Jeavons syndrome - Wiley Online Library

10 downloads 10501 Views 651KB Size Report
Epilepsy Center, Department of Neurological Sciences, Federico II University, Napoli, Italy; †Muscular and .... EMA therapy is disappointing in many patients (Apple- ton et al., 1993; Giannakodimos ..... Dev Med Child Neurol 19:3–8. Epilepsia ...
Epilepsia, 49(3):425–430, 2008 doi: 10.1111/j.1528-1167.2007.01524.x

FULL-LENGTH ORIGINAL RESEARCH

A pilot trial of levetiracetam in eyelid myoclonia with absences (Jeavons syndrome) ∗

†Pasquale Striano, ‡Vito Sofia, §Giuseppe Capovilla, ¶Guido Rubboli, §Carlo Di Bonaventura, ∗ Antonietta Coppola, ‡Giuseppina Vitale, #Luis Fontanillas, $Anna Teresa Giallonardo, ‡Roberto Biondi, #Antonino Romeo, #Maurizio Viri, †Federico Zara, and ∗ Salvatore Striano ∗

Epilepsy Center, Department of Neurological Sciences, Federico II University, Napoli, Italy; †Muscular and Neurodegenerative Disease Unit, Institute “G. Gaslini,” Genova, Italy; ‡Epilepsy Center, Department of Neurosciences, University of Catania, Catania, Italy; §Department of Child Neuropsychiatry, “C. Poma” Hospital, Mantova, Italy; ¶Department of Neurosciences, Bellaria Hospital, Bologna, Italy; #Epilepsy Center, Department of Child Neuropsychiatry, Fatebenefratelli e Oftalmico Hospital, Milano, Italy; and $Department of Neurological Sciences, “La Sapienza” University, Roma; Italy

SUMMARY Objective: Eyelid myoclonia with absences (EMA) or Jeavons syndrome characterized by eyelid myoclonia (EM) (with or without absences), eye closure-induced EEG paroxysms, and photosensitivity. We conducted an open-label trial of levetiracetam in EMA. Patients and Methods: Patients were recruited in different Italian Epilepsy Centres. Levetiracetam was administrated at starting dose of 10 mg/kg/day up to 50–60 mg/kg/day in two doses. Treatment period included a 5–6 week up-titration phase and a 12-week evaluation phase. The number of days with EM (i.e., days with seizures, DwS) and number of generalized tonic–clonic seizures (GTCS) were evaluated. Analysis of intent-to-treat population was performed using Fisher’s and Wilcoxon tests. Results: Thirty-five patients (23 F) with a mean age of 19 ± 6 years were recruited. Twenty-seven had previously undergone one to five adequate tri-

Eyelid myoclonia with absences (EMA) or Jeavons syndrome is a generalized form of epilepsy first described by Jeavons in 1977 (Jeavons, 1977). It is clinically characterized by the triad of eyelid myoclonia with or without Accepted November 26, 2007; Online Early publication December 18, 2007. Address correspondence to Dr. Pasquale Striano, M.D., Ph.D., Muscular and Neurodegenerative Disease Unit, Institute G. Gaslini, Genova; Epilepsy Center, Federico II University, Napoli, Italy. E-mail: [email protected] Blackwell Publishing, Inc.  C 2008 International League Against Epilepsy

als of antiepileptic drugs. The median number of DwS/month was 12 ± 8.2. Twenty-one patients experienced GTCS (median number/month: 1 ± 0.2). Thirty-four subjects completed the trial. Levetiracetam was well tolerated (mean dose: 1985 mg/day). Responders were 28/35 (80%) patients, nine taking levetiracetam as monotherapy. Six patients were seizure-free, 15 had ≥75% and seven >50% seizure reduction. GTCS remitted in 14 out of 21 (66.6%) patients. The number/month of DwS (median: 12 vs 5; p = 0.0001) and of GTCS (median: 1 vs 0; p = 0.0001) decreased compared to baseline period. Disappearance or clear reduction in paroxysmal abnormalities at eye closure occurred in 20 of the responders and photoparoxysmal response in 19. Mean follow-up was 23.9 ± 18.5 months. Conclusion: Levetiracetam is effective and well tolerated in EMA. Placebo-controlled studies should confirm these findings. KEY WORDS: Levetiracetam, EMA, Jeavons syndrome, Epilepsy, AEDs.

