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Lamotrigine for patients with juvenile myoclonic epilepsy following prior treatment with valproate: results of an open-label study
Epilepsy & Behavior Epilepsy & Behavior 5 (2004) 509–512 www.elsevier.com/locate/yebeh
Lamotrigine for patients with juvenile myoclonic epilepsy following prior treatment with valproate: results of an open-label studyq George L. Morris,a,* Anne E. Hammer,b Robert P. Kustra,b and John A. Messenheimerb b
a St. LukeÕs Medical Center, Milwaukee, WI, USA GlaxoSmithKline, Research Triangle Park, NC, USA
Received 13 January 2004; revised 6 April 2004; accepted 8 April 2004 Available online 10 May 2004
Abstract This open-label study was designed to evaluate lamotrigine monotherapy as a possible alternative in patients with juvenile myoclonic epilepsy who previously failed treatment with valproate. Patients (n ¼ 63) were transitioned from valproate to lamotrigine during an 8-week escalation phase followed by 24 weeks of lamotrigine monotherapy. On Week 24 of the treatment phase, investigators judged that 50 and 67% of patients completing the study had shown mild, moderate, or marked improvement in adverse events and global clinical status, respectively, and 76% of patients rated lamotrigine as somewhat better (13%) or much better (63%) than valproate. The majority of patients completing the study experienced no deterioration of seizure control when switching from valproate to lamotrigine. These results support additional research on lamotrigine in juvenile myoclonic epilepsy. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Lamotrigine; Valproate; Juvenile myoclonic epilepsy; Myoclonus
1. Introduction One of 10 epilepsy patients suffers from juvenile myoclonic epilepsy [1,2], which is characterized by myoclonic seizures that often occur on awakening and may also be precipitated by photic stimulation, sleep deprivation, fatigue, menstruation, and ingestion of alcohol [2,3]. Many patients suffer absence and/or generalized tonic–clonic seizures in addition to myoclonus. Valproate is the preferred treatment for otherwise healthy patients with juvenile myoclonic epilepsy, despite its association with side effects such as weight gain, edema, and hair loss [4]. The antiepileptic drug lamotrigine, like valproate, has a broad spectrum of efficacy against partial and generalized seizures in epilepsy [5]. Data from clinical practice and clinical studies suggest q
GlaxoSmithKline, maker of lamotrigine, funded the research described in this article. * Corresponding author. Fax: 1-414-385-8781. E-mail address: [email protected] (G.L. Morris). 1525-5050/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2004.04.002
that lamotrigine may be useful for some patients with juvenile myoclonic epilepsy [6–9]. For example, in a 12patient case series [6], seizures were controlled and valproate-associated side effects of weight gain, hair loss, and edema were mitigated or eliminated in patients with juvenile myoclonic epilepsy by switching from valproate to lamotrigine or by adding lamotrigine to a reduced valproate dose. Designed to extend these observations, this open-label study evaluated the tolerability and, secondarily, the efficacy of lamotrigine administered to patients with juvenile myoclonic epilepsy who had failed valproate therapy because of unacceptable side effects or inadequate seizure control.
