urgical Treatment
`ofEpil psy
`
`EDITED BY
`WILLIAM H. THEODORE
`Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke,
`Bethesda, MD, USA
`
`EPILEPSY RESEARCH
`·sUPPLEMENT NO. 5
`
`1992
`
`ELSEVIER
`AMSTERDAM · LONDON · NEW YORK · TOKYO
`
`Epilepsy Res., 1992, Suppl. 5
`
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`

`
`© 1992, Elsevier Science Publishers B. V., All rights reserved.
`Surgical Treatment of Epilepsy (Epilepsy Res. Suppl. 5)
`W.H. Theodore (Ed.)
`
`CHAPTER 7
`
`29
`
`Drug treatment of uncontrolled seizures
`
`Richard H. Mattson
`
`Department of Neurology, Yale University School of Medicine, New Haven, CT (USA) and the Department of Veterans Affairs Medical
`Center, Epilepsy Center, West Haven, CT06516 (USA)
`
`Introduction
`
`Consideration for referral of a patient for epilep(cid:173)
`sy surgery assumes that antiepileptic drug (AED)
`therapy has failed to provide adequate seizure con(cid:173)
`trol, despite using all appropriate drugs alone and
`in combination and in quantities sufficient to pro(cid:173)
`duce adequate seizure control without unaccepta(cid:173)
`ble side effects. Several issues are important in this
`consideration. One needs to ask: (1) what drug or
`combination of drugs should be used, (2) for what
`period of time should they be given, and (3) how
`should they be administered before drug failure
`can be established. It is also important to know
`what is the probability that failure of one drug can
`be overcome by administration of an alternative or
`by addition of other drugs.
`The response of patients to AED therapy varies
`over a wide range depending on epilepsy type, sei(cid:173)
`zure type and a variety of other factors that may be
`poorly defined. Nonetheless, the adequacy of sei(cid:173)
`zure control without unacceptable side effects
`from medication is very wide. Patients having idio(cid:173)
`pathic generalized epilepsy with absence, myoclo(cid:173)
`nic and tonic-clonic seizures can be fully control(cid:173)
`led in approximately 75-80% of cases without im(cid:173)
`5
`portant drug side effects. 2
`6 Because idiopathic
`'
`'
`generalized epilepsy is usually very successfully
`treated and because the disorder is generalized in(cid:173)
`stead of localized, surgical resection would not be
`indicated and consideration for corpus calloso(cid:173)
`tomy would only rarely be appropriate. Patients
`
`Correspondence to: R.H. Mattson, M.D., Neurology
`Service/127, DVA Medical Center, 950 Campbell Ave(cid:173)
`nue, West Haven, CT 06516, USA.
`
`with partial idiopathic-type epilepsy (benign rolan(cid:173)
`dic epilepsy) are easily and successfully treated. 1
`Many patients with symptomatic partial epilepsy
`having secondarily generalized tonic-clonic sei(cid:173)
`zures also can be well controlled with any of the
`primary AEDs including carbamazepine, pheno(cid:173)
`barbital, phenytoin, primidone or valproate. 11
`13
`15
`'
`,
`Patients are best managed initially by one of these
`drugs but may require combinations to achieve
`control of partial seizures. Many patients with this
`type of epilepsy are not controlled despite therapy
`with co-administered AEDs. 15
`Secondary generalized epilepsies are syndromes
`that usually arise in children or preteens and are
`associated with diffuse or multifocal brain disturb(cid:173)
`ance. Such diffuse brain disturbance may arise
`from a wide variety of etiologies including infec(cid:173)
`tion, trauma, and congenital abnormalities, but at
`times are of unknown cause. In certain secondary
`generalized epilepsies (e.g., Lennox-Gastaut syn(cid:173)
`drome), seizure control is poor in most patients re(cid:173)
`gardless of number or type of drugs administered.
`Seizures accompanying these epilepsies are fre(cid:173)
`quently multiple and include those of tonic-clonic,
`partial, absence, tonic, atonic, and myoclonic type.
`Many of these seizure types occur in the same pa(cid:173)
`tient. For most patients, neither a single AED nor
`a combination of drugs is effective in more than
`ameliorating the frequency and severity of attacks.