absences, eye closure-induced seizures with EEG paroxysms, and photosensitivity (Appleton et al., 1993; Giannakodimos & Panayiotopoulos, 1996; Panayiotopoulos et al., 1996; Incorpora et al., 2002; Striano et al., 2002; Destina Yalcin et al., 2006; Sevgi et al., 2007). Typical onset of EMA is in childhood, with a peak around 8 years of age (range: 2–14) and a preponderance among girls. Eyelid myoclonia (EM), not the absences, are the hallmark of the syndrome and consist of marked jerking of the eyelids often associated with jerky upward deviation of the eyeballs and retropulsion of the head. These seizures are

425

426 P. Striano et al. brief (3–6 ) and occur mainly after eye closure and consistently many times per day (Appleton et al., 1993; Giannakodimos & Panayiotopoulos, 1996; Panayiotopoulos et al., 1996; Striano et al., 2002). EM may be associated with or followed by mild impairment of consciousness (EM with absences). Photosensitivity is almost invariably present, although its clinical and EEG expressivity usually decreases with age and can be modified by antiepileptic drugs (AEDs) (Appleton et al., 1993; Giannakodimos & Panayiotopoulos, 1996; Panayiotopoulos et al., 1996; Incorpora et al., 2002; Striano et al., 2002; Sevgi et al., 2007). Generalized tonic–clonic seizures (GTCS), either light induced or spontaneous, occur in most patients in the long term (Giannakodimos & Panayiotopoulos, 1996; Panayiotopoulos et al., 1996; Striano et al., 2002). Lifestyle and avoidance of seizure precipitants are important to achieve seizure control in some cases and nonpharmacological treatments used for photosensitive patients (e.g., wearing special glasses) often have a beneficial effect (Appleton et al., 1993; Panayiotopoulos et al., 1996). The more commonly used AEDs in EMA are valproate, ethosuximide, benzodiazepines, and phenobarbital. However, EMA therapy is disappointing in many patients (Appleton et al., 1993; Giannakodimos & Panayiotopoulos, 1996; Panayiotopoulos et al., 1996; Richens, 1996; Striano et al., 2002). Levetiracetam is a new AED with a unique preclinical profile and mechanism of action and has been demonstrated to be effective in both adults and children with focal and generalized epilepsy, with good pharmacokinetics and tolerability profile (Lynch et al., 2004; Glauser et al, 2006). A number of studies have shown that levetiracetam is effective in refractory juvenile myoclonic epilepsy (Specchio et al., 2006; UCB/N166 study), severe myoclonic epilepsy of infancy (Dravet syndrome) (Striano et al., 2007), and in idiopathic generalized epilepsies (IGEs) with uncontrolled tonic–clonic seizures (Berkovic et al., 2007). Of the newer AEDs, levetiracetam may be potentially very useful in EMA, particularly because of its well-known antimyoclonic properties (Gelisse et al., 2003; Crest et al., 2004; Magaudda et al., 2004; Specchio et al., 2006; Striano et al., 2005). The use of levetiracetam in EMA has been previously reported only in two subjects from a series of IGEs with significant seizure reduction in one patient and no change in seizure frequency in another one (Di Bonaventura et al., 2005). We conducted a multicenter, open-label prospective trial to evaluate the efficacy and the safety of orally administrated levetiracetam in a large series of EMA patients.

PATIENTS AND M ETHODS Patient population Patients were recruited in an open-label study from six different Italian epilepsy centers with the following incluEpilepsia, 49(3):425–430, 2008 doi: 10.1111/j.1528-1167.2007.01524.x

