Assessment Report: the Clinical Effectiveness and Cost-Effectiveness

The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy

Report commissioned by: NHS R&D HTA Programme

On behalf of: The National Institute for Clinical Excellence

Produced by: West Midlands Health Technology Assessment Collaboration, Department of Public Health and Epidemiology, The University of Birmingham

Authors: alphabetical Prof Stirling Bryan Senior health economist# Dr Martin Connock Systematic reviewerÃ Dr Carole Cummins Paediatric trials adviser† Emma Frew Health economist# Anne Fry-Smith Information specialistÃ Beti-Wynn Jones Systematic reviewer‡ Prof Alain Li Wan Po Pharmacological adviser†† Josie Sandercock Senior reviewerÃ

Ã Department of Public Health and Epidemiology, The University of Birmingham. # Health Economics Facility, Health Services Management Centre, The University of Birmingham. † Institute of Child Health, Whittal Street, Birmingham. †† Centre for Evidence-Based Pharmacotherapy, Aston University, Birmingham. ‡ Department of Medicine Management, Keele University

Correspondence to:

J. Sandercock, Tel 0121-414-2247. Email [email protected] M. Connock, Tel 0121-414-7507. Email [email protected] West Midlands Health Technology Collaboration, Department of Public Health and Epidemiology, The University of Birmingham, Edgbaston, Birmingham B15 2TT. FAX 0121- 414-7878

Date completed: February 2003

Expiry Date: Expiry date

Newer Drugs for Children with Epilepsy

PUBLICATION INFORMATION How to reference this publication: Connock M, Frew E, Jones B, Bryan S, Cummins C, Fry-Smith A, Li Wan Po A, Sandercock J. The clinical effectiveness and cost effectiveness of newer drugs for children with epilepsy. Birmingham: West Midlands Health Technology Collaboration, University of Birmingham, February 2003

ABOUT “HOME UNIT” The West Midlands Health Technology Assessment Collaboration (WMHTAC) produces rapid systematic reviews about the effectiveness of healthcare interventions and technologies, in response to requests from West Midlands Health Authorities or the HTA programme. Reviews usually take 3-6 months and aim to give a timely and accurate analysis of the quality, strength and direction of the available evidence, generating an economic analysis (where possible a cost-utility analysis) of the intervention.

CONTRIBUTIONS OF AUTHORS Josie Sandercock Directed the review, assisted with the review of effectiveness, contributed to development of the decision-analytic model, wrote sections of the report Martin Connock Led the review of effectiveness, extracted data, wrote sections of the report Stirling Bryan Helped direct review, assessed industry models, conceived, developed and analysed decision-analytic model, wrote sections of the report Beti-Wynn Jones Developed and piloted data extraction form, extracted data, wrote sections of the report Emma Frew Assessed industry models, conceived, developed and analysed model, wrote sections of the report Anne Fry-Smith Performed literature searches, wrote sections of report Carole Cummins Wrote sections of the report, advised on paediatric aspects of the report Alain Li Wan Po Wrote sections of report, advised on pharmacology

CONFLICTS OF INTEREST: Source of funding This report was commissioned by the NHS R&D HTA programme. Relationship of reviewer(s) with sponsor No members of the review team or the units to which they belong at the University of Birmingham, University of Aston , or Birmingham Children’s Hospital have any pecuniary relationship with sponsors, specific or non-specific.

ACKNOWLEDGEMENTS We gratefully acknowledge the assistance of the following: Dr William Whitehouse, Dr Tim Betts, Professor David Chadwick, Dr Tony Johnson, Dr Richard Appleton, Dr Helen Cross, Dr Colin Ferrie, Dr Robert Smith, Dr John Gibbs, Professor Frank Besag, Dr Pelham Barton, Janine Dretzke.

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CONTENTS

1. AIM OF THE REVIEW...... 13 “Newer” drugs for epilepsy ...... 14 2. BACKGROUND ...... 15 2.1 Description of underlying health problem...... 15 2.1.1 Nature of condition ...... 15 2.1.2 Epilepsy in children ...... 17 2.1.3 Diagnosis...... 20 2.1.4 Aetiology and pathology...... 21 2.1.5 Epidemiology...... 23 2.1.6 Prognosis...... 24 2.1.7 Significance in terms of ill-health...... 25 2.2 Current service provision...... 26 2.2.1 Goals of service provision...... 26 2.2.2 Standards of current service provision...... 27 2.2.3 Current service provision...... 28 2.2.4 Treatment with anti-epileptic drugs (AEDs) ...... 29 2.2.5 Non AED treatments...... 32 2.3 Description of new intervention ...... 35 2.3.1 Mechanism of action...... 35 3. EFFECTIVENESS...... 37 3.1 Methods for reviewing effectiveness...... 37 3.1.1 Search strategy...... 37 3.1.2 Inclusion and exclusion criteria ...... 38 3.1.3 Data extraction strategy ...... 38 3.1.4 Quality assessment strategy ...... 38 3.2 Results...... 39 3.2.1 Number and types of studies identified ...... 39 3.2.2 Mixed age studies ...... 41 3.2.3 Partial seizures (with or without secondary generalisation) ...... 43 3.2.4 Partial and generalised seizures (mixed population) ...... 65 3.2.5 Generalised seizures...... 70 3.2.6 Lennox-Gastaut syndrome...... 74 3.2.7 Infantile spasms (West’s syndrome)...... 80 3.2.8 Absence Epilepsy...... 88 3.2.9 BECTS ...... 91 3.2.10 Mixed population...... 93 3.2.11 Summary of RCT evidence...... 97 3.2.12 Ongoing Trials...... 98 4. ECONOMIC ANALYSIS OF NEWER ANTI-EPILEPTIC DRUGS IN CHILDREN...... 99 4.1 Summary ...... 99 4.1.1 Commentary on company submissions that modelled childhood epilepsy...... 99 4.1.2 Summary of the Birmingham epilepsy model ...... 99 4.2 Introduction...... 100

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4.3 Systematic review of existing economic analyses...... 100 4.3.1 Review of submission models ...... 100 4.4 Birmingham economic analysis...... 103 4.4.1 Overview of decision–analytic model ...... 103 4.4.2 Summary of model parameters ...... 106 4.4.3 Drug sequences compared in the analysis ...... 107 4.4.4 Quality of life for children with epilepsy...... 109 4.4.5 Costs associated with care for children with epilepsy ...... 111 4.4.6 Time spent in each model outcome ...... 113 4.4.7 Drug-specific proportions (for main outcome states) ...... 118 4.4.8 Proportions moving into secondary model states ...... 122 4.4.9 Methods of analysis ...... 123 4.4.10 Cost-effectiveness results...... 124 4.5 Conclusions...... 129 5. IMPLICATIONS FOR OTHER PARTIES ...... 130 6. DISCUSSION ...... 130 6.1 Clinical effectiveness...... 130 6.2 Cost-effectiveness...... 131 6.3 Assumptions, limitations and uncertainties ...... 131 6.4 Need for further research ...... 132 7. CONCLUSIONS ...... 132 8. APPENDICES ...... 133 9. REFERENCES...... 372

Appendices Appendix 1 Details of intervention drugs...... 134 Appendix 2 Treatment choices ...... 139 Appendix 3 Influential factors for adverse effects of AEDs in children ...... 147 Appendix 4 Long-term adverse effects...... 152 Appendix 5 Drug interactions with the contraceptive pill...... 154 Appendix 6 Teratogenecity...... 155 Appendix 7 Search strategies...... 158 Appendix 8 Studies with mixed age populations...... 170 Appendix 9 RCT publications of mixed-age studies ...... 173 Appendix 10 List of excluded studies...... 247 Appendix 11 Unobtainable publications...... 252 Appendix 12 Health state questionnaire...... 253 Appendix 13 Trial data ...... 254

TABLES Table 1 Prevalence and incidence of ILEA classified epilepsy syndromes of childhood...... 19 Table 2 Incidence of epilepsy in children of different age; (new cases /100,000 person years†) ...... 23 Table 3 Systematic reviews ...... 39 Table 4 Systematic reviews in preparation...... 41 Table 5 Mixed age studies giving age range of patients...... 41 Table 6 Summary of trials and trial design (newly diagnosed partial seizures)...... 45 Table 7 Quality assessment (newly diagnosed partial seizures) ...... 46 Table 8 Results (newly diagnosed partial seizures) ...... 47 Table 9 Adverse events (newly diagnosed partial seizures) ...... 48 Table 10 Summary of trials and trial design (previously diagnosed partial seizures) ...... 51 Table 11 Quality assessment (previously diagnosed partial seizures)...... 54 4 Newer Drugs for Children with Epilepsy

Table 12 Results (previously diagnosed partial seizures)...... 57 Table 13 Adverse events (previously diagnosed partial seizures) ...... 62 Table 14 Summary of trials and trial design (population with partial and generalised seizure types)66 Table 15 Quality assessment (population with partial and generalised seizure types)...... 67 Table 16 Results (population with partial and generalised seizure types)...... 68 Table 17 Adverse events (population with partial and generalised seizure types)...... 69 Table 18 Summary of trials and trial design (generalised seizures)...... 71 Table 19 Quality assessment (generalised seizures) ...... 72 Table 20 Results (generalised seizures) ...... 73 Table 21 Adverse events (generalised seizures) ...... 73 Table 22 Summary of trials and trial design (Lennox-Gastaut syndrome)...... 75 Table 23 Quality assessment (Lennox-Gastaut syndrome) ...... 76 Table 24 Results (Lennox-Gastaut syndrome) ...... 77 Table 25 Adverse events (Lennox-Gastaut syndrome)...... 79 Table 26 Summary of trials and trial design (infantile spasms / West’s syndrome)...... 82 Table 27 Quality assessment (infantile spasms / West’s syndrome)...... 83 Table 28 Results (infantile spasms / West’s syndrome)...... 84 Table 29 Adverse events (infantile spasms / West’s syndrome)...... 87 Table 30 Summary of trials and trial design (absense epilepsy) ...... 89 Table 31 Quality assessment (absence epilepsy)...... 89 Table 32 Results (absense epilepsy)...... 90 Table 33 Adverse events (absense epilepsy) ...... 90 Table 34 Summary of trials and trial design (BECTS) ...... 91 Table 35 Quality assessment (BECTS)...... 91 Table 36 Results (BECTS)...... 92 Table 37 Adverse events (BECTS)...... 92 Table 38 Summary of trials and trial design (mixed population) ...... 94 Table 39 Quality assessment (mixed population)...... 95 Table 40 Results (mixed population)...... 95 Table 41 Adverse events (mixed population)...... 95 Table 42 Relevant ongoing trials identified...... 98 Table 43 Review of economic analyses within the GlaxoSmithKline submissions...... 101 Table 44 Review of economic analyses within the Janssen-Cilag submission ...... 103 Table 45 Model parameter list...... 106 Table 46 EuroQol EQ-5D states and scores for the 6 epilepsy model states...... 110 Table 47 Costs‡ associated with all AEDs considered in the model ...... 112 Table 48 Resource use and costs for patients with neurological impairment...... 112 Table 49 Proportions moving into the main model outcome states...... 120 Table 50 Proportions moving into secondary model states...... 122 Table 51 Analysis results 1...... 125 Table 52 Analysis results 2...... 126 Table 53 Analysis results 3...... 127 Table 54 Analysis results 4...... 128 Table 55 Details of newer drugs for treatment of epilepsy...... 134 Table 56 Treatment choices for children for various seizure types and epilepsy syndromes †...... 139 Table 57 Licensed indications for anti-epileptic drugs ...... 140 Table 58 Putative factors for altered pharmacokinetics of AEDS in infancy and childhood...... 148 Table 59 Matrix showing interactions between antiepileptic drugs ...... 150 Table 60 Potential for adverse cognitive effects of commonly used anti-epileptic drugs...... 153 Table 61 Interaction of AEDs & oral contraceptives with potential loss of contraceptive cover...... 155 Table 62 Teratogenecity of AEDs...... 156 Table 63 Mixed age publications listed by diagnosis, drug and year of publication...... 170 Table 64 [1] Aika, 1999 137 ...... 173 Table 65 [2] Lindberger, 2000138 ...... 174 Table 66 [3]. Binnie, 1989139...... 175 Table 67 [4]. Cramer, 2000140 ...... 176 Table 68 [5]. Barcs, 2000141...... 177 Table 69 [6]. Cramer, 2001287 ...... 177 Table 70 [7]. Brodie, 1997142 abstract...... 179 Table 71. [8] Tanganelli,1993143...... 180 Table 72 [9]. Canger, 1997144...... 180

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Table 73 [10]. Chadwick, 1999145 ...... 182 Table 74 [11]. Andrews, 1990146[UK gabapentin group] ...... 183 Table 75 [12]. Sivenius, 1991147...... 184 Table 76 [13]. McLean, 1993148 [US gabapentin study group] ...... 185 Table 77 [14]. Anhut, 1994149 ...... 185 Table 78 [15]. Leach, 1997150...... 187 Table 79 [16]. Lopes-Lima, 1999288 abstract ...... 188 Table 80 [17]. Schapel, 1993151 ...... 189 Table 81 [18] Smith, 1993152...... 190 Table 82 [19]. Severi, 1994153 ...... 191 Table 83 [20]. Cereghino, 2000154 ...... 192 Table 84 [21]. Cramer, 2000155 ...... 193 Table 85 [22]. Shorvon, 2000156 [same patient group as Boon 2002289]...... 194 Table 86 [23] Boon, 2002289 [same patient group as Shorvon 2000156]...... 194 Table 87 [24]. Schachter, 1999157...... 195 Table 88 [25]. Lee, 1999158 [Korean topiramate study group] ...... 196 Table 89 [26]. Dodrill, 1993290 [same trial as French, 1993 299]...... 198 Table 90 [27] Grunewald,1994159...... 198 Table 91 [28]. Brodie, 1999160 ...... 200 Table 92 [29]. Dodrill, 1997161 [some details from Uthman, 1998291] ...... 201 Table 93 [30]. Uthman, 1998291...... 201 Table 94 [31]. Dodrill, 2000162 ...... 203 Table 95 [32]. Beran, 1996163 ...... 203 Table 96 [33]. Ben Menachem, 1995164...... 205 Table 97 [34]. Ben Menachem, 2000165...... 206 Table 98 [35]. Sachdeo, 1997166 ...... 207 Table 99 [36]. Rimmer, 1984167...... 208 Table 100 [37]. Gram, 1984168...... 210 Table 101 [38]. Cramer, 1995169 ...... 211 Table 102 [39]. Provinciali, 1996170...... 212 Table 103 [40]. Chadwick, 1996171 ...... 213 Table 104 [41]. Beran, 1998172 ...... 213 Table 105 [42]. Biton, 1999173...... 214 Table 106 [43]. Chadwick, 1999174 ...... 216 Table 107 [44]. Brodie, 1995175 ...... 217 Table 108 [45]. Dam, 1996176 ...... 217 Table 109 [46]. Reunanen, 1996292 ...... 219 Table 110 [47]. Steiner, 1999177 ...... 219 Table 111 [48]. Gillham, 2000293 [details as Brodie, 1995175] ...... 221 Table 112 [49]. Kalogjera, 2000178 abstract...... 222 Table 113 [50]. Biton, 2001242...... 222 Table 114 [51]. Edwards, 2001294; details as Biton, 2001242...... 223 Table 115 [52]. Dam, 1989179 ...... 225 Table 116 [53]. Aikia, 1992295 ...... 226 Table 117 [54]. Bill, 1997300 ...... 227 Table 118 [55]. Christe, 1997181 ...... 228 Table 119 [56]. Wheless, 2001182 abstract ...... 229 Table 120 [57]. Kalviainen, 1995183 ...... 229 Table 121 [58]. Binnie, 1987184...... 231 Table 122 [59]. Betts, 2000185...... 231 Table 123 [60]. Houtkooper, 1987186 ...... 232 Table 124 [61]. Coles, 1999296 abstract ...... 233 Table 125 [62]. Loiseau, 1986187...... 234 Table 126 [63]. Tartara, 1986188...... 235 Table 127 [64]. Rimmer, 1987189...... 237 Table 128 [65]. Tassinari, 1987190 ...... 238 Table 129 [66]. Reynolds, 1988192 abstract...... 239 Table 130 [67]. Reynolds, 1991191 ...... 240 Table 131 [68]. Gillham, 1993193 [same trial as McKee, 1993297]...... 240 Table 132 [69]. McKee, 1993297 [same trial as Gillham, 1993193]...... 242 Table 133 [70]. Carmant, 1999194 abstract interim results only...... 243

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Table 134 [71]. Kerr, 1999298 abstract interim results only...... 243 Table 135 [72]. Montouras, 1999195 abstract [interim results only] ...... 244 Table 136 [73]. Fakhoury, 2000196 abstract...... 246 Table 137 List of excluded studies with reasons for exclusion...... 247 Table 138 List of unobtainable publications ...... 252

FIGURES Figure 1 CONFIDENTIAL INFORMATION REMOVED ...... 103 Figure 2 CONFIDENTIAL INFORMATION REMOVED ...... 103 Figure 3 Patient pathway for a child with newly diagnosed partial epilepsy ...... 104 Figure 4 No New Drug Strategy...... 108 Figure 5 Time to withdrawal due to toxicity or lack of efficacy, estimated from Chadwick et al, 1999 ...... 116 Figure 6 Extrapolation of Chadwick et al data beyond 12 months...... 116 Figure 7 Treatment retention curves for withdrawal due to side effects and lack of efficacy...... 117 Figure 8 Relative percentage renal and hepatic elimination of anti-epileptic drugs...... 148

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EXECUTIVE SUMMARY

Description of proposed service Since 1989, seven “newer” anti-epileptic drugs (AEDs) have become available: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and vigabatrin. These AEDs have variously different licensed indications and modes of action; levetiracetam is licensed for use only in patients over the age of 16 and is thus not considered in this review. The aim of AED treatment is to reduce epilepsy seizure frequency and enhance patient’s quality of life with as few side effects and as few co- medications as possible while minimising long-term detrimental effects. This systematic review examines the clinical effectiveness and cost effectiveness of these newer AEDs for epilepsy in children.

Epidemiology and background A large proportion of epilepsy begins in childhood. In an average health authority there will be ~40 to 140 new consultations per annum for epilepsy in children 0-15 years old, and ~50-150 for children between 0 and 19 years old. Many more consultations will occur for seizures not diagnosed as epilepsy. The prevalence of epilepsy in children (up to 15 years old) is about 5-7/1000. Many types of epilepsy occur in children, with diagnosis depending on the type of seizure (simple partial, complex partial, partial becoming generalised, generalised) and aetiology (symptomatic, idiopathic, cryptogenic); several epileptic syndromes have been described, including Lennox-Gastaut, infantile spasms (or West’s syndrome), childhood absence epilepsy, benign epilepsy with centro-temporal spikes. There are many possible causes of epilepsy but often this cannot be determined. Diagnosis is difficult and misdiagnosis may be frequent. Although some childhood epilepsies are relatively benign, but some have detrimental impact on psychological, social and intellectual development, and in severe cases the effect on individual, carer(s) and family can be devastating.

Number and quality of studies, and direction of evidence The quality of the RCT data was generally poor, with many giving cause for concern over the integrity of randomisation, quality of blinding, and/or analytical methods employed. Most of the trials were conducted for licensing purposes and are thus of limited use in informing clinical practice; whilst it is clear that these agents may be useful additions to the list of AEDs available, there is very little data upon which to base a rational prescribing strategy.

Twenty trials were identified which reported outcome data for children with epilepsy; 15 have been published in full and 5 in abstract form only. Trials were identified in children with partial seizures (with or without secondary generalisation), generalised seizures (including Lennox-Gastaut syndrome), Lennox-Gastaut syndrome, infantile spasms, absence epilepsy and BECTS. Fifteen of the 20 trials identified used placebo as comparator, with 5 trials using active comparator treatments.

8 Newer Drugs for Children with Epilepsy

Summary of benefits

For each of the epilepsy sub-types considered in RCTs identified for this review (partial epilepsy with or without secondary generalisation, Lennox-Gastaut syndrome, infantile spasms, absence epilepsy and BECTs), there is some evidence from placebo- controlled trials that the newer agents tested are of some value in the treatment of these conditions. Where active controls have been used the limited evidence available does not indicate a difference in effectiveness between newer and older drugs. The data are not sufficient to inform a prescribing strategy for any of the newer agents in any of these conditions. In particular, there is no clinical evidence to suggest that the newer agents should be considered as a first choice treatment in any form of epilepsy in children.

Costs

Annual drug costs of the newer agents ranges from around £400 to £1200, depending on age and concomitant medications. An AED which is ineffective or has intolerable side effects will only be used for a short period of time, whilst many patients achieving seizure freedom will successfully withdraw from drug treatment without relapsing.

Cost/QALY

The results suggest that the uncertainty in the model is greater than the differences between the drug strategies, with results varying from dominance (the use of newer drugs reduces the utility of treatment) to clearly cost-effective (cost per QALY well within an acceptable range). The results do not suggest that the use of the newer agents in any of the scenarios considered is clearly cost-effective, but similarly, do not indicate that they are clearly not cost-effective.

Other issues

It is important to note that there is a substantial difference between the population of newly or recently diagnosed patients, many of whom will have extremely good outcomes regardless of which AEDs are chosen for initial treatment, and the smaller population with intractable epilepsy, who experience little or no benefit after trying a number of different treatments. There is reasonably clear evidence from placebo- controlled trials of the newer agents that they may have some beneficial impact on the disease, and it is desirable that as many treatment options as possible remain available for this group of patients. The cost of using the newer agents in this context for these patients is likely to be small, due to the relatively small proportion of patients reaching this stage and the likelihood that the duration of treatment would be short unless the drugs were perceived to be of benefit. 9 Newer Drugs for Children with Epilepsy

Need for further research Better information is required from RCTs before any rational evidence-based prescribing strategy could be developed. Ideally, RCTs should be conducted from a ‘public health’ perspective, making relevant comparisons and incorporating outcomes of interest to clinicians and patients, with sufficiently long-term follow-up to reliably determine the clinical utility of different treatments, particularly with respect to treatment retention and the balance between effectiveness and tolerability. RCTs should mirror clinical practice with respect to diagnosis, focusing on defined syndromes or, where no syndrome is identified, on groups defined by specific seizure type(s) and aetiology.

Epilepsy in children is a complex disease, with a variety of quite distinct syndromes, many alternative treatment options, and outcomes. Diagnosis-specific decision- analytic models are required; further research may be required to adequately inform parameter values with respect to epidemiology and clinical practice.

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ABBREVIATIONS A & E Accident and emergency ACTH Adrenocorticotrophic hormone AE Adverse events AED Antiepileptic drug ANOVA Analysis of variance ARIF Aggressive Research Intelligence Facility BECTS Benign (partial) Epilepsy with Centrotemporal Spikes CBZ Carbamazepine CCTR Controlled Clinial Trials Register (Cochrane) CEA Cost effectiveness analysis CI Confidence interval CRD Centre for Reviews and Dissemination CT Computed tomography CUA Cost utility analysis DARE Database of reviews of effectiveness DB Double blind EED Economic evaluation database EEG Electro-encephalogram EIAED Enzyme inducing antiepileptic drug EL Executive letter GABA Gamma-amino-butyric acid GPRD General practice research database HEED Health economic evaluation database HRQL Health related quality of life ICER Incremental cost effectiveness ratio ILAE International League Against Epilepsy ITT Intention to treat analysis JME Juvenile myoclonic epilepsy LTG Lamotrigine MHD Mono hydroxy derivative MRI Magnetic resonance imaging NA Not applicable NGPSE National General Practice Study of Epilepsy NMDA N-methyl-D-aspartate ONS Office of National Statistics OXC Oxcarbazepine PET Positron emission tomography PHT Phenytoin QALY Quality adjusted life year RCT Randomised controlled trial SPECT Single photon emission computed tomography VNS Vagus nerve stimulation VPA Valproate

11 Newer Drugs for Children with Epilepsy

DEFINITIONS OF TERMS CT Computed tomography is a non-invasive imaging technique using X-rays to produce pictures as though they were successive slices through the body. Cytochrome P A family of enzyme systems, especially rich in the liver, which modify drugs monooxygenase and a wide variety of other molecules by introducing an oxygen molecule into their structure using molecular oxygen as a source. They are important in sending drugs on their elimination pathway from the body and/or in activating drugs to their therapeutic form. EEG EEG uses a system of electrodes placed in various positions over the scalp that detect the electrical activity in underlying regions of the brain. The electrode signals are displayed as wave patterns through time. Abnormal patterns can help in the diagnosis of epilepsy and in some cases aid the localization of the part of the brain initiating seizure activity. EEG is best performed and interpreted by experienced personnel. MRI Magnetic resonance imaging. A non-invasive imaging method based on the principles of nuclear magnetic resonance. Use of contrast agents improves sensitivity and/or specificity of the imaging. MRI allows detection and localization of damaged or abnormal brain structures. Functional MRI gives images depending on blood oxygen supply to brain structures which reflect their functional performance. PET Positron Emission Tomography is an imaging system that highlights active regions of the brain. It uses a glucose-like tracer molecule tagged with a radioactive atom that decays by emitting a positron. The emitted positron immediately collides with an electron, they mutually annihilate and their mass energy is converted into back-to-back gamma rays that travel out of the brain and are detected with gamma cameras. The information gathered by the cameras is integrated to form an image. Active regions of the brain will contain more tracer and produce a stronger signal.

SPECT SPECT imaging involves the rotation of a photon detector array around the body to acquire data from multiple angles.

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1. AIM OF THE REVIEW

Objectives / Purpose of review

Since the 1980s several new drugs for treatment of epilepsies have been developed and have gradually diffused into clinical practice. In childhood epilepsy they are most often used as add on therapy to conventional drugs or as a second line mono-therapy; but some are used as first line therapy (e.g. lamotrigine for generalized seizures and vigabatrin for infantile spasms) and there is a clear potential for other uses in first line mono-therapy. Tolerability as well as effectiveness is a primary consideration, particularly as in cases of refractory epilepsy drug administration is often gradually titrated to the maximally tolerated dosage before changing to an alternative or trying additional drugs.

The following questions will be addressed concerning the use of these drugs:

1. What is the clinical effectiveness, tolerability and cost effectiveness of newer antiepileptic drugs used in mono-therapy when compared with current standard drug treatment for epilepsy in children? 2. What is the clinical effectiveness, tolerability and cost effectiveness of newer antiepileptic drugs used as add-on therapy when compared with current standard drug treatment for epilepsy in children?

The population of interest for this review is children with newly diagnosed epilepsy or treatment-resistant (refractory) epilepsy. Single seizures, status epilepticus, seizures following neurosurgery or head injury, febrile convulsions and trigeminal neuralgia are excluded from the appraisal. As effectiveness and the balance between harm and benefits of drug treatment vary according to epilepsy syndrome and seizure type, the above questions will need to addressed for both individual syndromes (e.g. Lennox- Gastaut syndrome and West’s syndrome) and for broad groups of seizure types (e.g. generalised, absence or partial).

Children are defined here as neonates (birth to 1 month), infants (1 month to 2 years), children (2 to 12 years) and adolescents (12 to 18 years). Some studies containing information relevant for this review may be trials in adults that include a substantial proportion of people under 18 years old.

The optimal choice of drug for adolescents may differ from that for younger children, as side effects, particularly cosmetic ones, may reduce the acceptability of the drug. Given the teratogenic potential of some AEDs and also that some enzyme-inducing AEDs reduce the effectiveness of oral contraceptives special consideration needs to be given to their use in adolescent girls.

Some kinds of epilepsy are associated with brain damage or, rarely, frequent severe seizures may lead to brain damage. Anti-epileptic treatment for these children requires careful monitoring as some treatments may cause or exacerbate learning difficulties and adverse effects of treatment may be difficult to ascertain.

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Nature of the disease

Epilepsy is a condition in which epileptic seizures recur. The many seizure types can be defined as intermittent, paroxysmal stereotyped disturbances of consciousness, behaviour, emotion, motor function, perception or sensation (which may occur singly or in any combination) that on clinical grounds result from cortical neuronal discharge. Important consequences for children and young people with epilepsy include not only the seizures themselves, but also the social, educational and psychological impact of the condition and treatment. Seizures can be broadly categorised as ‘partial’ that begin locally, or as ‘generalised’ (including absence seizures) that involve abnormal activity in both cortical hemispheres. Partial seizures can be subcategorised as simple (consciousness unimpaired) or complex (consciousness impaired). Seizure type, age at onset, EEG findings and associated features, including whether the epilepsy is symptomatic or cryptogenic, may allow the identification of an epilepsy syndrome (e.g. West's and Lennox-Gastaut syndromes), but in 30 to 40% of children it is not possible to identify a syndrome. The choice of drug treatment and the prognosis of childhood epilepsy depend upon the syndrome, or where a syndrome has not been identified, upon the seizure type. About a quarter of patients have epilepsy resistant to traditional therapy; in children refractory seizures are most often generalized.

“Newer” drugs for epilepsy

Since 1989, seven new anti-epileptic drugs have become available in the UK for use in the treatment of epilepsy; gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and vigabatrin. Licensed indications vary within the age group of 0 to18 years, and with the exception of tiagabine and levetiracetam, are licensed to some extent for in children aged 12 and under.

“Standard” treatments and comparisons to be made.

Current standard treatments include older anti-epileptics (e.g. carbamazepine, phenytoin, valproate), surgery and, rarely, ketogenic diet. This review will consider the use of the newer anti-epileptic drugs compared to current best practice in the UK, ie treatment which would be recommended if none of the newer agents were available (‘standard’ treatment). Note that for some conditions, standard treatment may not involve the use of anti-epileptic drugs.

Drug doses with anti-epileptics are dependent on the pharmacokinetics and pharmacodynamics of the drugs in individual patients which in turn depend on factors such as age/size of patient and concomitant drug treatment. A particularly important aspect of RCTs is therefore that appropriate doses of both intervention and comparator drug have been employed so that a valid assessment can be made of the relative effectiveness and tolerability of the intervention. Appropriate doses of comparators will be taken into account when assessing the quality of studies.

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2. BACKGROUND

2.1 Description of underlying health problem

2.1.1 Nature of condition Epilepsy is a condition in which epileptic seizures recur. Epileptic seizures are episodes of sudden disruption of brain function associated with abnormal high firing rates and synchronisation of neurons in defined regions of the brain.1 Synchronised high firing rate of populations of neurons is in itself a normal brain activity, but the following distinguishing features characterise an epileptic event:2 • Paroxysmal nature- sudden emergence from and quick return toward previously relatively normal neuronal brain activity. • Disruption of normal brain function. • Involvement of all or most of the neurons in a defined brain region. • Association with high firing rate in many of the neurons in the involved region. The diagnosis of epilepsy, however, is made on clinical grounds, and the history of the events is critically important, as further investigations may be negative in the presence of epilepsy. Many other conditions of childhood and adolescence can be mistaken for epilepsy, and where a child with apparent epilepsy does not respond to treatment, the diagnosis may need to be reviewed.3 An epileptic seizure is a single episode of disturbance. Seizures are enormously diverse and are accompanied by an array of clinical manifestations; they are broadly categorised into partial seizures, involving a small localised region of the brain in one hemisphere, and generalised which simultaneously involve both sides of the brain. Partial seizures may evolve secondarily into generalised. Partial seizures accompanied by impaired consciousness are termed complex in distinction from simple seizures in which consciousness is unaffected; during a complex partial seizure the patient may appear as if in a trance and may exhibit automated behaviours such as lip smacking or fidgeting hand movements. It can be difficult to correctly identify sizures, for example, determination of an infant’s state of consciousness is difficult. The precise form of partial seizures is determined by their site of origin and may involve, for example, twitching on one side of the body or experience of sensations such as deja- vu. Generalised seizures may be of the following forms: • Tonic seizures cause a sudden increase in muscle tone, they may result in falling backwards. • Atonic seizures cause a sudden loss in muscle tone and may result in falling forwards (a form of “drop attack”). • Clonic seizures are marked by alternate contraction and relaxation of muscle(s) occurring in rapid succession. • Myoclonic seizures have sudden brief shock like contractions of muscles that may involve the whole body or be restricted to one area. • Absence seizures involve very brief losses of consciousness in which entry and exit from seizure state is rapid. May involve minor automatisms (Previously known as petit mal).

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• Atypical absence seizures involve more gradual exit from and entry into loss of consciousness. • Tonic-clonic seizures characterised by immediate loss of consciousness, then a tonic phase followed by a clonic phase, accompanied by laboured breathing, incontinence, tongue/mouth biting, and skin colour changes. (Previously known as grand mal) The many seizure types can be defined as “intermittent, paroxysmal stereotyped disturbances of consciousness, behaviour, emotion, motor-function, of perception or sensation, which may occur singly or in any combination”.3 But as many other conditions can mimic seizures, a careful clinical diagnosis with a full history is needed, and a single seizure is not generally sufficient to make a diagnosis of epilepsy. Consequences of epilepsy include the risk inherent in seizures which include the possiblility of accidents in the course of a seizure and the serious metabolic consequences of long-lasting seizures (status epilepticus) which require immediate treatment and often inpatient care including intensive care. Additionally there are social, psychological and educational consequences. Classifications of epilepsy and of epileptic seizures proposed by the International League Against Epilepsy (ILAE) in 19814 and 19895 have become widely adopted especially for research studies of epilepsy. Alternative classifications have been proposed.6,7 The 1989 proposal introduced the concept of “epileptic syndrome”. An epileptic syndrome is “an epileptic disorder characterized by a cluster of signs and symptoms occurring together”; these include items such as seizure type(s), etiology, anatomy, precipitating factors, age of onset, severity, timing, diurnal and circadian cycling, and sometimes prognosis. A recent proposal by an ILAE task force published in 20018 suggested the status of syndromes should be characterised as “accepted” or “in development”. This proposal introduced the concept of “diagnostic entity” based on precise identification of seizure type(s); it was envisaged that diagnostic entity be used to supplement syndromic diagnoses, or to stand alone when syndromic diagnosis could not be established.

Syndromes are broadly separated into those with seizure initiation that is of local origin (partial seizures, focal, or localisation-related seizures) irrespective of subsequent generalisation, or those of generalised origin (initiation involving activity in both brain hemispheres). This dichotomy cannot contain all seizures or syndromes because many intermediate abnormalities exist (e.g. multi-focal, diffuse hemispheric, bilaterally symmetrical focal). Classification into syndromes is generally viewed as a clinically useful tool rather than a precisely accurate representation of reality. Many of the clues that allow the localisation-related/generalised distinction to be made for adult epilepsy can be unavailable in the case of infants and children. Further subdivisions that define separate syndromes are based on the presumed aetiology of the condition; idiopathic, symptomatic or cryptogenic (probably symptomatic but with no brain lesion identified) disorders are distinguished. Further designation may be based on the degree of impairment caused by the condition5 or simply whether the condition is benign or severe in outcome.

16 Newer Drugs for Children with Epilepsy

2.1.2 Epilepsy in children Clinicians communicating with each other about epilepsy in children commonly do so in terms of epileptic syndrome and this may foster a more precise tailoring of therapies.9 The majority of epilepsy syndromes start in infancy or childhood.10 For about 30 to 40% of young epileptic patients it is not possible to designate a syndrome. In practice therapy is then based on seizure type(s) and simple description and classification of ictal behaviours. The recent ILAE task force recommendations provide a framework for this.

Epilepsy in young people differs from that in adults in a number of important respects including:3

• Greater multiplicity of epileptic conditions. • Heterogeneity with respect to syndrome types, causes and prognoses. • Usual refractory seizure type is generalised rather than partial. • Condition may change with age, one syndrome may evolve into another. • Greater potential impact on the social, educational and behavioural spheres of life.

Post-natal brain maturation continues for many years. In the neonate the balance of excitatory pathways to inhibitory is at its’ highest and this may lower the “seizure threshold” and explain the high incidence of seizures in infants. Synaptogenesis is still pronounced after birth as are other developmental changes including myelination of neurons, dendritic arborisation, alterations in dendritic spine morphology, alterations in neurotransmitters and neuronal pruning. A complex developing system can be expected to be more sensitive to derangement than one in steady state. This may represent one reason why incidence of epilepsy is highest in infancy and gradually declines through childhood and then adolescence

The prolonged maturation of the brain is coupled to gradual acquisition of many behavioural attributes.11 Basic motor skills and some essentials of language are achieved early on. Although the trajectory of development slows until adulthood is attained these faculties continue to be refined to a greater and greater degree throughout childhood and adolescence. Communication develops in childhood as do other cognitive and social skills. In adolescence abstract concepts, cause-effect associations, deeper inter-personal relationships, and social interactions involving cooperation, competitiveness and ideas of right and wrong develop. Epilepsy and epilepsy treatment can impact on many aspects of development.

Attitudes to epilepsy in society vary but individuals with epilepsy still meet considerable prejudice in their social interactions. Epileptic fits frighten unaccustomed observers and people with epilepsy may become stigmatised or rejected. There are psychological consequences for the person with epilepsy resulting from fear of seizures, their unpredictable occurrence, their embarrassing nature and physical consequences. Carers of children with epilepsy may become overprotective and unnecessarily restrict the child’s activities, the child may be bullied at school, or may sustain seizure related injuries.

Therefore important consequences for children and young people include not only the seizures themselves but also the impacts of the condition and its treatment upon social life (variety of activities, acceptability by others), on relationships (with friends and

17 Newer Drugs for Children with Epilepsy peers, siblings, and parents), on educational progress (cognitive attainment), and upon psychology (behaviour, self esteem, loss of original hopes). Additional impacts, such as social stigma, and parental and sibling stress, are sustained by the family unit. Specific measuring tools that aim to encapsulate such impacts have been proposed.12

In a prospective population based cohort of patients with childhood-onset epilepsy, 27% of patients experienced status epilepticus, with more than half of those patients having two or more episodes (Sillanpaa and Shinnar, 200213); 73% of cases occurred at onset and 90% within 12 months of onset. Younger age at onset (<6) and partial epilepsy were associated with a higher risk of status. A further prospective population based study reported status in 9%.14 Hence status epilepticus with its attendant risks and need for hospital treatment is relatively common in childhood epilepsy.

Adolescents with epilepsy have needs of their own which must be addressed. In this transitional period, adolescents need to develop independence and learn to manage their condition themselves. New factors enter into the choice of and compliance with AED therapy, as cosmetic side effects, reproductive health issues and new social behaviours including drinking alcohol enter the equation. Seizure control has important social consequences in terms of driving and occupation.3 Epilepsies relevant to children3 include the following:

1] Lennox-Gastaut syndrome.15,16 Syndrome definitions vary but this condition is recognised as a devastating paediatric epilepsy. Mean age of onset is 26-28 months; it is associated with severe seizures of multiple types, frequent injuries incurred during seizure (especially tonic-clonic and atonic), developmental delay, retarded and regressive mental capacity, and behavioural problems that may place a great burden on carers and families. The patho-physiology is unknown but some have postulated a common pathogenic mechanism as infantile spasms. Seizures are often resistant to therapy, and mortality is high at 3% (mean follow up 8.5 years) to 7% (mean follow up 9.7 years) with death often related to accidents. LGS accounts for 1-4% of chilhood epilepsies and for 10% of epilepsy with onset less than 5 years of age.

2] Infantile spasms. Infantile spasms16,17 represent a unique seizure type and according to the ILEA also an epileptic syndrome. West’s syndrome is an older syndrome term for patients with infantile spasms, hypsarrhythmic EEG pattern, and mental retardation and represents about 1-5% of all childhood epilepsy. Patients with infantile spasms may suffer other seizure types that may precede or accompany spasms. Several disorders mimic infantile spasms and correct diagnosis relies on video-EEG monitoring. Infantile spasms “are brief 1-5 sec contractions of trunk with extension and elevation of the arms, tonic extension of the legs, with clusters of 3 – 20 spasms typically occurring several times a day in untreated patients”.16 Most patients present within the first year of life, with peak onset between 4 and 6 months. Most spasms remit spontaneously, with or without treatment, by mid-childhood, however other seizure types arise in 50 – 70% and chronic intractable epilepsy occurs in about half with a history of spasms. Some patients with spasms evolve to Lennox-Gastaut syndrome. High case fatality rates have been reported with most deaths occurring before the age of 10 years with the most common cause being infection.

18 Newer Drugs for Children with Epilepsy

3] Childhood Absence Epilepsy (CAE). This syndrome is relatively common (> 5% of childhood epilepsies, with higher incidence in girls than boys) and is characterised by absence seizures as the initial and predominant seizure type and by particular features of EEG pattern. Age of onset is between 3 – 12 years of age3 with peak onset at 6 – 7 years of age. Although CAE is relatively benign it may be associated with minor cognitive/learning difficulties18 which rarely may outlast the epilepsy and be a life long problem.11 A proportion (~15%) of CAE patients may later exhibit juvenile myoclonic epilepsy (JME) which is probably a life long condition but usually is controlled with drug therapy. JME accounts for 5-10% of childhood epilepsy. A 30% rate of inadvertent pregnancy has been reported in young adult girls who had CAE19 indicative of poor social outcome for CAE.

4] Benign partial epilepsy with centro-temporal (Rolandic) spikes (BECTS) The most common childhood form of partial epilepsy, BECTS account for 10-15% of childhood epilepsy. Age of onset is between 3 and 13 years of age with a peak between 7 and 9.3 As seizures usually cease by mid adolescence, prognosis is excellent.

There are many other epilepsy syndromes of adolescence and childhood, often they are age dependent, some are common and some of occur rarely. For 30-40% of children, however, a specific epileptic syndrome will not be identified.3 Table 1 shows epilepsy diagnoses in prevalence and incidence studies that have used the ILAE classification. The syndromes described above, although important, consitute a minority of childhood epilepsy syndromes. It should be noted that evidence on effectiveness of a treatment in one epilepsy type or syndrome cannot be generalised to all childhood epilepsy types or syndromes. Table 1 Prevalence and incidence of ILEA classified epilepsy syndromes of childhood. PREVALENCE INCIDENCE Endziniene 20 Eriksson 21 Freitag22Germ Berg 14 Lithuania 1995 Finland 1992 any 1999 USA‡ 1993-97 preva- n % lence n % n % n % /1000 LOCALISATION RELATED 189 50.0 2.13 134 41.0 21 58.3 359 58.6 EPILEPSIES idiopathic 15 4.0 0.17 24 8.0 8 22.2 61 10

symptomatic 63 17.7 0.71 35 11.0 4 11.1 195 31.8

cryptogenic 111 29.4 1.25 75 22.0 9 25.0 103 16.8

GENERALISED EPILEPSIES 113 29.9 1.27 158 48.0 14 38.9 126 20.6 idiopathic 55 14.6 0.62 75 23.0 9 25.0 0.0

cryptogenic / symptomatic 18 4.8 0.20 45 14.0 4 11.1 52 8.5

symptomatic 35 9.3 0.39 38 12.0 1 2.8 0.0

cryptogenic 5 1.3 0.06 - - 0 0.0 0.0 UNDETERMINED PARTIAL OR GENERALISED 60 15.9 0.68 5 2.0 1 2.8 76 12.4 presumably symptomatic 16 4.2 16 4.2 0.18 0.0

cryptogenic 44 11.6 44 11.6 0.50 0.0

19 Newer Drugs for Children with Epilepsy

BOTH PARTIAL & GENERALIZED - - 5 0.8

UNCLASSIFIED 16 4.2 0.18 71 11.6

TOTAL 378 32 36 613

BENIGN EPILEPSY WITH - - 16 5 7 19.4 - CENTRO-TEMPORAL SPIKES CHILDHOOD ABSENSE EPILEPSY - - 21 6 1 2.8 74

WEST’S/INFANTILE SPASMS - - 25 8 0 0 24

LENNOX-GASTAUT - - 6 2 0 0 4

‡ Connecticut.

The treatment of immediate post-traumatic seizures, status epilepticus, febrile convulsions and neonatal seizures is beyond the scope of this report.

2.1.3 Diagnosis A recent systematic review23 considered what elements (e.g. expertise, services, and tests) were required to make an accurate first diagnosis, initiate and monitor treatment. The reviewers were unable to identify an agreed gold standard for use in first diagnosis or in diagnostic studies of epilepsy. The evidence base for diagnostic procedures was found to be weak with, for example, only 3 of 42 studies with a diagnostic focus reporting sensitivity and specificity values. A National Clinical Guideline for Diagnosis and Management of epilepsy in adults24 categorised the literature pertinent to diagnosis at the lowest level, grade C, indicating an absence of directly applicable clinical studies of good quality. Similarly a recent national statement on good practice for care of people with epilepsy25 identified literature pertinent to diagnosis as dependent only on expert and user opinion. However reports focussing on misdiagnoses were judged to depend on well designed non-experimental studies.

In their systematic review Ross et al (2001)23 found evidence to support the following conclusions: • Diagnostic procedures supported by the literature to rule in a diagnosis of epilepsy, prevent delayed or missed diagnosis, and predict remission outcome are: a complete history and physical examination, including neuropsychological assessment and a standard EEG. • Other diagnostic interventions (eg. CT and MRI) are more important to rule out secondary causes of seizures or to resolve uncertain diagnoses.

According to the UK Good Practice statement25 all patients with a first seizure should be seen by a specialist with an interest (and presumed expertise) in epilepsy within 28 days of referral. Detection and recognition of seizures and seizure types is fundamental for diagnosis and requires a detailed description of the supposed epileptic event by a first hand witness who for epilepsy in children is likely to be parent, guardian or carer. Video recordings of the event are particularly useful as are recordings of examples of epileptic and non-epileptic seizure that can be shown to parents to discover if any resemble their child’s attacks. Verbal accounts by the patient add useful information regarding states of consciousness, post-seizure amnesia and the presence of an aura, but are clearly not available from pre-verbal children.

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Some infantile seizures may be extremely subtle and difficult to detect even with skilled observers so that they remain undetected and under-appreciated.26

Because some seizure types result in falls that may incur physical injury there may be a tendency for premature diagnosis in an attempt to forestall harm. For this reason, because there are many medical causes of seizure other than epilepsy27 and because of the inherent difficulties in distinguishing possible causes and types of seizure that occur in children,28 misdiagnosis may possibly be frequent.29,30 Grunewald et al31 reported that of 15 cases of juvenile myoclonic epilepsy referred to a specialist epilepsy clinic only one had been assigned a putative diagnosis of JME and definitive diagnosis had been delayed by a mean of 14.5 years. Recent concerns have been expressed about the frequency of misdiagnosis of children’s epilepsy in the UK32 and the opinion expressed that it’s origins may be attributable to a dearth of available specialist paediatric neurologists and paediatricians with interest and expertise in epilepsy, and to inadequate recording and interpretation of EEG results. There is a lack of evidence bearing on the nature of training and experience desirable for specialist care-givers.23

Further to seizure description and EEG imaging methods may be employed that can strengthen and or extend diagnosis. Their use depends on prognosis of the epilepsy, especially with regard to the likelihood that surgery may be beneficial (see below). Procedures include CT scan, positron emission tomography (PET), single photon emission computed tomography, and magnetic resonance imaging (MRI). Guidelines for imaging children with epilepsy have been produced by the British Paediatric Association.33

2.1.4 Aetiology and pathology For about three quarters of childhood epilepsies no cause can be found. It is presumed that many of these have an as yet unidentified genetic basis.

Causes are extremely numerous, in many cases very rare, and include the following:

• tumours and developmental malformations (e.g. tuberous sclerosis) with associated brain pathologies • chromosomal abnormalities and mitochondrial diseases • metabolic disorders including monogenetic disturbances such as those involving oxidation of long chain fatty acids, turnover of phospho- and sphingo-lipids • a mutation specifically resulting in epilepsy (e.g. potassium channel mutation in benign familial neonatal convulsions) or in a complex syndrome often involving epilepsy (e.g. tuberus sclerosis34 • infections • head injury • hypoxic-ischaemic injury

Investigations have sought to unravel the mechanisms underlying the development of epileptic seizures but details of the phenomenon are poorly understood. Basic understanding of the cellular physiology of neurons and their supporting glia cells has revealed the fundamental involvement of voltage-gated ion channels, that regulate neuron excitability, and synaptic processes responsible for communication among neurons. Potassium channels (regulating hyper-polarisation of neuronal plasma

21 Newer Drugs for Children with Epilepsy membrane) and factors controlling the levels of the neurotransmitter GABA and its interaction with post-synaptic receptors have emerged as important factors. In most circumstances GABAergic neurons exert inhibitory influences that can be construed as constraints on potential spread of excitation to large populations of neurons with attendant reduced risk of seizure. In other circumstances neurons may respond aberrantly to GABA so that it exerts an excitatory effect. Such differences may apply in different syndromes and provide one explanation for the observation that a given therapeutic strategy may reduce seizures for one patient but exacerbate them for another.

It is difficult to investigate individual neurone behaviour simultaneously in large populations such as are known to be involved in an epileptic seizure. However epileptic neuronal events involve such large populations of cells that the concomitant electrical changes invoked can often be detected with electrodes applied externally to the scalp during an EEG (electro-encephalogram) examination. Sometimes localising the origin of seizures requires use of depth electrodes. Features of ictal (during seizure) EEG records when integrated with all available clinical data can characterise particular types of epilepsy and may aid localisation of the brain region involved.35 The ictal features of EEG recordings in infants exhibit a wide range of patterns that are not efficiently identified by available automated algorithms so that complete review of the recording is recommended.

New methods of analysis can allow detection of hidden patterns within EEG recordings that define a so-called pre-ictal state for some seizures in some epilepsies (e.g. focal temporal lobe epilepsy).36 Such procedures offer the possibility of anticipating seizures and ultimately therefore of avoiding them.

It is possible that recurrent seizures may damage brain tissue.37 Laboratory studies demonstrate that hyperactivity of neurons can be cytotoxic and result in cell death. Evidence indicates that this is due to accumulation of intracellular calcium as a result of prolonged stimulation of γ amino butyric acid (GABA) receptors especially those of N-methyl D aspartate (NMDA) variety. Some epilepsies are associated with progressive neurological deterioration, neuron loss and cognitive deficits, and others with sclerotisation in particular brain regions. Hermann et al38 reported that deficits in temporal tissue volume and poorer cognitive status are associated with early onset of temporal lobe epilepsy. The tissue deficit was extended to areas away from the focal origin of seizures and the associations were independent of the duration of disease and its treatment suggesting that the important factor was the early developmental stage of the brain in early onset. Thus the developing brain could be more susceptible to damage than the mature brain. An alternative notion expressed is that the plasticity of a developing brain might offer compensative capacity for reorganisation and repair in face of damage. However it is always uncertain whether a common underlying factor causes both seizures and damage, or whether seizures and their treatment cause or exacerbate the damage. The majority of children with epilepsy, however, do not experience progressive cognitive decline. Learning difficulties are relatively common, and may result from underlying lesions, unrecognised seizures, subclinical epileptiform activity, adverse effects of AEDs and emotional and psychological problems.3

22 Newer Drugs for Children with Epilepsy

2.1.5 Epidemiology Estimates of the amount of children’s epilepsy in the UK are problematic. Reliability depends on epidemiological studies with unbiased sample selection, precisely defined, meaningful and accurately applied diagnostic criteria, and efficient case ascertainment. The heterogeneous and complex nature of the condition means correct diagnosis is difficult, especially in the very young. In consequence of lack of consensus on definitive diagnostic criteria definitions of epilepsy employed in epidemiological studies appear mainly to be dictated by features of the data-base available; thus even studies published by the same authors within a few years of each other may employ varying definitions. Studies are best served by specialist diagnosis of cases performed on an individual basis.

Recently two types of study have provided age related information. Wallace et al39 exploited the ONS GPRD that included 2,052,922 persons highly representative of the UK population. In this study diagnosis of ascertained cases could not be done on an individual basis, and case definition was determined from a composite of database entry details. Kurtz et al,40 MacDonald et al,41 and Heaney et al42 performed prospective studies in which case ascertainment was likely to be high, diagnoses were based on individual case assessment (usually by a specialist) and the “unselected” study population was based on 13 to 20 general practices or a cohort defined at birth. Case definition and methods of case ascertainment were not the same in these studies and this is reflected in differing reported estimates in incidence for given age bands and the variation in observed incidence trends with age (Table 2). Because of these disparities, and to place UK studies in context, Table 2 includes incidence reported in similarly conducted prospective studies for European and Canadian populations resembling that of the UK.

Using the range of incidence values from prospective studies of UK populations and the age structure of England & Wales (ONS Census 2001) we calculate that the annual number of new consultations for children with epilepsy to be in the range: 4000 to 14000 (for ages 0 to 14) and 5000 to 15000 for ages 0 to 19 years. Approximately one percent of these would occur in an average sized health authority of 500,000.

Many new consultations follow seizures where epilepsy is suspected (possible or likely) but where definitive diagnosis of epilepsy does not result. Using the data of Kurtz40 the ratio of possible plus likely cases to validated cases up to the age of 16 yrs is approximately 35. A ratio of only about one to one (definite epilepsy: possible epilepsy + other seizures) was observed in the National General Practice Study of Epilepsy amongst newly diagnosed cases in a cohort of 1195 (all ages) identified from 275 general practices.43 Taking consultations for these conditions into account would greatly inflate, to an uncertain degree, the estimate of the number of new consultations. Table 2 Incidence of epilepsy in children of different age; (new cases /100,000 person years†) Heaney et MacDonald Wallace Kurtz Bielmann Frietag et al Camfield et al 2002 et al 2000 1998. 1998.¶ et al ’99 2001 al ’96 Novia UK UK UK UK Estonia44 Germany22 Scotia45 Study type/ Prospective Prospective GPRD Prospective Prospective Prospective Retrospect- population 20 GPs 13 urban Based on Cohort at 7 counties 2 cities ive. GPs 294 GPs birth 581,887 448,553 Province 2,052,922 850,000 Case One or Two or Composite ¶ Two or Two or Two or definition more more ¶ more more more 23 Newer Drugs for Children with Epilepsy

unprovoked unprovoked unprovoked unprovoked unprovoked seizure seizures seizures seizures seizures N, or 56,615 py 100,230 380,360 17,414 161,202 59,647 226,700 Person Yrs 0-14 yrs 5-19 yrs < 20 yrs <15 yrs <16 yrs (py) †† Age band 0-4 190 (138- 86 58 76 62 62‡‡‡ 262) (60-96) ‡ (30-114)‡ ‡ 5-9 46 63 (50 -79) 36 54 (42-68) 50 (24-91) 43 5-14 75 (52 33 -109) 10-14 94 54(42-68) 29 44 (34-57) 56 (28-100) 27 15-19 52 101 (84- 26 13 (6-19) 121) ¶ Case definitions: Wallace et al 1998: person receiving any of 11 named anti-epileptic drugs and who was entered in the ONS GPRD under any diagnostic code denoting any epilepsy syndrome, seizure type, or a synonym for epilepsy (eg. Seizure); Kurtz et al 1998: child with recurrent paroxysmal disturbances of consciousness, sensation, or movement that were primarily cerebral in origin and not associated with acute febrile episodes. ‡ excluding 0-1 month. ‡‡ Data for 1 yr to 4. Separate data for 0-1 yr [excluding first month life] inc= 145.8 (47-340). ‡‡‡ 0-1 yr 118 (93-143). For the 0-4 yr age group the reports of Heaney et al and MacDonald differ by a factor >2 (86 v 190) the same ascertainment methods were used but case definitions differed. † all figures rounded to nearest whole number. †† whole population (all ages) except where stated.

Prevalent cases of epilepsy in children will increase service demand above that provided for incident and suspected cases. The impact of prevalent cases on services is difficult to gauge; it has been estimated that about 20 to 30% of all epilepsies in children are severe (depending on definition used) and would require close medical monitoring and repeated consultation. Prevalence has defined as the proportion of all the individuals of a defined age that are diagnosed as having “active epilepsy”. Because the occurrence of seizures is intermittent and seizure frequency is highly variable difficulties arise in defining “active epilepsy”. Various definitions have been used. Kurtz et al40 identified children who were continuing AED therapy or who had had a seizure (i.e. further to a previous seizure) during the previous two years and reported prevalence gradually rising from 3.9/1000 at age 7 years, to 4.9/1000 at age 16 years. This rise in prevalence with test age may reflect a higher rate of accumulation of new cases than rate of remission of established cases or sampling problems with a small cohort. Similar prevalence estimates based on various definitions of active epilepsy have been reported for children in other European populations that can be expected to broadly resemble the UK: Norway 5.1/1000 (6 to 12 year olds);46 Sweden 4.2/1000 (0 to 16 year olds);47 Finland 3.94/1000 (0 to 15 year olds);21 Lithuania 4.25/1000 (0 to 15 year olds);20 Estonia 4.3/1000 (5 to 9 year olds).48 Based on a review of many studies Cowan49 estimated prevalence to the age of 15 years to be ~5 to 7/1000.

2.1.6 Prognosis Clinical experience makes it obvious that prognosis of children’s epilepsies varies with seizure type and syndrome. For some syndromes, such as typical rolandic epilepsy, essentially all patients achieve permanent remission.11,50,51 It is probable that approximately one third of all epilepsies that start in childhood will, by puberty, have shown a remission which is usually sustained throughout adult life.3 However accurate estimations of the proportions of patients with persistent disease and with more or less severe disease are hampered by:

• Complex and multifaceted definitions of syndromes and seizure types • Lack of consensus on the definition of ‘remission’

24 Newer Drugs for Children with Epilepsy

• Lack of consensus on the definition of ‘refractory’, ‘intractable’ and ‘uncontrolled’ epilepsy • Referral bias inherent in hospital based series • Differences in length of follow up • Problems with loss to follow up

To determine outcome and identify early prognostic factors Berg et al52 prospectively studied a community-based cohort of children (N=613; >1 month to <16 years old) newly diagnosed with epilepsy. Follow up was at 2 years and 4 years after diagnosis; losses to follow up were <5%. Of 595 children followed up at 2 years 53% were classified as having good outcome (one year of remission [seizure-free] at time of follow up), 7.7% as having bad outcome (intractable epilepsy defined as: a] failure of two AEDs for seizure control, or b] failure of one for seizure control and two for intolerable side effects and at least one seizure/month on average over an 18 month period), and 38.3% had indeterminate outcome (neither good nor bad). At 4 years follow up (N=390) 65% were in two years of remission (i.e. seizure free), 10% were intractable (as above) without two-year remission, and 23.5% had indeterminate outcome. Most (83% and 87% respectively) classified as good and bad outcomes at 2 years remained so at 4 years. However 55% of those with indeterminate outcome at 2 years were reclassified as good outcome at 4 years. Only 0.5% and 8% with good and intermediate outcome respectively at 2 years were reclassified as bad outcome at 4 years. Such results might argue that waiting for remission in refractory children’s epilepsy may be a false hope and that exploration of suitability for surgery should be undertaken relatively early.

The National General Practice Study of Epilepsy43 identified a cohort of 792 patients (209 26% < 15 years old) with newly diagnosed epilepsy (564 definite epilepsy, 228 probable). It was reported that 54% of those with definite epilepsy had experienced 1 year seizure-free remission at 1 yr follow up and 79% at two year follow up. At 4 years follow up 78% had experienced 2 years remission. These numbers correspond reasonably to those of Berg et al.52

Berg et al52 identified prognostic factors at two years follow up. Positively associated with bad outcome were:- age at onset of

2.1.7 Significance in terms of ill-health

A Europe-based cohort study53 in which 25% of participants were < 15 years old reported modestly increased risk of accident (hazard ratio 1.6; 95%CI 1.3-2.1) and of illness (hazard ratio 1.3; 95% CI 1.2-1.4) in people with epilepsy (excluding symptomatic epilepsy) compared with age and sex matched controls recruited amongst relatives and friends of patients. Age specific data was not presented. Recruitment was from hospitals with relatively advanced facilities so that the patients studied likely represent those with more severe epilepsy. Population-based studies would be expected to generate lower estimates of relative risk but have not been performed.

25 Newer Drugs for Children with Epilepsy

Children with epilepsy carry increased risk of premature death (review Breningstall 200154) but this depends partly on conditions co-morbid with epilepsy which may carry increased mortality. In a population based retrospective cohort study of 692 patients diagnosed with epilepsy in childhood, Camfield et al55 reported that at 20 years from diagnosis, 6.1% of the cohort had died. The frequency of death was 5.3 (95% CI 2.29-8.32) higher than in the reference population in the 1980s and 8.8 (95% CI 4.16-13.43) times higher in the 1990s. This study was done in Nova Scotia that has a predominantly Scottish, German, and Arcadian population and where organization of medical services favours complete case ascertainment. Children with secondarily generalised epilepsy were at greater risk than those with absence, generalised or partial epilepsy, and patients with neurological disorders at much greater risk (22.2) of death at twenty years post diagnosis than those without. Of the 26 deaths, 22 were “not unexpected” and resulted from disorders severe enough to cause functional neurological defecit. The remaining deaths were two suicides, one homicide and one case of probable sudden unexpected death in epilepsy (SUDEP) in a 21 year old. A Dutch prospective hospital based cohort study was estimated to have recriuted 80% of the population and followed 472 children for five years from diagnosis.56 There were nine deaths, a mortality rate of 3.8 per 1000 person years. All of the deaths were in children with symptomatic epilepsy and none filled the criteria for SUDEP. The overall mortality risk relative to the general population was 0 (95% C.I. 0-2.2) in children with nonsymptomatic epilepsy and 22.9 (7.9-37.9) in children with symptomatic epilepsy. A study that used multiple sources to ascertain possible cases of SUDEP in persons aged under 18 in Ontario between 1988 and 1998,57 however, found 27 cases (mostly patients with generalised tonic clonic seizures), eight of which were in children with idiopathic epilepsy. The rate of SUDEP was estimated as 2 per 10,000 person years.

It can be concluded that: • much of the excess mortality following a childhood diagnosis of epilepsy occurs in patients with symptomatic epilepsy/neurological disorder • mortality in childhood in children with idiopathic epilepsy is very little different to that of the general child population • SUDEP is rare in childhood, but has been reported.

The study by Cockerell et al58 put the burden of epilepsy in the UK at a cost of £1,930 million/year. The estimate was based on cost analysis of patients who were part of the National Epilepsy Survey and the National General Practice Study of Epilepsy (begun in 1984) and was published in 1994. About 64% of the cost was attributed to losses of employment, while direct and indirect medical costs accounted for 9% with most due to “active epilepsy”. Other estimates have been published59,60 but subdivisions of estimates to determine the proportion accounted for by children have not been calculated.

2.2 Current service provision

2.2.1 Goals of service provision.

“In clinical practice the goal of therapy for epilepsy is the best quality of life maintained over the longest time with the fewest seizures (preferably none), fewest

26 Newer Drugs for Children with Epilepsy side effects, and fewest medications together with a minimisation of hidden or overt long term detrimental after effects”.61 These outcomes are unlikely to be routinely recorded in many UK settings and an evidence base upon which judgements about which are the most efficient and appropriate therapies and services to achieve these outcomes is largely absent.

Medical management of epilepsy involves hospital specialists and GPs. According to reporters of the UK National General Practice Study of Epilepsy (NGPSE)62 the most widely followed model of epilepsy management in the UK is one of referral from primary care to hospital clinics followed by investigation, treatment and follow up at primary, secondary or shared care levels. Systematic reviews23,63have concluded that the current literature can only partially assist in developing management programmes for patients with epilepsy and that the most clinically effective model for outpatient and general practice care for epilepsy patients is unknown.

A systematic review63 comparing general neurology outpatient clinics with specialist epilepsy clinics commented on the relative lack of relevant quality studies. More research evidence was available on whether specialist epilepsy nurses improve outcomes relative to usual care in primary, secondary and tertiary care settings. No significant differences in terms of seizure frequency or severity were found. One RCT that compared quality of life outcomes found no difference between specialist epilepsy nurse provision and usual care. Evidence from the paediatric setting is lacking, but paediatric neurology services will often include a clinical nurse specialist.

2.2.2 Standards of current service provision.

Great concern has been expressed in government reports, local and national audit reports, and patient satisfaction questionnaires over the standard of epilepsy services in the UK (e.g. Kitson, 200064 and Hanna et al 200265). Generally standards of care have been described as inadequate and poor. Problems of service provision identified include: • patchy access to service provision across the country • lack of systematic follow up of patients • investigations not always used appropriately • insufficient access to specialised investigations • patients often seen in hospital by non-specialist • low numbers of specialists with clinical-pharmacological expertise in epilepsy • use of inappropriate polypharmacy • patient non-compliance with medication • low levels of patient knowledge and instruction

Government policy on epilepsy care was set out in executive letter EL(95)12066 the purpose of which was to encourage improvement in the efficiency and delivery of epilepsy care in the primary and secondary medical services and to ensure continuity of care throughout the patients life, to plan services according to the patient’s and their carers wishes, and to avoid discrimination against people with epilepsy in the NHS workplace. A short-term assessment of the impact of the policy statement was made Brown and Lee (1998)67 and a further assessment followed in Brown et al (1999).68

27 Newer Drugs for Children with Epilepsy

More recently the National Sentinel Audit of epilepsy-related deaths65 sought to establish whether deficiencies in the standard of clinical management or overall health-care package, could have contributed to deaths of persons with epilepsy in the UK. Three key areas relating to deaths of people with epilepsy were reviewed: investigations into the deaths; care prior to death; contact with the bereaved family.

The audit was poorly served by the quality of death certification and the true number of epilepsy related deaths was impossible to determine. Of the 81 children (<18 years old) reported to the audit as having died in the year Sept ’99 to Aug: 2000 with epilepsy mentioned on their death certificate it was possible to use data to assess the care received by only 22. Of these, 17 had never seen a consultant and two others had only seen one in an A&E department. For 17 care was considered less than adequate. The opinion was expressed that 50% of these 22 deaths were potentially or possibly avoidable for medical reasons. The report urged caution in the interpretation of the results because analysis was only possible where adequate medical records were available leading to a small and possibly non-representative sample.

The Government has given a commitment to consider in full the recommendations of the National Sentinel Audit and to develop an action plan to address key issues within three months of the publication of the report (Hansard 2002; answer by Jacqui Smith to question by Dr Evan Harris (56669)).

2.2.3 Current service provision

Diagnosis of childhood epilepsy, initiation of therapy and initial follow-up is provided by paediatricians and paediatric neurologists. Most follow-up care for people with epilepsy in the UK is undertaken in general practices. Follow-up of children is likely to be shared with the hospital consultant. With the exception of epilepsies developing very soon after birth (i.e. in hospital setting) and the new cases that present at A & E units the majority of presentations will be in general practice. Also GPs are involved in the routine management of chronic epilepsy and are well placed to monitor effectiveness of therapy.

Because of the difficulties of diagnosis it is widely recommended65 25,69 that following the first seizure patients be promptly referred to a specialist clinician with particular interest in epilepsy (e.g. a paediatric neurologist usually based at a tertiary centre, or a paediatrician). At present in the UK there are 61 paediatric neurologists, approximately 1 per million of population,32,65 hence many children will see a general paediatrician, ideally one with an interest in epilepsy. Recommendations have been made to double the number of paediatric neurologists in the next decade and to increase the number of consultants in neurology from 326 (in 2001) to 496 by 2010. A 1996 audit indicated that only 18% clinics reached the desired target of less than 1 month waiting time from the time of suspected seizure. A study of 119 general practices in the UK published in 199570 indicated that only 6% of patients with epilepsy attended a specialist epilepsy clinic. There are approximately 100 epilepsy specialist nursing posts which have been developed in hospital and community settings; the number of posts filled by qualified personnel is uncertain.

Children judged to have a low likelihood of seizure recurrence after a first seizure and those found to have a low seizure rate are likely to be monitored without initiating

28 Newer Drugs for Children with Epilepsy treatment. At this and other times some children with epilepsy may have special needs with respect to learning or behavioural difficulties for which there should be concurrent provision.

Adolescents with epilepsy need services appropriate to their needs, providing transitional care that allows adolescents to move securely to independent and informed management of their own condition and to adult services.

Once diagnosis has been established and a treatment strategy selected the following checklist has been suggested for first review of the patient by the primary care team:

• discuss diagnosis • review seizure frequency and consider a seizure diary • discuss risks and benefits of AEDs • inform the carer/ parent/ patient’s gaps in knowledge • discuss impact on patient’s life quality • provide contact details for patient organisations • discuss pregnancy and contraception with girls and women as appropriate • agree a time table for follow up

In practice it is likely that monitoring is often reactive rather than proactive so that changes in frequency or severity of seizures or intolerance to AEDs or altered status of the patient (e.g. approach of sexual maturity, potential pregnancy) may remain undetected until the patient approaches the GP. Probably about 30% children with epilepsy will continue to experience seizures despite treatment, they will be identified by GPs and through hospital follow-up and may require further specialist follow-up and may be considered for changes in therapy and other treatment modalities.

The systematic review by Ross et al23 concluded that there was good evidence that some patients do well without treatment, the difficulty being the correct identification of these individuals. For typical benign rolandic epilepsy, which has excellent prognosis (the disorder disappears in 100% of cases by mid-teenage years), treatment is optional and becoming less popular with parents due to concern over potential side effects of AEDs.

2.2.4 Treatment with anti-epileptic drugs (AEDs) Use of an AED is the first treatment option considered. Surveys have shown that in the Netherlands and USA >80% of children with epilepsy are treated with AEDs;71,72 it is likely similar practice occurs in the UK, Appendix 2 page 139 summarises AED treatment choices suggested in The Royal College of Paediatrics and Child Health’s formulary. Treatments will be guided by diagnosis and age.

The clinician that treats epileptic children with AED therapy confronts several difficulties including: 1) Multiple diagnoses within which typical and several atypical categories may co- exist. 2) Multiple drug choices with • Differing supposed effectiveness for different seizure types and syndromes • Different side effect profiles • Different interactions with other drugs 29 Newer Drugs for Children with Epilepsy

• Different enzyme inducing properties and different interactions with endocrine functions • Different dose regimes, with sometimes complex titration programmes with attendant difficulties of gauging advisable dose for children of different ages and different cognitive development • Indeterminate and unpredictable long-term undesirable side effects. 3) Problems of judging the relative success of the adopted therapy in the face of: • Likely frequent but indeterminate non-compliance73 • Inherent unpredictability of seizure frequency through time • Necessity in most cases for the patient’s parent /carer to record frequency and types of seizures. • Lack of easily monitored patient-centred validated outcome measures. 4) Difficulties of deciding if and when to stop or change AED therapy. 5) Lack of paediatric-specific published guidelines for treatment validated by high level evidence. (A list of guidelines is provided in Appendix 8 of Epilepsy Care: Making it Happen74) 6) The necessity / desirability to consider the use of AEDs outside their licensed indications.

The systematic review by Ross et al23 found some evidence to support the view that access to health care professionals with clinical / pharmacological expertise would optimise patient care and minimise mistakes in the choice of dosage, timing and selection of AED. However they comment that studies define optimum outcome uni- dimentionally (seizure frequency) and that studies might be subject to bias since they were led by academic neurologists and suggested expertise lay with academic neurologists.

Because controlled studies of AEDs in children have been small in number and have been conducted to answer regulatory questions the use of AEDs has been largely guided by as yet un-validated positive effects observed in case reports, open clinical trials and short duration controlled trials.10 For approximately 1/3 of drugs serious problems are identified post-approval; examples amongst AEDs include pancreatitis for valproate, aplastic anaemia for felbamate, and visual field defects for vigabatrin. Herranz et al75 studied 392 children given long-term monotherapy with phenobarbitol, primidone, phenytoin, carbamazepine, or valproate and found that side effects occurred in 50%. For various reasons adverse events profiles of AEDs may not be the same as for adults. More detailed consideration of these factors is given in Appendix 3 page 147 and Appendix 4 page 152, while in Appendix 5 page 154 interaction of AEDs with the contraceptive pill is considered, and in Appendix 6 page 155 AEDs and teratogenicity.

Because of the many potential unwanted effects of AEDs (e.g. aggravation of seizures, appearance of new seizure types, AED-induced encephalopathy, possible AED-associated deterioration in learning, memory and cognitive abilities) clinicians have expressed concern about widespread over-treatment of children.76 Facets of over-treatment include:77 unnecessarily fast escalation of dosage; use of AED when not required; unnecessary long-term continuation of therapy; inappropriate use of poly-therapy. Despite clinical consensus that febrile convulsions do not require prophylactic therapy the practice is wide-spread; the 12 year follow-up study of children with febrile convulsions conducted by the NGPSE78 reported 11% of 220

30 Newer Drugs for Children with Epilepsy children had received medication, in 1/3 of these cases this was for simple febrile convulsions.

Assessment of risks associated with taking AEDs is difficult, especially in special populations such as children, as drugs have in the past often been only tested in trials after initial approval of a drug by a regulatory authority, and then only for limited indications and in limited age ranges. Post marketing surveillance and alert observation by prescribers help to progressively reduce the degree of uncertainty about risk. However poor reporting, lack of standardisation, and difficulties of collation of data, mean that risk from side effects and adverse events is difficult to quantify. Unfortunately only one prescription event monitoring (PEM) study for an AED has been published (for gabapentin79). A report of postmarketing experience of topiramate with particular reference to cognition has also been published.80 An unpublished PEM study failed to detect the visual field defects associated with vigabatrin,81 yet a case control study82 estimated that 52% of vigabatrin patients had definite visual field defects (compared with 0% of control epileptics not taking vigabatrin) and a retrospective study83 of vigabatrin-treated patients who attended a regional epilepsy clinic found that 43% of 98 tested had visual field abnormality with no alternative cause. In a follow up study84 16 of 29 children treated with vigabatrin (mean 35.7 months) showed evidence of visual abnormality. With these risks in mind, except for the case of West’s syndrome, it is likely vigabatrin would be used as a last resort AED.

Thus the use of AEDs in paediatric epilepsy, like many realms of clinical practice in the management of the condition, is poorly supported by the literature. A consequence of this is that paediatricians often prescribe drugs in an “off licence” (drug or formulation not licensed) or “off label” (drug not licensed for child’s age range, indication, formulation or dose) manner. Without such prescribing, paediatricians’ therapeutic options would be severely limited, but there may be no relevant randomised control trial or pharmacokinetic evidence.

Several attempts have been made to rationalise drug treatment options by integrating data from clinical trials with that derived from other studies61,85-88 and some of these apply specifically to children. Such “rational” strategies implicitly or explicitly score or categorize drugs across a matrix of characteristics which encompass such features as mechanism of action, pharmacokinetics, ease of use for children of different ages, drug interactions, efficacy (seizure reduction), neurotoxicity, psychiatric interactions, idiosyncratic reactions, chronic adverse effects, teratogenicity, comfort factor (clinicians personal experience determining confidence in predicted effects).

Valproate, carbamazepine and vigabatrin or steroids are the usual drugs of first choice in the UK for children with generalised and typical absence seizures, for partial seizures with or without secondary generalisation, and for infantile spasms, respectively.

Should the first drug deliver intolerable side effects and/or fail to achieve seizure control an additional or substitute drug is considered. Substitute monotherapy is a possible choice on the grounds that unwanted side effects are more likely with two than one drug. Careful withdrawal of the first drug and gradual introduction of the substitute is mandatory. Alternatively withdrawal of the first drug may be delayed so

31 Newer Drugs for Children with Epilepsy that combined treatment lasts for sufficient time to assess the second drug as a possible line of treatment.89

The range of second line drugs, used as add on or substitute, is more varied than first line and includes consideration of additional standard and newer AEDs such as lamotrigine, ethosuximide, clonazepam, topiramate, levetiracetam, gabapentin, tiagabine and benzodiazepines depending on diagnosis and clinical judgement.10,85,90 Some may reduce frequency of one type of seizure but increase another type, close monitoring is desirable. Effects of AEDs can influence hormone metabolism and thereby endocrine profiles, menstrual cycles, and other aspects of reproductive physiology. This and the potential interactions in drug metabolism during dual or poly-therapy have to be taken into consideration when tailoring drug therapy for the individual patient.91

2.2.5 Non AED treatments

When pharmacotherapy has failed then evaluation for other treatment options should be undertaken. Ideally a logical tailored treatment strategy should be developed in which potential benefits and risks are balanced. Non-drug options most likely to be considered are surgery, vagus nerve stimulation (VNS) and a ketogenic diet. Clinicians must make a decision about when AEDs have failed. This judgement may be influenced as much by the local availability of alternative treatments, and lack of reliable information regarding their efficacy, as by outcome measures of the current AED treatment the child is receiving. Some might consider AEDs to have failed when 2 mono-therapy options have been tried but without delivering acceptable outcome in terms of seizure relief and freedom from side effects; however with the availability of an increasingly wide choice of AEDs others may be judge it reasonable to attempt multiple changes in mono-therapy and then, in face of continued failure, combination (add on) therapy. However prognosis for seizure control with add-on AED treatment after failure of mono-therapy is not good.92

Surgery is a radical intervention and a treatment option associated with high initial cost. Some children with refractory partial epilepsy might benefit from surgical treatment. Operative treatment includes hemispherectomy (where a child with very severe epilepsy has a prexisting hemiplegia associated with a contralateral defect), corpus callosotomy, focal cortical resection of the temporal lobe, focal cortical resection of extra-temporal regions of the brain, and multiple subpial resections. The aim is to remove tissue responsible for seizures while leaving functional parts (the “eloquent cortex”) as intact as possible. Hence suitability for surgery depends upon the ability to identify the responsible tissue and also upon the likely functional impact upon the patient. In the past a surgical option for epilepsy, especially for children, has been adopted with caution because of: • Hesitancy in adapting surgical procedures developed for adults • Uncertainty that the epilepsy might be self limiting • Worries concerning post-operative neurological deficit • Inherent risk of surgery in small children • Risk associated with invasive work-up procedures (e.g. intra-cranial electrode recordings)

32 Newer Drugs for Children with Epilepsy

• Lack of strong recommendation in practice guidelines because of an absence of RCT evidence on efficacy • Apparent lack of resources and perceived costs of pre-operative procedures to determine whether the patient is a good candidate for surgery

A systematic review published in 199993 estimated that approximately 8-25% of children newly diagnosed with epilepsy might go forward for assessment for surgery (modern MRI imaging + EEG). Of those with normal MRI about 1 to 5% may have further explorative imaging (SPECT or PET) which may identify a lesion. Functional MRI (monitoring functional areas by detecting changes in cerebral blood flow during performance of tasks) may be used to delineate functional regions. Approximately half of those assessed will be judged suitable for some form of surgery. The review concluded that there was observational evidence that surgery renders significant numbers of refractory patients seizure-free. An RCT published subsequent to the review94 found that after 1 year 58% of patients (N=40) receiving surgery for refractory temporal-lobe epilepsy were seizure free compared with 8% of patients (N=40) who received medical management with AEDs (p<0.001). Epilepsy-specific quality of life scores were also significantly better in the surgery group (p<0.001).

Vagus nerve stimulation involves an invasive procedure in which a programmable generator is implanted beneath the left collarbone and stimulates the left vagus nerve via an electrode implanted around the nerve . Mechanism of action is uncertain. Criteria for the selection of patients are lacking. In the USA up to Jan 2002 approximately 14,500 <18 years olds had been implanted of which 70% had co- morbidity with mental retardation and developmental delay. In the USA treatment must be used out of licence for children less than 12 years old. Side effects, which include coughing and voice changes during stimulation and drooling and ear pain in a small proportion of children under 12 years old, appear appealingly mild compared with those associated with multiple AED therapies. Reductions in seizure frequency in refractory paediatric patients also appear promising and apparently improve with prolonged treatment. However no RCT has been conducted in children comparing VNS with medical management or with surgery and quality information regarding continuation on therapy is wanting. For adult patients with refractory partial epilepsy RCTs have been performed. VNS has been subject of a Technology Assessment Report published in 199995 which concluded that for refractory partial epilepsy seizure relief was comparable to that of the newer AEDs. For less severely affected patients efficacy was unknown. Cramer et al 200196 attempted a comparison of risk- benefit profiles of newer AEDs and VNS used as add-on therapy for adults with refractory partial epilepsy. Data from RCTs was synthesised into a success score (proportion achieving >50% reduction in seizure rate in active arm minus proportion in placebo arm) and a “complaint score” (composite summing measure of all adverse events using COSTART or WHO-ART terms in active arm minus placebo arm). Of 8 treatments (7 drugs + VNS) VNS registered the lowest “success” score and the second worst “complaint score”. The authors acknowledged that the “success score” for VNS may be underestimated since the invasive nature of VNS dictated that RCTs have a pseudo-placebo arm that administered low level stimulation from which some benefit might be derived.

A ketogenic diet is one in which a major proportion of metabolizable calories come from fatty acids derived from tri-glycerides. Maintenance on a ketogenic diet produces high plasma levels of ketone-bodies (acetoacetate, β−hydroxybutyrate and 33 Newer Drugs for Children with Epilepsy acetone). The source of ketone-bodies is hepatic acetate (acetyl-CoA) derived from oxidation of fatty acids. The metabolic situation induced mimics starvation in which body fat stores are metabolised in order to spare structural protein and limited carbohydrate reserves. High levels of ketone-bodies are achieved gradually as the diet is maintained and metabolic adaptation occurs in many tissues in which there is a shift from glucose to ketone-bodies as an energy source of prime importance. Work on laboratory animals demonstrates a rise in seizure threshold with raised plasma ketone- body levels, and prospective studies have indicated efficacy with some child and infant epilepsies.97,98 The mechanism(s) of action are uncertain. Potential benefits of the ketogenic diet include its lack of a sedative effect with greater alertness of patients (improvements in attention, comprehension, activity level and endurance). Potential side effects include cardiac complications, acidosis leading to kidney stones, and bone demineralisation. In addition, compliance with this difficult diet is not always good and can result in discontinuation. The profound metabolic changes imposed by the ketogenic diet mean it should be introduced under close supervision preferably in a hospital setting. A recent audit survey (51% response rate) in the UK reported that 17% hospitals used ketogenic diet with 1/3 initiating the diet at home and 2/3 in hospital.99 No consistent policy on vitamin supplementation existed.

34 Newer Drugs for Children with Epilepsy

2.3 Description of new intervention Description of technologies Since 1989, seven new antiepileptic drugs have been introduced in the UK: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and vigabatrin.

The licensed indications of these drugs vary, with oxcarbazepine, lamotrigine and vigabatrin licensed as mono- and add-on therapy (vigabatrin as monotherapy for West's Syndrome only), and gabapentin, levetiracetam, tiagabine, and topiramate for add-on therapy only. The drugs also vary in the age groups they are indicated for, with thresholds of 2, 6, 12, and 16 years. Levetiretecam is only licensed for age 16 and over and is thus not considered further in this review.

Appendix 1 page 134 gives details of the licensed indications for each drug, along with information on dosage, adverse effects, and cost. At least nine other new AEDs are in various stages of clinical and pre-clinical development.100

2.3.1 Mechanism of action Under normal circumstances, neuronal activity depends on a controlled balance between excitatory and inhibitory influences on the electrical activity across the cell membrane. The pathophysiology of epilepsy probably involves a local imbalance among these factors which leads to a focus of neuronal instability. Two main mechanisms appear to be important in the action of AEDs: • inhibition of sodium channel function, to limit the spread of neuronal instability e.g. lamotrigine, oxcarbazepine • enhancement of the inhibitory actions of gamma-amino-butyric acid (GABA) e.g. tiagabine, vigabatrin, topiramate Other mechanisms include inhibition of calcium channels, and inhibition of glutamate activity e.g. lamotrigine, topiramate.

The particular mechanisms of action of each of the newer drugs is summarised below.

Gabapentin (Neurontin − Parke-Davis) available as 100mg, 300mg, 400mg capsules, and 600mg, 800mg tablets. Gabapentin is structurally related to the neurotransmitter gamma-amino-butyric acid (GABA) but its mechanism of action is different from that of several drugs that interact with GABA synapses. The identification and function of the gabapentin binding site has not been elucidated. As well as being used for the treatment of epilepsy, gabapentin is indicated for the treatment of neuropathic pain.

Lamotrigine (Lamictal − GlaxoSmithKline) available as 25mg, 50mg, 100mg, 200mg tablets, and 2mg, 5mg, 25mg, 100mg dispersible/chewable tablets. Results from pharmacological studies suggest that lamotrigine is a use-dependent blocker of voltage gated sodium channels. It produces a use- and voltage-dependent block of sustained repetitive firing in cultured neurones and inhibits pathological release of glutamate, as well as inhibiting glutamate-evoked bursts of action potentials.

35 Newer Drugs for Children with Epilepsy

Levetiracetam (Keppra − UCB Pharma) available as 250mg, 500mg, 1000mg tablets. Levetiracetam is a pyrrolidone derivative chemically unrelated to existing antiepileptic therapies. The mechanism of action of levetiracetam is unknown, but does not appear to involve inhibitory or excitatory neurotransmission.