`Valproate is most often recommended due to its
`broad spectrum of ac~ion against all seizure types.
`The other major AEDs (i.e., carbamazepine, phe(cid:173)
`nobarbital, phenytoin, and primidone) are some(cid:173)
`what effective for partial, tonic-clonic and perhaps
`tonic seizures, but are of little value for the atonic,
`myoclonic and absence types. Indeed, some evi-
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`30
`
`100
`
`:::)
`
`<.9
`~ 80
`z
`~ 60
`0
`(.)
`1- 40
`z
`w
`(.) 5 20
`
`()_
`
`\\\.
`
`o......_
`'fk
`-........
`
`~--..
`~-o ___ o_
`
`--._.
`- - ... --.._
`-._. _ _
`-o-----..-------+--
`--o----o-._
`~~ o----o---o----o---o---o---~
`'-~~
`~~ ... -
`-.:r-~b--- ---·6-- -- -o.
`
`&.----&.=PB
`o--.=PHT
`.o.----...o.=PRM
`o---o=CBZ
`0~--~---L--~----~~~---L--~~--~--~--~--~--~
`24
`27
`21
`18
`30
`33
`36
`0
`12
`15
`3
`6
`9
`
`6.---·
`
`Fig. 1. Cumulative percentage of patients with simple and complex partial seizures successfully treated with each drug during 36 months of
`follow-up (from: N Engl.l Med., 313 (1985) 145, with permission).
`
`MONTHS
`
`the pro(cid:173)
`that they aggravate
`dence suggests
`blem.24'25 In such patients, the co-administration
`of one or more of these major epileptic drugs with
`ethosuximide or a benzodiazepine is therefore a
`common practice. When AED therapy has failed
`to control the seizures sufficiently to prevent injury
`from falls associated with recurrent attacks, sur(cid:173)
`gery may be considered for these medically intract(cid:173)
`able patients. Because a single resectable epileptic
`focus is not usually identifiable, palliative corpus
`callosotomy is the operation selected to prevent
`drug refractory seizures causing injury.26
`
`Localization-related (partial) symptomatic epilep(cid:173)
`sies
`
`Pharmacological treatment of localization-rela(cid:173)
`ted (partial) epilepsies is less successful than for
`idiopathic generalized epilepsies. Cortical surgical
`resection is primarily considered in those patients
`who have persistent partial and/ or secondary gen(cid:173)
`eralized tonic-clonic seizures despite optimal medi(cid:173)
`cal therapy. It is also assumed that optimal medical
`therapy has failed to produce control without un(cid:173)
`acceptable side effects. It is possible to extinguish
`virtually all seizures with sufficient administration
`of parenteral barbiturates, even in the most refrac(cid:173)
`tory cases of status epilepticus. Such aggressive
`treatment, of course, also produces coma. This ex(cid:173)
`treme example makes clear that efficacy alone is
`not the limiting factor in AED therapy. The combi-
`
`nation of efficacy and toxicity, or the therapeutic
`index of a drug or combination of drugs is the pri(cid:173)
`mary consideration. Although specific seizure types
`and side effects can be quantified, using a variety of
`rating scales 7
`, they often fail to relate specifically to
`an individual's quality of life. Patients respond dif(cid:173)
`ferently to the same drugs. For example, combina(cid:173)
`tion therapy causing sedation might prove unac(cid:173)
`ceptable for a student but be only an annoyance
`for another patient unable to attend school or be
`employed for other reasons. Excellent seizure con(cid:173)
`trol by drugs producing impotence might have a
`very satisfactory result for some sexually inactive
`patients but be intolerable for others. These princi(cid:173)
`ples are particularly important because more than
`one drug or combination of drugs needs to be used
`before concluding that a medication has failed.