2. Methods 2.1. Patients Patients at least 12 years of age with a diagnosis of juvenile myoclonic epilepsy supported by documented
510
G.L. Morris et al. / Epilepsy & Behavior 5 (2004) 509–512
clinical features and EEG data were eligible for the study if they had experienced at least one generalized motor seizure (classifiable by the International Classification of Seizures [10]) since diagnosis. Females were eligible only if they had a negative urine or serum pregnancy test at screening and agreed to use acceptable contraceptive methods during the study or were incapable of bearing children. Eligible patients were receiving valproate for juvenile myoclonic epilepsy and needed to discontinue it because of unacceptable side effects or inadequate seizure control or had previously received no therapy or inappropriate therapy for juvenile myoclonic epilepsy. Data from the latter group of patients are the subject of a separate publication (in preparation). The decision about whether patients qualified for the study on the basis of unacceptable side effects or ineffective seizure control was based on the investigatorÕs clinical judgment; no specific criteria were applied. Patients were excluded from the study if they had used any investigational drug within 4 weeks of initiation of the study or had been previously exposed to lamotrigine; were being treated with more than one antiepileptic drug; adhered to the ketogenic diet; had severe organic disease; had a history of alcohol or other drug abuse or dependence; or planned during the study period to undergo vagal stimulation or surgery to control seizures. All patients provided written, informed consent. 2.2. Procedures The protocol for this open-label study was approved by an institutional review board for each of the 18 US study sites. The study comprised a 2-week screening phase, during which eligibility was verified and baseline physical and seizure assessments were obtained; a doseescalation phase lasting up to 8 weeks, during which lamotrigine dose was increased while concurrent valproate was tapered; and a 24-week treatment phase, during which lamotrigine monotherapy was maintained. For the dose-escalation phase, lamotrigine (as 25 and 100 mg Lamictal tablets) was started at a dose of 25 mg every other day and increased, at the investigatorsÕ judgment based on patientsÕ clinical response, to minimum and maximum maintenance doses of 100 and 500 mg/day, respectively. Concomitant valproate was gradually discontinued after Week 5 of the dose-escalation phase at a rate determined by the investigators. The treatment phase began when patients had achieved an initial maintenance dose of lamotrigine monotherapy. Lamotrigine dose could be adjusted during the treatment phase to achieve optimal therapeutic response. Clinic visits to review seizure diaries and adverse events (defined as any untoward medical occurrence regardless of its suspected cause) occurred during the screening phase and on Treatment Weeks 1, 12, and 24. On Week 24, investigators rated patientsÕ global clinical
status and their seizure frequency, seizure duration, seizure intensity, adverse events, social functioning, intellectual functioning, and motor functioning as markedly, moderately, or mildly deteriorated; not changed; or markedly, moderately, or mildly improved. Patients rated their satisfaction with lamotrigine therapy as much better than, somewhat better than, the same as, somewhat worse than, or much worse than valproate therapy. During the dose-escalation and treatment phases, patients or their parents/guardians recorded in diaries the number of days with myoclonus and the number of seizures (by seizure type). Seizure frequency was also retrospectively determined for the 3 months prior to the first screening visit to obtain a baseline against which to compare effects of lamotrigine. All data were summarized using descriptive statistics; no formal statistical analyses were performed.
3. Results Sixty-three patients enrolled in the study and received at least one dose of lamotrigine. The numbers of patients qualifying for the study because of ineffective seizure control and unacceptable side effects were 11 and 52, respectively. All 63 patients were included in the demographic and tolerability summaries. Patient disposition is shown in Fig. 1. All patients completing the study (n ¼ 30) were included in the efficacy summaries. The majority of patients were female (73%) and white (81%). PatientsÕ mean age was 29.3 years. Median number of seizures per month during the 3 months prior to study entry was 1.8; median number of days per month with myoclonic seizures was 6. During the treatment phase, the mean lamotrigine monotherapy maintenance dose was 314 mg/day.
Fig. 1. Patient disposition.