Oxcarbazepine (Trileptal − Novartis) available as 150mg, 300mg, 600mg tablets. The pharmacological activity of oxcarbazepine is primarily manifested through its metabolite the monohydroxy derivative (MHD). Oxcarbazepine is the 10-keto analogue of carbamazepine, which is an established AED. The mechanism of action of oxcarbazepine and MHD is believed to be based on blockage of voltage-sensitive sodium channels, resulting in stabilisation of hyperexcited neural membranes, inhibition of repetitive neuronal firing and reduced propagation of synaptic impulses. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects.

Tiagabine (Gabitril − Sanofi-Synthelabo) available as 5mg, 10mg, 15mg tablets. Tiagabine is a potent and selective inhibitor of both neuronal and glial GABA uptake, which results in an increase in GABA mediated inhibition in the brain. Tiagabine lacks significant affinity for the neurotransmitter receptor binding sites and/or uptake sites.

Topiramate (Topamax − Janssen-Cilag) available as 25mg, 50mg, 100mg, 200mg tablets, and 15mg, 25mg, 50mg sprinkle capsules. Topiramate is classified as a sulphamate-substituted monosaccharide. Three pharmacological properties of topiramate have been identified that may contribute to its anticonvulsant activity: (1) it reduces the frequency at which action potentials are generated when neurones are subjected to a sustained depolarisation, indicative of a state-dependent blockade of voltage-sensitive sodium channels; (2) it markedly enhances the activity of GABA at some types of GABA receptors but has no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype; and (3) it weakly antagonises the excitatory activity of kainate/AMPA subtype of glutamate receptor. Topiramate also inhibits some isoenzymes of carbonic anhydrase, but this pharmacologic effect is weaker than that of acetazolamide (a known carbonic anhydrase inhibitor), and is not believed to be a major component of topiramate's antiepileptic activity.

Vigabatrin (Sabril − Aventis) available as 500mg tablets and 500mg powder sachets. Treatment with vigabatrin leads to an increase in the concentration of GABA, the major inhibitory neurotransmitter in the brain. Vigabatrin was designed as a selective irreversible inhibitor of GABA-transaminase, the enzyme responsible for the breakdown of GABA.

36 Newer Drugs for Children with Epilepsy

3. EFFECTIVENESS

3.1 Methods for reviewing effectiveness

3.1.1 Search strategy

Studies employing the new antiepileptic drugs gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and vigabatrin were searched. A scoping search was undertaken to identify existing and ongoing reviews.

Primary studies were identified using the following sources:

• Bibliographic databases. Since the NHS CRD were undertaking a TAR of newer drugs for epilepsy in adults, there was collaboration between the two centres, with the work shared as indicated and references exchanged.

o MEDLINE (Ovid) 1966 – Oct 2001 (Bham) o MEDLINE and PreMEDLINE (Silverplatter) 1999 – March 2002 (NHSCRD) o EMBASE (Ovid) 1980 – Feb 2002 (Bham) o Cochrane Library (CCTR) 2002 Issue 1 (Bham) o Science Citation Index (Web of Science) 1981 – Feb 2002 (Bham) o National Research Register 2002 Issue 1 (Bham) • Checking citations of relevant studies • Contact with experts in the field • Invited industry submissions

No date or language restrictions were placed on the literature searches.

Data for the economic model were identified by further searches of the following sources to identify existing decision analytic models, costs, cost effectiveness and quality of life:

o Bibliographic databases: o MEDLINE (Ovid) 1966 – Mar 2002 o EMBASE (Ovid) 1980 – Mar 2002 o NHS Economic Evaluation Database (EED) o NHS Database of Reviews of Effectiveness (DARE) o NHS CRD administration database (undertaken by NHSCRD) o Health Economic Evaluation Database (HEED) May 2002 • Internet sites of national health economic units.

Details of search strategies are provided in Appendix 7 page 158.

37 Newer Drugs for Children with Epilepsy

3.1.2 Inclusion and exclusion criteria Inclusion criteria • Study design: Randomised controlled trials of any of the newer anti-epileptic drugs as mono-therapy or combined therapy for treatment of epilepsy. • Study population: Persons with epilepsy under 18 years old and mixed age groups with epilepsy if including persons less than 18 years old. Exclusion criteria • Trials recruiting only patients with single seizure, status epilepticus, seizures following surgery, febrile convulsions, trigeminal neuralgia or cortical myoclonus.

3.1.3 Data extraction strategy Two reviewers independently abstracted the data. A third reviewer resolved discrepancies. One reviewer screened foreign language publications using English abstracts if available. Translations were obtained where necessary. Studies with mixed age groups were identified during the inclusion/exclusion process. The data reported in these studies were categorised according to whether: 1) the study results report data for the different age groups separately; 2) the number of participants in different age-groups. Data for under 18s in these trials were extracted where possible.

Data was extracted on the following:

Study design. Study population: (seizure types and frequencies, and epileptic syndrome); baseline comparability of intervention and control groups. Intervention and comparator including: drug; doses; mode of administration; duration of treatment. Outcomes measured including: identification of all outcomes which study protocols state would be measured; the specific measurement tool or data collection method; when, how and by whom the outcome data was collected; drop-outs; cross-overs and losses to follow-up for each outcome. Study results: as raw numbers where available, plus any summary measures with standard deviations, p-value and confidence intervals where reported.

3.1.4 Quality assessment strategy The quality of RCTs was assessed by examining methods of randomisation, concealment of allocation, blinding, losses to follow up, and methods of analysis (intention to treat). Two reviewers independently examined trial quality. Disagreements were resolved by consensus.

38 Newer Drugs for Children with Epilepsy

3.2 Results

3.2.1 Number and types of studies identified The searches identified 4062 studies. Removal of duplicate references reduced this number to 3585. One reviewer scanned these to eliminate obviously irrelevant studies. Two reviewers scanned the remaining 1307 references. 396 studies were identified that were judged by at least one reviewer to possibly fulfill inclusion criteria. Hard copies of these 396 publications were sought from library and other sources. This yielded 360 hard copies. Seven of these were missed duplicate references leaving 353. Thirty-six references were not obtainable in hard copy. They are tabulated in Appendix 11 page 252. All except 6 of these were cited as journal supplements or conference proceedings. Four of the 36101-104 were excluded on the basis of closer examination of titles and or abstracts or contact with authors.

Two reviewers examined the 353 unique retrieved hard copies according to inclusion criteria. Agreement between reviewers was moderate to good (kappa score 0.67). Disagreements were resolved by discussion. One hundred and one publications were identified, reporting on a total of 84 trials which met inclusion criteria. Only twenty studies were identified in which data specific to patients under 18 years old was reported. In all but one of these the vast majority of trial participants were < 18 years of age. Five of these 20 studies had been published in abstract form only, the other 15 were published as full papers. Trial details are tabulated in Appendix 13 page 254.

In the 64 other included studies the majority of patients were >18 years of age and in 63/64 no outcome data was presented for those <18. On the basis of information in the trial reports they were judged definitely or likely to contain under 18 year olds in both intervention and comparator arms of the trial. The reports are listed Appendix 8 and details regarding study population, intervention and study design in each publication provided in Appendix 9 page 173 onwards.

A list of the excluded publications with brief comment on reason for exclusion is shown in Appendix 10 page 247,Table 137.

Three systematic reviews of AED use in children were found, one105,106 considered drug treatment for infants and children with West’s syndrome, another treatments for acute tonic-clonic convulsions including status epilepticus,107 and the third treatment for generalised convulsive status epilepticus.108 In addition other systematic reviews were identified (listed in Table 3) that analysed the use of the newer AEDs that are the topic of the present review, or other new or standard AEDs, and were based on trials in adults or populations of mixed ages very predominantly adult or on a mixture of adult/mixed age and child trials with the great majority being adult/mixed age trials. The use of these reviews to draw conclusions with regard to children would require very cautious extrapolation in the absence of evidence directly comparing a drug across adult and child populations. Table 3 Systematic reviews Newer AEDs reference drug(s) mode epilepsy Castillo S, 2001. Oxcarbazepine add-on for drug-resistant add- 1 partial epilepsy (Cochrane Review). In: Cochrane Library oxcarbazepine partial 109 on Issue, 4, 2001; Chaisewikul R, 2001. Levetiracetam add-on for drug-resistant add- 2 levetiracetam partial localization related (partial) epilepsy (Cochrane Review). In: on

39 Newer Drugs for Children with Epilepsy

Cochrane Library Issue, 4, 2001;110 Jette NJ, 2001. Topiramate for drug-resistant partial epilepsy add- 3 111 topiramate partial (Cochrane Review). In: Cochrane Library Issue, 4, 2001; on Marson AG, 2001. Gabapentin add-on for drug-resistant partial add- 4 epilepsy (Cochrane Review). In: Cochrane Library Issue, 4, gabapentin partial 112 on 2001; Marson AG, 2001. Levetiracetam, oxcarbazepine, remacemide levetiracetam, 5 and zonisamide for drug resistant localization-related epilepsy: - partial 113 oxcarbazepine a systematic review. Epilepsy Res 2001; 46(3):259-270; Mumford JP & Dam M. 1989. Meta-analysis of European placebo controlled studies of vigabatrin in drug resistant 6 epilepsy. British Journal of Clinical Pharmacology 1989; vigabatrin - epilepsy 27(SUPPL. 1):101S-107S. Pereira J, 2002. Tiagabine add-on for drug-resistant partial add- 7 114 tiagabine partial epilepsy. ). In: Cochrane Library Issue, 3, 2002. on Ramaratnam S, 2001. Lamotrigine add-on for drug-resistant add- 8 partial epilepsy (Cochrane Review). In:4 Cochrane Library lamotrigine partial 115 on Issue, 4, 2001; Richens A & Yuen AW. 1991. Overview of the clinical efficacy 9 lamotrigine - various of lamotrigine. Epilepsia 1991; 32 Suppl 2:S13-S16. Other AEDs reference drug(s) mode epilepsy Appleton RE, Martland T, Phillips B. Drug management for tonic-clonic, acute tonic-clonic convulsions including convulsive status 10 various - status epilepticus in children (Cochrane Review). In: Cochrane 107 epilepticus Library Issue, 4, 2002; Baker GA, 2000. Quality-of-life and behavioral outcome measures in randomized controlled trials of antiepileptic drugs: 11 various - various A systematic review of methodology and reporting standards. Epilepsia 2000; 41(11):1357-1363;116 Chadwick DW & Marson AG. Zonisamide add-on for drug- add- 12 resistant partial epilepsy (Cochrane Review). In: Cochrane zonisamide partial 117 on Library Issue, 4, 2001; Chadwick DW. An overview of the efficacy and tolerability of 13 new antiepileptic drugs. Epilepsia 1997; 38(SUPPL.1):S59- various - various S62; 118 Chaisewikul R, 2001. Calcium antagonists as an add-on add- 14 therapy for drug-resistant epilepsy (Cochrane Review). In: various various 119 on Cochrane Library Issue, 4, 2001; Claassen J, 2002, Treatment of refractory status epilepticus status 15 with pentobarbital, propofol, or midazolam: a systematic various - 120 epilepticus review. Epilepsia 2002; 43(2):146-153; French J, Edrich P, Cramer JA. A systematic review of the 16 safety profile of levetiracetam: A new antiepileptic drug. levetiracetam - various Epilepsy Research 2001; 47(1-2):77-90.;121 Leach JP, 2002. Remacemide for drug-resistant localization add- 17 related epilepsy (Cochrane Review). In: Cochrane Library remacemide partial on Issue, 4, 2002 Marson AG, 1996. New antiepileptic drugs: A systematic 18 review of their efficacy and tolerability. British Medical Journal various - various 1996; 313(7066):1169-1174; 122 Marson AG, 2001 Carbamazepine versus valproate carbamazepine 19 monotherapy for epilepsy (Cochrane Review). In: Cochrane mono epilepsy 123 & valproate Library Issue, 4, 2001; Marson AG, 2002 Carbamazepine versus valproate carbamazepine 20 monotherapy for epilepsy: a meta-analysis. Epilepsia 2002; 43; mono partial 124 & valproate 505-513; Privitera MD. 1999 Evidence-based medicine and antiepileptic 21 125 various - various drugs. Epilepsia 1999; 40 (suppl5) S47-S56. Ramsat ER. 1997 Tonic-clonic seizures: a systematic review of 22 antiepilepsy drug efficacy and safety. Clinical Therapeutics various - tonic-clonic 1997; 19, 433-446;126 Taylor S, 2001 Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalised onset phenobarbitone partial or 23 mono tonic-clonic seizures (Cochrane Review). In: Cochrane Library & phenytoin generalised Issue, 4, 2001;127 Tudur Smith C, 2001. Phenytoin versus valproate monotherapy for partial onset and generalised onset tonic- phenytoin & partial or 24 mono clonic seizures (Cochrane Review). In: Cochrane Library valproate generalised Issue, 4, 2001; 128 Tudur Smith C, 2002 Carbamazepine versus phenytoin Carbamazepine partial or 25 monotherapy for epilepsy (Cochrane Review). In: Cochrane mono 129 & phenytoin generalised Library Issue, 4, 2002; A number of protocols for ongoing systematic reviews were also identified and are listed in table below.

40 Newer Drugs for Children with Epilepsy

Table 4 Systematic reviews in preparation Reference Adab N, Winterbottom J, Tudur Smith C, Williamson PR. Common antiepileptic drugs in pregnancy 1 130 in women with epilepsy (protocol for a Cochrane Review). In: Cochrane Library Issue, 4, 2001; Hancock E, Cross H. Treatment of Lennox-Gastaut syndrome (protocol for a Cochrane Review). In: 2 131 Cochrane Library Issue, 4, 2001; Kalviainen R, Chadwick DW. Vigabatrin versus carbamazepine monotherapy for epilepsy (protocol 3 132 for a Cochrane Review). In: Cochrane Library Issue, 4, 2001; WITHDRAWN IN 2002 Posner EB, Mohamed K. Ethosuximide, sodium valproate or lamotrigine for typical absence 4 seizures of childhood and adolescence (protocol for a Cochrane Review). In: Cochrane Library Issue, 4, 2001; 133 Preston CL, Marson AG, Williamson PR. Lamotrigine versus carbamazepine monotherapy for 5 134 epilepsy (protocol for a Cochrane Review). In: Cochrane Library Issue, 4, 2002; Tudur Smith C, Marson AG, Williamson PR, Hutton JL, Chadwick DW. Carbamazepine versus 6 phenobarbitone monotherapy for epilepsy (protocol for a Cochrane Review). In: Cochrane Library Issue, 4, 2001; 135 ‡ 136 ‡ published 2003

3.2.2 Mixed age studies

The information reported on the age of trial participants varied in these publications. Age range data was reported in 59 of the 64 studies (Table 5). Some only reported an age range for eligible patients that would imply inclusion of <18 year olds. Others reported the age range of all randomised patients or of the participants in each study arm. Five provided no information on the age range of eligible or randomised patients but did supply median or mean ages, or mean and standard deviation, sometimes for all randomised patients or sometimes by study arm. These were considered likely to have <18 year olds on the basis that their mean/median ages were similar with those quoted for studies that definitely included <18 year olds.

A few (N=4) small studies provided individual patient ages; two of these had no patients ≤ 16 years of age and the other two only one each. In 22 studies (3 reported in duplicate) the age range of the randomised patients in each study arm was provided. In only 18 of these trials were there patient(s) in both study arms of ≤ 16 years of age. A further 16 studies (one reported in duplicate) provided the age range of all randomised patients but not by study arm. In five of these there were no patients ≤ 16 years of age, and in three the low end of the age range was 16 years. Out of the 59 studies (in 68 reports) providing information on age range the low end of the age range was 17 years in 9, 16 years in 17, 15 years in 8, 14 years in 3, 13 years in 4, 12 years in 10, 11 years in 1, 10 years in 3; and in 3 studies the lower end of the age range was < 10 years. The mean, median and mode of the upper end of the age ranges were 64, 65 and 70 years respectively. In one study the lower end of the range was specified as <16 years. It is clear that in the great majority of these “mixed age” studies the proportion of patients that were children or adolescents was small yielding little useful information about younger patients at the level of the clinical trial.

Table 5 Mixed age studies giving age range of patients. mean median age # drug Reference N age age range 1 ti Aikia M. Epilepsia 1999; 40 Suppl 7:51. 137 67 ------15-75 Lindberger M, et al. Epilepsia 2000; 41(10):1289-1295. 2 ga 102 33.7 --- 13-68 138 Binnie CD, et al. Epilepsy Research 1989; 4(3):222- 3 la 30 37.1 --- 16-51 229. 139 Cramer JA, et al. Epilepsy Research 2000; 41(1):29- 4 le ? 38.7 --- 16-70 38. 140 5 ox Barcs G, et al. Epilepsia 2000; 41(12):1597-1607. 141 694 34.5 --- 15-66 6 ti Brodie MJ, et al. Epilepsia 1997; 38 Suppl 3:66-67. 142 ? ------12-85 41 Newer Drugs for Children with Epilepsy

Tanganelli P, et al. Bollettino Lega Italiana Contro 7 vi 11 29.5 --- 17-58 L'Epilessia 1993; (82-83):137-138. 143 Canger R & Saltarelli A. Bollettino - Lega Italiana 8 vi Contro L'Epilessia 1997; Issue 99 Suppl 1 (pp 33-36). 16 27.7 --- 17-40 144 9 vi Chadwick D. Lancet 1999; 354 (9172):13-19. 145 446 35.5 --- 12-75 Andrews J, et al. Lancet 1990; 335 (8698):1114-1117. 10 ga 146 127 30.5 --- 14-73

11 ga Sivenius J, et al. Epilepsia 1991; 32(4):539-542. 147 43 39 --- 16-59 McLean MJ, et al. Neurology 1993; 43(11):2292-2298. 12 ga 148 306 34.2 --- 16-70

13 ga Anhut H, et al. Epilepsia 1994; 35(4):795-801. 149 272 32 --- 12-67 Leach JP, et al. Journal of Neurology, Neurosurgery & 14 ga 150 27 ------16-67 Psychiatry 1997; 62(4):372-376. Schapel GJ et al. Journal of Neurology, Neurosurgery 15 la 151 41 31 28 17-63 & Psychiatry 1993; 56(5):448-453. 16 la Smith D, et al. Epilepsia 1993; 34(2):312-322. 152 81 33.7 --- 15-67 Severi S, et al. Bollettino Lega Italiana Contro 17 la 153 27 39.7 --- 17-58 L'Epilessia 1994; (86-87):149-151. 18 le Cereghino JJ, et al. Neurology 2000; 55(2):236-242. 154 294 38 --- 16-70 19 le Cramer JA, et al.. Epilepsia 2000; 41(7):868-874. 155 246 38.7 --- 16-70 Shorvon SD, et al. Epilepsia 2000; 41(9):1179-1186. 20 le 156 324 36.7 --- 14-68

21 ox Schachter SC, et al. Neurology 1999; 52(4):732-737.157 102 33.5 --- 11-65 Lee BI, et al. Epilepsia 1999; 40(12):1767-1774. 22 to 158 177 29.6 --- 16-65 Korean Topiramate group Grunewald RA, et al. Journal of Neurology, 23 vi 159 45 --- 27, 29 16-59 Neurosurgery & Psychiatry 1994; 57(9):1057-1063. Brodie MJ & Mumford JP. Epilepsy Research 1999; 24 vi 160 215 --- 36, 37 12-78 34(2-3):199-205. 25 ti Dodrill CB, et al. Neurology 1997; 48(4):1025-1031. 161 297 34 --- 12-77 Dodrill CB, et al. Epilepsy Research 2000; 42 (2- ‡ 26 ti 162 277 37.5 --- 3):123-132. <16-? 27 vi Beran RG, et al. Seizure 1996; 5(4):259-265.163 ? ------17-64 Ben Menachem E, et al. Epilepsy Research 1995; 28 ga 164 36 37 --- 16-66 21(3):231-236. Ben Menachem E, & Falter U. Epilepsia 2000; 29 le 165 286 36.5 --- 16-70 41(10):1276-1283. Sachdeo RC, et al. Archives of Neurology 1997; 30 ti 166 318 33.8 --- 12-67 54(5):595-601. 31 vi Rimmer EM, et al. Lancet 1984; 1(8370):189-190. 167 ? 33 --- 16-61 Gram L, et al. Annals of Neurology 1985; 17(3):262- 32 vi 168 ? ------17-63 266. 33 vi Cramer J, et al. Epilepsia 1995; 36(11):1111-1117. 169 ? ------16-50 Provinciali L, et al. Acta Neurologica Scandinavica 34 vi 170 40 36.5 --- 17-66 1996; 94(1):12-18. Chadwick D, et al. Epilepsy Research 1996; 25(3):191- 35 ga 171 129 29.5 --- 13-62 197. 36 la Beran RG, et al. Epilepsia 1998; 39(12):1329-1333. 172 26 29 --- 15-50

37 to Biton V, et al. Neurology 1999; 52(7):1330-1337. 173 † 80 26.2 --- 3-59 Chadwick DW, et al. Neurology 1998; 51(5):1282- 38 ga 174 292 35.5 --- 12-86 1288. 39 la Brodie MJ, et al. Lancet 1995; 345(8948):467-479. 175 260 --- 27, 28 13-81 Dam M. Lamotrigine: A Brighter Future -International 40 la 176 343 ------12-72 Congress & Symposium 1996; Series 214: 17-21. 41 la Steiner TJ, et al. Epilepsia 1999; 40(5):601-607. 177 181 --- 27, 28 13-74 Kalogjera SD, et al. Epilepsia 2000; 41 Suppl 7:116- 42 la 178 133 ------12-? 117. 179 33, 43 ox Dam M, et al. Epilepsy Research 1989; 3(1):70-76. 194 --- 14-63 32.5 Bill PA, et al.. Epilepsy Research 1997; 27(3):195-204. 44 ox 180 287 26.8 --- 15-91

Christe W, et al. Epilepsy Research 1997; 26(3):451- 45 ox 181 249 32.5 --- 15-65 460. Wheless JW, et al. Neurology 2001; 56(8 Suppl 46 to 182 626 ------6-?** 3):A234-A235. Kalviainen R, et al. Archives of Neurology 1995; 47 vi 183 100 35 --- 15-64 52(10):989-996. Binnie CD, et al. Epilepsy Research 1987; 1(3):202- 48 la 184 10 30.5 --- 16-46 208. 49 le Betts T, et al. Seizure 2000; 9(2):80-87. 185 119 38 --- 16-70 Houtkooper MA, et al. Epilepsia 1987; 28(6):693-698. 50 ox 186 ? --- 29, 29 15-50

42 Newer Drugs for Children with Epilepsy

51 vi Loiseau P, et al. Epilepsia 1986; 27(2):115-120. 187 22 28.9 24 10-58 52 vi Tartara A, et al. Epilepsia 1986; 27(6):717-723. 188 23 30.5 30 17-50 Rimmer EM, et al. Epilepsy Research 1987; 1(6):339- 53 vi 189 6 18 --- 10-25 346. Tassinari CA, et al. Archives of Neurology 1987; 54 vi 190 31 28.9 --- 10-58 44(9):907-910. Reynolds EH, et al. Epilepsia 1991; 32(4):530-538. 191 55 vi 192 20 ------16-65 same as Gillham RA, et al. Journal of Neurology Neurosurgery 56 vi 193 48 32.5 --- 17-53 and Psychiatry 1993; 56:1271-1275. Carmant L, et al. European Journal of Neurology 1999; 57 la 194 ? ------2-? 6(Supplement 3):72. Montouris G, et al. Neurology 1999; 52(6):A523-A524. 58 la 195 29 --- 25, 26 12-?

59 la Fakhoury T, et al. Epilepsia 2000; 41 Suppl 7:107. 196 ? ------16-? If necessary the mean age has been averaged for all arms of trial. When reported the median age is given for each arm of the trial. † Data presented for 13 placebo & 8 topiramate patients ≤ 16 years old. **119 patients ≤16 years old. ‡ 13 patients < 16 years old.

3.2.3 Partial seizures (with or without secondary generalisation) Eight randomised controlled trials were identified; 2 of these were conducted in a newly diagnosed population and 6 in populations which were refractory or inadequately controlled on existing anti-epileptic drug treatment.

Newly diagnosed partial seizures

Two trials were identified conducted in a newly diagnosed population. Nieto Barrera, 2001197 compared lamotrigine and carbamazepine in a mixed age population. Zamponi, 1999198 compared vigabatrin and carbamazepine in children. Both trials were ‘open label’, that is treatment was not blinded. Blinding may be difficult or impossible when active controls have characteristic and easily identifiable side effects, also choice of formulation, differences in dose and titration periods may make blinding more difficult while not altogether precluding it).

Quality assessment Neither trial gives an adequate description of the method of randomisation or concealment of allocation.

There are particular concerns about the randomisation in Zamponi, 1999.198 This trial report says only that patients were ‘treated in a random fashion’, but it is not clear that an appropriate method of randomisation was used. This concern is based on two points. Firstly, there is quite a large difference in the numbers randomised to each arm for a single centre study (32 vs 38), although this imbalance could arise from the use of simple randomisation. Secondly, there is a very large difference in the ages of the patients on the two arms, with a mean age of 9 years 5 months on carbamazepine vs 7 years 4 months on vigabatrin. The impression of two separate cohorts rather than a randomised comparison is strengthened by the reporting of this trial which reports on both groups entirely separately and at no point attempts to directly compare the two groups.

The standard of reporting was better for Nieto-Barrera, 2001197 but details of randomisation and allocation concealment are not given in the trial report. Most baseline characteristics are only reported for the whole (mixed age) group with some, including baseline seizure frequency, reported separately for age groups <2 years, 2-

43 Newer Drugs for Children with Epilepsy

12 years, 13-64 years and >64 years. Baseline seizure frequency does appear to be somewhat higher in the carbamazepine treated group age 2-12 years; mean 10/month vs 6.8/month; this difference could arise by chance with appropriate randomisation but does nothing to ease concerns about the integrity of randomisation where this is in doubt. A major weakness of this trial is that intention-to-treat analysis was not used, with the primary effectiveness measures excluding patients who did not have follow- up to 22 weeks and 18 weeks respectively.

Results Both trials suggest that carbamazepine may be slightly more effective but with more side effects. Nieto-Barrera, 2001 reports better treatment retention during the 6 month follow-up period of the trial, with more patients withdrawing early due to adverse effects on carbamazepine, but this effect appears to be due in large part to much worse treatment retention for carbamazepine in the elderly population (>64 years old).

There are no significant differences reported for any outcome (for children) in either trial. Interpretation of these results for either trial is difficult given the methodological shortcomings outlined.

44 Newer Drugs for Children with Epilepsy

Table 6 Summary of trials and trial design (newly diagnosed partial seizures) Trial ID Nieto-Barrera, 2001 Zamponi, 1999 Newer drug(s) lamotrigine vigabatrin investigated Target maintenance dose lamotrigine 2-15 mg/kg/day (oral); vigabatrin 50-60mg/kg/day; (mode) carbamazepine 5-40mg/kg/day carbamazepine 1520mg/kg/day (oral) (oral) [typo?] Seizure or syndrome newly diagnosed partial epilepsy newly diagnosed partial epilepsy Type of trial design parallel parallel Add-on or monotherapy? monotherapy monotherapy Control(s) carbamazepine carbamazepine Study start and end dates Not stated not reported Centres and location Multicentre; Europe, Egypt and 1 centre in Italy Mexico Baseline None none Titration period 6 weeks 4 weeks (defined for lamotrigine arm only) Maintenance 18 weeks 100 weeks (assumed from "2 year follow-up") Withdrawal None None Inclusion criteria Newly diagnosed or currently Children with newly diagnosed untreated partial epilepsy; no age partial epilepsy restrictions Timing and additional NA (no baseline phase) NA (no baseline period) eligibility for randomisation/continuatio n on study Comments on design Titration schedule much more Very poor quality of reporting; not clearly defined for lamotrigine; clear that trial was randomised. patients on lamotrigine arm 'withdrawn' if dose reduction required during escalation phase or whilst on lowest maintenance dose, but no similar criteria given for carbamazepine.

45 Newer Drugs for Children with Epilepsy

Table 7 Quality assessment (newly diagnosed partial seizures) Trial ID Nieto-Barrera, 2001 Zamponi, 1999 Was assignment of Yes Yes treatment described as random? Was method of No (except stratified by age No randomisation described? and country) Was the method really Can't tell Can't tell random? Was allocation of treatment Can't tell Can't tell concealed? Who was blinded to Open label study Open study treatment? Was method of blinding NA NA adequately described? Were eligibility criteria Yes No described? Were groups comparable at Yes (data not reported for Can't tell; large imbalance in study entry? children separately) numbers randomised for a small single centre study, big age difference, patient characteristics poorly reported Were groups treated Can't tell Can't tell identically apart from the intervention? Was ITT used? No Can't tell Were withdrawals stated? Yes (but see comment) Yes Were reasons for Information incomplete Yes (but see comment) withdrawals stated? Was a power calculation No No done? Was monitoring of plasma No No levels done (including study drug)? Were arrangements to blind NA NA (open study) plasma monitoring results mentioned? Comments Mixed age trial, ages 2-83 Very poor quality of reporting years. Patients aged 13-64 Reasons for withdrawal were regarded as single group stated but cannot be certain but results for age-group 2- that these were complete data. 12 reported separately; these results will be used for this review. Numbers withdrawing stated for some but not all reasons; Kaplan-Meier curve for all-cause withdrawal provides estimate of percentage withdrawing.

46 Newer Drugs for Children with Epilepsy

Table 8 Results (newly diagnosed partial seizures) Trial ID Nieto-Barrera, 2001 Zamponi, 1999 Carbamazepine Lamotrigine Carbamazepine Vigabatrin Number randomised 75 153 32 38 Number analysed 64 134 Not stated Not stated Maintenance dose Mean 16.9mg/day Mean 3.4mg/day 1520mg/kg/day 50 to 60mg/kg/day achieved Median 16.0, 5.2-36.5 Median 2.7, 0.05-10.5 [typographical error in source?] Withdrawals including Total withdrawals 11 (15) 21 (13) Total withdrawals 8 6 reasons where Adverse events 5 (7) 8 (5) Lack of efficacy 2 5 specified Adverse events 6 1

Results CI;p-value Results CI;p-value Primary outcome(s) 1. Seizure-free in CBZ: 48/64 (75%) None stated NA NA last 16 weeks and LTG: 89/134 (66%) -22-5%; p = .205 follow-up to wk 22

2. Seizure-free in CBZ: 48/75 (64%) last 16 weeks and LTG 89/158 (56%) -21-6%; p = ns follow-up to wk 18 Secondary outcomes 1. Global Survival analysis not Not reported None stated NA NA effectiveness reported (time to Kaplan-Meier curves withdrawal from [proportions not given for 2-12 yrs study) CBZ: 11 (15%) age group LTG: 21 (13%)] 'Ad hoc' outcomes 1. Proportion CBZ: 5/75 (7%) p=0.761 1. Number of CBZ: 7/32 (21.9%) No comparative withdrawn for LTG: 8/158* (5%) relapses (not VBT: 9/38 (23.7%) analysis reported adverse events defined; assumed *not clear if this is a to be recurrence typo of seizures)

47 Newer Drugs for Children with Epilepsy

Table 9 Adverse events (newly diagnosed partial seizures)

Trial ID Nieto-Barrera, 2001 Zamponi, 1999 Criteria for reporting Events in more Carbamazepine Lamotrigine None stated Carbamazepine Vigabatrin than 6% pts Events Any AE 47 (63) 80 (51) Irritability/excitabilit 0 6 (15.7) Infection 0 (-) 20 (13) y 3 (9.3) 10 (26.3) Headache 12 (16) 12 (8) Weight gain 6 (18.7) 0 (-) Asthenia 1 (1) 4 (3) Excessive sedation 6 (18.7) 0 (-) Somnolence 7 (9) 5 (3) Rash Pharyngitis 8 (11) 13 (8) Rash 6 (8) 11 (7) Dizziness 11 (15) 1 (<1) Serious AE 1 (1) 9 (6) Drug-related 30 (40%) 35 (22%)

112 events in 47/75 206 events in 80/158 patients patients

48 Newer Drugs for Children with Epilepsy

Previously diagnosed partial seizures Eight randomised controlled trials were identified. All were placebo-controlled trials investigating the addition of a new drug to existing therapy. Two trials used gabapentin, two used vigabatrin, with one trial for each of lamotrigine, oxcarbazepine, tiagabine and topiramate. Quality assessment Four of the trials, Shapiro, 2000,199 Litzinger, 1998,200 Valentine, 1998,201 and Van Orman, 1998202 were reported in abstract form only and thus there is very limited information available.

Duchowny, 1999,203 Glauser, 2000204 and Elterman, 1999205 all gave adequate descriptions of the method of randomisation and allocation concealment; Appleton, 1999206 did not give details beyond describing the trial as randomised. Patient characteristics in the four trials were balanced, although there was some difference in baseline seizure rates in Duchowny, 1999; this imbalance could have arisen by chance and does not in itself cast doubt on the randomisation.

These four trials were described as double blind, although Duchowny, 1999 is the only one to give any indication of how blinding was achieved (matching tablets). Of some concern is that all four of these trials described dose titration schedules for the active treatment group only; clearly with appropriate blinding a similar titration schedule would be followed for the placebo group also. Whilst this may seem a trivial omission, reporting of dose titration for the placebo group, and reporting of the maintenance placebo doses achieved, is important if only to indicate that adequate blinding was maintained throughout the trial.

Duchowny, 1999 is the only one of these three trials where AED plasma levels were explicitly not monitored; they report that one investigator did measure plasma levels and entered these on patient notes thus breaking the blinding. None of the other three trials, where plasma levels were monitored as part of the trial requirements, mention any attempts to keep the results blinded from the investigators, raising some concern about adequate blinding in these trials.

Appleton, 1999 claims that ITT analysis was used but then define ITT as ‘all patients who received study medication’, which is not the ITT population; it is not clear from the paper how many patients were randomised (as opposed to how many were included in the ITT population). Duchowny 1999 and Elterman, 1999 both report ITT analysis; Glauser, 2000 may have used ITT but it is not clear whether 3 patients excluded from the analysis were excluded because their data was missing or were deliberately excluded because they withdrew from treatment. Results Duchowny, 1999, Glauser, 2000, Elterman, 1999, Valentine, 1998 and Van Orman, 1998 all report some differences in reduction of seizure rate compared to placebo; The first three of these reported median % reduction in seizure rate and all report similar results, with around 10% reduction with placebo and around 35% reduction on active treatment. Shapiro, 2000 found a small trend in favour of gabapentin (using the unusual endpoint of response ratio) but this trial was too small to demonstrate any benefit, or indeed to rule out a benefit. Appleton, 1999 used an inappropriate

49 Newer Drugs for Children with Epilepsy definition of the ITT population and furthermore the report is dominated by results from a ‘modified ITT’ population; the results reported for the (inappropriately defined) ‘ITT’ population in this trial did not reveal any significant differences between gabapentin and placebo.

As would be expected, more patients withdrew due to adverse events on active treatment compared to placebo, with the exception of Elterman, 1999 which reported no withdrawals due to adverse events on topiramate in this small trial.

50 Newer Drugs for Children with Epilepsy

Table 10 Summary of trials and trial design (previously diagnosed partial seizures) Trial ID Appleton, 1999 (1) Shapiro, 2000 Duchowny, 1999 Newer drug(s) gabapentin gabapentin lamotrigine investigated Target maintenance dose 600-1800mg/day dependent on 40mg/kg/day (oral syrup) 1-15mg/kg/day, maximum (mode) weight (?mode) 750mg/day (oral; chewable/dispersible caplets or tablets) Seizure or syndrome partial seizures partial seizures partial seizures Type of trial design parallel parallel parallel Add-on or monotherapy? add-on add-on add-on Control(s) placebo placebo placebo Study start and end dates 1993 to 1996 Not reported Not reported Centres and location 54 centres in Europe, S Africa and Not reported 40 centres in US, France USA Baseline 6 weeks 2 days 8 weeks Titration period 3 days No titration 6 weeks Maintenance 81 days 3 days 12 weeks Withdrawal None None None (tapering phase not part of RCT results) Inclusion criteria Medically uncontrolled partial Partial seizures not controlled by at Partial seizures incompletely seizures; age 12 years or younger least 1 AED; age 1 to 36 mos controlled by existing therapy; age 2 to 16 yrs (USA) or 2 to 12 yrs (France) Timing and additional Post-baseline; patients - Post-baseline; actual critera for eligibility for experiencing at least 1 seizure randomisation not stated but at randomisation/continuatio every 2 weeks and 4 seizures in screening patients were expected n on study total during baseline to have at least 4 seizures during each consecutive 4-week period of the baseline phase Comments on design Dose titration refers explicitly to Monitoring of seizure rate by gabapentin only; unclear how/if continuous video-EEG recording placebo was titrated in same way. over 72 hours.

51 Newer Drugs for Children with Epilepsy

Trial ID Glauser, 2000 Litzinger, 1998 Elterman, 1999 Newer drug(s) oxcarbazepine tiagabine topiramate investigated Target maintenance dose 30-46mg/kg/day (oral - tablets) 0.7mg/kg/day (assumed /day) 125-400mg/day (oral) (mode) Seizure or syndrome partial seizures refractory partial seizures partial seizures Type of trial design parallel parallel parallel Add-on or monotherapy? add-on add-on add-on Control(s) placebo placebo placebo Study start and end dates Not reported [May 95 to Sep 97 Not reported [abstract only] Not reported (ind submsn)] Centres and location 47 centres in Argentina, Chile, Not reported [abstract only] 17 centres in US, Costa Rica Uruguay, Australia, New Zealand, Canada, Israel, USA Baseline 8 weeks 8 weeks 8 weeks Titration period 2 weeks Not reported [abstract only] 8 weeks Maintenance 14 weeks 12 weeks 8 weeks Withdrawal Not reported [abstract only] Not reported [abstract only] None Inclusion criteria Medically uncontrolled partial Not reported [abstract only] Medically uncontrolled partial seizures; age 3 to 17 years seizures, with or without secondarily generalised seizures; age between 1 and 16 years

Timing and additional Post-baseline; patients Not reported [abstract only] Post-baseline; patients eligibility for experiencing at least 1 seizure experiencing at least 6 partial randomisation/continuatio every 4 weeks and at least 8 seizures (at least 1 every 4 week n on study seizures in total during 8 week interval) during baseline baseline period Comments on design Dose titration refers explicitly to Abstract with few details of design. Dose titration refers explicitly to oxcarbazepine only; unclear how/if topiramate only; not clear how/if placebo was titrated in same way. placebo was titrated in same way.

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Trial ID Valentine, 1998 Van Orman, 1998 Newer drug(s) vigabatrin vigabatrin investigated Target maintenance dose 1.5-4g/day (oral) 20, 60, 100mg/kg/day (?mode) (mode) Seizure or syndrome uncontrolled complex partial uncontrolled complex partial seizures with or without secondary seizures with or without secondary generalisation generalisation Type of trial design parallel parallel Add-on or monotherapy? add-on add-on Control(s) placebo placebo Study start and end dates not reported not stated Centres and location Multicentre (n=?) multicentre (n=?) Baseline 6 weeks not stated Titration period 10 weeks 6 weeks Maintenance 7 weeks 8 weeks Withdrawal Not stated Not stated Inclusion criteria Not stated Not stated Timing and additional Not stated Not stated eligibility for randomisation/continuatio n on study Comments on design Randomised only 75% of target of dose-response study 120 patients.

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Table 11 Quality assessment (previously diagnosed partial seizures) Trial ID Appleton, 1999 (1) Shapiro, 2000 Duchowny, 1999 Glauser, 2000 Was assignment of treatment Yes Yes Yes Yes described as random? Was method of randomisation No - [abstract only] Yes Yes described? Was the method really random? Can't tell - [abstract only] Yes Yes Was allocation of treatment Can't tell - [abstract only] Yes Yes concealed? Who was blinded to treatment? Described as 'double-blind' Described as 'double blind'; Described as 'double-blind' Described as 'double- EEG assessor blinded. blind' Was method of blinding adequately No description - 'lamotrigine and matching Yes described? [abstract only] placebo' Were eligibility criteria described? Yes - Yes Yes [abstract only] Were groups comparable at study Yes Yes Baseline seizure rates for Yes entry? simple and complex partial seizures appear substantially higher in placebo group Were groups treated identically apart Can't tell (no description of - Can’t tell; dose titration Can't tell; dose titration from the intervention? blinding, and dose titration [abstract only] refers explicitly to refers to oxcarbazepine refers to gabapentin group lamotigine only, not clear group only only) how/if placebo doses titrated in same way Was ITT used? Claimed, but not used. "ITT - [abstract only] Yes Not clear (see comment) population defined as all randomized patients who received study medication" Were withdrawals stated? Yes - [abstract only] Yes Yes Were reasons for withdrawals stated? Yes - [abstract only] Yes Yes Was a power calculation done? No - [abstract only] Yes Yes

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Trial ID Appleton, 1999 (1) Shapiro, 2000 Duchowny, 1999 Glauser, 2000 Was monitoring of plasma levels Yes; including study drug - [abstract only] No (but see comments) Yes; including study drug done (including study drug)? Were arrangements to blind plasma No - [abstract only] NA No monitoring results mentioned? Comments - Abstract with few details One investigator measured No follow-up available on plasma lamotrigine levels 3 patients who in 3 patients and entered discontinued treatment concentrations in charts, prematurely, but not clear violating the blinding; these if this data was 'missing', patients were allowed to excluded or never sought complete the study. The (31 patients discontinued study site was closed after in total) all study medication properly discontinued.

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Trial ID Litzinger, 1998 Elterman, 1999 Valentine, 1998 Van Orman, 1998 Was assignment of treatment - [abstract only] Yes Yes Yes described as random? Was method of randomisation - [abstract only] Yes No Not stated described? Was the method really random? - [abstract only] Yes Can't tell Can't tell Was allocation of treatment - [abstract only] Yes Can't tell Can't tell concealed? Who was blinded to treatment? - [abstract only] Patients, investigators, Not stated Not stated study monitors and observers Was method of blinding adequately - [abstract only] No description No description No description described? Were eligibility criteria described? - [abstract only] Yes No No Were groups comparable at study - [abstract only] Yes Can't tell Can't tell entry? Were groups treated identically apart -[abstract only] Can't tell; no description of Can't tell Can't tell from the intervention? blinding, and dose titration refers to topiramate group only Was ITT used? - [abstract only] Yes Claimed. Claimed Were withdrawals stated? - [abstract only] Yes No No Were reasons for withdrawals stated? - [abstract only] Yes No No Was a power calculation done? - [abstract only] Yes Yes Yes Was monitoring of plasma levels - [abstract only] Yes; including study drug No No done (including study drug)? Were arrangements to blind plasma - [abstract only] No NA NA monitoring results mentioned? Comments Abstract with few details - 127 patients entered Randomised only 63% of baseline; 88 were target of 200 patients. randomised.

Abstract with few details. Abstract with few details.

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Table 12 Results (previously diagnosed partial seizures) Trial ID Appleton, 1999 (1) Shapiro, 2000 placebo gabapentin Placebo Gabapentin Number randomised Not stated Not stated 38 38 Number analysed 128 119 Not reported Not reported Maintenance dose Not reported Not reported Not reported Not reported achieved Withdrawals including Total withdrawals 28 (21.9) 21 (17.6) - Not reported Not reported reasons where Lack of efficacy 19 (14.8) 11 (9.2) specified Adverse events 3 (2.3) 6 (5.0) Change in AED 2 (1.6) 0 (-) Other 4 (3.1) 4 (3.4) Results CI; p-value Results CI; p-value Primary outcome(s) 1. Response ratio placebo -0.079 p=0.1246 1. Response ratio Placebo -0.048 gabapentin -0.146 (see comment) Gabapentin +0.018 ns

2. Responder No data reported ns rate Secondary outcomes 1. >= 50% placebo 18%, p=ns - - - reduction gabapentin 21%

'Ad hoc' outcomes ------Comments (including All results adjusted for centre. Abstract only; very limited information. whether unadjusted results reported) No ITT results available. Report defined ITT as ‘all patients treated and even then, only reported most outcomes for ‘modified ITT’ population.

Response ratio also reported for 'ITT' population using rank- transformed data due to 'evidence of non-normality'; non-normality would be expected with this statistic and ANOVA is not an ideal means of analysis. Result for 'modified ITT' population reported without transformation and with no comment on normality.

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Trial ID Duchowny, 1999 Glauser, 2000 Placebo Lamotrigine placebo oxcarbazepine Number randomised 101 98 129 138 Number analysed 101 98 128 136 Maintenance dose Not reported EIAEDs + no VPA Not reported median achieved (n=53), mean 11.6 SD 31.4mg/kg/day (6.4- 3.6, median 12.9 51.4) mg/kg/day; No EIAEDs + VPA (n=22), mean 2.7 SD 0.4, median 2.7mg/kg/day; EIAEDs + VPA (n=18), mean 3.9 SD 0.9, median 4.2 mg/kg/day Withdrawals including Total withdrawals 18 (17.8) 14 (14.2) Total withdrawals 10 (7.8) 21 (15.2) reasons where Poor response 8 (7.9) 6 (6.1) Lack of efficacy 4 (3.1) 0 (-) specified Adverse events 6 (5.9) 5 (5.1) Adverse events 4 (3.1) 14 (10.1) Withdrew consent 2 (1.9) 1 (1.0) Non-compliance 0 (-) 4 (2.9) Protocol violations 2 (1.9) 2 (2.0) Withdrew consent 1 (0.8) 2 (4.3) Lost to follow-up 1 (0.8) 0 (-) Results CI; p-value Results CI; p-value Primary outcome(s) 1. [median] % % change in placebo -9% p=0.0001 change in frequency of all oxcarbazepine -35% frequency of all partial seizures (median % change) partial seizures per 28 days during: during DB entire 18 week placebo -6.7% treatment follow-up lamotrigine -36.1% p=0.008

12 week placebo -12.8% maintenance lamotrigine -44% p=0.012 period

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Trial ID Duchowny, 1999 Glauser, 2000 Results CI; p-value Results CI; p-value Secondary outcomes 1. % change in not based on whole p<0.05 1. >= 50% placebo 22% p=0.0005 frequency of population reduction in all oxcarbazepine 41% secondarily partial seizure generalised frequency seizures

2. Proportion of results available p<0.05 2. % change in pts with <= 25%, graphically only frequency of: 26-49% and >= simple partial 45% OXC vs 16% not reported 50% reduction in complex partial 42% vs 10% not reported all partial seizures secondarily 78% vs 33% p=0.0012 generalised 3. Number of days placebo +3.2% p=0.003 when each pt was lamotrigine +28.0% seizure-free (all (median change) partial szs) 'Ad hoc' outcomes - - - Seizure free placebo 1/128 vs not reported patients oxc 5/136 Comments (including % change in seizure frequency adjusted for centre effects 50% responder rates reported for 135 (not ITT population of 136) oxc whether unadjusted patients (no explanation for missing patient). results reported) Percentage changes reported are median (weekly) % changes Changes reported for each seizure type apply only to patients with that type of seizure at baseline.

Sample size slightly less than target given in power calculation (267 vs 274).

Analysis of responder rate adjusted for centre, sex, age and weight.

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Trial ID Litzinger, 1998 Elterman, 1999 placebo tiagebine Placebo Topiramate Number randomised - - 45 41 Number analysed - 45 41 Maintenance dose - - Not reported Median 5.9mg/kg/day achieved Withdrawals including - - - Total withdrawals 2 (4.4) 0 (-) reasons where Adverse events 1 (2.2) 0 (-) specified Patient choice 1 (2.2) 0 (-) Results CI; p-value Results CI; p-value Primary outcome(s) - - - % change in frequency of all placebo -10.5% p=0.034 partial seizures (average monthly topiramate -33.1% rate) (median % reduction) Secondary outcomes - - - 1. % change in secondarily placebo +10.6% Not reported generalised seizures topiramate -31.6%

2.% with >= 50% reduction in all placebo 9 (20.0) p=ns partial seizures topiramate 16 (39.0)

3.% with >= 75% reduction in all placebo 1 (2.2) p=0.019 partial seizures topiramate 7 (17.0)

4.% with 100% reductoin in all placebo 0 (-) p=ns partial seizures topiramate 2 (4.8)

5. Parental global evaluation (results not reproduced here) (results not reproduced here) 'Ad hoc' outcomes ------Comments (including Data reported on a subset of patients Results adjusted for centre only. whether unadjusted from a larger randomised trial; no data results reported) extractable.

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Trial ID Valentine, 1998 Van Orman, 1998 placebo vigabatrin placebo vigbatrin: 20, 60, 100mg Number randomised Total 88 not stated by arm total 126, not stated by arm Total 88 not stated by arm Number analysed 88 not stated by arm 126 not stated by arm Maintenance dose not stated 1.5-4g/day not stated not stated achieved Withdrawals including not reported - - not stated - - reasons where specified Results CI; p-value Results CI; p-value Primary outcome(s) 1. >=50% reduction in placebo 26.7% p=0.0089 1. Reduction in patient not stated p=0.0142 (100mg seizure frequency vigabatrin 55.8% mean monthly seizure group v. placebo) frequency greater reduction for active arm. Secondary outcomes ------'Ad hoc' outcomes ------Comments (including - - whether unadjusted results reported)

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Table 13 Adverse events (previously diagnosed partial seizures) Trial ID Appleton, 1999 (1) Shapiro, 2000 Criteria for reporting Events in >=2% placebo gabapentin Most frequent Placebo Gabapentin of pts in either group: Events Viral infection 4 (3.1) 13 (10.9) Somnolence Not reported Not reported Fever 4 (3.1) 12 (10.1) Nausia Not reported Not reported Nausea/vomiting 9 (7.0) 10 (8.4) Vomiting Not reported Not reported Somnolence 6 (4.7) 10 (8.4) Pharyngitis 11 (8.6) 10 (8.4) Hostility 3 (2.3) 9 (7.6) Upper RTI 8 (6.3) 7 (5.9) Headache 8 (6.3) 6 (5.0) Rhinitis 6 (4.7) 6 (5.0) Emotional lability 2 (1.6) 5 (4.2) Weight increase 1 (0.8) 4 (3.4) Fatigue 2 (1.6) 4 (3.4) Bronchitis 1 (0.8) 4 (3.4) Diarrhea 4 (3.1) 3 (2.5) Convulsions 4 (3.1) 3 (2.5) Dizziness 2 (1.6) 3 (2.5) Hyperkinesia 1 (0.8) 3 (2.5) Respiratory infn 1 (0.8) 3 (2.5) Anorexia 3 (2.3) 2 (1.7) Coughing 4 (3.1) 2 (1.7) Otitis media 4 (3.1) 1 (0.8)

Considered 20% 34% related to study drug (??% events or pts)

Severe AEs 3 pts (3 events) 14 pts (23 events)

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Trial ID Duchowny, 1999 Glauser, 2000 Criteria for reporting Events in >10% Placebo Lamotrigine Events in >=10% of placebo oxcarbazepine of pts in either pts in either group: group Events Vomiting 19 (18.8) 22 (22.4) Viral infection 21 (16.2) 19 (13.7) Somnolence 18 (17.8) 24 (24.4) Fever 20 (15.5) 21 (15.2) Infection 22 (21.7) 21 (21.4) Nausea/vomiting 26 (20.1) 80 (57.9) Dizziness 5 (4.9) 21 (21.4) Somnolence 18 (13.9) 48 (34.7) Rash 18 (17.8) 16 (16.3) Pharyngitis 15 (11.6) 12 (8.6) Headache 15 (14.8) 18 (18.3) Upper RTI 15 (11.6) 10 (7.2) Rhinits 17 (16.8) 14 (14.2) Headache 23 (17.8) 44 (31.8) Accidental injury 15 (14.8) 14 (14.2) Rhinitis 11 (8.5) 16 (11.5) Diarrhoea 13 (12.8) 13 (13.2) Fatigue 11 (8.5) 18 (13.0) Fever 12 (11.8) 14 (14.2) Dizziness 10 (7.7) 40 (28.9) Abdominal pain 7 (6.9) 13 (13.2) Anorexia 13 (10.0) 9 (6.5) Tremor 2 (1.9) 12 (12.2) Ataxia 6 (4.6) 19 (13.7) Nausea 2 (1.9) 11 (11.2) Abnormal gait 4 (3.1) 14 (10.1) Otitis media 11 (10.8) 9 (9.1) Nystagmus 2 (1.5) 14 (10.1) Pharyngitis 10 (9.9) 11 (11.2) Diplopia 1 (0.7) 23 (16.6) Ataxia 2 (1.9) 10 (10.2) Abnormal vision 2 (1.5) 19 (13.7) Asthenia 6 (5.9) 11 (11.2) Abdominal pain 13 (10.0) 12 (8.6)

Proportion of Proportion of 106 (82) 126 (91) patients reporting 96 (95.0) 92 (93.8) patients reporting at least one AE >=1 adverse event

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Trial ID Litzinger, 1998 Elterman, 1999 Criteria for reporting - placebo tiagebine Events in >=10% of Placebo Topiramate pts in topiramate group Events - - - Upper RTI 36% 41% Sinusitis 27% 17% Coughing 11% 15% Diarrhoea 22% 10% Somnolence 13% 12% Anorexia 11% 12% Emotional lability 4% 12% Difficulty concentrating 2% 12% Mood problems 11% 10% Aggressive reaction 7% 10% Nervousness 7% 10% Viral infection 4% 15% Otitis media 11% 10% Rash 9% 12% Purpura 4% 15% Fever 24% 29% Injury 9% 20% Fatigue 7% 15%

Serious AEs 3 (6.6) 1 (2.4)

Trial ID Valentine, 1998 Van Orman, 1998 Criteria for reporting treatment-related placebo vigabatrin treatment-related placebo vigabatrin: adverse events adverse events 20mg 60mg 100mg Events all events (66.7) (65.9) all events (61.3) (42.3), (65.5), (86.7) somonolence not reported not reported somnolence not reported not reported headache not reported not reported dizziness not reported not reported dizziness not reported not reported increased seizure not reported not reported increased seizure not reported not reported frequency frequency

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3.2.4 Partial and generalised seizures (mixed population)

One RCT (Guerreiro, 1997207) was identified which included a mixed population of newly diagnosed patients with partial seizures (with or without secondary generalisation) or with generalised tonic-clonic seizures. The trial compared oxcarbazepine with phenytoin as first-line treatment.

Quality assessment

The trial was of fairly high quality. It is one of the few trials of those identified which described measures taken to conceal the results of drug plasma level monitoring from investigators; results were provided to investigators labelled only as zero, low, within range or high.

Most endpoints were assessed only on those patients who did not withdraw during the titration period and so, with the exception of the time to treatment withdrawal outcome the results are not based on the principle of intention-to-treat. Another concern is the choice of phenytoin as the comparator for this trial when (as the author’s acknowledge) it would not normally be considered as a first choice treatment for these patients. Ideally, a trial with an active control would use the most effective comparator treatment available.

Results

No differences were found between the two treatments in terms of proportion achieving seizure freedom, or in seizure frequency during the maintenance period. Similar numbers of patients discontinued treatment due to poor therapeutic effect in the two arms but substantially more patients discontinued phenytoin due to adverse events. The proportion discontinuing oxcarbazepine in this trial is substantially lower than reported in Glauser, 2000204 (in previously diagnosed partial epilepsy); the long (8 week) titration period used in Guerreiro, 1997 may have contributed to the low rate of discontinuation. Overall, time to treatment withdrawal was longer on the oxcarbazepine arm; it is not clear why this difference is reported statistically by means of the odds ratio when the hazard ratio and logrank statistic is the appropriate form of analysis for this kind of data (the logrank p-value is reported for time to discontinuation due to adverse events).

Subjective overall evaluations from clinicians and patients were also reported. No differences were reported in the overall evaluations, but both clinicians and patients reported better tolerability of oxcarbazepine. The difference in tolerability is clear in the results of this trial despite the use of a relatively low dose of phenytoin; it is not clear what effect the use of a higher dose of phenytoin might have had on the results for effectiveness and tolerability.

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Table 14 Summary of trials and trial design (population with partial and generalised seizure types) Trial ID Guerreiro, 1997 Newer drug(s) oxcarbazepine investigated Target maintenance dose 450-2400 mg/day (oral) (mode) Seizure or syndrome Newly diagnosed partial seizures with or without secondary generalization, and generalized tonic-clonic seizures Type of trial design parallel Add-on or monotherapy? monotherapy Control(s) phenytoin Study start and end dates 1991 to 1995 Centres and location Multi centre; Brazil and Argentina. Baseline Retrospective baseline Titration period 8 weeks Maintenance 48 weeks Withdrawal No withdrawal phase (optional non- RCT continuation to open study) Inclusion criteria Newly diagnosed epilepsy with partial seizures, with or without secondary generalisation; age 5-18 years. Timing and additional NA (retrospective baseline) eligibility for randomisation/continuatio n on study Comments on design No clear justification given for the use of phenytoin as comparator when it is not generally a first choice treatment.

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Table 15 Quality assessment (population with partial and generalised seizure types) Trial ID Guerreiro, 1997 Was assignment of Yes treatment described as random? Was method of Yes randomisation described? Was the method Yes really random? Was allocation of Can't tell treatment concealed? Who was blinded to Described as 'double treatment? blind' Was method of "tablets … with blinding adequately identical appearance" described? Were eligibility Yes criteria described? Were groups Yes comparable at study entry? Were groups treated Can’t tell identically apart from the intervention? Was ITT used? No (except for time to withdrawal outcome) Were withdrawals Yes stated? Were reasons for Yes withdrawals stated? Was a power Yes calculation done? Was monitoring of Yes plasma levels done (including study drug)? Were arrangements Yes (results reported to blind plasma only as zero, low, monitoring results within range, or high) mentioned? Comments -

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Table 16 Results (population with partial and generalised seizure types) Trial ID Guerreiro, 1997 Phenytoin Oxcarbazepine Number randomised 96 97 Number analysed 77 81 Maintenance dose Mean 5.8mg/kg/day Mean 18.8mg/kg/day achieved (at start of (at start of maintenance maintenance period) period) Withdrawals including Total withdrawals 34 24 reasons where Loss to follow up 9 8 specified Adverse events 14 2 Non-compliance 5 6 Poor efficacy 3 4 Protocol violation 2 3 Concom. illness 0 1 Discontinued at 1 0 baseline Results CI; p-value Primary outcome(s) Proportion of 46/77 phenytoin p=0.91 (by logistic seizure-free 49/81 oxcarbazepine regression) patients (of those Not based on ITT who reached population maintenance period and had at least one seizure assessment during the maintenance period)

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Trial ID Guerreiro, 1997 Phenytoin Oxcarbazepine Secondary outcomes 1. Seizure PHT:mean 0.04 p=ns frequency during OXC: mean 0.07 (not based on ITT maintenance population)

2. Overall No data reported; not evaluation (4 point clear if ITT analysis p=ns ordinal scale)

3. Premature discontinuation 3 phenytoin, 4 p=ns due to poor oxcarbazepine therapeutic effect

4. Premature discontinuation 14 phenytoin, 2 (logrank p=0.002) due to adverse oxcarbazepine events

5. Overall p=0.001 (physician evaluation of Not reproduced here assessment) tolerability (4 point p=0.038 (patient ordinal scale) assessment)

6. Clinical utility 34/96 phenytoin, (time to premature 24/97 oxcarbazepine discontinuation for any reason) OR (PHT v. OXC) 1.99 1.0-3.9; p=0.046 'Ad hoc' outcomes - - - Comments (including Not clear why logistic regression used to analyse treatment retention; whether unadjusted survival analysis would be more appropriate. Note that OR obtained in results reported) this way will be numerically greater than HR obtained by the appropriate analysis.

Table 17 Adverse events (population with partial and generalised seizure types) Trial ID Guerreiro, 1997 Criteria for reporting >5% pts in either Phenytoin Oxcarbazepine group Events Somnolence (29.8) (25.0) Dizziness (22.3) (9.4) Headache (14.9) (13.5) Gum hyperplasia (25.5) (2.1) Apathy (10.6) (11.5) Ataxia (13.8) (0) Nervousness (11.7) (2.1) Nausia (7.4) (5.2) Abnormal thinking (6.4) (5.2) Rash (5.3) (4.2) Abdominal pain (4.3) (5.2) Hypertrichosis (8.5) (0) Vomiting (5.3) (0) Increase in GGT (5.3) (0)

At least one adverse event 84/94 (89.4%) 79/96 (82.3)

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3.2.5 Generalised seizures

One trial (Eriksson, 1998208) was identified in patients with generalised seizures (rather than a specific syndrome associated with generalised seizures). The trial compared lamotrigine against placebo as add-on treatment. The trial used a complex design. Initially, all patients were treated with lamotrigine for a variable period of time. Those gaining some benefit from lamotrigine were then randomised to continue lamotrigine or withdraw to placebo. After 12 week follow-up on the randomised treatment, patients were crossed over, so that lamotrigine was reintroduced for those originally randomised to placebo, and lamotrigine withdrawn for those originally randomised to lamotrigine.

Quality assessment

This trial is poorly reported. A number of methodological details are not available from the trial report, especially with regard to the methods used to conceal allocation and maintain blinding, although the report does state that the results of drug plasma levels were known only to a single study coordinator (it is not stated whether or not this coordinator was involved in patient care). The report states that there was a three week ‘wash-out’ period between each 12 week follow-up period, but it is not clear what happened in these three weeks; a wash-out period is usually a drug-free period in cross over trials, but in this case it seems more likely that the period was used to gradually withdraw/reintroduce lamotrigine.

The trial was analysed using each patient as their own control rather than the conventional methods of analysis for a cross over trial, although some information is given about order effects and treatment x period interaction.

Results

17 were randomised, with 2 patients later withdrawn at parental request. In order to be randomised, patients had to experience some benefit after lamotrigine was introduced: 7 had >50% reduction in seizure frequency; 9 had a <50% reduction in seizure frequency and 1 had an increase (of 39%) but nevertheless were perceived to benefit from lamotrigine in terms of reduction in seizure severity or in behaviour or motor skills.

No patients experienced more seizures on placebo than on lamotrigine, and 9/15 experienced >50% reduction on lamotrigine compared to placebo phase.

No adverse events were reported for lamotrigine after randomisation; on the placebo arm 10 patients experienced fatigue and 4 experienced ‘more intense’ seizures. The interpretation of the adverse event data is complicated by the fact that this is a withdrawal trial with all patients receiving (and tolerating) a stable dose of lamotrigine at randomisation.

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Table 18 Summary of trials and trial design (generalised seizures) Trial ID Eriksson, 1998 Newer drug(s) lamotrigine investigated Target maintenance dose not reported (mode) Seizure or syndrome generalised seizures Type of trial design ‘Response-mediated' withdrawal/crossover trial Add-on or monotherapy? add-on Control(s) placebo Study start and end dates not reported Centres and location 1 centre, Scandinavia Baseline 8 weeks Titration period up to 12 months (mean 5 months) Maintenance 2x12 weeks Withdrawal 3 week washout in between titration and first 12 week period, and before second 12 week period Inclusion criteria Refractory or intractable generalised epilepsy; age >2 yrs Timing and additional Patients experiencing >=50% eligibility for reduction in seizure frequency or in randomisation/continuatio seizure severity (or both), or with n on study definite improvements in behaviour or motor skills or both were randomised to continue lamotrigineor withdraw. Non- responders were defined as without positive effects of lamotrigine with plasma levels <=10mcg/ml or children who had adverse events during the titration phase Comments on design The way in which improvement in behavioural skills or motor improvements were assessed is not explained which makes the definition of responder very subjective, although it seems from the definition of 'non-responder' that responder was defined by default.

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Table 19 Quality assessment (generalised seizures) Trial ID Eriksson, 1998 Was assignment of Yes treatment described as random? Was method of No randomisation described? Was the method Can't tell really random? Was allocation of Can't tell treatment concealed? Who was blinded to Described as 'double- treatment? blind' Was method of No blinding adequately described? Were eligibility Yes criteria described? Were groups Can't tell comparable at study entry? Were groups treated Can’t tell (methods of identically apart from blinding not clear) the intervention? Was ITT used? Yes (2 patients withdrawn from lamotrigine arm at family request) Were withdrawals Yes stated? Were reasons for Yes withdrawals stated? Was a power No calculation done? Was monitoring of Yes (including study plasma levels done drug) (including study drug)? Were arrangements Results only known to blind plasma to a single monitoring results coordinator (implies mentioned? but does not state that this coordinator was not responsible for patient care or assessment) Comments -

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Table 20 Results (generalised seizures) Trial ID Eriksson, 1998 Placebo/Lamotrigine Lamotrigine/Placebo Number randomised 8 9 Number analysed 8 7 Maintenance dose Not reported Not reported achieved Withdrawals including Total withdrawals 0 2 reasons where Consent - 2 specified withdrawn Results (diff, or by CI for difference; p- arm) value Primary outcome(s) 1. % reduction in results reported for p<0.0001 average monthly each individual; 14/15 order effect: p=0.13 seizure frequency had lower seizure rate period x treatment: during DB phase in lamotrigine period, p=0.83 1/15 no change period effect: not mentioned Secondary outcomes 1. Seizure Not reported Not reported severity Not reported Not reported 2. Functional status of patients 'Ad hoc' outcomes 1. >50% reduction 9/15 patients Not reported in seizure frequency on lamotrigine period compared to placebo period

2. Analysis of Results not Not reported results by seizure reproduced here type and in patients with Lennox-Gastaut syndrome Comments (including Atypical absences and myoclonic events excluded from analyses due whether unadjusted to difficulty identifying these events in this patient population; not clear results reported) what effect this might have, or whether this decision was made prior to unblinding data.

2 patients experienced atonic seizures when lamotrigine was added.

Table 21 Adverse events (generalised seizures) Trial ID Eriksson, 1998 Criteria for reporting Not stated Placebo Lamotrigine Events Fatigue 10 (58.8) None More intense 4 (23.5) seizures

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3.2.6 Lennox-Gastaut syndrome

Two trials were identified in patients with Lennox-Gastaut syndrome, . Both were placebo controlled trials of add-on therapy, one using lamotrigine (Motte, 1997209) and one topiramate (Sachdeo , 1999210). Sachdeo, 1999 included patients up to 30 years of age; although no data are reported separately for the children included in this trial, a substantial proportion of patients were under 18 and Lennox-Gastaut syndrome occurs exclusively in childhood and thus this trial is included in this review.

Quality assessment

Motte, 1997 is poorly reported, with no details given regarding the method of randomisation, treatment concealment or blinding. There is some imbalance in sex between the arms and a large difference in the numbers randomised to each arm (90 vs 79). The dose titration information refers exclusively to lamotrigine; whilst it may appear trivial to detail dose titration for placebo, this detail helps to confirm confidence in the blinding procedures. Sachdeo, 1999 does explicitly refer to titration in both arms of the trial, and overall is much better reported. Of concern for both trials is that drug plasma levels were monitored but no mention is made of any arrangements to conceal the results from investigators; if these results were revealed to investigators during the trial this would somewhat compromise blinding.

Results

Both trials found substantial reductions in seizure frequency compared to placebo; the magnitude of the treatment effects is similar in both trials. Motte 1997 reports more placebo patients withdrawing for adverse events on placebo than on lamotrigine. Sachdeo reports no patients withdrawing due to adverse events; however, the dose of topiramate used in this trial is relatively low and furthermore, clinicians were allowed to withdraw the drug during follow-up and then rechallenge, which may also have contributed to the lack of withdrawals due to adverse events. No patients in either trial withdrew due to poor efficacy on the active treatment arm.

The results of these trials suggest that lamotrigine and topiramate are more effective than no treatment in this group of patients. Both trials are small, and there are some methodological issues which need to be addressed.

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Table 22 Summary of trials and trial design (Lennox-Gastaut syndrome) Trial ID Motte, 1997 Sachdeo, 1999 Newer drug(s) lamotrigine topiramate investigated Target maintenance dose 50-300mg/day (oral) 6mg/kg/day (oral assumed) (mode) Seizure or syndrome Lennox-Gastaut syndrome Lennox-Gastaut Type of trial design parallel parallel Add-on or monotherapy? add-on add-on Control(s) placebo placebo Study start and end dates 1994 to 1995 Not reported Centres and location 43 centres in US, Europe 12 centres in the USA Baseline 4 weeks 4 weeks Titration period 6 weeks 3 weeks Maintenance 10 weeks 8 weeks Withdrawal None None Inclusion criteria More than one type of Drop attacks (tonic-atonic) + predominantly generalized seizure history of or active atypical including tonic-clonic seizures and absence seizures;age 1-30 years; drop attacks for at least one year; medically uncontrolled age <11 years at onset of epilepsy; itellectual impairment or a clinical impression of intellectual deterioration Timing and additional Post-baseline; no additional Post-baseline; patients who eligibility for eligibility criteria 'qualified for entry' were randomisation/continuatio randomised, but no specific criteria n on study for this are mentioned Comments on design Dose titration refers explicitly to Trial includes patients up to the lamotrigine only; not clear how/if age of 30; results are not reported placebo doses titrated in same way separately for children but this trial is included as a substantial proportion of patients are under 18 and Lennox-Gastaut is a syndrome which occurs only in childhood, and thus this data would otherwise be excluded from both reviews being prepared for NICE.

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Table 23 Quality assessment (Lennox-Gastaut syndrome) Trial ID Motte, 1997 Sachdeo, 1999 Was assignment of Yes Yes treatment described as random? Was method of No Yes randomisation described? Was the method Can't tell Yes really random? Was allocation of Can't tell Yes treatment concealed? Who was blinded to Described as 'double-blind'. Investigators, patients, study treatment? monitors and observers Was method of No description 'Blinded medication’; no further blinding adequately details described? Were eligibility Yes Yes criteria described? Were groups No; some imbalance in sex, and Yes comparable at study also a relatively large difference entry? in the numbers randomised to the two groups (90 vs 79) Were groups treated Can’t tell (no description of Yes identically apart from blinding, and dose titration the intervention? refers to gabapentin group only) Was ITT used? Not clear (see comment) Yes Were withdrawals Yes Yes stated? Were reasons for Yes Yes withdrawals stated? Was a power No Yes calculation done? Was monitoring of Yes, including lamotrigine Yes plasma levels done (including study drug)? Were arrangements No No to blind plasma monitoring results mentioned? Comments Two patients are excluded for Titration refers explicitly to both ‘lack of completeness’; the arms of trial (ie including report does not state which placebo). arm(s) these patients were allocated to.

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Table 24 Results (Lennox-Gastaut syndrome) Trial ID Motte, 1997 Sachdeo, 1999 Placebo Lamotrigine Placebo Topiramate Number 90 79 50 48 randomised Number analysed 89 78 50 48 Maintenance dose Not reported <= 25kg + VPA 13.0 92% achieved target median achieved (4.9) dose 5.8mg/kg/day <= 25kg no VPA 3.7 71% achieved target (0.9) dose (6mg/kg/day) >25kg + VPA 8.4 (3.3) >25kg no VPAl 3.7 (1.5) Withdrawals Total withdrawals 14 (15.5) 7 (8.8) Total withdrawals 0 1 including reasons Adverse events 7 (7.7) 3 (3.7) Patient choice 0 1 where specified Worse seizure 2 (2.2) 0 (-) ctrl 3 (3.3) 4 (5.0) Protocol violation 1 (1.1) 0 (-) Loss to follow-up 1 (1.1) 0 (-) Withdrew consent Results CI; p-value Results CI; p-value Primary outcome(s) % change in placebo –9% p=0.002 1. % reduction in average Placebo -8.8% p=ns frequency of lamotrigine –32% monthly seizure rate Topiramate -20.6% major motor (median reduction) seizures (drop 2. Composite: % reduction in drop attacks: attacks and average monthly drop attack placebo +5.1% tonic-clonic rate & parental global topiramate -14.8% p=0.041 seizures) evaluation (PGE) PGE: data not reproduced p=0.037

composite p<0.01

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Trial ID Motte, 1997 Sachdeo, 1999 Results CI Results CI Secondary 1. % change in placebo -9% 1. % reduction average placebo median 5.2% outcomes frequency of drop lamotrigine - p=0.01 monthly seizure rate (tonic, topiramate median p=0.015 attacks 34% atonic and tonic-clonic only) 25.8%

2. % change in placebo +10% 2. % responders frequency of tonic- lamotrigine - p=0.03 Drop attacks: clonic seizures 36% >=50% reduction 14% placebo vs 28% p=0.071 >=75% reduction 6% vs 17% not reported 3. % change in placebo -38% 100% reduction 0 vs 1 patient not reported frequency of atypical lamotrigine - p=0.96 absences 13% Drop attacks or tonic-clonic: >=50% reduction 8% placebo vs 33% p=0.002 4. Responder rate, placebo 16% >=75% reduction 4% vs 17% not reported defined as >= 50% lamotrigine 33% p=0.01 100% reduction 0 vs 1 patient not reported reduction in major motor seizures All seizure types: >=50% reduction 'no difference' p=ns >=75% reduction 0 vs 4 patients not reported 100% reduction not reported not reported

'Ad hoc' outcomes ------Comments Results adjusted for country effects. Results adjusted for investigator. (including whether unadjusted results reported)

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Table 25 Adverse events (Lennox-Gastaut syndrome) Trial ID Motte, 1997 Sachdeo, 1999 Criteria for reporting - Placebo Lamotrigine >10% greater Placebo Topiramate incidence in top arm (I.e.tx- emergent events) Events Infection 7 (7.7) 10 (12.6) somnolence (22) (42) Fever 12 (13.3) 10 (12.6) anorexia (20) (40) Nausea/vomiting 6 (6.6) 7 (8.8) nervousness (10) (21) Somnolence 4 (4.4) 3 (3.7) behavioural (10) (21) Pharyngitis 9 (10.0) 11 (13.9) fatigue (4) (19) Cold/viral illness 0 (-) 4 (5.0) dizziness (0) (10) Headache 6 (6.6) 3 (3.7) weight loss (0) (10) Rhinitis 7 (7.7) 4 (5.0) Otitis media 4 (4.4) 1 (1.2) severe adverse (10) (23) Bronchitis 6 (6.6) 7 (8.8) events Constipation 2 (2.2) 4 (5.0) Convulsions 6 (6.6) 1 (1.2) Rash 6 (6.6) 7 (8.8) Injury/accident 6 (6.6) 7 (8.8)

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3.2.7 Infantile spasms (West’s syndrome)

Three trials were identified in infantile spasms (West’s syndrome), all using vigabatrin. Appleton, 1999 (2)211 was a placebo-controlled trial of vigabatrin as monotherapy in newly diagnosed and previously untreated patients. Vigevano, 1997212 and Chiron, 1997213 used ACTH and hydrocortisone respectively as control treatments in ‘response-mediated’ open cross-over designs. Chiron, 1997 recruited patients with infantile spasms which were caused by tuberous sclerosis.

Quality assessment

Appleton, 1999 (2) is well reported. The trial had a short follow-up period of just 5 days. The short follow-up was to allow a placebo-controlled trial in a newly diagnosed population without requiring active treatment to be withheld for a protracted period of time; it is not clear why an active control was considered inappropriate.

Vigevano, 1997 and Chiron, 1997 are reasonably well reported, although neither give details of randomisation procedures and they were not blinded (blinding may be difficult or impossible when active controls have characteristic and easily identifiable side effects). It is not clear whether Chiron, 1997 included all randomised patients in the report. Vigevano, 1997 did not define any outcomes in the methods section. All three trials had very small sample sizes (40, 42 and 22 patients).

Results

The results of Appleton, 1999 suggest that vigabatrin may be effective in these patients compared to no treatment.

Vigevano, 1997 and Chiron, 1997 both use a ‘response-mediated’ cross over design, in which patients who do not respond well to the allocated treatment are crossed over to the alternative treatment during the trial, with responders continuing with the original allocated treatment. This sort of design is ideal for comparing treatment strategies, but are not particularly effective in comparing individual drugs. Neither trial is analysed appropriately for the design, and so the results we have used are taken from the first period of each trial only, making each, in effect, a simple parallel trial with a shorter follow-up period.

Vigevano, 1997 suggests that ACTH is somewhat more effective in eliminating spasms but may be less well tolerated than vigabatrin. Chiron, 1997 reports that all patients (11/11) on vigabatrin were spasm-free in the first period compared to 5/11 on hydrocortisone, with hydrocortisone also less well tolerated. The authors suggest that time to response was shorter but there is no data presented which clearly demonstrates this. There are some discrepancies in data reported in tables and text of this trial report, and some suggestion that cross-over criteria were not applied consistently; for example, it is not clear why two patients who responded to hydrocortisone during the first period were crossed over to vigabatrin. This trial is not sufficiently reliable to confirm the belief that vigabatrin may be particularly effective in infantile spasms due to tuberous sclerosis.

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All of these trials are very small, and there are some methodological difficulties, particularly with the two cross-over trials which are methodologically weak and poorly reported.

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Table 26 Summary of trials and trial design (infantile spasms / West’s syndrome) Trial ID Appleton, 1999 (2) Vigevano, 1997 Chiron, 1997 Newer drug(s) vigabatrin vigabatrin vigabatrin investigated Target maintenance dose 50-150mg/kg/day (not stated) lowest effective tolerated dose, 150mg/kg/day (?mode) (mode) 110-150mg/kg/day (?mode) Seizure or syndrome infantile spasms newly diagnosed infantile infantile spasms due to spasms tuberous sclerosis Type of trial design parallel "response-mediated" open X- 'response-mediated' open over study cross over Add-on or monotherapy? monotherapy monotherapy monotherapy Control(s) placebo ACTH hydrocortisone Study start and end dates not reported 1992 to 1995 not reported Centres and location 40 centres; Europe, Canada, Italy multicentre, France France Baseline 2 or 3 days None Not clear Titration period 5 days 9 days No titration Maintenance None 20 days, then continuation One month, then cross-over of (responders) or cross-over non-responders and (non-responders) for a further continuation of responders 20 days andcross-overs for further month Withdrawal None None None Inclusion criteria Newly diagnosed and Newly diagnosed and Infantile spasms due to previously untreated infantile previously untreated infantile tuberous sclerosis spasms; age 1 to 20 months spasms (diagnosed within 3 weeks of entry) Timing and additional Post-baseline; no additional NA (newly diagnosed NA eligibility for criteria population) randomisation/continuatio n on study Comments on design Baseline period varied for Trial design compares Patients 'recently' diagnosed; patients with and without strategies rather than prior AED treatment was not clusters of spasms. treatments. an exclusion criteria.

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Table 27 Quality assessment (infantile spasms / West’s syndrome) Trial ID Appleton, 1999 (2) Vigevano, 1997 Chiron, 1997 Was assignment of treatment described Yes Yes Yes as random? Was method of randomisation described? Yes No No Was the method really random? Yes Can't tell Can't tell Was allocation of treatment concealed? Yes Can't tell Can't tell Who was blinded to treatment? Described as Open label study Open label study 'double-blind' Was method of blinding adequately No NA NA described? Were eligibility criteria described? Yes Not in any detail Yes Were groups comparable at study entry? Yes Some imbalance in sex No; differences compatible with chance in a ratios such a small trial (see comment) Were groups treated identically apart from Yes (if blinding Can't tell Can't tell the intervention? adequate) Was ITT used? Yes Yes Can't tell; possibly not (see comment) Were withdrawals stated? Yes Yes Yes Were reasons for withdrawals stated? Yes Yes Yes Was a power calculation done? Yes No No Was monitoring of plasma levels done No No No (including study drug)? Were arrangements to blind plasma NA NA NA monitoring results mentioned? Comments - - Report refers to 22 'evaluable patients'; it is not clear that all randomised patients were included. The limited information on the method of randomisation and some imbalances in patient characteristics, especially with respect to duration of infantile spasms prior to the trial, give further cause for concern.

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Table 28 Results (infantile spasms / West’s syndrome) Trial ID Appleton, 1999 (2) Vigevano, 1997 Placebo Vigabatrin ACTH Vigabatrin Number randomised 20 20 19 23 Number analysed 20 20 19 23 Maintenance dose mean 148 mg/kg mean 133 mg/kg 10 IU/day 100 to 150mg/kg/day achieved Withdrawals None stated - - Total withdrawals 1 1 including reasons Irritability/agitation 0 1 where specified Irritabilit/ raised BP 1 0 Results CI; p-value Results CI; p-value Primary outcome(s) 1. % change - - - spasm frequency:

24 hour placebo-25.9% 95% CI -56% to 65% assessment vigabatrin -77.9% 95% CI 55% to 89%, p=0.02

2 hour placebo -54.6% 95% CI 4% to 78% assessment vigabatirn -71.9% 95% CI 42% to 86%, p=0.342

2. Seizure placebo 2 (10%) (spasm)-free vigabatrin 7 (35%) p=0.063 patients

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Trial ID Appleton, 1999 (2) Vigevano, 1997 Placebo Vigabatrin ACTH Vigabatrin Secondary outcomes 1. Investigator placebo: 3 (15%) - - - 'global marked/moderate assessment' improvement 4 (20%) patients deteriorated p<0.0001

vigabatrin: 16 (80%) marked/moderate improvement 0 deteriorated

2. Repeated EEG hypsarrhythmia - recordings resolved in 1/2 seizure-free placebo patients vs 5/7 on vigabatrin 'Ad hoc' outcomes >70% 1. Proportion 14/19 (74) ACTH p=0.12 improvement: spasm-free in 11/23 (48) Vigabatrin - 24 hour placebo 3/20 (15%) Not reported phase 1 assessment vigabatrin 8/20 (40%)

- 2 hour placebo 11/20 (55%) Not reported assessment vigabatrin 13/17 (76%)

No change or placebo 9/20 (45%) Not reported worse (24 hour) vigabatrin 4/20 (20%) Comments (including All means and CIs adjusted for geographical region and baseline whether unadjusted spasm rate. results reported) Three patients appear to be missing from lamotrigine group for the 2 hour results.

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Trial ID Chiron, 1997 hydrocortisone vigabatrin Number randomised Not stated Not stated Number analysed 11 11 Maintenance dose 15mg/kg/day, except 2 pts 10/11, (& 7/7 after X-over) 150 achieved mg/kg/day; 1 pt 100mg/kg/day. Withdrawals including Total withdrawals 2 (18.2) 0 reasons where Lack of efficacy 0 0 specified Adverse events 2 (18.2) 0 Change in AED 0 0 Other 0 0 Results CI; p-value Primary outcome(s) 1. Proportion spasm-free 5/11 hydrocortisone at 1 month 11/11 vigabatrin p < .01

Secondary outcomes 2. Development quotient Not ITT, only 8 hydrocortisone Not reported and 9 vigabatrin patients evaluated 'Ad hoc' outcomes Time to response (days on drug Mean time to response: prior to becoming spasm-free) Vigabatrin:4 days (range 0.5-14) p=0.058 HC: 12.8 days (range 3-30 days) Comments (including Cross-over criteria were defined as 'non-responders at one month', with no further criteria given. Criteria whether unadjusted do not seem to have been applied consistently, or there are some errors in the text. For example: results reported) Two patients responded to HC at day 30, both had side effects, one was crossed over and one was not; One patient responded to HC at day 19, listed as having no side effects but was crossed over to vigabatrin.

The tabulated data implies that 7 patients crossed over from HC to vigabatrin (including the two mentioned above that had responded to HC), but the text implies that there wqere only 6 non- responders who should have crossed over (text states that 5/11 responded).

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Table 29 Adverse events (infantile spasms / West’s syndrome) Trial ID Appleton, 1999 (2) Vigevano, 1997 Criteria for reporting Not stated Placebo Vigabatrin Not stated ACTH Vigabatrin Events Drowsiness Not reported 8 All events 7 (37) 3 (13) Behaviour change Not reported 1 Drowsiness -- 2 (9) (irritability) Hypotonia -- 2 (9) Irritability 7 (37) 1 (4) Number reporting >=1 AE 6 (30%) 12 (60%) Hypertension 7 (37) --

Trial ID Chiron, 1997 Criteria for reporting Events reported to or hydrocortisone vigabatrin observed by investigator; (n events) (n events) data relates to both study periods Events Adverse events (all) 17 8 Drowsiness - 3 Hyper-excitability/kinesia 5 (1 severe) 3 (1 severe) Sleep disorders 3 (1 severe) - Weight 3 - Abdominal distension 2 (1 severe) - Axial hypertonia 1 1 (severe) Hypotonia - 1 Hypertension 2 - Cushing syndrome 1 -

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3.2.8 Absence Epilepsy

One trial was identified in absence epilepsy, comparing lamotrigine monotherapy against placebo in newly diagnosed typical absence seizures (Frank, 1999214). A ‘withdrawal’, or ‘responder-enriched’ design was used; all patients were initially treated with lamotrigine with those achieving complete seizure freedom being randomised to ‘continue’ or ‘withdraw’ active treatment.