`While these general concepts are important, it is
`also evident that an adequate trial of the best drug
`or drugs should be tested. Selection can be based
`on increasing evidence that has accumulated in re(cid:173)
`cent large multi-center studies which support find(cid:173)
`'13- 15 Over(cid:173)
`ings of smaller or uncontrolled trials. 11
`all, carbamazepine and phenytoin were found to be
`most successful in the treatment of partial and sec(cid:173)
`ondarily generalized tonic-clonic seizures in the VA
`Cooperative Study which c.ompared carbamaze(cid:173)
`pine, phenobarbital, phenytoin, and primidone
`(Fig. 1). The main reason for a more successful
`outcome of these two drugs was relatively less inci(cid:173)
`dence of side effects. Little efficacy difference could
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`31
`
`TABLE I
`
`SEIZURE CONTROL WITH 2 OR MORE ANTIEPILEPTIC DRUGS
`
`CBZ = carbamazepine; PHT =phenytoin; CZP = clorazepate; GVG = uigabatrin; PB phenobarbital; PRM = primidine.
`
`Study
`
`Baseline AED
`
`Added AED
`
`Patients
`(No.)
`
`Improved
`(%)
`
`Controlled
`(%)
`
`Follow-up
`(months)
`
`Rodin et al. 23
`Kosteljanetz et a1. 29
`Temkin/Wilensky30
`Browne et al. 3
`Mattson et a1. 15
`Dean and Penry 10
`
`PHT
`PB orPRM
`PHT
`Varied
`CBZ, PB, PfiT, PRM
`CBZ
`
`PRM orCBZ
`PHTorCBZ
`PB or CZP
`GVG
`Any
`VPA
`
`46
`23
`43
`84
`82
`100
`
`53
`39
`39
`
`17
`16
`7
`6
`11
`17
`
`3
`2
`4
`3
`12
`18
`
`be detected among drugs, although complete con(cid:173)
`trol of partial seizures was significantly better
`using carbamazepine compared to the barbiturates
`(Table 1). Heller et al. 13 and DeSilva et a1. 11 carried
`out a similar large comparative multi-center trial in
`the United Kingdom but studied valproate rather
`than primidon. They found no difference in effica(cid:173)
`cy among the four drugs but noted different types
`of side effects. Similar findings have been reported
`in controlled efficacy trials comparing these drugs
`when used as add-on or in crossover trials. 4
`27
`23
`'
`,
`
`Alternate monotherapy trials
`
`Because of the individual variation in response,
`it may be possible to give any one of these medica(cid:173)
`tions in higher and more effective doses than an(cid:173)
`other. Multiple medications with comparable ef(cid:173)
`ficacy in clinical trials still need to be tried sepa(cid:173)
`rately for each inadequately controlled individual
`patient. Troupin et al. 27 found that some patients
`responded better to carbamazepine and others to
`phenytoin in a crossover trial, despite the overall
`conclusion that both were equally effective. In the
`VA multi-center study, patients whose drug failed
`due to a combination of toxicity and insufficient
`efficacy were able to be adequately managed on an
`alternative drug in 46% of cases. 16 Approximately
`70% of these second drug treatments were success(cid:173)
`ful due to lesser toxicity, but some were a conse(cid:173)
`quence of improved seizure control. The number
`of patients converted from one drug to a second
`single drug was not sufficient to determine statisti(cid:173)
`cally a sequence of drug or drugs that was more
`
`successful, although there was a tendency suggest(cid:173)
`ing that carbamazepine and phenytoin elicited a
`more favorable response. Dean and Penry 10 stu(cid:173)
`died patients with partial epilepsy having partial
`and secondarily generalized tonic-clonic seizures.
`These patients had not been adequately controlled
`despite taking high carbamazepine doses up to the
`point of causing side effects. A crossover to valpro~
`ate resulted in improvement in 73% of patients.
`The largest improvement was seen in control of to(cid:173)
`nic-clonic seizures. They did not perform a cross(cid:173)
`over study placing patients on carbamazepine who
`had failed a trial of valproate but it may be expec(cid:173)
`ted that some such patients would profit from the
`crossover. No study has ever been done to deter(cid:173)
`mine how many AEDs need to be tried before one
`can conclude that the patient represents a mono(cid:173)
`therapy failure. Without sufficient data to make a
`definitive statement, it is the impression at our
`medical center that carbamazepine, phenytoin,
`one of the barbiturates, and valproate, alone or in
`combination, should each have been given ade(cid:173)
`quate trial. We do not proceed to an invasive surgi(cid:173)
`cal program until such treatment has been attemp(cid:173)
`ted but do not require trials of drugs such as me(cid:173)
`phenytoin, phenacemide or ethytoin.