G.L. Morris et al. / Epilepsy & Behavior 5 (2004) 509–512
During lamotrigine treatment, study medication-related adverse events that occurred at an incidence of at least 10% were headache (21%), dizziness (17%), tremor (11%), and rash (10%). Adverse events considered by the investigator to be related to study medication led to the discontinuation of 13 patients—5 for nonserious rash, and 1 each for dizziness; headache; hand clenching, loss of coordination, and headache; epigastric pain and diarrhea; increased frequency of auras; insomnia, vomiting, and increased seizure severity; dizziness, tremor, and blurred vision; and increased seizure activity. Six patients discontinued because of adverse events considered not drug-related. Investigators judged that 67% of completing patients had shown mild, moderate, or marked improvement in global clinical status during lamotrigine therapy; 23% had no change; and 10% had mild, moderate, or marked deterioration. Approximately one-third to two-thirds of patients were judged to be mildly, moderately, or markedly improved on adverse events (n ¼ 15, 50%), intellectual function (n ¼ 14, 47%), motor function (n ¼ 13, 43%), social function (n ¼ 18, 60%), seizure duration (n ¼ 11, 37%), seizure frequency (n ¼ 14, 46%), and seizure intensity (n ¼ 13, 43%). The percentages of patients judged to have no change in these parameters were 40% for adverse events, 43% for intellectual function, 53% for motor function, 37% for social function, 53% for seizure duration, 40% for seizure frequency, and 50% for seizure intensity. The percentages of patients judged to have mildly, moderately, or markedly deteriorated in these parameters were 10% for adverse events, 10% for intellectual function, 3% for motor function, 3% for social function, 10% for seizure duration, 134% for seizure frequency, and 76% for seizure intensity. The majority of patients completing the study rated lamotrigine as somewhat better or much better than valproate (Fig. 2). The majority of patients completing the study experienced no deterioration in seizure control when switched from valproate to lamotrigine (Fig. 3). Over
Fig. 2. Patient global assessments of lamotrigine monotherapy (n ¼ 30).
511
Fig. 3. Summary of change from baseline in seizure frequency in patients completing the study.
the lamotrigine treatment period, the percentages of patients with at least a 50% reduction from prestudy baseline in days with generalized tonic–clonic seizures, myoclonus, or absence seizure types were 50, 52, and 82%, respectively (Fig. 3). Few patients experienced clinically relevant increases in myoclonus or absence seizure types (Fig. 3). Of the 9 patients who entered the study seizure-free (any seizure type), 6 remained seizurefree during the treatment phase. Of the 13 patients who entered the study myoclonus-free, 9 remained free of myoclonic seizures during the treatment phase. Of the 20 patients who entered the study free of absence seizures, 20 remained free of absence seizures during the treatment phase.
4. Discussion The results of this study suggest that lamotrigine monotherapy is a possible alternative to valproate among patients with juvenile myoclonic epilepsy experiencing unacceptable side effects or inadequate seizure control with valproate monotherapy. The efficacy data, which should be interpreted cautiously because of the open-label design and the small sample size, suggest that conversion to lamotrigine is associated with improvements in seizure control as reflected by seizure frequency and investigator assessment of patientsÕ clinical status. These data are consistent with previous reports [6–11] including results of a recent retrospective study of 72 consecutively treated patients with juvenile myoclonic epilepsy [11]. In that study, which unlike the current one did not limit enrollment to patients refractory to or experiencing unacceptable side effects with valproate, seizure outcome did not differ between the groups receiving valproate monotherapy (n ¼ 36) and lamotrigine monotherapy (n ¼ 14) or between the groups receiving
512
G.L. Morris et al. / Epilepsy & Behavior 5 (2004) 509–512
valproate polytherapy (n ¼ 22) and lamotrigine polytherapy (n ¼ 21). The authors concluded that lamotrigine is an effective alternative to valproate in the treatment of juvenile myoclonic epilepsy. The finding that lamotrigine is an effective replacement for valproate is encouraging in light of the tolerability profile of lamotrigine. In the patients completing the study, investigators considered adverse events to have mildly, moderately, or markedly improved in 50% of patients. The most common adverse events attributed to lamotrigine were nonserious rash, headache, dizziness, and tremor. Most patients completing the study experienced no deterioration in seizure control when switched from valproate to lamotrigine. These findings corroborate previous reports from clinical practice and small clinical studies of lamotrigine after valproate failure in juvenile myoclonic epilepsy [6–9]. This study has several shortcomings, one of which is its open-label design. Success with lamotrigine may be a result of the displeasure with valproate in that valproate-associated side effects might lead the patient and physician to conclude that any treatment was better. A control group would be difficult and may be unethical as it would expose patients to risk of injury [12]. A second limitation of the study is the use of retrospective baseline data. Seizure counts from memory may be inaccurate and may under- or overestimate seizure frequencies. Days with myoclonus are likely to be underreported because of the lack of disturbance they create. Tonic– clonic seizures may be more likely than other seizure types to be recalled. Another disadvantage of the study design was that the patients enrolled had already failed at least one antiepileptic drug and may have been refractory to treatment. Also, efficacy analyses in this study were not subject to formal statistical analysis, and they were based on patients completing the study. The latter group comprised less than 50% of the patients enrolled. This limitation notwithstanding, the finding that only two patients withdrew from the study because of lack of efficacy is consistent with the possibility that the sample of patients completing the study was representative of the intent-to-treat population in terms of therapeutic response to lamotrigine. Juvenile myoclonic epilepsy is a lifelong disorder requiring chronic drug therapy; approximately 90% of patients relapse if antiepileptic medication is withdrawn [13]. Ideally, drug therapy for juvenile myoclonic epilepsy is effective and well-tolerated throughout the life span. Lamotrigine as monotherapy or adjunctive therapy has been demonstrated as a first-line option for partial and generalized seizures in children, adolescents, adults, and elderly patients with epilepsy [5,14,15]. The results of this study support additional research on
lamotrigine in juvenile myoclonic epilepsy in more rigorous, double-blind, randomized clinical trials.