Quality assessment

The trial report is of reasonable quality, but gives no details of the method of randomisation, or concealment of allocation; some imbalances in sex and weight, whilst consistent with chance in such a small trial, do not increase confidence in the methods used. Drug plasma levels were monitored but no mention is made of any efforts to conceal the results from investigators; failure to do so would somewhat compromise blinding.

Results

Substantially more patients remained seizure-free whilst continuing with lamotrigine compared to the group withdrawn to placebo (64% vs 21%). Several adverse events are reported for patients receiving lamotrigine but no information about frequency is given.

This is a small trial with some concerns about methodological quality. It suggests that patients who have achieved complete seizure freedom on lamotrigine are more likely to remain seizure-free if it is not withdrawn, although a substantial proportion of patients did remain seizure free on the placebo arm.

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Table 30 Summary of trials and trial design (absense epilepsy) Trial ID Frank, 1999 Newer drug(s) investigated Lamotrigine Target maintenance dose (mode) maximum 1000mg/day (oral) Seizure or syndrome typical absence seizures (newly diagnosed) Type of trial design withdrawal Add-on or monotherapy? monotherapy Control(s) placebo Study start and end dates not reported Centres and location multi-centre, USA Baseline NA Titration period Minimum 4 weeks Maintenance NA Withdrawal 4 weeks Inclusion criteria Newly diagnosed typical absence seizures; age 2 to 16 years Timing and additional eligibility for Patients achieving seizure freedom during randomisation/continuation on study titration phase were randomised to continue lamotrigine or switch to placebo Comments on design

Table 31 Quality assessment (absence epilepsy) Trial ID Frank, 1999 Was assignment of treatment described Yes as random? Was method of randomisation described? No Was the method really random? Can't tell Was allocation of treatment concealed? Can't tell Who was blinded to treatment? Described as 'double-blind' Was method of blinding adequately No description, other than that study medication described? matched for size, shape, colour, taste Were eligibility criteria described? Yes Were groups comparable at study entry? Yes (some imbalance in age and weight, consistent with chance and the small sample size) Were groups treated identically apart from Yes (if blinding adequate) the intervention? Was ITT used? Yes Were withdrawals stated? Yes Were reasons for withdrawals stated? Yes Was a power calculation done? Yes Was monitoring of plasma levels done Yes, including lamotrigine (including study drug)? Were arrangements to blind plasma No monitoring results mentioned? Comments One patient withdrew consent at start of randomised phase.

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Table 32 Results (absense epilepsy) Trial ID Frank, 1999 Placebo Lamotrigine Number randomised 14 15 14 Number analysed 14 14 14 Maintenance dose Not reported median 5.0mg/kg/day Not reported achieved (range 2 to 15mg/kg/day) Withdrawals including 0 1 (6.6) 0 reasons where - 1 (6.6) - specified Results (diff, or CI for difference; p- Results (diff, or by by arm) value arm) Primary outcome(s) 21% placebo vs p=0.03 21% placebo vs 64% 64% lamotrigine lamotrigine Secondary outcomes - - - 'Ad hoc' outcomes - - - Comments (including Maintenance dose achieved - this is the median dose taken by whether unadjusted patients who became seizure-free during the open phase results reported)

Table 33 Adverse events (absense epilepsy) Trial ID Frank, 1999 Criteria for reporting Events reported Placebo Lamotrigine by >=5% of patients Events Nervous system Not reported Frequencies not complaints(e.g. reported asthenia, headache, Nervous system dizziness, complaints(e.g. hyperkinsia) asthenia, headache, Rash dizziness, hyperkinsia) Events related to Rash infections, Events related to ailments common infections, ailments to childhood, or common to childhood, flu syndromes or flu syndromes

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3.2.9 BECTS

One trial trial was identified in benign epilepsy with centro-temporal spikes (BECTS),215 comparing gabapentin monotherapy against placebo in newly diagnosed patients. The trial has been reported in abstract form only and so only limited information is available, summarised in the tables below.

Table 34 Summary of trials and trial design (BECTS) Trial ID Bourgeois, 1998 Newer drug(s) investigated gabapentin Target maintenance dose (mode) 30mg/kg/day Seizure or syndrome Benign partial epilepsy with centro-temporal spikes Type of trial design parallel Add-on or monotherapy? monotherapy Control(s) placebo Study start and end dates Not reported Centres and location Not clear Baseline Not reported Titration period Not reported Maintenance 36 weeks Withdrawal None Inclusion criteria At least one and not more than 10 partial or generalised seizures within 6 months of entry; age 4-13 yrs Timing and additional eligibility for - randomisation/continuation on study Comments on design Abstract with few details of design

Table 35 Quality assessment (BECTS) Trial ID Bourgeois, 1998 Was assignment of treatment described as Yes random? Was method of randomisation described? No Was the method really random? Can't tell Was allocation of treatment concealed? Can't tell Who was blinded to treatment? Described as double blind Was method of blinding adequately No description described? Were eligibility criteria described? Yes Were groups comparable at study entry? Not reported Were groups treated identically apart from Can't tell the intervention? Was ITT used? Yes Were withdrawals stated? Yes Were reasons for withdrawals stated? Yes Was a power calculation done? Not reported Was monitoring of plasma levels done No (including study drug)? Were arrangements to blind plasma NA monitoring results mentioned? Comments Abstract with very limited information.

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Table 36 Results (BECTS) Trial ID Bourgeois, 1998 placebo gabapentin Number randomised 112 113 Number analysed 112 113 Maintenance dose Not reported Not reported achieved Withdrawals including Adverse events 0 (0) (3.5%) reasons where specified Results (diff, or by CI for difference; p- arm) value Primary outcome(s) 1. Time to No data p=0.06 for difference by treatment failure log rank test Secondary outcomes - - - 'Ad hoc' outcomes - - - Comments (including whether unadjusted results reported)

Table 37 Adverse events (BECTS) Trial ID Bourgeois, 1998 Criteria for reporting None reported placebo gabapentin Events - - -

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3.2.10 Mixed population

One trial was identified in a mixed population (Chiron, 1996216), recruiting patients who had been treated with vigabatrin on a variety of different clinical trials and had been receiving the drug for various lengths of time with limited benefit. The trial used a ‘withdrawal’ design, randomising patients to continue with vigabatrin or withdraw to placebo.

Quality assessment

This trial is poorly reported, with no details of randomisation, concealment of allocation or method of blinding reported. There are substantial imbalances in patient characteristics which, whilst consistent with chance in such a small trial, add to concerns about these methodological aspects of the trial. Only the primary outcome could be analysed by intention to treat due to patients being ‘dropped’ if they experienced a worsening of seizure frequency or severity on withdrawal of vigabatrin.

Results

Fewer patients were withdrawn due to a worsening of seizure frequency or severity on the vigabatrin arm compared to placebo (7% vs 54%).

The results suggest that patients experiencing a modest benefit with vigabatrin may continue to receive benefit whilst they remain on the drug. There are a number of methodological concerns, and this is a very small trial. Of interest is that 4 of the 28 patients selected because vigabatrin was of some benefit had actually experienced an increases of 120-200% in seizure rate compared to the period before starting the drug; the benefits were perceived to be in behavioural and functional outcomes.

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Table 38 Summary of trials and trial design (mixed population) Trial ID Chiron, 1996 Newer drug(s) investigated vigabatrin Target maintenance dose (mode) no dose information (not stated) Seizure or syndrome any Type of trial design withdrawal Add-on or monotherapy? add-on Control(s) placebo Study start and end dates Not stated (patients selected from cohort treated in vigabatrin trials 1987 to 1990) Centres and location 1 centre; France Baseline 2 months (possibly retrospective) Titration period NA (patients on vigabatrin for 3-39 months prior to entry) Maintenance None Withdrawal 2 months Inclusion criteria Partial improvement in terms of seizure frequency or severity, or parental perception of benefit despite lack of response, after at least 3 months on vigabatrin as add-on therapy

Note: Patients selected from a total of 196 included in various vigabatrin trials at one hospital Timing and additional eligibility for None stated randomisation/continuation on study Comments on design Not clear if the two month baseline phase was retrospective. Placebo patients were withdrawn from vigabatrin during the first 2 months; the remaining patients were withdrawn over the following 2 months (described as 'single blind', implying that the patients were not informed that all active treatment would be withdrawn during this period). The data extracted here is from the first 2 month (double blind) period.

Patients were 'dropped' and the randomisation code broken if seizure frequency increased by >50% or increased in severity compared to baseline.

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Table 39 Quality assessment (mixed population) Trial ID Chiron, 1996 Was assignment of treatment described Yes as random? Was method of randomisation described? No Was the method really random? Can't tell Was allocation of treatment concealed? Can't tell Who was blinded to treatment? Described as 'double-blind' Was method of blinding adequately No described? Were eligibility criteria described? Yes Were groups comparable at study entry? No; 7/9 patients with infantile spasms were allocated 'continue vigabatrin, 'continue vigabatrin' group had a longer mean duration of vigabatrin treatment at entry (12.2 vs 8.6 months) but a shorter median (7 vs 9), with standard deviations 10.2 vs 4.1 Were groups treated identically apart from Can't tell the intervention? Was ITT used? Yes (for primary outcome; see comment) Were withdrawals stated? Yes Were reasons for withdrawals stated? Yes Was a power calculation done? No Was monitoring of plasma levels done No (including study drug)? Were arrangements to blind plasma NA monitoring results mentioned? Comments The policy of 'dropping' patients if they experienced a worsening of seizure frequency or severity makes ITT impossible for most endpoints except for the primary endpoint used here (proportion of patients completing phase)

Table 40 Results (mixed population) Trial ID Chiron, 1996 Placebo Vigabatrin Number randomised 13 15 Number analysed 13 15 Maintenance dose Not reported Not reported achieved Withdrawals including Not reported Not reported Not reported reasons where specified Results (diff, or by CI for difference; p- arm) value Primary outcome(s) 1. Number of placebo 7 (46.1) p<0.01 patients vigabatrin 12 (93.3) completingfirst phase Secondary outcomes 1. Seizure frequency placebo median 95 p<0.05 vigabatrin median 46 'Ad hoc' outcomes - - 0 Comments -

Table 41 Adverse events (mixed population) Trial ID Chiron, 1996 Criteria for reporting None reported Placebo Vigabatrin Events - - - 95 Newer Drugs for Children with Epilepsy

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3.2.11 Summary of RCT evidence

The quality of the RCT data was generally poor, with many giving cause for concern over the integrity of randomisation, quality of blinding, and/or analytical methods employed. Most of the trials were conducted for licensing purposes and are thus of limited use in informing clinical practice; whilst it is clear that these agents may be useful additions to the list of AEDs available, there is very little data upon which to base a rational prescribing strategy.

Twenty trials were identified which reported outcome data for children with epilepsy; 18 of these were conducted exclusively in children. Trials were identified in children with partial seizures (with or without secondary generalisation), generalised seizures (including Lennox- Gastaut syndrome), Lennox-Gastaut syndrome, infantile spasms, absence epilepsy and BECTS.

Fifteen of the 20 trials identified used placebo as comparator. In most cases these trials used the newer drug as add-on to existing therapy; some trials used a ‘responder enriched’ design where all patients were initially started on the newer drug and ‘responders’ were then randomised to ‘withdraw’ or ‘continue’. Most of the placebo-controlled trials were in previously diagnosed populations, but two were in newly diagnosed patients, one in infantile spasms with very short (5 day) follow-up and the other in benign epilepsy where active treatment is not considered necessary for all patients. These trials provide reasonably convincing evidence that the newer agents have some beneficial impact on the disease but offer little information as to how, and when, they are best used, and in particular how they compare to alternative drug treatments.

Five of the 20 trials identified employed active comparator treatments; 2 in newly diagnosed partial epilepsy (both using carbamazepine as comparator), one in a mixed population with partial or generalised seizure types (using phenytoin as comparator), and two in infantile spasms (using ACTH and hydrocortisone respectively). One very small trial suggested that vigabatrin was considerably more effective than hydrocortisone in the treatment of infantile spasms due to tuberous sclerosis, but this was based on data from just 22 patients. None of the other four trials found any clear evidence of a difference in effectiveness between the older and newer drugs compared, but in each case there was some evidence that the newer drugs might be better tolerated than the comparator treatments. Interpretation of these comparisons is complicated by variations in the choice of comparator, choice of drug doses and titration schedules, and the lack of any confirmatory data from trials using similar designs and comparators.

Thus, for each of the epilepsy sub-types considered in RCTs identified for this review (partial epilepsy with or without secondary generalisation, Lennox-Gastaut syndrome, infantile spasms, absence epilepsy and BECTs), there is some evidence from placebo-controlled trials that each of the newer agents tested are of some value in the treatment of these conditions. Where active controls have been used, the newer agents appear no more effective but with better tolerability. The data are not sufficient to inform a prescribing strategy for any of the newer agents in any of these conditions. In particular, there is no evidence to suggest that the newer agents should be considered as a first choice treatment in any form of epilepsy in children.

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3.2.12 Ongoing Trials Relevant ongoing RCTs (Table 42) were identified by contact with experts, from industrial submissions to NICE and by searching the National Research Register, and the Clinical Trials Meta Register.

Table 42 Relevant ongoing trials identified. TRIAL; Start /finish; N Population; age Intervention / outcomes comment range comparator SANAD‡ Long term Patients with Monotherapy. [a] Time to withdraw (lack Largest AED RCT clinical outcomes and epilepsy [a] Carbamazepine of efficacy, intolerability, undertaken. Economic cost effectiveness of managed by v. lamotrigine or addition of other AED). study included. Head standard and new AEDs monotherapy topiramate or [b] Time to 1 year sz-free. to head study of 1998/2004 >=5 yrs gabapentin. Others include:- AEDs. Clinically N= 3150. [b] [a] Time to first sz. meaningful outcomes, (450 in each of 7 arms) Valproate v. [b] Psycho -social likely to yield best lamotrigne or functioning. available evidence on topiramate. [c] Analysis of costs. new AEDs. MESS Multicentre Study Recent history ≥ Immediate v. [a] Time to sz recurrence. of Early Epilepsy and 1 unprovoked delayed intervention [b] Proportion to long term Single seizures sz. with AED. remission. 1999/ 2002 5 mos -85 yrs. [c] Psychosocial function. N= target 1800; Recruited 1443. UKISS‡‡ Infants with Vigabatrin v. [a] No: sz-free for a min of Head to head trial. United Kingdom infantile spasms prednisolone or 48 hrs at 14 days Infantile Spasm Study (not tuberous ACTH treatment N=target 250. sclerosis). [b] Psychomotor Recruited 107. development age 12-14 April 1998/ Aug 2003 mos of age final follow up. [c] Epilepsy outcome at 12-14 mos of age. Valproate v. lamotrigine Patients aged 13 Valproate v. [a] Freedom from seizures. Head to head ttrial [alone or in yrs or older lamotrigine as add [b] Side effects. combination] in patients on or monotherpy. failing monotherapy. N=178 [by jan 2003] Topomax (Topiramate) Children with Open label [a] Efficacy. as adjunctive therapy chronic epilepsy Topiramate v ? [b] Side effects for partial szs with or without secondary generalisation. † VNS v. new AEDs Epilepsy VNS v. new AED [a] Reduction in sz Economic study 2000-2003 refractory to 2 (gabapentin, or frequency. included. Proportion different AEDs lamotrigine, or [b] Reduction in sz <18 years likely to be (as mono or tiagabine, or severity. small. +on). ≥16yrs topiramate, or [c] Tolerability & safety. vigabatrin). [d] QOL [e] Cost Valproate v. lamotrigine Women newly Valproate v. [a] Presence of polycystic Proportion <18 years or topiramate diagnosed with lamotrigine or ovaries on ultrasound. old likely to be small. 2000-2004. epilepsy topiramate [b] Change in biochemical requiring parameters of treatment. hyperandrogenaemia. 16-45 yrs Levitiracetam as +on for adults and Levetiracetam v. Not head to head trial. idiopathic generalized children placebo epilepsy & PGTC szs † CONFIDENTIAL INFORMATION REMOVED ‡ http://www.liv.ac.uk/neuroscience/sanad/docs/protocol.pdf ‡‡ RCT nested within epidemiological study. † Limited details from National Research Register. VNS = vagus nerve stimulation.

98 Newer Drugs for Children with Epilepsy

4. ECONOMIC ANALYSIS OF NEWER ANTI-EPILEPTIC DRUGS IN CHILDREN

4.1 Summary

4.1.1 Commentary on company submissions that modelled childhood epilepsy.

GlaxoSmithKline submission § The first analysis concerned the use of lamotrigine as monotherapy in patients 12 years of age and over, with either partial or generalised seizure types. The comparison is of lamotrigine (first line) with two older AEDs (carbamazepine and sodium valproate). The results indicate an incremental cost effectiveness ratio for lamotrigine as first line monotherapy of £13,045 per QALY gained. § The second analysis considered the use of lamotrigine as add-on therapy in children 2 years and over. The comparison, drawing upon trial data, was with placebo add-on therapy. This analysis resulted in an ICER of £16,456 per QALY gained.

Janssen-Cilag submission § The main analysis presented in this report concerned the use of topiramate as adjunctive therapy in patients with partial seizure types. The comparison was of adjunctive topiramate with adjunctive lamotrigine (i.e. one newer AED is being compared to a second newer AED). The results indicate that topiramate dominates lamotrigine; it is associated with a lower mean cost and greater level of benefit.

4.1.2 Summary of the Birmingham epilepsy model

§ A simulation model was constructed that considered the use of the newer AEDs as part of the drug sequence that a child might experience over the course of their childhood with epilepsy.

§ Clearly each patient can potentially be subject to many different treatments during their time in the model, depending on the success or otherwise of their current treatment. In order to reflect this complexity, the analysis considered a pre-defined sequence and strategy for the use of drugs and drug combinations. The policy change considered was the introduction of each of the new drugs in turn, in line with its licensed indications.

§ Data to populate the model were sparse. Where available data were drawn from RCTs but there remain assumptions and judgements that had to be made given the paucity of data relating to the use of newer AEDs in children.

§ The expected total cost of caring for the average child diagnosed with epilepsy, managed according to a no new drug therapy strategy, is just under £5,000 (from the age of diagnosis through to 18 years of age). This includes both the cost of the drugs plus the costs of other health service resources. Such a patient is expected to experience just under 7.5 QALYs from this strategy, again through to the time when they reach the age of 18 years.

99 Newer Drugs for Children with Epilepsy

The analysis that considered the use of lamotrigine as monotherapy (either first-line or second-line), indicated a positive incremental cost but no strong evidence of important health benefits. For the analyses looking at the use of the newer AEDs as add-on therapies, the findings were again of positive incremental costs and no strong evidence of important health benefits.

4.2 Introduction

In line with the objectives stated in the protocol for this review, the economic analysis has addressed the following question concerning the use of anti-epileptic drugs (AEDs):

What is the cost effectiveness of newer anti-epileptic drugs used in mono-therapy, and/or combination therapy, when compared with other drug treatments for epilepsy in children?

There were two components to the economics aspects of this work: a review of existing economic analyses (including the analyses reported in the sponsor submissions), and a new model-based analysis. These are described in detail in the following sections.

4.3 Systematic review of existing economic analyses

The details of the literature search are provided earlier in the report.

It was clear at the outset that a review of the cost-utility of using AED therapy in children with epilepsy was going to be unachievable given the lack of published studies with utility- based quality of life data in this age group. In fact, no published economic studies reviewing the use of AED therapy in the treatment of epilepsy in childhood were identified. The reason for exclusion in the majority of articles reviewed was that the AEDs were being used in a study population that did not match the age range specified in the review inclusion criteria. Therefore, the focus of this review is on the economic evidence submitted to NICE by the manufacturers of newer AEDs for treatment of epilepsy in childhood. Only two of the manufacturer submissions included an analysis of the use of the AED in children: the submissions by GlaxoSmithKline and Janssen-Cilag. Given that the analyses relating to the use of AEDs in adults is the subject of a separate review, we chose to focus solely on the submissions from GlaxoSmithKline and Janssen-Cilag.

4.3.1 Review of submission models

The two submissions are reviewed with respect to the appropriateness and the accuracy of the economic analyses presented. The quality of the economic data is appraised according to the following categories detailed in the cost-effectiveness review outlined in the protocol:

§ Details of the study characteristics such as form of economic analysis, comparators, perspective, time horizon, and modelling used.

100 Newer Drugs for Children with Epilepsy

§ Details of the effectiveness and cost parameters such as: effectiveness data; health state valuations; resource use data; unit cost data; price year; discounting assumptions, productivity costs. § Details of the results and sensitivity analyses.

Table 43 and Table 44 provide an overall summary of the methods and results of the economic analyses reported in the manufacturer submissions.

GlaxoSmithKline submission Table 43 Review of economic analyses within the GlaxoSmithKline submissions AED Lamotrigine Lamotrigine

Manufacturer GlaxoSmithKline GlaxoSmithKline

Patient group Patients with either partial or generalised Patients with either partial or generalised seizure types, aged 12 years and over seizure types, aged 2 years and over

Treatment Comparison of three drugs as first line Comparison of lamotrigine as add-on comparison monotherapy: lamotrigine vs therapy with placebo add-on therapy carbamazepine vs sodium valproate

Analysis Cost-utility analysis Cost-utility analysis

Model Simple decision tree No formal decision model reported

Time horizon 1 year 1 year

Model This is a simple decision tree that models No model is reported. description first and second line treatments. If a patient remains refractory after second line The analysis simply used efficacy data treatment, no further treatment is from placebo controlled trials and applied considered. utility weights to the main trial outcome (i.e. reduction in seizures). Side effects The model includes states relating to were not considered. seizures and states relating to drug side effects.

The model assumes that partial control of seizures or unacceptable side effects result in a change of treatment. If the patient experiences unacceptable side effects from the second drug, the model assumes that no further treatment is considered.

Outcome QALYs QALYs measure Health state New utility data are reported. Utility data New utility data are reported. Utility data valuation collected using a standard gamble question collected using a standard gamble question

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from 64 adults (none of whom had from 64 adults (none of whom had epilepsy themselves). The data relate to 7 epilepsy themselves). The data relate to 7 states in the model described in terms of states in the model described in terms of seizure control and associated side effects seizure control and associated side effects (with the drug name stated in the state (with the drug name stated in the state description). Respondents asked to description). Respondents asked to consider themselves in the states. consider themselves in the states.

Source of Initial mean and titration doses derived Resource use data focussed solely on resource data from published references. drugs. Initial mean and titration doses derived from published references. Other resource use data generated from Delphi panel of experts.

Discounting N/A N/A

Sensitivity Effectiveness data varied (data from Effectiveness data varied (data from analyses different trials used). different trials used), allowing comparison Time to discontinuation of therapy varied. of different seizure types. Utility scores varied within 95% confidence intervals. Results not highly sensitive to these Results not highly sensitive to these variations. variations.

Model base Mean ICER for lamotrigine (compared to Mean ICER for lamotrigine (compared to case results either carbamazepine or sodium valproate) placebo) is £16,456 per QALY gained is £13,045 per QALY gained

GlaxoSmithKline manufacture lamotrigine. Two economic analyses are reported in their submission, following the licensing restrictions on the use of lamotrigine.

§ The first (and most substantial) analysis concerns the use of lamotrigine as monotherapy in patients 12 years of age and over with either partial or generalised seizure types. The comparison is of lamotrigine (first line) with two older AEDs (carbamazepine and sodium valproate). The results indicate an incremental cost effectiveness ratio for lamotrigine as first line monotherapy of £13,045 per QALY gained.

§ The second analysis considered the use of lamotrigine as add-on therapy in children 2 years and over. The comparison, drawing upon trial data, was with placebo add-on therapy. This analysis resulted in an ICER of £16,456 per QALY gained.

A simple decision tree was constructed that considered first and second line treatments only. The model followed patients for period of 1 year only. An interesting aspect of the analysis was the primary research that involved the collection of new utility-based health related quality of life data. Epilepsy specific health states were defined and participants in the survey were asked to complete a series of standard gamble exercises in order that a utility score could be derived. The states included reference to the drugs in question in order that

102 Newer Drugs for Children with Epilepsy

issues of side effects would also be captured. However, the data were collected from adults who were asked to imagine themselves in the states in question and so the relevance of such data to an analysis of the use of lamotrigine in children has to be questioned.

Janssen-Cilag submission

CONFIDENTIAL INFORMATION REMOVED

Table 44 Review of economic analyses within the Janssen-Cilag submission

CONFIDENTIAL INFORMATION REMOVED

Figure 1 CONFIDENTIAL INFORMATION REMOVED

CONFIDENTIAL INFORMATION REMOVED

Figure 2 CONFIDENTIAL INFORMATION REMOVED

CONFIDENTIAL INFORMATION REMOVED

4.4 Birmingham economic analysis

Given the paucity of published economic analyses of treatments for children with epilepsy, we chose to undertake a new analysis using a cost-utility approach, with quality-adjusted life years (QALYs) as the outcome measure. We have constructed a decision-analytic model and used this as the framework through which to explore both the effectiveness and cost- effectiveness of the newer AEDs. The details of the model structure and the information used to populate it are described in the following sections.

4.4.1 Overview of decision–analytic model

The model is an individual sampling model whereby individual simulated patients progress through the model along the patient pathways illustrated in Figure 3. The model follows individual newly diagnosed patients with partial epilepsy from the point of diagnosis. The youngest patients at entry into the model are 3 years (infantile epilepsy is not considered in the model) and the oldest are just under 18 years. This represents a model of epilepsy in childhood and so patients exit on reaching the age of 18 years. Therefore, the longest simulated time period a patient can be in the model for is 15 years, and the shortest period is a matter of days. As patients progress through the model their treatment pathways and experience of epilepsy are monitored. The cohort of patients followed in the model includes some patients with neurological impairment and some without.

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Figure 3 Patient pathway for a child with newly diagnosed partial epilepsy 104 Newer Drugs for Children with Epilepsy

It is not possible to model every form of childhood epilepsy within this assessment, and no model could reasonably cope with too broad a range of diagnoses. We therefore decided to model those conditions which:

§ account for a substantial proportion of diagnoses, § have been adequately addressed within RCTs, and § for which there are clearly a number of alternative prescribing strategies.

We have therefore modelled partial seizures (with or without secondarily generalised seizures). A similar model structure could be employed to model generalised tonic-clonic seizures, although cost and utility data would have to be obtained separately for this patient group. However, only 2 RCTs included patients with generalised tonic-clonic seizures; one in a mixed population including patients with partial seizures and the other recruited a broad range of patients, with 70% having Lennox-Gastaut syndrome. The only substantial RCT data available in generalised seizures is in patients with Lennox-Gastaut syndrome, which is a relatively rare and very severe syndrome and would require more substantial amendment of the model structure. Given the poor quality and low quantity of the data available for Lennox-Gastaut syndrome, it is not clear that decision-analytic modelling would add anything. The only remaining licensed indication for any of the newer drugs is vigabatrin for infantile spasms, which would require a completely different model structure, given the evolving nature of the syndrome (with many patients going on to develop different forms of epilepsy, including Lennox-Gastaut syndrome). Again, it is not clear that modelling could add substantially to the currently available clinical evidence for this diagnosis.

A patient enters the model with a new diagnosis of partial epilepsy. Personal characteristics for the individual (i.e. sex, age and the presence of neurological impairment) are then assigned to the patient through a process of repeated samplings from appropriate distributions for these characteristics. The patient is initially prescribed monotherapy with an AED (with the choice of drug defined by the fixed sequence described in the next section). There are then 4 broadly defined outcomes of drug treatment:

§ intolerable side-effects, leading to early discontinuation (outcome 1) § lack of effect on seizure rate, leading to early discontinuation (outcome 2) § partial efficacy with tolerable side effects (outcome 3) § complete seizure freedom with tolerable side effects (outcome 4)

Patients discontinuing early (i.e. moving into outcomes 1 and 2) go on to receive alternative treatment if they wish; we assume that further drug treatment is likely to involve a (gradual) switch rather than an adjunctive therapy for these outcomes.

Patients with some reduction in seizure frequency (outcome 3) may or may not go on to receive adjunctive therapy. It is assumed that willingness to try adjunctive treatment, and willingness to continue on drug treatment at all, will depend on the number of treatments already tried by this point. We have allowed for these patients to discontinue the drug and try alternative treatment at some stage (i.e. a different monotherapy).

It is assumed that patients achieving complete seizure freedom (outcome 4) would not go on to receive additional treatment, but that some would attempt to withdraw from drug therapy altogether after a certain period of seizure freedom. An unsuccessful withdrawal of the drug

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(i.e. experience of seizures after withdrawal) is assumed to be followed by re-introduction of the original drug. We have assumed that the proportion discontinuing due to late toxicity or reduction in efficacy over time is negligible.

We assume that the amount of time before discontinuing an unsuccessful drug (outcomes 1 and 2) is dependent on the reason for discontinuing rather than the drug. In other words, we assume that the average time to develop side effects and/or time to establish lack of efficacy, does not vary substantially by drug; differences between drugs are thus mainly due to differences in the proportions experiencing each outcome. (We do recognise that patterns of early discontinuation due to side effects will depend to some extent on starting dose and titration schedule; we have assumed ‘optimal’ titration schedules, which will vary by drug.)

On the basis of clinical advice, the model assumes a similar prescribing practice for boys and girls. That is, we have not built into the model a policy for young girls to be prescribed drugs thought to be less teratogenic in order to avoid the need for later treatment changes.

In addition, the policy on discontinuation and withdrawal of drugs is assumed to be the same for patients receiving monotherapy and adjunctive therapy. For example, we assume that a patient achieving complete seizure freedom on a two drug combination would attempt to withdraw from both drugs.

As shown in Figure 3, we acknowledge that at any point after the first drug treatment patients may be referred for surgery or for confirmation of diagnosis (with the exception of those achieving complete seizure freedom with the first drug). However, we have worked on the assumption that the proportions referred for surgery or confirmation of diagnosis will not vary across the alternative AEDs and so these factors are not explicitly considered in the model.

4.4.2 Summary of model parameters

A list of the parameters upon which data are required is given in Table 45. Further details on how these parameters were estimated for the model are given in the subsequent sections of this report.

Table 45 Model parameter list Parameter Description Age Age distribution at diagnosis

Weight Normal growth charts

Learning difficulties Proportion of children with focal epilepsy experiencing learning difficulties

Life expectancy Life expectancy for patients with diagnosis of epilepsy

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Prescribing Ranked list of old drugs; and list of newer drugs which would be strategies considered for inclusion in the strategy

Target doses and Target therapeutic dose, starting dose and dose increments titration schedules Licensed indications Whether drug is licensed for newly-diagnosed and/or refractory partial epilepsy, as mono- and/or add-on therapy

Drug-specific Proportion expected to experience each of the 4 main outcomes on each proportions of the old and new drugs considered

Time spent in each Survival distribution for time to discontinuation or planned withdrawal outcome

Proportions Proportions moving into secondary states from ‘partial efficacy’ and withdrawing ‘seizure freedom’ treatment, using add-on therapy, etc. Quality of life and Utility weights specific to this population and for each main outcome utilities

Costs Costs of drugs; and cost of management for each outcome

4.4.3 Drug sequences compared in the analysis

Clearly each patient can potentially be subject to many different treatments during their time in the model, depending on the success or otherwise of current (and past) treatment. In order to reflect this complexity, the analysis considers a pre-defined sequence for the use of drugs and drug combinations. The sequences modelled are based on published prescribing guidance in childhood epilepsy, and advice from our clinical experts. In addition, despite the widespread use of AEDs outside of their licensed indication in childhood, we have only considered the use of drugs within license. This is in line with restrictions on the scope of the NICE appraisal process, but our decision to restrict the scope of the modelling was due to the lack of RCT data in non-licensed indications.

First, we defined a No New Drug strategy of monotherapy and add-on therapies for the situation where the newer AEDs were not available. This is shown in Figure 4.

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Monotherapy Add-on therapy**

Carbamazepine

Valproate Valproate and carbamazepine

Valproate and phenytoin

Valproate and drug X

Phenytoin Phenytoin and carbamazepine

Phenytoin and valproate

Phenytoin and drug X

Drug X Drug X and carbamazepine

Drug X and valproate

Drug X and phenytoin

**Drug only used in combination if, in earlier use in this patient, it was not associated with unacceptable side- effects or unacceptable efficacy. Figure 4 No New Drug Strategy

All patients initially receive carbamazepine as monotherapy; those in outcome states 1, 2 or 3 then move onto sodium valproate, again as monotherapy. Failure on this will then lead either to a third monotherapy (i.e. phenytoin) or a combination involving valproate and either carbamazepine (if, and only if, carbamazepine was partially effective and well tolerated as a monotherapy) or phenytoin. For each patient in the model, a tracker variable monitors whether or not drugs used as monotherapies (earlier in the sequence) are partially effective (i.e. if outcome state 3 is experienced). If this is the case then the drug will be available for use as combination; otherwise any combination involving the drug is avoided. The fourth line monotherapy for the base case is an unspecified generic older AED that has features of carbamazepine, valproate and phenytoin. If a patient exhausts all of the named drugs in the sequence then they will switch to another unspecified generic older AED. How the newer drugs enter the patient pathway (shown in Figure 3) to allow comparison with the “no new drug strategy” is described in section 4.4.7 (page 118).

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4.4.4 Quality of life for children with epilepsy

The model seeks to compare the predicted outcomes of different prescribing strategies using older and newer agents, and takes into account effects on health-related quality of life in order that QALYs might be estimated. In the model we have made the assumption that the quality of life associated with a particular outcome (e.g. partial efficacy and tolerable side effects) is independent of the particular AED being used.

One of the principal difficulties we faced in this project was that we do not have access to data on health-related quality of life (HRQL) for children in a form that we require for the modelling work. For use in adult populations, generic utility-based HRQL instruments (such as the EuroQol EQ-5D) have been developed that provide both a description of health but also information on how, in general, people value particular health states. Such utility measures can be used in economic analyses where the focus is on treatments for adult patient groups, but they have not been designed for use with children.

We have searched and identified many studies that have investigated the issue of quality of life in epilepsy (Aldenkamp et al, 1998;217 Austin and Dunn, 2000;218 Camfield et al, 2001;12 Cramer et al, 1999;219 Hanai, 1996;220 Hoare, 1993;221 Jacoby, 1996;222 Norrby et al, 1999;223 Ronen et al, 1999;224 Sabaz et al, 2001;225 Wildrick et al, 1996226). A consistent finding is that children with epilepsy are associated with poorer academic performance compared to other children, and score significantly lower on measures of intelligence, psychomotor speed, memory and behaviour. However, these studies do not provide the sort of information we require because they:

§ have been conducted in adult populations exclusively (and we do not wish to rely solely on adult data for our review); § have used qualitative approaches, thereby not allowing a quantitative assessment of HRQL; § have used instruments that provide quantitative scores but not on a generic ‘utility- based’ scale.

The literature strongly supports the view that adult quality of life estimates are wholly inadequate for modelling the experience of children with epilepsy. For example, complete seizure avoidance is reported to be of major importance in adult life given the adverse consequences of seizures for everyday activities such as holding a driver’s licence. The issue of drug side-effects associated with adverse impacts on educational achievements is viewed by some as a major issue in childhood. Thus, our aim was to explore the extent to which data relating to children with epilepsy might differ from those relating to adults.

Ideally, primary research would be conducted involving children and their parents. However, we were not in a position to conduct such work within the timescale and resources available. Given this, we sought views from clinical experts with experience in the care of children with epilepsy. In order, simply, to give us some quality of life information for use in our analyses we asked these experts to complete a modified version of the EuroQoL EQ-5D instrument (Hennessay and Kind, 2002227). This is an important area where data are lacking and we urge

109 Newer Drugs for Children with Epilepsy the Appraisal Committee to exercise appropriate caution in their interpretation of these results.

We approached 5 clinical experts and asked them to consider 6 broadly defined outcomes of treatment for epilepsy in childhood (including no treatment) that related to states in our model. The states are listed below.

§ The patient experiences unacceptable side effects of the drug (that cannot be controlled by adjusting the dose) such that the drug will be withdrawn (state A) § After an adequate trial of the drug, the patient still experiences an unacceptable frequency of seizures such that a change of therapy will be initiated and the drug withdrawn (i.e. not considered to be having sufficient beneficial effect) (state B) § The patient experiences an acceptable reduction in frequency of seizures and acceptable side effects, such that the drug is continued (state C) § The patient experiences seizure freedom and acceptable side effects, such that the drug is continued (state D) § The patient experiences seizure freedom following withdrawal of a successful drug, or successful surgery (state E) § The patient is not seizure free but prefers to remain untreated (state F)

Clinical experts were asked to consider how good or bad each state is for an average child with focal epilepsy, between the ages of 7 and 12 years, and with no motor impairments. Separate responses were requested for children with moderate learning difficulties and children without such difficulties.

The first task was simply to rank the states, separately for a child with or without moderate learning difficulties. The second task was to classify each state using the EuroQol EQ-5D health state descriptor (modified slightly to consider childhood issues), again separately for a child with or without moderate learning difficulties. An example of the questions asked is shown in Appendix 12 page 253. The health states described were converted into ‘utility’ scores (on a 0 – 1 scale) using the MVH A1 tariff (derived from a time trade-off survey of the general population of the UK –Dolan, 1997228).

The model provides an estimate of the time spent in each health state for all simulated patients. These time estimates were adjusted to reflect the quality of life associated with each state, using the mean health state utility score from the data provided by the clinical experts, summarised in Table 46. This allowed calculation of an individual QALY score for each simulated patient in the model. Table 46 EuroQol EQ-5D states and scores for the 6 epilepsy model states Epilepsy states

A B C D E F Expert 1 Without learning 11222 12222 11212 11111 11111 11122 difficulties With learning 12222 22222 12212 12211 12211 22222 difficulties Expert 2 Without learning 11222 11212 11111 11111 11111 11212 difficulties With learning 12222 12211 12211 12111 11111 12211 110 Newer Drugs for Children with Epilepsy

difficulties Expert 3 Without learning 22222 11212 11112 11111 11111 11112 difficulties With learning 23212 12212 12212 11211 11211 11211 difficulties

Expert 1 Without learning 0.689 0.585 0.812 1 1 0.725 difficulties With learning 0.585 0.516 0.708 0.779 0.779 0.516 difficulties Expert 2 Without learning 0.689 0.812 1 1 1 0.812 difficulties With learning 0.585 0.779 0.779 0.815 1 0.779 difficulties Expert 3 Without learning 0.516 0.812 0.848 1 1 0.848 difficulties With learning 0.26 0.708 0.708 0.883 0.883 0.883 difficulties

Mean without learning 0.631 0.736 0.886 1 1 0.795 difficulties Mean with learning 0.476 0.667 0.731 0.825 0.887 0.726 difficulties

4.4.5 Costs associated with care for children with epilepsy

The analysis of costs has been undertaken from the perspective of the NHS, and so costs incurred by patients and costs falling on other agencies have not been included in the analysis. Given that costs are incurred over the course of the child’s treatment, which can happen over many years, discounting for the timing of costs should be undertaken. (However, due to time constraints the results reported here are undiscounted.)

There are two principal components to the cost analysis.

§ Costs associated with drug therapy (and monitoring related to such therapy) § Other more general resource use and costs associated with a diagnosis of epilepsy and time spent in each of the model states

The drug cost information and the dose information is reported in Table 46.

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Table 47 Costs‡ associated with all AEDs considered in the model AEDs Cost per mg Titration dose (per day) Maintenance dose (per (pence) day) Newer AEDs Gabapentin 0.0023 Age >12 years: 20mg/kg Age >12 years: 30mg/kg others: 275mg others: 1100mg Lamotrigine 0.016 Age < 12 years: 1.5mg/kg Age < 12 years: 3mg/kg others: 75mg others: 150mg Oxcarbazepine 0.0013 20mg/kg 30mg/kg

Topiramate 0.0146 2mg/kg 7mg/kg

Older AEDs Carbamazepine 0.00028 200 mg/day 1-5 years: 300mg/day 6-10 years: 500mg/day 11-18 years: 800mg/day Valproate 0.00028 Up to 20kg: 20mg/kg Up to 20kg: 20mg/kg Over 20kg: 30 mg/kg Over 20kg: 35 mg/dkg Phenytoin 0.00089 6mg/kg 6mg/kg

‡ These unit costs are taken from the BNF (September 2002).

Data on the more general NHS resources associated with model states were gathered from a questionnaire completed by a single clinical expert experienced in providing care for children with epilepsy. The questionnaire asked for the average use of services that would be expected for an average child within each health state. In line with the definition used in the quality of life questionnaire, the expert was asked to consider an average child with focal epilepsy, between the ages of 7 and 12 years, and with no motor impairments. Data were gathered separately for the situation of a child with and a child without moderate learning difficulties. The resource use data for each state relate to the full breadth of treatment that a patient may have received in the time leading up to being in the health state in question (e.g. monitoring of patient during titration period of drug). The resource items upon which data were collected included: GP consultations, outpatient consultations, A&E visits, phone calls to clinical departments from patients (and family) for advice, and inpatient stays.

Resource data and information on unit costs (and sources for unit costs) are presented in Table 48 for children (at this time, data are not available separately for children with and without neurological impairment).

Table 48 Resource use and costs for patients with neurological impairment Model states Description Resource Use Unit Cost Total cost for 1 year Over 3 months Over 1 year Unacceptable GP consultations 0.25 1 21 21 side effects Outpatient consultations 3 12 109 1308 A&E visits 3 12 61 732 Phonecalls 3 12 4.5 54 Inpatient days 0.5 2 260 520

112 Newer Drugs for Children with Epilepsy

Unacceptable GP consultations 0.1 0.4 21 8.4 efficacy Outpatient consultations 3 12 109 1308 A&E visits 0.25 1 61 61 Phonecalls 3 12 4.5 54 Inpatient days 0.5 2 260 520 Partial efficacy GP consultations 0 0 21 0 & partial side Outpatient consultations 2 8 109 872 effects A&E visits 0 0 61 0 (the drug is Phonecalls 0 0 4.5 0 continued) Inpatient days 0 0 260 0 Seizure freedom GP consultations 0 0 21 0 & acceptable Outpatient consultations 1 4 109 436 side effects A&E visits 0 0 61 0 (the drug is Phonecalls 0 0 4.5 0 continued) Inpatient days 0 0 260 0 Seizure freedom GP consultations 0 0 21 0 following Outpatient consultations 1 4 109 436 withdrawal A&E visits 0 0 61 0 Phonecalls 0 0 4.5 0 Inpatient days 0 0 260 0 Untreated state GP consultations 1 4 21 84 Outpatient consultations 2 8 109 872 A&E visits 0.5 2 61 122 Phonecalls 2 8 4.5 36 Inpatient days 0.25 1 260 260

4.4.6 Time spent in each model outcome Time to withdrawal due to side effects or poor efficacy

We identified several related population-based cohort studies which had attempted to estimate treatment retention for several newer AEDs, and to examine the factors which influence treatment retention Wong et al, 1999,229 Lhatoo et al, 2000 (a),230 Lahtoo et al, 2000 (b),231 Wong et al, 2001.232

These studies were all conducted to a high standard. Patients were identified retrospectively, but care was taken to exclude those which had started treatment with the newer AED outside the centre, avoiding referral and survival bias. Differences in drug doses were accounted for by using ‘defined daily doses’ to establish the relative dose levels for each drug, although these were not adjusted fully for comcomitant medications (which will affect target doses).

Unfortunately, cohort studies of this type cannot be used to directly compare drugs and none of these studies report information on time to withdrawal due to specific reasons, although proportions withdrawing for various reasons are reported. There are however, some useful general points which arise from these studies.

Remission rates in these (highly) refractory populations are low; 1-3% had been in complete remission for 6 months prior to being included in the studies.

113 Newer Drugs for Children with Epilepsy

Long-term treatment retention in this population is disappointing. For partial epilepsies retention rates are 50-60% at one year, 30-40% at 3 years, and 10-20% at 5 years.

Higher maintenance doses are associated with lower drop out for both adverse effects and lack of effectiveness, suggesting that higher doses achieved by those who tolerate the drugs well may result in better seizure control. Wong et al, 2000 report that higher starting doses of lamotrigine resulted in worse treatment retention, reflecting the need for careful dose titration.

Wong et al, 2000 noted that 6% of patients had experienced a worsening of seizures on lamotrigine; most of these were discontinued within 3 months and the problem resolved. This phenomenon may account to some extent for the treatment retention curves in Lhatoo et al, 2000(b), with the lamotrigine curve dipping sharply below topiramate early on but with the difference between the two then decreasing with time. This suggests that, ideally, the rare outcome of a worsening of seizures should be dealt with as a separate outcome for the purpose of estimating treatment retention, as a worsening of seizures is likely to be established earlier in the treatment course than a failure to substantially reduce seizure rates.

The number of concomitant AEDs influenced retention rates, with patients taking more AEDs more likely to discontinue, probably reflecting both side effects and the severity of the condition.

Lhatoo et al, 2000(a) noted that patients with learning difficulties were less likely to discontinue due to adverse events, probably reflecting the greater difficulty in identifying events in these patients. Similarly, patients with a younger age of onset were less likely to discontinue, which might reflect less severe epilepsy in this group or greater difficulty in identifying side effects in young children.

All studies noted higher rates of discontinuation due to adverse events than noted in RCTs of these agents which, at least in part, is likely to reflect the extent of follow-up in RCTs compared to these cohorts. The authors also note that the two key reasons for discontinuation, adverse events and lack of effect, cannot be precisely disaggregated; a patient may discontinue a drug due to an unsatisfactory trade-off between side effects and effect on seizure rate.

The only alternative source of treatment retention data we identified is from the RCTs identified for the clinical effectiveness review. Although most of the RCTs do not report treatment retention as a ‘time to event’ outcome, four of the RCTs identified for the review of clinical effectiveness report some overall treatment retention data in the form of survival distributions.

One of these has been published (twice) in abstract form only (Hes et al, 1995233 and Bourgeois et al, 1998215); this trial is a placebo-controlled trial of gabapentin in benign childhood epilepsy with centrotemporal spikes (BECTS) and so the data available from this trial might be of limited value in informing a model for other conditions.

The three RCTs which reported treatment retention and have been published in full all give survival curves for this endpoint. All three trials are in newly diagnosed epilepsy, two

114 Newer Drugs for Children with Epilepsy including children and adults patients with partial seizures, one including children with both partial and generalised seizures.

One of these trials (Chadwick et al 1999145) comparing vigabatrin and carbamazepine in children and adults with newly diagnosed partial epilepsy, is particularly useful, giving separate survival curves for discontinuation due to adverse events and for overall time to ‘treatment failure event’ (withdrawal due to adverse event or lack of effect). The other two trials only give a composite survival curve based on all cause withdrawal and are thus less useful in informing survival estimates for specific withdrawal events.

There are two problems with the Chadwick et al trial data. The first is that the two survival curves are based on slightly different patient populations. According to the text the only patients excluded from the ‘safety’ analysis were lost to follow-up at the start of the trial, contributing no follow-up, and thus should make no difference to the estimated Kaplan-Meier survival curves. However, there are some small differences in the numbers of patients ‘at risk’ over time; it is not clear how these differences could have arisen. Although the discrepancies are small, they will have some effect on the survival estimates obtained from the plots.

The second problem is that the printed plots are quite small, with thick lines and a small gap between the axes, making it especially difficult to get accurate estimates of the survival rates. Estimates were obtained by measuring from the x axis to the centre of each curve, and subtracting the size of the gap between the x and y axes, and dividing the result by the height at t=0 (ie 100%).

We used these curves to estimate Weibull distributions for time to withdrawal due to side effects and lack of efficacy; the former being fitted directly to the curve reported by Chadwick et al, the latter being estimated by considering the result of combining the two estimated distributions and fitting the result to the ‘time to treatment failure’ curve reported by Chadwick et al. The results are plotted below (Figure 5); we have also used these estimates to reproduce the results of Chadwick and extrapolate these beyond the 12 month follow-up period of the trial (Figure 6).

115 Newer Drugs for Children with Epilepsy

1.00 Withdrawal due to adverse events 0.90 Withdrawal due to lack of efficacy 0.80

0.70 0.60

0.50

0.40

0.30

0.20

0.10

0.00 0 6 12 18 24

Figure 5 Time to withdrawal due to toxicity or lack of efficacy, estimated from Chadwick et al, 1999

1.00 0.90 0.80

0.70

0.60 0.50 0.40 0.30 0.20 0.10 0.00 0 1224364860

Figure 6 Extrapolation of Chadwick et al data beyond 12 months

It is interesting to note that the extrapolated curves cross soon after 12 months, such that the treatment which appeared to have better treatment retention up to one year (the less effective but also less toxic treatment) has worse retention later on.

This sort of pattern is entirely plausible, as withdrawal due to adverse events is more likely to occur early on in the treatment with fewer withdrawals, whilst it may take some time to establish whether or not a treatment is working.

However, these curves are estimated from a single trial, and there are substantial problems in deriving the data we have used to fit the curves. The curve for withdrawal due to lack of effect appears to be reasonably plausible, with a long flat shoulder before patients and clinicians begin to conclude that seizure rates have not been substantially affected, with a few taking 18 months or more to determine whether or not the treatment is worth continuing with.

116 Newer Drugs for Children with Epilepsy

The estimated curve for side effects is perhaps somewhat less plausible, with a substantial number of patients dropping out due to side effects at a very late stage (>10% after 2 years).

The RCT evidence suggests that the newer agents tend to be less toxic and, if anything, somewhat less effective than the older agents, with their perceived advantage being in improved treatment retention due to the more favourable side effect profile. The curves shown above suggests that this advantage might not be maintained in the long-term, as more and more patients withdraw later on due to insufficient benefit (which may take some time to establish, especially in forms of epilepsy with relatively low seizure rates). However, this is speculation and better reason-specific treatment retention data would be required to investigate this further.

Given the uncertainties involved, it would be problematic to use the curves shown above. Given that the trial data we have available are all based on short follow-up periods, differences in withdrawal due to ‘lack of efficacy’ would be penalised particularly heavily, due to the long flat shoulder of the curve shown above; this curve is used to predict the proportion of patients who will eventually withdraw for this reason given the number reported over the period of follow-up, and for some trials in this data set predicts that implausibly large numbers of patients will eventually withdraw for lack of effect.

We have therefore chosen instead to use ‘hypothetical’ survival distributions which will not penalise the newer agents to such an extent. This is arbitrary, but arguably no worse than relying on the weakly evidence-based curves above. The distributions are both Weibull distributions with shape and location parameters 0.8 and 2.0 for side effects and 1.2 and 6.0 for lack of effect. These are plotted below (Figure 7).

1.00 Withdr awal due to adver se events

0.90 Withdr awal due to lack of ef f icacy

0.80

0.70

0.60

0.50

0.40

0.30 0.20

0.10

0.00

0 6 12 18 24

Figure 7 Treatment retention curves for withdrawal due to side effects and lack of efficacy

117 Newer Drugs for Children with Epilepsy

Time on treatment which is partially effective or gives complete seizure freedom

It is assumed that patients will continue on drugs which are beneficial with acceptable side effects, but that at some point later on there will be further decisions to be made which may include discontinuation of the drug for various reasons (Figure 3). In the absence of better information, we have assumed that the time to make a change in treatment (switch, add-on or discontinue drug treatment) will follow a Weibull distribution with shape parameter 4 and location parameter 2; this distribution gives very few patients making a change within 6 months, with nearly 2/3 having made a change by 2 years.

We assume that patients achieving complete seizure freedom who are willing to try to withdraw from drug treatment will do so, on average, after two years of drug treatment.

4.4.7 Drug-specific proportions (for main outcome states)

Proportions withdrawing early due to side effects or lack of efficacy

These were estimated for each drug from the relevant RCT data available. The proportions were calculated from the trial data by obtaining the numbers withdrawing for these reasons, adjusting the sample size for other drop-outs (eg loss to follow-up) and for length of follow- up, to derive a predicted total proportion withdrawing for each reason.

For example, Nieto-Barrera, 2001197 reports 8 and 13 patients on lamotrigine withdrawing for toxicity and lack of effect respectively. The total sample size for this group was 158 with 3 patients lost to follow-up for other reasons. Assuming that these other patients were lost to follow-up at random time points during the follow-up, this gives an ‘effective sample size’ of 156.5. Thus the proportions withdrawing for side effects and lack of effect were 5.1% and 8.3% respectively during a follow-up period of 6 months. Based on our hypothetical treatment retention curves for these outcomes, we expect around 82% of withdrawals due to side effects to have withdrawn by 6 months and around 63% of those withdrawing for lack of effect to have withdrawn by this time. Thus, we predict that the overall proportions eventually withdrawing for these reasons will be 6% and 13%. Where a trial did not report any patients falling into a particular outcome (which is not plausible), we derived a proportion for this outcome which would be one standard deviation from zero. This solution is not unproblematic, but the alternative is to use data which we know cannot reflect the truth and which will give substantial advantage to the drugs concerned.

Proportions achieving complete remission

Time to achieve remission is reported in Chadwick et al, 1999;145 remission rates over time are also reported from the National General Practice Study of Epilepsy (Cockerell, 1995234). Both publications suggest that those patients who will achieve complete remission do so quickly (usually within the titration period), and that most complete remissions are sustained in the long-term. The proportions achieving complete remission will therefore be estimated from the proportions reported within the trials, on the assumption that no further complete remissions would have been achieved beyond the follow-up period of the trial and that all complete remissions would be successfully maintained whilst the patient remained on the

118 Newer Drugs for Children with Epilepsy drug treatment. The proportions were calculated using the numbers reported to be seizure- free at the end of the trial, adjusting the sample size for losses to follow-up as previously described.

Proportions achieving partial efficacy with acceptable side effects

This proportion is assumed to include all the remaining patients; ie those who did not withdraw for adverse events or lack of efficacy and did not achieve complete seizure freedom.

Drug-specific proportions entering each outcome at different stages of treatment

The RCT data available for this model consists of a single trial for each newer drug used as add-on therapy in more or less refractory populations (but with insufficient data available from the trial using tiagabine), and a single trial using lamotrigine as first-line therapy in these patients; two trials of newer agents used carbamazepine as first-line monotherapy. Although oxcarbazepine is also licensed for use as monotherapy, the only RCT we identified using oxcarbazepine monotherapy was based on a mixed patient population and thus the results are not appropriate to populate this model. There is data for vigabatrin both as first- line monotherapy and as later add-on therapy, but current advice regarding the use of vigabatrin (except in infantile spasms) is that it should be considered only as a treatment of last resort due to troublesome side effects, particularly visual field defects.

The structure of this model allows different therapies to be introduced at a number of different stages, and so we need to be able to estimate the appropriate proportions to apply at different stages (ie after variable numbers of ‘failed’ treatments).

We have used the RCT data available as ‘anchor points’, shown in table 4 (marked in bold). The trials of add-on therapy all included patients with variable disease history, but the performance of placebo in these trials is broadly similar and so we have assumed that the trial data is reasonably representative of what will occur at fourth-line treatment.

Lamotrigine is the only agent for which we have trial data at two different timepoints, as first-line monotherapy and later use as add-on. This is a very sparse data set upon which to base assumptions about the changing effectiveness of AEDs as the patients become more heavily pre-treated and more refractory to treatment. However, it is the best data that we have within the scope of this research. The proportions withdrawing due to toxicity are very similar in the two lamotrigine trials, as are the proportions withdrawing due to lack of effect. We have thus kept these parameters constant across all stages for all drugs. Reducing the proportion achieving complete seizure freedom by a constant factor of 0.4 is consistent with the lamotrigine data, allowing for a small increase in efficacy when the drug is used in combination as compared to monotherapy.

The data for first-line carbamazepine monotherapy are based on the trial data from Nieto- Barrera, 2001197 and Zamponi, 1999198 combined (the results for carbamazepine for both trials is similar). Meta-analyses of the older drugs123,129suggest that they are of similar effectiveness with some differences in toxicity, with the order of preference being carbamazepine, valproate, phenytoin and others. On the assumption that this is a rational order of preference, we have based estimates for valproate, phenytoin and ‘generic older

119 Newer Drugs for Children with Epilepsy drug’ on a slight increase in toxicity and a slight decrease in effectiveness by comparison with the drug immediately before it in the sequence; we used a constant multiplier of 1.05 for withdrawal due to side effects and lack of efficacy and 0.95 for complete seizure freedom to derive estimates for valproate, phenytoin and a ‘generic older drug’. Adjustments to toxicity and effectiveness were made in order to derive data for the older agents used in combination rather than as monotherapy; the multipliers used here were based on the differences in these proportions in the lamotrigine data.

This allowed us to build the data shown in Table 49, but it should be stressed that the trial data is very sparse, and the means by which we filled in the gaps where there are no trials are essentially arbitrary.

Table 49 Proportions moving into the main model outcome states Treatment First-line treatment Second-line treatment Third-line treatment Fourth-line + Proportion sd Proportion sd Proportion sd Proportion sd carbamazepine USE 0.113 0.029 0.113 0.113 0.113 UE 0.107 0.029 0.107 0.107 0.107 PE 0.153 0.529 0.679 0.739 CSF 0.626 0.047 0.250 0.100 0.040 valproate USE 0.119 0.119 0.119 0.119 UE 0.113 0.113 0.113 0.113 PE 0.174 0.531 0.673 0.730 CSF 0.595 0.238 0.095 0.038 phenytoin USE 0.125 0.125 0.125 0.125 UE 0.119 0.119 0.119 0.119 PE 0.192 0.531 0.666 0.721 CSF 0.565 0.226 0.090 0.036 lamotrigine USE 0.062 0.019 0.062 0.019 0.062 0.019 0.062 0.019 UE 0.131 0.027 0.131 0.027 0.131 0.027 0.131 0.027 PE 0.238 0.579 0.716 0.770 CSF 0.569 0.040 0.227 0.040 0.091 0.040 0.036 0.040 valproate+old USE 0.131 0.131 0.131 0.131 UE 0.105 0.105 0.105 0.105 PE 0.110 0.503 0.660 0.723 CSF 0.654 0.262 0.105 0.042 phenytoin+old USE 0.137 0.137 0.137 0.137 UE 0.110 0.110 0.110 0.110 PE 0.131 0.504 0.653 0.713 CSF 0.622 0.249 0.099 0.040 generic old drug USE 0.131 0.131 0.131 0.131 UE 0.124 0.124 0.124 0.124 PE 0.208 0.530 0.659 0.710 CSF 0.537 0.215 0.086 0.034 gabapentin+old USE 0.081 0.025 0.081 0.025 0.081 0.025 0.081 0.025 UE 0.266 0.041 0.266 0.041 0.266 0.041 0.266 0.041 PE 0.252 0.492 0.588 0.627 CSF 0.401 0.015 0.160 0.015 0.064 0.015 0.026 0.015 lamotrigine+old USE 0.069 0.026 0.069 0.026 0.069 0.026 0.069 0.026 UE 0.123 0.033 0.123 0.033 0.123 0.033 0.123 0.033 PE 0.186 0.560 0.709 0.769

120 Newer Drugs for Children with Epilepsy

CSF 0.622 0.020 0.249 0.020 0.100 0.020 0.040 0.020

121 Newer Drugs for Children with Epilepsy

oxcarbazepine+old USE 0.143 0.030 0.143 0.030 0.143 0.030 0.143 0.030 UE 0.062 0.014 0.062 0.014 0.062 0.014 0.062 0.014 PE 0.225 0.567 0.704 0.759 CSF 0.570 0.016 0.228 0.016 0.091 0.016 0.036 0.016 topiramate+old USE 0.120 0.044 0.124 0.044 0.124 0.044 0.124 0.044 UE 0.190 0.044 0.194 0.044 0.194 0.044 0.194 0.044 PE 0.010 0.377 0.560 0.634 CSF 0.680 0.034 0.305 0.034 0.122 0.034 0.049 0.034 tiagabine+old No data available from RCTs identified for the review oxcarbazepine No data available from RCTs identified for the review Key: USE = Unacceptable side effects; UE = Unacceptable efficacy; PE = Partial efficacy & acceptable side effects; CSF = Seizure freedom and acceptable side effects. 4.4.8 Proportions moving into secondary model states

Table 50 shows the proportions we have used for the various decisions taken after the main 4 outcomes used in the model have occurred, with average time on drug also given where this is relevant. These figures are based upon the very limited literature that is available but, in truth, are more or less arbitrary (at the moment). Further work is being undertaken to improve these estimates where possible and clinical opinion will be sought on this.

The assumption has been made that these proportions do not vary by whether the patient has learning disabilities and are independent of patient age. In addition, the time to try alternative treatment strategy (after partial response) may vary over cycles.

Table 50 Proportions moving into secondary model states PRIMARY SECONDARY First-line Second-line Third-line Fourth- OUTCOMES OUTCOMES line & beyond Unacceptable try another drug 90% 95% 90% 80% efficacy no further drugs 10%* 5% 10% 20%

Unacceptable try another drug 90% 95% 90% 80% side effects no further drugs 10%* 5% 10% 20%

Partial efficacy, continue 0% 5% 10% 20% acceptable side add-on 0% 30% 40% 60% effects no further drugs 10%* 5% 10% 20% try different drug 90% 60% 40% 0% Seizure continue indefinitely 0% 0% 10% 20% freedom, withdraw unsuccessfully 50% 50% 45% 40% acceptable side withdraw successfully 50% at 50% at 45% at 40% at effects t=2yrs t=2yrs t=2yrs t=2 yrs

*10% not going on to any further drug treatment chosen to approximate proportion going on to have successful surgery

122 Newer Drugs for Children with Epilepsy

4.4.9 Methods of analysis The model has been constructed and run using TreeAge DATA Professional (release 6). The results are based on a Monte Carlo simulation with a sample of 10,000 simulated patients.

Initially the model was run for the No New Drug sequence, and the costs and QALYs associated with this sequence were estimated.

The policy change considered was the introduction of each of the new drugs in turn, in line with its licensed indications.

Our plan was to consider the two new AEDs licensed as monotherapies for use in children: lamotrigine (for use in children over 12 years) and oxcarbazepine (for use in children over 6 years). However, no data were available for the use of oxcarbazepine as monotherapy and so the focus for monotherapy use was exclusively lamotrigine. This drug was considered as first-line monotherapy and second line monotherapy, after carbamazepine had failed. The costs and QALYs for the average patient were calculated for this monotherapy strategy. This then allowed the incremental cost (i.e. the cost of the new drug monotherapy strategy minus the cost of the No New Drug strategy) and the incremental QALYs (i.e. the QALYs for the new drug monotherapy strategy minus the QALYs for the No New Drug strategy) to be calculated.

The newer AEDs that can be used as add-on therapies are lamotrigine, gabapentin, topiramate, oxcarbazepine and tiagabine. Vigabatrin is licensed for use as an add-on therapy in partial epilepsy but is recommended for use only as a treatment of last resort due to problematic side effects; we have therefore not included it in this analysis. Each new drug was considered for use as the first choice add-on therapy following a decision to switch from monotherapy. Due to lack of data, we were not able to consider tiagabine in our analysis. The costs and QALYs for the average patient were calculated for these five add-on strategies, again allowing the incremental cost and the incremental QALYs to be calculated.

To summarise, the strategies for which results are presented in this report are:

No new drug strategy First-line use of lamotrigine as monotherapy Second-line use of lamotrigine as monotherapy Use of lamotrigine as first choice add-on therapy Use of gabapentin as first choice add-on therapy Use of topiramate as first choice add-on therapy Use of oxcarbazepine as first choice add-on therapy

For all strategies except the first-line use of lamotrigine, we decided to exclude the costs and QALYs accrued by patients successfully treated with carbamazepine. The reason for this is that these costs and effects are common to both the No New Drug strategy and the new drug strategies (when the new drugs are not used as first line) but add noise to the comparison of strategies. Thus, the estimates of costs and effects presented for these stategies are estimates from the point of failure on carbamazepine.

123 Newer Drugs for Children with Epilepsy

Where first-line use is considered, the results for this analysis consider the costs and QALYs for patients from the point of initiation of drug therapy for epilepsy. The No New Drug strategy was then re-run to allow the incremental calculation of costs and effects to use comparable strategies.

Small differences in costs and effects between strategies were expected, given the results from the trial evidence. Runs of 10,000 simulated patients were used and these were repeated 20 times for each strategy to give some indication of the sampling variability in the results. 4.4.10 Cost-effectiveness results The results of the analyses are reported in Table 51 to Table 54. Given that the model has been run 20 times for each strategy, the results from each run are presented on a cost- effectiveness plane for each comparison made. The incremental analysis has always used the No New Drug strategy as the point of comparison.

The expected total cost of caring for the average child diagnosed with epilepsy, managed according to the drug therapy strategy outlined in Figure 2, is just under £5,000 (from the age of diagnosis through to 18 years of age). This includes both the cost of the drugs plus the costs of other health service resources. Such a patient is expected to experience just under 7.5 QALYs from this strategy, again through to the time when they reach the age of 18 years. As expected, when we focus on patients who fail on the first monotherapy (i.e. carbamazepine) and count costs and QALYs from the point of failure, the mean cost estimate is a little lower and the mean QALY estimate is substantially lower (i.e. about 4.2 QALYs).

The analysis that considered the use of lamotrigine as monotherapy (either first-line or second-line), produced results indicating a positive incremental cost. The results indicate that for some runs of the model the incremental QALY estimate is positive (indicating health benefits from the use of lamotrigine) and for other runs the incremental QALY estimate is negative. There is no strong evidence from this analysis that monotherapy use of lamotrigine is associated with important health benefits.

For the analyses looking at the use of the newer AEDs as add-on therapies, the findings in terms of incremental costs and the incremental QALY scores are similar to the results for lamotrigine monotherapy. Positive incremental costs are found, and a mixture of positive and negative incremental QALY estimates. Therefore, there is no strong evidence from this analysis that add-on therapy use of the new drugs considered is associated with important health benefits.

124 Newer Drugs for Children with Epilepsy

Table 51 Analysis results 1

Costs and QALYs accrued from diagnosis of epilepsy Costs and QALYs accrued from time of failure on CBZ No new drugs No new drugs Costs QALYs Costs QALYs Run Mean SD Mean SD Mean SD Mean SD

1 £4,916 4038 7.4314 4.2018 £4,767 4535 4.2675 3.4814 2 £4,968 4017 7.4787 4.2406 £4,740 4436 4.2456 3.4505 3 £4,901 3988 7.4191 4.2237 £4,793 4569 4.2463 3.4481 4 £4,834 3886 7.3634 4.2793 £4,750 4505 4.2538 4.4419 5 £4,874 3974 7.4092 4.251 £4,804 4571 4.3123 3.4736 6 £4,893 3823 7.4542 4.2504 £4,865 4703 4.2832 3.4431 7 £4,886 4013 7.4196 4.2258 £4,691 4456 4.2346 3.4321 8 £4,902 3984 7.4376 4.2321 £4,715 4500 4.2565 3.4744 9 £4,934 4006 7.3734 4.2242 £4,757 4481 4.2701 3.4489 10 £4,863 3959 7.4163 4.2468 £4,720 4547 4.2935 3.4587 11 £4,963 4013 7.4571 4.2241 £4,802 4513 4.2734 3.4450 12 £4,909 3980 7.4672 4.2729 £4,760 4483 4.2701 3.4593 13 £4,908 3995 7.3909 4.2657 £4,702 4492 4.2033 3.440 14 £4,942 4019 7.4845 4.2451 £4,747 4561 4.2733 3.4584 15 £4,858 3883 7.3422 4.273 £4,700 4421 4.2624 3.4770 16 £4,887 3917 7.3881 4.2186 £4,765 4613 4.2677 3.4492 17 £4,841 3869 7.366 4.2317 £4,789 4563 4.2551 3.4189 18 £4,862 3919 7.4491 4.2621 £4,792 4535 4.3123 3.4453 19 £4,884 3917 7.4247 4.2237 £4,725 4471 4.2653 3.4810 20 £4,874 3892 7.4507 4.2344 £4,678 4446 4.2041 3.4228

125 Newer Drugs for Children with Epilepsy

Table 52 Analysis results 2

Costs and QALYs accrued from start of treatment Costs and QALYs accrued from time of failure on CBZ Lamotrigine (first-line monotherapy) Lamotrigine (second-line monotherapy) Costs QALYs Incremental ICER Costs QALYs Incremental ICER Run Mean Mean Cost QALYs Mean Mean Cost QALYs

1 £5,141 7.4365 £225 0.0051 £44,118 £4,917 4.1313 £150 -0.1362 -£1,101 2 £5,239 7.465 £271 -0.0137-£19,781 £5,010 4.2112 £270 -0.0344 -£7,849 3 £5,161 7.3885 £260 -0.0306 -£8,497 £4,995 4.2498 £202 0.0035 £57,714 4 £5,213 7.4013 £379 0.0379 £10,000 £5,037 4.2710 £287 0.0172 £16,686 5 £5,140 7.4433 £266 0.0341 £7,801 £5,004 4.2497 £200 -0.0626 -£3,195 6 £5,195 7.3815 £302 -0.0727 -£4,154 £5,000 4.2204 £135 -0.0628 -£2,150 7 £5,092 7.4431 £206 0.0235 £8,766 £4,919 4.1928 £228 -0.0418 -£5,455 8 £5,209 7.4271 £307 -0.0105 -£29,238 £5,045 4.2685 £330 0.0120 £27,500 9 £5,174 7.4226 £240 0.0492 £4,878 £5,045 4.2163 £288 -0.0538 -£5,353 10 £5,078 7.3693 £215 -0.0470 -£4,574 £4,967 4.2612 £247 -0.0323 -£7,647 11 £5,137 7.3336 £174 -0.1235 -£1,409 £4,981 4.2691 £179 -0.0043 -£41,628 12 £5,157 7.4363 £248 -0.0309 -£8,026 £4,969 4.2468 £209 -0.0233 -£8,970 13 £5,128 7.3963 £220 0.0054 £40,741 £4,946 4.2601 £244 0.0568 £4,296 14 £5,177 7.3795 £235 -0.1050 -£2,238 £5,058 4.2937 £311 0.0204 £15,245 15 £5,166 7.4115 £308 0.0693 £4,444 £5,041 4.2391 £341 -0.0233 -£14,635 16 £5,131 7.473 £244 0.0849 £2,874 £4,991 4.2423 £226 -0.0254 -£8,898 17 £5,160 7.4122 £319 0.0462 £6,905 £5,009 4.2775 £220 0.0224 £9,821 18 £5,141 7.3206 £279 -0.1285 -£2,171 £5,027 4.2563 £235 -0.0560 -£4,196 19 £5,158 7.411 £274 -0.0137-£20,000 £5,046 4.2871 £321 0.0218 £14,725 20 £5,189 7.3934 £315 -0.0573 -£5,497 £4,941 4.3012 £263 0.0971 £2,709 Cost-effectiveness plane Cost-effectiveness plane

126 Newer Drugs for Children with Epilepsy

Table 53 Analysis results 3

Costs and QALYs accrued from time of failure on CBZ Lamotrigine (first choice add-on therapy) Gabapentin (first choice add-on therapy) Costs QALYs Incremental ICER Costs QALYs Incremental ICER Run Mean Mean Cost QALYs Mean Mean Cost QALYs

1 £4,813 4.2211 £46 -0.0464 -£991 £4,976 4.1742 £209 -0.0933 -£2,240 2 £4,975 4.2885 £235 0.0429 £5,478 £4,951 4.1969 £211 -0.0487 -£4,333 3 £4,893 4.2716 £100 0.0253 £3,953 £5,002 4.2234 £209 -0.0229 -£9,127 4 £4,821 4.2376 £71 -0.0162 -£4,383 £4,983 4.3096 £233 0.0558 £4,176 5 £4,895 4.2243 £91 -0.0880 -£1,034 £4,913 4.1569 £109 -0.1554 -£701 6 £4,877 4.2483 £12 -0.0349 -£344 £5,021 4.2099 £156 -0.0733 -£2,128 7 £4,790 4.2412 £99 0.0066 £15,000 £4,899 4.1989 £208 -0.0357 -£5,826 8 £4,864 4.3307 £149 0.0742 £2,008 £4,997 4.2516 £282 -0.0049 -£57,551 9 £4,802 4.2418 £45 -0.0283 -£1,590 £4,971 4.2435 £214 -0.0266 -£8,045 10 £4,885 4.2818 £165 -0.0117 -£14,103 £4,854 4.1884 £134 -0.1051 -£1,275 11 £4,909 4.2858 £107 0.0124 £8,629 £4,897 4.2091 £95 -0.0643 -£1,477 12 £4,926 4.2094 £166 -0.0607 -£2,735 £4,942 4.2617 £182 -0.0084 -£21,667 13 £4,903 4.1904 £201 -0.0129 -£15,581 £4,945 4.1904 £243 -0.0129 -£18,837 14 £4,874 4.2623 £127 -0.0110 -£11,545 £4,962 4.2253 £215 -0.0480 -£4,479 15 £5,017 4.2788 £317 0.0164 £19,329 £4,973 4.2614 £273 -0.0010 -£273,000 16 £4,871 4.2931 £106 0.0254 £4,173 £4,938 4.2339 £173 -0.0338 -£5,118 17 £4,897 4.2599 £108 0.0048 £22,500 £4,919 4.2256 £130 -0.0295 -£4,407 18 £4,846 4.279 £54 -0.0333 -£1,622 £5,023 4.2395 £231 -0.0728 -£3,173 19 £4,853 4.2349 £128 -0.0304 -£4,211 £5,009 4.2218 £284 -0.0435 -£6,529 20 £4,899 4.2524 £221 0.0483 £4,576 £4,956 4.2152 £278 0.0111 £25,045 Cost-effectiveness plane Cost-effectiveness plane

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Table 54 Analysis results 4

Costs and QALYs accrued from time of failure on CBZ (base case analysis) Topiramate (first choice add-on therapy) Oxcarbazepine (first choice add-on therapy) Costs QALYs Incremental ICER Costs QALYs Incremental ICER Run Mean Mean Cost QALYs Mean Mean Cost QALYs

1 £5,079 4.2341 £312 -0.0334 -£9,341 £4,871 4.2286 £104 -0.0389 -£2,674 2 £5,074 4.2948 £334 0.0492 £6,789 £4,868 4.2766 £128 0.0310 £4,129 3 £5,040 4.2412 £247 -0.0051 -£48,431 £4,862 4.2425 £69 -0.0038 -£18,158 4 £5,083 4.2543 £333 0.0005 £666,000 £4,803 4.2305 £53 -0.0233 -£2,275 5 £5,133 4.252 £329 -0.0603-£5,456 £4,831 4.265 £27 -0.0473 -£571 6 £5,083 4.2885 £218 0.0053 £41,132 £4,892 4.2815 £27 -0.0017 -£15,882 7 £5,144 4.308 £453 0.0734 £6,172 £4,877 4.2153 £186 -0.0193 -£9,637 8 £5,235 4.3006 £520 0.0441 £11,791 £4,820 4.2455 £105 -0.0110 -£9,545 9 £5,101 4.2492 £344 -0.0209 -£16,459 £4,852 4.2501 £95 -0.0200 -£4,750 10 £5,040 4.2079 £320 -0.0856 -£3,738 £4,838 4.246 £118 -0.0475 -£2,484 11 £5,125 4.3012 £323 0.0278 £11,619 £4,786 4.2054 -£16 -0.0680 £235 12 £5,182 4.2837 £422 0.0136 £31,029 £4,848 4.2712 £88 0.0011 £80,000 13 £5,029 4.2504 £327 0.0471 £6,943 £4,759 4.1856 £57 -0.0177 -£3,220 14 £5,108 4.2853 £361 0.0120 £30,083 £4,800 4.253 £53 -0.0203 -£2,611 15 £5,103 4.1952 £403 -0.0672 -£5,997 £4,908 4.3172 £208 0.0548 £3,796 16 £5,184 4.2543 £419 -0.0134 -£31,269 £4,780 4.1515 £15 -0.1162 -£129 17 £5,031 4.2319 £242 -0.0232 -£10,431 £4,767 4.2795 -£22 0.0244 -£902 18 £5,046 4.2312 £254 -0.0811 -£3,132 £4,857 4.2876 £65 -0.0247 -£2,632 19 £5,086 4.2989 £361 0.0336 £10,744 £4,872 4.2587 £147 -0.0066 -£22,273 20 £5,126 4.283 £448 0.0789 £5,678 £4,912 4.3036 £234 0.0995 £2,352 Cost-effectiveness plane Cost-effectiveness plane

128 Newer Drugs for Children with Epilepsy

4.5 Conclusions

The model we have presented in this report has strengths and weaknesses. We have constructed an individual sampling model that considers simulated children over their childhood from the age at diagnosis through to 18 years. A particular advantage of this approach is that a cohort of patients can then be considered, comprising individuals with a mix of personal characteristics. In the results we report here the cohorts include patients who vary in terms of the age at diagnosis (from 3 to 18 years), their sex, and whether or not they experience learning difficulties. Other appropriate personal characteristics (for which data are available) could easily be incorporated into the model. The model does not work with a fixed cycle time, as would be required by a Markov process. The time spent in outcome states is sampled from distributions for every simulated patient. An assumption is made that longer durations in states with reasonable efficacy and side-effect profiles represents a positive outcome.

Drug sequences, and the introduction of the newer AEDs into an existing drug sequence, are explicitly considered. This mirrors clinical practice where, for patients not experiencing efficacy or experiencing unacceptable side effects, new drugs (either as monotherapy or add- on therapy) will be introduced. However, additional variations in the sequences might be modelled. For example, the newer AEDs might be considered as last resort therapy only; this scenario has not been considered in the analysis reported here. Drug sequences have been defined considering the use of all AEDs within their licence only. However, it is widely recognised that in childhood there is considerable use of AEDs outside of their licensed indications.

A weakness in the model is its limited scope, which results largely from data limitations. It does not consider the effect of AEDs on the likelihood of patients being referred for surgery, being re-diagnosed as not having epilepsy and mortality. The structure of the model is capable of accommodating all of these issues.

Other limitations of the analysis reported here that should be highlighted are listed below.

§ One of the more concerning data limitations that faced us related to the lack of reliable data on quality of life issues in children (that can be used in a cost-utility analysis). § The model currently assumes that the time in the outcome states (and the quality of life experienced whilst in those states) is independent of the drug used. It is the likelihood of entering the states that varies by the AEDs. § There are also limitations in the analytical methods used due to time constraints. The cost and QALY streams estimated in the model have not been discounted. More extensive sensitivity analysis, including a probabilistic sensitivity analysis (using distributions around the proportions of patients going into the main outcome states) has not yet been undertaken.

129 Newer Drugs for Children with Epilepsy

5. IMPLICATIONS FOR OTHER PARTIES

An optimal prescribing strategy for children with epilepsy would improve outcomes for the patients, families and carers, and might reduce the burden on other services. However, it is clear from the available evidence that the differences between the various AEDs are small. What differences there are appear mainly in the trade-off between tolerability and effectiveness, with older drugs appearing generally more effective but with a less favourable side effect profile. Further research, specific to the various epilepsy syndromes of interest, would be needed to determine how different prescribing choices might affect outcomes for other parties. It is important to note that there is a substantial difference between the population of newly or recently diagnosed patients, many of whom will have extremely good outcomes regardless of which AEDs are chosen for initial treatment, and the much smaller population with intractable epilepsy, who experience little or no benefit after trying a number of different treatments. For the latter group (that might be ~20% of pediatric epilepsy patients attending a district general hospital), there is reasonably clear evidence from placebo-controlled trials of the newer agents that they may have some beneficial impact on the disease, and desirable that as many treatment options as possible remain available for this small group of patients. The cost of using the newer agents as a last resort for these patients is likely to be small, due to the low proportion of patients reaching this stage and the likelihood that the duration of treatment would be short unless the drugs were perceived to be of benefit.

6. DISCUSSION

6.1 Clinical effectiveness

The quality of the RCT data was generally poor, with many giving cause for concern over the integrity of randomisation, quality of blinding, and/or analytical methods employed.

Most of the trials were conducted for licensing purposes and are thus of limited use in informing clinical practice; whilst it is clear that these agents may be useful additions to the list of AEDs available, there is very little data upon which to base a rational prescribing strategy.

Twenty trials were identified which reported outcome data for children with epilepsy; 18 of these were conducted exclusively in children. For each of the epilepsy sub-types considered in these RCTs (partial epilepsy with or without secondary generalisation, Lennox-Gastaut syndrome, infantile spasms, absence epilepsy and BECTs), there is some evidence from placebo-controlled trials that the newer agents tested are of some value in the treatment of these conditions. Where active controls have been used, the newer agents do not appear any more effective than older agents but seem to be better tolerated. The data are not sufficient to inform a prescribing strategy for any of the newer agents in any of these conditions. In

130 Newer Drugs for Children with Epilepsy particular, there is no evidence to suggest that the newer agents should be considered as a first choice treatment in any form of epilepsy in children.

6.2 Cost-effectiveness

A decision-analytic model was constructed to estimate the cost-effectiveness of the newer agents in children with partial seizures, the only condition where there was a sufficient quantity and quality of trial data to inform a model. The model was based on a complex patient pathway which attempted to reflect the variety of treatment decisions made and outcomes experienced by patients treated for epilepsy in childhood. Even with a relatively simplified pathway and straightforward prescribing strategy, the complexity of the disease requires a large number of parameters to be estimated. Some parameters are specific to the drugs considered whilst others relate to more general clinical decisions, prognosis following different outcomes, and patient preferences. There was little reliable data available either for the drug-specific parameters (from the RCTs identified for the clinical effectiveness review) or for many of the more general parameters (from epidemiological and other literature). The model was based on an individual patient sampling procedure, and so the results obtained are subject to some random variation. We therefore obtained several sets of results for each scenario where a newer agent was introduced into the prescribing strategy. The results suggest that the uncertainty in the model is greater than the differences between the drug strategies, with results varying from dominance (the use of newer drugs reduces the utility of treatment) to clearly cost-effective (cost per QALY well within an acceptable range). The results do not suggest that the use of the newer agents in any of the scenarios considered is clearly cost-effective, but similarly, do not indicate that they are clearly not cost-effective.

6.3 Assumptions, limitations and uncertainties

There are a number of assumptions and limitations in the decision-analytic model. We have not explicitly modelled the impact of surgery or other non-drug treatments, or the effect of patients who have been misdiagnosed. Our model attempts to model a reasonable spread of ‘good clinical practice’, with respect to changes in treatment and the use of monotherapy or polytherapy, but there is no clear consensus regarding good clinical practice. Reports of clinical audits or population-based cohorts are of some use in determining what happens in practice, but the consensus is shifting and so these reports are of limited use in defining current practice, which is shifting away from over-treatment and the widespread use of polytherapy towards a preference for monotherapy unless there are clear reasons to add-on rather than switch treatments. The evidence base for AEDs, both newer and older agents, is weak; there are very few trials, a number of methodological difficulties with most of the trials, few comparative trials against older AEDs and none comparing the newer AEDs to each other in children. In addition, the complexity of the model provides for many many different patient pathways, each one subject to it’s own uncertainties in the parameters used. In these circumstances, obtaining an accurate estimate of cost-effectiveness is not a plausible aim, and we have attempted here only to quantify some of the uncertainty surrounding the true value.

131 Newer Drugs for Children with Epilepsy

6.4 Need for further research Better information is required from RCTs before any rational evidence-based prescribing strategy could be developed. Ideally, RCTs should be conducted from a ‘public health’ perspective, making relevant comparisons and incorporating outcomes of interest to clinicians and patients, with sufficiently long-term follow-up to reliably determine the clinical utility of different treatments, particularly with respect to treatment retention and the balance between effectiveness and tolerability. RCTs should mirror clinical practice with respect to diagnosis, focusing on defined syndromes or, where no syndrome is identified, on groups defined by specific seizure type(s) and aetiology.

Epilepsy in children is a complex disease, with a variety of quite distinct syndromes, many alternative treatment options, and outcomes. Diagnosis-specific decision-analytic models are required; further research may be required to adequately inform parameter values with respect to epidemiology and clinical practice.

7. CONCLUSIONS The prognosis for children diagnosed with epilepsy is generally good, with a large proportion responding well to the first treatment given. A substantial proportion, however, will not respond well to treatment, and for these patients the clinical goal is to find an optimal balance between the benefits and side effects of any treatment given.