`The emphasis to this point has been placed on
`selection of specific AEDs for treatment. Failures
`which occurred in th~ past cannot be considered
`reason to assume a similar lack of success at a la(cid:173)
`ter time. For example, historical detail may make it
`difficult to be sure that optimal dose was delivered
`in a continuous way to provide drug concentra(cid:173)
`tions up to the point of side effects. AED levels in
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`32
`
`the therapeutic range are not sufficient evidence of
`an adequate drug trial. It has been well established
`that some patients can tolerate levels of drugs such
`as carbamazepine or phenytoin well in excess of the
`so-called therapeutic range which produces side ef(cid:173)
`fects in many patients. 19 Full control may be
`achieved with these higher levels. Early drug fail(cid:173)
`ures especially during childhood may have resul(cid:173)
`ted from side effects less likely to be as prominent
`or important in adult life. An example is the dys(cid:173)
`morphic or cosmetic side effects of phenytoin seen
`in childhood such as increased body hair and gum
`hypertrophy. Vigorous dental hygiene may mini(cid:173)
`mize the latter problem in adult life or be tolerable
`if seizure control can be obtained. Hyperkinetic be(cid:173)
`havior produced by barbiturates in children may be
`replaced by sedation in the adult which again may
`be tolerated by some individuals. Full utilization of
`our knowledge of pharmacokinetics of AEDs may
`not have been available or used in early treatment,
`thereby causing earlier management problems.
`Large doses or inadequately spaced doses of carba(cid:173)
`mazepine may have produced toxicity at times of
`peak effect which might have been avoided by
`more even distribution of dosage. Optimal dosing
`of phenytoin may not have been carried out due to
`failure to understand saturation kinetics. The pa(cid:173)
`tient may have been treated with incremental do(cid:173)
`ses of a magnitude that led to phenytoin concentra(cid:173)
`tions going from the low therapeutic range into the
`toxic zone by the excessive addition of 100 mg to
`the daily dosage. Treatment with carbamazepine,
`primidone, or valproate may have been aban(cid:173)
`doned at an early time because initiation of drug
`therapy was too rapid to allow tolerance to early
`side effects. In summary, many apparent drug fail(cid:173)
`ures may at times better be described as manage(cid:173)
`ment failure by the physician or treating team.
`
`Seizure-inducing factors
`
`Control failure might also be the fault of the pa(cid:173)
`tient rather than the drug or physician. If the pa(cid:173)
`tient is involved in behavior which increases excit(cid:173)
`ability, recurrent seizures may be a consequence.
`The most frequent causes of such recurrent exacer(cid:173)
`bation is non-compliance with the treatment regi(cid:173)
`men. Some information about this factor is often
`available from the patient or family and a positive
`
`(but not a negative) report of failure to take medi(cid:173)
`cation can be assumed to be accurate. 8 Pill counts
`or frequency of prescription refills gives some indi(cid:173)
`cation of the total amount used over a period of
`time but gives no information about day-to-day in(cid:173)
`take. If a prescribed regimen of twice daily dosing
`has been prescribed, 60 tablets should be consumed
`in a month. The refill of a bottle of 60 at that time
`does not prove the two pills were taken on a daily
`basis. Four might be taken one day causing toxicity
`and none the next with consequent breakthrough
`seizures. Such a report would suggest that seizures
`were occurring despite excessive side effects. Deter(cid:173)
`mination of AED levels constituted a major ad(cid:173)
`vance in assessing medication use but primarily if
`a sample can be obtained close to the time of are(cid:173)
`current seizure. Recent introduction of a daily
`monitoring system using Medication Event Moni(cid:173)
`toring System (MEMS)8
`9 fills an important gap in
`'
`the understanding of this critical measure of deter(cid:173)
`mination of true AED failure. 12 In addition to
`medication compliance issues, the patient may
`have recurrent seizures as a consequence of other
`factors that modify cerebral excitability including
`excessive alcohol use or sleep deprivation. 17
`
`Duration of drug trial
`
`The duration of time over which a drug trial
`should be carried out is unclear. Remission data
`from the United Kingdom13 and the VA study18
`suggest that a significant number of patients enter
`remission in the first 2 years. Consequently, at least
`a 2-year period of poor control despite optimal
`AED therapy should be documented before drug
`failure is assumed.