sion criteria (Striano et al., 2002; Capovilla et al., 2006): EM (with or without absences) associated to EEG generalized paroxysmal activity, triggered by eye-closure and intermittent photic stimulation (IPS); parents or caregivers able to comply regularly with drug therapy and seizure diary. Concomitant occurrence of acute medical illness or previous exposure to levetiracetam were exclusion criteria. Information about the type and the dosage of previously administered AEDs were carefully collected. Patients were considered to be drug-resistant if at least one previous adequate trial of AEDs did result in any significant clinical improvement or intolerable side effects. The study was conducted according to the Declaration of Helsinki criteria and no pharmaceutical support was obtained. The study was approved by the Institutional Ethics Committees and informed consent was required of the parents. Family and personal history were taken and neurological examinations performed in all patients. Study design This open-label trial contained an 8-week baseline period. Concomitant medications remained at unchanged doses for at least 2 months prior to study entry and throughout the duration of the study. Levetiracetam was administrated at a starting dose of approximately 10 mg/kg/day followed by 10 mg/kg/day increments at 1-week intervals up to the dose of 50–60 mg/kg/day given in two divided doses. The titration phase included the week in which the target dose was reached. The treatment period was composed of a 5–6 week up-titration phase and a 12-week evaluation phase. Safety procedures Adverse events were recorded in a diary and levetiracetam was discontinued in the event of intolerable side effects or clear seizure aggravation (i.e., increased seizures number ≥ 50% from baseline). Moreover, neurological examinations together with complete peripheral blood count, urinary analysis and measurement of blood creatinine, alanine, and aminotrasferase levels were performed at the end of the titration phase and at the end of the trial. Clinical evaluation Number of days with EM (i.e., days with seizures, DwS) were recorded in a diary by patients or caregivers over an 8-week period before starting levetiracetam treatment. In addition, patients were asked to record GTCS. Responders were differentiated for category (i.e., >50%, ≥75% seizure reduction, and seizure-free). Patients experiencing ≤50% seizure reduction were considered as nonresponders. In addition to the daily seizure recording, prolonged video-EEG recordings, including repeated eye-closure and IPS (Striano et al., 1979; Striano et al., 2002), were performed before the trial, at the beginning of the evaluation period, and at the end of the trial for all subjects. After the

427 LEV in Jeavons Syndrome Table 1. Demographic and baseline characteristics of enrolled patients Variable No. of patients (M/F) Age, range (mean ± SD) years Epilepsy onset, range (mean ± SD) years No. previous AEDs, range (mean) (27 pts) No. concomitant AEDs, range (mean) (24 pts) Median DwS/month at baseline Median number/month of GTCS at baseline

35 (12/23) 8–30 (19 ± 6) 0.11–17 (9.8 ± 3.6) 1–5 (1.9) 1–2 (1.08) 12 ± 8.2 1 ± 0.2

AEDs, antiepileptic drugs; DwS, days with seizures; GTCS, generalized tonic–clonic seizures.

end of the trial, patients entered an observational extension study. Statistical analysis The intent-to-treat population included subjects who took at least one dose of levetiracetam. Statistical analysis was performed using Fisher’s exact and c with MedCalc software (MedCalc, Mariakerke, Belgium).

R ESULTS

Figure 1. Response of eyelid myoclonia to levetiracetam at the end of the trial compared to the baseline period. C ILAE Epilepsia 

During the baseline period, the median number of DwS/month was 12 ± 8.2. In addition, 21 (60%) patients experienced GTCS with a median number/month of 1 ± 0.2.

Patient population Thirty-five patients (23 F, 12 M), aged 8–30 years (mean, 19 ± 6), entered the study. Their baseline demographic and seizure characteristics are summarized in Table 1. Mean age at epilepsy onset was 9.8 ± 3.6 years (range: 11 months to 17 years). Twenty-seven of the 35 patients had previously undergone 1–5 (mean, 1.9) adequate trials of AEDs before the levetiracetam treatment and were considered to be drug-resistant. At the beginning of the trial, 22 patients were taking one AED and two were on bitherapy. The concomitant AEDs are shown in Table 2. Eleven participants were not receiving any AED and started levetiracetam as monotherapy. These included four newly diagnosed patients and seven by which therapy had been never accepted (one subject) or spontaneously withdrawal (six subjects) at least 1 year before levetiracetam trial.

Efficacy Thirty-four (97.1%) participants completed the trial. The mean levetiracetam dose achieved was 1985 mg/day (range: 1,000–4,000). At the end of the trial, 28/35 (80%) were responders, nine taking levetiracetam as monotherapy. Six patients were seizure free, 15 patients had ≥75% and seven >50% reduction in EM seizure (Fig. 1). In addition, GTCS remitted in 14 out of 21 (66.6%) patients. Overall, the number per month of DwS (median: 12 vs 5; p = 0.0001) and of GTCS (median: 1 vs 0; p = 0.0001) was decreased compared to baseline period (Table 3). Effect of levetiracetam was not related to sex (p = 0.67), age of onset (p = 0.79), duration of epilepsy (p = 0.31) and concomitant AEDs (p = 0.29). Moreover, there was no significant difference (p = 0.63) between patients who received

Table 2. Antiepileptic drugs (AEDs) concomitant to levetiracetam therapy

Table 3. Effect of levetiracetam treatment on seizure frequency

AEDs

No.