Acknowledgments The authors thank Jane Saiers, Ph.D., for assistance with writing the manuscript. The following investigators participated in the study: Kenneth Askin (Charlotte, NC), Ricardo Ayala (Tallahassee, FL), Victor Biton (Little Rock, AK), Enrique Carrazana (Miami, FL), Deborah Combs-Cantrell (Irving, TX), Jose Cavazos (Denver, CO), OÕNeill Francis DÕCruz (Chapel Hill, NC), Paul McCabe (Hershey, PA), Thomas Perkins (Raleigh, NC), Phillip Riback (Albany, NY), Joel Rutman (San Antonio, TX), Steven Schachter (Boston, MA), James Schimschock (Portland, OR), Michael Sperling (Philadelphia, PA), William Tatum (Tampa, FL).
References [1] Gr€ unewald RA, Panayiotopoulos CP. Juvenile myoclonic epilepsy: a review. Arch Neurol 1993;50:594–8. [2] Panayiotopoulos CP, Obeid T, Tahan AR. Juvenile myoclonic epilepsy: a 5-year prospective study. Epilepsia 1994;35:285–96. [3] Pedersen SB, Petersen KA. Juvenile myoclonic epilepsy: clinical and EEG features. Acta Neurol Scand 1998;97:160–3. [4] Karceski S, Morrell M, Carpenter D. The expert consensus guideline series: treatment of epilepsy. Epilepsy Behav 2001;2:A1– A50. [5] Matsuo F. Lamotrigine. Epilepsia 1999;40(Suppl 5):S30–6. [6] Buchanan N. The use of lamotrigine in juvenile myoclonic epilepsy. Seizure 1996;5:149–51. [7] Sharpe C, Buchanan N. Juvenile myoclonic epilepsy: diagnosis, management and outcome. Med J Aust 1995;162:133–4. [8] Gericke CA, Picard F, de Saint-Martin A, et al. Efficacy of lamotrigine in idiopathic generalized epilepsy syndromes: a videoEEG-controlled, open study. Epileptic Disord 1999;1:159–65. [9] Timmings PL, Richens A. Efficacy of lamotrigine as monotherapy in juvenile myoclonic epilepsy: pilot study results. Epilepsia 1993;34(Suppl 2):160. [10]Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1989;30:389–99. [11] Prasad A, Kuzniecky RI, Knowlton RC, et al. Evolving antiepileptic drug treatment in juvenile myoclonic epilepsy. Arch Neurol 2003;60:1100–5. [12] Chadwick D. Monotherapy clinical trials of new antiepileptic drugs: design, indications, and controversies. Epilepsia 1997;38(Suppl 9):S16–20. [13] Janz D. Epilepsy with impulsive petit mal (juvenile myoclonic epilepsy). Acta Neurol Scand 1985;72:449–59. [14] Messenheimer J. Efficacy and safety of lamotrigine in pediatric patients. J Child Neurol 2002;17(Suppl 2):2S34–42. [15] Messenheimer J, Mullens EL, Giorgi L, et al. Safety review of adult clinical trial experience with lamotrigine. Drug Saf 1998;18:281–96.