`
`Combination drug therapy
`
`Drug therapy for some patients with partial epi(cid:173)
`lepsy will continue to give unsatisfactory control
`despite optimal administration of all the major
`AEDs and a lifestyle minimizing unfavorable sei(cid:173)
`zure threshold change .. At such a time a second or
`even a third drug is usually tried in an attempt to
`improve control (Fig. 2). Yahr et al. 28 reported
`that the combination of phenytoin and phenobar(cid:173)
`bital provided improved control of seizures com(cid:173)
`pared to use of either alone. The study was carried
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`
`33
`
`ANTIEPILEPTIC DRUG TREATMENT
`SINGLE DRUG TREATMENT
`
`Unsatisfactory Control
`35%
`~
`TWO DRUG TREATMENT
`
`NEW ONSET
`SEIZURE
`DISORDER
`
`Unsatisfactory Control
`25%
`~
`MULTIPLE DRUG TREATMENT
`
`Fig. 2. Flow chart of estimated percentages of patients whose seizures cannot be managed on single or multiple drug treatment.
`
`out in the era before AED blood levels were avail(cid:173)
`able to assure adequate dosage had been used and
`the trial was not in keeping with present concepts
`of a controlled design. VA study patients who failed
`monotherapy were placed on two drugs. These
`might be any combination of phenobarbital or pri(cid:173)
`midone with carbamazepine or phenytoin, as well
`as phenytoin plus carbamazepine. At the 12-
`month follow-up, improved control was obtained
`in 39% of patients. This was achieved at least in
`part by acceptance of greater side effects by the pa(cid:173)
`tients.15 Only 9% achieve complete control of all
`seizures. Dean and Penry10 used the combination
`of carbamazepine and valproate in a group of 100
`patients with partial epilepsy who could not be
`controlled with maximum tolerated doses of single
`drug therapy. On this program of duo-therapy,
`conducted over 2 years, improvement was ob(cid:173)
`tained and 17 patients achieved full control. A
`number of other studies have been carried out for
`shorter periods of time, usually during the course
`of trials for efficacy of new AEDs. These were
`
`usually given as medication added to a standard
`treatment and compared to placebo. Some in(cid:173)
`volved crossover comparisons. Using these designs
`carbamazepine, eterobarb, vigabatrin, clonazepam
`and other drugs (Table I) were studied for efficacy
`'20- 22'27 Although these trials in(cid:173)
`4
`and side· effects. 3
`'
`dicated efficacy for the combination of drugs there
`is no clear evidence that the primary AED, to
`which the investigational drug was added, was
`being administered in a maximally tolerated dose.
`Consequently, the trials provide evidence that the
`investigational drugs possessed efficacy, a require(cid:173)
`ment of the Food and Drug Administration for a
`New Drug Application (NDA), but do not clearly
`show evidence that the two (or three) drug combi(cid:173)
`nations possessed a better therapeutic index than
`one drug used optimally. Although the number of
`patients achieving complete control varied some(cid:173)
`what, in general, only 1 in 10 patients in these stu(cid:173)
`dies came under complete control even for short
`periods of observation on two or more drug combi(cid:173)
`nations. The conclusion that can be reached from
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`
`34
`
`available evidence is that combination drug ther(cid:173)
`apy may improve control, although usually at the
`expense of greater side effects. Only a very small
`percent of those individuals unsatisfactorily trea(cid:173)
`ted by monotherapy will achieve full control on
`combination drug treatment. It may be that a com(cid:173)
`parison between patients initially treated with two
`drugs compared to those treated with one drug
`would result in a greater number fully controlled
`on two-drug therapy, but such a case study has
`never been conducted. Perhaps patients failing sev(cid:173)
`eral trials of optimally managed single-drug ther(cid:173)
`apy may already be candidates for epilepsy sur(cid:173)
`gery.