For the newly, or recently, diagnosed population, the key question for the newer drugs is how soon they should be tried. The cost-effectiveness of using these agents early, in place of one of the older agents, will depend on the effectiveness and tolerability of these agents compared to the older agents; the evidence from the available trial data so far suggests that the newer agents are no more effective but may be somewhat better tolerated than the older agents, and so the cost-effectiveness for early use will depend on the trade-off between effectiveness and tolerability, both in terms of overall (long-term) treatment retention and overall utility associated with effects on seizure rate and side effects. There is insufficient data available to accurately estimate the nature of this trade off either in terms of long-term treatment retention or utility. For the proportion of patients with intractable epilepsy, which has failed to respond to a number of previous treatments, it may be desirable that the newer agents would be made available at some point despite a lack of evidence regarding cost-effectiveness, with newer anti-epileptic drugs being considered after other treatment options have failed, and after carefully reviewing the diagnosis of epilepsy. The cost impact of this on the NHS is likely to be small. If an agent were to be approved for use in this context, appropriate monitoring would be required to ensure that use remains within appropriate guidelines and is not prolonged when the patient is not clearly obtaining benefit from treatment.

132 Newer Drugs for Children with Epilepsy

8. APPENDICES

133 Newer Drugs for Children with Epilepsy

Appendix 1 Details of intervention drugs Details given in Table 55 are taken in each case from the approriate Summary of Products Characteristics. Table 55 Details of newer drugs for treatment of epilepsy. Drug Indications for treatment in Dosage Documented side effects and drug interactions Cost & launch date the UK (MIMS January 2003) Gabapentin Adults and children >12 years: Adults and children >12 years: Adults: most common somnolence, dizziness, ataxia, fatigue. Also Capsules: Add-on therapy for partial Titration according to manufacturer's nystagmus, tremor, diplopia, amblyopia, dysarthria, amnesia, asthenia, 100mg £22.86 x100 (Neurontin) seizures with or without guidance to maximum of 2400mg/day, paraesthesia, arthralgia, purpura, leucopenia, dyspepsia, anxiety, 300mg £53.00 x100 secondary generalisation not taken in three divided doses. weight gain. Rare reports of pancreatitis, elevated liver function tests 400mg £61.33 x100 Launched: satisfactorily controlled with (LFTs), erythema multiforme, Stevens Johnson Syndrome (SJS). May 1993 & other AED(s). licensed in Children 6 to 12 years: Children 6 to 12 years: Children (aged 3 to 12 years): most common emotional lability, Tablets: children aged ≥6 Add-on therapy for partial Titration according to manufacturer's nervousness, thinking abnormally. Also somnolence, fatigue, weight 600mg £106.00 x100 years in seizures with or without guidance to recommended dose of gain, hostility, dizziness, hyperkinesia, nausea/vomiting. 800mg £122.66 x100 November 1999 secondary generalisation in between 25mg/kg/day and 35mg/kg/day. patients not satisfactorily Patients taking gabapentin can experience mood and behavioural controlled with other AED(s), disturbances. Caution is recommended in patients with a history of or who cannot tolerate other psychotic illness. AED(s). A neurological specialist should initiate and Antacids can reduce the bioavailability of gabapentin. No interactions supervise treatment. have been demonstrated between gabapentin and phenytoin, valproate, carbamazepine, or phenobarbital.

Monitoring of gabapentin plasma concentrations is not required.

134 Newer Drugs for Children with Epilepsy

Lamotrigine Adults and children >12 years: Monotherapy: Include: diplopia, blurred vision, conjunctivitis, dizziness, drowsiness, Tablets: Monotherapy or add-on therapy Titration according to manufacturer's headache, tiredness, gastrointestinal disturbance, irritability/aggression, 25mg £21.95 x56 (Lamictal) of simple partial, complex guidance until optimal response achieved. tremor, agitation, confusion, hallucinations. 50mg £37.31 x56 partial, secondarily generalised The usual maintenance dose is 100mg to 100mg £64.37 x56 and primary generalised tonic- 200mg/day. Up to 500mg has been used. Adverse skin reactions, generally within the first 8 weeks of 200mg £109.42 x56 Launched: clonic seizures. lamotrigine treatment; most cases mild and self-limiting. Serious 1991 Add-on therapy: reactions, including SJS, toxic epidermal necrolysis, and a Dispersible/chewable Dose dependent on concomitant hypersensitivity syndrome have been reported. The approximate tablets: medication, with higher initial and incidence of rashes reported as SJS in adults and children >12 years is 2mg £9.37 x30 maintenance doses used for patients also 1 in 1000. The risk in children under 12 is greater than this. The 5mg £8.75 x28 taking enzyme-inducing AEDs (e.g. overall risk of rash appears to be associated with high initial doses of 25mg £21.95 x56 phenytoin, carbamazepine). lamotrigine, and concomitant use of valproate. 100mg £64.37 x56 The usual maintenance dose is 100mg to 200mg/day in non-users of enzyme- Haematological abnormalities (neutropenia, leucopenia, anaemia, inducing AEDs, and 200mg to 400mg in thrombocytopenia, pancytopenia, aplastic anaemia granulocytosis), users of enzyme-inducing AEDs. movements disorders, and elevated LFTs have been reported. Children 2 to 12 years: Add-on therapy for simple Dose dependent on concomitant Enzyme-inducing AEDs enhance the metabolism of lamotrigine, which partial, complex partial, medication, with higher initial and may increase dosage requirements. Valproate reduces the metabolism secondarily generalised and maintenance doses used for patients also of lamotrigine, increasing its half life. There is no evidence that primary generalised tonic- taking enzyme-inducing AEDs (e.g. lamotrigine affects the pharmacokinetics of other AEDs. clonic seizures. phenytoin, carbamazepine). The usual maintenance dose is 1mg to 5mg/kg/day in non-users of enzyme- Treatment of seizures inducing AEDs, and 5mg to 15mg/kg/day associated with the Lennox- in users of enzyme-inducing AEDs. Gastaut syndrome. Levetiracetam Adults and adolescents >16 Adults: most common somnolence, asthenia, dizziness. Others Tablets: years: Titration according to manufacturer's include: headache, amnesia, ataxia, convulsion, tremor, depression, 250mg £29.70 x60 (Keppra) Add-on therapy for partial- guidance to 3g/day (taken in two divided emotional lability, hostility, insomnia, nervousness, abnormal 500mg £49.50 x60 onset seizures with or without doses) behaviour, aggression, anger, anxiety, confusion, hallucination, 1000mg £94.50 x60 Launched: secondary generalisation. irritability, psychotic disorder. November 2000 No interactions have been demonstrated between levetiracetam and carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproate, digoxin or warfarin.

Plasma level monitoring of levetiracetam is not required.

135 Newer Drugs for Children with Epilepsy

Oxcarbazepine Adults and children aged 6 Common include: fatigue, asthenia, dizziness, headache, somnolence, Tablets: years and over: Titration according to manufacturer's ataxia, emotional lability, nystagmus, tremor, impaired concentration, 150mg £10.00 x50 (Trileptal) Monotherapy or add-on therapy guidance. Therapeutic effects seen at nausea, vomiting, constipation, diarrhoea, acne, alopecia, rash, 300mg £20.00 x50 for partial seizures with or doses of between 600mg and diplopia, vision disorders, vertigo, hyponatraemia. Uncommon or rare 600mg £40.00 x50 Launched: without secondary generalised 2400mg/day. effects include angioedema, leucopenia, increases in transaminases March 2000 tonic-clonic seizures. and/or alkaline phosphatase, hepatitis, SJS, systemic lupus erythematosus.

Approximately 25-30% of patients who have exhibited hypersensitivity reactions to carbamazepine may experience hypersensitivity reactions with oxcarbazepine.

Interactions: oxcarbazepine both inhibits and induces the activity of some of the cytochrome P450 enzymes in the liver, resulting in increases or decreases in the plasma levels of some AEDs and other drugs (e.g. it accelerates the metabolism of hormonal contraceptives).

Plasma monitoring is not required to optimise oxcarbazepine therapy. Tiagabine Adults and children over 12 Titration according to manufacturer's Include dizziness, tiredness, nervousness, tremor, diarrhoea, Tablets: years: guidance to usual maintenance dose of concentration difficulties, depressed mood, emotional lability, 5mg £45.37 x100 (Gabitril) Add-on therapy for partial 15−30mg daily. Patients taking enzyme- slowness in speech. In patients with a history of serious behavioural 10mg £90.74 x100 seizures with or without inducing AEDs may require higher problems, there is a risk of symptom recurrence during treatment with 15mg £136.11 x100 secondary generalisation where maintenance doses of 30−45mg. tiagabine. Launched: control is not achieved by September 1998 optimal doses of at least one Others (rare): spontaneous bruising, hallucination, delusion, visual other AED. field defects. If visual symptoms develop, referral to an ophthalmologist is recommended.

Enzyme-inducing AEDs enhance the metabolism of tiagabine. Tiagabine does not interact with phenytoin, carbamazepine, phenobarbital, warfarin, digoxin, theophylline, hormonal contraceptives. Tiagabine reduces the plasma concentration of valproate (not considered clinically significant).

136 Newer Drugs for Children with Epilepsy

Topiramate Adults and children over 2 Adults and children >16 years: Adults: abdominal pain, ataxia, anorexia, asthenia, confusion, Tablets: years: Titration to usual maintenance dose of difficulty with concentration/attention and memory, diplopia, and other 25mg £22.02 x60 (Topamax) Add-on therapy (where control 200mg to 400mg. CNS effects. Others include abnormal gait, aggressive reaction, 50mg £36.17 x60 is inadequate using apathy, cognitive problems. 100mg £64.80 x60 Launched: conventional first line AEDs) Children aged 2 to 16 years: 200mg £125.83 x60 1995 for partial seizures with or Titration to usual maintenance dose of Children: somnolence, anorexia, fatigue, insomnia, nervousness, without secondarily 5−9mg/kg/day. personality disorder, and other CNS effects. Others include emotional Sprinkle capsules: generalisation; seizures lability, agitation, apathy, cognitive problems, psychomotor slowing, 15mg £16.88 x60 associated with Lennox-Gastaut confusion, hallucination, depression and leucopenia. 25mg £25.32 x60 Syndrome; and primary 50mg £41.60 x60 generalised tonic-clonic Rare: nephrolithiasis, acute myopia with secondary angle-closure seizures. glaucoma

Interactions with other AEDs: addition of topiramate to phenytoin may increase phenytoin plasma concentrations. Phenytoin and carbamazepine decrease plasma concentrations of topiramate. Topiramate increases the clearance of oestrogen in oral contraceptives so a high strength preparation should be used.

Plasma monitoring of topiramate is not required to optimise therapy.

137 Newer Drugs for Children with Epilepsy

Vigabatrin Treatment in combination with Adults: Adults; CNS effects such as somnolence, fatigue, drowsiness, and Tablets: other AEDs for patients with Titration according to manufacturer's impaired concentration predominate. 500mg £44.85 x100 (Sabril) resistant partial epilepsy with or guidance. Maximal efficacy seen in the without secondary 2g to 3g/day range. Children, excitation or agitation is frequent. Powder sachets: Launched: generalisation, where all other 500mg £24.33 x50 1989 appropriate drug combinations Children: Others include: headache, weight gain, tremor, oedema, nausea, have proved inadequate or have Starting dose is 40mg/kg/day. abdominal pain, blurred vision, diplopia, nystagmus. Rare: not been tolerated. Maintenance doses recommended in encephalopathic symptoms, angioedema, urticaria, optic neuritis, optic relation to body weight are: atrophy. Monotherapy in the treatment 10-15kg: vigabatrin 0.5-1g/day of infantile spasms (West's 15-30kg: vigabatrin 1-1.5g/day Visual field defects: reported in ~1 in 3 patients receiving vigabatrin. syndrome). 30-50kg: vigabatrin 1.5-3g/day The degree of visual field restriction may be severe. Most cases have >50kg: vigabatrin 2-3g/day been asymptomatic − this effect can only be reliably detected by Vigabatrin should only be systematic perimetry which is usually possibly only in patients with a initiated by a specialist in When used as monotherapy for infantile developmental age of > 9 years. In children aged ≥ 3 years, a epileptology, neurology, or spasms (West’s Syndrome) the specifically developed method based on field specific Visual Evoked paediatric neurology, and recommended starting dose is Potentials is available from the manufacturer to test the presence of follow-up should be arranged 50mg/kg/day, which may be titrated over peripheral vision. This method has currently not been validated in the under supervision of one of one week if necessary. Doses of up to detection of vigabatrin attributed visual field defects. these specialists. 150mg/kg/day have been used. Electroretinography may be useful but should be used only in children < 3 years of age. Available data suggest that visual field defects are irreversible even after discontinuation of vigabatrin, hence it should only be used after careful assessment of the balance of benefits and risk compared with alternatives. Use in patient with any pre-existing clinically significant visual field defect is not recommended.

Interactions: used with phenytoin, decreases in phenytoin plasma concentrations have been observed. No clinically significant interactions have been demonstrated with carbamazepine, phenobarbital or valproate.

Plasma monitoring: there is no correlation between plasma concentration and efficacy.

138 Newer Drugs for Children with Epilepsy

Appendix 2 Treatment choices

Off license and off label prescribing is far more common in paediatric than in adult practice. This is a consequence of the limitations of existing drug labelling whereby many drugs are not licensed for use in children or for children of certain ages. The indications for which drugs are licensed may also be narrower for children than for adults. Thus in order to access adequate therapeutic choices, paediatricians prescribe drugs off label (drug not licensed for a child of that age, or for that indication, or in that formulation or at that dose) and more rarely off license (no UK licence exists). Off label and off licence prescribing is acceptable, within the limits of generally accepted good practice.. An indication of what is considered good prescribing practice in paediatrics is given in the Royal College of Paediatrics and Child Health publication, “Medicines for Children”, one aim of which is to “present current practice based on the authority of experts”. Although ideally prescribing should be based upon high quality research evidence, such evidence is often not available to support paediatric prescribing.

Medicines for children provides some general guidance on good practice in prescribing AEDs. Monotherapy is preferred: “drugs should be used alone and in sequence”, but treatment with two drugs can result in “significantly improve seizure control in 5-10% of children”. The use of three AEDs is not generally acceptable. It also states that routine blood monitoring of AED levels is not justified, and haematological and biochemical monitoring should only be undertaken if clinically indicated.

The Royal College of Paediatrics and Child Health’s formulary suggests the treatment choices shown in Table 56 for the various seizure types and Epilepsy syndromes and the licensed indications for the anti-epileptic drugs on the United Kingdom market are shown below (Medicines for Children. Royal College of Paediatrics and Child Health. London 1999). Table 56 Treatment choices for children for various seizure types and epilepsy syndromes †.

Seizure Type/Epilepsy First Choice Alternatives Syndrome Generalised Sodium valproate Gabapentin Tonic-clonic (tonic and/or Sodium valproate, Lamotrigine, phenobarbitone, phenytoin, clonic) Carbamazepine topiramate Atonic (astatic) Sodium valproate Clobazam, lamotrigine, phenytoin, topiramate Myoclonic Sodium valproate Clonazepam, lamotrigine Absence Sodium valproate Clonazepam, ethosuximide, lamotrigine Partial Carbamazepine Gabapentin, lamotrigine Simplex/Complex Carbamazepine Sodium valproate, topiramate, vigabatrin Infantile spasms (West Vigabatrin Nitrazepam, prednisolone, hydrocortisone or Syndrome) ACTH, sodium valproate Lennox-Gastaut Sodium valproate Carbamazepine, clobazam, lamotrigine, topiramate Landau-Kleffner Prednisolone Clobazam, lamotrigine, sodium valproate, vigabatrin † recommended by the Royal College of Paediatrics and Child Health (Medicines for Children, 1999).

139 Newer Drugs for Children with Epilepsy

Table 57 Licensed indications for anti-epileptic drugs Drug Indication Age group Conditions Posology Dosage attached titration Carbamazepine ● Partial Usually 10- (Tegretol) seizures 20mg/kg/day ● Generalised in several tonic-clonic divided doses 10-15 years 600-1000mg ● 100-200mg in divided initially doses ● Increment slowly 5-10 years 400-600mg ● 100-200mg daily in initially divided doses ● Increment slowly 1-5 years 200-400mg ● 100mg daily in initially divided doses ● Increment slowly Ethosuximide ● Absence Children over 500mg- ● 500mg daily (Emeside) seizures (Petit 6 years 2000mg daily for 4 to seven mal) even days when ● Increment of complicated 250mg daily with Grand every 5 to 7 mal days up to (Generalised maximum of tonic clonic 2000mg seizures) ● Control ● Myoclonic usually in seizures range 1000- 1500mg daily

Ethosuximide ● Absence Children over 500mg to ● 500mg daily (Zarontin) seizures (Petit 6 years 2000mg daily for 4 to seven mal) days ● Absence ● Increment of seizures (Petit 250mg daily mal) every 4 to 7 complicated days up to with Grand maximum of mal 2000mg (Generalised tonic clonic seizures) and other forms of epilepsy. However other AED needed in this case.

Infants and 250mg daily- ● 250mg daily children under 20mg/kg/day ● Small 6 increments usually to 20mg/kg/day

140 Newer Drugs for Children with Epilepsy

Gabapentin Add-on Over 12 years Patients who 900-1200mg ● 300mg on (Neurontin) therapy for have not daily day 1 ● Partial achieved ● 300mg twice seizures satisfactory daily on day 2 ● Partial control with or ● 300mg three seizures with who are times daily on secondary intolerant to day 3 generalisation standard ● Increment of anticonvulsant 300mg daily s used alone or until optimum in combination response up to a maximum of 2400mg daily 6-12 years As for children 25 to 35 10mg/kg/day over 12 years mg/kg/day on day 1 but only if risk- given in three 20mg/kg/day benefit is divided doses on day 2 considered 25- favourable. 35mg/kg/day Drug should be on day 3 initiated and Maintenance supervised by dose a neurological 900mg/day for specialist children weighing 26- 36kg 1200mg/day for children weighing 37- 50kg Children under Not 6 years recommended Lamotrigine Monotherapy Over 12 years Not Usually 100 – ● 25mg once (Lamictal) of recommended 200mg/day daily for 2 ● Partial as as a once weeks seizures monotherapy daily dose or ● 50mg daily ● Partial for those aged two divided for 2 weeks seizures with under 12 doses ● Increment of secondary 50-100mg generalised every 1-2 tonic-clonic weeks until seizures optimum ● Primary response up to generalised 500mg/day tonic-clonic seizures

141 Newer Drugs for Children with Epilepsy

Add-on Over 12 years For patients ● 25mg once therapy of on sodium daily on ● Partial valproate with alternate days seizures or without for two weeks ● Partial other AED. or 12.5mg seizures with Usually 100- once daily secondary 200mg daily every day generalised as one single ● Increment of tonic-clonic or two divided 25-50mg every seizures doses 1-2 weeks until ● Primary optimum. generalised tonic-clonic seizures

Over 12 years For patients ● 50mg once on enzyme daily for two inducing anti- weeks epileptic ● 50mg twice drugs (AED) daily for 2 with or weeks without other ● Increment of AED except up to 100mg valproate. daily every 2-3 Usually 200- weeks until 400mg/day in optimum up to two divided a maximum of doses 700mg/day 2-12 years Do not give if For patients ● 0.15mg/kg calculated on valproate once daily for dose is less with or two weeks than 1mg/day without AED. ● 0.3mg/day (see last Usual for weeks 3 column) maintenance and 4 1-5mg/kg/day ● Increment of 0.3mg/kg every 1-2 weeks until optimum to maximum of 5mg/kg daily as one or two divided doses 2-12 years For patients 0.6mg/kg/day on enzyme in two divided inducing AED doses for 2 with or weeks, without other 1.2mg/kg/day AED except for 2 weeks. valproate. Maximum Usual increment of maintenance 1.2mg/kg 5- every 1-2 15mg/kg/day weeks.

142 Newer Drugs for Children with Epilepsy

Oxcarbazepin Monotherapy Recommende 8- ● 8- e and adjunctive d for use in 10mg/kg/day 10mg/kg/day (Trileptal) therapy children aged in two divided in two divided ● Partial 6 years and doses to doses seizures above maximum of ● Increment of ● Partial 46mg/kg/day maximum of seizures with 10mg/kg/day secondary at weekly generalised intervals to a tonic-clonic maximum daily seizures dose of 46mg/kg/day Phenytoin ● Partial Infants and 5mg/kg/day in ● 5mg/kg/day (Epanutin) seizures children two divided ● Increment to ● Tonic-clonic doses to maximum of seizures maximum of 300mg daily ● Combination 300mg daily Primidone ● Partial Children over 750-1500mg ● 125mg once (Focal) 9 years usually daily in the seizures in two divided evening ●Generalised doses ● Increment by (Grand mal) 125mg daily myoclonic every 3 days jerks until 500mg daily ● Increment by 250mg daily to maximum of 1.5g total daily dose Children 6-9 750-1000mg ● 125mg once years in two divided daily in the doses evening ● Increment by 125mg daily every 3 days until 500mg daily ● Increment by 125mg to maximum of 1g total daily dose Children 2-5 500-750mg ● 125mg once years in two divided daily in the doses evening ● Increment by 125mg daily every 3 days until 500mg daily ● Increment by 125mg to maximum of 750mg total daily dose

143 Newer Drugs for Children with Epilepsy

Children up to 250-500mg ● 125mg once 2 years in two divided daily in the doses evening ● Increment by 125mg daily every 3 days until 500mg daily Tiagabine Add-on Children over For patients 10mg – First dose with therapy of 12 years only not controlled 45mg/day breakfast and ● Partial by optimal second dose seizures doses of at with evening ● Partial least one other meal seizures with AED ● 5mg twice secondary daily for week generalised 1 seizures ● 5mg morning and 10mg evening for week 2 ● 10 mg morning and evening for week 3 ● 15 mg morning and evening for week 4 ● For patients taking enzyme- inducing AED usual maintenance is 30- 45mg/day with doses daily doses above 30mg given in three divided doses ● For patients not on enzyme- inducing AED, maintenance dose expected to be in the range of 30mg/kg

144 Newer Drugs for Children with Epilepsy

2-12 years For patients ● 0.6mg/kg on enzyme- given as two inducing AED divided doses with or for two weeks without other ● 1.2mg/kg for AED except 2 weeks given valproate as two divided doses ● Increments of 1.2mg/kg every 1-2 weeks until optimum to maximum of 15mg/kg as two divided doses Under 2 years Not recommended Topiramate Add-on Over 16 years 200mg per ● 25mg daily therapy of day minimum for one week ● Partial 200mg to ● Increment of seizures 400mg daily 25-50mg at 1- ● Partial in two divided 2 weekly seizures with doses intervals in two secondary divided doses generalised until optimum seizures to 800mg per ● Primary day generalised tonic-clonic seizures ● Seizures associated with Lennox- Gastaut Syndrome 2-16 years 5 to ● 25mg nightly 9mg/kg/day in for the first two divided week doses ● Increment of 1 to 3 mg/kg/day in two divided doses at 1-2 weekly intervals (exceptionally up to 30mg/kg/day0

145 Newer Drugs for Children with Epilepsy

Valproate ● Partial Children 15mg/kg/day ● 15mg/kg/day (Convulex) seizures (undefined) to ● Increment of ● Generalised 30mg/kg/day 5-10mg/kg/day seizures in 2 to 4 up to divided doses 30mg/kg/day (slow increase) ● Increase or decrease dose if concomitant AED used (no details given) Valproate ● Partial Children over 20- ● 400mg/day (Epilim seizures 20kg 30mg/kg/day ● Spaced Chrono) ● Generalised Increment seizures ● usually to 20- Other epilepsy 30mg/kg/day and maximum of 35mg/kg/day Children under Formulation 20kg not recommended Valproate ● Partial Children over 400mg/day to ● 400mg/day (Epilim EC) seizures 20kg 35mg/kg ● Spaced ● Generalised body weight Increment seizures ● usually to 20- Other epilepsy 30mg/kg/day and maximum of 35mg/kg/day Children under 20mg/kg/day ● 20mg/kg/day 20kg ● Increment in severe cases but plasma level monitoring is required ● Above 40mg/kg/day clinical and haematologica l parameters required Valproate As with Epilim (Epilim Syrup) EC

146 Newer Drugs for Children with Epilepsy

Vigabatrin ● Partial Children (age Add-on when ● Bodyweight ● 40mg/kg/day seizures not defined) other 10-15kg; 0.5- initailly ● Partial appropriate 1g/day seizures with combinations ● Bodyweight secondary are inadequate 15 to 30kg; 1- generalisation or intolerable 1.5g/day s Monotherapy ● Bodyweight for Infantile 30-50kg; 1.5- spasms (West 3g/day Syndrome) ● Bodyweight ● To be >50kg; 2- initiated by a 3g/day specialist in Upper dose epileptology, not to be neurology or exceeded paediatric neurology ● Follow-up by a specialist ● Gradual withdrawal if ineffective

Infants (age Monotherapy 50mg/kg/day- ● 50mg/kg/day not defined) for Infantile 150mg/kg/da ● Increment spasms (West y over a period Syndrome) of one week ● To be up to initiated by a 150mg/kg/day specialist in epileptology, neurology or paediatric neurology ● Follow-up by a specialist ● Gradual withdrawal if ineffective

Appendix 3 Influential factors for adverse effects of AEDs in children

Factors (Table 58) contributing to children having different adverse effect profiles to adults include the following:

1. During the neonatal and infantile periods, maturation of the gastro-intestinal system is still highly active, leading to substantial changes in gastro-intestinal pH, gastric emptying, enzymic activity and intestinal flora.235-237 From a theoretical perspective, it is to be expected that the pharmacokinetic profile of drugs would be highly variable and different to that of adults in this developmental period. This may explain the reported erratic absorption of phenytoin and phenobarbitone in the neonates.238 Unfortunately given the increasing difficulty in undertaking clinical studies in infancy, there have been few recent studies on the subject.

147 Newer Drugs for Children with Epilepsy

2. Changes in body fat ratio will also alter the distribution of the various antiepileptic drugs due to changes in volume of distribution. Lipophilic drugs would be expected to have a lower volume of distribution in neonates than in adults and older children due to the higher total body water to total body fat ratio in the younger subjects. However as infants also have lower albumin levels than older subjects, other factors such as extent of protein binding will alter the apparent volume of distribution, making predictions difficult. For example phenytoin and valproic acid are highly protein bound. Therefore clinical experience and close monitoring is necessary particularly with the newer anti-epileptic agents. 3. Changes in renal function 4. Changes in hepatic metabolic activity Table 58 Putative factors for altered pharmacokinetics of AEDS in infancy and childhood. Factor Neonates/Infants Children Renal elimination Lower† Same† Metabolic activity Cytochrome P monooxygenase Lower Higher† Uridine Diphosphate glucuronyltransferase Lower Same Albumin levels and protein binding Lower Same † Activity or concentration levels relative to adults.

Renal function reaches that of adults by 2 to 3 years of age but is only about a quarter at birth and 50-75% at 6 months of age. The extents of renal elimination of antiepileptic drugs are shown in Figure 8.

100

% Elimination 40

20 HEPATIC

0 RENAL

Phenytoin Tiagabine Primidone Vigabatrin Felbamate Topiramate Zonisamide Gabapentin Lamotrigine Valproic acid Phenobarbital Ethosuximide Levetiracetam Oxcarbazepine Carbamazepine Drug

Figure 8 Relative percentage renal and hepatic elimination of anti-epileptic drugs.

148 Newer Drugs for Children with Epilepsy

The differences in metabolic and pharmacokinetic profiles of the newer anti-epileptic agents are often promoted as justification for preferring the newer agents over the older AED since efficacy may be similar. While some of the newer agents have a lower propensity for drug- drug interactions, have linear pharmacokinetics and are less reliant on a single clearance pathway, the extent to which these translate in clear clinical benefits is debatable. (See Appendix 5 for interactions with oral contraceptives). For example, gabapentin is essentially completely eliminated renally and is therefore not susceptible to hepatic enzyme induction or inhibition interactions. This is often perceived to be an advantage. However, it has also been suggested239 that drugs which are less reliant on a single route of clearance (hepatic or renal) may be preferable to those that are eliminated by one route only (e.g oxcarbazepine versus carbamazepine). This argument is only valid in the presence of one organ dysfunction, most notably renal impairment. Despite the debate, less reliance on hepatic elimination is generally an advantage, particularly when inducible metabolic enzymes are involved.

The complexity of the likely drug-drug interactions between AED is shown in the interaction matrix (Table 59). This indicates that it may often be more profitable to consider the drug interaction profile rather than any single drug-drug interaction.

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Table 59 Matrix showing interactions between antiepileptic drugs

Gabapenti Drug 1 Carbamazepine Lamotrigine Levetiracetam Oxcarbazepine Phenobarbitone Phenytoin Primidone Tiagabine Topiramate* Valproic acid Vigabatrin Drug 2 n

Carbamazepin P0, S↑, NCS(2), NCS(2), O Ф(2)(1) (M), (2) (2) (2) ? (2) (2)?, A(2) NCS(2) e E(1), E(1) (1) Gabapentin O P0(2) Ф(2)(1) O O O A(2) Ф(2)(1) E(2)P0(1) E(2) Lamotrigine P0, S↑, E(2), P0(1) P0(1) E(2) P0(1) P0(1) P0(1) A(2) P0(1) P0(1) P0(1) ↓(2) P0(1) Ф(2)(1) Levetiracetam Ф(2)(1) Ф(2)(1) Ф(2)(1) Ф(2)(1) Ф(2)(1) Ф(2)(1)A(2) P0(2) (1), Ф(1), (M) Oxcarbazepine (M), (1) P0(2) (1), (M) (M) A(2)

Phenobarbiton NCS(2), (1) O E(1) P0(2) Ф(2)(1) (2), (M) ? NCS(2) A(2) NCS(2) e E(1) E(1) P0(2) NCS(2), NCS(2)*1 (1)(2), Phenytoin (1) ? O Ф(2)(1) (2), (M) ? A(2) , ?, A(2) ↓(1) E(1) (1) ? Primidone (1) O E(1) P0(2) Ф(2)(1) A(1) E(1) NCS(2) A(2) NCS(1), NCS(1), NCS(1), Tiagabine P0(2) E(2) A(2) NCS(1) E(2) E(2) E(2) NCS(1)*1, Topiramate NCS(1), (2) P0(2) NCS(1) NCS(1) NCS(2),(1) (2) Ф(2), (M) Valproic acid O P0(2) A(1) Ф(2)(1),A(1) A(1) ?, A(1) A(1) A(1) NCS(2),(1) A(1) (1)?, A(1) A(1) Vigabatrin NCS(1) P0(2) NCS(1) (1)(2), ? NCS(2) A(2) Ф: No effect on the drug shown in brackets. O: No interaction be found to date. : Increases the plasma concentration of the antiepileptic shown in brackets. : Decreases the plasma concentration of the antiepileptic shown in brackets A: Pharmacodynamic effect of the drug is altered, so clinical observation is recommended Cl↑: Increases the clearance of the drug shown in brackets Cl↓: Decreases the clearance of the drug shown in brackets E: Increases the metabolism of drug shown. M: The monohydroxy derivative of oxcarbazepine, the pharmacologically active metabolite. Newer Drugs for Children with Epilepsy

NCS: Any interaction likely to be not clinically significant. P: Protein binding sites. P0 No effect on protein binding site. Pc Competes for protein binding site. S↑: Side effect of drug enhanced. ?: Significance and direction of reported interaction unclear, more work needed. ↑ effect enhanced. ↓ effect inhibited. *1: some patients may show increased plasma concentrations of Phenytoin; Monitoring of phenytoin levels advised.

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Appendix 4 Long-term adverse effects

While short-term adverse events of moderate frequency are generally adequately captured by short-term clinical trials, the rarer and/or longer-term adverse effects are not. Adverse effects, which may be cumulative and which have been suggested for some AEDs are considered below with particular reference to paediatric patients.

Effect on body weight, mineral bone density and growth

All three of these potential long-term adverse effects of AED are of particular importance in the pharmacotherapy of children. Valproate240 and gabapentin241 appear the most prone to induce weight gain, which can be marked and progressive. Carbamazepine may also be associated with some weight gain, while lamotrigine and phenytoin appear to have no effect.242 Topiramate, on the other hand, may reduce food intake and cause weight loss.243 Marked weight gain may lead to obesity and marked weight loss to impaired growth. Adolescent girls in particular may consider such events sufficiently detrimental to become non-compliant with therapy.

Long-term use of phenytoin, phenobarbital and primidone have been associated with decreased bone density. A suggested mechanism is that via potent induction of hepatic metabolic enzymes they increase the breakdown of vitamin D and hence interfere with bone mineralization. From this it has been assumed that AEDs which do not induce the cytochrome P450 system would be free from this adverse effect. A recent study has shown that this inference is flawed.244 In their study comparing valproate monotherapy with phenytoin monotherapy and control subjects matched for age and sex, bone mineral density decreased by 13% in the valproate group and 13% in the phenytoin group compared to the control group. In a substantial number of patients the demineralisation was marked enough for the subjects to be classified as having osteoporosis. Elevation of serum calcium level and suppression of formation of 1,25-dihydroxy vitamin D through a negative feed-back loop has been suggested. However, more recent work points to a direct effect of the AED on bone cells.245 Unlike phenytoin, valproate has no significant hepatic enzyme inducer activity. Some case reports suggest these effects may result in an increased likelihood of bone fracture but confirmation through controlled studies is clearly needed.236,246

Whether AED effects on body weight and bone mineral density alter growth in children has not been explored in detail. However one observational study247 of 103 children over 6-71 months, suggests that lamotrigine does not interfere with growth, an observation consistent with its lack of effect on weight. Longer-term comparative studies are necessary to confirm this. Similar studies on topiramate and felbamate, AEDs most frequently associated with weight loss, are required.

Cognitive effects

A substantial literature has accumulated on this topic largely characterised by inconclusive or contradictory observations contingent upon methodological difficulties and pitfalls associated with this line of enquiry.248 Although certain AEDs appear to be involved more than others Newer Drugs for Children with Epilepsy as cause of cognitive impairment it is probable that no single drug causes impairment in every patient and that no drug can be assumed never to impair. Subgroups of patients at higher risk cannot be defined.

Phenobarbitone, primidone and topiramate are generally perceived as having more detrimental cognitive effects than the other anti-epileptic agents in common use.239 Carbamazepine, phenytoin, sodium valproate (valproic acid) and zonisamide fall in an intermediate group in this respect while gabapentin, lamotrigine, tiagabine, levetiracetam, vigabatrin and oxcarbazepine are regarded as having little or no effect (Table 60). However the evidence base is of low quality and controlled studies have generally been short-term (for up to 12 weeks) so that longer-term effects have not been reliably probed. Despite case reports of impairment of memory and concentration, placebo-controlled studies using batteries of cognitive tests and tests of mood and adjustment, have failed to show any adverse effects for vigabatrin and tiagabine;161,249 whether the newer AEDs are associated with adverse cognitive effects in the longer term remains to be answered through controlled studies. Table 60 Potential for adverse cognitive effects of commonly used anti-epileptic drugs. Marked Some Little or None Phenobarbitone Carbamazepine Gabapentin Primidone Phenytoin Lamotrigine Topiramate Valproic acid Levetiracetam Zonisamide Oxcarbazepine Tiagabine Vigabatrin

Fatal adverse drug reactions

Reported fatal adverse drug reactions to AEDs are rare, and are unlikely to occur with a short term clinical trial. Anticonvulsants, however, were associated with 65 out of 390 suspected fatal adverse drug reactions reported via the UK Committee on Safety of Medicines Yellow Card Scheme between 1964 and 2000 (Clarkson and Choonara250). Anticonvulsants were the class of drugs most often associated with fatalities. Although there is probably under- reporting, association of a drug does not necessarily indicate a causal link. Equally adverse drug reactions are under-reported, so fatalities related to anticonvulsants may have been underestimated. It is notable that almost one third of the fatalities, 20 deaths, were associated with newer drugs, despite the shorter duration of use.. Valproate was associated with 31 deaths, including 21 with liver failure. Some of these were in young children in whom caution in prescribing valproate is advised, and hence lower rates of hepatoxicity might be expected in future. As the authors suggest, prospective studies of both older and newer AEDs are required.

Antiepileptic drugs and polycystic ovarian syndrome.

The polycystic ovarian syndrome is characterised by enlarged ovaries with multiple follicular cysts. Patients with the syndrome present with chronic anovulatory cycles and symptoms of hyperandrogenesis, notably hirsutism, acne and menstrual irregularities. Associated endocrine and metabolic effects include elevation of the ratio of levels of luteinizing hormone to follicle stimulating hormone, insulin resistance, abnormal lipid profiles and obesity. Valproate therapy has been reported to increase the rate of occurrence of the polycystic

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ovarian syndrome (Isojarvi et al., 1993251), which is already substantially higher than in the non-epileptic population (Herzog, 2001252). Other antiepileptic drugs do not seem to be associated with any substantial risk of the syndrome. In fact it has been reported that switching from valproate to lamotrigine therapy led to reversal of features of the syndrome (Isojarvi, 1998253).

Appendix 5 Drug interactions with the contraceptive pill.

One potential adverse effect of AEDs is upon the metabolism of contraceptive steroids leading to potential loss of contraceptive cover with oral contraceptives and implants. A prospective Northern England population-based study of a cohort of 400 women with epilepsy taking AEDs attributed failure of oral contraception as the cause of unplanned pregnancy found at a rate of > 50% among 300 women responding to interview254.

Many of the anti-epileptic drugs are potent inducers of liver enzymes also involved in the metabolism and clearance of oral contraceptive steroids. For example, it has been shown that phenytoin and carbamazepine can reduce the area under the blood level curve of ethinylestradiol and levonorgestrel by as much as half.255,256 The cytochrome monooxygnase isoenzymes, in particular the CYP3A family, are usually involved.257 As the levels of the steroids drop, contraceptive cover is impaired.

It has been often assumed that for AEDs with less important hepatic metabolism and enzyme induction so the risk of interaction with contraception is lowered. However the apparently clear hepatic mechanism of interaction between some AEDs and oral or implanted steroid contraceptive failure does not necessarily infer lack of interaction from AEDs that do not induce liver enzymes. For oxcarbazepine (structurally similar to carbamazepine258) the hepatic route of elimination is proportionately less than for carbamazepine (Figure 8 page148), and it has apparently little effect on the cytochrome enzymes, including CYP3A and does not undergo metabolic auto-induction. This altered metabolic profile relative to carbamazepine leads to more stable pharmacokinetics, less susceptibility of its own metabolism to other enzyme inducers such as erythromycin259 and verapamil260 but this is not translated into a lack of interaction with the contraceptive steroids. Indeed, recent studies suggest that oxcarbazepine reduces the plasma concentrations of both the oestrogen and progestogen component of oral contraceptive steroids sufficiently to lead to contraceptive failure.261 The mechanism of this interaction remains to be confirmed.

Liver metabolism accounts for only about 20% of topiramate’s clearance, which is predominantly renal (Figure 8 page 148). However, it too has been shown to interfere with the metabolism of oral contraceptive steroids sufficiently to suggest a risk of contraceptive failure. Serum levels of the steroids may drop by a fifth to a third.262 Again the mechanism of interaction is unclear as enzyme induction appears to be an insufficient explanation.263

Current summaries of product characteristics suggest that of the newer antiepileptic agents, oxcarbazepine and topiramate may reduce the efficacy of the contraceptive pill.

Some of the newer anti-epileptics are less prone to this interaction with contraceptive agents. Indeed there is positive evidence to suggest that gabapentin, lamotrigine, sodium valproate and tiagabine are free from it and therefore may have an advantage, at least in this respect, over AEDs that are not.

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Evidence in support of absence or presence of an interaction is identified in Table 61.

Table 61 Interaction of AEDs & oral contraceptives with potential loss of contraceptive cover. Likelihood Antiepileptic References (First author and Year) Evidence suggesting likely to Carbamazepine Crawford (1990)256 Phenobarbitone Phenytoin Odlind (1986)264; Haukkamaa(1986)265 (1986); Orme (1990)255 Primidone Oxcarbazepine Fattore (1999)261 Topiramate Doose (1994)262; Rosenfeld (1997)263 Evidence Uncertain Ethosuximide Felbamate Positive evidence against any interaction Gabapentin Eldon (1993 & 1998)266,267 Lamotrigine Holdich (1991)268 Sodium valproate Crawford (1985)269 Tiagabine Mengel (1994)270 Vigabatrin Bartoli (1997)271

Strategies, suggested in the literature, for dealing with this potential problem are (a) a switch to an antiepileptic agent which does not interfere with the contraceptive agent being used and (b) use of oral contraceptive agents with a higher estradiol content (to 50 micrograms or even higher if breakthrough bleeding still occurs). The optimal option would need to take account of the family history of the subject and whether the patient is stabilised on the anti-epileptic or contraceptive agent at the time when co-administration is considered.

Appendix 6 Teratogenecity. Epileptic women are more likely to give birth to children with congenital malformations, e.g. in a North of England prospective study of epileptic women taking AEDs malformations were reported significantly more common at 5% (95% CI 3.1-7.6%) than among the local population (odds ratio 2.15).254 Moreover it is generally accepted that the use of AEDs may increase this risk.272 Despite this increased risk the incidence of congenital abnormalities is still low although well-controlled studies of sufficient power to give precise risk data have not been undertaken both for ethical and pragmatic reasons. It is not surprising that there is no clear information on which of the newer AEDs, if any, is safer for use during pregnancy.

Current evidence about the teratogenicity of the older and newer AEDs is largely derived from preclinical animal studies and experience of clinical use and observational studies. Valproate is associated with a two fold increased risk of spina bifida (Table 62). Antiepileptic agents that render folate deficiency either through inhibition of dihydrofolate reductase or through an induced increase in utilisation of the vitamin, are often assumed to be teratogenic. Phenytoin, primidone, carbamazepine and phenobarbitone are the more potent metabolic

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enzyme inducers and folate supplementation is thought to reduce the risk of abnormalities from the use of these, but the evidence is not conclusive. Folate supplementation may lead to a reduction in the levels of some of the AEDs, most notably phenytoin, with potential loss of seizure control.273

Studies on the teratogenic potential of the newer AEDs are sparse and generally involve small numbers of subjects. In one study three of 46 newborns exposed in-utero to lamotrigine developed serious congenital abnormalities (Mackay, 1997274) while in a second report, two of 37 mothers exposed to the drug delivered babies with abnormalities. One case report describes minor multiple abnormalities in the newborn of a mother receiving topiramate monotherapy (Hoyme, 1998275). Growth deficiency and hirsutism were noted. Because oxcarbazepine, unlike carbamazepine, does not interfere with folate metabolism and is not metabolised to the 10-11 epoxide, it is sometimes assumed that it is less likely to be teratogenic. This inference is unsafe and serious malformations have been reported although a follow-up of 947 patients suggests that the risk is small (Friis et al., 1993276).

Vigabatrin is unique among the AED in being associated with a high incidence of visual field defects in long-term users. The adverse effect can be disabling and as many as a third of those on the drug may be affected. While the effect of in-utero exposure is unclear, the results of studies on albino rabbits suggest that retino-toxicity may be a problem. One case report describes multiple congenital abnormalities, including anophthalmia following exposure to vigabatrin, carbamazepine and dexamethasone during pregnancy (Lindhout and Omtzigt, 1994277).

Table 62 summarises relevant information about the risk of teratogenicity and foetotoxicity of current AEDs. Table 62 Teratogenecity of AEDs Effect on folate Observational studies, including case Drug Preclinical and animal data metabolism and reports activity Foetotoxic in rodents. Delayed Gabapentin ossification (McLean, 1999278). SPC suggests otherwise. Animal studies do not suggest any Several reports suggest some risk of Weak inhibitor of teratogenic effects (SPC). abnormalities to foetuses exposed to the dihydrofolate Lamotrigine drug (Mackay, 1997274; Richens, 1994279; reductase (Chang, Palmieri, 2002280). 1998281). Animal studies suggest a lower Serious birth defects, including cleft Does not interfere potential for teratogenicity. However, palate, possible (SPC). with folate Oxcarbazepine embryo mortality, delayed growth metabolism and malformations reported. (Isojarvi, 1997282). Reports of increased incidence of Enzyme induction congenital malformations including cleft leads to increased Phenytoin lip/palate and heart malformations. Foetal folate requirement growth retardation and mental deficiency and deficiency. reported (SPC). Possible increase incidence of congenital Enzyme induction malformations (SPC). leads to increased Primidone folate requirement and deficiency. No evidence of teratogenicity in Of 27 women exposed to tiagabine during animals (SPC). However, there is pregnancy, nine gave birth to live babies some evidence of peri and post-natal with only one anomaly (hip dislocation), Tiagabine toxicity (SPC). most likely not linked to the drug. Four had spontaneous miscarriages (Leppik, 1999283). Teratogenic in mice, rats and rabbits. Case report of multiple minor Right-sided digit abnormalities in rats abnormalities (Hoyme, 1998275). Topiramate and rib and vertebral malformations Hypospadias (abnormal siting of urethra) in rabbits (Glauser, 1999284). in males infants reported (SPC).

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Increased incidence of congenital malformations reported (SPC). Reported Valproic acid associated with 2 fold increased risk of spina bifida.285 No teratogenicity seen in rats or Increased incidence of abnormalities No significant rabbits but incidence of cleft palate reported (SPC). effect on folate Vigabatrin increased in rabbits (SPC). metabolism. Retinotoxicity is a possibility. SPC: Summary of Product Characteristics

The British Epilepsy Association has produced information for women about epilepsy and pregnancy.286

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Appendix 7 Search strategies.

Effectiveness search strategies

Source - Cochrane Library (CCTR) 2002 Issue 1

(((LABILENO or LAMICTAL) or LAMOTRIGINE) or LTG) (LAMICITIN or DICHLOROPHENYLTRIAZINEDIYLDIAMINE) EPILEP* EPILEPSY*:ME SEIZURE* SEIZURES*:ME CONVULSION* (#1 or #2) ((((#3 or #4) or #5) or #6) or #7) (#8 and #9) (((GABAPENTIN or GBP) or NEURONTIN) or NEUROTONIN) (#9 and #11) ((LEVETIRACETAM or ETIRACETAM) or KEPPRA) (#9 and #13) ((OXCARBAZEPINE or TRILEPTAL) or OXOCARBAZEPINE) (#9 and #15) ((TIAGABINE or GABITRIL) or TIABEX) (#9 and #17) (((TOPIRAMATE or EPITOMAX) or TOPAMAX) or TOPIMAX) (#9 and #19) ((VIGABATRIN or SABRIL) or SABRILEX) (#9 and #21) (BW 430C) BW-430C ((((((#10 or #12) or #14) or #16) or #18) or #20) or #22)

Source - Medline (Ovid)1966 - October 2001

1 randomized controlled trial.pt. (33379) 2 controlled clinical trial.pt. (6309) 3 randomized controlled trials/ (8400) 4 random allocation/ (5181) 5 double blind method/ (12409) 6 single blind method/ (2078) 7 or/1-6 (54307) 8 (animal not human).sh. (263556) 9 7 not 8 (50867) 10 clinical trial.pt. (67258) 11 exp clinical trials/ (21222) 12 (clin$ adj25 trial$).ti,ab. (21031) 13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab. (11868) 14 placebos/ (2187) 15 placebo$.ti,ab. (14464) 16 random$.ti,ab. (58660) Newer Drugs for Children with Epilepsy

17 research design/ (6838) 18 or/10-17 (130936) 19 18 not 8 (122599) 20 19 not 9 (73326) 21 9 or 20 (124193) 22 lamotrigine.mp. (503) 23 (labileno or lamictal or ltg).mp. [mp=title, abstract, registry number word, mesh subject heading] (113) 24 bw 430c.tw. (0) 25 bw 430 c.tw. (0) 26 bw 430c78.tw. (0) 27 84057-84-1.rn. (369) 28 or/22-27 (512) 29 exp epilepsy/ (9541) 30 epilep$.ti,ab. (7616) 31 seizure$.ti,ab. (7702) 32 convuls$.ti,ab. (1592) 33 or/29-32 (13421) 34 33 and 28 and 21 (100) 35 gabapentin.mp. (514) 36 goe 3450.tw. (1) 37 go 3450.tw. (0) 38 ci 945.tw. (7) 39 1 aminomethyl cyclohexaneacetic acid.tw. (6) 40 (neurontin or neurotonin or gbp).tw. (146) 41 "60142-96-3".rn. (392) 42 or/35-41 (585) 43 42 and 21 and 33 (67) 44 etiracetam.mp. (38) 45 1 1 carbamoylpropyl 2 pyrrolidinone.tw. (0) 46 alpha ethyl 2 oxo 1 pyrrolidineacetamide.tw. (0) 47 (etiracetam or keppra or levetiracetam).tw. (50) 48 lo 59.tw. (0) 49 ucb 6474.tw. (0) 50 ucb I059.tw. (0) 51 "ucb I 059".tw. (0) 52 102767-28-2.rn. (0) 53 or/44-52 (54) 54 53 and 21 and 33 (24) 55 (lamicitin or dichlorophenyltriazinediyldiamine).tw. (0) 56 28 or 55 (512) 57 56 and 33 and 21 (100) 58 oxcarbazepine.mp. (101) 59 gp 47680.tw. (0) 60 (oxocarbazepine or trileptal).tw. (3) 61 28721-07-5.rn. (56) 62 or/58-61 (102) 63 62 and 21 and 33 (29) 64 tiagabine.mp. (164)

159 Newer Drugs for Children with Epilepsy

65 (gabitril or tiabex).tw. (7) 66 "nnc 05 0328".tw. (0) 67 nnc 328.tw. (1) 68 "no 05 0328".tw. (0) 69 "no 05 0329".tw. (0) 70 no 328.tw. (1160) 71 no 329.tw. (1060) 72 115103-54-3.rn. (107) 73 or/64-72 (2358) 74 73 and 33 and 21 (54) 75 topiramate.mp. (259) 76 (epitomax or topamax or topimax).tw. (7) 77 mcn 4853.tw. (0) 78 rwj 17021.tw. (0) 79 rwj 17021-000.tw. (0) 80 97240-79-4.rn. (197) 81 or/75-80 (259) 82 81 and 21 and 33 (73) 83 vigabatrin.mp. (321) 84 (sabril or sabrilex).tw. (6) 85 3 amino 5 carboxyhexene.tw. (0) 86 4 amino 4 ethenylbutyric acid.tw. (0) 87 4 amino 4 vinylbutanoic acid.tw. (0) 88 4 amino 5 hexenoic acid.tw. (0) 89 4 aminohex 5 enoic acid.tw. (0) 90 4 vinyl 4 aminobutyric acid.tw. (0) 91 4 vinylaminobutyric acid.tw. (0) 92 4 vinylgaba.tw. (0) 93 gamma vinyl 4 aminobutyric acid.tw. (0) 94 gamma vinyl gaba.tw. (34) 95 gamma vinylgaba.tw. (1) 96 gamma vinyl gamma aminobutyric acid.tw. (5) 97 mdl 71754.tw. (1) 98 n vinyl 4 aminobutyric acid.tw. (0) 99 n vinyl gaba.tw. (0) 100 n vinyl gamma aminobutyric acid.tw. (0) 101 rmi 71754.tw. (1) 102 rmi 71890.tw. (0) 103 60643-86-9.rn. (238) 104 or/83-103 (323) 105 104 and 33 and 21 (65) 106 57 or 43 or 54 or 63 or 74 or 82 or 105 (281)

Source – MEDLINE and PreMEDLINE (Silverplatter) 1999 – Mar 2002

No. Records Request 1 3481 PT = "RANDOMIZED-CONTROLLED-TRIAL" 2 537 PT = "CONTROLLED-CLINICAL-TRIAL" 3 1295 "Randomized-Controlled-Trials"/ all subheadings

160 Newer Drugs for Children with Epilepsy

4 1335 "double-blind-method"/ all subheadings 5 247 "single-blind-method"/ all subheadings 6 6580 PT = "CLINICAL-TRIAL" 7 3007 explode "Clinical-Trials"/ all subheadings 8 2354 (clin* near trial*) in ti,ab 9 1862 (singl* or doubl* or tripl* or trebl*) near (blind* or mask*) 10 183 "Placebos"/ all subheadings 11 1689 placebo* in ti,ab 12 7106 random* in ti,ab 13 651 "Research-Design"/ all subheadings 14 623 "Random-Allocation" 15 7425 (control* near (trial* or stud*)) in ti,ab,mesh 16 375 crossover in ti,ab,mesh 17 8297 explode "Evaluation-Studies"/ all subheadings 18 14053 tg=comparative-study 19 33676 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 20 3355 editorial in pt 21 2387 comment in pt 22 7626 letter in pt 23 42015 TG = "ANIMAL" 24 113442 TG = "HUMAN" 25 27770 #23 not (#23 and #24) 26 28283 #19 not (#20 or #21 or #22 or #25) 27 0 labileno 28 0 lamictal 29 45 lamotrigine 30 0 lamicitin 31 0 dichlorophenyltrazinediyldiamine 32 10 ltg 33 0 bw 430c 34 0 bw 430 c 35 0 bw 430c78 36 57 gabapentin 37 2 neurontin 38 0 neurotonin 39 10 gbp 40 0 goe 3450 41 0 go 3450 42 0 ci 945 43 1 1 aminomethyl cyclohexaneacetic acid 44 13 etiracetam 45 1 keppra 46 33 lev 47 0 levetiracetum 48 0 1 1 carbamoylpropyl 2 pyrrolidinone 49 0 alpha ethyl 2 oxo 1 pyrrolidineacetamide 50 0 lo 59 51 0 ucb 6474

161 Newer Drugs for Children with Epilepsy

52 0 ucb I059 53 0 ucb I 059 54 15 oxcarbazepine 55 0 gp 47680 56 2 trileptal 57 0 oxocarbazepine 58 20 tiagabine 59 0 gabitril 60 0 nnc 05 0328 61 0 nnc 328 62 0 no 05 0328 63 0 no 05 0329 64 0 no 328 65 0 no 329 66 0 tiabex 67 42 topiramate 68 0 epitomax 69 0 mcn 4853 70 0 rwj 17021 71 0 rwj 17021-000 72 0 topamax 73 0 topimax 74 46 vigabatrin 75 0 3 amino 5 carboxyhexene 76 0 4 amino 4 thenylbutyric acid 77 0 4 amino 5 hexenoic acid 78 0 4 aminohex 5 anoic acid 79 0 4 vinylaminobutyric acid 80 0 4 vinylgaba 81 0 gamma vinyl 4 aminobutyric acid 82 4 gamma vinyl gaba 83 0 gamma vinylgaba 84 0 gamma vinyl gamma aminobutyric acid 85 0 mdl 71754 86 0 n vinyl 4 aminobutyric acid 87 0 n vinyl gaba 88 0 n vinyl gamma aminobutyric acid 89 0 rmi 71754 90 0 rmi 71890 91 0 sabril 92 0 sabrilex 93 3 gvg 94 26 "84057-84-1" in cas 95 38 "60142-96-3" in cas 96 11 "28721-07-5;" in CAS 97 11 "115103-54-3" in cas 98 30 "97240-79-4" in cas 99 33 "60643-86-9" in CAS 100 26 84057-84-1 in cas

162 Newer Drugs for Children with Epilepsy

101 38 60142-96-3 in cas 102 13 33996-58-6 in cas 103 11 115103-54-3 in cas 104 11 28721-07-5 in cas 105 30 97240-79-4 in cas 106 38 60142-96-3 in cas 107 4 oxc 108 33 "Vigabatrin"/ all subheadings 109 3157 #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #7 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57 or #58 or #59 or #60 or #61 or #62 110 154 #63 or #64 or #65 or #66 or #67 or #68 or #69 or #70 or #71 or #72 or #73 or #74 or #75 or #76 or #77 or #78 or #79 or #80 or #81 or #82 or #83 or #84 or #85 or #86 or #87 or #88 or #89 or #90 or #91 or #92 or #93 or #94 or #95 or #96 or #97 or #98 111 148 #99 or #100 or #101 or #102 or #103 or #104 or #105 or #106 or #107 or #108 112 3215 #109 or #110 or #111 113 2607 #26 and #112 114 1042 explode "Epilepsy"/ all subheadings 115 790 epilep* in ti ab 116 814 seizure* in ti ab 117 153 convuls* in ti ab 118 1438 #114 or #115 or #116 or #117 *119 62 #113 and #118

Source – EMBASE (Ovid) 1980 – Feb 2002

1 randomized controlled trial/ (62250) 2 exp clinical trial/ (231444) 3 exp controlled study/ (1326226) 4 double blind procedure/ (42691) 5 randomization/ (3918) 6 placebo/ (56460) 7 single blind procedure/ (3541) 8 (control adj (trial$ or stud$ or evaluation$ or experiment$)).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name] (25280) 9 ((singl$ or doubl$ or trebl$ or tripl$) adj5 (blind$ or mask$)).mp. (62468) 10 (placebo$ or matched communities or matched schools or matched populations).mp. (94204) 11 (comparison group$ or control group$).mp. (90140) 12 (clinical trial$ or random$).mp. (396527) 13 (quasiexperimental or quasi experimental or pseudo experimental).mp. (757) 14 matched pairs.mp. (1278) 15 or/1-14 (1618664) 16 (lamicitin or dichlorophenyltriazinediyldiamine).mp. (0) 17 bw 430c.tw. (8) 18 bw 430 c.tw. (5) 19 bw 430c78.tw. (2)

163 Newer Drugs for Children with Epilepsy

20 (labileno or lamictal or lamotrigine or ltg).mp. (2927) 21 84057-84-1.rn. (2836) 22 or/16-21 (2927) 23 epilep$.mp. (43625) 24 seizure$.mp. (44049) 25 convulsion$.mp. (13276) 26 exp "seizure epilepsy and convulsion"/ (72221) 27 or/23-26 (83514) 28 15 and 22 and 27 (747) 29 (gabapentin or neurontin or neurotonin or gbp).mp. (2974) 30 goe 3450.tw. (3) 31 ci 945.tw. (12) 32 1 aminomethyl cyclohexaneacetic acid.tw. (16) 33 60142-96-3.rn. (2729) 34 go 3450.tw. (3) 35 or/29-34 (2980) 36 35 and 15 and 27 (501) 37 (etiracetam or keppra or levetiracetam).mp. (259) 38 1 1 carbamoylpropyl 2 pyrrolidineacetamide.mp. (0) 39 alpha ethyl 2 oxo 1 pyrrolidineacetamide.mp. (1) 40 lo59.mp. (5) 41 ucb 6474.mp. (3) 42 ucb I059.mp. (0) 43 "ucb I 059".mp. (0) 44 102767-28-2.rn. (259) 45 or/37-44 (259) 46 45 and 15 and 27 (108) 47 (oxcarbazepine or oxocarbazepine or trileptal).mp. (808) 48 gp 47680.tw. (12) 49 28721-07-5.rn. (796) 50 or/47-49 (808) 51 50 and 15 and 27 (252) 52 (tiagabine or gabitril or tiabex).mp. (782) 53 "nnc 05 0328".mp. (4) 54 nnc 328.mp. (2) 55 "no 05 0328".mp. (4) 56 "no 05 0329".mp. (1) 57 no 328.mp. (4290) 58 no 329.mp. (3935) 59 115103-54-3.rn. (768) 60 or/52-59 (8928) 61 60 and 15 and 27 (307) 62 (topiramate or epitomax or topamax or topimax or topiramate).mp. (1134) 63 mcn 4853.mp. (5) 64 rwj 17021.mp. (3) 65 rwj 17021-000.mp. (2) 66 97240-79-4.rn. (1124) 67 or/62-66 (1134) 68 67 and 15 and 27 (358)

164 Newer Drugs for Children with Epilepsy

69 (vigabatrin or sabril or sabrilex).mp. (2619) 70 3 amino 5 carboxyhexene.mp. (0) 71 4 amino 4 ethenylbutyric acid.mp. (0) 72 4 amino 4 vinylbutanoic acid.mp. (0) 73 4 amino 5 hexenoic acid.mp. (5) 74 4 aminohex 5 enoic acid.mp. (6) 75 4 vinyl 4 aminobutyric acid.mp. (1) 76 4 vinylaminobutyric acid.mp. (0) 77 4 vinylgaba.mp. (0) 78 gamma vinyl 4 aminobutyric acid.mp. (1) 79 gamma vinyl gaba.mp. (345) 80 gamma vinylgaba.mp. (12) 81 gamma vinyl gamma aminobutyric acid.mp. (23) 82 mdl 71754.mp. (9) 83 n vinyl 4 aminobutyric acid.mp. (0) 84 n vinyl gaba.mp. (0) 85 n vinyl gamma aminobutyric acid.mp. (0) 86 rmi 71754.mp. (10) 87 rmi 71890.mp. (0) 88 60643-86-9.rn. (2597) 89 or/69-88 (2647) 90 89 and 15 and 27 (758) 91 28 or 36 or 46 or 51 or 61 or 68 or 90 (1723)

Source – Science Citation Index (Web of Science) 1981 – Feb 2002

The search strategy was limited to the drug terms and epilepsy:

labileno or lamictal or lamotrigine or lamicitin or dichlorophenyltrazinediyldiamine or ltg or gabapentin or neurontin or neurotonin or gbp or goe or aminomethyl cyclohexaneacetic acid or levetiracetam or etiracetam or keppra or lev or lvt or carbamoylpropyl or pyrrolidineacetamide or ucb or oxcarbazepine or trileptal or oxocarbazepine or oxc or tiagabine or gabitril or nnc or tiabex or tgb or topiramate or tpm or epitomax or mcn or rwj or topamax or topimax or vigabatrin or carboxyhexene or ethenybutyric acid or vinylbutyric acid or vinylbutanoic acid or aminobutyric acid or vinylaminobutyric acid or hexenoic acid or enoic acid or vinylgaba or gamma vinyl or gamma vinylgaba or vinyl gaba or mdl or rmi or sabril or sabrilex or gvg and epilep* or seizure* or convulsion* National Research Register 2002 Issue 1 See Cochrane Library (CCTR) strategy

Search strategies for the decision analysis model

Existing models

Source - MEDLINE (Ovid) 1966 - March 2002 1 exp epilepsy/ (59840) 2 epilep$.ti,ab. (42684) 3 seizure$.ti,ab. (39297) 4 convuls$.ti,ab. (14151) 5 or/1-4 (86797)

165 Newer Drugs for Children with Epilepsy

6 markov$.mp. (2677) 7 monte carlo method/ (4890) 8 exp models statistical/ (58231) 9 exp decision support techniques/ (24727) 10 or/6-9 (85935) 11 5 and 10 (507) 12 limit 11 to human (452) 13 5 and 6 (15) 14 limit 13 to human (12) 15 9 and model$.ti,ab. (5589) 16 model$.ti,ab. (503151) 17 9 and 16 (5589) 18 modle$.mp. (9) 19 model$.mp. (689115) 20 6 or 7 or 19 (691092) 21 5 and 20 (5963) 22 limit 21 to human (2309) 23 limit 22 to yr=2000-2002 (488) 24 decision analysis.ti,ab. (1645) 25 5 and 24 (10) 26 from 25 keep 1-10 (10)

Economic evaluation

Source – MEDLINE (Ovid) 1966-Mar 2002

1 lamotrigine.mp. (1109) 2 (labileno or lamictal or ltg).mp. [mp=title, abstract, cas registry/ec number word, mesh subject heading] (329) 3 bw 430c.tw. (0) 4 bw 430 c.tw. (0) 5 bw 430c78.tw. (0) 6 84057-84-1.rn. (844) 7 or/1-6 (1195) 8 exp epilepsy/ (59957) 9 epilep$.ti,ab. (42769) 10 seizure$.ti,ab. (39371) 11 convuls$.ti,ab. (14160) 12 or/8-11 (86940) 13 gabapentin.mp. (976) 14 goe 3450.tw. (1) 15 go 3450.tw. (2) 16 ci 945.tw. (10) 17 1 aminomethyl cyclohexaneacetic acid.tw. (16) 18 (neurontin or neurotonin or gbp).tw. (402) 19 "60142-96-3".rn. (756) 20 or/13-19 (1221) 21 etiracetam.mp. (82)

166 Newer Drugs for Children with Epilepsy

22 1 1 carbamoylpropyl 2 pyrrolidinone.tw. (0) 23 alpha ethyl 2 oxo 1 pyrrolidineacetamide.tw. (1) 24 (etiracetam or keppra or levetiracetam).tw. (98) 25 lo 59.tw. (0) 26 ucb 6474.tw. (0) 27 ucb I059.tw. (0) 28 "ucb I 059".tw. (0) 29 102767-28-2.rn. (0) 30 or/21-29 (110) 31 (lamicitin or dichlorophenyltriazinediyldiamine).tw. (0) 32 7 or 31 (1195) 33 oxcarbazepine.mp. (305) 34 gp 47680.tw. (2) 35 (oxocarbazepine or trileptal).tw. (10) 36 28721-07-5.rn. (204) 37 or/33-36 (306) 38 tiagabine.mp. (329) 39 (gabitril or tiabex).tw. (8) 40 "nnc 05 0328".tw. (2) 41 nnc 328.tw. (1) 42 "no 05 0328".tw. (3) 43 "no 05 0329".tw. (1) 44 no 328.tw. (4967) 45 no 329.tw. (4604) 46 115103-54-3.rn. (222) 47 or/38-46 (9823) 48 topiramate.mp. (427) 49 (epitomax or topamax or topimax).tw. (8) 50 mcn 4853.tw. (2) 51 rwj 17021.tw. (1) 52 rwj 17021-000.tw. (1) 53 97240-79-4.rn. (325) 54 or/48-53 (427) 55 vigabatrin.mp. (1145) 56 (sabril or sabrilex).tw. (17) 57 3 amino 5 carboxyhexene.tw. (0) 58 4 amino 4 ethenylbutyric acid.tw. (0) 59 4 amino 4 vinylbutanoic acid.tw. (0) 60 4 amino 5 hexenoic acid.tw. (2) 61 4 aminohex 5 enoic acid.tw. (3) 62 4 vinyl 4 aminobutyric acid.tw. (1) 63 4 vinylaminobutyric acid.tw. (0) 64 4 vinylgaba.tw. (0) 65 gamma vinyl 4 aminobutyric acid.tw. (1) 66 gamma vinyl gaba.tw. (324) 67 gamma vinylgaba.tw. (9) 68 gamma vinyl gamma aminobutyric acid.tw. (26) 69 mdl 71754.tw. (2) 70 n vinyl 4 aminobutyric acid.tw. (0)

167 Newer Drugs for Children with Epilepsy

71 n vinyl gaba.tw. (0) 72 n vinyl gamma aminobutyric acid.tw. (0) 73 rmi 71754.tw. (3) 74 rmi 71890.tw. (0) 75 60643-86-9.rn. (945) 76 or/55-75 (1220) 77 economics/ (8873) 78 exp "costs and cost analysis"/ (95129) 79 cost of illness/ (4160) 80 exp health care costs/ (13479) 81 economic value of life/ (3929) 82 exp economics medical/ (8842) 83 exp economics hospital/ (10301) 84 economics pharmaceutical/ (1013) 85 exp "fees and charges"/ (18628) 86 (cost or costs or costed or costly or costing).tw. (111619) 87 (economic$ or pharmacoeconomic$ or pricing).tw. (46851) 88 or/77-87 (221866) 89 32 or 20 or 30 or 37 or 47 or 54 or 76 (13279) 90 12 and 88 and 89 (47)

Source - EMBASE (Ovid) 1980- Mar 2002

1 (lamicitin or dichlorophenyltriazinediyldiamine).mp. (0) 2 bw 430c.tw. (8) 3 bw 430 c.tw. (5) 4 bw 430c78.tw. (2) 5 (labileno or lamictal or lamotrigine or ltg).mp. (2970) 6 84057-84-1.rn. (2878) 7 or/1-6 (2970) 8 epilep$.mp. (43885) 9 seizure$.mp. (44271) 10 convulsion$.mp. (13316) 11 exp "seizure epilepsy and convulsion"/ (72635) 12 or/8-11 (83963) 13 (gabapentin or neurontin or neurotonin or gbp).mp. (3045) 14 goe 3450.tw. (3) 15 ci 945.tw. (12) 16 1 aminomethyl cyclohexaneacetic acid.tw. (16) 17 60142-96-3.rn. (2795) 18 go 3450.tw. (3) 19 or/13-18 (3051) 20 (etiracetam or keppra or levetiracetam).mp. (270) 21 1 1 carbamoylpropyl 2 pyrrolidineacetamide.mp. (0) 22 alpha ethyl 2 oxo 1 pyrrolidineacetamide.mp. (1) 23 lo59.mp. (5) 24 ucb 6474.mp. (3) 25 ucb I059.mp. (0) 26 "ucb I 059".mp. (0)

168 Newer Drugs for Children with Epilepsy

27 102767-28-2.rn. (270) 28 or/20-27 (270) 29 (oxcarbazepine or oxocarbazepine or trileptal).mp. (828) 30 gp 47680.tw. (12) 31 28721-07-5.rn. (816) 32 or/29-31 (828) 33 (tiagabine or gabitril or tiabex).mp. (792) 34 "nnc 05 0328".mp. (4) 35 nnc 328.mp. (2) 36 "no 05 0328".mp. (4) 37 "no 05 0329".mp. (1) 38 no 328.mp. (4315) 39 no 329.mp. (3958) 40 115103-54-3.rn. (778) 41 or/33-40 (8986) 42 (topiramate or epitomax or topamax or topimax or topiramate).mp. (1168) 43 mcn 4853.mp. (5) 44 rwj 17021.mp. (3) 45 rwj 17021-000.mp. (2) 46 97240-79-4.rn. (1158) 47 or/42-46 (1168) 48 (vigabatrin or sabril or sabrilex).mp. (2635) 49 3 amino 5 carboxyhexene.mp. (0) 50 4 amino 4 ethenylbutyric acid.mp. (0) 51 4 amino 4 vinylbutanoic acid.mp. (0) 52 4 amino 5 hexenoic acid.mp. (5) 53 4 aminohex 5 enoic acid.mp. (7) 54 4 vinyl 4 aminobutyric acid.mp. (1) 55 4 vinylaminobutyric acid.mp. (0) 56 4 vinylgaba.mp. (0) 57 gamma vinyl 4 aminobutyric acid.mp. (1) 58 gamma vinyl gaba.mp. (346) 59 gamma vinylgaba.mp. (13) 60 gamma vinyl gamma aminobutyric acid.mp. (23) 61 mdl 71754.mp. (9) 62 n vinyl 4 aminobutyric acid.mp. (0) 63 n vinyl gaba.mp. (0) 64 n vinyl gamma aminobutyric acid.mp. (0) 65 rmi 71754.mp. (10) 66 rmi 71890.mp. (0) 67 60643-86-9.rn. (2613) 68 or/48-67 (2663) 69 7 or 19 or 28 or 32 or 41 or 47 or 68 (15487) 70 cost benefit analysis/ (13518) 71 cost effectiveness analysis/ (24959) 72 cost minimization analysis/ (409) 73 cost utility analysis/ (615) 74 economic evaluation/ (1050) 75 (cost or costs or costed or costly or costing).tw. (92118)

169 Newer Drugs for Children with Epilepsy

76 (economic$ or pharmacoeconomic$ or price$ or pricing).tw. (42697) 77 (technology adj assessment$).tw. (855) 78 or/70-77 (135768) 79 78 and 12 and 69 (99)

Source - Health Economic Evaluation Database (HEED) May 2002

Source – NHS Database of Reviews of Effectiveness (DARE), HTA Database, NHS Economic Evaluation Database (NHS EED), NHS CRD internal administration databases.

See Cochrane Library (CCTR) effectiveness search strategy.

Quality of Life

Source – MEDLINE (Ovid) 1966 - Mar 2002

1 epilepsy/ (31939) 2 quality of life/ (30464) 3 life style/ (15874) 4 health status/ (18422) 5 health status indicators/ (6272) 6 or/2-5 (65755) 7 1 and 6 (374) 8 limit 7 to (human and english language) (322)

Appendix 8 Studies with mixed age populations Seventy three publications were retrieved in which it was possible to determine that the study population was mostly ≥ 18 years old but contained some patient(s) < 18 years of age. In most of these studies the number of these patients was not reported but it was clear that in all of them the majority of patients were ≥ 18 years old. They are listed in Table 63 according to diagnosis, study drug, and publication date. Further details with regard to study population, intervention and trial design are provided in the Appendix 9.

Table 63 Mixed age publications listed by diagnosis, drug and year of publication. NEWLY DIAGNOSED PARTIAL SEIZURES

170 Newer Drugs for Children with Epilepsy

DRUG YR REFERENCE tiagabine 99 Aikia M. Epilepsia 1999; 40 Suppl 7:51.137 1 REFRACTORY PARTIAL SEIZURES DRUG YR REFERENCE gabapentin 00 Lindberger M, et al. Epilepsia 2000; 41(10):1289-1295.138 2 lamotrigine 89 Binnie CD, et al. Epilepsy Research 1989; 4(3):222-229.139 3 levetiracetam 00 Cramer JA, et al. Epilepsy Research 2000; 41(1):29-38.140 4 oxcarbazepine 00 Barcs G, et al. Epilepsia 2000; 41(12):1597-1607.141 5 tiagabine 01 Cramer J, et al. Epilepsia 2001; 42 Suppl 3:70-75.287 6 NEWLY DIAGNOSED PARTIAL SEIZURES WITH OR WITHOUT SECONDARY GENERALISATION DRUG YR REFERENCE 142 tiagabine 97 Brodie MJ, et al. Epilepsia 1997; 38 Suppl 3:66-67. 7 Tanganelli P, et al. Bollettino Lega Italiana Contro L'Epilessia 1993; vigabatrin 93 8 (82-83):137-138.143 Canger R & Saltarelli A. Bollettino - Lega Italiana Contro L'Epilessia vigabatrin 97 9 1997; Issue 99 Suppl 1 (pp 33-36).144 145 vigabatrin 99 Chadwick D. Lancet 1999; 354 (9172):13-19. 10 REFRACTORY PARTIAL SEIZURES WITH OR WITHOUT SECONDARY GENERALISATION DRUG YR REFERENCE 146 gabapentin 90 Andrews J, et al. Lancet 1990; 335 (8698):1114-1117. 11 147 gabapentin 91 Sivenius J, et al. Epilepsia 1991; 32(4):539-542. 12 148 gabapentin 93 McLean MJ, et al. Neurology 1993; 43(11):2292-2298. 13 149 gabapentin 94 Anhut H, et al. Epilepsia 1994; 35(4):795-801. 14 Leach JP, et al. Journal of Neurology, Neurosurgery & Psychiatry gabapentin 97 15 1997; 62(4):372-376.150 Lopes-Lima JM, et al. European Journal of Neurology 1999; gabapentin 99 16 6(Supplement 3):17.288 Schapel GJ et al. Journal of Neurology, Neurosurgery & Psychiatry lamotrigine 93 17 1993; 56(5):448-453.151 152 lamotrigine 93 Smith D, et al. Epilepsia 1993; 34(2):312-322. 18 Severi S, et al. Bollettino Lega Italiana Contro L'Epilessia 1994; (86- lamotrigine 94 19 87):149-151.153 levetiracetam 00 Cereghino JJ, et al. Neurology 2000; 55(2):236-242.154 20 levetiracetam 00 Cramer JA, et al.. Epilepsia 2000; 41(7):868-874.155 21 levetiracetam 00 Shorvon SD, et al. Epilepsia 2000; 41(9):1179-1186.156 22 levetiracetam 02 Boon P, et al. Epilepsy Research 2002; 48(1-2):77-89.289 23 oxcarbazepine 99 Schachter SC, et al. Neurology 1999; 52(4):732-737.157 24 Lee BI, et al. Epilepsia 1999; 40(12):1767-1774. Korean Topiramate topiramate 99 25 group.158 vigabatrin 93 Dodrill CB, et al. Neurology 1993; 43(12):2501-2507.290 26 Grunewald RA, et al. Journal of Neurology, Neurosurgery & vigabatrin 94 27 Psychiatry 1994; 57(9):1057-1063.159 Brodie MJ & Mumford JP. Epilepsy Research 1999; 34(2-3):199-205. vigabatrin 99 28 160 REFRACTORY COMPLEX PARTIAL SEIZURES DRUG YR REFERENCE tiagabine 97 Dodrill CB, et al. Neurology 1997; 48(4):1025-1031.161 29 tiagabine 98 Uthman BM, et al. Archives of Neurology 1998; 55(1):56-62.291 30 tiagabine 00 Dodrill CB, et al. Epilepsy Research 2000; 42(2-3):123-132.162 31 vigabatrin 96 Beran RG, et al. Seizure 1996; 5(4):259-265.163 32 REFRACTORY COMPLEX PARTIAL SEIZURES WITH OR WITHOUT SECONDARY GENERALISATION DRUG YR REFERENCE gabapentin 95 Ben Menachem E, et al. Epilepsy Research 1995; 21(3):231-236.164 33 levetiracetam 00 Ben Menachem E, & Falter U. Epilepsia 2000; 41(10):1276-1283.165 34 tiagabine 97 Sachdeo RC, et al. Archives of Neurology 1997; 54(5):595-601.166 35 vigabatrin 84 Rimmer EM, et al. Lancet 1984; 1(8370):189-190.167 36 vigabatrin 85 Gram L, et al. Annals of Neurology 1985; 17(3):262-266.168 37 vigabatrin 95 Cramer J, et al. Epilepsia 1995; 36(11):1111-1117.169 38 vigabatrin 96 Provinciali L, et al. Acta Neurologica Scandinavica 1996; 94(1):12-18. 39 171 Newer Drugs for Children with Epilepsy

170 REFRACTORY PRIMARY GENERALISED SEIZURES DRUG YR REFERENCE gabapentin 96 Chadwick D, et al. Epilepsy Research 1996; 25(3):191-197.171 40 lamotrigine 98 Beran RG, et al. Epilepsia 1998; 39(12):1329-1333.172 41 topiramate 99 Biton V, et al. Neurology 1999; 52(7):1330-1337.173 42 NEWLY DIAGNOSED PRIMARY GENERALISED SEIZURES OR PARTIAL SEIZURES DRUG YR REFERENCE gabapentin 98 Chadwick DW, et al. Neurology 1998; 51(5):1282-1288.174 43 lamotrigine 95 Brodie MJ, et al. Lancet 1995; 345(8948):467-479.175 44 Dam M. Lamotrigine: A Brighter Future -International Congress & lamotrigine 96 45 Symposium 1996; Series 214: 17-21.176 lamotrigine 96 Reunanen M, et al. Epilepsy Research 1996; 23(2):149-155.292 46 lamotrigine 99 Steiner TJ, et al. Epilepsia 1999; 40(5):601-607.177 47 lamotrigine 00 Gillham, R., et al. Seizure 2000; 9(6):375-379.293 48 lamotrigine 00 Kalogjera SD, et al. Epilepsia 2000; 41 Suppl 7:116-117.178 49 lamotrigine 01 Biton V, et al. Neurology 2001; 56(2):172-177.242 50 lamotrigine 01 Edwards KR, et al. Epilepsy & Behavior 2001; 2(1):28-36.294 51 oxcarbazepine 89 Dam M, et al. Epilepsy Research 1989; 3(1):70-76.179 52 oxcarbazepine 92 Aikia M, et al. Epilepsy Research 1992; 11(3):199-203.295 53 oxcarbazepine 97 Bill PA, et al.. Epilepsy Research 1997; 27(3):195-204.180 54 oxcarbazepine 97 Christe W, et al. Epilepsy Research 1997; 26(3):451-460.181 55 topiramate 01 Wheless JW, et al. Neurology 2001; 56(8 Suppl 3):A234-A235.182 56 vigabatrin 95 Kalviainen R, et al. Archives of Neurology 1995; 52(10):989-996.183 57 REFRACTORY PRIMARY GENERALISED SEIZURES OR PARTIAL SEIZURES DRUG YR REFERENCE lamotrigine 87 Binnie CD, et al. Epilepsy Research 1987; 1(3):202-208.184 58 levetiracetam 00 Betts T, et al. Seizure 2000; 9(2):80-87.185 59 oxcarbazepine 87 Houtkooper MA, et al. Epilepsia 1987; 28(6):693-698.186 60 topiramate 99 Coles H, et al. Epilepsia 1999; 40:285.296 61 vigabatrin 86 Loiseau P, et al. Epilepsia 1986; 27(2):115-120.187 62 vigabatrin 86 Tartara A, et al. Epilepsia 1986; 27(6):717-723.188 63 vigabatrin 87 Rimmer EM, et al. Epilepsy Research 1987; 1(6):339-346.189 64 vigabatrin 87 Tassinari CA, et al. Archives of Neurology 1987; 44(9):907-910.190 65 Reynolds et al. British Journal of Clinical Practice 1988; (Suppl) vigabatrin 88 66 61:33.192 vigabatrin 91 Reynolds EH, et al. Epilepsia 1991; 32(4):530-538.191 67 Gillham RA, et al. Journal of Neurology Neurosurgery and Psychiatry vigabatrin 93 68 1993; 56:1271-1275.193 vigabatrin 93 McKee PJW, et al. Epilepsia 1993; 34(5):937-943.297 69 EPILEPSY DIAGNOSED (no further details) DRUG YR REFERENCE Carmant L, et al. European Journal of Neurology 1999; lamotrigine 99 70 6(Supplement 3):72.194 lamotrigine 99 Kerr M, et al. European Journal of Neurology 1999; 6 (Supp 3):17.298 71 lamotrigine 99 Montouris G, et al. Neurology 1999; 52(6):A523-A524.195 72 lamotrigine 00 Fakhoury T, et al. Epilepsia 2000; 41 Suppl 7:107.196 73

172 Newer Drugs for Children with Epilepsy

Appendix 9 RCT publications of mixed-age studies Tabulated below are further details of RCT publications in which the study populations were predominantly adult but included some patients under 18 years of age. Study population newly diagnosed with partial seizures.

Table 64 [1] Aika, 1999 137 Drug(s) Tiagabine Target 10-20 mg/day (?mode) maintenance dose (mode) Seizure or newly diagnosed partial epilepsy syndrome Type of trial parallel design Add-on or monotherapy monotherapy Control(s) carbamazepine Eligible age Age 15-75 years carbamazepine tiagabine Number randomised 34 33 Age (wks, mos, yrs) not reported not reported (mean, SD; median, range)

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

173 Newer Drugs for Children with Epilepsy

Study population diagnosed with refractory partial seizures.

Table 65 [2] Lindberger, 2000138 Drug(s) gabapentin Target 1,800 mg/day gabapentin (oral); 1,000 mg/day vigabatrin (oral) maintenance dose (mode) Seizure or partial seizures syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) vigabatrin Eligible age Age 12-75 years

vigabatrin gabapentin Number randomised 52 50

Age (wks, mos, yrs) median 33.0 yrs median 34.5 yrs (mean, SD; median, range) range 14-56 range 13-68

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

174 Newer Drugs for Children with Epilepsy

Table 66 [3]. Binnie, 1989139 Drug(s) lamotrigine Target 75-200mg /day maintenance dose (mode) Seizure or refractory partial seizures with or without other seizure types syndrome Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo lamotrigine Number randomised 15 15

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm: mean 37.1, arm: mean 37.1, SD10.3yrs; range16-51 SD10.3yrs; range16-51

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported separately by not reported separately by syndrome(s), study arm study arm n (%) idiopathic/unknown 22 22 symptomatic 8 8 Baseline not reported not reported not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

175 Newer Drugs for Children with Epilepsy

Table 67 [4]. Cramer, 2000140 Drug(s) levetiracetam Target 1000 or 3000mg/day in two doses/day (oral) maintenance dose (mode) Seizure or inadequately controlled partial seizures syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age Age 16-70 years

placebo levetiracetam Number randomised not reported not reported

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm. mean 38.7, SD arm. mean 38.7, SD 10.9yrs 10.9yrs

Diagnosed not reported separately by not reported separately by seizure study arm. study arm. types, simple & complex n (%) partial (63) (63) simple & complex partial with secondary generalisation (32) (32) partial secondarily generalised (1.6) (1.6) Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

176 Newer Drugs for Children with Epilepsy

Table 68 [5]. Barcs, 2000141 Drug(s) oxcarbazepine Target 600, 1200, or 2400mg/day (oral) maintenance dose (mode) Seizure or uncontrolled partial epilepsy syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age Age 15-65 years

placebo oxc: 600;1200;2400 Number randomised 173 169, 178, 174 Age (wks, mos, yrs) mean 34.3 yrs mean 34.6; 33.8; 35.2 (mean, SD; median, range) range 15-65 yrs. range 15-65; 16-64; 15-66

Diagnosed secondarily generalised 51 (29) 49 (29); 68 (38); 60 (34) seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline all seizures median 8.6/mo median 9.6; 9.8; 10/mo seizure secondarily generalised frequency seizures median 3.5/mo median 3.5; 2.0; 2.4/mo (/dy, wk, mo) (mean, SD; median, range)

Table 69 [6]. Cramer, 2001287 177 Newer Drugs for Children with Epilepsy

Drug(s) tiagabine Target not reported maintenance dose (mode) Seizure or poorly controlled partial epilepsy syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) alternative standard AED (phenytoin or carbamazepine) Eligible age Age 15-65 years

standard AED tiag:+ carbam:; tiag: + phen: Number randomised 101 105 ; 67

Age (wks, mos, yrs) mean 33 yrs mean 37yrs; mean 41 yrs. (mean, SD; median, range)

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline complex partial mean 22, SD 66/mo mean13, SD 28/mo (CBZ) seizure seizures mean29, SD 82/mo (PHE) frequency (/dy, wk, mo) (mean, SD; median, range)

Study population newly diagnosed with partial seizures with or without secondary generalisation.