Lamotrigine for patients with juvenile myoclonic epilepsy following prior treatment with valproate: results of an open-label studyq George L. Morris,a,* Anne E. Hammer,b Robert P. Kustra,b and John A. Messenheimerb b
a St. LukeÕs Medical Center, Milwaukee, WI, USA GlaxoSmithKline, Research Triangle Park, NC, USA
Received 13 January 2004; revised 6 April 2004; accepted 8 April 2004 Available online 10 May 2004
Abstract This open-label study was designed to evaluate lamotrigine monotherapy as a possible alternative in patients with juvenile myoclonic epilepsy who previously failed treatment with valproate. Patients (n ¼ 63) were transitioned from valproate to lamotrigine during an 8-week escalation phase followed by 24 weeks of lamotrigine monotherapy. On Week 24 of the treatment phase, investigators judged that 50 and 67% of patients completing the study had shown mild, moderate, or marked improvement in adverse events and global clinical status, respectively, and 76% of patients rated lamotrigine as somewhat better (13%) or much better (63%) than valproate. The majority of patients completing the study experienced no deterioration of seizure control when switching from valproate to lamotrigine. These results support additional research on lamotrigine in juvenile myoclonic epilepsy. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Lamotrigine; Valproate; Juvenile myoclonic epilepsy; Myoclonus
1. Introduction One of 10 epilepsy patients suffers from juvenile myoclonic epilepsy [1,2], which is characterized by myoclonic seizures that often occur on awakening and may also be precipitated by photic stimulation, sleep deprivation, fatigue, menstruation, and ingestion of alcohol [2,3]. Many patients suffer absence and/or generalized tonic–clonic seizures in addition to myoclonus. Valproate is the preferred treatment for otherwise healthy patients with juvenile myoclonic epilepsy, despite its association with side effects such as weight gain, edema, and hair loss [4]. The antiepileptic drug lamotrigine, like valproate, has a broad spectrum of efficacy against partial and generalized seizures in epilepsy [5]. Data from clinical practice and clinical studies suggest q
GlaxoSmithKline, maker of lamotrigine, funded the research described in this article. * Corresponding author. Fax: 1-414-385-8781. E-mail address: [email protected] (G.L. Morris). 1525-5050/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2004.04.002
that lamotrigine may be useful for some patients with juvenile myoclonic epilepsy [6–9]. For example, in a 12patient case series [6], seizures were controlled and valproate-associated side effects of weight gain, hair loss, and edema were mitigated or eliminated in patients with juvenile myoclonic epilepsy by switching from valproate to lamotrigine or by adding lamotrigine to a reduced valproate dose. Designed to extend these observations, this open-label study evaluated the tolerability and, secondarily, the efficacy of lamotrigine administered to patients with juvenile myoclonic epilepsy who had failed valproate therapy because of unacceptable side effects or inadequate seizure control.