`
`Summary and conclusion
`
`The success of AED therapy for epileptic sei(cid:173)
`zures varies according to epilepsy and seizure
`type. The outcome is excellent in the idiopathic
`generalized epilepsies, poor in the secondary gener(cid:173)
`alized epilepsies and intermediate for the partial
`epilepsies. For this latter group, a table of out(cid:173)
`come is described in Table I. Overall, approximate(cid:173)
`ly 70% of. patients can be reasonably managed
`using one AED, although several may need to be
`tried before considering monotherapy to be a fail(cid:173)
`ure. Of the 30% unsatisfactorily managed by
`monotherapy, approximately another one-third
`can be adequately managed given a combination
`of two drugs. Combinations of more than two
`drugs provide little if any additional benefit. Evi(cid:173)
`dence that such combinations have efficacy is infer(cid:173)
`red from the observation of seizure exacerbation
`when one drug is removed purposely to elicit sei(cid:173)
`zures during evaluation for possible epilepsy sur(cid:173)
`gery. The remaining patients are often considered
`for trial of an investigational drug although pro(cid:173)
`spects for important improvement are very small
`even with use of agents shown to be effective and
`introduced for treatment of epilepsy. Thus, 15% of
`patients may conservatively be considered for sur(cid:173)
`gical therapy. This would not suggest that all such
`patients are appropriate candidates from other as(cid:173)
`pects, but at least they can be considered to have
`failed all reasonable drug therapy.
`
`References
`
`Blom, S. and Heijbel, J., Benign epilepsy of children with
`centrotemporal EEG foci: a follow-up study in adulthood
`of patients initally studied as children, Epilepsia, 23 (1982)
`629-632.
`2 Bourgeois, B., Beaumanoir, A., Blajev, B. et al., Mono(cid:173)
`therapy with valproate in primary generalized epilepsies,
`Epilepsia, 28, Suppl. 2 (1987) S8-S11.
`3 Browne, T.R., Mattson, R.H., Penry, J.K. et al., Vigaba(cid:173)
`trin for refactory complex partial seizure, Neurology, 37
`(1987) 184-189.
`4 Cereghino, J.J., Brock, J.T., Van Meter, J.C., Penry, J.K.,
`Smith, L.D. and White, B. G., The efficacy of carbamaze(cid:173)
`pine combinations in epilepsy, Clin. Pharmacal. Ther., 18
`(1975) 733-741.
`5 Chadwick, D.W., Valproate monotherapy in the manage(cid:173)
`ment of generalized and partial seizures, Epilepsia, 28,
`Suppl. 2 (1987) S12-S17.
`6 Convanis, A., Gupta, A.K. and Jeavons, P.M., Sodium
`valproate: monotherapy and polytherapy, Epilepsia, 23
`(1982) 293-320.
`7 Cramer, J.A., Smith, D.B., Mattson, R.H. et al., A method
`of quantification for the evaluation of antiepileptic drug
`therapy, Neurology, 33 (1983) 26-37.
`8 Cramer, J.A., Mattson, R.H., Prevey, M.L., Scheyer, R.
`and Ouellette, V., How often is medication taken as pre(cid:173)
`scribed? A novel assessment technique, lAMA, 261 (1989)
`3273-3277.
`9 Cramer, J.A., Scheyer, R. and Mattson, R., Compliance
`declines between clinic visits, Arch. Intern. M ed., 150
`(1990) 1509-1510.
`10 Dean, J.C. and Penry, J.K., Carbamazepine/valproate
`therapy in 100 patients with partial seizures failing carba(cid:173)
`mazepine monotherapy: long-term follow-up, Epilepsia, 29
`(1988) 687.
`11 DeSilva, M., McGowan, M., Reynolds, E.H., Neville, B.
`and Johnson, A.L., Monotherapy for newly diagnosed
`childhood epilepsy: comparative trial and prognostic eval(cid:173)
`uation, Epilepsia, 30 (1989) 662.
`12 Feinstein, A.R., On white coat effects and the electronic
`monitoring of compliance, Arch. Intern. Med., 150 (1990)
`1377-1388.
`13 Heller, A.J., Chesterman, P., Elwes, R.D.C., Reynolds,
`E.H., Crawford, P., Chadwick, D. and Johnson, A.L.,
`Monotherapy for newly diagnosed epilepsy: a compara(cid:173)
`tive trial and prognostic evaluation, Epilepsia, 30 (1989)
`648.