178 Newer Drugs for Children with Epilepsy

Table 70 [7]. Brodie, 1997142 abstract Drug(s) tiagabine Target 5-10 mg/day, in two doses /day maintenance dose (mode) Seizure or newly diagnosed partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or monotherapy monotherapy Control(s) carbamazepine Eligible age Age 12-85 years

carbamazepine tiagabine Number randomised not reported not reported

Age (wks, mos, yrs) not reported not reported (mean, SD; median, range)

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

179 Newer Drugs for Children with Epilepsy

Table 71. [8] Tanganelli,1993143 Drug(s) vigabatrin Target 3g /day (?mode) maintenance dose (mode) Seizure or newly diagnosed partial seizures with or without secondary generalisation syndrome Type of trial cross over design Add-on or monotherapy monotherapy Control(s) carbamazepine Eligible age

carbamazepine vigabatrin Number randomised 5 6

Age (wks, mos, yrs) 22, 25, 26, 29, 47yrs 17, 20, 31, 36, 43, 58yrs (mean, SD; median, range)

Diagnosed complex partial 5 (100) 6 (100) seizure secondarily generalised 2 (40) 0 (0) types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported here seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 72 [9]. Canger, 1997144 180 Newer Drugs for Children with Epilepsy

Drug(s) vigabatrin Target 2g /day maintenance dose (mode) Seizure or newly diagnosed simple or complex partial seizures with or without secondary syndrome generalisation Type of trial parallel design Add-on or monotherapy monotherapy Control(s) carbamazepine Eligible age

carbamazepine vigabatrin Number randomised 8 8

Age (wks, mos, yrs) 1 patient < 18 yrs old 0 patients < 18 yrs old (mean, SD; median, range)

Diagnosed not reported for all seizure randomised patients types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

181 Newer Drugs for Children with Epilepsy

Table 73 [10]. Chadwick, 1999145 Drug(s) vigabatrin Target 2g /day, in two doses /day (oral) maintenance dose (mode) Seizure or newly diagnosed partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or monotherapy monotherapy Control(s) carbamazepine Eligible age 12-65yrs

carbamazepine vigabatrin Number randomised 226 220

Age (wks, mos, yrs) mean 36, SD 16yrs; mean 35, SD 15yrs; (mean, SD; median, range) range 13-72 range 12-75

Diagnosed any seizures 226 (100) 220 (100) seizure simple partial 63 (28) 74 (34) types, complex partial 91 (40) 92 (42) n (%) secondarily generalised 150 (66) 139 (63) not known 8 (4) 8 (4)

Diagnosed not reported syndrome(s), n (%) Baseline NA seizure frequency (/dy, wk, mo) (mean, SD; median, range)

182 Newer Drugs for Children with Epilepsy

Study population diagnosed with refractory partial seizures with or without secondary generalisation. Table 74 [11]. Andrews, 1990146[UK gabapentin group] Drug(s) gabapentin Target 1200mg /day, in three doses /day (oral) maintenance dose (mode) Seizure or refractory partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo gabapentin Number randomised 66 61

Age (wks, mos, yrs) mean 31 yrs; mean 30 yrs; (mean, SD; median, range) range 14-73 range 15-62

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported not reported not reported syndrome(s), n (%) Baseline all seizures median 13/mo; range (1- median 13/mo; range (3- seizure 216) 368) frequency secondary tonic-clonic median 4/mo; range (0.3- median 5/mo; range (0.3- (/dy, wk, mo) 32) 47) (mean, SD; median, range)

183 Newer Drugs for Children with Epilepsy

Table 75 [12]. Sivenius, 1991147 Drug(s) gabapentin Target 900 or 1200mg /day (?mode) maintenance dose (mode) Seizure or refractory simple or complex partial with or without secondarily generalised syndrome seizures Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo gaba: 900mg,1200mg Number randomised 18 16; 9

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm: mean 39yrs; arm: mean 39yrs; range16-59 range16-59

Diagnosed simple partial 0 (0) 0 (0); 2 (22) seizure simple+complex partial 0 (0) 1 (6); 0 (0) types, complex partial 10 (56) 6 (37); 3 (33) n (%) complex partial+secondarily 7 (39) 9 (56); 4 (44) generalised secondarily generalised 1 (6) 0 (0); 0 (0)

Diagnosed not reported syndrome(s), n (%) Baseline all seizures median 36 /3mos median: 26, 23 /3mos seizure frequency (/dy, wk, mo) (mean, SD; median, range)

184 Newer Drugs for Children with Epilepsy

Table 76 [13]. McLean, 1993148 [US gabapentin study group] Drug(s) gabapentin Target 600, 900 or 1800 mg/day, in three doses /day (oral) maintenance dose (mode) Seizure or refractory partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age at least 16 years old

placebo gaba: 600, 1200, 1800mg Number randomised 98 53, 101, 54

Age (wks, mos, yrs) mean 34 yrs; mean: 34, 34, 35 yrs; (mean, SD; median, range) range 17-66 range: 16-67, 19-65, 18-70

Diagnosed not reported separately by not reported separately by seizure study arm study arm types, n (%) simple partial 154 (50) 154 (50) complex partial secondarily generalised 284 (98) 284 (98) partial 193 (63) 193 (63)

Diagnosed not reported syndrome(s), n (%) Baseline all partial mean 31.1/mo; mean 21.7, 51.7, 31.5/mo; seizure median 10.7/mo; median 10.0, 11.0, frequency range 2.3-455 12.7/mo; (/dy, wk, mo) range 2.0-272, 2.3-1093, (mean, SD; 3.7-208. median, range)

Table 77 [14]. Anhut, 1994149 185 Newer Drugs for Children with Epilepsy

Drug(s) gabapentin Target 900 or 1200 mg/day, in three times /day (oral) maintenance dose (mode) Seizure or refractory simple, complex and secondarily generalised partial seizures syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo gab: 900mg; 1200mg Number randomised 109 111, 52

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm, mean 32; arm, mean 32; range 12-67yrs, range 12-67yrs,

Diagnosed simple partial 40 (36.7) 42 (37.8); 23 (44.2) seizure complex partial 98 (89.9) 99 (89.2); 48 (92.3) types, secondarily generalised 58 (53.2) 61 (55.0); 31 (59.6) n (%) other 19 (17.4) 28 (25.2); 3 (5.8)

Diagnosed not reported syndrome(s), n (%) Baseline all partial median 9.3/mo median: 10.3/mo; 9.8/mo seizure simple partial median 3.8/mo median: 8.3/mo; 5.0/mo frequency complex partial median 7.8/mo median: 7.0/mo; 6.3/mo (/dy, wk, mo) secondarily generalised median 1.0/mo median: 2.0/mo; 1.3/mo (mean, SD; median, range)

186 Newer Drugs for Children with Epilepsy

Table 78 [15]. Leach, 1997150 Drug(s) gabapentin Target 400, 600 and 800 mg/day, in three doses /day (?mode) maintenance dose (mode) Seizure or refractory partial seizures with or without secondary generalisation syndrome Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo gabapentin Number randomised 13 14

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm. Range 16-67 yrs, 1 arm. Range 16-67 yrs, 1 patient <18 yrs. patient <18 yrs.

Diagnosed not reported separately by not reported separately by seizure study arm study arm types, n (%) simple partial 9 9

complex partial 17 17

secondarily generalised 17 17 tonic-clonic Diagnosed not reported syndrome(s), n (%) Baseline not reported separately by not reported separately by seizure study arm study arm frequency (/dy, wk, mo) seizures /wk median 7, range 3-212 median 7, range 3-212 (mean, SD; median, range)

187 Newer Drugs for Children with Epilepsy

Table 79 [16]. Lopes-Lima, 1999288 abstract Drug(s) gabapentin Target 1800-2400mg/day (mode?) maintenance dose (mode) Seizure or uncontrolled partial epilepsy with or without secondary generalisation syndrome Type of trial parallel design Add-on or monotherapy monotherapy Control(s) valproate Eligible age

valproate gabapentin Number randomised not reported not reported

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm. mean 37.8 yrs. arm. mean 37.8 yrs.

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

188 Newer Drugs for Children with Epilepsy

Table 80 [17]. Schapel, 1993151 Drug(s) lamotrigine Target 150 or 300 mg /day, in two doses/day (oral) maintenance dose (mode) Seizure or refractory partial seizures with or without secondary generalisation syndrome Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo lamotrigine Number randomised 21 20

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm: mean 31, median 28, arm: mean 31, median 28, range17-63 range 17-63

Diagnosed not reported seizure types, n (%)

Diagnosed idiopathic/unknown 11 (50) 8 (40) syndrome(s), symptomatic 10 (50) 12 (60) n (%) Baseline all seizures mean 10.4, SD 10.0/3mos mean 10.5, SD 9.5/3mos seizure range 0.5-46 range 0-37 frequency (/dy, wk, mo) (mean, SD; median, range)

189 Newer Drugs for Children with Epilepsy

Table 81 [18] Smith, 1993152 Drug(s) lamotrigine Target 200 or 400mg /day (?mode) maintenance dose (mode) Seizure or refractory partial seizures with or without secondary generalisation syndrome Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age 12-70 yrs

placebo lamotrigine Number randomised not reported separately not reported separately

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm: mean 33.7yrs, arm: mean 33.7yrs, range15-67 range15-67

Diagnosed not reported separately by not reported separately by seizure arm arm types, simple partial only 9 (11) 9 n (%) simple & complex partial 6 (7.4) 6 complex partial only 30 (37) 30 secondarily generalised tonic-clonic 36 (44) 36

Diagnosed not reported syndrome(s), n (%) Baseline not reported separately by not reported separately by seizure arm arm frequency (/dy, wk, mo) simpe partial mean 25.9/mo, range 2- mean 25.9/mo, range 2- (mean, SD; complex partial 70. 70. median, secondarily generalised mean 25.2/mo, range 1- mean 25.2/mo, range 1- range) 760. 760.

tonic-clonic mean 5.3/mo, range 1-27. mean 5.3/mo, range 1-27.

190 Newer Drugs for Children with Epilepsy

Table 82 [19]. Severi, 1994153 Drug(s) lamotrigine Target 100mg or 200mg /day (?mode) maintenance dose (mode) Seizure or partial seizures with and without secondary generalisation syndrome Type of trial parallel design Add-on or monotherapy monotherapy Control(s) carbamazeoine Eligible age

carbamazepine 100mg; 200mg lamotrigine Number randomised 9 9; 9

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm. Mean 39.7yrs; range arm. Mean 39.7yrs; range 17-58 17-58

Diagnosed not reported separately by not reported separately by seizure study arm study arm types, simple and or complex n (%) partial seizures 8 (30) 8 (30) simple and or complex partial with generalisation 19 (70) 19 (70)

Diagnosed not reported separately by study arm syndrome(s), n (%) cryptogenic partial epilepsy 15 (56) symptomatic partial epilepsy 12 (44) Baseline not reported here seizure frequency (/dy, wk, mo) (mean, SD; median, range)

191 Newer Drugs for Children with Epilepsy

Table 83 [20]. Cereghino, 2000154 Drug(s) levetiracetam Target 500 or 1500mg/day in two doses/day (oral) maintenance dose (mode) Seizure or refractory partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age Age 16-70 years

placebo leve: 500mg; 1500mg Number randomised 95 98 (low dose) 101 (high dose) Age (wks, mos, yrs) mean 38, SD 11yrs mean 38, SD 11yrs; mean (mean, SD; median, range) 38, SD 11yrs.

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline partial seizures median 1.77/wk median 2.53/wk (low) seizure 2.08/wk (high) frequency (/dy, wk, mo) (mean, SD; median, range)

192 Newer Drugs for Children with Epilepsy

Table 84 [21]. Cramer, 2000155 Drug(s) levetiracetam Target 1 or 3g /day, in two doses /day (?mode) maintenance dose (mode) Seizure or refractory simple or partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age 16-70 years old

placebo leve: 1g ; 3g Number randomised 81 80, 85

Age (wks, mos, yrs) mean 38.5, SD11.3yrs. mean 39.1, SD11.3yrs; (mean, SD; median, range) mean 38.5, SD 10.2yrs

Diagnosed simple or complex seizure partial (64.2) (65.0); (69.4) types, simple or complex n (%) partial with secondary generalisation (35.8) (31.3); (29.4) simple partial with secondarily generalisation (0) (3.7); (1.2) Diagnosed not reported syndrome(s), n (%) Baseline partial mean: 5.66, SD18.79/wk mean: 7.55, SD13.99/wk; seizure mean: 5.15, SD15.58/wk. frequency (/dy, wk, mo) (mean, SD; median, range)

193 Newer Drugs for Children with Epilepsy

Table 85 [22]. Shorvon, 2000156 [same patient group as Boon 2002289] Drug(s) levetiracetam Target 1000, or 2000mg/day; in two doses/day (oral) maintenance dose (mode) Seizure or uncontrolled simple or complex partial seizures with or without secondary syndrome generalisation Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age Age 16-65 years

placebo leve: 1000mg; leve: 2000mg Number randomised 112 106; 106

Age (wks, mos, yrs) mean 37, SD 12 yrs mean:36,SD 10; 37,SD12 (mean, SD; median, range) range 16-69 yrs. range: 16-68; 14-65.

Diagnosed simple partial 40 (36) 31 (29); 30 (28) seizure complex partial 93 (83) 84 (79); 93 (88) types, secondarily generalised 26 (23) 28 (26); 29 (27) n (%) other 8 (7) 4 (4); 10 (9)

Diagnosed not reported syndrome(s), n (%) Baseline all seizures median 2.5/wk median: 2.82/wk; 2.58/wk seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 86 [23] Boon, 2002289 [same patient group as Shorvon 2000156] 194 Newer Drugs for Children with Epilepsy

Drug(s) levetiracetam Target 1000, or 2000mg/day; in two doses/day (oral) maintenance dose (mode) Seizure or uncontrolled simple or complex partial seizures with or without secondary syndrome generalisation Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo v 1g; placebo v 2g leve: 1g v pla:; 1g v.2g. leve: 2g v pla:; 2g v.1g. Number randomised 58; 54. 53; 53. 54; 52. Age (wks, mos, yrs) mean: mean: (mean, SD; median, range) 37, SD11yrs; 37, SD13yrs; 37, SD9yrs; 36 SD11yrs; range:18-64; 16-69 range:17-68; 16-56. mean: 37, SD11yrs; 37, SD12yrs; range:18-64; 14-65. Diagnosed simple partial 21 (36), 19 (35) 12 (23), 19 (36) seizure 10 (19), 20 (38) types, complex partial 49 (84), 44 (81) 42 (79), 42 (79) n (%) 48 (89), 45 (87) secondarily generalised 15 (26), 11 (20) 11 (21), 17 (32) 14 (26), 15 (29) unclassifiable 7 (12), 1 (2) 2 (4), 2 (4) 4 (7), 6 (12) Diagnosed cryptogenic/idiopathic 30 (52), 32 (63) 29 (55), 30 (57) syndrome(s), 30 (56), 30 (58) n (%) Baseline all seizures median: 2.01, 2.65/wk median: 3.03, 2.55/wk seizure median: 2.10, 4.34/wk frequency (/dy, wk, mo) (mean, SD; median, range)

Table 87 [24]. Schachter, 1999157 195 Newer Drugs for Children with Epilepsy

Drug(s) oxcarbazepine Target 2400mg/day ; in two doses/day (oral) maintenance dose (mode) Seizure or refractory partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or monotherapy monotherapy Control(s) placebo Eligible age Age 11-65 years

placebo oxcarbazepine Number randomised 51 51

Age (wks, mos, yrs) mean 34 yrs mean 33 yrs (mean, SD; median, range)

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline all partial seizures mean 4.4/48 hrs prior to mean 4.9/48 hrs prior to seizure randomisation randomisation frequency (/dy, wk, mo) (mean, SD; median, range)

Table 88 [25]. Lee, 1999158 [Korean topiramate study group]

196 Newer Drugs for Children with Epilepsy

Drug(s) topiramate Target 600mg /day (oral) maintenance dose (mode) Seizure or refractory partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age Age 16-65 years

placebo topiramate Number randomised 86 91

Age (wks, mos, yrs) mean 29.77, SD 8.71 yrs mean 29.58, SD 7.80 yrs (mean, SD; median, range)

Diagnosed simple partial motor 5 (5.8) 11 (12.1) seizure complex partial 72 (83.7) 70 (76.9) types, secondarily generalised n (%) tonic-clonic 39 (34.9) 31 (34.1)

Diagnosed not reported syndrome(s), n (%) Baseline all seizures mean 11.5, SD 2.4/mo; mean 9.4, SD 14.8/mo; seizure median 5.6. median 5.6. frequency (/dy, wk, mo) (mean, SD; median, range)

197 Newer Drugs for Children with Epilepsy

Table 89 [26]. Dodrill, 1993290 [same trial as French, 1993 299] Drug(s) vigabatrin Target 3g /day maintenance dose (mode) Seizure or refractory complex partial seizures or partial seizures with secondary syndrome generalisation Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo vigabatrin Number randomised 85 83

Age (wks, mos, yrs) mean 34.39, SD 8.66yrs; mean 34.25, SD 8.24yrs; (mean, SD; median, range) range unreported range unreported

Diagnosed not reported for all seizure randomised patients types, n (%)

Diagnosed not reported for all syndrome(s), randomised patients n (%) Baseline not reported for all seizure randomised patients frequency (/dy, wk, mo) (mean, SD; median, range)

Table 90 [27] Grunewald,1994159 198 Newer Drugs for Children with Epilepsy

Drug(s) vigabatrin Target 3g /day, in two doses/day (?mode) maintenance dose (mode) Seizure or refractory simple and complex seizures with and without secondary syndrome generalisation Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo vigabatrin Number randomised 23 22

Age (wks, mos, yrs) median 27 yrs; range 16- median 29 yrs; range 17- (mean, SD; median, range) 55 59

Diagnosed not reported separately by not reported separately by seizure study arm study arm types, simple partial 35 35 n (%) complex partial 44 44 secondarily generalised 14 14

Diagnosed not reported syndrome(s), n (%) Baseline simple partial median 2 /8 wks; range 0- median 4 /8 wks; range 0- seizure 55 91 frequency complex partial median 8 /8 wks; range 0- median 15 /8 wks; range (/dy, wk, mo) 124 0-38 (mean, SD; secondarily generalised median 0 /8 wks; range 0- median 0 /8 wks; range 0- median, 13 17 range)

199 Newer Drugs for Children with Epilepsy

Table 91 [28]. Brodie, 1999160 Drug(s) vigabatrin Target 2-4g /day (oral) maintenance dose (mode) Seizure or refractory simple or partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) valproate Eligible age 12-75 years old

valproate vigabatrin Number randomised 107 108

Age (wks, mos, yrs) median 36 yrs; median 37 yrs; (mean, SD; median, range) range 16-66 range 12-78

Diagnosed all seizures 107 (100) 108 (100) seizure simple partial 35 (33) 33 (31) types, complex partial 71 (66) 74 (69) n (%) secondarily generalised 19 (18) 17 (16) not known 0 (0) 2 (2)

Diagnosed syndrome(s), n (%)

Baseline all seizures mean 6.9/mo; median mean 6.8/mo; median seizure 5/mo 5/mo frequency (/dy, wk, mo) (mean, SD; median, range)

200 Newer Drugs for Children with Epilepsy

Study population diagnosed with refractory complex partial seizures. Table 92 [29]. Dodrill, 1997161 [some details from Uthman, 1998291] Drug(s) tiagabine Target 16, 32, 56 mg/day (mode?) maintenance dose (mode) Seizure or intractable complex partial epilepsy syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age Age 12-77 years

placebo tiag; 13, 32, 56 Number randomised 91 61; 88; 57

Age (wks, mos, yrs) not reported separately not reported separately (mean, SD; median, range) all:-mean 34 yrs; range 12- all:-mean 34 yrs; range 12- 77 77

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed syndrome(s) n (%) Baseline all seizures median 8.6/mo median 9.7; 13.7; 9.1/mo seizure frequency secondarily generalised (/dy, wk, mo) seizures median 7.4/mo median 7.4; 8.5; 9.6/mo (mean, SD; range 2.8-109 range:2.6-170;2.2-401;2.1- median, 209 range)

Table 93 [30]. Uthman, 1998291 201 Newer Drugs for Children with Epilepsy

Drug(s) tiagabine Target 16, 32, 56 mg/day, in four doses/day (mode?) maintenance dose (mode) Seizure or intractable complex syndrome partial epilepsy Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age Age 12-77 years

placebo tiag; 13, 32, 56 Number randomised 91 61; 88; 57

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm. arm. mean 34 yrs; range 12-77 mean 34 yrs; range 12-77

Diagnosed not reported separately by not reported separately by seizure study arm study arm types, simple partial 166 (57) 166 (57) n (%) secondarily generalised tonic-clonic 106 (36) 106 (36)

Diagnosed not reported syndrome(s), n (%) Baseline simple partial seizures median 8.6/mo median 9.7; 13.7; 9.1/mo seizure frequency complex partial median 7.4/mo median 7.4; 8.5; 9.6/mo (/dy, wk, mo) seizures range 2.8-109 range:2.6-170;2.2-401;2.1- (mean, SD; 209 median, range)

202 Newer Drugs for Children with Epilepsy

Table 94 [31]. Dodrill, 2000162 Drug(s) tiagabine Target not reported (see ref ID 371) maintenance dose (mode) Seizure or complex partial seizures syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) phenytoin or carbamazepine Eligible age receiving carbamazepine or phenytoin; 13 patients < 16 years old excluded

cbz+phen ; phen+cbz cbz+tiag ; phen+tiag Number randomised 71; 66 82; 58

Age (wks, mos, yrs) mean 33.3, SD 13.1 yrs; mean 37.1, SD 13.1 yrs; (mean, SD; median, range) mean40.42, SD 12.2 yrs. mean 39.4, SD 13.5 yrs.

Diagnosed all partial 70 (99); 66 (100) 81 (99); 57 (98) seizure complex partial 70 (99); 66 (100) 81 (99); 58 (100) types, generalised tonic-clonic 23 (32); 20 (30) 24 (29); 22 (40) n (%)

Diagnosed not reported syndrome(s), n (%) Baseline total partial seizures median 7/mo; median median 6/mo; median seizure 6/mo 7/mo frequency complex partial (/dy, wk, mo) seizures median 10/mo; median median 7/mo; median (mean, SD; 8/mo 9/mo median, generalised tonic-clonic range) seizures median 2/mo; median median 2/mo; median 2/mo 1/mo

Table 95 [32]. Beran, 1996163

203 Newer Drugs for Children with Epilepsy

Drug(s) vigabatrin Target 2g/day or 3g/day (oral) maintenance dose (mode) Seizure or uncontrolled complex partial seizures syndrome Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age 16 to 65 yrs

placebo viga: 2g/day, 3g/day Number randomised unclear unclear

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm, range 17-64 yrs arm, range 17-64 yrs

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

204 Newer Drugs for Children with Epilepsy

Study population diagnosed with refractory complex partial seizures with or without secondary generalisation. Table 96 [33]. Ben Menachem, 1995164

205 Newer Drugs for Children with Epilepsy

Drug(s) gabapentin Target 900 or 1200 mg/day (?mode) maintenance dose (mode) Seizure or refractory complex partial seizures with or withiut secondary generalisation syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo gaba: 900mg, 1200mg Number randomised 12 16, 8

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm. mean 37; range 16- arm. mean 37; range 16- 66yrs. 66yrs.

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline reported by histogram approx: 20/mo approx: 37/mo , 50/mo seizure only frequency (/dy, wk, mo) (mean, SD; median, range)

Table 97 [34]. Ben Menachem, 2000165

206 Newer Drugs for Children with Epilepsy

Drug(s) levetiracetam Target 3g /day, in two doses /day (oral) maintenance dose (mode) Seizure or refractory complex partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or add-on (with secondary monotherapy for responders) monotherapy Control(s) placebo Eligible age 16-70 years old

placebo levetiracetam Number randomised 105 181

Age (wks, mos, yrs) mean 36, SD12yrs. mean 37, SD12yrs. (mean, SD; median, range)

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline partial median 1.75/wk median 1.69/wk seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 98 [35]. Sachdeo, 1997166

207 Newer Drugs for Children with Epilepsy

Drug(s) tiagabine Target 32mg/day, in 2 doses or 4 doses /day (oral) maintenance dose (mode) Seizure or refractory complex partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age 12-75 yrs old

placebo tiag: 2x/day, 4x/day Number randomised 107 106, 105

Age (wks, mos, yrs) mean 35.3 yrs; range 13- mean 33.4, 32.6 yrs; (mean, SD; median, range) 71. range 12-67, 12-66.

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline complex partial seizure seizures median 8.0/mo median: 8.4/mo, 7.9/mo. frequency (/dy, wk, mo) (mean, SD; median, range)

Table 99 [36]. Rimmer, 1984167

208 Newer Drugs for Children with Epilepsy

Drug(s) vigabatrin Target 3g /day (?mode) maintenance dose (mode) Seizure or refractory complex partial seizures with or without secondary generalisation syndrome Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo vigabatrin Number randomised not reported not reported

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm: mean 33 yrs; range arm: mean 33 yrs; range 16-61. 16-61.

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported for all seizure randomised patients frequency (/dy, wk, mo) (mean, SD; median, range)

209 Newer Drugs for Children with Epilepsy

Table 100 [37]. Gram, 1984168 Drug(s) vigabatrin Target 3g /day, in two doses /day (oral) maintenance dose (mode) Seizure or refractory complex partial seizures with or without generalisation syndrome Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo vigabatrin Number randomised not reported not reported

Age (wks, mos, yrs) not reported by arm: range not reported by arm: range (mean, SD; median, range) 17-63 yrs. 17-63 yrs.

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported not reported not reported syndrome(s), n (%) Baseline not reported not reported not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

210 Newer Drugs for Children with Epilepsy

Table 101 [38]. Cramer, 1995169 Drug(s) vigabatrin Target 4 g/day, in two doses /day (oral) maintenance dose (mode) Seizure or refractory complex partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age 16-50 years old

placebo vigabatrin Number randomised not reported not reported

Age (wks, mos, yrs) not reported not reported (mean, SD; median, range)

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

211 Newer Drugs for Children with Epilepsy

Table 102 [39]. Provinciali, 1996170 Drug(s) vigabatrin Target 2-3 g/day (?mode) maintenance dose (mode) Seizure or refractory complex partial seizures with or without secondary generalisation syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age 17-66 yrs old

placebo vigabatrin Number randomised 20 20

Age (wks, mos, yrs) median 38.2 yrs; range 20- median 34.8 yrs; range 17- (mean, SD; median, range) 66 66

Diagnosed complex partial 13 (65) 11 (55) seizure secondarily generalised 7 (35) 9 (45) types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline all seizures 4 /wk & 16/ mo medians or 5 /wk & 15/ mo medians or seizure means unclear means unclear frequency (/dy, wk, mo) (mean, SD; median, range)

212 Newer Drugs for Children with Epilepsy

Study population diagnosed with refractory primary generalised seizures. Table 103 [40]. Chadwick, 1996171 Drug(s) gabapentin Target 1200 mg/day (?mode) maintenance dose (mode) Seizure or refractory generalised seizures syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age 12 years and older

placebo gabapentin Number randomised 71 58

Age (wks, mos, yrs) mean 29 yrs; range 13-61 mean 30 yrs; range 16-62 (mean, SD; median, range)

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline generalised tonic-clonic mean 7.3 /mo; median 3.3; mean 7.4 /mo; median 3.9; seizure range 0-103.3 range 0-54.3 frequency (/dy, wk, mo) (mean, SD; median, range)

Table 104 [41]. Beran, 1998172 213 Newer Drugs for Children with Epilepsy

Drug(s) Lamotrigine Target 75 or 150mg/day (oral) maintenance dose (mode) Seizure or treatment resistent idiopathic generalised epilepsy syndrome Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age Age 15-50 years

placebo lamotrigine Number randomised total N=26;not reported total N=26;not reported separately by arm separately by arm Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm. Mean 29yrs; range arm. Mean 29yrs; range 15-50 15-50

Diagnosed not reported separately by not reported separately by seizure study arm study arm types, absence only 8 (31) 8 (31) n (%) absence & tonic-clonic 12 (42) 12 (42) tonic-clonic only 2 (8) 2 (8) myoclonic only 1 (4) 1 (4) myoclonic & tonic- clonic 1 (4) 1 (4) absence, myoclonic & 2 (8) 2 (8) tonic-clonic Diagnosed not reported separately by not reported separately by syndrome(s), study arm study arm n (%) idiopathic generalised 26 (100) 26 (100) Baseline not reported not reported not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 105 [42]. Biton, 1999173

214 Newer Drugs for Children with Epilepsy

Drug(s) topiramate Target 5.2-9.3mg/kg/day (depending on body mass), in two doses /day (oral) maintenance dose (mode) Seizure or refractory primary generalised tonic-clonic seizures with or without other syndrome generalised seizure types Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age at least 4 years old

placebo topiramate Number randomised 41 39

Age (wks, mos, yrs) mean 25.6, SD13.4yrs; mean 26.8, SD12.8yrs; (mean, SD; median, range) range 3.0-50; range 5.0-59; n=13 aged 16 yrs or less n=8 aged 16 yrs or less

Diagnosed tonic-clonic 40 (98) 39 (100) seizure tonic-clonic only 13 (32) 13 (33) types, absence 16 (39) 16 (41) n (%) tonic 10 (24) 9 (23) myoclonic 8 (20) 8 (21) drop attack 5 (12) 2 (5) atypical absence 4 (10) 2 (5) clonic 1 (2) 1 (3) other 1 (2) 1 (3) Diagnosed not reported syndrome(s), n (%) Baseline all seizures median 17.5/mo; median 15.3/mo; seizure range 2-79,109 range 1-1134 frequency primary generalised median 4.5/mo; median 5.0/mo; (/dy, wk, mo) tonic-clonic range 1-300 range 1-298 (mean, SD; median, range)

215 Newer Drugs for Children with Epilepsy

Study population mixed: some patients with newly diagnosed partial seizures and others with newly diagnosed primary generalised seizures. Table 106 [43]. Chadwick, 1999174 Drug(s) gabapentin Target 300mg, 900mg, or 1800mg /day (oral) maintenance dose (mode) Seizure or newly diagnosed partial seizures with or without secondary generalisation or syndrome generalised tonic-clonic seizures Type of trial parallel design Add-on or monotherapy monotherapy Control(s) carbamazepine Eligible age

carbamazepine gaba: 300; 900; 1800 Number randomised 74 72; 72; 74

Age (wks, mos, yrs) mean 34, SD 16.4yrs; mean: 37, SD 17.3yrs; 34, (mean, SD; median, range) range 13-72 SD 16.0yrs; 37, SD 16.9yrs; range:12-83; 15-73; 12-86 Diagnosed simple partial 32 (43) 17 (24); 21 (29); 27 (36) seizure complex partial 32 (43) 28 (39); 32 (44); 34(46) types, secondarily generalised n (%) tonic-clonic 37 (50) 32 (44); 38 (53); 41 (5) generalised tonic-clonic 17 (23) 22 (31); 14 (19); 11 (15)

Diagnosed not reported syndrome(s), n (%) Baseline NA seizure frequency (/dy, wk, mo) (mean, SD; median, range)

216 Newer Drugs for Children with Epilepsy

Table 107 [44]. Brodie, 1995175 Drug(s) lamotrigine Target 150 mg/day, in two doses /day (oral) maintenance dose (mode) Seizure or partial with & without secondary generalisation, primary & secondary tonic- syndrome clonic seizures Type of trial parallel design Add-on or monotherapy monotherapy Control(s) carbamazepine Eligible age 13 years old and older

carbamazepine lamotrigine Number randomised 129 131

Age (wks, mos, yrs) median 27 yrs; range 13- median 28 yrs; range 14- (mean, SD; median, range) 81 70

Diagnosed partial with & without seizure secondary types, generalisation, 73 (57) 73 (56) n (%) primary generalised tonic-clonic seizures 62 (48) 60 (46)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 108 [45]. Dam, 1996176 217 Newer Drugs for Children with Epilepsy

Drug(s) lamotrigine Target 100mg or 200mg /day (?mode) maintenance dose (mode) Seizure or newly diagnosed primary generalised seizures (presumed) or partial seizures syndrome with or without secondary generalisation Type of trial parallel design Add-on or monotherapy (presumed) monotherapy Control(s) carbamazepine Eligible age 12-72 years old

carbamazepine lamo: 100mg; 200mg. Number randomised 117 115; 111

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm. Range 12-72yrs. arm. Range 12-72yrs.

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

218 Newer Drugs for Children with Epilepsy

Table 109 [46]. Reunanen, 1996292 Drug(s) lamotrigine Target 100 or 200 mg/day, single dose /day (oral) maintenance dose (mode) Seizure or newly didagnosed or recurrent untreated partial and /or generalised tonic- syndrome clonic seizures Type of trial parallel design Add-on or monotherapy monotherapy Control(s) carbamazepine Eligible age more than 12 yrs old

carbamazepine lamot: 100mg; 200mg Number randomised 117 115,111

Age (wks, mos, yrs) mean 32 yrs; mean: 33 yrs; 30 yrs. (mean, SD; median, range) range 13-71 range: 13-72; 12-66

Diagnosed not reported seizure types, n (%)

Diagnosed "symptomatic" (25) (25), (22) syndrome(s), n (%) Baseline all seizures mean 14.5/6 mos; median mean: 9.3, 11.9 /6 mos; seizure 3.0 median 3.0, 3.0 /6mos frequency (/dy, wk, mo) (mean, SD; median, range)

Table 110 [47]. Steiner, 1999177 219 Newer Drugs for Children with Epilepsy

Drug(s) lamotrigine Target not specified maintenance dose (mode) Seizure or newly diagnosed untreated epilepsy syndrome Type of trial parallel design Add-on or monotherapy monotherapy Control(s) phenytoin Eligible age Age 14-75 years eligible

phenytoin lamotrigine Number randomised 95 86

Age (wks, mos, yrs) median 27 yrs median 28 yrs (mean, SD; median, range) range 13-74 range 13-70

Diagnosed partial only 26 (27) 24 (28) seizure partial with secondary types, generalisation 20 (21) 20 (23) n (%) primary generalised tonic-clonic 49 (52) 42 (49)

Diagnosed not reported syndrome(s), n (%) Baseline all seizures median 4 / 6mos; median 3 / 6mos; seizure range 1-200 range 2-600 frequency (/dy, wk, mo) (mean, SD; median, range)

220 Newer Drugs for Children with Epilepsy

Table 111 [48]. Gillham, 2000293 [details as Brodie, 1995175] Drug(s) lamotrigine Target 150 mg/day; in two doses /day (oral) maintenance dose (mode) Seizure or newly diagnosed epilepsy syndrome Type of trial parallel design Add-on or monotherapy monotherapy Control(s) carbamazepine Eligible age Age 13 years and older

carbamazepine lamotrigine Number randomised 129 131

Age (wks, mos, yrs) median 27 yrs median 28 yrs (mean, SD; median, range) range 13-81 range 14-70

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not repoerted seizure frequency (/dy, wk, mo) (mean, SD; median, range)

221 Newer Drugs for Children with Epilepsy

Table 112 [49]. Kalogjera, 2000178 abstract Drug(s) lamotrigine Target 200 to 500 mg/day (mode?) maintenance dose (mode) Seizure or new onset partial or generalised seizures syndrome Type of trial parallel design Add-on or unclear monotherapy Control(s) valproate Eligible age Age 12 years or older

valproate lamotrigine Number randomised 68 65

Age (wks, mos, yrs) not reported not reported (mean, SD; median, range)

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 113 [50]. Biton, 2001242 222 Newer Drugs for Children with Epilepsy

Drug(s) lamotrigine Target 200mg/day (oral) maintenance dose (mode) Seizure or epilepsy with any seizure type syndrome Type of trial parallel design Add-on or monotherapy monotherapy Control(s) valproate Eligible age At least 12 years old

valproate lamotrigine Number randomised 68 65

Age (wks, mos, yrs) mean 30.1, SD 14 yrs; mean 34.5, SD 16 yrs; (mean, SD; median, range) range 12-76; 19% <18 yrs. range 12-68; 18% <18 yrs.

Diagnosed complex partial 23 (34) 17 (26) seizure partial with secondary types, generalisation 18 (26) 18 (28) n (%) generalised tonic-clonic 55 (81) 50 (77)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 114 [51]. Edwards, 2001294; details as Biton, 2001242

223 Newer Drugs for Children with Epilepsy

valproate lamotrigine Number randomised 68 65

Age (wks, mos, yrs) mean 30.1, SD 14 yrs; mean 34.5, SD 16 yrs; (mean, SD; median, range) range 12-76; 19% <18 yrs. range 12-68; 18% <18 yrs.

Diagnosed complex partial (34) (26) seizure partial with secondary types, generalisation (26) (28) n (%) generalised tonic-clonic (81) (77)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

224 Newer Drugs for Children with Epilepsy

Table 115 [52]. Dam, 1989179 Drug(s) oxcarbazepine Target "best therapeutic dose with satisfactory tolerability" [at least 300mg /day] maintenance (?mode) dose (mode) Seizure or primary generalised seizures or partial seizures with or without secondary syndrome generalisation Type of trial parallel design Add-on or monotherapy monotherapy Control(s) carbamazepine Eligible age 15-65 years old

carbamazepine oxcarbazepine Number randomised 100 94

Age (wks, mos, yrs) median 33 yrs; median 32.5 yrs; (mean, SD; median, range) range 15-63 range 14-63

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported not reported not reported syndrome(s), n (%) Baseline unclear seizure frequency (/dy, wk, mo) (mean, SD; median, range)

225 Newer Drugs for Children with Epilepsy

Table 116 [53]. Aikia, 1992295 Drug(s) oxcarbazepine Target to achieve 30-120 µmol/l oxcarbazepine metabolite in plasma maintenance dose (mode) Seizure or newly diagnosed generalised seizures or partial seizures with or without syndrome secondary generalisation Type of trial parallel design Add-on or monotherapy monotherapy Control(s) phenytoin Eligible age

phenytoin oxcarbazepine Number randomised 18 19

Age (wks, mos, yrs) mean 32.7, SD 12.5yrs; mean 33.6, SD 14.0yrs; (mean, SD; median, range) not reported for all not reported for all randomised patients. randomised patients.

Diagnosed not reported for all seizure randomised patients types, n (%)

Diagnosed not reported for all syndrome(s), randomised patients n (%) Baseline not reported for all seizure randomised patients frequency (/dy, wk, mo) (mean, SD; median, range)

226 Newer Drugs for Children with Epilepsy

Table 117 [54]. Bill, 1997300 Drug(s) oxcarbazepine Target 450-2400mg/day, in three doses/day (oral) maintenance dose (mode) Seizure or newly diagnosed untreated seizures with partial or generalised onset syndrome Type of trial parallel design Add-on or monotherapy monotherapy Control(s) phenytoin Eligible age Age 16-65 years

phenytoin oxcarbazepine Number randomised 144 143

Age (wks, mos, yrs) mean 26.6 yrs mean 27.1 yrs (mean, SD; median, range) range 15-91 range 16-63

Diagnosed partial +/- seizure generalisation 98 (68) 84 (59) types, generalised without n (%) partial onset 46 (32) 58 (41) no main type 0 (0) 1 (1)

Diagnosed not reported syndrome(s), n (%) Baseline all seizures mean 0.84/wk; median mean 0.98/wk; median seizure 0.23/wk 0.20/wk frequency (/dy, wk, mo) (mean, SD; median, range)

227 Newer Drugs for Children with Epilepsy

Table 118 [55]. Christe, 1997181 Drug(s) oxcarbazepine Target 900-2400mg/day, in three doses/day (oral) maintenance dose (mode) Seizure or newly diagnosed seizures with partial or generalised onset syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) valproate Eligible age Age 15-65 years

valproate oxcarbazepine Number randomised 121 128

Age (wks, mos, yrs) mean 32.5 yrs mean 32.4 yrs (mean, SD; median, range) range 15-64 range 15-65

Diagnosed partial +/- seizure generalisation 78 (65) 76 (59) types, generalised without n (%) partial onset 43 (36) 52 (41)

Diagnosed not reported syndrome(s), n (%) Baseline all seizures mean 0.58/wk; median mean 1.09/wk; median seizure 0.13/wk 0.25/wk frequency (/dy, wk, mo) (mean, SD; median, range)

228 Newer Drugs for Children with Epilepsy

Table 119 [56]. Wheless, 2001182 abstract Drug(s) topiramate Target 100 or 200 mg/day (mode?) maintenance dose (mode) Seizure or newly diagnosed epilepsy (any seizure type or syndrome) syndrome Type of trial parallel design Add-on or monotherapy monotherapy Control(s) valproate, carbamazepine Eligible age Age 6 years or older

valproate/ topiramate carbamazepine Number randomised total N=626 (?);not not reported reported separately by arm Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm. 119 patients 6-16yrs arm. 119 patients 6-16yrs old old

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported not reported not reported syndrome(s), n (%) Baseline not reported not reported not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 120 [57]. Kalviainen, 1995183

229 Newer Drugs for Children with Epilepsy

Drug(s) vigabatrin Target 50mg?kg/day (?mode) maintenance dose (mode) Seizure or newly diagnosed tonic-clonic generalised seizures or partial seizures with or syndrome without generalisation Type of trial parallel design Add-on or monotherapy monotherapy Control(s) carbamazepine Eligible age 15-64 years old

carbamazepine vigabatrin Number randomised 50 50

Age (wks, mos, yrs) mean 37, SD 16yrs mean 33, SD 16yrs (mean, SD; median, range)

Diagnosed complex partial only 4 (8) 4 (8) seizure partial and secondarily types, generalised 11 (22) 10 (20) n (%) secondarily generalised only 27 (54) 25 (50) primary generalised 1 (2) 4 (8) unclassified generalised 7 (14) 7 (14) Diagnosed cryptogenic 40 (80) 35 (70) syndrome(s), n (%) Baseline NA seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Study population mixed: some patients diagnosed with refractory partial seizures others with refractory primary generalised seizures. 230 Newer Drugs for Children with Epilepsy

Table 121 [58]. Binnie, 1987184 Drug(s) lamotrigine Target 50-400mg /day, in two doses /day (to give peak of ~.003mg/ml in plasma) maintenance dose (mode) Seizure or refractory simple or complex partial, or atonic, or absence, or tonic-clonic, or syndrome myoclonic, Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo lamotrigine Number randomised 5 5 Age (wks, mos, yrs) Ages: 24, 29, 29, 29, 46yrs Ages:16, 25, 27, 37, 43yrs (mean, SD; median, range)

Diagnosed simple partial 1 (20) 0 (0) seizure complex partial 2 (40) 1 (20) types, tonic-clonic 0 (0) 1 (20) n (%) complex partial & tonic- clonic 1 (20) 2 (40) simple & complex partial , & myoclonic 1 (20) 0 (0) atonic & myoclonic & absence 0 (0) 1 (20)

Diagnosed not reported not reported not reported syndrome(s), n (%) Baseline not reported not reported not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 122 [59]. Betts, 2000185

231 Newer Drugs for Children with Epilepsy

Drug(s) levetiracetam Target 2g or 4g /day, in two doses /day (oral) maintenance dose (mode) Seizure or refractory generalised tonic-clonic seizures or partial seizures with or without syndrome secondary generalisation Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age 16-70 years old

placebo leve: 2g; 4g Number randomised 39 42; 38

Age (wks, mos, yrs) mean 35, SD 12yrs mean: 39, SD 13yrs; 40, (mean, SD; median, range) SD 12yrs.

Diagnosed not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 123 [60]. Houtkooper, 1987186 232 Newer Drugs for Children with Epilepsy

Drug(s) oxcarbazepine Target tolerable dose (oral) maintenance dose (mode) Seizure or refractory partial or generalised or mixed seizure types syndrome Type of trial cross over design Add-on or add on monotherapy Control(s) carbamazepine Eligible age

carbamazepine oxcarbazepine Number randomised not reported not reported

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm: median 29yrs, arm: median 29yrs, range15-50 range15-50

Diagnosed not reported separately by not reported separately by seizure study arm: study arm: types, generalised 9 (19) 9 (19) n (%) partial 10 (21) 10 (21) both generalised & partial 29 (60) 29 (60)

Diagnosed not reported syndrome(s), n (%) Baseline not reported for all seizure randomised patients frequency (/dy, wk, mo) (mean, SD; median, range)

Table 124 [61]. Coles, 1999296 abstract

233 Newer Drugs for Children with Epilepsy

Drug(s) topiramate Target not reported maintenance dose (mode) Seizure or refractory primary generalised or partial onset tonic-clonic syndrome Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo topiramate Number randomised total N=128;not reported total N=128;not reported separately by arm separately by arm Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm. median 39yrs arm. median 39yrs

Diagnosed not reported separately by not reported separately by seizure study arm. study arm. types, simple partial 29 (23) 29 (23) n (%) complex partial 79 (62) 79 (62) secondarily generalised partial 41 (32) 41 (32) primary generalised tonic-clonic 12 (9) 12 (9) Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 125 [62]. Loiseau, 1986187

234 Newer Drugs for Children with Epilepsy

Drug(s) vigabatrin Target 3g /day, in two doses /day (oral) maintenance dose (mode) Seizure or refractory complex partial or generalised seizures syndrome Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age

placebo vigabatrin Number randomised not reported not reported

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm: mean 28.9, arm: mean 28.9, SD14.9yrs; median 24yrs, SD14.9yrs; median 24yrs, range10-58 range10-58 Diagnosed not reported sepatately by not reported sepatately by seizure study arm. study arm. types, complex 10 (43) 10 (43) n (%) complex with secondary generalisation 9 (39) 9 (39) tonic-clonic, myoclonic, absence 1 (4) 1 (4) myoclonic absence 1 (4) 1 (4) tonic-clonic absence 1 (4) 1 (4) Diagnosed not reported syndrome(s), n (%) Baseline not reported for all seizure randomised patients frequency (/dy, wk, mo) (mean, SD; median, range)

Table 126 [63]. Tartara, 1986188

235 Newer Drugs for Children with Epilepsy

Drug(s) vigabatrin Target 2 or 3g /day, in two doses /day (oral) maintenance dose (mode) Seizure or refractory absence or atonic or partial with or without secondary generalisation syndrome Type of trial cross over design Add-on or add-on monotherapy Control(s) plaebo Eligible age 16-65 years old

placebo vigabatrin Number randomised not reported not reported

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm: arm: mean 30.5, SD 9.7yrs; mean 30.5, SD 9.7yrs; median 30yrs, range17-50 median 30yrs, range17-50 Diagnosed not reported separately by not reported separately by seizure study arm. study arm. types, complex partial 15 (65) 15 (65) n (%) complex partial with secondary generalisation 2 (9) 2 (9) simple partial with secondary generalisation 3 (13) 3 (13) absence 2 (9) 2 (9) atonic 1 (4) 1 (4) Diagnosed not reported syndrome(s), n (%) Baseline not reported for all seizure randomised patients frequency (/dy, wk, mo) (mean, SD; median, range)

236 Newer Drugs for Children with Epilepsy

Table 127 [64]. Rimmer, 1987189 Drug(s) vigabatrin Target acute single dose of 3g (oral) maintenance dose (mode) Seizure or light-triggered primary generalised tonic-clonic or complex partial with syndrome secondary generalisation Type of trial cross over design Add-on or mixed monotherapy Control(s) acute single dose of valproate of 1g (oral) Eligible age

valproate vigabatrin Number randomised total N=6;not reported total N=6;not reported separately by arm separately by arm Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm. mean 18yrs; range arm. mean 18yrs; range 10-25 10-25

Diagnosed not reported separately by not reported separately by seizure study arm. study arm. types, complex secondarily n (%) generalised 2 (33) 2 (33) primary generalised tonic-clonic 4 (66) 4 (66)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

237 Newer Drugs for Children with Epilepsy

Table 128 [65]. Tassinari, 1987190 Drug(s) vigabatrin Target 2-3g /day, in two doses /day (oral) maintenance dose (mode) Seizure or refractory primary generalised seizures or complex partial seizures with or syndrome without secondary generalisation. Type of trial parallel design Add-on or add-on monotherapy Control(s) placebo Eligible age 10 to 58 years old

placebo vigabatrin Number randomised 15 16

Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm:mean 28.9, arm:mean 28.9, SD11.5yrs, range10-58 SD11.5yrs, range10-58

Diagnosed not reported separately by not reported separately by seizure study arm: study arm: types, complex partial with or n (%) without secondarily generalised 15 (100) 15 (100) complex with atonic 8 (53) 8 (53) partial (various types) 7 (47) 7 (47) progressive myoclonic 1 (7) 1 (7)

Diagnosed not reported syndrome(s), n (%) Baseline not reported separately by not reported separately by seizure study arm; reported for 30 study arm; reported for 30 frequency of 31 randomised patients of 31 randomised patients (/dy, wk, mo) all seizures mean 12.2, SD17.8/wk; mean 12.2, SD17.8/wk; (mean, SD; range 1-89 range 1-89 median, range)

238 Newer Drugs for Children with Epilepsy

Table 129 [66]. Reynolds, 1988192 abstract Drug(s) vigabatrin Target 3g /day (?mode) maintenance dose (mode) Seizure or refractory generalised tonic-clonic seizures or partial seizures with or without syndrome generalisation Type of trial parallel ('responders' only randomised) design Add-on or add-on monotherapy Control(s) placebo Eligible age 16-61 rears old

placebo vigabatrin Number randomised total N=19;not reported total N=19;not reported separately by arm separately by arm Age (wks, mos, yrs) not reported for not reported for (mean, SD; median, range) randomised patients randomised patients

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported not reported not reported syndrome(s), n (%) Baseline not reported not reported not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

239 Newer Drugs for Children with Epilepsy

Table 130 [67]. Reynolds, 1991191 Drug(s) vigabatrin Target 3g /day, in two doses/day (oral) maintenance dose (mode) Seizure or refractory generalised seizures or partial seizures with or without secondary syndrome generalisation Type of trial parallel (after randomisation of "responders") design Add-on or add-on monotherapy Control(s) placebo Eligible age 16-65 years old

placebo vigabatrin Number randomised 10 10

Age (wks, mos, yrs) not reported not reported (mean, SD; median, range)

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported not reported not reported syndrome(s), n (%) Baseline not reported not reported not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 131 [68]. Gillham, 1993193 [same trial as McKee, 1993297] 240 Newer Drugs for Children with Epilepsy

Drug(s) vigabatrin Target 3g /day, in two doses /day (?mode) maintenance dose (mode) Seizure or refractory generalised tonic-clonic or complex partial seizures with or without syndrome secondary generalisation Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age 17-53 years old

placebo vigabatrin Number randomised total N=24;not reported total N=24;not reported separately by arm separately by arm Age (wks, mos, yrs) not reported separately by not reported separately by (mean, SD; median, range) arm. arm. mean 32.5,SD 9.9yrs. mean 32.5,SD 9.9yrs.

Diagnosed not reported separately by not reported separately by seizure study arm. study arm. types, complex partial 8 (33) 8 (33) n (%) complex partial and generalised tonic-clonic 14 (58) 14 (58) generalised tonic-clonic 2 (8) 2 (8)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

241 Newer Drugs for Children with Epilepsy

Table 132 [69]. McKee, 1993297 [same trial as Gillham, 1993193] Drug(s) vigabatrin Target 3g /day, in two doses /day (?mode) maintenance dose (mode) Seizure or refractory generalised tonic-clonic or complex partial seizures with or without syndrome secondary generalisation Type of trial cross over design Add-on or add-on monotherapy Control(s) placebo Eligible age 17-53 years old

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

242 Newer Drugs for Children with Epilepsy

Study population diagnosed with epilepsy or refractory epilepsy but with no further refinement. Table 133 [70]. Carmant, 1999194 abstract interim results only Drug(s) lamotrigine Target details industrial submission SCAB 3001 protocol maintenance dose (mode) Seizure or details industrial submission SCAB 3001 protocol syndrome Type of trial details industrial submission SCAB 3001 protocol design Add-on or monotherapy monotherapy Control(s) valproate Eligible age Age 2 years or older

valproate lamotrigine Number randomised not reported not reported

Age (wks, mos, yrs) not reported not reported (mean, SD; median, range)

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported not reported not reported syndrome(s), n (%) Baseline not reported not reported not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 134 [71]. Kerr, 1999298 abstract interim results only 243 Newer Drugs for Children with Epilepsy

Drug(s) lamotrigine Target details industrial submission SCAB 3001 protocol maintenance dose (mode) Seizure or details industrial submission SCAB 3001 protocol syndrome Type of trial details industrial submission SCAB 3001 protocol design Add-on or monotherapy monotherapy Control(s) valproate Eligible age Age 2 years or older

valproate lamotrigine Number randomised not reported not reported

Age (wks, mos, yrs) not reported not reported (mean, SD; median, range)

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported not reported not reported syndrome(s), n (%) Baseline not reported not reported not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

Table 135 [72]. Montouras, 1999195 abstract [interim results only]

244 Newer Drugs for Children with Epilepsy

Drug(s) lamotrigine Target 200-500mg /day (?mode) maintenance dose (mode) Seizure or not reported syndrome Type of trial parallel design Add-on or monotherapy monotherapy Control(s) valproate Eligible age at least 12 years old

valproate lamotrigine Number randomised 13 16

Age (wks, mos, yrs) median 25 yrs median 26 years (mean, SD; median, range)

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported not reported not reported syndrome(s), n (%) Baseline not reported not reported not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

245 Newer Drugs for Children with Epilepsy

Table 136 [73]. Fakhoury, 2000196 abstract Drug(s) lamotrigine Target not reported maintenance dose (mode) Seizure or uncontrolled epilepsy syndrome Type of trial parallel design Add-on or add on and monotherapy monotherapy Control(s) carbamazepine Eligible age Age 16 years or older

carbamazepine lamotrigine Number randomised not reported not reported

Age (wks, mos, yrs) not reported not reported (mean, SD; median, range)

Diagnosed not reported not reported not reported seizure types, n (%)

Diagnosed not reported syndrome(s), n (%) Baseline not reported seizure frequency (/dy, wk, mo) (mean, SD; median, range)

246 Newer Drugs for Children with Epilepsy

Appendix 10 List of excluded studies.

Table 137 List of excluded studies with reasons for exclusion. No: ID REFERENCE Reason for exclusion 1 3181 [Anon]. Irish Medical Journal 2000; 93(1):26.301 Letter. Abdulrazzak M, et al. Epilepsia 2000; 41 Suppl 7:228- 2 319 302 Not randomised. 229. 3 200 Aberg L, et al. Epilepsia 1999; 40(6):796-799.303 Not randomised. Aldenkamp AP et al. Epilepsia 1998; 39 Suppl 6:188- Abstract; No information on 4 372 304 189. age of patients. 305 Abstract. No information on 5 337 Aldenkamp AP, et al. Epilepsia 1999; 40 Suppl 7:83-84. age of patients. 6 3 Aldenkamp AP, et al. Epilepsia 2000; 41(9):1167-1178.306 Age range ≥18 yrs. 7 3990 Aldenkamp AP, et al. Epilepsia 2002; 43(1): 19-26.307 Healthy volunteers. 308 Abstract. No information on 8 2488 Anbut H, et al. Epilepsia 1995; 36:341. age of patients. 9 344 Anderson WT, III, et al. Epilepsia 1999; 40 Suppl 7:224.309 Not randomized. Angeleri F, et al. Italian Journal of Neurological Sciences 10 2026 310 Not randomised. 1992; 13(9):741-747. 11 1804 Anhut H, et al. Journal of Epilepsy 1995; 8(1):44-50.311 Open-label extension study. Appleton R, et al. Developmental Medicine and Child 12 2755 312 Open-label extension study. Neurology 2001; 43(4):269-273. Arteaga R, et al. Clinical Drug Investigation 1996; 13 1557 313 Open-label extension study. 12(6):287-297. 14 2062 Arteaga R, et al. Epilepsia 1992; 33(5):923-931.314 Not randomised. 15 3713 Arteaga R, et al. Epilepsy Research 1993; 14(1): 73-85.315 Intervention not relevant. Arzimanoglou A, et al. Revue Neurologique 2001; 16 15 316 Not randomised. 157(5):525-536. Banin E, et al. Investigative Ophthalmology & Visual 17 3903 317 Not randomised. Science 2000; 41(4): 1876 B122. 18 424 Bartoli A, et al. Epilepsia 1997; 38(6):702-707.271 Healthy volunteers. Bartolini M, et al. Bollettino - Lega Italiana Contro 19 1910 318 Not randomized. L'Epilessia 1993; Issue 84 (pp 161-162). 20 3033 Belmonte A, et al. Epilepsia 1999; 40:236.319 Not randomised. 21 497 Ben Menachem E, et al. Epilepsia 1996; 37(6):539-543.320 Patients ≥ 18yrs. 22 427 Ben Menachem E. Epilepsia 1997; 38 Suppl 1:S28-S30.321 Age range patients ≥ 18yrs.. Ben-Menachem-E- et al. seizures of non-focal origin. Abstract. No information on 23 423 322 Epilepsia 1997; 38 Suppl 3:60. age of patients.. 24 723 Beran R, et al. Epilepsia 2001; 42(10):1335-1339.323 Not randomised. Abstract. No information on 25 2491 Bergey GK, et al. Epilepsia 1995; 36:344.324 age of patients. Data superseded. 26 1457 Bergey GK, et al.. Neurology 1997; 49(3):739-745.325 Patients ≥ 18yrs. 27 1774 Bernardina BD, et al. Epilepsia 1995; 36(7):687-691.326 Not randomised. 28 1534 Besag FMC, et al. Seizure 1997; 6(1):51-56.327 Open-label extension study. 328 Abstract. No information on 29 384 Betts T, et al. Epilepsia 1998; 39 Suppl 6:68. age of patients.. 30 377 Beydoun A, et al. Epilepsia 1998; 39(2):188-193.329 Age range ≥18 yrs. 330 Abstract. No information on 31 1170 Beydoun A. Epilepsia 1999; 40(Suppl. 6):S13-S16. age of patients. 32 402 Beydoun AA, et al. Epilepsia 1998; 39 Suppl 6:48.331 Abstract; no data on age. 33 3431 Bielicka-Cymerman J, et al. Epilepsia 1999; 40:178.332 Patients ≥ 18yrs. 34 29 Birbeck GL, et al. Neurology 2000; 54(9):1822-1827.333 Age range ≥18 yrs. 334 Abstract. No information on 35 476 Biton V, et al. Epilepsia 1997; 38 Suppl 3:59-60. age of patients. 335 Abstract; No information on 36 373 Biton V, et al. Epilepsia 1998; 39 Suppl 6:125-126. age of patients. 37 3421 Biton V, et al. Epilepsia 1999; 40:218.336 Abstract of review. 38 333 Biton V, et al. Epilepsia 2000; 41 Suppl 7:89-90.337 Abstract, data superseded. 39 1183 Biton V. Neurology 1999; 53(5):1162.338 Correction for ID 1230. Biton, V, et al. Journal of the European College of 40 332 Neuropsychopharmacology 2000; 10(Supplement Abstract, data superseded. 3):S236.339 Boas J, et al. Acta Neurologica Scandinavica 1996; 41 494 340 Patients ≥ 18yrs. 94(4):247-252. Boati E, et al. Bollettino - Lega Italiana Contro L'Epilessia 42 1251 341 Patients ≥ 18yrs. 1998; Issue 102-103(pp 123-127). 43 564 Brodie MJ, et al. Epilepsia 1993; 34 (suppl. 6):68-69.342 Abstract. No information on 247 Newer Drugs for Children with Epilepsy

age of patients. 44 413 Brodie MJ, et al. Epilepsia 1998; 39 Suppl 2:2.343 Open-label extension study. 45 1187 Brodie MJ, et al. Epilepsy Research 1999; 37(1):81-87.344 Patients ≥ 18yrs. 46 1814 Brodie MJ. Lancet 1995; 345(8950):662.345 Correction for ID 524. 47 474 BrodieMJ, et al. Epilepsia 1997; 38 Suppl 3:60.346 Open-label extension study. Browne TR, et al. British Journal of Clinical Pharmacology 48 617 347 Patients ≥ 18yrs. 1989; 27 Suppl 1:95S-100S. 49 3623 Browne TR, et al. Epilepsia 1983; 24(4):521.348 Not randomised. 50 3616 Browne TR, et al. Epilepsia 1986; 27(5):641.349 Open-label extension study. 51 2158 Browne TR, et al. Neurology 1987; 37(2):184-189.350 Patients ≥ 18yrs. 52 2115 Browne TR, et al. Neurology 1991; 41(3):363-364.351 Open-label extension study. 53 2856 Brozmanova M, et al. Epilepsia 1995; 36:S111.352 Open-label extension study. 54 3907 Bruni J, et al. Seizure 2000; 9(3): 224-232.353 Patients ≥ 18yrs. Bruni J. Canadian Journal of Neurological Sciences 1998; 55 2309 354 Patients ≥ 18yrs. 25(2):134-140. 56 37 Bruni J. Epilepsia 1999; 40 Suppl 6:S27-S28.355 Not randomised. Buchanan N. Lamotrigine: A Brighter Future -International 57 4030 356 Not randomised. Congress & Symposium 1996; Series 214:89-102. 58 3213 Buchholt J & Uldall P. Epilepsia 1995; 36:S118-S119.357 Abstract; case series. Canger R, et al. Bollettino - Lega Italiana Contro 59 1429 358 Not randomised. L'Epilessia 1996; Issue 95-96(pp 251-253). Carrazana EJ & Wheeler SD. Neurology 2001; 60 3109 359 Abstract; case study. 56(10):1424. 360 Abstract. No information on 61 438 Chadwick D, et al. Epilepsia 1997; 38 Suppl 3:34. age of patients. 62 3141 Chiron C, et al. Lancet 2000; 356(9242):1638-1642.361 Intervention not relevant. 63 3415 Clark P, et al. Epilepsia 1999; 40:115.362 Not randomised. 64 631 Cocito L, et al. Epilepsy Research 1989; 3(2):160-166.363 Not randomised. 65 2261 Cocito L, et al. Seizure 1993; 2(4):301-307.364 Not randomised. 66 2577 Collins TL, et al. Seizure 2000; 9(4):291-293.365 Case series. 67 2857 Coppola G, et al. Epilepsia 1995; 36:S111-S112.366 Not randomised. Coppola G, et al. Epilepsy Research 2001; 43(3):255- 68 44 367 Not randomised. 260. 69 4359 Coppola G, et al. Epilepsy Research 2002; 49(1):45-48.368 Not randomised. 70 46 Cramer JA. Neurology 1999; 53(9):2212-2213.369 Letter on generalities 71 50 Crawford P, et al. Epilepsia 2001; 42(4):531-538.370 Age range ≥18. Crawford P, et al. Journal of Neurology, Neurosurgery & 72 644 371 Patients ≥ 18yrs. Psychiatry 1987; 50(6):682-686. 73 3690 Curatolo P. Neuropediatrics 1994; 25(1):55.372 Not randomised. 74 453 Czapinski P, et al. Epilepsia 1997; 38 Suppl 3.373 Age range patients ≥ 18yrs. 75 527 Dalla BB, et al. Epilepsia 1995; 36(7):687-691.374 Not randomised. Davies G, et al. Journal of the Neurological Sciences 1997; 76 428 375 Review. 150(Supplement):S163. De Romanis F & Sopranzi N. Clinica Terapeutica 1995; 77 1792 376 Patients ≥ 18yrs. 146(3):203-209. 78 218 Dean C, et al. Epilepsia 1999; 40(1):74-82.377 Patients ≥ 18yrs. 79 526 Dodrill CB, et al. Epilepsia 1995; 36(2):164-173.249 Patients ≥ 18yrs. 378 Abstract. No information on 80 2499 Dodrill CB, et al. Epilepsia 1995; 36:G1. age of patients. 379 Abstract. No information on 81 374 Dodrill CB, et al. Epilepsia 1998; 39 Suppl 6:147. age of patients. Dodrill CB, et al. Epilepsy Research 1999; 35(2):109- Not RCT; invalid comparitor 82 59 380 121. group 83 410 Dollar L, et al. Epilepsia 1998; 39 Suppl 6:190.381 Open-label extension study. Drory VE & Korczyn AD. New Trends in Clinical 84 2099 382 Review. Neuropharmacology 1991; 5(2):49-56. 383 Abstract. Non- randomized 85 3250 Dulac O, et al. Annals of Neurology 2001; 50(3):S104. pharmacokinetic study. Dulac O. Lamotrigine: A Brighter Future -International 86 4045 384 Review. Congress & Symposium 1996; Series 214:69-73. 385 Abstract. Randomisation 87 2630 Duric B, et al. Epilepsia 1999; 40:156. compromised. 88 318 Edwards K, et al. Epilepsia 2000; 41 Suppl 7:104.386 Abstract, data superseded. 89 2853 Eriksson AS, et al. Epilepsia 1995; 36:S110-S111.387 Abstract, data superseded. 90 906 Eriksson AS, et al. Epilepsia 2001; 42(2):230-236.388 Not randomised. 91 2879 Farrell K, et al. Annals of Neurology 1995; 38(3):506.389 Not randomised. 92 348 Fattore C, et al. Epilepsia 1999; 40(6):783-787.261 Healthy women. 93 1621 Faught E, et al. Neurology 1996; 46(6):1684-1690.390 Patients ≥ 18yrs. 94 436 Faught E. Epilepsia 1997; 38 Suppl 1:S24-S27.391 Review. 95 2631 Fichtner K, et al. Epilepsia 1999; 40:156.392 Open-label extension study. 96 2637 Franzoni E, et al. Epilepsia 1999; 40:239.393 Not randomised. 97 3710 French J, et al. Neurology 1993; 43(4):A 307.299 Abstract. No information on

248 Newer Drugs for Children with Epilepsy

age of patients. 98 1634 French JA, et al. Neurology 1996; 46(1):54-61.394 Patients ≥ 18yrs. Froscher W, et al. Clinical Neuropharmacology 1988; 99 2148 395 Intervention not relevant. 11(3):232-240. Frye MA, et al. Journal of Clinical Psychopharmacology 100 2563 396 Not epilepsy. 2000; 20(6):607-614. 101 3796 Galas-Zgorzalewicz B, et al. Epilepsia 1999; 40:273.397 Not randomised. 398 Abstract. No information on 102 2506 Garofalo E, et al. Epilepsia 1995; 36:S119-S120. age of patients. 103 2510 Garofalo E, et al. Epilepsia 1995; 36:S187.399 Not randomised. 103 1421 Gherpelli JLD, et al. Epilepsy Research 1997; 29(1):1-6.400 Not randomised. 104 454 Glauser TA, et al. Epilepsia 1997; 38 Suppl 3:94.401 Open-label extension study. Glauser TA, et al. Epilepsia 2000; 41(4 SUPPL.):S86- 105 1082 402 Open-label extension study. S90. 106 421 Glauser TA, et al. Epilepsia 1997; 38 Suppl 3:131.403 Abstract, data superseded. 107 412 Glauser TA, et al. Epilepsia 1998; 39 Suppl 2:2.404 Open-label extension study. 108 3498 Glauser TA, et al. Neurology 1998; 50(4):02045.405 Open-label extension study. 109 3636 Gobbi G, et al. Epilepsia 1995; 36:S102.406 Not randomised. Gram L, et al. Acta Neurologica Scandinavica 1983; 110 658 407 Not randomised. 68(1):34-39. Gross-Tsur V, et al. Annals of Neurology 1999; 46(3): 524- 111 3786 408 Not randomised. 525. Gross-Tsur V, et al. Annals of Neurology 2000; 48(1): 60- 112 3899 409 Case series. 64. 113 3161 Guberman A, et al. Seizure 2000; 9(2):112-118.410 Not randomised. 114 562 Hamilton MJ, et al. Epilepsia 1993; 34(1):166-173.411 Healthy volunteers. Handforth A, &Treiman DM. Epilepsia 1994; 35(5):1032- 115 545 412 Patients ≥ 18yrs. 1037. Hanefeld F. Aktuelle Neurologie 1992; 19(Suppl. 1):S17- 116 2056 413 Not randomised. S20. 117 3287 Hanny A et al. Epilepsia 1999; 40:132.414 Not randomised. Harding GFA, et al. Documenta Ophthalmologica 1998; 118 1126 415 Healthy volunteers. 97(2):179-188. 416 Abstract. No information on 119 2505 Hayes A, et al. Epilepsia 1995; 36:S119. age of patients. 120 2511 Hayes A, et al. Epilepsia 1995; 36:S187.417 Not randomised. 418 Abstract. No information on 121 2500 Hayes AG, et al. Epilepsia 1995; 36:G3. age of patients. 419 Abstract. No information on 122 417 Hogan RE, et al. Epilepsia 1998; 39 Suppl 6:125. age of patients. 420 No information on age of 123 93 Hogan RE, et al. Epilepsy Research 2000; 41(1):23-28. patients. 124 3425 Hosain S, et al. Annals of Neurology 1999; 46(3):532.421 Not randomised. Houtkooper M, et al. Acta Neurologica Scandinavica 1984; Abstract. No information on 125 3240 422 70(3):221-222. age of patients. 126 3638 Ignatowicz R, et al. Epilepsia 1995; 36:S103.423 Not randomised. 127 2842 Isojarvi JIT, et al. Epilepsia 1995; 36:290.424 Not randomised. 128 2874 Isojarvi JIT, et al. Epilepsia 1995; 36:S117.425 Not randomised. 129 620 Jawad S, et al. Epilepsia 1989; 30(3):356-363.426 Not randomised. Kalviainen R, et al. Epilepsy Research 1998; 30(1):31- 130 368 427 Age range ≥18 yrs. 40. 428 Abstract. No information on 131 416 Kalviainen R, et al. Epilepsia 1998; 39 Suppl 2:5. age of patients. Kalviainen R, et al. Epilepsy Research 1996; 25(3):291- 132 504 429 Patients ≥ 18yrs. 297. Kluger G, et al. European Journal of Paediatric Neurology 133 825 430 Not randomised. 2001; 5(1):37-40. 134 2682 Kohrman MH. Annals of Neurology 1998; 44(3):B14.431 Not randomised. 135 3641 Koul RL, et al. Epilepsia 1995; 36:S103-S104.432 Not randomised. 433 Abstract. No information on 136 379 Kraemer G, et al. Epilepsia 1998; 39 Suppl 6:132. age of patients. 434 Abstract. No information on 137 430 Lee S & Chang, Epilepsia 1997; 38 Suppl 3:70. age of patients. 138 1876 Leiderman D. Epilepsia 1994; 35(Suppl.5):S74-S76.435 Review. 139 2632 Leoni S, et al. Epilepsia 1999; 40:171-172.436 Not randomised. Levisohn PM. Journal of Child Neurology 2000; 15 Suppl 140 122 437 Review. 1:S22-S26. 438 Abstract. No information on 141 336 Lindberger M. Epilepsia 1999; 40 Suppl 7:98-99. age of patients. Livingston JH, et al. British Journal of Clinical 142 3596 439 Not randomised. Pharmacology 1989; 27:S109-S112. 143 608 Loiseau P, et al. Epilepsy Research 1990; 7(2):136-145.440 Patients ≥ 18yrs. 144 632 Luna D, et al. Epilepsia 1989; 30(4):430-437.441 Not randomised. 249 Newer Drugs for Children with Epilepsy

145 2378 Mandelbaum DE, et al. Neurology 2001; 56(8):A46.442 Not randomised. Marescauz C. Lamotrigine: A Brighter Future -International 146 4094 443 Review. Congress & Symposium 1996; Series 214:75-80. 147 282 Martin R, et al. Epilepsia 2001; 42(6):764-771.444 Age range ≥18 yrs. 148 2665 Martin R, et al. Neurology 1999; 52(2):321-327.445 Healthy volunteers. 446 Abstract. No information on 149 312 Martinez W, et al. Epilepsia 2000; 41 Suppl 7:100. age of patients. 150 3642 Martinezbermejo A, et al. Epilepsia 1995; 36:S104.447 Not randomised. 448 Abstract. No information on 151 3525 Martinezlage J, et al. Epilepsia 1995; 36:S149-S150. age of patients. 152 2636 Martinovic Z. Epilepsia 1999; 40:224.449 Not randomised. 153 503 Matsuo F, et al. Epilepsia 1996; 37(9):857-862.450 Patients ≥ 18yrs. 154 577 Matsuo F, et al. Neurology 1993; 43(11):2284-2291.451 Patients ≥ 18yrs. 155 403 Mattson RH, et al. Epilepsia 1998; 39 Suppl 6:55.452 Open-label extension study. McKee PJW, et al. British Journal of Clinical Pharmacology 156 1899 453 Not randomised. 1994; 37(1):27-32. 157 341 Meador KJ, et al. Epilepsia 1999; 40(9):1279-1285.454 Healthy volunteers. 158 3116 Meador KJ, et al. Neurology 2001; 56(9):1177-1182.455 Healthy volunteers. Mecarelli O, et al.. Clinical Neuropharmacology 2001; 159 132 456 Healthy volunteers. 24(1):23-26. 160 625 Mervaala E, et al. Epilepsia 1989; 30(2):189-193.457 Not randomised. 161 550 Messenheimer J, et al. Epilepsia 1994; 35(1):113-121.458 Patients ≥ 18yrs. Messenheimer JA, et al. Epilepsia 1998; 39 Suppl 6:51- 162 397 459 Open-label extension study. 52. Michelucci R, et al. Bollettino - Lega Italiana Contro 163 1428 460 Patients ≥ 18yrs. L'Epilessia 1996; Issue 95-96(pp 255-256). 164 3527 Michelucci R, et al. Epilepsia 1995; 36:S150.461 Patients ≥ 18yrs. 165 395 Michelucci R, et al. Epilepsia 1998; 39 Suppl 2:67.462 Abstract. Patients ≥ 18yrs. Michelucci R, et al. Journal of Epilepsy 1992; 5(4):248- 166 2031 463 Not randomised. 252. 167 1928 Michelucci R, et al. Journal of Epilepsy 1994; 7(2):88-93.464 Open-label extension study. 168 3032 Micheu C, et al. Epilepsia 1999; 40:229.465 Not randomised. 169 2515 Mikati M, et al. Neurology 1995; 45(4):A201-A202.466 Not randomised. Mims J, et al. Journal of Child Neurology 1997; 12(1):64- 170 2991 467 Not randomised. 67. Montouris GD, et al. Epilepsia 2000; 41 Suppl 1:S77- 171 135 468 Open-label extension study. S81. 172 3389 Morita DA, et al. Neurology 2000; 54(7):A193.469 Abstract; case control study. 470 Not randomized. Patients ≥ 173 258 Mortimore C, et al. Seizure 1998; 7(5):359-364. 18yrs. 174 141 Muscas GC, et al. Seizure 2000; 9(1):47-50.471 Not randomised. 175 2855 Muszkat M, et al. Epilepsia 1995; 36:S111.472 Not randomised. 176 387 Noachtar S, et al. Epilepsy Research 1998; 31(1):47-57.473 Healthy volunteers. O'Donoghue MF, et al. Lancet 1995; 345(8960):1300- 177 1791 474 Letter about ID 524. 1302. 178 1925 Oommen K, et al. Epilepsy Research 1994; 18(1):67-73.475 Open-label extension study. 476 Abstract. No information on 179 575 Penry KJ, et al. Epilepsia 1993; 34(Suppl. 6):67. age of patients. Pledger G, et al. Bollettino - Lega Italiana Contro 180 1430 477 Review. L'Epilessia 1996; Issue 95-96(pp 247-250). 181 515 Privitera M, et al. Neurology 1996; 46(6):1678-1683.478 Patients ≥ 18yrs. Ramsay RE, et al. Epilepsy Research 1991; 10(2-3):191- 182 604 479 Patients ≥ 18yrs. 200. 480 Abstract. Data superseded 183 356 Ramsey ER, et al. Epilepsia 1999; 40 Suppl 7:111. 2002. Regesta GG, & Tanganelli P. Journal of the Neurological Abstract. No information on 184 484 481 Sciences 1997;(Sept):S167. age of patients. Regesta GG, & Tanganelli P. Bollettino Lega Italiana 185 486 482 Patients ≥ 18yrs. Contro L'Epilessia 1997;(99 SUPPL. 1):27-32. Regesta GG, & Tanganelli P. Epilepsia 1997; 38 Suppl Abstract. No information on 186 483 483 3:58. age of patients. Reinikainen K, et al. Acta Neurol Scand 1984; 69(Suppl. 187 657 484 Patients ≥ 18yrs. 98):89-90. Reinikainen KJ, et al. Epilepsy Research 1987; 1(5):284- 188 641 485 Patients ≥ 18yrs. 289. 189 520 Richens A, et al. Epilepsy Research 1995; 21(1):37-42.486 Patients ≥ 18yrs. 487 Not a relevant intervention. 190 932 Richens A, et al. Seizure 2000; 9(8):537-543. Patients ≥ 18yrs. Richens A. Lamotrigine: A Brighter Future -International “Adults” but no other 191 4133 488 Congress & Symposium 1996; Series 214:9-14. information on age of patients. 192 169 Ritter F, et al. Epilepsia 2000; 41 Suppl 1:S82-S85.489 Open-label extension study. 490 Abstract, long term extension 193 394 Ritter FJ, et al.. Epilepsia 1998; 39 Suppl 2:2-3. of RCT. 250 Newer Drugs for Children with Epilepsy

491 Abstract. No information on 194 508 Rosenfeld W, et al. Epilepsia 1996; 37(Suppl 1):153. age of patients. 195 3432 Rosenfeld WE. Epilepsia 1999; 40:226.492 Not randomised. 196 1265 Rowbotham M, et al. JAMA 1998; 280(21):1837-1842.493 Not epilepsy. Patients ≥ 18yrs. 494 Abstract. No information on 197 3347 Sachdeo R, et al. Neurology 1995; 45(4):A202. age of patients. 198 457 Sachdeo RS, et al. Epilepsia 1997; 38 Suppl 3:80.495 Open-label extension study. Sander JWAS et al. Epilepsy Research 1990; 6(3):221- 199 2125 496 Patients ≥ 18yrs. 226. 200 2854 Sanmarti F, et al. Epilepsia 1995; 36:S111.497 Not randomised. 498 Abstract. No information on 201 3342 Schachter S et al. Epilepsia 1995; 36:S148. age of patients. Schachter SC, et al.. Journal of Epilepsy 1995; 8(3):201- 202 530 499 Patients ≥ 18yrs. 209. 203 534 Schachter SC. Epilepsia 1995; 36 Suppl 6:S2-S6.500 Review. 501 Abstract. No information on 203 458 Schacter SC, et al. Epilepsia 1997; 38 Suppl 3:30. age of patients. Schapel, G., et al. Australian & New Zealand Journal of 204 599 502 Abstract; data superseded. Medicine 1991; 21:620. 205 1937 Schlumberger E, et al. Epilepsia 1994; 35(2):359-367.503 Not randomised. 504 Abstract. No information on 206 560 Schmidt D, et al. Epilepsia 1993; 34(Suppl. 2):66. age of patients. Schmitz-Moormann W & Kruse R. Aktuelle Neurologie 207 2054 505 Not randomised. 1992; 19(Suppl. 1):S23-S25. Schwabe MJ & Wheless JW. Annals of Neurology 2000; 208 3381 506 Not randomised. 48(3):17. Sharief M, et al. Epilepsy Research 1996; 25(3):217- 209 495 507 Patients ≥ 18yrs. 224. 210 3022 Siemes H. Epilepsia 1999; 40:68.508 Not randomised. Sillanpaa M, & Pihlaja T. Acta Paediatrica Hungarica 1988; 211 639 509 Not randomised. 29(3-4):359-364. 212 376 Sinclair KR, et al. Epilepsia 1998; 39 Suppl 6:250-251.510 Healthy adults. 213 3643 Siskova D. Epilepsia 1995; 36:S104.511 Not randomised. 214 3621 Sivenius J, et al. Epilepsia 1985; 26(5):537.512 Not randomised. Sivenius J, et al. Upsala Journal of Medical Sciences Abstract. No information on 215 3618 513 1986;46. age of patients. Sivenius J. Acta Neurologica Scandinavica 1988; 216 3607 514 Open-label extension study. 77:139. 217 580 Smith D, et al. Epilepsia 1993; 34 (SUPPL. 5):S31-S35.515 Not randomised. Steiner TJ & Findley LJ. Lamotrigine: A Brighter Future - 218 4151 International Congress & Symposium 1996; Series 214:31- Not epilepsy. 35.516 Steinhoff BJ, et al. Epilepsy Research 1997; 29(1):35- 219 469 517 Healthy adults. 47. Stolarek I, et al. Journal of Neurology, Neurosurgery & No information on age of 220 558 518 Psychiatry 1994; 57(8):921-924. patients. 519 Abstract. No information on 221 3646 Tanganelli P & Regesta G. Epilepsia 1995; 36:S104. age of patients. Tanganelli P, & Regesta GG. Epilepsy Research 1996; 222 516 520 Patients ≥ 18yrs. 25(3):257-262. Tartara A, et al. Acta Neurologica Scandinavica 1992; 223 2064 521 Patients ≥ 18yrs.. 86(3):247-251. 522 Abstract. No information on 224 3526 Tassinari C, et al. Epilepsia 1995; 36:S150. age of patients. 225 496 Tassinari CA, et al. Epilepsia 1996; 37(8):763-768.523 Patients ≥ 18yrs. The Italian Study Group on Vigabatrin. Journal of 226 2276 524 Not randomised. Neurological Sciences 1992; 13(9):741-747. 227 511 Thomas L, et al. Seizure 1996; 5(3):205-208.525 Healthy volunteers. 526 Abstract. No information on 228 2490 Trudeau VL, et al. Epilepsia 1995; 36:343. age of patients. 229 3341 Uldall P, et al. Epilepsia 1995; 36:S147-S148.527 Not randomised. Uldall P, et al. Epilepsy Research 2000; 42(2-3):159- 230 188 528 Not randomised. 168. 529 Abstract. No information on 231 3357 Uthman B, et al. Annals of Neurology 1993; 34(2):272. age of patients. Wheless JW. Journal of Child Neurology 2000; 15 Suppl 232 193 530 Review. 1:S7-13. 233 2867 Wieser HG, et al. Epilepsia 1995; 36:S114-S115.531 Open-label extension study. 234 1779 Wieser HG. Ars Medici 1995; 85(6):449-453.532 Patients ≥ 18yrs. 235 199 Yen DJ, et al. Epilepsia 2000; 41(9):1162-1166.533 Patients ≥ 18yrs. Yuen AWC, et al. Can J Neurol 1993; 20 (suppl. 4): Abstract. No information on 236 573 534 S150 age of patients. 237 3654 Zahner B, et al. Epilepsia 1995; 36:S106.535 Abstract. No information on

251 Newer Drugs for Children with Epilepsy

age of patients.. 238 2951 Zakrzewska JM, et al. Pain 1997; 73(2):223-230.536 Not epilepsy.