2. Methods 2.1. Patients Patients at least 12 years of age with a diagnosis of juvenile myoclonic epilepsy supported by documented
510
G.L. Morris et al. / Epilepsy & Behavior 5 (2004) 509–512
clinical features and EEG data were eligible for the study if they had experienced at least one generalized motor seizure (classifiable by the International Classification of Seizures [10]) since diagnosis. Females were eligible only if they had a negative urine or serum pregnancy test at screening and agreed to use acceptable contraceptive methods during the study or were incapable of bearing children. Eligible patients were receiving valproate for juvenile myoclonic epilepsy and needed to discontinue it because of unacceptable side effects or inadequate seizure control or had previously received no therapy or inappropriate therapy for juvenile myoclonic epilepsy. Data from the latter group of patients are the subject of a separate publication (in preparation). The decision about whether patients qualified for the study on the basis of unacceptable side effects or ineffective seizure control was based on the investigatorÕs clinical judgment; no specific criteria were applied. Patients were excluded from the study if they had used any investigational drug within 4 weeks of initiation of the study or had been previously exposed to lamotrigine; were being treated with more than one antiepileptic drug; adhered to the ketogenic diet; had severe organic disease; had a history of alcohol or other drug abuse or dependence; or planned during the study period to undergo vagal stimulation or surgery to control seizures. All patients provided written, informed consent. 2.2. Procedures The protocol for this open-label study was approved by an institutional review board for each of the 18 US study sites. The study comprised a 2-week screening phase, during which eligibility was verified and baseline physical and seizure assessments were obtained; a doseescalation phase lasting up to 8 weeks, during which lamotrigine dose was increased while concurrent valproate was tapered; and a 24-week treatment phase, during which lamotrigine monotherapy was maintained. For the dose-escalation phase, lamotrigine (as 25 and 100 mg Lamictal tablets) was started at a dose of 25 mg every other day and increased, at the investigatorsÕ judgment based on patientsÕ clinical response, to minimum and maximum maintenance doses of 100 and 500 mg/day, respectively. Concomitant valproate was gradually discontinued after Week 5 of the dose-escalation phase at a rate determined by the investigators. The treatment phase began when patients had achieved an initial maintenance dose of lamotrigine monotherapy. Lamotrigine dose could be adjusted during the treatment phase to achieve optimal therapeutic response. Clinic visits to review seizure diaries and adverse events (defined as any untoward medical occurrence regardless of its suspected cause) occurred during the screening phase and on Treatment Weeks 1, 12, and 24. On Week 24, investigators rated patientsÕ global clinical
status and their seizure frequency, seizure duration, seizure intensity, adverse events, social functioning, intellectual functioning, and motor functioning as markedly, moderately, or mildly deteriorated; not changed; or markedly, moderately, or mildly improved. Patients rated their satisfaction with lamotrigine therapy as much better than, somewhat better than, the same as, somewhat worse than, or much worse than valproate therapy. During the dose-escalation and treatment phases, patients or their parents/guardians recorded in diaries the number of days with myoclonus and the number of seizures (by seizure type). Seizure frequency was also retrospectively determined for the 3 months prior to the first screening visit to obtain a baseline against which to compare effects of lamotrigine. All data were summarized using descriptive statistics; no formal statistical analyses were performed.
3. Results Sixty-three patients enrolled in the study and received at least one dose of lamotrigine. The numbers of patients qualifying for the study because of ineffective seizure control and unacceptable side effects were 11 and 52, respectively. All 63 patients were included in the demographic and tolerability summaries. Patient disposition is shown in Fig. 1. All patients completing the study (n ¼ 30) were included in the efficacy summaries. The majority of patients were female (73%) and white (81%). PatientsÕ mean age was 29.3 years. Median number of seizures per month during the 3 months prior to study entry was 1.8; median number of days per month with myoclonic seizures was 6. During the treatment phase, the mean lamotrigine monotherapy maintenance dose was 314 mg/day.
Fig. 1. Patient disposition.
G.L. Morris et al. / Epilepsy & Behavior 5 (2004) 509–512
During lamotrigine treatment, study medication-related adverse events that occurred at an incidence of at least 10% were headache (21%), dizziness (17%), tremor (11%), and rash (10%). Adverse events considered by the investigator to be related to study medication led to the discontinuation of 13 patients—5 for nonserious rash, and 1 each for dizziness; headache; hand clenching, loss of coordination, and headache; epigastric pain and diarrhea; increased frequency of auras; insomnia, vomiting, and increased seizure severity; dizziness, tremor, and blurred vision; and increased seizure activity. Six patients discontinued because of adverse events considered not drug-related. Investigators judged that 67% of completing patients had shown mild, moderate, or marked improvement in global clinical status during lamotrigine therapy; 23% had no change; and 10% had mild, moderate, or marked deterioration. Approximately one-third to two-thirds of patients were judged to be mildly, moderately, or markedly improved on adverse events (n ¼ 15, 50%), intellectual function (n ¼ 14, 47%), motor function (n ¼ 13, 43%), social function (n ¼ 18, 60%), seizure duration (n ¼ 11, 37%), seizure frequency (n ¼ 14, 46%), and seizure intensity (n ¼ 13, 43%). The percentages of patients judged to have no change in these parameters were 40% for adverse events, 43% for intellectual function, 53% for motor function, 37% for social function, 53% for seizure duration, 40% for seizure frequency, and 50% for seizure intensity. The percentages of patients judged to have mildly, moderately, or markedly deteriorated in these parameters were 10% for adverse events, 10% for intellectual function, 3% for motor function, 3% for social function, 10% for seizure duration, 134% for seizure frequency, and 76% for seizure intensity. The majority of patients completing the study rated lamotrigine as somewhat better or much better than valproate (Fig. 2). The majority of patients completing the study experienced no deterioration in seizure control when switched from valproate to lamotrigine (Fig. 3). Over
Fig. 2. Patient global assessments of lamotrigine monotherapy (n ¼ 30).
