect may be antici- pated ( 29 ). Induction interactions resulting in decreased AED concentration Most AEDs (e.g. gabapentin, lacosamide, lamotrigine, levetira- cetam, pregabalin, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide) are not associated with enzyme-inducing effects on the metaboli sm of concurrently administered AEDs. In con- trast, carbamazepine, phenytoin, phenobarbita l, and primidone are potent inducers of various CYP isoenzymes and they also induce UGT and epoxide hydrolases ( 3 ). Consequently, these AEDs stimulate the metabolism and decrease t he plasma concen- trations of numerous AEDs, including clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine and its active monohydroxy-metabolite, rufinamide, st iripentol, tiagabine, topiramate, valproic acid, and zonisamide. Rufinamide can decrease pl asma concentrations of carbamazepine and lamotrigine, probably via hepatic induction of met abolism ( 24 ). In addition, phenobarbital, phenytoin, and primidone can markedly induce th e metabolism of carbamazepine so that mean plasma carbamazepine concentrations are decrease d by 33 % , 44 % , and 25 % respectively ( 25 ). Co-medication of valproic acid with carbam azepine, pheno- barbital, or phenytoin can reduce mean plasma valproic acid con- centration s by 66 % , 76 % , and 49 % respectively ( 26 ). In addition, the metabolism of lamotrigine is signi \201 cantly enhanced by oxcar- bazepine ( 27 ) and methsuximide ( 28 ). Pharmacodynamic interactions Pharmacodynamic interactions are less well described because t hey occur at the site of action in the brain and are usually inferred by default when a cha nge in the clinical status of a patient cannot be attributable to a pharmacokinetic change in plasma concentra- tions. These interactions, which can be additive (when they equal the sum of the effects of the individual drugs), synergistic (when the combined effects are gre ater than expected from the sum of individual drugs) or antagonistic (when the combined eff ects are less than additive), are more common than previously thought and in order that a r ational approach to the use of AED combinations in the management of epilepsy can occur we must enhance our understanding of this type of interaction. A mechanistic approach, in which combinations of drugs acting via different mechanisms coul d be co-prescribed and thus facilitate the use of rational AED polytherapy is highly desira ble ( 30 ). Indeed, although our current knowledge of AED pharmacology is insuf \201 - cie nt universally to take this approach, there is some evidence that certain AED combinations (e.g. valproate plus lamotrigine and valproate plus ethosuximide) are associated with bene \201 cial inter- actions at the pharmacodynamic level ( 31 , 32 ). Such AED combi- nations act synergistically and are associated with seizure control in patients previously unrespo nsive to the highest tolerated dose of either drug given alone. Unfortunately, additive neu rotoxicity can also occur when AEDs that share a common mechanism of action (e.g. blockage of voltage-dependent sodium channels) are co-pre- scribed ( 33 ). These effects have been m ore commonly associated with the combinations of lamotrigine plus carbamazepine, lamot- rig ine plus valproate and oxcarbazepine plus carbamazepine ( 23 , 28 , 34 ).