Appendix 11 Unobtainable publications

Table 138 List of unobtainable publications Reference 1 Aikia M, Sivenius JK. Oxcarbazepine vs phenytoin in monotherapy for newly diagnosed epilepsy with a special reference to memory function. 18th International Epilepsy Congress 1989;91.537 2 Loiseau P, Bes AM. Double-blind placebo controlled crossover study of lamotrigine (Lamictal) as add-on therapy in patients with refractory partial seizures. 18th International Epilepsy Congress 1989;144.538 3 Sivenius J, Kalviainen RY. A double-blind study of gabapentin in the treatment of partial seizures. 18th International Epilepsy Congress 1989;91.539 4 Hsiang-Yu Y, Der-Jen Y, Chun-Hing Y, Ming-Shung S. Double-blind, placebo-controlled trial of topiramate as add-on therapy in patients with refractory partial epilepsy. Epilepsia 1999; 40:97.540 5 Kharlamov DA, Prityko AG, Ayvazian SO, Yavorskaya MM. Lamotrigine in the treatment of drug-resistant epilepsies in children. Epilepsia 1999; 40:175.541 6 Kivity S, Shorer Z, Unit S. Lamotrigine add-on therapy in children with drug-resistant epilepsy: Low incidence of rash associated with low initial and titration doses. Epilepsia 1999; 40:172.542 7 Mirza W, Biton V, Barrett P, Vuong A, Hammer A. Weight gain associated with valproate monotherapy in patients with epilepsy: An interim analysis of a randomized, double- blinded comparative clinical trial with lamotrigine. Epilepsia 1999; 40:282.543 8 Mojs E, Galas-Zgorzalewicz B. The long term prognosis of cognitive functioning in epileptic children and adolescents in bitherapy with vigabatrin. Epilepsia 1999; 40:275.544 9 Rintahaka PJ, Gaily E, Liukkonen E, Paetau R, Grandstrom ML. Topiramate in the treatment of intractable pediatric epilepsy. Epilepsia 1999; 40:135.545 10 Slapal R, Zaplatilova L. Quality of life with lamotrigine in epileptic children - Our five-year experience. Epilepsia 1999; 40:180-181.546 11 Sokic DV, Pavlovic Z, Jankovic SM, Levic Z. Lamotrigine for the treatment of juvenile myoclonic epilepsy. Epilepsia 1999; 40:38.547 12 Uran N, Calkavur SS, Kalkan S. Vigabatrin in the therapy-resistant childhood epilepsies. Epilepsia 1999; 40:255.548 13 Uran N, Serdarodlu G, Calkavur T, Serdarodlu E. Lamotrigine treatment in childhood drug resistant epilepsy. Epilepsia 1999; 40:176.549 14 Uysal S, Deda G, Karagol U. Lamotrigine monotherapy in childhood epilepsy and the comparative evaluation of the effects of other antiepileptic drugs on evoked potentials. Epilepsia 1999; 40:251-252.550 15 Biraben A, Beaussart M, Josien E, Pestre M, Schaff JL, Sevestre M. Tiagabine as adjunctive treatment of partial seizures in patients with epilepsy: A comparison of two dose regimens. Epilepsia 2000; 41 Suppl Florence:96.551 16 Brodie MJ, Anhut H, Murray G, Maton S. Gabapentin versus lamotrigine monotherapy: A double-blind comparison. Epilepsia 2000; 41 Suppl Florence:138.552 17 Carpay JA, Veendrick-Meekes MJBM, Beun AM, Arends LR, Schlosser A. Carer assessment of quality of life related to seizure severity and side effects of lamotrigine in mentally retarded epilepsy patients. Epilepsia 2000; 41 Suppl Florence:114.553 18 Gil KB, Nagel N, Verger K, Sol JM, Morralla C, Hernandez G. Safety of gabapentin vs. valproic acid as add-on therapy to carbamazepine. Epilepsia 2000; 41 Suppl Florence:105.554 19 Kazibutowska Z, Stelmach-Wawrzyczek A. Efficacy of therapy with new antiepileptic drugs (tiagabine, gabapentin, topiramate) in drug-resistant epilepsy. Epilepsia 2000; 41 Suppl Florence:38.555 20 Kwan SY, Yiu CH, Su MS. A double blind study of gabapentin in partial seizures. Epilepsia 2000; 41 Suppl Florence:69.556 21 Mecarelli O, de Feo MR, Del Priore D, Piacenti A, Pulitano P, Rinalduzzi S et al. Adverse events and neurophysiological modifications induced by a single dose of topiramate in healthy volunteers: A placebo- controlled study. Epilepsia 2000; 41 Suppl Florence:106.102 22 Meador KJ, Loring DW, Ray PG, Perrine KR, Vasquez BR, Kalbosa T. Cognitive side effects of carbamazepine and lamotrigine compared to non-drug state. Epilepsia 2000; 41 Suppl Florence:113.557 23 Neto W, Gassmann MC. Efficacy and tolerability of 200 mg/day topiramate in a placebo-controlled comparison of titration rates. Epilepsia 2000; 41 Suppl Florence:35.558 24 Privitera MD, Brodie MJ, Neto W, Wang S. Monotherapy in newly diagnosed epilepsy: Topiramate vs. investigator choice of carbamazepine or valproate. Epilepsia 2000; 41 Suppl Florence:138.559 25 Veendrick-Meekes MJBM, Beun AM, Carpay JA, Arends LR, Schlosser A. Use of lamotrigine as adjunctive therapy in patients with mental retardation and epilepsy: An interim analysis of a double blind study with evaluation of behavioural effects. Epilepsia 2000; 41 Suppl Florence:97.560

26 Abou KB. Long-term seizure freedom with levetiracetam. JNS 2001; 187(Suppl. 1).561 27 Cramer JA. Short-term treatment with levetiracetam enhances health-related quality of life in patients with refractory epilepsy. JNS 2001; 187(Suppl. 1).562 28 Kerr M, Moorat A, and CP. Lamotrigine compared to valproate: a randomised open label switch to monotherapy study in patients with uncontrolled epilepsy. JNS 2001; 187(Suppl. 1).563 29 O'Neill FF-G. Lamotrigine versus carbamazepine in adult and elderly patients with epilepsy. JNS 2001; 187(Suppl. 1).101 30 Remy C, Favel P, Tell G. Etude en double aveugle contre placebo en permutations croisees du vigabatrin dans l'epilepsie de l'adulte resistant a la therapeutique. Boll Lega Ital Epilessia 1986; 54:241-243.103

252 Newer Drugs for Children with Epilepsy

31 Michelucci R, Tassinari CA, Forti A, Ambrosetto G, Rubboli G, Iudice A et al. Vigabatrin in the treatment of drug-resistant epilepsy: Short-term results of 2 placebo - controlled trials. Bollettino - Lega Italiana Contro L'Epilessia 1988; Issue 64 (pp 167-169).564 32 Angeleri F, Scarpino O, Avanzini G, Binelli D, Baruzzi A, Procaccianti G et al. A multicenter study of Vigabatrin in refractory epilepsy. Bollettino - Lega Italiana Contro L'Epilessia 1990; Issue 70-71(pp 121-123).565 33 Dulac O, Chiron C, Luna D, Cusmai R, Pajot N, Beaumont D et al. Vigabatrin in childhood epilepsy. Journal of Child Neurology 1991; 6 (SUPPL. 2): 2S30-2S37.566 34 Kalviainen R, Aikia M, Partanen J, Sivenius J, Mumford J, Saksa M et al. Randomized controlled pilot study of vigabatrin versus carbamazepine monotherapy in newly diagnosed patients with epilepsy: an interim report. Journal of Child Neurology 1991; Suppl 2:S60-S69.567 35 Espelillo J, Ritter FJ, Frost MD, Spiegel RE, Reife R. Topiramate in childhood epilepsy - titration, adverse, events, and efficacy in multiple seizure types. Epilepsia 1995; 36:287.568 36 Belopitova L, Dimova P, Tomov V. Comparative study on the therapeutic effect of oxcarbazepine (trileptal) and carbamazepine (finlepsin) in children epilepsy. Bulgarian Medicine 2000; 8(1):12-15.104

Appendix 12 Health state questionnaire.

HEALTH STATE A

The patient experiences unacceptable side effects of drug therapy (that cannot be controlled by a change of dose) such that a change of therapy is initiated.

Below is the health state description section of the EuroQol instrument that has been slightly modified to relate to a child population. Drawing on your clinical experience and by placing a tick in one box in each group below, please indicate which statement best describes the average child in State A. The child has focal epilepsy, is between the ages of 7 and 12 years, has no motor impairments, and either does or does not have moderate learning difficulties.

Child of age 7-12 years with focal epilepsy and no motor impairments Without With learning moderate difficulties learning difficulties Mobility He/She has no problems walking about He/She has some problems walking about He/She is confined to bed

Self-care* He/She has no problems with self-care He/She has some problems with washing or dressing him/herself

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He/She is unable to wash or dress him/herself

Usual activities (e.g. going to school, hobbies, sports, playing)* He/She has no problems with usual activities He/She has some problems with usual activities He/She is unable to do his/her usual activities

Pain/Discomfort He/She has no pain or discomfort He/She has moderate pain or discomfort He/She has extreme pain or discomfort

Anxiety/Depression He/She is not anxious or depressed He/She is moderately anxious or depressed He/She is extremely anxious or depressed

* 'No problems' would suggest a healthy child with no impairment and no learning difficulties. Appendix 13 Trial data

Trial details Trial ID Nieto-Barrera, 2001 Drug(s) lamotrigine Target maintenance dose lamotrigine 2-15 mg/kg/day (oral); carbamazepine 5- (mode) 40mg/kg/day (oral) Seizure or syndrome newly diagnosed partial epilepsy Type of trial design parallel Add-on or monotherapy? monotherapy Control(s) carbamazepine Study start and end dates Not stated Centres and location Multicentre; Europe, Egypt and Mexico

Trial design Baseline None Titration (including details Lamotrigine: of schedule and frequency 6 weeks of doses) Dose escalated every 2 weeks from 0.5mg/kg/day to target of 2- 15mg/kg/day (2-12 years old) or 25mg/day to target of 200- 700mg/day (13-64 years old) One dose per day Carbamazepine: Titration period not stated Titration schedule not stated; "slow increase until best response was obtained, according to data sheet recommendations". Doses of 5-40mg/kg/day (2-12 years old) or 100-1500mg/day (13-64 years old) Maintenance 18 weeks Withdrawal None

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Timing and additional NA (no baseline eligibility for phase) randomisation/continuation on study Comments on design Titration schedule much more clearly defined for lamotrigine; patients on lamotrigine arm 'withdrawn' if dose reduction required during escalation phase or whilst on lowest maintenance dose, but no similar criteria given for carbamazepine. Quality Was assignment of Yes assessment treatment described as random? Was method of No (except stratified by age and country) randomisation described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to Open label study treatment? Was method of blinding NA adequately described? Were eligibility criteria Yes described? Were groups comparable at Yes (data not reported for children study entry? separately) Were groups treated Can't tell identically apart from the intervention? Was ITT used? No

Were withdrawals stated? Yes (but see comment) Were reasons for Information withdrawals stated? incomplete Was a power calculation No done? Comments Mixed age trial, ages 2-83 years. Patients aged 13-64 regarded as single group but results for age-group 2-12 reported separately; these results will be used for this review. Numbers withdrawing not stated for all reasons; Kaplan-Meier curve for all-cause withdrawal provides estimate of percentage withdrawing. Eligibility Inclusion criteria 1. Newly diagnosed or currently untreated partial epilepsy criteria 2. Seizures easily recognised by patient or carer & classifiable by the International Classification of Seizures 1981 3. At least 2 partial seizures in the 6 months previous to study with at least one partial seizure or secondarily generalised tonic-clonic seizure in the 3 months preceding study 4. Evidence of focal radiological or EEG abnormalities

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Exclusion criteria None reported

Baseline characteristics Carbamazepine Lamotrigine Number randomised 75 153 Number analysed 64 134 Age (wks, mos, yrs) Median 19, 2-83 yrs Median 20, 2-77 yrs (mean, SD; median, range) Male:female 53:47 53:47 Weight (kg, lbs) Mean 54kg Mean 54kg (mean, SD; median, range) Duration of epilepsy (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Age at diagnosis (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Newly diagnosed, n (%) Not reported Not reported

Previously diagnosed, n (%) Not reported Not reported Refractory, n (%) - - - definition of refractory Diagnosed seizure types, n Simple partial 88 (21%) 32 (16%) (%) Complex partial 185 (44%) 78 (39%) Secondarily generalised 228 (55%) 126 (63%) Generalised 6 (1%) 1 (<1%)

Diagnosed syndrome(s), n - - - (%)

Baseline seizure frequency All seizures Mean 10.07/month Mean 6.84 (/dy, wk, mo) Median 0.67, 0.2- Median 0.50, 0.2- (mean, SD; median, range) 1500 600

No concomitant AEDs, n None 100% 100% (%) Concomitant AEDs, n (%) - - -

Previous AEDs, n (%) - Not stated Not stated

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Comments Baseline characteristics reported for whole group only. Eligibility included currently untreated epilepsy; not clear if any patients previously treated. [Missing details may be available in industrial submission Zip file CHECK] Monitoring Was monitoring of plasma No and levels done (including study outcomes drug)? Were arrangements to blind NA plasma monitoring results mentioned? Who recorded seizure Patient or carer frequency? How often was seizure Daily (seizure frequency measured? diaries) Frequency of clinic visits 0, 4, 12, 24 wks (and on withdrawal if before 24 week) Primary outcome(s) 1. Proportion seizure-free in the last 16 weeks of treatment and including timepoints if who had not withdrawn before week 22 repeated 2. Proportion seizure-free in the last 16 weeks of treatment and who had not withdrawn before week 18

Secondary outcome(s) 1. Time to withdrawal from study (measure of global excluding AEs effectiveness combining efficacy and tolerability)

'Ad hoc' outcomes (if 1. Proportion withdrawn for adverse emphasised and not in events methods) Comments Primary outcomes include only patients that did not withdraw before weeks 22 and 18; this destroys the principle of intention to treat and compromises randomisation.

Results Carbamazepine Lamotrigine (ITT only; unadjusted where available) Median follow-up 24 months 24 months

Maintenance dose achieved Mean 16.9mg/day Mean 3.4mg/day Median 16.0, 5.2- Median 2.7, 0.05- 36.5 10.5 Withdrawals including Total withdrawals reasons where specified (all causes) 11 (15) 21 (13) Withdrawal for adverse events 5 (7) 8 (5)

Results (diff, or by CI for difference; arm) p-value

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Primary outcome(s) 1. Seizure-free in 48/64 (75) last 16 weeks and carbamazepine -22-5%; p = .205 follow-up to week 22 89/134 (66) lamotrigine

2. Seizure-free in last 16 weeks and 48/75 (64) follow-up to week 18 carbamazepine -21-6%; p = ns 89/158 (56) lamotrigine

ITT analysis not possible with these outcomes

Secondary outcomes 1. Global Proportions withdrawing: effectiveness (time to 11 (15%) carbamazepine withdrawal from 21 (13%) lamotrigine study) Kaplan-Meier curves not given for 2-12 yrs age group

'Ad hoc' outcomes 1. Proportion 5/75 (7%) p=.761 withdrawn for Carbamazepine adverse events 8/158 (5%) Lamotrigine

Comments (including whether unadjusted results Primary outcomes limit analysis to reported) patients that complete study to weeks 18 or 22; does not allow ITT analysis. Doses achieved in weeks 7-24 given in mg/day rather than mg/kg/day for age range 2-12 years.

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Trial details Trial ID Zamponi, 1999 Drug(s) vigabatrin Target maintenance dose vigabatrin 50-60mg/kg/day; carbamazepine 1520mg/kg/day (mode) (oral) [typo?] Seizure or syndrome newly diagnosed partial epilepsy Type of trial design parallel Add-on or monotherapy? monotherapy Control(s) carbamazepine Study start and end dates not reported Centres and location 1 centre in Italy

Trial design Baseline none Titration (including details 4 weeks of schedule and frequency carbamazepine - starting dose 5mg/kg/day increased at 3 to 4 of doses) day intervals (dose increments not stated) vigabatrin - starting dose 10 to 15mg/kg/day increased at 3 to 4 day intervals (dose increments not stated) 2 doses/day

Maintenance 100 weeks (assumed from "2 year follow-up", assumed to refer to total trial period) Withdrawal none Timing and additional NA (no baseline eligibility for period) randomisation/continuatio n on study Comments on design Very poor quality of reporting; not clear that trial was randomised.

Quality Was assignment of Yes assessment treatment described as random? Was method of No randomisation described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to Open study treatment? Was method of blinding NA adequately described? Were eligibility criteria No described? Were groups comparable Can't tell; large imbalance in numbers randomised for a small at study entry? single centre study, big age difference, patient characteristics poorly reported Were groups treated Can't tell identically apart from the intervention? Was ITT used? Can't tell Were withdrawals stated? Yes Were reasons for Yes (but see withdrawals stated? comment) Was a power calculation No

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done? Comments Very poor quality of reporting Reasons for withdrawal were stated but cannot be certain that these were complete data.

Eligibility Inclusion criteria Children with newly diagnosed partial criteria epilepsy

Exclusion criteria Not reported

Baseline characteristics Carbamazepine Vigabatrin Number randomised 32 38 Number analysed Not stated Not stated Age (wks, mos, yrs) mean 9 yrs 5 mean 7 yrs 4 (mean, SD; median, range) months months range 3-13 yrs 2 range 6 months-10 months yrs 3 months Male:female 17:15 21:17 Weight (kg, lbs) Not reported Not reported (mean, SD; median, range) Duration of epilepsy (wks, mos, yrs) <1 month 27 <1 month 35 (mean, SD; median, range) (84.3%); 2 yrs 2 (92.1%); 18 months (6.2%); no data 3 1 (2.6%); 5 yrs 2 (9.6%) (5.2%) Age at diagnosis (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Newly diagnosed, n (%) 32 (100%) 38 (100%) (8 patients had received a different drug started less than one month before) Previously diagnosed, n None None (%) Refractory, n (%) NA NA - definition of refractory Diagnosed seizure types, n complex partial 15 (46.8) 17 (44.7) (%) secondarily generalised 14 (43.7) 18 (47.3) unilateral 0 (-) 1 (2.6) partial with spasms 0 (-) 2 (5.2) partial elementary 3 (9.3) 0 (-)

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Diagnosed syndrome(s), n partial idiopathic 9 (28.1) 12 (31.5) (%) cryptogenic 16 (50) 16 (42.1) symptomatic 7 (21.8) 10 (26.3)

Baseline seizure frequency Number of seizures (/dy, wk, mo) prior to starting (mean, SD; median, range) treatment <10 28 (87.5) 30 (78.9) 10 to 50 4 (12.5) 5 (13.1) >50 0 (-) 3 (7.8)

No concomitant AEDs, n NA NA NA (%) Concomitant AEDs, n (%) NA NA NA

Previous AEDs, n (%) carbamazepine None, or not 6 (15.7) clobazam reported 1 (2.6) valproate 1 (2.6) (4 discontinued due to rash on carbamazepine; 4 discontinued due to lack of efficacy) Comments 8/38 patients on vigabatrin had started an alternative treatment within a month previous; no similar treatment switches described for the carbamazepine group. Raises question as to whether trial prospectively randomised and when treatment actually started. Monitoring Was monitoring of plasma No and levels done (including outcomes study drug)? Were arrangements to NA (open study) blind plasma monitoring results mentioned? Who recorded seizure Not reported frequency? How often was seizure Not reported frequency measured? Frequency of clinic visits Months 1, 3, 6, 12, 18, 24 Primary outcome(s) Not clear if any outcomes prespecified including timepoints if repeated

Secondary outcome(s) Not clear if any outcomes prespecified excluding AEs

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'Ad hoc' outcomes (if 1. Number of relapses (not defined) emphasised and not in methods) Comments

Results Carbamazepine Vigabatrin (ITT only; unadjusted where available) Median follow-up 2 years 2 years (assumed) (assumed) Maintenance dose achieved 1520mg/kg/day 50 to 60mg/kg/day [typo?] Withdrawals including Total withdrawals 8 6 reasons where specified Lack of efficacy 2 5 Adverse events 6 1

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) None stated NA NA

Secondary outcomes none stated NA NA

'Ad hoc' outcomes 1. Number of 7/32 (21.9%) No comparative relapses (not carbamazepine analysis reported defined; assumed to 9/38 (23.7%) be recurrence of vigabatrin seizures)

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Comments (including whether unadjusted results Very poor reported) reporting.

Adverse Criteria for reporting None stated Carbamazepine Vigabatrin Events Events Irritability/excitabili ty 0 6 (15.7) Weight gain 3 (9.3) 10 (26.3) Excessive sedation 6 (18.7) 0 (-) Rash 6 (18.7) 0 (-)

Comments Authors note that an increased risk of asymptomatic visual filed constriction may be associated with vigabatrin and that "in affected patients" the treatment was discontinued Conclusions Author's conclusions Vigabatrin and carbamazepine are of similar efficacy in children with newly diagnosed partial epilepsy

Our conclusions This trial is extremely poorly reported; it is not clear whether it was prospectively randomised, there are no inclusion or exclusion criteria given, unclear methodology, no definition of the outcome measure, etc.

The maintenance dose of carbamazepine is reported as per kg but appears more likely to be an absolute dose.

An abstract reporting preliminary results of this study was published in 1995 (#3637). At that time 57 pts were enrolled,

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30 randomised to vigabatrin, 27 to carbamazepine. Outcome seemed to be 'recurrences', again no definition.

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Trial details Trial ID Duchowny, 1999 Drug(s) lamotrigine Target maintenance dose 1-15mg/kg/day, maximum 750mg/day (oral; (mode) chewable/dispersible caplets or tablets) Seizure or syndrome partial seizures Type of trial design parallel Add-on or monotherapy? add-on Control(s) placebo Study start and end dates not reported Centres and location 40 centres in US, France Trial design Baseline 8 weeks Titration (including details 6 weeks of schedule and frequency Titrated in four stages to target daily maintenance dose of 1- of doses) 15mg/kg/day dependent on whether patients taking enzyme- inducing AEDs and/or valproate; maximum absolute doses from 150mg (valproate and no EIAED) to 750mg (EIAED and no valproate) Number of doses per day not stated Maintenance 12 weeks Withdrawal None (post- RCT Tapering of drug over 1 to 6 weeks, dependent on maintenance dose used during RCT study) Timing and additional Post-baseline; actual critera for randomisation not stated but eligibility for at screening pts were expected to have at least 4 seizures randomisation/continuatio during each consecutive 4-week period of the baseline phase n on study Comments on design Follow-up visit one week after tapering complete. Thus approach will lead to some variability in total follow-up for different patients. Tapering followed by open label study; patients entered this during tapering phase and so were either maintained on constant dose of lamotrigine or had lamotrigine introduced during this phase. Results after 18 weeks on study are therefore difficult to interpret. Quality Was assignment of Yes assessment treatment described as random? Was method of Yes randomisation described? Was the method really Yes random? Was allocation of treatment Yes concealed? Who was blinded to Described as 'double-blind' treatment? Was method of blinding 'lamotrigine and matching placebo' adequately described? Were eligibility criteria Yes described? Were groups comparable Baseline seizure rates for simple and complex partial seizures at study entry? appear substantially higher in placebo group Were groups treated Presumably, if blinding adequate; dose titration refers identically apart from the explicitly to lamotigine only, not clear how/if placebo doses intervention? titrated in same way Was ITT used? Yes Were withdrawals stated? Yes Were reasons for Yes withdrawals stated?

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Was a power calculation Yes done? Comments

Eligibility Inclusion criteria 1. Confirmed diagnosis of epilepsy limited to partial seizures criteria (simple partial, complex partial or partial becoming generalised) 2. Incompletely controlled by existing therapy (judged likely to experience at least 4 seizures in two consecutive 4 week periods during baseline) 3. Age 2 to 16 yrs (USA) or 2 to 12 yrs (France) 4. Weight at least 10kg (unless AED therapy was limited to enzyme-inducing AEDs) 5. Receiving up to 2 AEDs, excluding felbamate or gabapentin 6. Ability to maintain complete and accurate records of seizures throughout the study 7. Postpubescent girls required to use an appropriate method of contraception Exclusion criteria 1. Previous exposure to lamotrigine 2. Using corticosteroid therapy for asthma 3. Primary generalised, pseudo-, drug-induced or metabolic seizures 4. Intracerebral, structural lesions or history of status epilepticus within the previous 12 weeks 5. Demonstrated medical noncompliance, drug abuse (prescribed, illicit, legal), psychiatric disorders, or progressive neurologic disorders 6. Clinically significant chronic cardiac, renal, or hepatic condition 7. Vagal stimulation or ketogenic diet, or likelihood of surgical treatment for epilepsy during the study 8. Pregnancy 9. Use of other investigational or psychoactive drugs, except for methylphenidate, dextroamphetamine, or clonidine to treat ADHD Baseline characteristics Placebo Lamotrigine Number randomised 101 98 Number analysed 101 98 Age (wks, mos, yrs) 30 (29.7) <6 yrs; 62 27 (27.5) <6 yrs; 58 (mean, SD; median, range) (61.3) 6-12 yrs; 9 (59.1) 6-12 yrs; 13 (8.9) >12 yrs (13.2) >12 yrs Male:female 56:45 47:51 Weight (kg, lbs) mean 32.5 SD 19.1 mean 36.1 SD 19.4 (mean, SD; median, range) kg kg Duration of epilepsy (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Age at diagnosis (wks, mos, yrs) median age at first median age at first (mean, SD; median, range) seizure 1.0 yrs seizure 1.3 yrs (<1 (range <1 to 11) to 14) Newly diagnosed, n (%) None (assumed None (assumed from eligibility) from eligibility Previously diagnosed, n 101 (100%) 98 (100%) (%) Refractory, n (%) 101 (100%) 98 (100%) - definition of refractory - incompletely - incompletely

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controlled on controlled on existing therapy existing therapy Diagnosed seizure types, n Not reported Not reported (%) All patients had to All patients had to have epilepsy with have epilepsy with partial seizures partial seizures only only Secondarily generalised 'approximately half' 'approximately half' Diagnosed syndrome(s), n - - (%)

Baseline seizure frequency Data presented Data presented (/dy, wk, mo) graphically only graphically only (mean, SD; median, range) All partial seizures approx 7.5 approx 10 Secondarily generalised approx 1.8 approx 1.6 Partial (not secondarily approx 5.7 (by approx 8.4 (by generalised) subtraction) subtraction) No concomitant AEDs, n All patients All patients (%) receiving 1 or 2 receiving 1 or 2 concomitant AEDs; concomitant AEDs; ~50% were ~50% were receiving 1 vs 2 receiving 1 vs 2 Concomitant AEDs, n (%) Not reported Not reported

Previous AEDs, n (%) Not reported Not reported

Comments Some possible differences in baseline seizure rates.

Monitoring Was monitoring of plasma No (but see and levels done (including comments) outcomes study drug)? Were arrangements to NA (but see blind plasma monitoring comments) results mentioned? Who recorded seizure Not stated; daily diaries presumably completed by frequency? parent/guardian or patient How often was seizure Daily (diaries) frequency measured? Frequency of clinic visits 2 weekly (weeks 1-6), 4 weekly (weeks 7-18) Primary outcome(s) 1. % change in frequency of all partial seizures between including timepoints if baseline and entire DB period and maintenance phase of DB repeated period; calculated from average weekly seizure frequency

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Secondary outcome(s) 1. % change in frequency of secondarily generalised seizures excluding AEs 2. Proportion of pts with <= 25%, 26-49% and >= 50% reduction in all partial seizures 3. Number of days when each pt was seizure-free

'Ad hoc' outcomes (if Compliance emphasised and not in methods) Comments One investigator measured plasma lamotrigine levels in 3 patients and entered concentrations in charts, violating the blinding; these patients were allowed to complete the study. The study site was closed after all study medication properly discontinued. Results Placebo Lamotrigine (ITT only; unadjusted where available) Median follow-up 18 weeks 18 weeks 84/98 completed 18 83/101 completed weeks 18 weeks

Maintenance dose achieved EIAED (Enzyme Not reported EIAEDs + no VPA Inducing (n=53), mean 11.6 AntiEpileptic Drug) SD 3.6, median 12.9 mg/kg/day; No EIAEDs + VPA (n=22), mean 2.7 SD 0.4, median 2.7mg/kg/day; EIAEDs + VPA (n=18), mean 3.9 SD 0.9, median 4.2 mg/kg/day

Withdrawals including Total withdrawals 18 (17.8) 14 (14.2) reasons where specified Inadequate response 8 (7.9) 6 (6.1) Adverse events 6 (5.9) 5 (5.1) Withdrew consent 2 (1.9) 1 (1.0) Protocol violations 2 (1.9) 2 (2.0)

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) 1. [median] % change in frequency placebo -6.7% p=0.008 of all partial lamotrigine -36.1% seizures during: entire 18 week follow-up

12 week placebo -12.8% p=0.012 maintenance period lamotrigine -44%

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Secondary outcomes 1. % change in not based on whole p<0.05 frequency of population secondarily generalised seizures

2. Proportion of pts with <= 25%, 26- results available p<0.05 49% and >= 50% graphically only reduction in all partial seizures

3. Number of days placebo +3.2% p=0.003 when each pt was lamotrigine +28.0% seizure-free (all (median change) partial szs)

'Ad hoc' outcomes

Comments (including whether unadjusted results % change in seizure frequency adjusted reported) for centre effects

Percentage changes reported are median (weekly) % changes

Adverse Criteria for reporting Events in >10% of Placebo Lamotrigine Events pts in either group Events Vomiting 19 (18.8) 22 (22.4) Somnolence 18 (17.8) 24 (24.4) Infection 22 (21.7) 21 (21.4) Dizziness 5 (4.9) 21 (21.4) Rash 18 (17.8) 16 (16.3) Headache 15 (14.8) 18 (18.3) Rhinits 17 (16.8) 14 (14.2) Accidental injury 15 (14.8) 14 (14.2) Diarrhoea 13 (12.8) 13 (13.2) Fever 12 (11.8) 14 (14.2) Abdominal pain 7 (6.9) 13 (13.2) Tremor 2 (1.9) 12 (12.2) Nausea 2 (1.9) 11 (11.2) Otitis media 11 (10.8) 9 (9.1) Pharyngitis 10 (9.9) 11 (11.2) Ataxia 2 (1.9) 10 (10.2) Asthenia 6 (5.9) 11 (11.2)

Proportion of patients reporting 96 (95.0) 92 (93.8) at least one AE

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Comments p <= 0.05 for dizziness, tremor, nausea, ataxia

Rash includes erythema multiforme, maculopapular rash, urticaria, Stevens- Johnson syndrome, and vesiculobullous rash Conclusions Author's conclusions Lamotrigine is effective as adjunctive treatment for partial seizures . It is well tolerated although 2 patients were hospitalised due to rash. Results are applicable to clinical practice because dose adjustments were based on concurrent AED therapy, individual tolerability etc.

Our conclusions Not clear how apparent differences in baseline seizure frequency may have affected results; ideally need ANCOVA to explore this.

Although it is noted that the blinding was broken in 3 patients, it is not clear what happened to these patients or what influence this might have had on the results.

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Trial details Trial ID Appleton, 1999 (1) Drug(s) gabapentin Target maintenance dose 600-1800mg/day dependent on weight (mode) (?mode) Seizure or syndrome partial seizures Type of trial design parallel Add-on or monotherapy? add-on Control(s) placebo Study start and end dates 1993 to 1996 Centres and location 54 centres in Europe, S Africa and USA

Trial design Baseline 6 weeks Titration (including details 3 days of schedule and frequency Titrated to 23.2 - 35.3 mg/kg/day (total daily dose) of doses) 3 doses/day

Maintenance 81 days Withdrawal None Timing and additional Post-baseline; patients experiencing at least 1 seizure every 2 eligibility for weeks and 4 seizures in total during baseline randomisation/continuatio n on study Comments on design Dose titration refers explicitly to gabapentin only; not clear how/if placebo doses titrated in same way.

Quality Was assignment of Yes assessment treatment described as random? Was method of No randomisation described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to Described as treatment? 'double-blind'. Was method of blinding No description. adequately described? Were eligibility criteria Yes described? Were groups comparable Yes at study entry? Were groups treated Can't tell (no description of blinding, and dose titration refers identically apart from the to gabapentin group only) intervention? Was ITT used? Claimed, but not used. "ITT population defined as all randomized patients who received study medication" Were withdrawals stated? Yes Were reasons for Yes withdrawals stated? Was a power calculation No done?

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Comments

Eligibility Inclusion criteria 1. Medically uncontrolled seizures; classified as simple criteria partial, complex partial or partial becoming generalised 2. Age 12 years or younger 3. Weight 17-72kg at screening 4. Receiving 1-3 other AEDS (to remain unchanged throughout sudy)

Exclusion criteria 1. Absence seizures, or seizures related to drugs, alcohol or acute medical illness 2. Structural CNS lesions or encephalopathies, diagnosed as progressive within 2 years prior to screening 3. Benign epilepsy syndromes

Baseline characteristics placebo gabapentin Number randomised Not stated Not stated Number analysed 128 119 Age (wks, mos, yrs) mean 8.4, SD 2.7 mean 8.5, SD 2.4 (mean, SD; median, range) yrs; yrs; median 9.0, range median 9.0, range 3-12 3-12 Male:female 75:53 59:60 Weight (kg, lbs) Not reported Not reported (mean, SD; median, range) Duration of epilepsy (wks, mos, yrs) mean 5.4, SD 3.1 mean 5.7, SD 3.0 (mean, SD; median, range) yrs; yrs; median 5.3, <1- median 5.9, <1- 11.9 11.3 Age at diagnosis (wks, mos, yrs) mean 3.0, SD 2.5 mean 2.7, SD 2.6 (mean, SD; median, range) yrs; yrs; median 2.5, <1- median 5.9, <1-9.5 10.7 Newly diagnosed, n (%) 0 0 (but duration short (but duration short for some pts) for some pts) Previously diagnosed, n 128 (100%) 119 (100%) (%) (but see comment (but see comment above) above) Refractory, n (%) Not stated Not stated - definition of refractory - none given - none given Diagnosed seizure types, n simple partial 58 (45.3) 54 (45.4) (%) complex partial 112 (87.5) 99 (83.2) secondarily generalized 70 (54.7) 73 (61.3) myoclonic 12 (9.4) 16 (13.4) tonic-clonic 13 (10.2) 15 (12.6) tonic 11 (8.6) 8 (6.7) atonic 9 (7.0) 8 (6.7) atypical absence 7 (5.5) 7 (5.9) clonic 2 (1.6) 2 (1.7) absence 2 (1.6) 0 (-) unclassified 4 (3.1) 5 (4.2) 272 Newer Drugs for Children with Epilepsy

Diagnosed syndrome(s), n NA NA NA (%)

Baseline seizure frequency Partial seizures mean 63.3, SD mean 74.5, SD (/dy, wk, mo) 103.8; 268.3; (mean, SD; median, range) median 28.0, 1.3- median 24.1, 2.7- 698 2,893

No concomitant AEDs, n 1 44 (34.4) 31 (26.1) (%) 2 57 (44.5) 58 (48.7) 3 27 (21.1) 30 (25.2) Concomitant AEDs, n (%) Not reported - -

Previous AEDs, n (%) Not reported - -

Comments

Monitoring Was monitoring of plasma Yes (including study drug). "Gabapentin plasma levels and and levels done (including AED serum levels." outcomes study drug)? Were arrangements to No blind plasma monitoring results mentioned? Who recorded seizure Parents/guardians frequency? How often was seizure Daily (diaries) frequency measured? Frequency of clinic visits 4 weekly (weeks -6, 0, 4, 8, 12) Primary outcome(s) 1. Response ratio including timepoints if repeated

Secondary outcome(s) 1. Responder rate, defined as >= 50% reduction excluding AEs 2. % change in frequency of all partial seizures 3. % change in frequency for different types of partial seizure 4. Response ratio for different types of partial seizure 5. Investigator 'global assessment' 6. Parent/guardian 'global assessment' 'Ad hoc' outcomes (if emphasised and not in methods)

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Comments No reference given for 'response ratio', defined in text as (trt- baseline)/(trt+baseline); analysed using ANOVA but not clear that this is appropriate (assumes normally distributed data, which this won't be; data was transformed for non-normality on ad hoc basis). Results placebo gabapentin (ITT only; unadjusted where available) Median follow-up 12 weeks 12 weeks (assumed from low (assumed from low drop-out) drop-out) Maintenance dose achieved Not reported Not reported

Withdrawals including Total withdrawals 28 (21.9) 21 (17.6) reasons where specified Lack of efficacy 19 (14.8) 11 (9.2) Adverse events 3 (2.3) 6 (5.0) Change in AED 2 (1.6) 0 (-) Other 4 (3.1) 4 (3.4)

Median time to 24 days 13 days onset of AE resulting in withdrawal Median duration 6 days 7 days

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) 1. Response ratio placebo -0.079 p=0.1246 gabapentin -0.146 (NB: data non- normal; analysis of transformed data gave p=0.0299, but see comment below) Secondary outcomes 1. >= 50% placebo 18%, p=ns reduction gabapentin 21%

2. % change in not reported for not reported for frequency, all 'ITT' 'ITT' partial

3. % change in not reported for not reported for frequency by type of 'ITT' 'ITT' partial seizure

4. Response ratio by not reported for not reported for type of partial 'ITT' 'ITT' seizure

5. Physician 'global assessment: - seizure frequency (results not p=ns reproduced here) - well-being (results not p=ns reproduced here) 6. Parent/guardian 'global assessment': - seizure frequency (results not p=0.046 (favouring reproduced here) gabapentin)

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- well-being (results not p=ns reproduced here)

'Ad hoc' outcomes

Comments (including whether unadjusted results All results adjusted for centre. reported) Number randomised not reported; definition of ITT here implies that not all randomised patients included in analysis.

Most outcomes not reported for ITT population; note that ITT population used here does not meet technical definition of intention-to-treat (see comments on quality assessment).

Response ratio also reported for 'ITT' population using rank-transformed data due to 'evidence of non-normality'; non- normality would be expected with this statistic and ANOVA is not an ideal means of analysis. Result for 'modified ITT' population reported without transformation and with no comment on normality. Adverse Criteria for reporting Events in >=2% of placebo gabapentin Events pts in either group:

275 Newer Drugs for Children with Epilepsy

Events Viral infection 4 (3.1) 13 (10.9) Fever 4 (3.1) 12 (10.1) Nausea and/or vomiting 9 (7.0) 10 (8.4) Somnolence 6 (4.7) 10 (8.4) Pharyngitis 11 (8.6) 10 (8.4) Hostility 3 (2.3) 9 (7.6) Upper respiratory tract infection 8 (6.3) 7 (5.9) Headache 8 (6.3) 6 (5.0) Rhinitis 6 (4.7) 6 (5.0) Emotional lability 2 (1.6) 5 (4.2) Weight increase 1 (0.8) 4 (3.4) Fatigue 2 (1.6) 4 (3.4) Bronchitis 1 (0.8) 4 (3.4) Diarrhea 4 (3.1) 3 (2.5) Convulsions 4 (3.1) 3 (2.5) Dizziness 2 (1.6) 3 (2.5) Hyperkinesia 1 (0.8) 3 (2.5) Respiratory infection 1 (0.8) 3 (2.5) Anorexia 3 (2.3) 2 (1.7) Coughing 4 (3.1) 2 (1.7) Otitis media 4 (3.1) 1 (0.8)

Considered related 20% 34% to study drug (??% events)

Severe AEs 3 pts (3 events) 14 pts (23 events) Comments

Conclusions Author's conclusions Gabapentin administered as add-on therapy is effective in this highly refractory population, reducing the incidence of partial onset seizures without provoking or worsening the severity of generalised seizures or status epilepticus.

Doses comparable (by weight) to adult doses, but probably slightly low. Some evidence of increaed efficacy in adult population at higher doses.

Well-tolerated in this population. Lower incidence of CNS side effects than in previous trials with adult patients.

Lack of interaction with other AEDs is an advantage. Our conclusions Methodological weaknesses in design/conduct of trial difficult to quantify due to lack of information on procedures for randomisation and blinding. Lack of this information, along with monitoring of gabapentin plasma levels with no description of how clinicians were blinded to these results, gives some cause for concern.

Analytical methods very weak and subject to considerable bias in the use of an apparently non-ITT population (described as ITT but with a definition that does not meet the usual definition of ITT). Results for the 'ITT' population

276 Newer Drugs for Children with Epilepsy

under-emphasised compared to results for the 'modified ITT' population. No clearly unbiased results are presented, but the least biased set of results (for the 'ITT' population) give no clear evidence for increased efficacy compared to placebo.

A more complete analysis would be required before any firm conclusions could be drawn.

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Trial details Trial ID Shapiro, 2000 Drug(s) gabapentin Target maintenance dose 40mg/kg/day (oral (mode) syrup) Seizure or syndrome Partial seizures Type of trial design parallel Add-on or monotherapy? add-on Control(s) placebo Study start and end dates Not reported Centres and location Not reported

Trial design Baseline 2 days Titration (including details No titration of schedule and frequency 40/mg/kg/day of doses) 2 doses/day

Maintenance 3 days Withdrawal None Timing and additional eligibility for randomisation/continuation on study Comments on design Monitoring of seizure rate by continuous video-EEG recording over 72 hours.

Quality Was assignment of Yes assessment treatment described as random? Was method of No randomisation described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to Described as 'double blind'; EEG treatment? assessor blinded. Was method of blinding No description adequately described? Were eligibility criteria Yes described? Were groups comparable Yes at study entry? Were groups treated Can't tell identically apart from the intervention? Was ITT used? Can't tell Were withdrawals stated? Not reported Were reasons for NA withdrawals stated? Was a power calculation Not reported done?

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Comments Abstract with few details

Eligibility Inclusion criteria 1. Aged 1 to 36 mos criteria 2. Seizures not controlled by at least 1 AED 3. Partial seizures diagnosed by one of: matching clinical semiology with imaging/EEG evidence; EEG capture of a focal seizure

Exclusion criteria None stated

Baseline characteristics Placebo Gabapentin Number randomised 38 38 Number analysed Not reported Not reported Age (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Male:female Not reported Not reported Weight (kg, lbs) Not reported Not reported (mean, SD; median, range) Duration of epilepsy (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Age at diagnosis (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Newly diagnosed, n (%) None (assumed) None (assumed)

Previously diagnosed, n 38 (100%) 38 (100%) (%) (assumed from (assumed from eligibility) eligibility) Refractory, n (%) Not reported Not reported - definition of refractory Diagnosed seizure types, n Not reported (%)

Diagnosed syndrome(s), n Not reported (%)

279 Newer Drugs for Children with Epilepsy

Baseline seizure frequency Not reported (/dy, wk, mo) (mean, SD; median, range)

No concomitant AEDs, n Not reported (%) Concomitant AEDs, n (%) Not reported

Previous AEDs, n (%) Not reported

Comments

Monitoring Was monitoring of plasma No and levels done (including outcomes study drug)? Were arrangements to NA blind plasma monitoring results mentioned? Who recorded seizure A central EEG reader blinded to frequency? assignment. How often was seizure Continuously during baseline & frequency measured? maintenance phases Frequency of clinic visits Not reported Primary outcome(s) 1. Response ratio (measure of proportional change in rate of including timepoints if partial seizures between baseline and follow-up) repeated 2. Responder rate; proportion whose seizure rate decreased by at least 50% relative to baseline

Secondary outcome(s) excluding AEs

'Ad hoc' outcomes (if emphasised and not in methods) Comments

Results Placebo Gabapentin (ITT only; unadjusted where available) Median follow-up 3 days 3 days (assumed) (assumed) 280 Newer Drugs for Children with Epilepsy

Maintenance dose achieved Not reported Not reported Withdrawals including reasons where specified Not reported Not reported

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) 1. Response ratio Placebo -0.048 Gabapentin ns +0.018

2. Responder rate Placebo not ns reported Gabapentin not reported Secondary outcomes

'Ad hoc' outcomes

Comments (including whether unadjusted results reported)

Adverse Criteria for reporting Most frequent Placebo Gabapentin Events

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Events Somnolence Not reported Not reported Nausia Not reported Not reported Vomiting Not reported Not reported

Comments

Conclusions Author's conclusions Gabapentin was safe and well tolerated and reduced the rate of partial seizures.

Our conclusions Very limited information available from abstract. Trial was of very short duration, with small sample size.

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Trial details Trial ID Glauser, 2000 Drug(s) oxcarbazepine Target maintenance dose 30-46mg/kg/day (oral - tablets) (mode) Seizure or syndrome partial seizures Type of trial design parallel Add-on or monotherapy? add-on Control(s) placebo Study start and end dates Not reported [May 95 to Sep 97 (ind submsn)] Centres and location 47 centres in Argentina, Chile, Uruguay, Australia, New Zealand, Canada, Israel, USA Trial design Baseline 8 weeks Titration (including details 2 weeks of schedule and frequency Titrated in four stages to target daily dose of 30 to of doses) 46mg/kg/day (900mg [body weight 20-29kg], 1200mg [29.1- 39kg] or 1800mg [39.1kg or greater]) 2 doses/day

Maintenance 14 weeks Withdrawal None Timing and additional Post-baseline; patients experiencing at least 1 seizure every 4 eligibility for weeks and at least 8 seizures in total during 8 week baseline randomisation/continuatio period n on study Comments on design Dose titration refers explicitly to oxc only; not clear how/if placebo doses titrated in same way.

Quality Was assignment of Yes assessment treatment described as random? Was method of Yes randomisation described? Was the method really Yes random? Was allocation of treatment Yes concealed? Who was blinded to Described as treatment? 'double-blind' Was method of blinding Yes adequately described? Were eligibility criteria Yes described? Were groups comparable Yes at study entry? Were groups treated Can't tell (dose titration refers to oxcarbazepine group only) identically apart from the intervention? Was ITT used? Not clear (see comment) Were withdrawals stated? Yes Were reasons for Yes withdrawals stated? Was a power calculation Yes done?

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Comments No follow-up available on 3 patients who discontinued treatment prematurely, but not clear if this data was 'missing' or never sought (31 patients discontinued in total)

Eligibility Inclusion criteria 1. Medically uncontrolled seizures; classified as simple criteria partial, complex partial or partial becoming generalised (EEG features consistent with localization-related epilepsy) 2. Age 3 to 17 years 3. Serum sodium concentration at least 130 mmol/l 4. Receiving 1-2 other AEDs 5. Absence of a progressive lesion

Exclusion criteria 1. Generalised status epilepticus during 6 months prior to trial 2. Seizures of metabolic, neoplastic, or active infectious origin 3. Non-compliance with medical treatment 4. Any medical condition likely to impact on outcome of trial 5. Attempted suicide 6. Substance abuse 7. Clinically significant laboratory abnormalities including AST, ALT, WBC 8. Hypersensitivity to carbamazepine; previous use of oxcarbazepine; felbamate within 90 days of baseline; felodipine, verapamil, monoamine oxidase inhibitors within 30 days of baseline 9. Participation in other investigational drug trial within 60 days of screening visit 10. Pregnant or nursing females or those trying to conceive Baseline characteristics placebo oxcarbazepine Number randomised 129 138 Number analysed 128 136 Age (wks, mos, yrs) mean 11 yrs, range mean 11 yrs, range (mean, SD; median, range) 3-17 3-17 Male:female 71:58 70:68 Weight (kg, lbs) mean 44kg; range mean 44kg; range (mean, SD; median, range) 16-89 16-130 Duration of epilepsy (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Age at diagnosis (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Newly diagnosed, n (%) 0 0

Previously diagnosed, n 129 (100%) 138 (100%) (%) Refractory, n (%) Not stated Not stated - definition of refractory - none given - none given Diagnosed seizure types, n simple partial 44 (34.1) 41 (29.7) (%) complex partial 93 (72.1) 108 (78.2) secondarily 57 (44.1) 50 (36.2) generalized

Diagnosed syndrome(s), n NA NA NA (%)

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Baseline seizure frequency Partial seizures median 13, 2-554 median 12, 3-1470 (/dy, wk, mo) per 28 days per 28 days (mean, SD; median, range) Secondarily median 0, 0-176 generalized seizures median 0, 0-86 per per 28 days 28 days

No concomitant AEDs, n Not reported Not reported (%) Concomitant AEDs, n (%) Carbamazepine 55 (42.6) 77 (55.8) Valproate 31 (24.0) 23 (16.7) Lamotrigine 29 (22.5) 22 (15.9) Phenytoin 22 (17.1) 21 (15.2)

Previous AEDs, n (%) Not reported Not reported Not reported

Comments Typo in table 2 of paper; 27 oxcarbazepine patients reported with concomitant carbamazepine, but 77 consistent with % reported and text.

Monitoring Was monitoring of plasma Yes. "Concomitant AEDs" and of MHD (active and levels done (including oxcarbazepine metabolite) during maintenance phase. outcomes study drug)? Were arrangements to No blind plasma monitoring results mentioned? Who recorded seizure Parents/guardians frequency? How often was seizure Not reported frequency measured? (diaries) Frequency of clinic visits Weeks -8, 0, 2, 4, 6, 8, 12, 16 Primary outcome(s) 1. % change in frequency of all partial seizures per 28 including timepoints if repeated

Secondary outcome(s) 1. Responder rate, defined as >= 50% reduction in all partial excluding AEs seizure frequency per 28 days 2. % change in frequency of secondarily generalized seizures per 28 day

'Ad hoc' outcomes (if 1. % change in frequency of simple partial and complex emphasised and not in partial seizures per 28 days methods) 2. Seizure free patients Comments % change in frequency of different seizure types reported together below

Results placebo oxcarbazepine (ITT only; unadjusted where available)

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Median follow-up 16 weeks 16 weeks (assumed) (assumed) Maintenance dose achieved Not reported median 31.4mg/kg/day (6.4-51.4) Withdrawals including Total withdrawals 10 (7.8) 21 (15.2) reasons where specified Lack of efficacy 4 (3.1) 0 (-) Adverse events 4 (3.1) 14 (10.1) Non-compliance 0 (-) 4 (2.9) Withdrew consent 1 (0.8) 2 (4.3) Lost to follow-up 1 (0.8) 0 (-)

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) % change in placebo -9% p=0.0001 frequency of all oxcarbazepine - partial seizures per 35% 28 days during DB (median % change) treatment Secondary outcomes 1. >= 50% placebo 22% p=0.0005 reduction in all oxcarbazepine 41% partial seizure frequency

2. % change in frequency of: simple partial 45% OXC vs 16% not reported placebo

complex partial 42% vs 10% not reported

secondarily 78% vs 33% p=0.0012 generalized

'Ad hoc' outcomes Seizure free patients placebo n=1/128 not reported oxc n=5/136

Comments (including whether unadjusted results All changes in seizure frequency reported) reported as median reductions.

50% responder rates reported for 135 (not ITT population of 136) oxc patients (no explanation for missing patient).

Changes reported for each seizure type apply only to patients with that type of seizure at baseline.

Sample size slightly less than target given in power calculation (267 vs 274).

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Analysis of responder rate adjusted for centre, sex, age and weight.

Adverse Criteria for reporting Events in >=10% of placebo oxcarbazepine Events pts in either group: Events Viral infection 21 (16.2) 19 (13.7) Fever 20 (15.5) 21 (15.2) Nausea and/or vomiting 26 (20.1) 80 (57.9) Somnolence 18 (13.9) 48 (34.7) Pharyngitis 15 (11.6) 12 (8.6) Upper respiratory 10 (7.2) tract infecn 15 (11.6) Headache 23 (17.8) 44 (31.8) Rhinitis 11 (8.5) 16 (11.5) Fatigue 11 (8.5) 18 (13.0) Dizziness 10 (7.7) 40 (28.9) Anorexia 13 (10.0) 9 (6.5) Ataxia 6 (4.6) 19 (13.7) Abnormal gait 4 (3.1) 14 (10.1) Nystagmus 2 (1.5) 14 (10.1) Diplopia 1 (0.7) 23 (16.6) Abnormal vision 2 (1.5) 19 (13.7) Abdominal pain 13 (10.0) 12 (8.6)

Proportion of 106 (82) 126 (91) patients reporting >=1 adverse event

Comments Rash reported in 5% placebo, 4% oxc group

Conclusions Author's conclusions Oxcarbazepine treated patients experienced statistically significant improvements over placebo in the primary endpoint and in the number of patients with >=50% reduction in seizure frequency.

Oxcarbazepine is safe, effective and well tolerated in children with partial seizures.

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Our conclusions Fairly high quality study, with reasonable conclusions.

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Trial details Trial ID Litzinger, 1998 Drug(s) Tiagabine Target maintenance dose 0.7mg/kg/day (mode) (assumed /day) Seizure or syndrome Refractory partial seizures Type of trial design parallel Add-on or monotherapy? Add-on Control(s) placebo Study start and end dates Not reported Centres and location Not reported

Trial design Baseline 8 weeks Titration (including details Not reported of schedule and frequency of doses)

Maintenance 12 weeks Withdrawal Not reported Timing and additional eligibility for randomisation/continuation on study Comments on design Abstract with few details of design. Data not extractable, subgroup and post-randomised phase; Indicates existence of a trial that might be included and needs tracing if possible.

Quality Was assignment of Abstract only, no assessment treatment described as details random? Was method of No randomisation described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to Abstract only, no treatment? details Was method of blinding Abstract only, no adequately described? details Were eligibility criteria Abstract only, no described? details Were groups comparable Abstract only, no details at study entry? Were groups treated Abstract only, no identically apart from the details intervention? Was ITT used? Abstract only, no details Were withdrawals stated? Abstract only, no details Were reasons for Abstract only, no withdrawals stated? details Was a power calculation Abstract only, no done? details

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Comments Abstract only, no details

Eligibility Inclusion criteria Abstract only, no criteria details

Exclusion criteria Abstract only, no details

Baseline characteristics placebo tiagabine Number randomised Abstract only no Abstract only no details details Number analysed Abstract only no Abstract only no details. details. Age (wks, mos, yrs) Abstract only no Abstract only no (mean, SD; median, range) details details Male:female Abstract only no Abstract only no details details Weight (kg, lbs) Abstract only no Abstract only no (mean, SD; median, range) details details Duration of epilepsy (wks, mos, yrs) Abstract only no Abstract only no (mean, SD; median, range) details details Age at diagnosis (wks, mos, yrs) Abstract only no Abstract only no (mean, SD; median, range) details details Newly diagnosed, n (%) Abstract only no Abstract only no details details Previously diagnosed, n Abstract only no Abstract only no (%) details details Refractory, n (%) Abstract only no Abstract only no - definition of refractory details details Diagnosed seizure types, n Abstract only no Abstract only no (%) details details

Diagnosed syndrome(s), n Abstract only no Abstract only no (%) details details

290 Newer Drugs for Children with Epilepsy

Baseline seizure frequency (/dy, wk, mo) Abstract only no Abstract only no (mean, SD; median, range) details details

No concomitant AEDs, n Abstract only no Abstract only no (%) details details Concomitant AEDs, n (%) Abstract only no Abstract only no details details

Previous AEDs, n (%) Abstract only no Abstract only no details details

Comments Abstract only no details

Monitoring Was monitoring of plasma levels done Abstract only no and (including study drug)? details outcomes Were arrangements to blind plasma monitoring Abstract only no results mentioned? details Who recorded seizure Abstract only no frequency? details How often was seizure frequency measured? Abstract only no details Frequency of clinic visits Abstract only no details Primary outcome(s) including timepoints if Abstract only no repeated details

Secondary outcome(s) Abstract only no excluding AEs details

'Ad hoc' outcomes (if emphasised and not in methods) Comments Abstract only no details

Results placebo tiagabine (ITT only; unadjusted where available) Median follow-up Abstract only no Abstract only no details details

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Maintenance dose achieved Abstract only no Abstract only no details details Withdrawals including reasons where specified Abstract only no Abstract only no details details

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) Abstract only no details

Secondary outcomes Abstract only no details

'Ad hoc' outcomes Abstract only no details

Comments (including whether unadjusted results Abstract only no reported) details

Adverse Criteria for reporting placebo tiagabine Events

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Events Abstract only no details

Comments Abstract only no details

Conclusions Author's conclusions

Our conclusions

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Trial details Trial ID Elterman, 1999 Drug(s) Topiramate Target maintenance dose 125-400mg/day (mode) (oral) Seizure or syndrome partial seizures Type of trial design parallel Add-on or monotherapy? add-on Control(s) placebo Study start and end dates Not reported Centres and location 17 centres in US, Costa Rica Trial design Baseline 8 weeks Titration (including details 8 weeks of schedule and frequency Titrated from 25mg/day in four consecutive 2-week intervals of doses) to target of 125-400mg/day, based on body weight 1 dose/day for first 2 weeks then 2 doses/day

Maintenance 8 weeks Withdrawal None Timing and additional Post-baseline; patients experiencing at least 6 partial seizures eligibility for (at least 1 every 4 week interval) during baseline randomization / continuation on study Comments on design Dose titration refers explicitly to topiramate only; not clear how/if placebo doses titrated in same way.

Quality Was assignment of Yes assessment treatment described as random? Was method of Yes randomisation described? Was the method really Yes random? Was allocation of treatment Yes concealed? Who was blinded to Patients, investigators, study monitors and observers treatment? Was method of blinding No description adequately described? Were eligibility criteria Yes described? Were groups comparable Yes at study entry? Were groups treated Can't tell (no description of blinding, and dose titration refers identically apart from the to topiramate group only) intervention? Was ITT used? Yes Were withdrawals stated? Yes Were reasons for Yes withdrawals stated? Was a power calculation Yes done?

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Comments

Eligibility Inclusion criteria 1. Medically uncontrolled partial seizures, with or without criteria secondarily generalised seizures 2. Age between 1 and 16 years 3. Weight >16kg 4. Receiving 1-2 other AEDs (at constant dose) 5. CT or MRI exclusion of potentially progressive neurologic diseases 6. EEG/close cable television EEG confirmation of the diagnosis of partial epilepsy 7. Post-menarchal females only if physically incapable of bearing children, or practising acceptable method of birth control

Exclusion criteria 1. Lennox-Gastaut syndrome 2. Clinically significant ECG abnormalities 3. Generalised status epilepticus within the previous 3 months while complying with AEDs, or seizures occurring only in clustered pattern 4. Significant medical disease, nephrolithiasis, drug or alcohol abuse, recent significant psychiatric or mood disorder, use of drugs that increased the risk of renal stones (e.g. acetazolamide, high dose vitamin C, antacids or calcium supplements in chronic doses) 5. Felbamate or centrally acting sympathomimetics excluded (by protocol amendment for safety reasons) Baseline characteristics Placebo Topiramate Number randomised 45 41 Number analysed 45 41 Age (wks, mos, yrs) mean 9.0, SD 3.4 mean 8.8, SD 3.6 (mean, SD; median, range) yrs yrs range 2 to 16 range 2 to 16 Male:female 25:20 23:18 Weight (kg, lbs) mean 35.1, SD 16.3 mean 34.7, SD 15.8 (mean, SD; median, range) kg kg Duration of epilepsy (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Age at diagnosis (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Newly diagnosed, n (%) 0 (-) 0 (-) Previously diagnosed, n 45 (100%) 41 (100%) (%) Refractory, n (%) 45 (100%) 41 (100%) - definition of refractory Diagnosed seizure types, n simple partial 12 (26.6) 11 (26.8) (%) complex partial 37 (82.2) 31 (75.6) secondarily generalised 17 (37.7) 17 (41.4) other 3 (6.6) 3 (7.3)

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Diagnosed syndrome(s), n NA NA NA (%)

Baseline seizure frequency partial seizures median 19, 2-1133 median 22, 2-232 (/dy, wk, mo) (mean, SD; median, range) secondarily median 5, 1-273 median 6, 1-89 generalised seizures

No concomitant AEDs, n 1 24 (53.3) 15 (36.5) (%) 2 20 (44.4) 25 (60.9) 3 1 (2.2) 1 (2.4) Concomitant AEDs, n (%) carbamazepine 26 (57.7) 25 (60.9) valproate 10 (22.2) 10 (24.3) phenytoin 9 (20) 6 (14.6) gabapentin 4 (8.8) 10 (24.3) lamotrigine 5 (11.1) 5 (12.1) Previous AEDs, n (%) Not reported Not reported Not reported

Comments

Monitoring Was monitoring of plasma Yes ("plasma AED including topiramate periodically during and levels done (including baseline and double-blind phases") outcomes study drug)? Were arrangements to No blind plasma monitoring results mentioned? Who recorded seizure Parents/guardians frequency? How often was seizure Not reported frequency measured? (diaries used) Frequency of clinic visits Diary data collection days 1, 8, 15, 22, 50, 77 Primary outcome(s) % change in frequency of all partial seizures (average including timepoints if monthly rate) repeated

Secondary outcome(s) 1. % change in frequency of secondarily generalised seizures excluding AEs (average monthly rate) 2. Proportion of pts with >= 50% reduction in all partial seizures 3. Proportion of pts with >= 75% reduction in all partial seizures 4. Proportion of pts with >= 100% reductin in all partial seizures 5. Parental global evaluation 'Ad hoc' outcomes (if None emphasised and not in methods)

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Comments

Results Placebo Topiramate (ITT only; unadjusted where available) Median follow-up 16 weeks 16 weeks Maintenance dose achieved Not reported Median 5.9mg/kg/day Withdrawals including Total withdrawals 2 (4.4) 0 (-) reasons where specified Adverse events 1 (2.2) 0 (-) Patient choice 1 (2.2) 0 (-)

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) % change in placebo -10.5% p=0.034 frequency of all topiramate -33.1% partial seizures (median % (average monthly reduction) rate) Secondary outcomes 1. % change in placebo +10.6% Not reported frequency of topiramate -31.6% secondarily (median % generalised seizures reduction) (average monthly rate)

2. Proportion of pts placebo 9 (20.0) p=ns with >= 50% topiramate 16 reduction in all (39.0) partial seizures

3. Proportion of pts placebo 1 (2.2) p=0.019 with >= 75% topiramate 7 (17.0) reduction in all partial seizures

4. Proportion of pts placebo 0 (-) p=ns with >= 100% topiramate 2 (4.8) reductin in all partial seizures

5. Parental global (results not (results not evaluation reproduced here) reproduced here) 'Ad hoc' outcomes None NA NA

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Comments (including whether unadjusted results Results adjusted for centre only. reported)

Adverse Criteria for reporting Events in >=10% of Placebo Topiramate Events pts in topiramate group Events Upper respiratory tract infection 36% 41% Sinusitis 27% 17% Coughing 11% 15% Diarrhoea 22% 10% Somnolence 13% 12% Anorexia 11% 12% Emotional lability 4% 12% Difficulty concentrating/attent ion 2% 12% Mood problems 11% 10% Aggressive reaction 7% 10% Nervousness 7% 10% Viral infection 4% 15% Otitis media 11% 10% Rash 9% 12% Purpura 4% 15% Fever 24% 29% Injury 9% 20% Fatigue 7% 15%

Serious AEs 3 (6.6) 1 (2.4) Comments parental evaluation of mental status also rpeorted (verbal questioning of parents/guardians)

Conclusions Author's conclusions Topiramate improves seizure control in patients with partial onset seizures with/without secondarily generalisation. The doses of topiramate used in this study were lower than those used in others, therefore had higher doses been used a greater treatment effect may have been seen.

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Our conclusions Lack of information on how clinicians were blinded to plasma level moitoring results, and on how placebo dose was titrated raises questions as to how blinding was maintained.

There are three abstracts associated with this paper; 3507, 3510, and 422. There are two small differences between the abstracts and the full paper is that the abstracts say that age range was 2-17 years compared with the full paper 1-16 years. Also 422 says that three patients withdrew whereas the others say only 2 withdrew.

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Trial details Trial ID Valentine, 1998 Drug(s) vigabatrin Target maintenance dose 1.5-4g/day (oral) (mode) Seizure or syndrome uncontrolled complex partial seizures with or without secondary generalisation Type of trial design parallel Add-on or monotherapy? add-on Control(s) placebo Study start and end dates not reported Centres and location Multicentre (n=?)

Trial design Baseline 6 weeks Titration (including details of 10 weeks schedule and frequency of doses)

Maintenance 7 weeks Withdrawal None Timing and additional Not stated eligibility for randomisation/continuation on study Comments on design Underpowered, randomised only 75% of target of 120 patients.

Quality Was assignment of treatment Yes assessment described as random? Was method of randomisation No described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to treatment? Not stated Was method of blinding No description adequately described? Were eligibility criteria No described? Were groups comparable at Can't tell study entry? Were groups treated Can't tell identically apart from the intervention?

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Was ITT used? Claimed.

Were withdrawals stated? No Were reasons for withdrawals No stated? Was a power calculation Yes done? Comments Claimed of 127 patients entering baseline 88 were randomised and used for ITT analysis.

Eligibility Inclusion criteria Not stated criteria

Exclusion criteria Not stated

Baseline placebo vigabatrin characteristics Number randomised Total 88 not stated by Total 88 not stated by arm arm Number analysed 88 not stated by arm 88 not stated by arm Age (wks, mos, yrs) Range 3-16 years, not Range 3-16 years, not (mean, SD; median, range) stated by study arm stated by study arm Male:female not stated not stated Weight (kg, lbs) not stated not stated (mean, SD; median, range) Duration of epilepsy (wks, not stated not stated mos, yrs) (mean, SD; median, range) Age at diagnosis (wks, mos, not stated not stated yrs) (mean, SD; median, range) Newly diagnosed, n (%) not stated not stated

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Previously diagnosed, n (%) not stated not stated Refractory, n (%) not stated not stated - definition of refractory Diagnosed seizure types, n (%) not reported

Diagnosed syndrome(s), n (%) not reported

Baseline seizure frequency not reported (/dy, wk, mo) (mean, SD; median, range)

No concomitant AEDs, n (%) not reported

Concomitant AEDs, n (%) not reported

Previous AEDs, n (%) not reported

Comments

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Monitoring Was monitoring of plasma No and outcomes levels done (including study drug)? Were arrangements to blind NA plasma monitoring results mentioned? Who recorded seizure Not stated frequency? How often was seizure Not stated frequency measured? Frequency of clinic visits not stated

Primary outcome(s) including 1. >=50% reduction in timepoints if repeated seizure frequency

Secondary outcome(s) excluding AEs

'Ad hoc' outcomes (if emphasised and not in methods) Comments

Results placebo vigabatrin (ITT only; unadjusted where available) Median follow-up not stated not stated

Maintenance dose achieved not stated 1.5-4g/day

Withdrawals including reasons not reported where specified

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Results (diff, or by CI for difference; p- arm) value Primary outcome(s) 1. >=50% reduction in placebo 26.7% p=0.0089 seizure frequency vigabatrin 55.8%

Secondary outcomes

'Ad hoc' outcomes

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Comments (including whether unadjusted results reported)

Adverse Criteria for reporting treatment-related placebo vigabatrin Events adverse events Events all events (66.7) (65.9) somonolence not reported not reported headache not reported not reported dizziness not reported not reported increased seizure frequency not reported not reported

Comments

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Conclusions Author's conclusions Vigabatrin safe as add-on treatment for paediatric patients with uncontolled complexpartial seizures at a dose range of 0.5 to 4g/day.

Our conclusions Insufficient reported detail to judge validity of authors conclusion.

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Trial details Trial ID Van Orman, 1998 Drug(s) vigabatrin Target maintenance dose 20, 60, 100mg/kg/day (?mode) (mode) Seizure or syndrome uncontrolled complex partial seizures with or without secondary generalisation Type of trial design parallel Add-on or monotherapy? add-on Control(s) placebo Study start and end dates not stated Centres and location multicentre (n=?)

Trial design Baseline not stated Titration (including details of 6 weeks schedule and frequency of doses)

Maintenance 8 weeks Withdrawal None Timing and additional not stated eligibility for randomisation/continuation on study Comments on design dose-response study

Quality Was assignment of treatment yes assessment described as random? Was method of randomisation not stated described? Was the method really can't tell random? Was allocation of treatment can't tell concealed? Who was blinded to treatment? not stated Was method of blinding no description adequately described? Were eligibility criteria no described? Were groups comparable at can't tell study entry? Were groups treated can't tell identically apart from the intervention?

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Was ITT used? claimed.

Were withdrawals stated? no Were reasons for withdrawals no stated? Was a power calculation yes done? Comments Underpowered, randomised only 63% of target of 200 patients.

Eligibility Inclusion criteria not stated criteria

Exclusion criteria not stated

Baseline placebo viga: 20, 60, 100mg characteristics Number randomised total 126, not stated by total 126, not stated by arm arm Number analysed 126 not stated by arm 126 not stated by arm Age (wks, mos, yrs) range 3-16 yrs, not range 3-16 yrs, not (mean, SD; median, range) stated by study arm stated by study arm Male:female not stated not stated Weight (kg, lbs) not stated not stated (mean, SD; median, range) Duration of epilepsy (wks, not stated not stated mos, yrs) (mean, SD; median, range) Age at diagnosis (wks, mos, not stated not stated yrs) (mean, SD; median, range) Newly diagnosed, n (%) not stated not stated

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Previously diagnosed, n (%) not stated not stated Refractory, n (%) not stated not stated - definition of refractory Diagnosed seizure types, n (%) not stated

Diagnosed syndrome(s), n (%) not stated

Baseline seizure frequency not stated (/dy, wk, mo) (mean, SD; median, range)

No concomitant AEDs, n (%) not stated

Concomitant AEDs, n (%) not stated

Previous AEDs, n (%) not stated

Comments

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Monitoring Was monitoring of plasma No and outcomes levels done (including study drug)? Were arrangements to blind NA plasma monitoring results mentioned? Who recorded seizure not stated frequency? How often was seizure not stated frequency measured? Frequency of clinic visits not stated

Primary outcome(s) including 1. Reduction in patient mean monthly seizure timepoints if repeated frequency

Secondary outcome(s) excluding AEs

'Ad hoc' outcomes (if emphasised and not in methods) Comments

Results placebo viga: 20, 60, 100mg (ITT only; unadjusted where available) Median follow-up not stated not stated

Maintenance dose achieved not stated not stated

Withdrawals including reasons not stated where specified

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Results (diff, or by CI for difference; p- arm) value Primary outcome(s) 1. Reduction in patient not stated p=0.0142 (100mg mean monthly seizure group v. placebo) frequency greater reduction for active arm.

Secondary outcomes

'Ad hoc' outcomes

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Comments (including whether unadjusted results reported)

Adverse Criteria for reporting treatment-related placebo viga: 20, 60, 100mg Events adverse events Events all events (61.3) (42.3), (65.5), (86.7) somnolence not reported not reported dizziness not reported not reported increased seizure frequency not reported not reported

Comments

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Conclusions Author's conclusions Vigabatrin is safe and effective add-on treatment in paediatric patients with uncontolled complex partial seizures.

Our conclusions Insufficient reported detail to judge validity of authors conclusion.

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Trial details Trial ID Guerreiro, 1997 Drug(s) oxcarbazepine Target maintenance dose 450-2400 mg/day (mode) (oral) Seizure or syndrome Newly diagnosed partial seizures with or without secondary generalization, and generalized tonic-clonic seizures Type of trial design parallel Add-on or monotherapy? monotherapy Control(s) Phenytoin Study start and end dates 1991 to 1995 Centres and location Multi centre; Brazil and Argentina.

Trial design Baseline Retrospective baseline Titration (including details 8 weeks of schedule and frequency Oxcarbazepine: of doses) 150mg/day gradually increasing according to clinical response to target of 450-2400mg/day 3 doses/day Phenytoin: 50mg/day gradually increasing according to clinical response to target of 150-800mg/day 3 doses/day Maintenance 48 weeks Withdrawal None (optional non-RCT continuation to open study) Timing and additional NA (retrospective eligibility for baseline) randomisation/continuatio n on study Comments on design No clear justification given for the use of phenytoin as comparator when it is not generally a first choice treatment.

Quality Was assignment of Yes assessment treatment described as random? Was method of Yes randomisation described? Was the method really Yes random? Was allocation of treatment Can't tell concealed? Who was blinded to Described as treatment? 'double blind' Was method of blinding "tablets … with identical appearance" adequately described? Were eligibility criteria Yes described? Were groups comparable Yes at study entry? Were groups treated Can't tell identically apart from the intervention? Was ITT used? Yes (for time to withdrawal outcome) Were withdrawals stated? Yes

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Were reasons for Yes withdrawals stated? Was a power calculation Yes done? Comments Authors identify a primary outcome for each of: efficay, tolerability and clinical utility

Eligibility Inclusion criteria 1. Newly diagnosed epilepsy with partial seizures, with or criteria without secondary generalisation, or generalised tonoc-clonic seizures 2. Minimum of 2 seizures separated by at least 48 hrs in previous 6 months 3. 5-18 years old. 4. No previous anti-epileptic drug except for emergency treatment for a maximum of 3 weeks Exclusion criteria 1. Pregnant or risk of becoming pregnant 2. History of status epilepticus 3. Severe psychiatric disorder or severe mental retardation 4. Progressive neurological disorder 5. Alcoholism or drug abuse 6. Significant organic disease

Baseline characteristics Phenytoin Oxcarbazepine Number randomised 96 97 Number analysed 77 81 Age (wks, mos, yrs) mean 10.85; range mean 10.22; range (mean, SD; median, range) 6-17 5-17 Male:female 50:46 46:51 Weight (kg, lbs) mean 40.7kg; range mean 36.4kg; range (mean, SD; median, range) 21-96 16-72 Duration of epilepsy (wks, mos, yrs) mean 37.7wks; mean 30.2wks; (mean, SD; median, range) range 0.8-728 range 0.8-272 Age at diagnosis (wks, mos, yrs) Not stated Not stated (mean, SD; median, range) Newly diagnosed, n (%) 96 (100) 97 (100) (although duration (although duration of epilepsy very of epilepsy very long for some long for some patients) patients) Previously diagnosed, n 0 (-) 0 (-) (%) Refractory, n (%) None None - definition of refractory Diagnosed seizure types, n Partial seizures 78 (81.3) 73 (75.2) (%) (any type)

Generalized 17 (17.7) 22 (22.7)

Unclassified 1 (1) 2 (2.1)

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Diagnosed syndrome(s), n localization-related, (%) idiopathic 20 18

localization-related, symptomatic 5 7

localization-related, cryptogenic 50 46

generalized, idiopathic 11 11

generalized, cryptogenic or symptomatic 5 6

generalized, symptomatic 1 2

others 4 6

unclassified 0 1 Baseline seizure frequency All seizure types mean 0.66/wk; mean 0.68/wk; (/dy, wk, mo) median 0.33 median 0.25 (mean, SD; median, range) 2 seizures/wk (n) 47 40 3-10 seizures/wk (n) 38 45 11-99 seizures/wk (n) 7 11 >=100 seizures/wk (n) 4 1 No concomitant AEDs, n None 96 (100%) 97 (100%) (%) Concomitant AEDs, n (%) None 96 (100%) 97 (100%)

Previous AEDs, n (%) None 96 (100%) 97 (100%)

Comments

Monitoring Was monitoring of plasma Yes and levels done (including outcomes study drug)? Were arrangements to Yes (results reported only as zero, low, blind plasma monitoring within range, or high) results mentioned? Who recorded seizure Patient or carer frequency? How often was seizure Patient diaries (frequency not stated) frequency measured? Frequency of clinic visits Every 2 weeks during titration; every 8 weeks during maintainance 316 Newer Drugs for Children with Epilepsy

maintainance

Primary outcome(s) Proportion of seizure-free patients (of those who reached including timepoints if maintenance period and had at least one seizure assessment repeated during the maintenance period)

Secondary outcome(s) 1. Seizure frequency during maintenance excluding AEs 2. Overall evaluation of therapeutic effect (4 point ordinal scale) 3. Premature discontinuation due to unsatisfactory therapeutic effect 4. Premature discontinuation due to adverse events. 5. Overall evaluation of tolerability (4 point ordinal scale) 6. Clinical utility (time to premature discontinuation for any reason) 'Ad hoc' outcomes (if emphasised and not in methods) Comments Primary outcome measure precludes ITT analysis.

Results Phenytoin Oxcarbazepine (ITT only; unadjusted where available) Median follow-up 56 weeks 56 weeks

Maintenance dose achieved Mean Mean 5.8mg/kg/day 18.8mg/kg/day (at start of (at start of maintenance maintenance period) period) Withdrawals including Total withdrawals 34 24 reasons where specified Loss to follow up 9 8 Adverse experiences 14 2 Non-compliance 5 6 Unsatisfactory therapeutic effect 3 4 Protocol violation 2 3 Concomitant illness 0 1 Discontinuation at baseline 1 0

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) Proportion of 46/77 phenytoin p=0.91 (by logistic seizure-free patients 49/81 regression) (of those who oxcarbazepine Not based on ITT reached population maintenance period and had at least one seizure assessment during the maintenance period)

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Secondary outcomes 1. Seizure frequency mean 0.04, median p=ns during maintenance 0 phenytoin (not based on ITT mean 0.07, median population) 0 oxcarb

2. Overall No data reported; p=ns evaluation of not clear if ITT therapeutic effect (4 analysis point ordinal scale)

3. Premature 3 phenytoin, 4 p=ns discontinuation due oxcarbazepine to unsatisfactory therapeutic effect

4. Premature 14 phenytoin, 2 (logrank p=0.002) discontinuation due oxcarbazepine to adverse events

5. Overall Not reproduced p=0.001 (physician evaluation of here assessment) tolerability (4 point p=0.038 (patient ordinal scale) assessment)

6. Clinical utility 34/96 phenytoin, p=ns (time to premature 24/97 discontinuation for oxcarbazepine any reason) Odds ratio for 1.0-3.9; p=0.046 discontinuation (not based on (phen v. oxc) 1.99 logrank analysis) 'Ad hoc' outcomes

Comments (including whether unadjusted results Not clear why logistic regression used to reported) analyse treatment retention; survival analysis would be more appropriate. Note that OR obtained in this way will be numerically greater than HR obtained by the appropriate analysis.

Adverse Criteria for reporting Occurrence in more Phenytoin Oxcarbazepine Events than 5% pts in either group

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Events Somnolence (29.8) (25.0) Dizziness (22.3) (9.4) Headache (14.9) (13.5) Gum hyperplasia (25.5) (2.1) Apathy (10.6) (11.5) Ataxia (13.8) (0) Nervousness (11.7) (2.1) Nausia (7.4) (5.2) Abnormal thinking (6.4) (5.2) Rash (5.3) (4.2) Abdominal pain (4.3) (5.2) Hypertrichosis (8.5) (0) Vomiting (5.3) (0) Increase in gamma glutamyl transpeptidase (5.3) (0)

At least one adverse 84/94 (89.4%) 79/96 (82.3) event

Comments

Conclusions Author's conclusions Oxcarbazepine is efficacious and safe for use in children and adolescents with partial seizures and generalised tonic-clonic seizures. In addition oxcarbazepine has advantages over phenytoin in terms of tolerability and clinical utility (treatment retention).

Our conclusions Oxcarbazepine appears equally effective as phenytoin at reducing seizures (partial and generalised tonic-clonoic), however because ITT analysis was not performed and some patients were excluded from analysis were not provided, it is difficult to assess the reliability of this conclusion.

Authors state that the phenytoin dose was toward the low end of dose range used.

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Trial details Trial ID Eriksson, 1998 Drug(s) lamotrigine Target maintenance dose not reported (mode) Seizure or syndrome generalised seizures Type of trial design response-mediated' withdrawal/crossover Add-on or monotherapy? add-on Control(s) placebo Study start and end dates not reported Centres and location 1 centre, Scandinavia Trial design Baseline 8 weeks Titration (including details up to 12 months (mean 5 months) of schedule and frequency Titrated from 1mg/kg/day (or 0.5mg/kg/day if taking of doses) valproate), with dose increased by the same amount every 2 weeks until clinical response or adverse effects seen. Dose optimised for each patient 2 doses/day Maintenance 2x12 weeks Withdrawal 3 week washout periods between titration and first 12 week maintenance phase, and before second 12 week maintenance phase Timing and additional Only "responders" entered the DB phase i.e. patients eligibility for experiencing >=50% reduction in sz frequency or in sz randomisation/continuatio severity (or both), or with definite improvements in behaviour n on study or motor skills or both. Non-responders were defined as without positive effects of lam with plasma levels <=10mcg/ml or children who had adverse events during the titration phase Comments on design The way in which improvement in behavioural skills or motor improvements were assessed is not explained which makes the definition of responder very subjective, although it seems from the definition of 'non-responder' that responder was defined by default.

Methods do not describe correct analysis for crossover trial (although order and period effects are reported in results) Quality Was assignment of Yes assessment treatment described as random? Was method of No randomisation described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to Described as treatment? 'double-blind' Was method of blinding No adequately described? Were eligibility criteria Yes described? Were groups comparable Can't tell at study entry? Were groups treated Can't tell identically apart from the intervention?

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Was ITT used? Yes (2 patients withdrawn from lamotrigine arm at family request) Were withdrawals stated? Yes Were reasons for Yes withdrawals stated? Was a power calculation No done? Comments

Eligibility Inclusion criteria 1. Refractory or intractable generalised epilepsy criteria 2. Children and adolescents >2 yrs of age 3. More than 2 seizures per month

Exclusion criteria 1. Liver, renal, or progressive neurologic disease 2. Diagnosis of focal epilepsy

Baseline characteristics Placebo Lamotrigine /Lamotrigine /Placebo Number randomised 8 9 Number analysed 8 7 Age (wks, mos, yrs) mean 10.3 yrs mean 9.9 yrs (mean, SD; median, range) range 4.8-16.9 range 4.6-20.7 Male:female Not reported Not reported Weight (kg, lbs) Not reported Not reported (mean, SD; median, range) Duration of epilepsy (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Age at diagnosis (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Newly diagnosed, n (%) 0 (-) 0 (-) Previously diagnosed, n 100% 100% (%) Refractory, n (%) Not seizure-free 100% 100% - definition of refractory after treatment with at least 3 consecutive AEDs Diagnosed seizure types, n Tonic-clonic 5 (62.5) 5 (55.5) (%) Tonic/atonic 7 (87.5) 8 (88.8) Myoclonic 8 (100) 8 (88.8) Atypical absences 7 (87.5) 8 (88.8) Other 2 (25) 8 (88.8)

2 lamotrigine patients included above not included in analysis; both

321 Newer Drugs for Children with Epilepsy

experienced all 4 types of seizure

Diagnosed syndrome(s), n Lennox-Gastaut 5 (62.5) 8 (88.8) [2 (%) withdrew] No data 3 (37.5) 1 (11.1)

Baseline seizure frequency All seizures mean 98.8 mean 113 (/dy, wk, mo) (per month) median 78.5, range median 92, range (mean, SD; median, range) 16-242 13-315

Withdrawals: 167/month and 150/month No concomitant AEDs, n 1 1 (12.5) 0 (%) 2 4 (50) 5 (55.5) 3 3 (37.5) 4 (44.4) Concomitant AEDs, n (%) Carbamazepine 4 (50) 4 (44.4) [1 withdrawal] Clonazepam 4 (50) 5 (55.5) [1 withdrawal] Ethosuximide 2 (25) 1 (11.1) Phenobarbital 0 2 (22.2) Valproate 5 (62.5) 6 (66.6) Vigabatrin 3 (37.5) 4 (44.4) [2 withdrawals] Previous AEDs, n (%) Not reported Not reported Not reported

Comments Data for patients who entered randomised cross-over phase recorded here (n=17); characteristics of the two patients who withdrew after randomisation noted above. Most characteristics calculated from tables of individual patient data given in paper. Monitoring Was monitoring of plasma Yes (including and levels done (including study drug) outcomes study drug)? Were arrangements to Results only known to a single coordinator (implies but does blind plasma monitoring not state that this coordinator was not responsible for patient results mentioned? care or assessment) Who recorded seizure Parents/other frequency? caregivers How often was seizure Not stated (diaries) frequency measured? Frequency of clinic visits 2 weekly (1 day visit to clinic, including 4-hr observation of patient by nurse)

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Primary outcome(s) 1. % reduction in average monthly seizure frequency during including timepoints if randomised phase (both 12 week periods combined) repeated

Secondary outcome(s) 1. Seizure severity excluding AEs 2. Functional status

'Ad hoc' outcomes (if 1. Analysis of results by seizure type and in patients with emphasised and not in Lennox-Gastaut syndrome methods) Comments

Results Placebo/Lamotrigi Lamotrigine/Place (ITT only; unadjusted where available) ne bo Median follow-up 27 or 30 weeks 27 or 30 weeks (not clear if first (not clear if first wash-out period wash-out period before or after before or after randomisation) randomisation) Maintenance dose achieved Not reported Not reported Withdrawals including Total 0 2 reasons where specified Consent withdrawn - 2

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) 1. % reduction in results reported for p<0.0001 average monthly each individual; order effect: p=0.13 seizure frequency 14/15 had lower period x treatment: during DB phase seizure rate in p=0.83 lamotrigine period, period effect: not 1/15 no change mentioned

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Secondary outcomes 1. Seizure severity Not reported Not reported

2. Functional status Not reported Not reported of patients

'Ad hoc' outcomes 1. >50% reduction 9/15 patients Not reported in seizure frequency on lamotrigine period compared to placebo period 2. Analysis of Results not Not reported results by seizure reproduced here type and in patients with Lennoux Gastaut syndrome Comments (including whether unadjusted results Atypical absences and myoclonic events reported) excluded from analyses due to difficulty identifying these events in this patient population; not clear what effect this might have, or whether this decision was made prior to unblinding data.