511
Fig. 3. Summary of change from baseline in seizure frequency in patients completing the study.
the lamotrigine treatment period, the percentages of patients with at least a 50% reduction from prestudy baseline in days with generalized tonic–clonic seizures, myoclonus, or absence seizure types were 50, 52, and 82%, respectively (Fig. 3). Few patients experienced clinically relevant increases in myoclonus or absence seizure types (Fig. 3). Of the 9 patients who entered the study seizure-free (any seizure type), 6 remained seizurefree during the treatment phase. Of the 13 patients who entered the study myoclonus-free, 9 remained free of myoclonic seizures during the treatment phase. Of the 20 patients who entered the study free of absence seizures, 20 remained free of absence seizures during the treatment phase.
4. Discussion The results of this study suggest that lamotrigine monotherapy is a possible alternative to valproate among patients with juvenile myoclonic epilepsy experiencing unacceptable side effects or inadequate seizure control with valproate monotherapy. The efficacy data, which should be interpreted cautiously because of the open-label design and the small sample size, suggest that conversion to lamotrigine is associated with improvements in seizure control as reflected by seizure frequency and investigator assessment of patientsÕ clinical status. These data are consistent with previous reports [6–11] including results of a recent retrospective study of 72 consecutively treated patients with juvenile myoclonic epilepsy [11]. In that study, which unlike the current one did not limit enrollment to patients refractory to or experiencing unacceptable side effects with valproate, seizure outcome did not differ between the groups receiving valproate monotherapy (n ¼ 36) and lamotrigine monotherapy (n ¼ 14) or between the groups receiving
512
G.L. Morris et al. / Epilepsy & Behavior 5 (2004) 509–512
valproate polytherapy (n ¼ 22) and lamotrigine polytherapy (n ¼ 21). The authors concluded that lamotrigine is an effective alternative to valproate in the treatment of juvenile myoclonic epilepsy. The finding that lamotrigine is an effective replacement for valproate is encouraging in light of the tolerability profile of lamotrigine. In the patients completing the study, investigators considered adverse events to have mildly, moderately, or markedly improved in 50% of patients. The most common adverse events attributed to lamotrigine were nonserious rash, headache, dizziness, and tremor. Most patients completing the study experienced no deterioration in seizure control when switched from valproate to lamotrigine. These findings corroborate previous reports from clinical practice and small clinical studies of lamotrigine after valproate failure in juvenile myoclonic epilepsy [6–9]. This study has several shortcomings, one of which is its open-label design. Success with lamotrigine may be a result of the displeasure with valproate in that valproate-associated side effects might lead the patient and physician to conclude that any treatment was better. A control group would be difficult and may be unethical as it would expose patients to risk of injury [12]. A second limitation of the study is the use of retrospective baseline data. Seizure counts from memory may be inaccurate and may under- or overestimate seizure frequencies. Days with myoclonus are likely to be underreported because of the lack of disturbance they create. Tonic– clonic seizures may be more likely than other seizure types to be recalled. Another disadvantage of the study design was that the patients enrolled had already failed at least one antiepileptic drug and may have been refractory to treatment. Also, efficacy analyses in this study were not subject to formal statistical analysis, and they were based on patients completing the study. The latter group comprised less than 50% of the patients enrolled. This limitation notwithstanding, the finding that only two patients withdrew from the study because of lack of efficacy is consistent with the possibility that the sample of patients completing the study was representative of the intent-to-treat population in terms of therapeutic response to lamotrigine. Juvenile myoclonic epilepsy is a lifelong disorder requiring chronic drug therapy; approximately 90% of patients relapse if antiepileptic medication is withdrawn [13]. Ideally, drug therapy for juvenile myoclonic epilepsy is effective and well-tolerated throughout the life span. Lamotrigine as monotherapy or adjunctive therapy has been demonstrated as a first-line option for partial and generalized seizures in children, adolescents, adults, and elderly patients with epilepsy [5,14,15]. The results of this study support additional research on
lamotrigine in juvenile myoclonic epilepsy in more rigorous, double-blind, randomized clinical trials.