`14 Hosking, G., The pediatric epiteg trial. In: D. Chadwick
`(Ed.), Fourth International Symposium on Sodium Valpro(cid:173)
`ate and Epilepsy, Roy. Soc. Med. Services, London, 1989,
`pp. 71-80.
`15 Mattson, R.H., Cramer, J.A .. et al., Comparison of carba(cid:173)
`mazepine, phenobarbital, phenytoin, and primidone in
`partial and secondary generalized tonic-clonic seizures, N.
`Engl. J. Med., 313 (1985) 145-151.
`16 Mattson, R.H., Cramer, J.A. and Collins, J.F., VA Epilep(cid:173)
`sy Cooperative Study Group, Success with alternate anti(cid:173)
`epileptic drug selection, Epilepsia, 27 (1986) 645.
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2005 page 7
`
`

`
`17 Mattson, R.H., Fay, M.L., Sturman, J.K., Cramer, J.A.,
`Wallace, J.D. and Mattson, E.M., The effect of various
`patterns of alcohol use on seizures in patients with epilep(cid:173)
`sy. In: R.J .. Porter, R.H. Mattson, J.A. Cramer, I. Dia(cid:173)
`(Eds.), Alcohol and Seizures, F.A. Davis,
`mond
`Philadelphia, PA, 1990, pp. 233-240.
`18 Mattson, R.H. and Cramer, LA., VA Epilepsy Coopera(cid:173)
`tive Study Group, Seizure remission after active epilepsy,
`Epilepsia, in press.
`19 Porter, R., How to use antiepileptic drugs. In: R.H. Levy,
`F.E. Dreifuss, R.H. Mattson, B.S. Meldrum and J.K. Pen(cid:173)
`ry, (Eds.), Antiepileptic Drugs, 3rd edn., Raven Press, New
`York, 1989, pp. 117-132.
`20 Reynolds, E.H., Chadwick,· D. and Galbraith, A.W., One
`drug (phenytoin) in the treatment of epilepsy, Lancet, i
`(1983) 923-926.
`21 Richens, A. and Ahmad, S., Controlled trial of sodium
`valproate in severe epilepsy, Br. Med. J., 4 (1975) 255-256.
`22 Rodin, E.A., Rim, C.A. and Rennick, P.M., The effects of
`carbamazepine on patients with psychomotor epilepsy: re(cid:173)
`sults of a double-blind study, Epilepsia, 15 (1974) 547-561.
`23 Rodin, E., Choo, S., Hideki, K., Lewis, R. and Rennick,
`P., A comparison of the effectiveness of primidone versus
`carbamazepine in epileptic outpatients, J. Nerv. Ment.
`Dis., 163 (1976) 41-46.
`
`35
`
`24 Snead, O.C. and Hosey, L.C., Excerbation of seizures in
`children by carbamazepine, N. Engl. J. Med., 31 (1985)
`916-921.
`25 Shields, W.D. and Saslow, E., Myoclonic, atonic and ab(cid:173)
`sence seizures following carbamazepine therapy in chil(cid:173)
`dren, Neurology, 33 (1983) 1487-1489.
`26 Spencer, S.S., Corpus callosum section and other discon(cid:173)
`nection procedures for medically intractable epilepsy,
`Epilepsia, 29 (1988) S85-S99.
`27 Troupin, A.S., Green, J.R. and Halpern, I.M., Carbama(cid:173)
`zepine (Tegretol) as an anticonvulsant: a controlled dou(cid:173)
`ble-blind comparison of diphenylhydantoin (Dilantin),
`Acta Neural. Scand., 75, Suppl. 1 (1975) S13-S26.
`28 Yahr, M.D., Sciarra, D. and Carter, S., Evaluation of
`standard anticonvulsant therapy of 319 patients, JAMA,
`150 (1952) 663-667.
`29 Kosteljanetz, M., Christiansen, J., Dam, A.M. et al., Car(cid:173)
`bamazepine versus phenytoin, Arch. Neural., 36 (1979)
`22-24.
`30 Temkin, N.R. and Wilensky, A.J., New AEDs: are the
`compounds or the studies ineffective?, Epilepsia, 27 (1986)
`644-645.
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2005 page 8