2 patients had atonic seizures when lamotrigine was added (not previously).

Adverse Criteria for reporting Not stated Placebo phase Lamotrigine phase Events

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Events Fatigue 10 (58.8) None More intense seizures 4 (23.5)

Comments Adverse event data listed here are those occurring during the randomised phase.

Conclusions Author's conclusions Compared with placebo lamotrigine produced a 'clear reduction' in seizure counts in responding children with refractory generalised epilepsies. Sample was representative of children with intractable generalised epilepsies (Lennox- Gastaut ~70% of these). Authors justify their more lax definition of responder as their definition encompasses clinically meaningful treatment effects in a population such as studied here. Differences (improvements) in behaviour and alertness were seen with lamotrigine (over placebo) irrespective of whether seizure frequency reduced. Our conclusions The use of a cross over design presents some difficulty in interpretation. In particular it is not clear how, or if, drug was withdrawn during the 3 week 'washout' periods; this terminology would usually be used to refer to a 'drug-free' period, but in this trial it may have been used in order to titrate lamotrigine dose up or down prior to entering the maintenance phases.

Neither of the defined secondary endpoints was reported.

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Trial details Trial ID Motte, 1997 Drug(s) Lamotrigine Target maintenance dose 50-300mg/day (tablets - oral) (mode) Seizure or syndrome Lennox-Gastaut syndrome Type of trial design parallel Add-on or monotherapy? add-on Control(s) placebo Study start and end dates 1994 to 1995 Centres and location 43 centres in US, Europe Trial design Baseline 4 weeks Titration (including details 6 weeks of schedule and frequency Initial and target doses dependent on body weight and of doses) concomitant valproate use (being lower if valproate taken) number of doses/day not stated

Maintenance 10 weeks Withdrawal None Timing and additional Post-baseline; no additional eligibility eligibility for criteria randomisation/continuatio n on study Comments on design Dose titration refers explicitly to lamotrigine only; not clear how/if placebo doses titrated in same way

For the first 2 weeks of the maintenance phase, (weeks 7-8) patients took fixed doses of treatment achieved during the titration phase. During weeks 8 or 12 the dose of lamotrigine could be increased if seizures continued to the maximum stated daily dose (100-200mg if taking valproate, 300-400mg if not)

During withdrawal phase, dose reduced to 50% for 2 weeks, then by further 50% to 25% for 2 weeks Quality Was assignment of Yes assessment treatment described as random? Was method of No randomisation described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to Described as 'double-blind'. treatment? Was method of blinding No description adequately described? Were eligibility criteria Yes described? Were groups comparable No; some imbalance in sex, and also a relatively large at study entry? difference in the numbers randomised to the two groups (90 vs 79) Were groups treated Can't tell (no description of blinding, and dose titration refers identically apart from the to gabapentin group only)

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intervention? Was ITT used? Not clear (see comment) Were withdrawals stated? Yes Were reasons for Yes withdrawals stated? Was a power calculation No done? Comments Two patients are excluded for 'lack of completeness'; the report does not state which arm(s) these patients were allocated to.

Eligibility Inclusion criteria 1. More than one type of predominantly generalized seizure criteria including tonic-clonic seizures and drop attacks for at least one year 2. Age younger than 11 years at onset of epilepsy 3. Seizures at least every other day or with a similar average frequency 4. Intellectual impairment or a clinical impression of intellectual deterioration 5. Recent EEG demonstrating an abnormal background and a pattern of slow spike-and-wave complexes (<2.5Hz) Exclusion criteria 1. Progressive neurodegenerative disorder 2. Receiving >3 AEDs 3. Body weight <15kg and taking valproate

Baseline characteristics Placebo Lamotrigine Number randomised 90 79 Number analysed 89 78 Age (wks, mos, yrs) mean 10.9, SD 5.9 mean 9.6, SD 5.2 (mean, SD; median, range) Male:female 45:45 54:25 Weight (kg, lbs) mean 34.3 kg, SD mean 32.5 kg, SD (mean, SD; median, range) 19.7 18.1 Duration of epilepsy (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Age at diagnosis (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) (had to be <11 (had to be <11 years to be years to be enrolled) enrolled) Newly diagnosed, n (%) 0 0 Previously diagnosed, n 90 (100%) 79 (100%) (%) Refractory, n (%) Not stated Not stated - definition of refractory - none given - none given

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Diagnosed seizure types, n Infantile spasms 37 (41%) had 31 (39%) had (%) (history of) history of infantile history of infantile spasms spasms

Diagnosed syndrome(s), n Lennox-Gastaut 100% 100% (%) syndrome

Baseline seizure frequency Major seizures median 13.5 (1.5 to median 16.4 (3.1 to (/dy, wk, mo) (drop attacks and 592.8) per week 249.4) per week (mean, SD; median, range) tonic-clonic)

No concomitant AEDs, n Not reported Not reported (%) (all patients on 1-3 (all patients on 1-3 concomitant AEDs) concomitant AEDs) Concomitant AEDs, n (%) Carbamazepine 30 (33.3) 16 (20.2) Valproate 50 (55.5) 53 (67.0) Phenytoin 13 (14.4) 10 (12.6) Others 9 (10.0) 11 (13.9)

Previous AEDs, n (%) Not reported Not reported

Comments Other' AEDs taken included oxcarbazepine, clobazam, vigabatrin, clonazepam, phenobarbital, ethosuximide, nitrazepam, primidone.

Monitoring Was monitoring of plasma Yes, including and levels done (including lamotrigine outcomes study drug)? Were arrangements to No blind plasma monitoring results mentioned? Who recorded seizure Parents/guardians frequency? How often was seizure Daily (diaries) frequency measured? Frequency of clinic visits weeks -4, 2, 4, 8, 12, 16, 20 Primary outcome(s) 1. % change in frequency of major motor seizures (drop including timepoints if attacks and tonic-clonic seizures) repeated

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Secondary outcome(s) 1. median change in frequency of drop attacks excluding AEs 2. median change in frequency of tonic-clonic seizures 3. median change in frequency of atypical absences 4. responder rate, defined as >= 50% reduction in major motor seizures+C29

'Ad hoc' outcomes (if - emphasised and not in methods) Comments Two patients were excluded from the analyses because of incomplete data

Results Placebo Lamotrigine (ITT only; unadjusted where available) Median follow-up 16 weeks 16 weeks (assumed) (assumed) Maintenance dose achieved Not reported pts <= 25kg + val 13.0 (4.9) pts <= 25kg no val 3.7 (0.9) pts >25kg + val 8.4 (3.3) pts >25kg no val 3.7 (1.5) Withdrawals including Total withdrawals 14 (15.5) 7 (8.8) reasons where specified Adverse events 7 (7.7) 3 (3.7) Worse seizure control 2 (2.2) 0 (-) Protocol violation 3 (3.3) 4 (5.0) Loss to follow-up 1 (1.1) 0 (-) Consent withdrawn 1 (1.1) 0 (-)

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) % change in placebo -9% p=0.002 frequency of major lamotrigine -32% motor seizures (median reduction) (drop attacks and tonic-clonic seizures)

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Secondary outcomes 1. % change in placebo -9% p=0.01 frequency of drop lamotrigine -34% attacks

2. % change in placebo +10% p=0.03 frequency of tonic- lamotrigine -36% clonic seizures

3. % change in placebo -38% p=0.96 frequency of lamotrigine -13% atypical absences

4. Responder rate, placebo 16% p=0.01 defined as >= 50% lamotrigine 33% reduction in major motor seizures

'Ad hoc' outcomes - - -

Comments (including whether unadjusted results Results adjusted for country effects. reported)

Adverse Events in >=4% of Placebo Lamotrigine Events pts in either group: Events Infection 7 (7.7) 10 (12.6) Fever 12 (13.3) 10 (12.6) Nausea and/or vomiting 6 (6.6) 7 (8.8) Somnolence 4 (4.4) 3 (3.7) Pharyngitis 9 (10.0) 11 (13.9) Cold/viral illness 0 4 (5.0) Headache 6 (6.6) 3 (3.7) Rhinitis 7 (7.7) 4 (5.0) Otitis media 4 (4.4) 1 (1.2) Bronchitis 6 (6.6) 7 (8.8) Constipation 2 (2.2) 4 (5.0) Rash 6 (6.6) 7 (8.8) Injury/accident 6 (6.6) 7 (8.8)

330 Newer Drugs for Children with Epilepsy

Comments Statistical difference between groups in cold/viral illness incidence (p=0.05)

Conclusions Author's conclusions Add-on lamotrigine therapy reduces the frequency of seizures in children with Lennox-Gastaut syndrome (but not atypical absences) compared with placebo

Our conclusions Methodological weaknesses in design/conduct of trial difficult to quantify due to lack of information on procedures for randomisation and blinding, and on whether ITT analysis used. Lack of this information, along with monitoring of AED plasma levels with no description of how clinicians were blinded to these results, gives some cause for concern.

The trial is too small to claim evidence of any sub-group effects; the apparent benefit to placebo for atypical absence seizures could easily have arisen by chance.

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Trial details Trial ID Sachdeo, 1999 Drug(s) topiramate Target maintenance dose 6mg/kg/day (oral assumed) (mode) Seizure or syndrome Lennox-Gastaut Type of trial design parallel Add-on or monotherapy? add-on Control(s) placebo Study start and end dates Not reported Centres and location 12 centres in the USA Trial design Baseline 4 weeks Titration (including details 3 weeks of schedule and frequency week 1: 1mg/kg/day; week 2: 3 mg/kg/day; week 3: 6 of doses) mg/kg/day (target dose) 2 doses / day

Maintenance 8 weeks Withdrawal None Timing and additional Post-baseline; patients who 'qualified for entry' were eligibility for randomised, but no specific criteria for this are mentioned randomisation/continuatio n on study Comments on design Titration explicitly refers to both arms

Quality Was assignment of Yes assessment treatment described as random? Was method of Yes randomisation described? Was the method really Yes random? Was allocation of treatment Yes concealed? Who was blinded to Investigators, patients, study monitors and observers treatment? Was method of blinding 'blinded medication'; no further details adequately described? Were eligibility criteria Yes described? Were groups comparable Yes at study entry? Were groups treated Yes identically apart from the intervention? Was ITT used? Yes Were withdrawals stated? Yes Were reasons for Yes withdrawals stated? Was a power calculation Yes done?

332 Newer Drugs for Children with Epilepsy

Comments Trial includes patients up to the age of 30; results are not reported separately for children but this trial is included as a substantial proportion of patients are under 18 and Lennox- Gastaut is a syndrome which occurs only in childhood, and thus this data would otherwise be excluded from both reviews being prepared for NICE. Eligibility Inclusion criteria 1. >1 year old and <30 years old, weighing at least 11.5 Kg. criteria 2. Female patients practicing birth control or pre-menarchal 3. Drop attacks (tonic or atonic seizures) and either a history of or active atypical absence seizures 4. EEG showing slow spike-and-wave pattern. 5. 60 seizures (including tonic-clonic, myoclonic, partial onset) in month prior to baseline while on 1 or 2 standard AEDs Exclusion criteria 1. History of recent significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, or hematologic illness, ormalignancy or nephro-lithiasis 2. Seizures due to progressive disease 3. Documented status epilepticus within 3 months of baseline. 4. Drug/alcohol abuse, psychiatric or mood disorder requiring ECT or medication within 6 months of baseline 5. Treatment with experimental drug, acetazolamide or zonisamide within 60 days of baseline 6. Ketogenic diet or ACTH within 6 months of study 7. Use of benzodiazepines other than on an occasional basis (unless as concomitant AED) 8. History of poor compliance or inability to keep seizure calender 9. Clinically significant electrocardiogram abnormalities Baseline characteristics Placebo Topiramate Number randomised 50 48 Number analysed 50 48 Age (wks, mos, yrs) mean 11.2, SD 7.7 mean 11.2, SD 6.2 (mean, SD; median, range) yrs; range 2 – 42 yrs; range 2 – 29 Male:female 25:25 28:20 Weight (kg, lbs) mean 31.6, SD 17.8 mean 36.7, SD 19 (mean, SD; median, range) kg; range 12-82.2 kg; range 13.8-99.9 Duration of epilepsy (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Age at diagnosis (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Newly diagnosed, n (%) None (from None (from eligibility) eligibility) Previously diagnosed, n 50 (100) (from 48 (100) (from (%) eligibility) eligibility) Refractory, n (%) Not reported Not reported - definition of refractory Diagnosed seizure types, n All patients (%) drop attacks (tonic and atonic) 95 (93) atonic 90 (88) atypical absence 70 (69) tonic 51 (50) myoclonic 46 (45) tonic-clonic 38 (37) complex partial 16 (16) absence 9 (9) secondarily generalised. 4 (4) 333 Newer Drugs for Children with Epilepsy

clonic 2 (2) unspecified types 6 (6)

Diagnosed syndrome(s), n Lennox-Gastaut 50 (100) 48 (100) (%)

Baseline seizure frequency drop attacks (tonic median 98/mo; median 90/mo; (/dy, wk, mo) and atonic) range 1-4324 range 2-2459 (mean, SD; median, range) drop attacks + median 354/mo; median 288/mo; tonic-clonic range 1-4324 range 2-2459

all seizure types median 244/mo; median 267/mo; range 7-4324 range 13-3795 No concomitant AEDs, n 1 20 (40) 19 (40) (%) 2 29 (58) 27 (56) 3 1 (2) 2 (<1) Concomitant AEDs, n (%) Not reported but see - - comment

Previous AEDs, n (%) Not reported - -

Comments Protocol change after about 50% of patients recruited disallowed felbamate as a concomitant AED (due to new safety information about felbamate becoming available); at this time 8 pts in placebo arm and 7 in the topiramate arm had been recruited who were taking felbamate which was subsequently withdrawn in 1 of the placebo and 2 of the topiramate patients. Monitoring Was monitoring of plasma Yes and levels done (including outcomes study drug)? Were arrangements to No blind plasma monitoring results mentioned? Who recorded seizure Parent/guardian or patient frequency? How often was seizure Daily (diaries) frequency measured? Frequency of clinic visits Not clear

334 Newer Drugs for Children with Epilepsy

Primary outcome(s) 1. % reduction v baseline in average monthly seizure rate for including timepoints if all seizure types repeated 2. Composite outcome based on % reduction in average monthly seizure rate for drop attacks (tonic + atonic), and parental global evaluation of improvement in seizure severity Secondary outcome(s) 1. % reduction in average monthly seizure rate for major excluding AEs seizures (tonic, atonic and tonic-clonic) 2. % responders

'Ad hoc' outcomes (if - emphasised and not in methods) Comments The second primary outcome is rather strange; it's not clear why these outcomes are combined. The results for each outcome are reported separately and via the combined approach. Results Placebo Topiramate (ITT only; unadjusted where available) Median follow-up 11 weeks (assumed 11 weeks (assumed from low drop out from low drop out rate) rate) Maintenance dose achieved 92% achieved median target dose 5.8mg/kg/day 71% achieved target dose (6mg/kg/day) Withdrawals including Total withdrawals 0 1 reasons where specified Patient choice 0 1

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) 1. % reduction in placebo median - ns average monthly 8.8% seizure rate topiramate median - 20.6%

2. Composite: % drop attacks: reduction in placebo median average monthly +5.1% drop attack rate & topiramate median parental global -14.8% p=0.041 evaluation (PGE) PGE: data not reproduced here p=0.037

composite p<0.01

335 Newer Drugs for Children with Epilepsy

Secondary outcomes Sz 1. % reduction placebo median type (s) average monthly 5.2% p=0.015 seizure rate (tonic, topiramate median atonic and tonic- 25.8% clonic only)

2. % responders Drop attacks: >=50% reduction 14% placebo vs p=0.071 28% >=75% reduction 6% vs 17% not reported

100% reduction 0 vs 1 patient not reported

Drop attacks or tonic-clonic: >=50% reduction 8% placebo vs 33% p=0.002 >=75% reduction 4% vs 17% not reported 100% reduction 0 vs 1 patient not reported

All seizure types: >=50% reduction 'no difference' p=ns >=75% reduction 0 vs 4 patients not reported 100% reduction not reported not reported

'Ad hoc' outcomes - - -

Comments (including whether unadjusted results Results adjusted for investigator. reported)

Adverse Criteria for reporting >10% greater Placebo Topiramate Events incidence in top arm (I.e.tx- emergent events)

336 Newer Drugs for Children with Epilepsy

Events somnolence (22) (42) anorexia (20) (40) nervousness (10) (21) behavioural problems (10) (21) fatigue (4) (19) dizziness (0) (10) weight loss (0) (10)

severe adverse (10) (23) events

Comments

Conclusions Author's conclusions Study demonstrates that topiramate is effective as adjunct therapy for Lennox Gastaut syndrome. Improvemnts in the frequency of drop attacks without limiting toxicity indicates topiramate represents an important addition to the treatments available.

Our conclusions This is a good trial which is well-designed and fairly well reported. The results of this study are encouraging, but the follow-up period is very short and the dose of topiramate fairly low; withdrawal of drug and rechallenge during maintenance period was allowed, which would be likely to minimise the proportions withdrawing due to adverse events during this short follow-up; no data is reported on drug withdrawal and rechallenge. Longer term data would be needed to establish the tolerability in clinical practice.

337 Newer Drugs for Children with Epilepsy

Trial details Trial ID Appleton, 1999 (2) Drug(s) vigabatrin Target maintenance dose 50-150mg/kg/day (not stated) (mode) Seizure or syndrome infantile spasms Type of trial design parallel Add-on or monotherapy? monotherapy Control(s) placebo Study start and end dates not reported Centres and location 40 centres; Europe, Canada, France

Trial design Baseline 2 or 3 days Titration (including details 5 days of schedule and frequency Titration in 3 steps; after 24 hours if spasms not ceased, and of doses) again after 48 hours according to the investigator's assessment of spasm frequency. Once established on a dose for >48 hours the dose could only be changed in response to concerns abour safety Number of doses per day not statedd Maintenance None Withdrawal None Timing and additional None eligibility for randomisation/continuatio n on study Comments on design Baseline period was to determine baseline sz frequency. Duration of 2 days for pts experiencing clusters of spasms, 3 days for pts with isolated spasms that did not cluster

Quality Was assignment of Yes assessment treatment described as random? Was method of Yes randomisation described? Was the method really Yes random? Was allocation of treatment Yes concealed? Who was blinded to Described as treatment? 'double-blind' Was method of blinding No adequately described? Were eligibility criteria Yes described? Were groups comparable Yes at study entry? Were groups treated Yes (if blinding adequate) identically apart from the intervention? Was ITT used? Yes

Were withdrawals stated? Yes Were reasons for Yes withdrawals stated? Was a power calculation Yes done?

338 Newer Drugs for Children with Epilepsy

Comments

Eligibility Inclusion criteria 1. Newly diagnosed (EEG proven) and previously untreated criteria infantile spasms (classic or modified hypsarrhythmia) 2. Age 1 to 20 months 3. Infants whose parents/guardians able to give informed consent and who were considered capable of completing seizure diaries and attending clinic appointments

Exclusion criteria 1. Use of any medication (including prednisolone, hydrocortisone, or ACTH) that could be considered to be an AED, within 2 months before entry into the study

Baseline characteristics Placebo Vigabatrin Number randomised 20 20 Number analysed 20 20 Age (wks, mos, yrs) mean 8 months mean 8 months (mean, SD; median, range) range 4-17 range 5-20 Male:female 8:12 11:9 Weight (kg, lbs) Not reported Not reported (mean, SD; median, range) Duration of epilepsy (wks, mos, yrs) mean 7 weeks mean 6 weeks (mean, SD; median, range) range 2-12 range 2-13 Age at diagnosis (wks, mos, yrs) at onset of spasms, at onset of spasms, (mean, SD; median, range) mean 6 months, mean 7 months, range 1-15 range 2-18 Newly diagnosed, n (%) 20 (100%) 20 (100%)

Previously diagnosed, n 0 0 (%) Refractory, n (%) 0 0 - definition of refractory Diagnosed seizure types, n Not reported Not reported Not reported (%)

Diagnosed syndrome(s), n Infantile spasms 20 (100) 20 (100) (%) (West's)

339 Newer Drugs for Children with Epilepsy

Baseline seizure frequency (/dy, wk, mo) Not reported Not reported (mean, SD; median, range)

No concomitant AEDs, n NA NA NA (%) Concomitant AEDs, n (%) NA NA NA

Previous AEDs, n (%) NA NA NA

Comments

Monitoring Was monitoring of plasma No and levels done (including outcomes study drug)? Were arrangements to NA blind plasma monitoring results mentioned? Who recorded seizure Nursing staff and parents/guardians frequency? How often was seizure Daily and for 2 hours of intensive monitoring each day frequency measured? Frequency of clinic visits Days -2, 0, 5 (1 and 3 also implied) Primary outcome(s) 1. % change in daily spasm frequency (24 hour and 2 hour including timepoints if assessments) repeated 2. Spasm-free patients on day 5

Secondary outcome(s) 1. Investigator 'global assessment' excluding AEs 2. Repeated EEG recordings

'Ad hoc' outcomes (if 1. Patients with 70% improvement on final day of follow-up emphasised and not in (24 hour and 2 hour assessments) methods) 2. Patients with no change or worsening in spasm frequency on final day of follow-up (24 hour assessment) Comments

Results Placebo Vigabatrin

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(ITT only; unadjusted where available) Median follow-up 5 days 5 days

Maintenance dose achieved mean 148 mg/kg mean 133 mg/kg Withdrawals including None stated 0 0 reasons where specified

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) 1. % change in daily spasm frequency placebo-25.9% 95% CI -56% to 24 hour assessment vigabatrin -77.9% 65%

2 hour assessment placebo -54.6% 95% CI 55% to vigabatirn -71.9% 89%, p=0.02

2. Seizure (spasm)- placebo 2 (10%) 95% CI 4% to 78% free patients vigabatrin 7 (35%) 95% CI 42% to 86%, p=0.342

p=0.063 Secondary outcomes 1. Investigator placebo: 'global assessment' 3 (15%) marked/moderate improvement 4 (20%) patients p<0.0001 deteriorated

vigabatrin: 16 (80%) marked/moderate improvement 0 deteriorated -

2. Repeated EEG hypsarrhythmia recordings resolved in 1 of 2 seizure-free patients on placebo vs 5 of 7 on vigabatrin 'Ad hoc' outcomes >70% improvement: placebo 3/20 (15%) - 24 hour vigabatrin 8/20 assessment (40%) -

placebo 11/20 - 2 hour (55%) assessment vigabatrin 13/17 - (76%)

No change or worse placebo 9/20 (45%) (24 hour) vigabatrin 4/20 -

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(20%)

Comments (including whether unadjusted results All means and CIs adjusted for reported) geographical region and baseline spasm rate

Three patients appear to be missing from lamotrigine group for the 2 hour results.

Adverse Criteria for reporting Not stated Placebo Vigabatrin Events Events Drowsiness Not reported 8 Behaviour change Not reported 1 (irritability)

Number reporting 6 (30%) 12 (60%) >=1 AE

Comments Adverse events in placebo group not described.

Conclusions Author's conclusions Study design has some limitations, with a short duration of follow-up, small sample size, questionable utility/validity of 2 hour assessments (intensive monitoring).

Results suggest that vigabatrin is effective; trial did not include patients with tuberous sclerosis, in whom vigabatrin might be most effective.

342 Newer Drugs for Children with Epilepsy

Our conclusions Trial is of reasonable quality but, as the authors point out, the sample size is very small. Nevertheless, reasonably convincing evidence that vigabatrin is effective compared to no treatment.

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Trial details Trial ID Vigevano, 1997 Drug(s) vigabatrin Target maintenance dose lowest effective and tolerated dose, 110-150mg/Kg/day (mode) (?mode) Seizure or syndrome newly diagnosed infantile spasms Type of trial design "response-mediated" open X-over study Add-on or monotherapy? monotherapy Control(s) ACTH Study start and end dates 1992 to 1995 Centres and location Italy

Trial design Baseline None Titration (including details 9 days vigabatrin in three 3-day stages: of schedule and frequency 1. 100 mg/Kg/d for 3 days of doses) 2. If no response and if tolerant then 125 mg/Kg/day for 3 days 3. If no response and tolerant then 150mg/Kg/day 2 doses/day ACTH No titration. Dose 10 IU 1 dose/day Maintenance 20 days, then continuation (responders) or cross-over (non- responders) for a further 20 days Withdrawal None Timing and additional NA (newly diagnosed population) eligibility for randomisation/continuatio n on study Comments on design Overall, the trial compares strategies rather than treatments, ie the strategy of starting with vigabatrin and switching to ACTH if unsuccessful, vs starting with ACTH and switching to vigabatrin. The first 20 day period could be regarded as a simple parallel trial. [Results for the comparison of strategies are not in fact reported, ie comparing the two original randomised groups, and so in effect this is a simple parallel trial with 20 day follow-up]. Quality Was assignment of Yes assessment treatment described as random? Was method of No randomisation described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to Open label study treatment? Was method of blinding NA adequately described? Were eligibility criteria Not in any detail described? Were groups comparable Some imbalance in sex ratios; could be a chance effect and at study entry? does not necessarily cast doubt on the randomisation Were groups treated Can't tell identically apart from the intervention? Was ITT used? Yes

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Were withdrawals stated? Yes Were reasons for Yes withdrawals stated? Was a power calculation No done? Comments

Eligibility Inclusion criteria Newly diagnosed and previously untreated infantile spasms criteria (diagnosed within 3 weeks of entry)

Exclusion criteria Not reported

Baseline characteristics ACTH Vigabatrin Number randomised 19 23 Number analysed 19 23 Age (wks, mos, yrs) Not reported (will Not reported (will (mean, SD; median, range) be similar to age at be similar to age at diagnosis) diagnosis) Male:female 7:12 14:9 Weight (kg, lbs) Not reported Not reported (mean, SD; median, range) Duration of epilepsy (wks, mos, yrs) < 3 wks (by < 3 wks (by (mean, SD; median, range) eligibility criteria) eligibility criteria) Age at diagnosis (wks, mos, yrs) mean 5.3 mos; mean 5.8 mos; (mean, SD; median, range) range 2-9. range 2.5-9. Newly diagnosed, n (%) 19 (100) 23 (100)

Previously diagnosed, n __ __ (%) Refractory, n (%) NA NA - definition of refractory Diagnosed seizure types, n Infantile spasms 19 (100) 23 (100) (%)

Diagnosed syndrome(s), n Symptomatic (%) infantile spasms 11 (58) 16 (70)

hypoxic/ischaemic cerebral 5 (26) 6 (26) malformation 3 (16) 4 (17)

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tuberous 1 (5) 3 (13) sclerosis 1 (5) 0 (0(

neurofibromatosis unknown cause 1 (5) 3 (13) Cryptogenic infantile spasms 8 (42) 7 (30)

Baseline seizure frequency - Not reported Not reported (/dy, wk, mo) (mean, SD; median, range)

No concomitant AEDs, n - None None (%) Concomitant AEDs, n (%) - NA NA

Previous AEDs, n (%) - NA NA

Comments

Monitoring Was monitoring of plasma No and levels done (including outcomes study drug)? Were arrangements to NA blind plasma monitoring results mentioned? Who recorded seizure Not reported frequency? How often was seizure Video-EEG recordings of sleep-wake cycle every 10 days. frequency measured? Further details not reported. Frequency of clinic visits Not reported Primary outcome(s) None stated including timepoints if repeated

Secondary outcome(s) - excluding AEs

'Ad hoc' outcomes (if 1. Proportion spasm-free after 20 days (phase 1) emphasised and not in methods)

346 Newer Drugs for Children with Epilepsy

Comments No outcomes defined in the methods.

Outcomes reported for whole (40 day) trial period not analysed appropriately (ie by randomised treatment arm); results reproduced here relate only to the first phase, equivalent to a standard parallel groups trial. Results ACTH Vigabatrin (ITT only; unadjusted where available) Median follow-up 40 days 40 days (assumed from low (assumed from low drop-out) drop-out) Maintenance dose achieved 10 IU/day 100 to 150mg/kg/day Withdrawals including Withdrawals during reasons where specified phase 1 1 1

Irritability & agitation 0 1

Irritability & raised BP 1 0 Results (diff, or by CI for difference; arm) p-value Primary outcome(s)

Secondary outcomes

'Ad hoc' outcomes 1. Proportion 14/19 (74) ACTH p=0.12 spasm-free in phase 11/23 (48) 1 Vigabatrin

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Comments (including whether unadjusted results reported)

Adverse Criteria for reporting Not stated ACTH Vigabatrin Events Events All events 7 (37) 3 (13) Drowsiness -- 2 (9) Hypotonia -- 2 (9) Irritability 7 (37) 1 (4) Hypertension 7 (37) --

Comments

Conclusions Author's conclusions The study supports the belief that vigabatrin offers an effective therapy for management of infantile spasms and may be safer than ACTH , and that a therapeutic response is usually quick to appear. Vigabatrin may be particularly effective for patients with tuberous sclerosis, and may effective for some patients resistent to ACTH. In view of well recognised limitations for the use of ACTH clinicians should consider using VGB as a first line therapy for infantile spasms. Our conclusions The trial is too small to come to any firm conclusions regarding the comparative efficacy and safety of vigabatrin and ACTH; there is a strong trend favouring ACTH in terms of efficacy, whilst vigabatrin appears to be associated with fewer adverse events.

The trial is much too small to draw any conclusions about effectiveness in particular subgroups of patients.

Data on time to response is not reported in a way that allows comparison of time to achieve response. These data are 348 Newer Drugs for Children with Epilepsy

reported completely separately for the two arms: 7/11 patients on vigabatrin responded in <3 days (range 1-14), whilst 11/14 patients on ACTH responded in <5 days (range 2-12).

The analysis used for the whole period of the trial is inappropriate to the design, and so there are no data reported enabling comparison of prescribing strategies (ie preferred drug order).

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Trial details Trial ID Chiron, 1997 Drug(s) vigabatrin Target maintenance dose 150mg/kg/day (?mode) (mode) Seizure or syndrome infantile spasms due to tuberous sclerosis Type of trial design 'response-mediated' open cross over Add-on or monotherapy? monotherapy Control(s) hydrocortisone Study start and end dates not reported Centres and location multicentre, France Trial design Baseline Not clear Titration (including details No titration of schedule and frequency vigabatrin 150mg/kg/day of doses) hydrocortisone 15mg/day. Dose frequency not reported

Maintenance One month, then cross-over of non-responders and continuation of responders andcross-overs for further month Withdrawal None Timing and additional NA eligibility for randomisation/continuatio n on study Comments on design Patients described as newly diagnosed, but would be more accurate to say 'recently' diagnosed, as duration of epilepsy varied from 2 weeks to 10 months and prior AED treatment was not an exclusion criteria. Quality Was assignment of Yes assessment treatment described as random? Was method of No randomisation described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to Open label study treatment? Was method of blinding NA adequately described? Were eligibility criteria Yes described? Were groups comparable No; differences compatible with chance in a such a small trial at study entry? (see comment) Were groups treated Can't tell identically apart from the intervention? Was ITT used? Can't tell; possibly not (see comment) Were withdrawals stated? Yes Were reasons for Yes withdrawals stated? Was a power calculation No done?

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Comments Report refers to 22 'evaluable patients'; it is not clear that all randomised patients were included. The limited information on the method of randomisation and some imbalances in patient characteristics, especially with respect to duration of infantile spasms prior to the trial, give further cause for concern. Eligibility Inclusion criteria 1.Tuberous sclerosis according to Gomez criteria. criteria 2. Epileptic spasms recorded by EEG or seen by an experienced physician. 3. Diffuse interictal activity. 4. Age 1 month to 2 years. 5. Withdrawn from anti-epileptic drugs > 1 week before commencement of study. Exclusion criteria 1. Previously treated with vigabatrin or ACTH or oral steroids.

Baseline characteristics hydrocortisone vigabatrin Number randomised Not stated Not stated Number analysed 11 11 Age (wks, mos, yrs) mean 7.9 SD 4.4 mean 6.6, SD (mean, SD; median, range) mos; median 6, 1.7mos ; median 7, range 2-17 range 4-9 Male:female 5:6 5:6 Weight (kg, lbs) (mean, SD; median, range) Duration of epilepsy (wks, mos, yrs) mean 36.4 SD 31.9 mean 24.4 SD 25.6 (mean, SD; median, range) days; range 15-300 days; range 15-90 Age at diagnosis (wks, mos, yrs) mean 5.9 SD 3.2 mean 5.8 SD 1.8 (mean, SD; median, range) mos; range 1-14 mos; range 3-9 Newly diagnosed, n (%) Not reported Not reported

Previously diagnosed, n Not reported Not reported (%) Refractory, n (%) Uncertain Uncertain - definition of refractory Diagnosed seizure types, n infantile spasms 11 (100) 11 (100) (%) partial seizures 5 (45.4) 2 (18.2)

Diagnosed syndrome(s), n infantile spasms due 11 (100) 11 (100) (%) to tuberous sclerosis

Baseline seizure frequency Infantile spasms mean 3.64 SD 1.12 mean 2.27 SD (/dy, wk, mo) (clusters)/day /day; median 4.0, 1.01/day; median (mean, SD; median, range) range 2-6 2.0, range 1-4

Partial Not reported Not reported

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No concomitant AEDs, n none - - (%) Concomitant AEDs, n (%) none - -

Previous AEDs, n (%) No details given Not reported Not reported

Comments

Monitoring Was monitoring of plasma No and levels done (including outcomes study drug)? Were arrangements to NA blind plasma monitoring results mentioned? Who recorded seizure Parents/guardians frequency? How often was seizure Daily (diaries) frequency measured? Frequency of clinic visits At randomisation, after 1 and 2 months Primary outcome(s) 1. Proportion spasm-free at one month including timepoints if repeated

Secondary outcome(s) 1. Change in development quotient (monitored at entry and at excluding AEs 2 month)

'Ad hoc' outcomes (if 1. Time to response, defined as days on drug prior to emphasised and not in becoming spasm-free. methods) Comments The 'response mediated' crossover design does not allow a straightforward comparison of the drugs at 2 months; results reported here are for the first (one month) period only, as for a simple parallel design. Results hydrocortisone vigabatrin (ITT only; unadjusted where available) Median follow-up 2 months 2 months Maintenance dose achieved 15mg/kg/day, 10/11, (& 7/7 after except 2 pts X-over) 150 mg/kg/day; 1 pt 100mg/kg/day.

352 Newer Drugs for Children with Epilepsy

Withdrawals including Total withdrawals 2 (18.2) 0 reasons where specified Lack of efficacy 0 0 Adverse events 2 (18.2) 0 Change in AED 0 0 Other 0 0

Median time to not reported onset of AE resulting in withdrawal Median duration not reported

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) 1. Proportion 5/11 spasm-free hydrocortisone p < .01 at 1 month 11/11 vigabatrin

Secondary outcomes 1. Tolerability 9/11 p= 0.006 hydrocortisone 5/11 vigabatrin 2. Development quotient Not ITT, only 8 hydrocortisone and 9 vigabatrin patients evaluated

'Ad hoc' outcomes Time to response Mean time to (days on drug prior response: p=0.058 to becoming spasm- Vigabatrin: 4 days free) (range 0.5-14) HC: 12.8 days (range 3-30 days) Comments (including whether unadjusted results Cross-over criteria were defined as 'non- reported) responders at one month', with no further criteria given. Criteria do not seem to have been applied consistently, or there are some errors in the text. For example: Two patients responded to HC at day 30, both had side effects, one was crossed over and one was not; One patient responded to HC at day 19, listed as having no side effects but was crossed over to vigabatrin. The tabulated data implies that 7 patients crossed over from HC to

353 Newer Drugs for Children with Epilepsy

vigabatrin (including the two mentioned above that had responded to HC), but the text implies that there were only 6 non-responders who should have crossed over (text states that 5/11 responded).

Adverse Criteria for reporting Events reported to hydrocortisone vigabatrin Events or observed by (n events) (n events) investigator; data relates to both study periods Events Adverse events (all) 17 8 Drowsiness - 3 Hyper-excitability/- kinesia 5 (1 severe) 3 (1 severe) Sleep disorders 3 (1 severe) - Weight 3 - Abdominal distension 2 (1 severe) - Axial hypertonia 1 1 (severe) Hypotonia - 1 Hypertension 2 - Cushing syndrome 1 -

Comments 5 patients experienced adverse events while receiving vigabatrin, 9 while receiving HC

Conclusions Author's conclusions Vigabatrin is effective with good safety and should be used for first line therapy for infantile spasms due to tuberous sclerosis. HC induced recovery rate may be only marginally greater than spontaneous recovery rate and is associated with more adverse events than vigabatrin.

354 Newer Drugs for Children with Epilepsy

Our conclusions Although these results are very encouraging, this study is very small and the results should be interpreted cautiously. Furthermore, there are some concerns about the methodological quality, particularly regarding the method of randomisation and a query as to whether all randomised patients were included in the analysis. Some anomalies in the reporting of the results also require some clarification.

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Trial details Trial ID Frank, 1999 Drug(s) Lamotrigine Target maintenance dose maximum 1000mg/day (oral - chewable, dispersible caplets) (mode) Seizure or syndrome typical absence seizures (newly diagnosed) Type of trial design withdrawal Add-on or monotherapy? monotherapy Control(s) placebo Study start and end dates not reported Centres and location multi-centre, USA

Trial design Baseline NA Titration (including details Minimum 4 weeks; until seizure-free or maximum dose of schedule and frequency reached of doses) Titration fixed for 4 weeks to 1mg/kg/day, then increased in increments of 1mg/kg/day according to clinical response 2 doses/day

Maintenance 0 Withdrawal 4 weeks Timing and additional Patients achieving seizure freedom during titration phase eligibility for were randomised to continue lamotrigine or switch to placebo randomisation/continuatio n on study Comments on design

Quality Was assignment of Yes assessment treatment described as random? Was method of No randomisation described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to Described as treatment? 'double-blind' Was method of blinding No description, other than that study medication matched for adequately described? size, shape, colour, taste Were eligibility criteria Yes described? Were groups comparable Yes (some imbalance in age and weight, consistent with at study entry? chance and the small sample size) Were groups treated Yes (if blinding adequate) identically apart from the intervention? Was ITT used? Yes Were withdrawals stated? Yes Were reasons for Yes withdrawals stated? Was a power calculation Yes done?

356 Newer Drugs for Children with Epilepsy

Comments One patient withdrew consent at start of randomised phase.

Although randomised groups described as "reasonably balanced demographically" there were differences in mean age and weight (8.8 yrs SD 3.1 placebo vs 6.9 yrs SD 2.3 lamotrigine; weight 40.0kg SD 16 placebo vs 30.2kg SD 9.9 lamotrigine) Eligibility Inclusion criteria 1. Newly diagnosed typical absence seizures criteria 2. Age 2 to 16 years

Exclusion criteria 1. Known or suspected structural lesion 2. History of poor compliance with medication or abuse of drugs 3. Progressive neurologic illness 4. Psychiatric disorder requiring medication 5. Chronic cardiovascular, renal, or hepatic disease 6. Use of investigational drug within previous 12 weeks 7. Any disease thought to interfere with absorption, distribution, metabolism, or excretion of drugs in general Baseline characteristics Placebo Lamotrigine Number randomised 14 15 Number analysed 14 14 Age (wks, mos, yrs) mean 8.8, SD 3.1 mean 6.9, SD 2.3 (mean, SD; median, range) yrs yrs Male:female 5:9 5:9 Weight (kg, lbs) 40.0, SD 16 kg 30.2, SD 9.9 kg (mean, SD; median, range) Duration of epilepsy (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Age at diagnosis (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Newly diagnosed, n (%) 14 (100) 14 (100)

Previously diagnosed, n 0 0 (%) Refractory, n (%) 0 0 - definition of refractory Diagnosed seizure types, n typical absence 14 (100) 14 (100) (%) seizures

Diagnosed syndrome(s), n NA NA NA (%)

357 Newer Drugs for Children with Epilepsy

Baseline seizure frequency NA Not reported Not reported (/dy, wk, mo) (mean, SD; median, range)

No concomitant AEDs, n NA NA NA (%) Concomitant AEDs, n (%) NA NA NA

Previous AEDs, n (%) NA NA NA

Comments One patient in lamotrigine group withdrew consent after randomisation.

Monitoring Was monitoring of plasma Yes, including and levels done (including lamotrigine outcomes study drug)? Were arrangements to No blind plasma monitoring results mentioned? Who recorded seizure Provocation testing frequency? How often was seizure 24 hour HV-EEG records obtained at baseline, end of dose frequency measured? titration, end of withdrawal phase Frequency of clinic visits Can't tell Primary outcome(s) Proportion of patients who remained seizure-free during including timepoints if withdrawal phase repeated

Secondary outcome(s) - excluding AEs

'Ad hoc' outcomes (if - emphasised and not in methods) Comments Hyperventilation tests used to establish seizure-freedom.

Results Placebo Lamotrigine (ITT only; unadjusted where available)

358 Newer Drugs for Children with Epilepsy

Median follow-up Not stated Not stated Maintenance dose achieved Not reported median 5.0mg/kg/day (range 2 to 15mg/kg/day) Withdrawals including Total withdrawals 0 1 (6.6) reasons where specified Withdrew consent - 1 (6.6)

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) Proportion of pts 21% placebo vs p=0.03 who remained sz- 64% lamotrigine free during DB phase

Secondary outcomes - - -

'Ad hoc' outcomes - - -

Comments (including whether unadjusted results Maintenance dose achieved - this is the reported) median dose taken by patients who became seizure-free during the open phase

Adverse Criteria for reporting Events reported by Placebo Lamotrigine Events >=5% of patients

359 Newer Drugs for Children with Epilepsy

Events Nervous system Not reported Frequency not complaints(e.g. reported asthenia, headache, dizziness, hyperkinsia) Rash Events related to infections, ailments common to childhood, or flu syndromes

Comments Events believed to be attributable to lamotrigine and reported by >1 patient also documented: abdominal pain, headache, nausea, anorexia, dizziness, hyperkinesia Conclusions Author's conclusions Lamotrigine is effective treatment for children with newly diagnosed typical absence seizures.

Our conclusions The study is of reasonable quality, although lack of information on randomisation and blinding, along with monitoring of lamotrigine plasma levels with no description of how clinicians were blinded to these results, gives some cause for concern.

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Trial details Trial ID Bourgeois, 1998 Drug(s) gabapentin Target maintenance dose 30mg/kg/day (mode) Seizure or syndrome benign partial epilepsy with centrotemporal spikes (BECTS) Type of trial design parallel Add-on or monotherapy? monotherapy Control(s) placebo Study start and end dates Not reported Centres and location Not clear

Trial design Baseline Not reported Titration (including details Not reported of schedule and frequency of doses)

Maintenance 36 weeks Withdrawal None Timing and additional eligibility for randomisation/continuation on study Comments on design Abstract with few details of design

Quality Was assignment of Yes assessment treatment described as random? Was method of No randomisation described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to Described as double treatment? blind Was method of blinding No description adequately described? Were eligibility criteria Yes described? Were groups comparable Not reported at study entry? Were groups treated Can't tell identically apart from the intervention? Was ITT used? Yes Were withdrawals stated? Yes Were reasons for Yes withdrawals stated? Was a power calculation Not reported done?

361 Newer Drugs for Children with Epilepsy

Comments Abstract with few details of design

Eligibility Inclusion criteria 1. 4-13 yrs old criteria 2. At least one and not more than 10 partial or generalised seizures within 6 months of entry.

Exclusion criteria Not reported

Baseline characteristics placebo gabapentin Number randomised 112 113 Number analysed 112 113 Age (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Male:female Not reported Not reported Weight (kg, lbs) Not reported Not reported (mean, SD; median, range) Duration of epilepsy (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Age at diagnosis (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Newly diagnosed, n (%) Not reported Not reported

Previously diagnosed, n Not reported Not reported (%) Refractory, n (%) None (assumed) None (assumed) - definition of refractory Diagnosed seizure types, n Not reported - - (%)

Diagnosed syndrome(s), n Benign partial 112 (100) 113 (100) (%) epilepsy with centro-temporal spikes Baseline seizure frequency Not reported - - (/dy, wk, mo) (mean, SD; median, range)

362 Newer Drugs for Children with Epilepsy

No concomitant AEDs, n Not reported - - (%) Concomitant AEDs, n (%) Not reported - -

Previous AEDs, n (%) Not reported - -

Comments

Primary outcome(s) 1. Time to treatment failure (defined as:-one secondary tonic- including timepoints if clonic seizure, or 3 partial seizures, or status epilepticus, or repeated seizure activity that had worsened)

Secondary outcome(s) Not reported excluding AEs

'Ad hoc' outcomes (if - emphasised and not in methods) Comments

Results Placebo Gabapentin (ITT only; unadjusted where available) Median follow-up Not reported Not reported Maintenance dose achieved Not reported Not reported

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Withdrawals including Adverse events 0 (0) -3.50% reasons where specified

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) 1. Time to treatment No hazard ratio; p=0.06 for failure Kaplan Meier difference by log survival plots not in rank test abstract

Secondary outcomes Not reported - -

'Ad hoc' outcomes - - -

Comments (including whether unadjusted results - reported)

Adverse Criteria for reporting Not reported placebo gabapentin Events

364 Newer Drugs for Children with Epilepsy

Events - - -

Comments -

Conclusions Author's conclusions Gabapentin administered as monotherapy is effective in controlling seizures in children with BECTS.

Our conclusions Insufficient information to judge the efficacy of gabapentin. This benign syndrome is associated with good prognosis and is left untreated in many instances since side effects associated with AEDs might be less desirable than the disadvantages of the condition.

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Trial details Trial ID Chiron, 1996 Drug(s) vigabatrin Target maintenance dose no dose information (not stated) (mode) Seizure or syndrome any Type of trial design withdrawal Add-on or monotherapy? add-on Control(s) placebo Study start and end dates Not stated (patients selected from cohort treated in vigabatrin trials 1987 to 1990) Centres and location 1 centre; France

Trial design Baseline 2 months (possibly retrospective) Titration (including details NA (patients on vigabatrin for 3-39 months prior to entry) of schedule and frequency of doses)

Maintenance None Withdrawal 2 months Timing and additional None stated eligibility for randomisation/continuatio n on study Comments on design Not clear if the two month baseline phase was retrospective. Placebo patients were withdrawn from vigabatrin during the first 2 months; the remaining patients were withdrawn over the following 2 months (described as 'single blind', implying that the patients were not informed that all active treatment would be withdrawn during this period). The data extracted here is from the first 2 month (double blind) period.

Patients were 'dropped' and the randomisation code broken if seizure frequency increased by >50% or increased in severity compared to baseline. Quality Was assignment of Yes assessment treatment described as random? Was method of No randomisation described? Was the method really Can't tell random? Was allocation of treatment Can't tell concealed? Who was blinded to Described as treatment? 'double-blind' Was method of blinding No adequately described? Were eligibility criteria Yes described? Were groups comparable Can't tell; 7/9 patients with infantile spasms were allocated at study entry? 'continue vigabatrin, 'continue vigabatrin' group had a longer mean duration of vigabatrin treatment at entry (12.2 vs 8.6 months) but a shorter median (7 vs 9), with standard deviations 10.2 vs 4.1 Were groups treated Can't tell identically apart from the 366 Newer Drugs for Children with Epilepsy

identically apart from the intervention? Was ITT used? Yes (for primary outcome; see comment) Were withdrawals stated? Yes Were reasons for Yes withdrawals stated? Was a power calculation No done? Comments The policy of 'dropping' patients if they experienced a worsening of seizure frequency or severity makes ITT impossible for most endpoints except for the primary endpoint used here (proportion of patients completing phase)

Eligibility Inclusion criteria 1. Partial improvement in terms of seizure frequency or criteria severity, or parental perception of benefit despite lack of response, after at least 3 months on vigabatrin as add-on therapy

Note: Patients selected from a total of 196 included in various vigabatrin trials at one hospital

Exclusion criteria 1. Patients who had become and remained seizure-free when treated with vigabatrin 2. Patients who had experienced an increase in seizure frequency or severity with no parental perception of benefit

Note: 4/28 patients were included due to some benefit in terms of severity or parental perception despite an increased seizure rate on vigabatrin; compared to before vigabatrin treatment started, 2 patients had experienced 120% increase (both allocated vigabatrin), the other two increased by 160% and 200% respectively (both allocated placebo) Baseline characteristics Placebo Vigabatrin Number randomised 13 15 Number analysed 13 15 Age (wks, mos, yrs) mean 7.9 yrs mean 9.3 yrs (mean, SD; median, range) range 1.5-18.6 range 1.7-17.6 Male:female Not reported Not reported Weight (kg, lbs) Not reported Not reported (mean, SD; median, range) Duration of epilepsy (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Age at diagnosis (wks, mos, yrs) Not reported Not reported (mean, SD; median, range) Newly diagnosed, n (%) 0 0 Previously diagnosed, n 13 (100%) 15 (100%) (%) Refractory, n (%) - - - definition of refractory Diagnosed seizure types, n Complex partial 5 (38.4) 6 (40) (%) Simple partial 3 (23.0) 1 (6.6) Secondarily generalised. 5 (38.4) 2 (13.3) Spasms 4 (30.7) 5 (33.3) Primary 4 (30.7) 5 (33.3) generalised (incl. tonic-clonic,

367 Newer Drugs for Children with Epilepsy

absence, myoclonic, clonic, tonic)

Diagnosed syndrome(s), n Partial 7 (53.8) 5 (33.3) (%) Infantile spasms 2 (15.3) 7 (46.6) Lennox-Gastaut syndrome 1 (7.6) 1 (6.6) Symptomatic generalised 2 (15.3) 1 (6.6) Myoclonic 1 (7.6) 1 (6.6) Baseline seizure frequency All seizures, per mean 61.7, 59.4 mean 50.6, 41.1 (/dy, wk, mo) month median 46, 4-200 median 40, 2.5-120 (mean, SD; median, range)

No concomitant AEDs, n 1 1 (7.6) 6 (40) (%) 2 11 (84.6) 9 (60) 3 1 (7.6) 0 Concomitant AEDs, n (%) Carbamazepine 10 (76.9) 10 (66.6) Clobazam 2 (15.3) 5 (33.3) Clonazepam 2 (15.3) 2 (13.3) (see comment) Hydrocortisone 0 1 (6.6) (see comment) Phenytoin 5 (38.4) 4 (26.6) Progabide 3 (23.0) 1 (6.6) Valproate 4 (30.7) 1 (6.6) Previous AEDs, n (%) - - -

Comments Patient characteristics were not tabulated; these data calculated from individual patient data provided in the paper.

Duration of vigabatrin treatment prior to entry into this study ranged from 3 to 39 months.

Some errors in abbreviations used for concomitant AEDs (HZ probably instead of HC and CZB probably instead of CBZ). Monitoring Was monitoring of plasma No and levels done (including outcomes study drug)? Were arrangements to NA blind plasma monitoring results mentioned?

368 Newer Drugs for Children with Epilepsy

Who recorded seizure Not reported frequency? How often was seizure Not reported frequency measured? Frequency of clinic visits Not reported

Primary outcome(s) 1. Number of patients remaining in the study at the end of the including timepoints if DB phase repeated

Secondary outcome(s) 1. Seizure excluding AEs frequency

'Ad hoc' outcomes (if - emphasised and not in methods) Comments

Results Placebo Vigabatrin (ITT only; unadjusted where available) Median follow-up 2 months 2 months

Maintenance dose achieved Not reported Not reported Withdrawals including Not reported Not reported Not reported reasons where specified

Results (diff, or by CI for difference; arm) p-value Primary outcome(s) 1. Number of placebo 7 (46.1) p<0.01 patients remaining vigabatrin 12 (93.3) in the study at the end of the DB phase

369 Newer Drugs for Children with Epilepsy

Secondary outcomes 1. Seizure frequency placebo median 95 p<0.05 vigabatrin median 46

'Ad hoc' outcomes - -

Comments (including whether unadjusted results Two patients in the vigabatrin group reported) remained on study despite >50% increase in seizure frequency; one patient in placebo group was 'dropped' due to an increase in seizure severity but not >50% increase in seizure frequency. Results analysed and reported both ways; result above is for those meeting the pre-defined criteria for this endpoint.

Adverse Criteria for reporting None stated Placebo Vigabatrin Events Events Not reported Not reported Not reported

370 Newer Drugs for Children with Epilepsy

Comments

Conclusions Author's conclusions Authors acknowledge methodological issues, and propose that study design be considered and improved for future trials in childhood epilepsy.

Our conclusions There are a number of methodological problems with this trial. The design is quirky; an extremely heterogeneous population was recruited; the sample size is very small. The results are difficult to interpret.

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9. REFERENCES

1 Wallace SJ. Definitions. In: Wallace SJ, editor. Epilepsy in Children. Chapman & Hall; 1996. p. 1-4. 2 Jefferys JGR, Traub RD. Cellular mechanisms of epilepsy pathogenesis. In: Wallace SJ, editor. Epilepsy in Children. Chapman & Hall; 1996. p. 109-142. 3 Appleton R, Gibbs J. Epilepsy in Childhood and Adolescence. 1 ed. Martin Dunitz; 1995. 4 Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981; 22(4):489-501. 5 Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989; 30(4):389-399. 6 Moreno G. Reflections on classification of epileptic seizures. Rev Neurol 2002; 34(6):532-536. 7 Parra J, Augustijn PB, Geerts Y, van Emde B. Classification of epileptic seizures: a comparison of two systems. Epilepsia 2001; 42(4):476-482. 8 Engel J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia 2001; 42(6):796-803. 9 Trevathan E. Epilepsy syndrome-specific anti-epileptic drug therapy for children. Lancet 2000; 356(9242):1623-1624. 10 Pellock JM. Managing pediatric epilepsy syndromes with new antiepileptic drugs. Pediatrics 1999; 104(5):1106-1116. 11 Camfield P, Camfield C. Epileptic syndromes in childhood: clinical features, outcomes, and treatment. Epilepsia 2002; 43 Suppl 3:27-32. 12 Camfield C, Breau L, Camfield P. Impact of pediatric epilepsy on the family: a new scale for clinical and research use. Epilepsia 2001; 42(1):104-112. 13 Sillanpaa M, Shinnar S. Status epilepticus in a population-based cohort with childhood-onset epilepsy in Finland. Ann Neurol 2002; 52(3):303-310. 14 Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, Beckerman B. Early development of intractable epilepsy in children: A prospective study. Neurology 2001; 56(11):1445-1452. 15 Glauser T.A, Morita DA. Lennox-Gastaut syndrome. e medicine 2002. 16 Trevathan E. Infantile spasms and Lennox-Gastaut syndrome. J Child Neurol 2002; 17 Suppl 2:2S9- 2S22. 17 Appleton RE. West syndrome: long-term prognosis and social aspects. Brain & Development 2001; 23(7):688-691. 18 Olsson I, Campenhausen G. Social adjustment in young adults with absence epilepsies. Epilepsia 34(5):846-851. 19 Wirrell EC, Camfield CS, Camfield PR, Dooley JM, Gordon KE, Smith B. Long-term psychosocial outcome in typical absence epilepsy. Sometimes a wolf in sheeps' clothing. Arch Pediatr Adolesc Med 1997; 151(2):152-158. 20 Endziniene M, Pauza V, Miseviciene I. Prevalence of childhood epilepsy in Kaunas, Lithuania. Brain Dev 1997; 19(6):379-387. 21 Eriksson KJ, Koivikko MJ. Prevalence, classification, and severity of epilepsy and epileptic syndromes in children. Epilepsia 1997; 38(12):1275-1282. 22 Freitag CM, May TW, Pfafflin M, Konig S, Rating D. Incidence of epilepsies and epileptic syndromes in children and adolescents: a population-based prospective study in Germany. Epilepsia 2001; 42(8):979- 985. 23 Ross SD, Estok R, Chopra S, et al. Management of newly diagnosed patients with epilepsy: a systematic review of the literature. Evid Rep Technol Assess 2001;(39):1-3. 24 Anon. Diagnosis and management of epilepsy in adults: A National Clinical Guideline recommended for use in Scotland. Scottish Intercollegiate Guidelines Network 1997;1-55. 25 Frost,S, Crawford,P, Chappell,B. National Statement of Good Practice for the Treatment and Care of People who have Epilepsy. Joint Epilepsy Council; 2002. Report No.: 26 Nordli DR, Bazil CW, Scheuer ML, Pedley TA. Recognition and classification of seizures in infants. Epilepsia 1997; 38(5):553-560. 27 Delanty N, Vaughan CJ, French JA. Medical causes of seizures. Lancet 1998; 352(9125):383-390.

372 Newer Drugs for Children with Epilepsy

28 Stephenson JBP. Nonepileptic seizure, anoxic-epileptic seizures, and epileptic-anoxic seizures. In: Wallace SJ, editor. Epilepsy in Children. Chapman & Hall; 1996. p. 5-26. 29 Chadwick D, Smith D. The misdiagnosis of epilepsy. BMJ 2002; 324(7336):495-496. 30 Gibbs J, Appleton RE. False diagnosis of epilepsy in children. Seizure 1992; 1(1):15-18. 31 Grunewald RA, Chroni E, Panayiotopoulos CP. Delayed diagnosis of juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry 1992; 55(6):497-499. 32 Appleton RE. Misdiagnosis of epilepsy. Misdiagnosis occurs particularly in children. BMJ 2002; 324(7347):1219. 33 British Paediatric Associatioon Standing Committee on Paediatric Practice Guidelines. Imaging in children with epilepsy (BPA (1995) June). 1995. Report No.: Reference number CO/96/02. 34 Slegtenhorst Mv, Hoogt Rd, Hermans C, Nellist M, Janssen B, Verhoef S, et al. Identification of the Tuberous Sclerosis Gene TSC1 on Chromosome 9q34. Science 1997; 277(5327):805-808. 35 Drury I. EEG in Benign and Malignant Epileptic Syndromes of Childhood. Epilepsia 2002; 43(suppl 3):17-26. 36 Navarro V, Pons A, Romero A, Bernardo M. Topiramate for clozapine-induced seizures. American Journal of Psychiatry 2001; 158(6):968-969. 37 Duncan JS. Seizure-induced neuronal injury: Human data. Neurology 2002; 59(9 Suppl 5):S15-S20. 38 Hermann B, Seidenberg M, Bell B, Rutecki P, Sheth R, Ruggles K, et al. The neurodevelopmental impact of childhood-onset temporal lobe epilepsy on brain structure and function. Epilepsia 2002; 43(9):1062-1071. 39 Wallace H, Shorvon S, Tallis R. Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2,052,922 and age-specific fertility rates of women with epilepsy. Lancet 352(9145):1970-1973. 40 Kurtz Z, Tookey P, Ross E. Epilepsy in young people: 23 year follow up of the British national child development study. BMJ 1998; 316(7128):339-342. 41 MacDonald BK, Cockerell OC, Sander JW, Shorvon SD. The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain 2000; 123 ( Pt 4):665- 676. 42 Heaney DC, MacDonald BK, Everitt A, Stevenson S, Leonardi GS, Wilkinson P, et al. Socioeconomic variation in incidence of epilepsy: prospective community based study in south east England. British Medical Journal 2002; 325:1013-1016. 43 Sander JW, Hart AP, Johnson AL, Shorvon S. National General Practice Study of Epilepsy: newly diagnosed epileptic seizures in ageneral population. Lancet 1990; 336:1267-1271. 44 Beilmann A, Napa A, Hamarik M, Soot A, Talvik I, Talvik T. Incidence of childhood epilepsy in Estonia. Brain Dev 1999; 21(3):166-174. 45 Camfield CS, Camfield PR, Gordon K, Wirrell E, Dooley JM. Incidence of epilepsy in childhood and adolescence: a population-based study in Nova Scotia from 1977 to 1985. Epilepsia 1996; 37(1):19-23. 46 Waaler PE, Blom BH, Skeidsvoll H, Mykletun A. Prevalence, classification, and severity of epilepsy in children in western Norway. Epilepsia 2000; 41(7):802-810. 47 Sidenvall R, Forsgren L, Heijbel J. Prevalence and characteristics of epilepsy in children in northern Sweden. Seizure 1996; 5(2):139-146. 48 Beilmann A, Napa A, Soot A, Talvik I, Talvik T. Prevalence of childhood epilepsy in Estonia. Epilepsia 1999; 40(7):1011-1019. 49 Cowan LD, Bodensteiner JB, Leviton A, Doherty L. Prevalence of the epilepsies in children and adolescents. Epilepsia 1989; 30:94-106. 50 Bouma PA, Bovenkerk AC, Westendorp RG, Brouwer OF. The course of benign partial epilepsy of childhood with centrotemporal spikes: a meta-analysis. Neurology 1997; 48(2):430-437. 51 Peters JM, Camfield CS, Camfield PR. Population study of benign rolandic epilepsy: is treatment needed? Neurology 2001; 57(3):537-539. 52 Berg AT, Shinnar S, Levy SR, Testa FM, Smith R, Beckerman B, et al. Defining early seizure outcomes in pediatric epilepsy: the good, the bad and the in-between. Epilepsy Res 2001; 43(1):75-84. 53 Beghi E, Cornaggia C. Morbidity and accidents in patients with epilepsy: results of a European cohort study. Epilepsia 2002; 43(9):1076-1083. 54 Breningstall GN. Mortality in pediatric epilepsy. Pediatr Neurol 2001; 25(1):9-16. 55 Camfield CS, Camfield PR, Veugelers PJ. Death in children with epilepsy: a population-based study. Lancet 2002; 359(9321):1891-1895. 56 Callenbach PM, Westendorp RG, Geerts AT, Arts WF, Peeters EA, van Donselaar CA, et al. Mortality risk in children with epilepsy: the Dutch study of epilepsy in childhood. Pediatrics 2001; 107(6):1259- 1263. 373 Newer Drugs for Children with Epilepsy

57 Donner EJ, Smith CR, Snead OC. Sudden unexplained death in children with epilepsy. Neurology 2001; 57(3):430-434. 58 Cockerell OC, Hart YM, Sander JW, Shorvon SD. The cost of epilepsy in the United Kingdom: an estimation based on the results of two population-based studies. Epilepsy Res 1994; 18(3):249-260. 59 Jacoby A, Graham-Jones S, Baker G, Ratoff L, Heyes J, Dewey M, et al. A general practice records audit of the process of care for people with epilepsy. British Journal of General Practice 1996; 46(411):595- 599. 60 NHS Executive. Burden of Disease: A discussion document. Department of Health; 1996. Report No.: 61 Glauser TA. Integrating clinical trial data into clinical practice. Neurology 2002; 58 (12 Suppl 7):S6-12. 62 Lhatoo SD, Sander JWAS, Shorvon SD. The dynamics of drug treatment in epilepsy: An observational study in an unselected population based cohort with newly diagnosed epilepsy followed up prospectively over 11-14 years. Journal of Neurology, Neurosurgery & Psychiatry 2001; 71(5):632-637. 63 Meads,C, Bradley,P, Burls,A. The effectiveness of specialist epilepsy services. Birmingham, UK: 2001. Report No.: 27. 64 Kitson,A,Shorvon,S. Services for patients with epilepsy: a report of a CSAG Committee. London: HMSO; 2000. Report No.: 65 Hanna,DJ, Black,M, Sander,JW, Smithson,WH, Appleton,R, et al. National Sentinel Clinical Audit on Epilepsy-Related Death; epilepsy-death in the shadows. The Stationary Office; 2002. Report No.: 66 NHS Executive Letter. EL (95) 120. 1996. Leeds, NHS. Ref Type: Pamphlet 67 Brown SW, Lee P. Developments in UK service provision for people with epilepsy: the impact of the NHS Executive Letter 95/120. Seizure 1998; 7(3):185-187. 68 Brown SW, Lee P, Buchan S, Jenkins A. A 2 year follow-up of NHS Executive Letter 95/120: where is the commitment to quality? Seizure 1999; 8(2):128-131. 69 Clinical Standards Advisory Group. Services for People with Epilepsy. London: HMSO; 1999. Report No.: 70 Hart YM, Shorvon SD. The nature of epilepsy in the general population. II. Medical care. Epilepsy Res 1995; 21(1):51-58. 71 Carpay HA, Arts WF, Geerts AT, Stroink H, Brouwer OF, Boudewyn P, et al. Epilepsy in childhood: an audit of clinical practice. Arch Neurol 1998; 55(5):668-673. 72 Berg AT, Levy SR, Testa FM, Shinnar S. Treatment of newly diagnosed pediatric epilepsy: a community-based study. Arch Pediatr Adolesc Med 1999; 153(12):1267-1271. 73 Whitehouse W, Morris B. Paediatric out-patient antiepileptic drug doses recorded in the medical charts are not reliable: implications for the notion of noncompliance. Seizure 1997; 6(1):41-42. 74 British Epilepsy Association. Epilepsy care: Making It Happen. A tool kit for today. Leeds, British Epilepsy Association: 1999. Report No.: 75 Herranz JL, Armijo JA, Arteaga R. Clinical side effects of phenobarbital, primidone, phenytoin, carbamazepine, and valproate during monotherapy in children. Epilepsia 1988; 29(6):794-804. 76 Holmes GL. Overtreatment in children with epilepsy. Epilepsy Research 2002; 52(1):35-42. 77 Perucca E. Overtreatment in epilepsy: adverse consequences and mechanisms. Epilepsy Research 2002; 52(1):25-33. 78 MacDonald BK, Johnson AL, Sander JW, Shorvon SD. Febrile convulsions in 220 children-- neurological sequelae at 12 years follow-up. Eur Neurol 1999; 41(4):179-186. 79 Wilton LV, Shakir S. A postmarketing surveillance study of gabapentin as add-on therapy for 3,100 patients in England. Epilepsia 2002; 43(9):983-992. 80 Tatum WOI, French JA, Faught E, Morris III GL, Liporace J, Kanner A, et al. Postmarketing experience with topiramate and cognition. Epilepsia 2001; 42(9):1134-1140. 81 French JA. Postmarketing surveillance of new antiepileptic drugs: the tribulations of trials. Epilepsia 2002; 43(9):951-955. 82 Lawden MC, Eke T, Degg C, Harding GFA, Wild JM. Visual field defects associated with vigabatrin therapy. Journal of Neurology, Neurosurgery & Psychiatry 1999; 67(6):716-722. 83 Nicolson A, Leach JP, Chadwick DW, Smith DF. The legacy of vigabatrin in a regional epilepsy clinic. J Neurol Neurosurg Psychiatry 2002; 73(3):327-329. 84 Koul R, Chacko A, Ganesh A, Bulusu S, Al Riyami K. Vigabatrin associated retinal dysfunction in children with epilepsy. Arch Dis Child 2001; 85(6):469-473. 85 Glauser TA. Expanding first-line therapy options for children with partial seizures. Neurology 2000; 55(11 SUPPL. 3):S30-S37. 86 Brodie MJ, Kwan P. The star systems: overview and use in determining antiepileptic drug choice. Cns Drugs 2001; 15(1):1-12. 374 Newer Drugs for Children with Epilepsy

87 Brodie MJ, Kwan P. Staged approach to epilepsy management. Neurology 2002; 58(90085):2S-8. 88 French J. The long-term therapeutic management of epilepsy. Ann Intern Med 1994; 120(5):411-422. 89 Neville BG. Epilepsy in childhood. BMJ 1997; 315(7113):924-930. 90 Pellock JM, Appleton R. Use of new antiepileptic drugs in the treatment of childhood epilepsy. [Review] [88 refs]. Epilepsia 1999; 40 Suppl 6:S29-S38. 91 Crumrine PK. Antiepileptic drug selection in pediatric epilepsy. J Child Neurol 2002; 17 Suppl 2:2S2- 2S8. 92 Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342 (5):314-319. 93 Chilcott,J, Howell,S, Kemeny,A, Ritteu,CDC, Richards,C. Effectiveness of Surgery in the Management of Epilepsy. Trent Institute for Health Services Research, Universities of Leicester, Nottingham and Sheffield 1999.; 1999. Report No.: InterDEC Report No: 15/1999. 94 Wiebe S, Blume WT, Girvin JP, Eliasziw M, the Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A Randomized, Controlled Trial of Surgery for Temporal-Lobe Epilepsy. N Engl J Med 2001; 345(5):311-318. 95 Fisher RS, Handforth A. Reassessment: vagus nerve stimulation for epilepsy: a report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1999; 53(4):666-669. 96 Cramer JA, Menachem EB, French J. Review of treatment options for refractory epilepsy: New medications and vagal nerve stimulation. Epilepsy Research 2001; 47(1-2):17-25. 97 Freeman JM, Vining EPG, Pillas DJ, Pyzik PL, Casey JC, Kelly MT. The efficacy of the ketogenic diet - 1998: A prospective evaluation of intervention in 150 children. Pediatrics 1998; 102(6):1358-1363. 98 Nordli DR, Kuroda MM, Carroll J, Koenigsberger DY, Hirsch LJ, Bruner HJ, et al. Experience with the ketogenic diet in infants. Pediatrics 2001; 108(1):129-133. 99 Magrath G, MacDonald A, Whitehouse W. Dietary practices and use of the ketogenic diet in the UK. Seizure 2000; 9(2):128-130. 100 Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E. Progress report on new antiepileptic drugs: A summary of the Fifth Eilat Conference (EILAT V). Epilepsy Research 2001; 43(1):11-58. 101 O'Neill FF-G. Lamotrigine versus carbamazepine in adult and elderly patients with epilepsy. JNS 2001; 187(Suppl. 1). 102 Mecarelli O, de Feo MR, Del Priore D, Piacenti A, Pulitano P, Rinalduzzi S, et al. Adverse events and neurophysiological modifications induced by a single dose of topiramate in healthy volunteers: A placebo-controlled study. Epilepsia 2000; 41 Suppl Florence:106. 103 Remy C, Favel P, Tell G. Double-blind, placebo-controlled, crossover study of vigabatrin in drug- resistant epilepsy of the adult. Boll Lega Ital Epilessia 1986; 54:241-243. 104 Belopitova L, Dimova P, Tomov V. Comparative study on the therapeutic effect of oxcarbazepine (trileptal) and carbamazepine (finlepsin) in children epilepsy. Bulgarian Medicine 2000; 8(1):12-15. 105 Hancock E, Osborne JP, Milner P. The treatment of West syndrome: A Cochrane review of the literature to December 2000. Brain & Development 2001; 23(7):624-634. 106 Hancock E, Osborne J, Milner P. Treatment of infantile spasms (Cochrane Review). In: Cochrane Library Issue, 4, 2002. 107 Appleton R, Martland T, Phillips B. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children (Cochrane Review). Cochrane Database Syst Rev 2002;(4):CD001905. 108 Gilbert DL, Gartside PS, Glauser TA. Efficacy and mortality in treatment of refractory generalized convulsive status epilepticus in children: a meta-analysis. J Child Neurol 1999; 14(9):602-609. 109 Castillo S, Schmidt DB, White S. Oxcarbazepine add-on for drug-resistant partial epilepsy. Cochrane Database of Systematic Reviews [Computer File] 2000;(3):CD002028. 110 Chaisewikul R, Privitera MD, Hutton JL, Marson AG. Levetiracetam add-on for drug-resistant localization related (partial) epilepsy. Cochrane Database Syst Rev 2001; 1:CD001901. 111 Jette NJ, Marson AG, Kadir ZA, Hutton JL. Topiramate for drug-resistant partial epilepsy. Cochrane Database of Systematic Reviews [Computer File] 2000;(2):CD001417. 112 Marson AG, Kadir ZA, Hutton JL, Chadwick DW. Gabapentin add-on for drug-resistant partial epilepsy. [update of Cochrane Database Syst Rev. 2000;(2):CD001415]. Cochrane Database of Systematic Reviews [Computer File] 2000;(3):CD001415. 113 Marson AG, Hutton JL, Leach JP, Castillo S, Schmidt D, White S, et al. Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review. Epilepsy Res 2001; 46 (3):259-270. 375 Newer Drugs for Children with Epilepsy

114 Pereira J, Marson AG, Hutton JL. Tiagabine add-on for drug-resistant partial epilepsy. In: Cochrane Library Issue, 3, 2002;(3):CD001908. 115 Ramaratnam S, Marson AG, Baker GA. Lamotrigine add-on for drug-resistant partial epilepsy. Cochrane Database of Systematic Reviews [Computer File] 2000;(3):CD001909. 116 Baker GA, Hesdon B, Marson AG. Quality-of-life and behavioral outcome measures in randomized controlled trials of antiepileptic drugs: A systematic review of methodology and reporting standards. Epilepsia 2000; 41(11):1357-1363. 117 Chadwick DW, Marson AG. Zonisamide add-on for drug-resistant partial epilepsy (Cochrane Review). In: Cochrane Library Issue, 4, 2001. 118 Chadwick DW. An overview of the efficacy and tolerability of new antiepileptic drugs. Epilepsia 1997; 38(SUPPL. 1):S59-S62. 119 Chaisewikul R, Baillie N, Marson AG. Calcium antagonists as an add-on therapy for drug-resistant epilepsy. Cochrane Database Syst Rev 2001;(4):CD002750. 120 Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002; 43(2):146-153. 121 French J, Edrich P, Cramer JA. A systematic review of the safety profile of levetiracetam: A new antiepileptic drug. Epilepsy Research 2001; 47(1-2):77-90. 122 Marson AG, Kadir ZA, Chadwick DW. New antiepileptic drugs: A systematic review of their efficacy and tolerability. British Medical Journal 1996; 313(7066):1169-1174. 123 Marson AG, Williamson PR, Hutton JL, Clough HE, Chadwick DW. Carbamazepine versus valproate monotherapy for epilepsy (Cochrane Review). In: Cochrane Library Issue, 4, 2001. 124 Marson AG, Williamson PR, Clough H, Hutton JL, Chadwick DW. Carbamazepine versus valproate monotherapy for epilepsy: a meta-analysis. Epilepsia 2002; 43(5):505-513. 125 Privitera MD. Evidence-based medicine and antiepileptic drugs. Epilepsia 1999; 40 Suppl 5:S47-S56. 126 Ramsay ER. Tonic-clonic seizures: a systematic review of antiepilepsy drug efficacy and safety. Clinical Therapeutics 1997; 19(3):433-446. 127 Taylor S, Tudur Smith C, Williamson PR, Marson AG. Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalised onset tonic-clonic seizures (Cochrane Review). In: Cochrane Library Issue, 4, 2001. 128 Tudur Smith C, Marson AG, Williamson PR. Phenytoin versus valproate monotherapy for partial onset and generalised onset tonic-clonic seizures (Cochrane Review). In: Cochrane Library Issue, 4, 2001. 129 Tudur SM, Marson AG, Clough HE, Williamson PR. Carbamazepine versus phenytoin monotherapy for epilepsy (Cochrane Review). In: Cochrane Library Issue, 4, 2002;CD001911. 130 Adab N, Winterbottom J, Tudur Smith C, Williamson PR. Common antiepileptic drugs in pregnancy in women with epilepsy (protocol for a Cochrane Review). In: Cochrane Library Issue, 4, 2001. 131 Hancock E, Cross H. Treatment of Lennox-Gastaut syndrome (protocol for a Cochrane Review). In: Cochrane Library Issue, 4, 2001. 132 Kalviainen R, Chadwick DW. Vigabatrin versus carbamazepine monotherapy for epilepsy (protocol for a Cochrane Review). In: Cochrane Library Issue, 4, 2001. 133 Posner EB, Mohamed K. Ethosuximide, sodium valproate or lamotrigine for typical absence seizures of childhood and adolescence (protocol for a Cochrane Review). In: Cochrane Library Issue, 4, 2001. 134 Preston CL, Marson AG, Williamson PR. Lamotrigine versus carbamazepine monotherapy for epilepsy (protocol for a Cochrane Review). In: Cochrane Library Issue, 4, 2002. 135 Tudur Smith C, Marson AG, Williamson PR, Hutton JL, Chadwick DW. Carbamazepine versus phenobarbitone monotherapy for epilepsy (protocol for a Cochrane Review). In: Cochrane Library Issue, 4, 2001. 136 Tudur SM, Marson AG, Williamson PR. Carbamazepine versus phenobarbitone monotherapy for epilepsy (Cochrane Review). Cochrane Database Syst Rev 2003;(1):CD001904. 137 Aikia MM-K. The cognitive effects of initial tiagabine monotherapy. Epilepsia 1999; 40 Suppl 7:51. 138 Lindberger M, Alenius M, Frisen L, Johannessen SI, Larsson S, Malmgren K, et al. Gabapentin versus vigabatrin as first add-on for patients with partial seizures that failed to respond to monotherapy: a randomized, double-blind, dose titration study. GREAT Study Investigators Group. Gabapentin in Refractory Epilepsy Add-on Treatment. Epilepsia 2000; 41(10):1289-1295. 139 Binnie CD, Debets RM, Engelsman M, Meijer JW, Meinardi H, Overweg J, et al. Double-blind crossover trial of lamotrigine (Lamictal) as add-on therapy in intractable epilepsy. Epilepsy Research 1989; 4(3):222-229. 140 Cramer JA, Arrigo C, Van Hammee G, Bromfield EB. Comparison between the QOLIE-31 and derived QOLIE-10 in a clinical trial of levetiracetam. Epilepsy Research 2000; 41(1):29-38.