Acknowledgments The authors thank Jane Saiers, Ph.D., for assistance with writing the manuscript. The following investigators participated in the study: Kenneth Askin (Charlotte, NC), Ricardo Ayala (Tallahassee, FL), Victor Biton (Little Rock, AK), Enrique Carrazana (Miami, FL), Deborah Combs-Cantrell (Irving, TX), Jose Cavazos (Denver, CO), OÕNeill Francis DÕCruz (Chapel Hill, NC), Paul McCabe (Hershey, PA), Thomas Perkins (Raleigh, NC), Phillip Riback (Albany, NY), Joel Rutman (San Antonio, TX), Steven Schachter (Boston, MA), James Schimschock (Portland, OR), Michael Sperling (Philadelphia, PA), William Tatum (Tampa, FL).
References [1] Gr€ unewald RA, Panayiotopoulos CP. Juvenile myoclonic epilepsy: a review. Arch Neurol 1993;50:594–8. [2] Panayiotopoulos CP, Obeid T, Tahan AR. Juvenile myoclonic epilepsy: a 5-year prospective study. Epilepsia 1994;35:285–96. [3] Pedersen SB, Petersen KA. Juvenile myoclonic epilepsy: clinical and EEG features. Acta Neurol Scand 1998;97:160–3. [4] Karceski S, Morrell M, Carpenter D. The expert consensus guideline series: treatment of epilepsy. Epilepsy Behav 2001;2:A1– A50. [5] Matsuo F. Lamotrigine. Epilepsia 1999;40(Suppl 5):S30–6. [6] Buchanan N. The use of lamotrigine in juvenile myoclonic epilepsy. Seizure 1996;5:149–51. [7] Sharpe C, Buchanan N. Juvenile myoclonic epilepsy: diagnosis, management and outcome. Med J Aust 1995;162:133–4. [8] Gericke CA, Picard F, de Saint-Martin A, et al. Efficacy of lamotrigine in idiopathic generalized epilepsy syndromes: a videoEEG-controlled, open study. Epileptic Disord 1999;1:159–65. [9] Timmings PL, Richens A. Efficacy of lamotrigine as monotherapy in juvenile myoclonic epilepsy: pilot study results. Epilepsia 1993;34(Suppl 2):160. [10]Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1989;30:389–99. [11] Prasad A, Kuzniecky RI, Knowlton RC, et al. Evolving antiepileptic drug treatment in juvenile myoclonic epilepsy. Arch Neurol 2003;60:1100–5. [12] Chadwick D. Monotherapy clinical trials of new antiepileptic drugs: design, indications, and controversies. Epilepsia 1997;38(Suppl 9):S16–20. [13] Janz D. Epilepsy with impulsive petit mal (juvenile myoclonic epilepsy). Acta Neurol Scand 1985;72:449–59. [14] Messenheimer J. Efficacy and safety of lamotrigine in pediatric patients. J Child Neurol 2002;17(Suppl 2):2S34–42. [15] Messenheimer J, Mullens EL, Giorgi L, et al. Safety review of adult clinical trial experience with lamotrigine. Drug Saf 1998;18:281–96.