376 Newer Drugs for Children with Epilepsy

141 Barcs G, Walker EB, Elger CE, Scaramelli A, Stefan H, Sturm Y, et al. Oxcarbazepine placebo- controlled, dose-ranging trial in refractory partial epilepsy. Epilepsia 2000; 41(12):1597-1607. 142 Brodie MJ, Bomhof MAM, Kalviainen R, Beran R, Richens A, Edwards D, et al. Double-blind comparison of tiagabine and carbamazepine monotherapy in newly diagnosed epilepsy. Epilepsia 1997; 38 Suppl 3:66-67. 143 Tanganelli, P., Ottonello, G.-A., Monzeglio, R.-M., et al. Vigabatrin vs Carbamazepine in monotherapy in newly diagnosed patients with partial epilepsy: A randomized cross-over study (preliminary data). Bollettino Lega Italiana Contro L'Epilessia 1993; -(82-83):137-138. 144 Canger R, Saltarelli A. Vigabatrin versus Carbamezapine as first line monotherapy in newly diagnosed patients: A double blind randomized parallel group study. Bollettino - Lega Italiana Contro L'Epilessia 1997; Issue 99 SUPPL. 1(pp 33-36). 145 Chadwick D. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. Vigabatrin European Monotherapy Study Group. Lancet 1999; 354(9172):13-19. 146 Andrews J, Chadwick D, Bates D, Cartlidge N, Boddie G, Bolel P, et al. Gabapentin in partial epilepsy. Lancet 1990; 335(8698):1114-1117. 147 Sivenius J, Kalviainen R, Ylinen A, Riekkinen P. Double-blind study of Gabapentin in the treatment of partial seizures. Epilepsia 1991; 32(4):539-542. 148 McLean MJ, Ramsay RE, Leppik LE, Rowan AJ, Shellenberger MK, Wallace J. Gabapentin as add-on therapy in refractory partial epilepsy: A double- blind, placebo-controlled, parallel-group study. Neurology 1993; 43(11):2292-2298. 149 Anhut H, Ashman P, Feuerstein TJ, Sauermann W, Saunders M, Schmidt B, et al. Gabapentin (neurontin) as add-on therapy in patients with partial seizures: A double-blind, placebo-controlled study. Epilepsia 1994; 35(4):795-801. 150 Leach JP, Girvan J, Paul A, Brodie MJ. Gabapentin and cognition: a double blind, dose ranging, placebo controlled study in refractory epilepsy. Journal of Neurology, Neurosurgery & Psychiatry 1997; 62(4):372-376. 151 Schapel GJ, Beran RG, Vajda FJ, Berkovic SF, Mashford ML, Dunagan FM, et al. Double-blind, placebo controlled, crossover study of lamotrigine in treatment resistant partial seizures. Journal of Neurology, Neurosurgery & Psychiatry 1993; 56(5):448-453. 152 Smith D, Baker G, Davies G, Dewey M, Chadwick DW. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia 1993; 34(2):312-322. 153 Severi S, Muscas GC, Bianchi A, Zolo P. Efficacy and safety of Lamotrigine monotherapy in partial epilepsy. Bollettino Lega Italiana Contro L'Epilessia 1994; -(86-87):149-151. 154 Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ, Leppik I. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000; 55(2):236-242. 155 Cramer JA, Arrigo C, Van Hammee G, Gauer LJ, Cereghino JJ. Effect of levetiracetam on epilepsy- related quality of life. Epilepsia 2000; 41(7):868-874. 156 Shorvon SD, Lowenthal A, Janz D, Bielen E, Loiseau P. Multicenter double-blind, randomized, placebo- controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group. Epilepsia 2000; 41(9):1179-1186. 157 Schachter SC, Vazquez B, Fisher RS, Laxer KD, Montouris GD, Combs-Cantrell DT, et al. Oxcarbazepine: double-blind, randomized, placebo-control, monotherapy trial for partial seizures. [see comments]. Neurology 1999; 52(4):732-737. 158 Korean-Topiramate-Study-Group. Topiramate in medically intractable partial epilepsies: Double-blind placebo-controlled randomized parallel group trial. Epilepsia 1999; 40(12):1767-1774. 159 Grunewald RA, Thompson PJ, Corcoran R, Corden Z, Jackson GD, Duncan JS. Effects of vigabatrin on partial seizures and cognitive function. Journal of Neurology, Neurosurgery & Psychiatry 1994; 57(9):1057-1063. 160 Brodie MJ, Mumford JP. Double-blind substitution of vigabatrin and valproate in carbamazepine- resistant partial epilepsy. Epilepsy Research 1999; 34(2-3):199-205. 161 Dodrill CB, Arnett JL, Sommerville KW, Shu V. Cognitive and quality of life effects of differing dosages of tiagabine in epilepsy. Neurology 1997; 48(4):1025-1031. 162 Dodrill CB, Arnett JL, Deaton R, Lenz GT, Sommerville KW. Tiagabine versus phenytoin and carbamazepine as add-on therapies: effects on abilities, adjustment, and mood. Epilepsy Research 2000; 42(2-3):123-132. 163 Beran RG, Berkovic SF, Buchanan N, Danta G, Mackenzie R, Schapel G, et al. A double-blind, placebo- controlled crossover study of vigabatrin 2 g/day and 3 g/day in uncontrolled partial seizures. Seizure 1996; 5(4):259-265. 377 Newer Drugs for Children with Epilepsy

164 Ben Menachem E, Soderfelt B, Hamberger A, Hedner T, Persson LI. Seizure frequency and CSF parameters in a double-blind placebo controlled trial of gabapentin in patients with intractable complex partial seizures. Epilepsy Research 1995; 21(3):231-236. 165 Ben Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: A multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia 2000; 41(10):1276-1283. 166 Sachdeo RC, Leroy RF, Krauss GL, Drake MEJ, Green PM, Leppik IE, et al. Tiagabine therapy for complex partial seizures: A dose-frequency study. Archives of Neurology 1997; 54(5):595-601. 167 Rimmer EM, Richens A. Double-blind study of gamma-vinyl GABA in patients with refractory epilepsy. Lancet 1984; 1(8370):189-190. 168 Gram L, Klosterskov P, Dam M. gamma-Vinyl GABA: a double-blind placebo-controlled trial in partial epilepsy. Annals of Neurology 1985; 17(3):262-266. 169 Cramer J, Vachon L, Desforges C, Sussman NM. Dose frequency and dose interval compliance with multiple antiepileptic medications during a controlled clinical trial. Epilepsia 1995; 36(11):1111-1117. 170 Provinciali L, Bartolini M, Mari F, Del Pesce M, Ceravolo MG. Influence of vigabatrin on cognitive performances and behaviour in patients with drug-resistant epilepsy. Acta Neurologica Scandinavica 1996; 94(1):12-18. 171 Chadwick D, Leiderman DB, Sauermann W, Alexander J, Garofalo E. Gabapentin in generalized seizures. Epilepsy Research 1996; 25(3):191-197. 172 Beran RG, Berkovic SF, Dunagan FM, Vajda FJ, Danta G, Black AB, et al. Double-blind, placebo- controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy. Epilepsia 1998; 39(12):1329-1333. 173 Biton V, Montouris GD, Ritter F, Riviello JJ, Reife R, Lim P, et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Neurology 1999; 52(7):1330-1337. 174 Chadwick DW, Anhut H, Greiner MJ, Alexander J, Murray GH, Garofalo EA, et al. A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. Neurology 1998; 51(5):1282-1288. 175 Brodie MJ, Richens A, Yuen AWC. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995; 345(8948):467+476-467+479. 176 Dam M. Lamotrigine versus carbamazepine open-label comparative trial. Lamotrigine: A Brighter Future - International Congress and Symposium 1996; Series 214:17-21. 177 Steiner TJ, Dellaportas CI, Findley LJ, Gross M, Gibberd FB, Perkin GD, et al. Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin. Epilepsia 1999; 40(5):601-607. 178 Kalogjera SD, Sackellares C, Kwong J, Vuong A, Hammer AE, and-Barrett PS. Quality of life improvements with lamotrigine monotherapy: A randomized, double-blind comparison with valproate. Epilepsia 2000; 41 Suppl 7:116-117. 179 Dam M, Ekberg R, Loyning Y, Waltimo O, Jakobsen K. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Research 1989; 3(1):70-76. 180 Bill PA, Vigonius U, Pohlmann H, Guerreiro CA, Kochen S, Saffer D, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in adults with previously untreated epilepsy. Epilepsy Research 1997; 27(3):195-204. 181 Christe W, Kramer G, Vigonius U, Pohlmann H, Steinhoff BJ, Brodie MJ, et al. A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Research 1997; 26(3):451-460. 182 Wheless JW, Neto W, and WS. Topiramate, carbamazepine, and valproate in children with newly diagnosed epilepsy: a unique trial design. Neurology 2001; 56(8 Suppl 3):A234-A235. 183 Kalviainen R, Aikia M, Saukkonen AM, Mervaala E, Riekkinen Sr PJ. Vigabatrin vs carbamazepine monotherapy in patients with newly diagnosed epilepsy: A randomized, controlled study. Archives of Neurology 1995; 52(10):989-996. 184 Binnie CD, Beintema DJ, Debets RM, Van Emde BW, Meijer JW, Meinardi H, et al. Seven day administration of lamotrigine in epilepsy: placebo-controlled add-on trial. Epilepsy Research 1987; 1(3):202-208. 185 Betts T, Waegemans T, Crawford P. A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. Seizure-European Journal of Epilepsy 2000; 9(2):80-87. 186 Houtkooper MA, Lammertsma A, Meyer JW, Goedhart DM, Meinardi H, van Oorschot CA, et al. Oxcarbazepine (GP 47.680): a possible alternative to carbamazepine? Epilepsia 1987; 28(6):693-698. 378 Newer Drugs for Children with Epilepsy

187 Loiseau P, Hardenberg JP, Pestre M, Guyot M, Schechter PJ, Tell GP. Double-blind, placebo-controlled study of vigabatrin (gamma-vinyl GABA) in drug-resistant epilepsy. Epilepsia 1986; 27(2):115-120. 188 Tartara A, Manni R, Galimberti CA, Hardenberg J, Orwin J, Perucca E. Vigabatrin in the treatment of epilepsy: a double-blind, placebo-controlled study. Epilepsia 1986; 27(6):717-723. 189 Rimmer EM, Milligan NM, Richens A. A comparison of the acute effect of single doses of vigabatrin and sodium valproate on photosensitivity in epileptic patients. Epilepsy Research 1987; 1(6):339-346. 190 Tassinari CA, Michelucci R, Ambrosetto G, Salvi F. Double-blind study of vigabatrin in the treatment of drug-resistant epilepsy. Archives of Neurology 1987; 44(9):907-910. 191 Reynolds EH, Ring HA, Farr IN, Heller AJ, Elwes RD. Open, double-blind and long-term study of vigabatrin in chronic epilepsy. Epilepsia 1991; 32(4):530-538. 192 Reynolds EH, Ring H, Heller A. A controlled trial of gamma-vinyl-GABA (vigabatrin) in drug-resistant epilepsy. British Journal of Clinical Practice 1988; Supplement. 61:33. 193 Gillham RA, Blacklaw J, McKee PJW, Brodie MJ. Effect of vigabatrin on sedation and cognitive function in patients with refractory epilepsy. Journal of Neurology Neurosurgery and Psychiatry 1993; 56(12):1271-1275. 194 Carmant L, Bryant CL, and MA. Switching patients to monotherapy: improved tolerability for lamictal(r) compared to valproate. European Journal of Neurology 1999; 6(Supplement 3):72. 195 Montouris G, Mirza WU, Biton V, Vuong A, Barrett P, Hammer A. Effects of LAMICTAL (R) and DEPAKOTE (R) monotherapy on body weight in patients with epilepsy: Interim analysis of a randomized, double-blind clinical trial. Neurology 1999; 52(6):A523-A524. 196 Fakhoury T, Gazda S, Nanry KP, Hammer AE, and-Barrett PS. Comparison of monotherapy with lamotrigine versus carbamazepine in patients with uncontrolled epilepsy with a broad spectrum of seizure types. Epilepsia 2000; 41 Suppl 7:107. 197 Nieto-Barrera M, Brozmanova M, Capovilla G, Christe W, Pedersen B, Kane K, et al. A comparison of monotherapy with lamotrigine or carbamazepine in patients with newly diagnosed partial epilepsy. Epilepsy Research 2001; 46(2):145-155. 198 Zamponi N, Cardinali C. Open comparative long-term study of vigabatrin vs carbamazepine in newly diagnosed partial seizures in children. Archives of Neurology 1999; 56(5):605-607. 199 Shapiro DY, Nordli D, Glauser TA, Knapp LE, Greiner M, Purcell TJ, et al. Gabapentin as add-on therapy for refractory partial seizures in children 1-36 months of age: A novel, short-term, placebo- controlled trial. Epilepsia 2000; 41 Suppl 7:106. 200 Litzinger MJ, Hanny A. Tiagabine therapy in a small group of pediatric patients with refractory partial seizure. Annals of Neurology 1998; 44(3):B16. 201 Valentine C, Mettert N, Mosier M, Michon AM, and VP. A parallel group study comparing oral adjunctive vigabatrin with placebo in children with uncontrolled complex partial seizures. Epilepsia 1998; 39 Suppl 6:166. 202 Van Orman CB, Ruckh S, Mosier M, and VP. Efficacy and safety of vigabatrin in children with uncontrolled complex partial seizures: a dose response study. Epilepsia 1998; 39 Suppl 6:166. 203 Duchowny M, Pellock JM, Graf WD, Billard C, Gilman J, Casale E, et al. A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children. Lamictal Pediatric Partial Seizure Study Group. Neurology 1999; 53(8):1724-1731. 204 Glauser TA, Nigro M, Sachdeo R, Pasteris LA, Weinstein S, Abou-Khalil B, et al. Adjunctive therapy with oxcarbazepine in children with partial seizures. The Oxcarbazepine Pediatric Study Group. Neurology 2000; 54(12):2237-2244. 205 Elterman RD, Glauser TA, Wyllie E, Reife R, Wu SC, Pledger G. A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Topiramate YP Study Group. Neurology 1999; 52(7):1338-1344. 206 Appleton R, Fichtner K, LaMoreaux L, Alexander J, Halsall G, Murray G, et al. Gabapentin as add-on therapy in children with refractory partial seizures: A 12-week, multicentre, double-blind, placebo- controlled study. Epilepsia 1999; 40(8):1147-1154. 207 Guerreiro MM, Vigonius U, Pohlmann H, de Manreza ML, Fejerman N, Antoniuk SA, et al. A double- blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Research 1997; 27(3):205-213. 208 Eriksson A-S, Nergardh A, Hoppu K. The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: A randomized, double-blind, cross over study. Epilepsia 1998; 39(5):495-501. 209 Motte J, Trevathan E, Arvidsson JFV, Barrera MN, Mullens EL, Manasco P. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. New England Journal of Medicine 1997; 337(25):1807-1812. 379 Newer Drugs for Children with Epilepsy

210 Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger G, et al. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Neurology 1999; 52(9):1882-1887. 211 Appleton RE, Peters AC, Mumford JP, Shaw DE. Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. Epilepsia 1999; 40(11):1627-1633. 212 Vigevano F, Cilio MR. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study. Epilepsia 1997; 38(12):1270-1274. 213 Chiron C, Dumas C, Jambaque I, Mumford J, Dulac O. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Research 1997; 26(2):389-395. 214 Frank LM, Enlow T, Holmes GL, Manasco P, Concannon S, Chen C, et al. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia 1999; 40(7):973-979. 215 Bourgeois B, Brown LW, Pellock JM, Buroker M, Greiner M, Garofalo EA, et al. Gabapentin (Neurontin) monotherapy in children with benign childhood epilepsy with centrotemporal spikes (BECTS): a 36-week, double-blind, placebo-controlled study. Epilepsia 1998; 39 Suppl 6:163. 216 Chiron C, Dulac O, Gram L. Vigabatrin withdrawal randomized study in children. Epilepsy Research 1996; 25(3):209-215. 217 Aldenkamp AP, Alpherts WC, Sandstedt P, Blennow G, Elmqvist D, Heijbel J, et al. Antiepileptic drug- related cognitive complaints in seizure-free children with epilepsy before and after drug discontinuation. Epilepsia 1998; 39(10):1070-1074. 218 Austin JK, Dunn DW. Children with epilepsy: quality of life and psychosocial needs. [Review] [56 refs]. Annual Review of Nursing Research 2000; 18:26-47. 219 Cramer JA, Westbrook LE, Devinsky O, Perrine K, Glassman MB, Camfield C. Development of the Quality of Life in Epilepsy Inventory for Adolescents: the QOLIE-AD-48. Epilepsia 1999; 40(8):1114- 1121. 220 Hanai T. Quality of life in children with epilepsy. Epilepsia 1996; 37 Suppl 3:28-32. 221 Hoare P. The quality of life of children with chronic epilepsy and their families. Seizure 1993; 2(4):269- 275. 222 Jacoby A. Assessing quality of life in patients with epilepsy. [Review] [132 refs]. Pharmacoeconomics 1996; 9(5):399-416. 223 Norrby U, Carlsson J, Beckung E, Nordholm L. Self-assessment of well-being in a group of children with epilepsy. Seizure 1999; 8(4):228-234. 224 Ronen GM, Rosenbaum P, Law M, Streiner DL. Health-related quality of life in childhood epilepsy: the results of children's participation in identifying the components. [see comments.]. Developmental Medicine & Child Neurology 1999; 41(8):554-559. 225 Sabaz M, Cairns DR, Lawson JA, Bleasel AF, Bye AM. The health-related quality of life of children with refractory epilepsy: a comparison of those with and without intellectual disability. Epilepsia 2001; 42(5):621-628. 226 Wildrick D, Parker-Fisher S, Morales A. Quality of life in children with well-controlled epilepsy. Journal of Neuroscience Nursing 1996; 28(3):192-198. 227 Hennessy S, Kind P. Measuring health status in children: developing and testing a child-friendly version of EQ-5D. EuroQol Scientific Meeting, York 12'th September 2002 2002. 228 Dolan P. Modelling valuations for EuroQol Health States. Medical Care 1997; 35:1095-1108. 229 Wong IC, Chadwick DW, Fenwick PB, Mawer GE, Sander JW. The long-term use of gabapentin, lamotrigine, and vigabatrin in patients with chronic epilepsy. Epilepsia 1999; 40(10):1439-1445. 230 Lhatoo SD, Wong ICK, Sander JWAS. Prognostic factors affecting long-term retention of topiramate in patients with chronic epilepsy. Epilepsia 2000; 41(3):338-341. 231 Lhatoo SD, Wong ICK, Polizzi G, Sander JWAS. Long-term retention rates of lamotrigine, gabapentin, and topiramate in chronic epilepsy. Epilepsia 2000; 41(12):1592-1596. 232 Wong IC, Mawer GE, Sander JW, Lhatoo SD. A pharmacoepidemiologic study of factors influencing the outcome of treatment with lamotrigine in chronic epilepsy. Epilepsia 2001; 42(10):1354-1358. 233 Hes MS, Trudeau VL, Kilgore MB, Poulter CJ, Garofalo EA, Koto EP. A double-blind, placebo- controlled, randomized multicenter trial of gabapentin (GBP Neurontin) in pediatric-patients with benign childhood epilepsy with centrotemporal spikes (BECTS). Epilepsia 1995; 36:531. 234 Cockerell OC, Johnson AL, Sander JW, Hart YM, Shorvon SD. Remission of epilepsy: results from the National General Practice Study of Epilepsy. Lancet 1995; 346(8968):140-144. 235 Anderson GD. Children versus adults: pharmacokinetic and adverse-effect differences. Epilepsia 2002; 43 Suppl 3:53-59. 236 Morselli PL, Franco M, Bossi L. Clinical pharmacokinetics in newborns and infants. Age-related differences and therapeutic implications. Clin Pharmacokinet 1980; 5(6):485-527.

380 Newer Drugs for Children with Epilepsy

237 Stewart CF, Hampton EM. Effect of maturation on drug disposition in pediatric patients. Clin Pharm 1987; 6(7):548-564. 238 Painter MJ, Pippenger C, MacDonald H, Pitlick W. Phenobarbital and diphenylhydantoin levels in neonates with seizures. J Pediatr 1978; 92(2):315-319. 239 Asconape JJ. Some common issues in the use of antiepileptic drugs. Semin Neurol 2002; 22(1):27-39. 240 Gidal BE, Anderson GD, Spencer NW. Valproate-associated weight gain in patients with epilepsy: potential relationship to energy expenditure and metabolism. Journal of Epilepsy 1996; 9:234-241. 241 Gidal BE, Maly MM, Nemire RE, Haley K. Weight gain and gabapentin therapy. Ann Pharmacother 1995; 29(10):1048. 242 Biton V, Mirza W, Montouris G, Vuong A, Hammer AE, Barrett PS. Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Neurology 2001; 56(2):172-177. 243 Smith U, Axelsen M, Hellebo-Johanson E, et al. Topiramate a novel antiepileptic drug, reduces body weight and food intake in obesity. Obesity Research 2000; 8(Suppl 1):10S. 244 Sato Y, Kondo I, Ishida S, Motooka H, Takayama K, Tomita Y, et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 2001; 57:445-449. 245 Tsukahara H, Kimura K, Todoroki Y, Ohshima Y, Hiraoka M, Shigematsu Y, et al. Bone mineral status in ambulatory pediatric patients on long-term anti-epileptic drug therapy. Pediatr Int 2002; 44(3):247- 253. 246 Pavlakis SG, Chusid RL, Roye DP, Nordli DR. Valproate therapy: predisposition to bone fracture? Pediatr Neurol 1998; 19(2):143-144. 247 Ueberall MA. Normal growth during lamotrigine monotherapy in pediatric epilepsy patients - a prospective evaluation of 103 children and adolescents. Epilepsy Research 2001; 46:63-67. 248 Bourgeois BF. Differential cognitive effects of antiepileptic drugs. J Child Neurol 2002; 17 Suppl 2:2S28-2S33. 249 Dodrill CB, Arnett JL, Sommerville KW, Sussman NM. Effects of differing dosages of vigabatrin (Sabril) on cognitive abilities and quality of life in epilepsy. Epilepsia 1995; 36(2):164-173. 250 Clarkson A, Choonara I. Surveillance for fatal suspected adverse drug reactions in the UK. Arch Dis Child 2002; 87(6):462-466. 251 Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993; 329(19):1383-1388. 252 Herzog AG. Polycystic ovarian syndrome in women with epilepsy: epileptic or iatrogenic? Ann Neurol 1996; 39(5):559-560. 253 Isojarvi JI, Rattya J, Myllyla VV, Knip M, Koivunen R, Pakarinen AJ, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol 1998; 43(4):446-451. 254 Fairgrieve SD, Jackson M, Jonas P, Walshaw D, White K, Montgomery TL, et al. Population based prospective study of the care of women with epilepsy in pregnancy. British Medical Journal 2000; 321:674-675. 255 Orme M, Back DJ, Chadwick DJ, Crawford P, Martin C, Tjia J. The interaction of phenytoin and carbamazepine with oral contraceptive steroids. European Journal of Clinical Pharmacology 1990; 183:1029-1030. 256 Crawford P, Chadwick DJ, Martin C, Tjia J, Back DJ, Orme M. The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids. Br J Clin Pharmacol 1990; 30(6):892-896. 257 Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine. Clinical Pharmacokinetics 1996; 31(3):198-214. 258 Grant SM, Faulds D. Oxcarazepine- a review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia and affective disorders. Drugs 1992; 43(6):873-888. 259 Keranen T, Jolkkonen J, Jensen PK, Menge GP, Andersson P. Absence of interaction between oxcarbazepine and erythromycin. Acta Neurologica Scandinavica 1992; 86(2):120-123. 260 Kramer G, Tettenborn B, Flesch G. Oxcarbazepine-verapamil drug interaction in healthy volunteers. Epilepsia 1991; 32(Suppl 1):70-71. 261 Fattore C, Cipolla G, Gatti G, Limido GL, Sturm Y, Bernasconi C, et al. Induction of ethinylestradiol and levonorgestrel metabolism by oxcarbazepine in healthy women. Epilepsia 1999; 40(6):783-787. 262 Doose D, Rosenfeld W, Schaefer P, Walker SA, Nayak RK. Evaluation of a potential pharmacokinetic interaction between topiramate and the oral contraceptive combination norethindrone ethinylestradiol. Journal of Clinical Pharmacology 1994; 34:1031. 263 Rosenfeld WE, Doose DR, Walker SA, Nayak RK. Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia 1997; 38(3):317-323.

381 Newer Drugs for Children with Epilepsy

264 Odlind V, Olsson SE. Enhanced metabolism of levonorgestrel during phenytoin treatment in a woman with Norplant implants. Contraception 1986; 33(3):257-261. 265 Haukkamaa M. Contraception by Norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant treatment. Contraception 1986; 33(6):559-565. 266 Eldon MA, Underwood BA, Randinitis EJ, Posvar EL, Sedman AJ. Lack of effect of gabapentin on the pharmacokinetics of a norethindrone acetate/ethinyl estradiol-containing oral contraceptive. Neurology 1993; 43(Suppl. 2):A307-A308. 267 Eldon MA, Underwood BA, Randinitis EJ, Sedman AJ. Gabapentin does not interact with a contraceptive regimen of norethindrone acetate and ethinyl estradiol. Neurology 1998; 50(4):1146-1148. 268 Holdich T, Whiteman P, Orme M, Black D, Ward S. Effect of lamotrigine on the pharmacology of the oral contraceptive pill. Epilepsia 1991; 32(Suppl. 1):96. 269 Crawford P, Chadwick D, Cleland P, Tjia J, Cowie A, Back DJ, et al. Sodium valproate and oral contraceptive steroids. British Journal of Clinical Pharmacology 1985; 20:288P-289P. 270 Mengel H, Houston A, Back DJ. An interaction of the interaction between tiagabine and oral contraceptives in female volunteers. Journal of Pharmaceutical Medicine 1994; 4:141-150. 271 Bartoli A, Gatti G, Cipolla G, Barzaghi N, Veliz G, Fattore C, et al. A double-blind, placebo-controlled study on the effect of vigabatrin on in vivo parameters of hepatic microsomal enzyme induction and on the kinetics of steroid oral contraceptives in healthy female volunteers. Epilepsia 1997; 38 (6):702-707. 272 Holmes LB, Harvey EA, Coull BA, Huntington KB, Khoshbin S, Hayes AM, et al. The teratogenicity of anticonvulasant drugs. New England Journal of Medicine 2001; 344:1132-1138. 273 Berg M, Fincham R, Ebert EB, Schottelius DD. Phenytoin pharmacokinetics before and after folic acid administration. Epilepsia 1992;712-720. 274 Mackay FJ, Wilton LV, Pearce GL, Freemantle SN, Mann RD. Safety of long-term lamotrigine in epilepsy. Epilepsia 1997; 38(8):881-886. 275 Hoyme HE, Hauck L, Quinn D. Minor abnormalities accompanying prenatal exposure to topiramate [abstract] . Epilepsia 1998; 56:119A. 276 Friis ML, Kristensen O, Boas J, Dalby M, Deth SH, Gram Mikkelsen LM, et al. Therapeutic experiences with 947 epileptic out-patients in oxcarbazepine treatment. Acta Neurologica Scandinavica 1993; 87(3):224-227. 277 Lindhout D, Omtzigt JG. Teratogenic effects of antiepileptic drugs: implications for the management of epilepsy in women of the childbearing age. Epilepsia 1994; 45 :409-411. 278 McLean MJ. Gabapentin in the management of convulsive disorders. [Review] [127 refs]. Epilepsia 1999; 40 Suppl 6:S39-S50. 279 Richens A. Safety of lamotrigine. Epilepsia 1994; 35 Suppl 5:S37-S40. 280 Palmieri C, Canger R. Teratogenic Potential of the Newer Antiepileptic Drugs: What is Known and How Should This Influence Prescribing? Cns Drugs 2002; 16:755-764. 281 Chang SI, McAuley JW. Pharmacotherapeutic issues for women of childbearing age with epilepsy. Annals of Pharmacotherapy 1998; 32(7-8):794-801. 282 Isojarvi JIT, Pakarinen AJ, Myllyla VV. Basic haematological parameters, serum gammaglutamyl- transferase activity, and erythrocyte folate and serum vitamin B12 levels during carbamazepine and oxcarbazepine therapy. Seizure 1997; 6(3):207-211. 283 Leppik IE, Gram L, Deaton R, Sommerville KW. Safety of tiagabine: summary of 53 trials. Epilepsy Research 1999; 33(2-3):235-246. 284 Glauser TA. Topiramate. Epilepsia 1999; 40(SUPPL. 5):S71-S80. 285 Meadow R. Anticonvulsants in pregnancy. Arch Dis Child 1991; 66(1 Spec No):62-65. 286 British Epilepsy Association. Epilepsy and Pregnancy; The Facts. URL: http://www.epilepsy.org.uk/info/pregnancy1.html 287 Cramer J, Ryan J, Chang J, Sommerville K, Study Group. The short-term impact of adjunctive tiagabine on health-related quality of life. Epilepsia 2001; 42 Suppl 3:70-75. 288 Lopes-Lima JM, Pereira H, Sol JM, Morralla C, and HG. Gabapentin vs valproate in partial epilepsy uncontrolled by carbamazepin. European Journal of Neurology 1999; 6(Supplement 3):17. 289 Boon P, Chauvel P, Pohlmann-Eden B, Otoul C, Wroe S. Dose-response effect of levetiracetam 1000 and 2000 mg/day in partial epilepsy. Epilepsy Research 2002; 48(1-2):77-89. 290 Dodrill CB, Arnett JL, Sommerville KW, Sussman NM. Evaluation of the effects of vigabatrin on cognitive abilities and quality of life in epilepsy. Neurology 1993; 43 (12):2501-2507. 291 Uthman BM, Rowan AJ, Ahmann PA, Leppik IE, Schachter SC, Sommerville KW, et al. Tiagabine for complex partial seizures: a randomized, add-on, dose-response trial. Archives of Neurology 1998; 55(1):56-62.

382 Newer Drugs for Children with Epilepsy

292 Reunanen M, Dam M, Yuen AW. A randomised open multicentre comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy. Epilepsy Research 1996; 23(2):149-155. 293 Gillham, R., Kane, K., Bryant C, L., et al. A double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy with health-related quality of life as an outcome measure. Seizure 2000; 9(6):375-379. 294 Edwards KR, Sackellares JC, Vuong A, Hammer AE, Barrett PS. Lamotrigine monotherapy improves depressive symptoms in epilepsy: a double-blind comparison with valproate. Epilepsy & Behavior 2001; 2(1):28-36. 295 Aikia M, Kalviainen R, Sivenius J, Halonen T, Riekkinen PJ. Cognitive effects of oxcarbazepine and phenytoin monotherapy in newly diagnosed epilepsy: one year follow-up. Epilepsy Research 1992; 11(3):199-203. 296 Coles H, Baker G, O'Donoghue M. Seizure severity in patients with partial onset (POS) or primary generalised tonic clonic (PGTC) seizures following treatment with topiramate. A comparison of two different methodologies in a randomised controlled trial. Epilepsia 1999; 40:285. 297 McKee PJW, Blacklaw J, Friel E, Thompson GG, Gillham RA, Brodie MJ. Adjuvant vigabatrin in refractory epilepsy: A ceiling to effective dosage in individual patients? Epilepsia 1993; 34(5):937-943. 298 Kerr M, Kane K, and MA. Switching patients to monotherapy: efficacy and tolerability for lamictal(r) compared to valproate. European Journal of Neurology 1999; 6(Supplement 3):17. 299 French J, Pellock J, Ferrendelli J, Sommerville K, Sherry K, Ahlbrandt R, et al. Results of a multicenter, placebo-controlled, parallel study of vigabatrin (VGB, Sabril(R)) in patients with focal epilepsy whose seizures are difficult to control. Neurology 1993; 43(4):A307. 300 Canger, and S, A.-. Vigabatrin versus Carbamezapine as first line monotherapy in newly diagnosed patients: A double blind randomized parallel group study. Bollettino Lega Italiana Contro L'Epilessia 1997;(99 SUPPL. 1):33-36. 301 [Anon]. Head-to-head epilepsy studies demonstrate benefits of switching to monotherapy with lamictal. Irish Medical Journal 2000; 93(1):26. 302 Abdulrazzak M, Kutluay E, Passaro EA, Milling CJ, Minecan DN, Kothary S, et al. Long term efficacy and safety of oxcarbazepine as adjunctive therapy or monotherapy in patients with refractory partial onset seizures. Epilepsia 2000; 41 Suppl 7:228-229. 303 Aberg L, Kirveskari E, Santavuori P. Lamotrigine therapy in juvenile neuronal ceroid lipofuscinosis. Epilepsia 1999; 40(6):796-799. 304 Aldenkamp AP, Baker G, Mulder OG, Rentmeester TW, Hulsman J, Overweg J, et al. A randomized observer-blind clinical study comparing the cognitive effects of topiramate versus valproate in a first-line add-on design. Epilepsia 1998; 39 Suppl 6:188-189. 305 Aldenkamp AP, Baker G, Mulder OG, Rentmeester TW, Hulsman J, Overweg J, et al. A randomized clinical study comparing the cognitive effects of topiramate versus valproate in a first-line add-on design. Epilepsia 1999; 40 Suppl 7:83-84. 306 Aldenkamp AP, Baker G, Mulder OG, Chadwick D, Cooper P, Doelman J, et al. A multicenter, randomized clinical study to evaluate the effect on cognitive function of topiramate compared with valproate as add-on therapy to carbamazepine in patients with partial-onset seizures. Epilepsia 2000; 41(9):1167-1178. 307 Aldenkamp AP, Arends J, Bootsma HP, Diepman L, Hulsman J, Lambrechts D, et al. Randomized Double-blind Parallel-group Study Comparing Cognitive Effects of a Low-dose Lamotrigine with Valproate and Placebo in Healthy Volunteers. Epilepsia 2002; 43(1):19-26. 308 Anhut H, Greiner MJ, Murray GH. Double-blind, fixed-dose comparison study of gabapentin (GBP Neurontin (R)) and carbamazepine (CBZ) monotherapy in patients with newly-diagnosed partial epilepsy. Epilepsia 1995; 36:341. 309 Anderson WT, III, Sakhoury T, Nasreddine W, Abou KB, and BA. Gabapentin monotherapy for newly diagnosed partial epilepsy. Epilepsia 1999; 40 Suppl 7:224. 310 Angeleri F, Scarpino O, Avanzini G, Binelli D, Baruzzi A, Procaccianti G, et al. Single-blind, placebo- controlled multicenter trial of vigabatrin in the treatment of epilepsy. Italian Journal of Neurological Sciences 1992; 13(9):741-747. 311 Anhut H, Ashman PJ, Feuerstein TJ, Quebe-Fehling E, Saunders M, Baron BA, et al. Long-term safety and efficacy of gabapentin (neurontin) as add-on therapy in patients with refractory partial seizures. Journal of Epilepsy 1995; 8(1):44-50. 312 Appleton R, Fichtner K, LaMoreaux L, Alexander J, Maton S, Murray G, et al. Gabapentin as add-on therapy in children with refractory partial seizures: a 24-week, multicentre, open-label study. Developmental Medicine and Child Neurology 2001; 43(4):269-273. 383 Newer Drugs for Children with Epilepsy

313 Arteaga R, Herranz JL, Armijo JA. Add-on vigabatrin in children with refractory epilepsy. A 4-year follow-up study. Clinical Drug Investigation 1996; 12(6):287-297. 314 Arteaga R, Herranz JL, Valdizan EM, Armijo JA. gamma-Vinyl GABA (vigabatrin): Relationship between dosage, plasma concentrations, platelet GABA-transaminase inhibition, and seizure reduction in epileptic children. Epilepsia 1992; 33(5):923-931. 315 Arteaga R, Herranz JL, Armijo JA. Platelet gaba-transaminase in epileptic children-influence of epilepsy and anticonvulsants. Epilepsy Research 1993; 14(1):73-85. 316 Arzimanoglou A, Kulak I, Bidaut-Mazel C, Baldy-Moulinier M. Optimal use of lamotrigine in clinical practice: results of an open multicenter trial in refractory epilepsy. Revue Neurologique 2001; 157(5):525-536. 317 Banin E, Gross-Tsur V, Shachar E, Lahat E, Shalev RS. Impaired visual function in epileptic children treated with vigabatrin. Investigative Ophthalmology & Visual Science 2000; 41(4):1876B122. 318 Bartolini M, Del Pesce M, Mari F, Judice A, Quattrini A, Provinciali L. Influence of vigabatrin on cognitive functions and behaviour in patients with drug-resistant epilepsy. Bollettino - Lega Italiana Contro L'Epilessia 1993; Issue 84(pp 161-162). 319 Belmonte A, Ferrari R, Battini R, Guerrini R. Add-on lamotrigine treatment in children and young adults with severe partial epilepsy: an open, prospective study. Epilepsia 1999; 40:236. 320 Ben Menachem E, Henriksen O, Dam M, Mikkelsen M, Schmidt D, Reid S, et al. Double-blind, placebo- controlled trial of topiramate as add-on therapy in patients with refractory partial seizures. Epilepsia 1996; 37(6):539-543. 321 Ben Menachem E. Clinical efficacy of topiramate as add-on therapy in refractory partial epilepsy: the European experience. Epilepsia 1997; 38 Suppl 1:S28-S30. 322 Ben Menachem E, and the topiramate YTC group. A double-blind trial of topiramate in patients with generalised tonic-clonic seizures of non-focal origin. Epilepsia 1997; 38 Suppl 3:60. 323 Beran R, Berkovic S, Black A, Danta G, Dunne J, Frasca J, et al. AUStralian study of titration to effect profile of safety (AUS-STEPS): High-dose gabapentin (neurontin) in partial seizures. Epilepsia 2001; 42(10):1335-1339. 324 Bergey GK, Crockatt JG, Leiderman DB, Malicsi M, Garofalo EA. Multicenter double-blind-study of gabapentin (GBP Neurontin (R)) monotherapy in hospitalised patients with refractory epilepsy. Epilepsia 1995; 36:344. 325 Bergey GK, Morris HH, Rosenfeld W, Blume WT, Penovich PE, Morrell MJ, et al. Gabapentin monotherapy: I. An 8-day, double-blind, dose-controlled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures. Neurology 1997; 49(3):739-745. 326 Bernardina BD, Fontana E, Vigevano F, Fusco L, Torelli D, Galeone D, et al. Efficacy and tolerability of vigabatrin in children with refractory partial seizures: A single-blind dose-increasing study. Epilepsia 1995; 36(7):687-691. 327 Besag FMC, Dulac O, Alving J, Mullens EL. Long-term safety and efficacy of lamotrigine (Lamictal(TM)) in paediatric patients with epilepsy. Seizure 1997; 6(1):51-56. 328 Betts T, Laskar P, Crawford PM, Debrabandere L, Selak I. Efficacy and tolerability of levetiracetam (ucb L059) as add-on therapy in patients with refractory partial and generalized seizures. Epilepsia 1998; 39 Suppl 6:68. 329 Beydoun A, Fakhoury T, Nasreddine W, Abou KB. Conversion to high dose gabapentin monotherapy in patients with medically refractory partial epilepsy. Epilepsia 1998; 39(2):188-193. 330 Beydoun A. Monotherapy trials with gabapentin for partial epilepsy. Epilepsia 1999; 40(SUPPL. 6):S13- S16. 331 Beydoun AA, Sachdeo R, Rosenfeld W, D'Souza J, Kramer L. Safety and efficacy of oxcarbazepine monotherapy in patients with medically refractory partial epilepsy. Epilepsia 1998; 39 Suppl 6:48. 332 Bielicka-Cymerman J, Golebiwska M, Pakszys M. Clinical efficacy of Topiramate as add-on therapy in refractory partial seizures in children. Preliminary report. Epilepsia 1999; 40:178. 333 Birbeck GL, Kim S, Hays RD, Vickrey BG. Quality of life measures in epilepsy: how well can they detect change over time? Neurology 2000; 54(9):1822-1827. 334 Biton V, Montouris GD, and-the-YTC-Study-Team-. Topiramate double-blind trial in patients with generalised tonic-clonic seizures of non-focal origin. Epilepsia 1997; 38 Suppl 3:59-60. 335 Biton V, Vasquez B, Sachdeo RC, Lenz GT, Deaton R, and-Sommerville KW. Adjunctive tiagabine compared with phenytoin and carbamazepine in the multicenter, double-blind trial of complex partial seizures. Epilepsia 1998; 39 Suppl 6:125-126. 336 Biton V, Rosenfeld WE, Twyman R, Lim P. Topiramate (TPM) in juvenile myoclonic epilepsy (JME): Observations from randomized controlled trials in primary generalized tonic-clonic seizures (PGTCS). Epilepsia 1999; 40:218. 384 Newer Drugs for Children with Epilepsy

337 Biton V, Mirza W, Montouris GD, Vuong A, Hammer AE, and-Barrett PS. Weight gain associated with valproate vs. lamotrigine monotherapy in patients with epilepsy: A randomized, double-blind clinical trial. Epilepsia 2000; 41 Suppl 7:89-90. 338 Biton V. Erratum: A randomized, placebo-controlled study of topiramate in primary generalized tonic- clonic seizures (Neurology (1999) 52 (1330-1337)). Neurology 1999; 53(5):1162. 339 Biton, V, Mirza, W, Montouris, G, et al. Weight gain associated with valproate vs. Lamotrigine monotherapy in patients with epilepsy: a randomized, double-blind comparative clinical trial. Journal of the European College of Neuropsychopharmacology 2000; 10(Supplement 3):S236. 340 Boas J, Dam M, Friis ML, Kristense O, Pedersen B, Gallagher J. Controlled trial of lamotrigine (Lamictalregistered trade mark) for treatment-resistant partial seizures. Acta Neurologica Scandinavica 1996; 94(4):247-252. 341 Boati E, Defanti CA, Franza A, Scaturro M. Vigabatrin versus carbamazepine in patients with newly diagnosed partial epilepsy. Bollettino - Lega Italiana Contro L'Epilessia 1998; Issue 102-103(pp 123- 127). 342 Brodie, M.-J, McKee, P.-J.-W., Blacklaw, J., et al. Double-blind, placebo-controlled interaction study between oxcarbazepine and carbamazepine, valproate, and phenytoin in epileptic patients. Epilepsia 1993; 34 (suppl. 6):68-69. 343 Brodie MJ, Biton V, Montouris GD, and-Shu CW. Topiramate therapy in patients with generalized tonic- clonic seizures without focal onset: long-term outcome. Epilepsia 1998; 39 Suppl 2:2. 344 Brodie MJ, Overstall PW, Giorgi L. Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. Epilepsy Research 1999; 37(1):81-87. 345 Brodie MJ. Erratum: Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy (The Lancet (February 25) (476)). Lancet 1995; 345(8950):662. 346 Brodie-MJ-and-The-Topiramate-YTC-E-Study-Group-. Topiramate as long-term therapy in generalised tonic-clonic seizures of non-focal origin. Epilepsia 1997; 38 Suppl 3 :60. 347 Browne TR, Mattson RH, Penry JK, Smith DB, Treiman DM, Wilder BJ, et al. A multicentre study of vigabatrin for drug-resistant epilepsy. British Journal of Clinical Pharmacology 1989; 27 Suppl 1:95S- 100S. 348 Browne TR, Mattson RH, Napoliello MJ, Penry JK, Smith DB, Treiman DM, et al. Multicenter single- blind study of gamma-vinyl-GABA for refractory partial seizures. Epilepsia 1983; 24(4):521. 349 Browne TR, Smith DB, Mattson RH, Penry JK, Sherry KM, Treiman DM, et al. Multicenter single-blind study of vigabatrin for refractory complex partial seizures-long term follow-up. Epilepsia 1986; 27(5):641. 350 Browne TR, Mattson RH, Penry JK. Vigabatrin for refractory complex partial seizures: Multicenter single-blind study with long-term follow-up. Neurology 1987; 37(2):184-189. 351 Browne TR, Mattson RH, Penry JK, Smith DB, Treiman DM, Wilder BJ, et al. Multicenter long-term safety and efficacy study of vigabatrin for refractory complex partial seizures: An update. Neurology 1991; 41(3):363-364. 352 Brozmanova M, Tkacova J, Szabova I. Add-on trial with lamotrigine in refractory epilepsies in childhood-two and half years follow-up study. Epilepsia 1995; 36:S111. 353 Bruni J, Guberman A, Vachon L, Desforges C. Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind, placebo-controlled multicentre study. Seizure-European Journal of Epilepsy 2000; 9(3):224-232. 354 Bruni J. Outcome evaluation of gabapentin as add-on therapy for partial seizures. "NEON" Study Investigators Group. Neurontin Evaluation of Outcomes in Neurological Practice. Canadian Journal of Neurological Sciences 1998; 25(2):134-140. 355 Bruni J. Gabapentin as adjunctive therapy for partial seizures. Epilepsia 1999; 40 Suppl 6:S27-S28. 356 Buchanan N. The efficacy of lamotrigine on seizure control in 34 children, adolescents and young adults with intellectual and physical disability. Lamotrigine: A Brighter Future - International Congress and Symposium 1996; Series 214:89-102. 357 Buchholt J, Uldall P. Oxcarbazepine in childhood epilepsy. Epilepsia 1995; 36:S118-S119. 358 Canger R, Avanzini G, Tartara A, Durisotti C, Guidolin L, Binelli S, et al. Topiramate efficacy and tolerability as add-on therapy: Interim analysis of an open multicenter study. Bollettino - Lega Italiana Contro L'Epilessia 1996; Issue 95-96(pp 251-253). 359 Carrazana EJ, Wheeler SD. Exacerbation of juvenile myoclonic epilepsy with lamotrigine. Neurology 2001; 56(10):1424.

385 Newer Drugs for Children with Epilepsy

360 Chadwick D, Anhut H, Murray G, Greiner M, Alexander J. Gabapentin (GBP; Neurontin) monotherapy in patients with newly-diagnosed epilepsy: results of a double-blind fixed-doses study comparing three dosages of gabapentin and open-label carbamazepine. Epilepsia 1997; 38 Suppl 3:34. 361 Chiron C, Marchand MC, Tran A, Rey E, d'Athis P, Vincent J, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. Lancet 2000; 356(9242):1638-1642. 362 Clark P, Glauser TA, Hamant E, McGee K, Khoury P. Topiramate's effect on height and weight in children with partial-onset seizures. Epilepsia 1999; 40:115. 363 Cocito L, Maffini M, Perfumo P, Roncallo F, Loeb C. Vigabatrin in complex partial seizures: a long-term study. Epilepsy Research 1989; 3(2):160-166. 364 Cocito L, Maffini M, Loeb C. Vigabatrin in chronic epilepsy: a 7-year follow-up study of responder patients. Seizure 1993; 2(4):301-307. 365 Collins TL, Petroff OAC, Mattson RH. A comparison of four new antiepileptic medications. Seizure- European Journal of Epilepsy 2000; 9(4):291-293. 366 Coppola G, Bove RM, Nazzaro A, Pascotto A. Lamotrigine in children with refractory epilepsy- an open trial. Epilepsia 1995; 36:S111-S112. 367 Coppola G, Caliendo G, Terracciano MM, Buono S, Pellegrino L, Pascotto A. Topiramate in refractory partial-onset seizures in children, adolescents and young adults: a multicentric open trial. Epilepsy Research 2001; 43(3):255-260. 368 Coppola G, Capovilla G, Montagnini A, Romeo A, Spano M, Tortorella G, et al. Topiramate as add-on drug in severe myoclonic epilepsy in infancy: an Italian multicenter open trial. Epilepsy Res 2002; 49(1):45-48. 369 Cramer JA. Oxcarbazepine in a monotherapy trial for partial seizures--placebo-controlled studies in neurology: where do they stop? Neurology 1999; 53(9):2212-2213. 370 Crawford P, Meinardi H, Brown S, Rentmeester TW, Pedersen B, Pedersen PC, et al. Tiagabine: efficacy and safety in adjunctive treatment of partial seizures. Epilepsia 2001; 42(4):531-538. 371 Crawford P, Ghadiali E, Lane R, Blumhardt L, Chadwick D. Gabapentin as an antiepileptic drug in man. Journal of Neurology, Neurosurgery & Psychiatry 1987; 50(6):682-686. 372 Curatolo P. Vigabatrin for refractory partial seizures in children with tuberous sclerosis. Neuropediatrics 1994; 25(1):55. 373 Czapinski P, Terczynski A, Czapinska E. Open randomised comparative study of vigabatrin (VGB) and lamotrigine (LTG) efficacy in monotherapy of patients with drug-resistant epilepsy with partial complex seizures resistant to carbamazepine. Epilepsia 1997; 38 Suppl 3. 374 Dalla BB, Fontana E, Vigevano F, Fusco L, Torelli D, Galeone D, et al. Efficacy and tolerability of vigabatrin in children with refractory partial seizures: a single-blind dose-increasing study. Epilepsia 1995; 36(7):687-691. 375 Davies G, Sweet R, Mullens EL, Messenheimer J. Clinical trial experience with lamotrigine (Lamictal) in the management of adults with epilepsy. Journal of the Neurological Sciences 1997; 150(Supplement):S163. 376 De Romanis F, Sopranzi N. Lamotrigine: First Italian trials. Clinica Terapeutica 1995; 146(3):203-209. 377 Dean C, Mosier M, Penry K. Dose-Response Study of Vigabatrin as add-on therapy in patients with uncontrolled complex partial seizures. Epilepsia 1999; 40(1):74-82. 378 Dodrill CB, Arnett JL, Hayes AG, Garofalo EA, Greeley CA, Mann ME, et al. Evaluation of Quality of life during a dopuble-blind multicenter study of gabapentin (GBP Neurontin (R)) monotherapy in patients with medically refractory partial seizures. Epilepsia 1995; 36:G1. 379 Dodrill CB, Arnett J, Deaton R, Lenz GT, Sommerville KW. Adjunctive tiagabine, phenytoin, and carbamazepine, and neuropsychological tests in a multicenter trial for partial seizures. Epilepsia 1998; 39 Suppl 6:147. 380 Dodrill CB, Arnett JL, Hayes AG, Garofalo EA, Greeley CA, Greiner MJ, et al. Cognitive abilities and adjustment with gabapentin: results of a multisite study. Epilepsy Research 1999; 35(2):109-121. 381 Dollar L, French J, Krauss G, Ruckh S. The safety of long-term add-on therapy with Sabril (vigabatrin) in patients with uncontrolled complex partial seizures. Epilepsia 1998; 39 Suppl 6:190. 382 Drory VE, Korczyn AD. Apparent placebo effect in epilepsy. New Trends in Clinical Neuropharmacology 1991; 5(2):49-56. 383 Dulac O, D'Souza J, Motte J. Multicenter study of oxcarbazepine pharmacokinetics and tolerability in children with refractory epilepsy. Annals of Neurology 2001; 50(3):S104. 384 Dulac O. Efficacy and safety of lamotrigine in children. Lamotrigine: A Brighter Future - International Congress and Symposium 1996; Series 214:69-73.

386 Newer Drugs for Children with Epilepsy

385 Duric B, Marjanovic B, Zamurovic D, Jovic N, Rajcic N. Gabapentin as add-on therapy in children with refractory partial seizures: A 12-week, double blind placebo-controlled study and open-label extension of a double-blind study. Epilepsia 1999; 40:156. 386 Edwards K, Kalogjera SD, Sackellares C, Vuong A, Hammer AE, Barrett PS. Lamotrigine monotherapy improves mood in epilepsy: A randomized, double-blind comparison with valproate. Epilepsia 2000; 41 Suppl 7:104. 387 Eriksson AS, Nergardh A, Boreus L, Knutsson E. Double-blind cross-over study of lamotrigine in children with Lennox-Gastaut syndrome and other types of generalized intractable epilepsy. Epilepsia 1995; 36:S110-S111. 388 Ericksson AS, Knutsson E, Nergardh A. The effect of lamotrigine on epileptiform discharges in young patients with drug-resistant epilepsy. Epilepsia 2001; 42(2):230-236. 389 Farrell K, Connolly M, Munn R, Peng SM, Berg M. Open study of lamotrigine in children with intractable generalized epilepsy. Annals of Neurology 1995; 38(3):506. 390 Faught E, Wilder BJ, Ramsay RE, Reife RA, Kramer LD, Pledger GW, et al. Topiramate placebo- controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages. Neurology 1996; 46(6):1684-1690. 391 Faught E. Efficacy of topiramate as adjunctive therapy in refractory partial seizures: United States trial experience. Epilepsia 1997; 38 Suppl 1:S24-S27. 392 Fichtner K, Appleton R, Murray G, Maton S, Alexander J. Gabapentin as add-on therapy in children with refractory partial seizures: A 24-week, open-label extension study. Epilepsia 1999; 40:156. 393 Franzoni E, Marchiani V, Pignotti M, Moscano FC, Migliore MR. Gabapentin (GBP) as add-on treatment in children and adolescents with refractory epilepsy. Epilepsia 1999; 40:239. 394 French JA, Mosier M, Walker S, Sommerville K, Sussman N, Barry E, et al. A double-blind, placebo- controlled study of vigabatrin three g/day in patients with uncontrolled complex partial seizures. Neurology 1996; 46(1):54-61. 395 Froscher W, Bulau P, Burr W, Penin H, Rao ML, De Beukelaar F. Double-blind placebo-controlled trial with flunarizine in therapy-resistant epileptic patients. Clinical Neuropharmacology 1988; 11(3):232- 240. 396 Frye MA, Ketter TA, Kimbrell TA, Dunn RT, Speer AM, Osuch EA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. Journal of Clinical Psychopharmacology 2000; 20(6):607-614. 397 Galas-Zgorzalewicz B, Steinborn B, Zgorzalewicz M. Vigabatrin in the treatment of drug resistant childhood and adolescence epilepsies: A three-year study prospective. Epilepsia 1999; 40:273. 398 Garofalo E, Hayes A, Greeley C, Hes MK, Mann M, Greiner M, et al. Gabapentin (Neurontin) monotherapy in patients with medically refractory partial seizures- an open-label extension study. Epilepsia 1995; 36:S119-S120. 399 Garofalo E, Hayes A, Hes M, Mann M, Greeley C, Pierce M. Quality-of-life assessments during open- label multicenter study evaluating gabapentin (Neurontin) monotherapy in medically refractory patients with partial seizures. Epilepsia 1995; 36:S187. 400 Gherpelli JLD, Guerreiro MM, da Costa JC, Rotta NT, Manreza MLG, Reed UC, et al. Vigabatrin in refractory childhood epilepsy. The Brazilian multicenter study. Epilepsy Research 1997; 29(1):1-6. 401 Glauser TA, Elterman R, Wyllie E, and the Topiramate YP Study Team. Open-label topiramate in paediatric partial epilepsy. Epilepsia 1997; 38 Suppl 3:94. 402 Glauser TA, Levisohn PM, Ritter F, Sachdeo RC, Crumrine P, Ferreira J, et al. Topiramate in Lennox- Gastaut syndrome: Open-label treatment of patients completing a randomized controlled trial. Epilepsia 2000; 41(4 SUPPL.):S86-S90. 403 Glauser TA, Sachdeo RC, Ritter FJ, Reife R, Lim P, and Topiramate YL Study Group. A double-blind trial of topiramate in Lennox-Gastaut syndrome (LGS). Epilepsia 1997; 38 Suppl 3:131. 404 Glauser TA, Wyllie E, Elterman R, Shu-Chen W. Topiramate initiated as add-on therapy in children with partial-onset seizures: long-term findings. Epilepsia 1998; 39 Suppl 2:2. 405 Glauser TA, Elterman R, Wyllie E, Wu SC. Long-term topiramate therapy in children with partial-onset seizures. Neurology 1998; 50(4):02045. 406 Gobbi G, Bertani G, Pini A, Guerrini R, Tiberti A, Valseriati D, et al. 1'st line vigabatrin monotherapy in childhood partial epilepsy. Epilepsia 1995; 36:S102. 407 Gram L, Lyon BB, Dam M. Gamma-vinyl-GABA: a single-blind trial in patients with epilepsy. Acta Neurologica Scandinavica 1983; 68(1):34-39. 408 Gross-Tsur V, Shalev RS, Shahar E, Lahat E. Ophthalmological abnormalities in children with epilepsy treated with vigabatrin. Annals of Neurology 1999; 46(3):524-525.

387 Newer Drugs for Children with Epilepsy

409 Gross-Tsur V, Banin E, Shahar E, Shalev RS, Lahat E. Visual impairment in children with epilepsy treated with vigabatrin. Annals of Neurology 2000; 48(1):60-64. 410 Guberman A, Bruni J. Long-term open multicentre, add-on trial of vigabatrin in adult resistant partial epilepsy. Seizure-European Journal of Epilepsy 2000; 9(2):112-118. 411 Hamilton MJ, Cohen AF, Yuen AW, Harkin N, Land G, Weatherley BC, et al. Carbamazepine and lamotrigine in healthy volunteers: relevance to early tolerance and clinical trial dosage. Epilepsia 1993; 34(1):166-173. 412 Handforth A, Treiman DM. Efficacy and tolerance of long-term, high-dose gabapentin: additional observations. Epilepsia 1994; 35(5):1032-1037. 413 Hanefeld F. Effectivity and tolerability of vigabatrin in childhood and adolescent. Aktuelle Neurologie 1992; 19(SUPPL. 1):S17-S20. 414 Hanny A, Litzinger MJ. Tiagabine add-on treatment improves neurobehavioral and epilepsy-related symptoms in pediatric seizure patients. Epilepsia 1999; 40:132. 415 Harding GFA, Robertson KA, Edson AS, Barnes P, Wild J. Visual electrophysiological effect of a GABA transaminase blocker. Documenta Ophthalmologica 1998; 97(2):179-188. 416 Hayes A, Garofalo E, Mann M, Hes MK, Greeley C, Greiner M, et al. Gabapentin (Neurontin) monotherpay- a double-blind study in patients with medically refractory partial seizures. Epilepsia 1995; 36:S119. 417 Hayes A, Garofalo E, Mann M, Hes MK, Greeley C, Pierce M. Quality-of-life assessments during a double-blind-study of gabapentin (Neurontin) in patients with medically refractory partial seizures. Epilepsia 1995; 36:S187. 418 Hayes AG, Garofalo EA, Greeley CA, Mann ME, Hes MS, Greiner MJ, et al. A double-blind multicenter study of gabapentin (GBP Neurontin(R)) monotherapy in patients with medically refractory partial seizures. Epilepsia 1995; 36:G3. 419 Hogan RE, Lenz GT, Deaton R, Sommerville KW. Weight changes with adjunctive therapy of phenytoin, carbamazepine, or tiagabine in a multicenter trial of partial seizures. Epilepsia 1998; 39 Suppl 6:125. 420 Hogan RE, Bertrand ME, Deaton RL, Sommerville KW. Total percentage body weight changes during add-on therapy with tiagabine, carbamazepine and phenytoin. Epilepsy Research 2000; 41(1):23-28. 421 Hosain S, Solomon G, Joshi C, Chutorian A. Efficacy of topiramate in infants and children with symptomatic generalized epilepsies. Annals of Neurology 1999; 46(3):532. 422 Houtkooper M, Vanoorschot C, Hoppener RJ. Oxcarbamazepine (GP-47680) versus carbamazepine- double blind crossover study in patients with epilepsy. Acta Neurologica Scandinavica 1984; 70(3):221- 222. 423 Ignatowicz R, Chmielik J, Michalowicz R, Ignatowicz L, Jozwiak S, Karkowska B. Sabril (Vigabatrin) efficacy in therapy in epilepsy in children. Epilepsia 1995; 36:S103. 424 Isojarvi JIT, Tapanainen J, Rattya J, Knip M, Pakarinen AJ, Tekay A, et al. Changes in body-weight, fasting serum-insulin and testosterone levels and ovarian structure in women with epilepsy after substituting lamotrigine for valproate. Epilepsia 1995; 36:290. 425 Isojarvi JIT, Tapanainen J, Rattya J, Pakarinen AJ, Knip M, Tekay A, et al. Body-weight, serum testosterone levels, and ovarian structure in women with epilepsy after replacement of valproate with lamotrigine. Epilepsia 1995; 36:S117. 426 Jawad S, Richens A, Goodwin G, Yuen WC. Controlled trial of lamotrigine (Lamictal) for refractory partial seizures. Epilepsia 1989; 30(3):356-363. 427 Kalviainen R, Brodie MJ, Duncan J, Chadwick D, Edwards D, Lyby K. A double-blind, placebo- controlled trial of tiagabine given three-times daily as add-on therapy for refractory partial seizures. Epilepsy Research 1998; 30(1):31-40. 428 Kalviainen R, Nousiainen I, Nikoskelainen E, Partanen J, Partanen K, Mantyjarvi M, et al. Visual field defects associated with initial vigabatrin monotherapy as compared with initial carbamazepine monotherapy. Epilepsia 1998; 39 Suppl 2:5. 429 Kalviainen R, Aikia M, Mervaala E, Saukkonen AM, Pitkanen A, Riekkinen PJ, Sr. Long-term cognitive and EEG effects of tiagabine in drug-resistant partial epilepsy. Epilepsy Research 1996; 25(3):291-297. 430 Kluger G, Berz K, Holthausen H. The long-term use of vigabatrin and lamotrigine in patients with severe childhood onset epilepsy. European Journal of Paediatric Neurology 2001; 5(1):37-40. 431 Kohrman MH. Use of gabapentin adjunctive therapy for nocturnal partial seizures with secondary generalization during adolescence. Annals of Neurology 1998; 44(3):B14. 432 Koul RL, Aithala GR, Joshi RM, Elbualy MS. Vigabatrin as add-on therapy in severely intractable seizures in children in oman. Epilepsia 1995; 36:S103-S104.

388 Newer Drugs for Children with Epilepsy

433 Kraemer G, Canger R, Deisenhammer E, Moore A, Sterm Y. Double-blind, multicenter, noncomparative assessment of the retention rate of b.i.d. administration of oxcarbazepine as monotherapy for epilepsy in adults. Epilepsia 1998; 39 Suppl 6:132. 434 Lee S-K, Chang I. Comparative add-on trial of vigabatrin and valproic acid on intractable partial seizures with carbamazepine monotherapy. Epilepsia 1997; 38 Suppl 3 :70. 435 Leiderman DB. Gabapentin as add-on therapy for refractory partial epilepsy: Results of five placebo- controlled trials. Epilepsia 1994; 35(SUPPL. 5):S74-S76. 436 Leoni S, Guerra A, Galli V, Rozzi N, Cavazzuti GB. Evaluation of the efficacy and tolerance to gabapentin in pharmacoresistant partial epilepsy in children. Epilepsia 1999; 40:171-172. 437 Levisohn PM. Safety and tolerability of topiramate in children. Journal of Child Neurology 2000; 15 Suppl 1:S22-S26. 438 Lindberger M. A Nordic multicenter, randomized, double-blind, comparative study of gabapentin and vigabatrin. Epilepsia 1999; 40 Suppl 7:98-99. 439 Livingston JH, Beaumont D, Arzimanoglou A, Aicardi J. Vigabatrin in the treatment of epilepsy in children. British Journal of Clinical Pharmacology 1989; 27:S109-S112. 440 Loiseau P, Yuen AW, Duche B, Menager T, Arne-Bes MC. A randomised double-blind placebo- controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures. Epilepsy Research 1990; 7(2):136-145. 441 Luna D, Dulac O, Pajot N, Beaumont D. Vigabatrin in the treatment of childhood epilepsies: A single- blind placebo-controlled study. Epilepsia 1989; 30(4):430-437. 442 Mandelbaum DE, Kugler SL, Wenger EC, Wollack JB, Venkat A. Clinical experience with Levetiracetam and Zonisamide in children with intractable epilepsy. Neurology 2001; 56(8):A46. 443 Marescauz C. Lamotrigine and generalized paediatric epilepsy syndromes. Lamotrigine: A Brighter Future - International Congress and Symposium 1996; Series 214:75-80. 444 Martin R, Meador K, Turrentine L, Faught E, Sinclair K, Kuzniecky R, et al. Comparative cognitive effects of carbamazepine and gabapentin in healthy senior adults. Epilepsia 2001; 42(6):764-771. 445 Martin R, Kuzniecky R, Ho S, Hetherington H, Pan J, Sinclair K, et al. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 1999; 52(2):321-327. 446 Martinez W, Kaminow L, Nanry KP, Hammer AE, Barrett PS. Evaluation of lamotrigine versus carbamazepine, phenytoin, or divalproex sodium as monotherapy for epilepsy patients who failed or could not tolerate previous antiepileptic drug therapy. Epilepsia 2000; 41 Suppl 7:100. 447 Martinezbermejo A, Lopezmartin V, Arcas J, Roche C, Tendero A, Castroviejo I. Vigabatrin in resistant childhood epilepsy. Epilepsia 1995; 36:S104. 448 Martinezlage J, Ben-Menachem E, Shorvon SD, Weber M. Double-blind, placebo-controlled trial of 400 mg/day topiramate as add-on therapy in patients with refractory partial epilepsy. Epilepsia 1995; 36:S149-S150. 449 Martinovic Z. Gabapentin in the treatment of children and adolescents with partial epilepsy. Epilepsia 1999; 40:224. 450 Matsuo F, Gay P, Madsen J, Tolman KG, Rollins DE, Risner ME, et al. Lamotrigine high-dose tolerability and safety in patients with epilepsy: a double-blind, placebo-controlled, eleven-week study. Epilepsia 1996; 37(9):857-862. 451 Matsuo F, Bergen D, Faught E, Messenheimer JA, Dren AT, Rudd GD, et al. Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. Neurology 1993; 43(11):2284- 2291. 452 Mattson RH, Kamin M, Siu C. Seizure freedom with topiramate: results from an open-label follow-on to a double-blind titration study. Epilepsia 1998; 39 Suppl 6:55. 453 McKee PJW, Blacklaw J, Forrest G, Gillham RA, Walker SM, Connelly D, et al. A double-blind, placebo-controlled interaction study between oxcarbazepine and carbamazepine, sodium valproate and phenytoin in epileptic patients. British Journal of Clinical Pharmacology 1994; 37(1):27-32. 454 Meador KJ, Loring DW, Ray PG, Murro AM, King DW, Nichols ME, et al. Differential cognitive effects of carbamazepine and gabapentin. Epilepsia 1999; 40(9):1279-1285. 455 Meador KJ, Loring DW, Ray PG, Murro AM, King DW, Perrine KR, et al. Differential cognitive and behavioral effects of carbamazepine and lamotrigine. Neurology 2001; 56(9):1177-1182. 456 Mecarelli O, Rinalduzzi S, Accornero N. Changes in color vision after a single dose of vigabatrin or carbamazepine in healthy volunteers. Clinical Neuropharmacology 2001; 24(1):23-26. 457 Mervaala E, Partanen J, Nousianinen U, Sivenius J, Riekkinen P. Electrophysiologic effects of gamma- vinyl GABA and carbamazepine. Epilepsia 1989; 30(2):189-193.

389 Newer Drugs for Children with Epilepsy

458 Messenheimer J, Ramsay RE, Willmore LJ, Leroy RF, Zielinski JJ, Mattson R, et al. Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, cross-over trial. Epilepsia 1994; 35(1):113-121. 459 Messenheimer JA, Haynie CJ, Risner ME. Long-term tolerability of Lamictal in pediatric patients. Epilepsia 1998; 39 Suppl 6:51-52. 460 Michelucci R, Passarelli D, Di Fazio M, Tassinari CA. Topiramate in the treatment of drug-resistant epilepsy: A long-term follow-up study. Bollettino - Lega Italiana Contro L'Epilessia 1996; Issue 95- 96(pp 255-256). 461 Michelucci R, Passarelli D, Tassinari CA. Topiramate in the treatment of refractory partial epilepsy - a double-blind-study with long-term follow-up. Epilepsia 1995; 36:S150. 462 Michelucci R, Passarelli D, Riguzzi P, Volpi L, Tassinari CA. Long-term follow-up of TPM [topiramate] in refractory partial seizures. Epilepsia 1998; 39 Suppl 2:67. 463 Michelucci R, Cavaciocchi P, Riguzzi P, Passarelli D, Parmeggiani L, Santangelo M, et al. Single-blind, placebo-controlled dose-modification study of vigabatrin in refractory epileptic patients. Journal of Epilepsy 1992; 5(4):248-252. 464 Michelucci R, Veri L, Passarelli D, Zamagni M, Strumia S, Buzzi AM, et al. Long-term follow-up study of vigabatrin in the treatment of refractory epilepsy. Journal of Epilepsy 1994; 7(2):88-93. 465 Micheu C, Foisoreanu V. Study on efficacy of lamotrigine in child epilepsies. Epilepsia 1999; 40:229. 466 Mikati M, Khurana D, Riviello J, Holmes G, Helmers S, Anderson J. Efficacy of gabapentin in children with refractory partial seizures. Neurology 1995; 45(4):A201-A202. 467 Mims J, Penovich P, Ritter F, Frost MD. Treatment with high doses of lamotrigine in children and adolescents with refractory seizures. Journal of Child Neurology 1997; 12(1):64-67. 468 Montouris GD, Biton V, Rosenfeld WE. Nonfocal generalized tonic-clonic seizures: response during long-term topiramate treatment. Topiramate YTC/YTCE Study Group. Epilepsia 2000; 41 Suppl 1:S77- S81. 469 Morita DA, Glauser TA, Hamant E, Guo SS. Effect of topiramate on linear growth in children with refractory complex partial seizures. Neurology 2000; 54(7):A193. 470 Mortimore C, Trimble M, Emmers E. Effects of gabapentin on cognition and quality of life in patients with epilepsy. Seizure 1998; 7(5):359-364. 471 Muscas GC, Chiroli S, Luceri F, Mastio MD, Balestrieri F, Arnetoli G. Conversion from thrice daily to twice daily administration of gabapentin (GBP) in partial epilepsy: analysis of clinical efficacy and plasma levels. Seizure 2000; 9(1):47-50. 472 Muszkat M, Rizzutti S, Decampos CJR. Lamotrigine in refractory childhood epilepsy. Epilepsia 1995; 36:S111. 473 Noachtar S, von Maydell B, Fuhry L, Buttner U. Gabapentin and carbamazepine affect eye movements and posture control differently: a placebo-controlled investigation of acute CNS side effects in healthy volunteers. Epilepsy Research 1998; 31(1):47-57. 474 O'Donoghue MF, Sander JWAS, Eeg-Olofsson O, Reynolds EH, Brodie MJ, Richens A, et al. Lamotrigine versus carbamazepine in epilepsy [2]. Lancet 1995; 345(8960):1300-1302. 475 Oommen K, Penry J, Riela A, Rowan A, Rosenbaum D, Schear M, et al. The long-term safety and efficacy of gabapentin (Neurontin(TM)) as add-on therapy in drug-resistant partial epilepsy. Epilepsy Research 1994; 18(1):67-73. 476 Penry KJ, Wilder BJ, Sachdeo RC, Vaughan LU, Ahlbrandt RA. Multicenter dose-response study of vigabatrin in adults with focal (partial) epilepsy. Epilepsia 1993; 34(Suppl. 6):67. 477 Pledger G, Reife R, Lim P, Karim R. Overview of topiramate efficacy from adjunctive therapy trials. Bollettino - Lega Italiana Contro L'Epilessia 1996; Issue 95-96(pp 247-250). 478 Privitera M, Fincham R, Penry J, Reife R, Kramer L, Pledger G, et al. Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 600-, 800-, and 1,000-mg daily dosages. Topiramate YE Study Group. Neurology 1996; 46(6):1678-1683. 479 Ramsay RE, Pellock JM, Garnett WR, Sanchez RM, Valakas AM, Wargin WA, et al. Pharmacokinetics and safety of lamotrigine (Lamictal) in patients with epilepsy. Epilepsy Research 1991; 10(2-3):191-200. 480 Ramsey ER, Veloso F, Bomhof M, Pledger G, Wu SC. Patient factors affecting response to early AED monotherapy in partial-onset seizures: Observations from a randomized controlled trial with topiramate (TPM). Epilepsia 1999; 40 Suppl 7:111. 481 Regesta G, Tanganelli P. Vigabatrin vs Carbamazepin monotherapy in newly diagnosed focal epileptics. A randomized response conditional cross-over study [Abstract]. Journal of the Neurological Sciences 1997;(Sept):S167. 482 Regesta G, Tanganelli P. Vigbatrin monotherapy in newly diagnosed focal epilepsy. Bollettino Lega Italiana Contro L'Epilessia 1997;(99 SUPPL. 1):27-32. 390 Newer Drugs for Children with Epilepsy

483 Regesta G, Tanganelli P. Vigabatrin versus carbamazepine monotherapy in newly diagnosed focal epileptics: a randomised response condition cross-over study. Epilepsia 1997; 38 Suppl 3:58. 484 Reinikainen K, Keranen T, Hallikainen E, Riekkinen PJ. Substitution of diphenylhydantoin by oxcarbazepine or carbamazepine: Double-blind study. Acta Neurol Scand 1984; 69(SUPPL. 98):89-90. 485 Reinikainen KJ, Keranen T, Halonen T, Komulainen H, Riekkinen PJ. Comparison of oxcarbazepine and carbamazepine: a double-blind study. Epilepsy Research 1987; 1(5):284-289. 486 Richens A, Chadwick DW, Duncan JS, Dam M, Gram L, Mikkelsen M, et al. Adjunctive treatment of partial seizures with tiagabine: a placebo-controlled trial. Epilepsy Research 1995; 21(1):37-42. 487 Richens A, Mawer G, Crawford P, Harrison B. A placebo-controlled, double-blind cross-over trial of adjunctive one month remacemide hydrochloride treatment in patients with refractory epilepsy. Seizure 2000; 9(8):537-543. 488 Richens A. Lamotrigine versus carbamazephine double-blind comparative trial. Lamotrigine: A Brighter Future - International Congress and Symposium 1996; Series 214:9-14. 489 Ritter F, Glauser TA, Elterman RD, Wyllie E. Effectiveness, tolerability, and safety of topiramate in children with partial-onset seizures. Topiramate YP Study Group. Epilepsia 2000; 41 Suppl 1:S82-S85. 490 Ritter FJ, Glauser TA, Sachdeo RC, Shu-Chen W. Long-term experience with topiramate in Lennox- Gastaut syndrome. Epilepsia 1998; 39 Suppl 2:2-3. 491 Rosenfeld WE, Abou-Khalil BW, Reife R, Hegadus R, Pledger G, Johnson RW. Placebo-controlled trial of topiramate as adjunctive therapy to carbamazepine or phenytoin for partial-onset epilepsy. Epilepsia 1996; 37(Suppl 1):153. 492 Rosenfeld WE. Topiramate, a broad-spectrum agent, in patients with juvenile myoclonic epilepsy. Epilepsia 1999; 40:226. 493 Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: A randomized controlled trial. Journal of the American Medical Association 1998; 280(21):1837-1842. 494 Sachdeo R, Leroy R, Krauss G, Green P, Drake M, Leppik I, et al. Safety and efficacy of bid and qid dosing with tiagabine hcl versus placebo as adjunctive treatment for partial seizures. Neurology 1995; 45(4):A202. 495 Sachdeo RC, Narang-Sachdeo S. Placebo controlled trial of oxcarbazepine in recent onset partial seizures. Epilepsia 1997; 38 Suppl 3:80. 496 Sander JWAS, Patsalos PN, Oxley JR, Hamilton MJ, Yuen WC. A randomised double-blind placebo- controlled add-on trial of lamotrigine in patients with severe epilepsy. Epilepsy Research 1990; 6(3):221- 226. 497 Sanmarti F, Pires M, Pineda M, Conill J, Vernet A, Campistol J, et al. Lamotrigine in 68 children with refractory epilepsy. Epilepsia 1995; 36:S111. 498 Schachter S, Biton V, Boellner S, Edwards K, Cybulski K, Shu V, et al. Safety and efficacy of tiagabine HCl monotherapy in the treatment of partial seizures- high dose versus low dose. Epilepsia 1995; 36:S148. 499 Schachter SC, Leppik IE, Matsuo F, Messenheimer JA, Faught E, Moore EL, et al. Lamotrigine: A six- month, placebo-controlled, safety and tolerance study. Journal of Epilepsy 1995; 8(3):201-209. 500 Schachter SC. Tiagabine monotherapy in the treatment of partial epilepsy. Epilepsia 1995; 36 Suppl 6:S2-S6. 501 Schacter SC, Vasquez B, Fisher R, Bennett D. Placebo-controlled inpatient monotherapy trial of oxcarbazepine. Epilepsia 1997; 38 Suppl 3:30. 502 Schapel, G., Beran, R., Vajda, F., et al. Double-blind, placebo controlled, crossover study of lamotrigine in treatment resistant partial seizures. Australian & New Zealand Journal of Medicine 1991; 21:620. 503 Schlumberger E, Chavez F, Palacios L, Rey E, Pajot N, Dulac O. Lamotrigine in treatment of 120 children with epilepsy. Epilepsia 1994; 35(2):359-367. 504 Schmidt D, Reid S, Rapp P. Add-on treatment with lamotrigine for intractable partial epilepsy: A placebo-controlled cross-over trial. Epilepsia 1993; 34(Suppl. 2):66. 505 Schmitz-Moormann W, Kruse R. Vigabatrin long-term therapy in symptomatic epilepsies with complex focal seizures in pediatrics. Aktuelle Neurologie 1992; 19(SUPPL. 1):S23-S25. 506 Schwabe MJ, Wheless JW. Clinical experience with topiramate (Topamax) dosing and serum levels in children 12 years or younger with epilepsy. Annals of Neurology 2000; 48(3):17. 507 Sharief M, Viteri C, Ben Menachem E, Weber M, Reife R, Pledger G, et al. Double-blind, placebo- controlled study of topiramate in patients with refractory partial epilepsy. Epilepsy Research 1996; 25(3):217-224. 508 Siemes H. Lamotrigine as add-on therapy an difficult-to-treat epilepsies in children and adolescents. Epilepsia 1999; 40:68. 391 Newer Drugs for Children with Epilepsy

509 Sillanpaa M, Pihlaja T. Oxcarbazepine (GP 47 680) in the treatment of intractable seizures. Acta Paediatrica Hungarica 1988; 29(3-4):359-364. 510 Sinclair KR, Martin R, Kuzniecky R, Ho S, Hetherington H, Pan J, et al. Comparative cognitive effects of topiramate, gabapentin, and lamotrigine: an acute and steady-state dosing study in healthy young adults. Epilepsia 1998; 39 Suppl 6:250-251. 511 Siskova D, Dolansky J, Hadac J. Efficacy of Sabril in treatment of epilepsy in children. Epilepsia 1995; 36:S104. 512 Sivenius J, Ylinen A, Matilainen R, Reinikainen K, Riekkinen P. Double-blind dose reduction study in complex partial epilepsy with vigabatrin - an interim-report. Epilepsia 1985; 26(5):537. 513 Sivenius J, Ylinen A, Matilainen R, Murros K, Riekkinen PJ. Double-blind dose reduction study in complex partial epilepsy with gamma-vinyl-gaba. Upsala Journal of Medical Sciences 1986;46. 514 Sivenius J. Long-term therapy with vigabatrin in patients with complex partial epilepsy. Acta Neurologica Scandinavica 1988; 77:139. 515 Smith D, Chadwick D, Baker G, Davis G, Dewey M. Seizure severity and the quality of life. Epilepsia 1993; 34(SUPPL. 5):S31-S35. 516 Steiner TJ, Findley LJ. Safety data from a placebo-controlled trial of lamotrigine. Lamotrigine: A Brighter Future - International Congress and Symposium 1996; Series 214:31-35. 517 Steinhoff BJ, Freudenthaler N, Paulus W. The influence of established and new antiepileptic drugs on visual perception. 1. A placebo-controlled, double-blind, single-dose study in healthy volunteers. Epilepsy Research 1997; 29(1):35-47. 518 Stolarek I, Blacklaw J, Forrest G, Brodie MJ. Vigabatrin and lamotrigine in refractory epilepsy. Journal of Neurology, Neurosurgery & Psychiatry 1994; 57(8):921-924. 519 Tanganelli P, Regesta G. Vigabatrin versus carbamazepine in newly-diagnosed epileptic patients - a randomized-response conditional cross-over study. Epilepsia 1995; 36:S104. 520 Tanganelli P, Regesta G. Vigabatrin vs. carbamazepine monotherapy in newly diagnosed focal epilepsy: a randomized response conditional cross-over study. Epilepsy Research 1996; 25(3):257-262. 521 Tartara A, Manni R, Galimberti CA, Morini R, Mumford JP, Iudice A, et al. Six-year follow-up study on the efficacy and safety of vigabatrin in patients with epilepsy. Acta Neurologica Scandinavica 1992; 86(3):247-251. 522 Tassinari C, Chauvel P, Chodkiewicz J, Shorvon SD, Henriksen O, Dam M, et al. Double-blind, placebo- controlled trial of 600 mg/day topiramate as add-on therapy in patients with refractory partial epilepsy. Epilepsia 1995; 36:S150. 523 Tassinari CA, Michelucci R, Chauvel P, Chodkiewicz J, Shorvon S, Henriksen O, et al. Double-blind, placebo-controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsy. Epilepsia 1996; 37(8):763-768. 524 Single-blind, placebo-controlled multicenter trial of vigabatrin in the treatment of epilepsy. The Italian Study Group on Vigabatrin. Italian Journal of Neurological Sciences 1992; 13(9):741-747. 525 Thomas L, Trimble M. The effects of vigabatrin on attention, concentration and mood: an investigation in healthy volunteers. Seizure 1996; 5(3):205-208. 526 Trudeau VL, Dimond KR, Smith FB, Wilensky AJ, Chmelir T, Ricker B, et al. Gabapentin (gbp neurontin(r)) monotherapy compared with carbamazepine (cbz) monotherapy and combination gbp plus cbz (gbp/cbz) therapy in patients with medically refractory partial seizures - a 3-way cross-over trial (94536). Epilepsia 1995; 36:343. 527 Uldall P, Bulteau C, Pedersen SA, Dulac O, Meinild H, Lassen LC. Single-blind study of safety, tolerability, and preliminary efficacy of tiagabine as adjunctive treatment of children with epilepsy. Epilepsia 1995; 36:S147-S148. 528 Uldall P, Bulteau C, Pedersen SA, Dulac O, Lyby K. Tiagabine adjunctive therapy in children with refractory epilepsy: a single-blind dose escalating study. Epilepsy Research 2000; 42(2-3):159-168. 529 Uthman B, Rowan AJ, Ahmann P, Wannamaker B, Schachter S, Rask C. Safety and efficacy of 3 dose levels of tiagabine hcl versus placebo as adjunctive treatment for complex partial seizures. Annals of Neurology 1993; 34(2):272. 530 Wheless JW. Use of topiramate in childhood generalized seizure disorders. Journal of Child Neurology 2000; 15 Suppl 1:S7-13. 531 Wieser HG, Truog B, Vogt H, Honneger UE. The Swiss lamotrigine study - results of an open, multicenter, add-on treatment with lamotrigine in drug-resistant epileptic patients. Epilepsia 1995; 36:S114-S115. 532 Wieser HG. The Swiss Lamotrigine (Lamictal(TM)) study. Results of an open, multicenter add-on- treatment in therapy resistant epilepsy. Ars Medici 1995; 85(6):449+451-449+453.

392 Newer Drugs for Children with Epilepsy

533 Yen DJ, Yu HY, Guo YC, Chen C, Yiu CH, Su MS. A double-blind, placebo-controlled study of topiramate in adult patients with refractory partial epilepsy. Epilepsia 2000; 41(9):1162-1166. 534 Yuen AW, Chapman A. Interim report on an open multicentre lamotrigine (lamictal) versus carbamazepine monotherapy trial in patients with epilepsy. Can J Neurol Sci 1993; 20(Suppl. 4):S150. 535 Zahner B, Stefan H, Blankenhorn V, Kramer G, Richens A, Thumler R. Double-blind cross-over study comparing once-daily versus twice-daily vigabatrin add-on therapy in patients with previously refractory epilepsy. Epilepsia 1995; 36:S106. 536 Zakrzewska JM, Chaudhry Z, Nurmikko TJ, Patton DW, Mullens EL. Lamotrigine (Lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover trial. Pain 1997; 73(2):223-230. 537 Aikia M, Sivenius JK. Oxcarbazepine vs phenytoin in monotherapy for newly diagnosed epilepsy with a special reference to memory function. 18th International Epilepsy Congress 1989;91. 538 Loiseau P, Bes AM. Double-blind placebo controlled crossover study of lamotrigine (Lamictal) as add- on therapy in patients with refractory partial seizures. 18th International Epilepsy Congress 1989;144. 539 Sivenius J, Kalviainen RY. A double-blind study of gabapentin in the treatment of partial seizures. 18th International Epilepsy Congress 1989;91. 540 Hsiang-Yu Y, Der-Jen Y, Chun-Hing Y, Ming-Shung S. Double-blind, placebo-controlled trial of topiramate as add-on therapy in patients with refractory partial epilepsy. Epilepsia 1999; 40:97. 541 Kharlamov DA, Prityko AG, Ayvazian SO, Yavorskaya MM. Lamotrigine in the treatment of drug- resistant epilepsies in children. Epilepsia 1999; 40:175. 542 Kivity S, Shorer Z, Unit S. Lamotrigine add-on therapy in children with drug-resistant epilepsy: Low incidence of rash associated with low initial and titration doses. Epilepsia 1999; 40:172. 543 Mirza W, Biton V, Barrett P, Vuong A, Hammer A. Weight gain associated with valproate monotherapy in patients with epilepsy: An interim analysis of a randomized, double- blinded comparative clinical trial with lamotrigine. Epilepsia 1999; 40:282. 544 Mojs E, Galas-Zgorzalewicz B. The long term prognosis of cognitive functioning in epileptic children and adolescents in bitherapy with vigabatrin. Epilepsia 1999; 40 :275. 545 Rintahaka PJ, Gaily E, Liukkonen E, Paetau R, Grandstrom ML. Topiramate in the treatment of intractable pediatric epilepsy. Epilepsia 1999; 40:135. 546 Slapal R, Zaplatilova L. Quality of life with lamotrigine in epileptic children - Our five-year experience. Epilepsia 1999; 40:180-181. 547 Sokic DV, Pavlovic Z, Jankovic SM, Levic Z. Lamotrigine for the treatment of juvenile myoclonic epilepsy. Epilepsia 1999; 40:38. 548 Uran N, Calkavur SS, Kalkan S. Vigabatrin in the therapy-resistant childhood epilepsies. Epilepsia 1999; 40:255. 549 Uran N, Serdarodlu G, Calkavur T, Serdarodlu E. Lamotrigine treatment in childhood drug resistant epilepsy. Epilepsia 1999; 40:176. 550 Uysal S, Deda G, Karagol U. Lamotrigine monotherapy in childhood epilepsy and the comparative evaluation of the effects of other antiepileptic drugs on evoked potentials. Epilepsia 1999; 40:251-252. 551 Biraben A, Beaussart M, Josien E, Pestre M, Schaff JL, Sevestre M. Tiagabine as adjunctive treatment of partial seizures in patients with epilepsy: A comparison of two dose regimens. Epilepsia 2000; 41 Suppl Florence:96. 552 Brodie MJ, Anhut H, Murray G, Maton S. Gabapentin versus lamotrigine monotherapy: A double-blind comparison. Epilepsia 2000; 41 Suppl Florence:138. 553 Carpay JA, Veendrick-Meekes MJBM, Beun AM, Arends LR, Schlosser A. Carer assessment of quality of life related to seizure severity and side effects of lamotrigine in mentally retarded epilepsy patients. Epilepsia 2000; 41 Suppl Florence:114. 554 Gil KB, Nagel N, Verger K, Sol JM, Morralla C, Hernandez G. Safety of gabapentin vs. valproic acid as add-on therapy to carbamazepine. Epilepsia 2000; 41 Suppl Florence:105. 555 Kazibutowska Z, Stelmach-Wawrzyczek A. Efficacy of therapy with new antiepileptic drugs (tiagabine, gabapentin, topiramate) in drug-resistant epilepsy. Epilepsia 2000; 41 Suppl Florence:38. 556 Kwan SY, Yiu CH, Su MS. A double blind study of gabapentin in partial seizures. Epilepsia 2000; 41 Suppl Florence:69. 557 Meador KJ, Loring DW, Ray PG, Perrine KR, Vasquez BR, Kalbosa T. Cognitive side effects of carbamazepine and lamotrigine compared to non-drug state. Epilepsia 2000; 41 Suppl Florence:113. 558 Neto W, Gassmann-Mayer C. Efficacy and tolerability of 200 mg/day topiramate in a placebo-controlled comparison of titration rates. Epilepsia 2000; 41 Suppl Florence:35. 559 Privitera MD, Brodie MJ, Neto W, Wang S. Monotherapy in newly diagnosed epilepsy: Topiramate vs. investigator choice of carbamazepine or valproate. Epilepsia 2000; 41 Suppl Florence:138. 393 Newer Drugs for Children with Epilepsy

560 Veendrick-Meekes MJBM, Beun AM, Carpay JA, Arends LR, Schlosser A. Use of lamotrigine as adjunctive therapy in patients with mental retardation and epilepsy: An interim analysis of a double blind study with evaluation of behavioural effects. Epilepsia 2000; 41 Suppl Florence:97. 561 Abou KB. Long-term seizure freedom with levetiracetam. JNS 2001; 187(Suppl. 1). 562 Cramer JA. Short-term treatment with levetiracetam enhances health-related quality of life in patients with refractory epilepsy. JNS 2001; 187(Suppl. 1). 563 Kerr M, Moorat A, Curtis P. Lamotrigine compared to valproate: a randomised open label switch to monotherapy study in patients with uncontrolled epilepsy. JNS 2001; 187(Suppl. 1). 564 Michelucci R, Tassinari CA, Forti A, Ambrosetto G, Rubboli G, Iudice A, et al. Vigabatrin in the treatment of drug-resistant epilepsy: Short-term results of 2 placebo - controlled trials. Bollettino - Lega Italiana Contro L'Epilessia 1988; Issue 64(pp 167-169). 565 Angeleri F, Scarpino O, Avanzini G, Binelli D, Baruzzi A, Procaccianti G, et al. A multicenter study of Vigabatrin in refractory epilepsy. Bollettino - Lega Italiana Contro L'Epilessia 1990; Issue 70-71(pp 121-123). 566 Dulac O, Chiron C, Luna D, Cusmai R, Pajot N, Beaumont D, et al. Vigabatrin in childhood epilepsy. Journal of Child Neurology 1991; 6(SUPPL. 2):2S30-2S37. 567 Kalviainen R, Aikia M, Partanen J, Sivenius J, Mumford J, Saksa M, et al. Randomized controlled pilot study of vigabatrin versus carbamazepine monotherapy in newly diagnosed patients with epilepsy: an interim report. Journal of Child Neurology 1991; Suppl 2:S60-S69. 568 Espe-Lillo J, Ritter FJ, Frost MD, Spiegel RE, Reife R. Topiramate in childhood epilepsy- titration,adverse events, and efficacy in multiple seizure types. Epilepsia 1995; 36(Suppl 4):287.

394