%

Valproate Phenobarbital Primidone Lamotrigine Topiramate Ethosuximide

17 3 2 2 1 1

70.8 12.5 8.3 8.3 4.1 4.1

Levetiracetam treatment Before After p-value∗ ∗

Median seizure number per month Eyelid myoclonia

GTCS

12 5 p = 0.0001

1 0 p = 0.0001

Wilcoxon test.

Epilepsia, 49(3):425–430, 2008 doi: 10.1111/j.1528-1167.2007.01524.x

428 P. Striano et al.

Figure 2. A–D. CDL, female, 19 years: before levetiracetam treatment, eye closure induced generalized paroxysmal activity (A) which was not evident on levetiracetam therapy (B). SM, female, 16 years: EEG recordings showing changes of photoparoxysmal response induced by intermittent photic stimulation before (C) and during levetiracetam treatment (D). C ILAE Epilepsia  levetiracetam in monotherapy and those who received the drug as adjunctive treatment. Video-EEG recordings revealed disappearance or improvement in paroxysmal response (i.e., a decline of more than 50% in the paroxysmal activity) upon eye closure in 20 and in photoparoxysmal response (i.e., disappearance or reduction from type IV to I–II; Kasteleijn-Nolst Trenite et al., 1999) in 19 of the responders, respectively (Fig. 2A– D). Photoparoxysmal response also improved in one of the nonresponders. Tolerability During the titration phase, one (2.8%) child withdrew because of severe diarrhea. Levetiracetam was well tolerated by patients who completed the study. Four subjects experienced transitory agitation or irritability; mild sleepiness or sedation occurred in three, and headache in one patient during the titration Epilepsia, 49(3):425–430, 2008 doi: 10.1111/j.1528-1167.2007.01524.x

phase. There were no significant changes in lab test values at the end of the trial. Follow-up duration To date, all patients who completed the trial are still on levetiracetam (mean follow-up: 23.9 ± 18.5 months; range: 8–45).

D ISCUSSION Although first described in 1977 and widely reported by several authors within the last few years (Giannakodimos & Panayiotopoulos, 1996; Panayiotopoulos et al., 1996; Incorpora et al., 2002; Striano et al., 2002; Sevgi et al., 2007), EMA has not been yet recognized as a definite epileptic syndrome by the ILAE whereas EM with or without absences has been proposed as new seizure type (Engel, 2001). However, when strict criteria are applied to the diagnosis, EMA appears to be a distinctive

429 LEV in Jeavons Syndrome condition that should be considered a myoclonic epileptic syndrome with myoclonia limited to eyelids, rather than an epileptic syndrome with absences (Appleton et al., 1993; Giannakodimos & Panayiotopoulos, 1996; Panayiotopoulos et al., 1996; Striano et al., 2002). EMA is a life-long disorder and its prognosis is similar to that of juvenile myoclonic epilepsy with photosensitivity (Giannakodimos & Panayiotopoulos, 1996; Panayiotopoulos et al., 1996). As there has been no trial of AEDs, pharmacological therapy in EMA is based on a few anecdotal reports generally suggesting a combination of valproate, ethosuximide, and benzodiazepines. Phenobarbital is also used to control GTCS (Appleton et al., 1993; Giannakodimos & Panayiotopoulos, 1996; Panayiotopoulos et al., 1996; Richens, 1996; Striano et al., 2002). Some AEDs, such as carbamazepine, vigabatrin, and phenytoin may aggravate the clinical picture and are not indicated; insufficient data are available for lamotrigine (Giannakodimos & Panayiotopoulos, 1996; Panayiotopoulos et al., 1996). There is nowadays a large body of evidence that levetiracetam is effective in various conditions featuring chronic myoclonus including progressive myoclonus epilepsies (Gelisse et al., 2003; Crest et al., 2004; Magaudda et al., 2004; Striano et al., 2005) as well as other welldefined myoclonic epileptic syndromes (Specchio et al., 2006; Striano et al., 2007; UCB/N166 study). In this trial of LEV in EMA we demonstrated that the drug is effective at a target dose of 50–60 mg/kg/day given in mono or adjunctive therapy showing good efficacy on EM but also on GTCS. In addition, our results suggest that levetiracetam should not necessarily be used only when the other AEDs fail but could be also considered in selected cases as first-line drug in EMA patients. Although some patients experienced mild and transient side effects predominantly occurring during the initial phase of treatment, levetiracetam was overall well tolerated in line with its generally reported good tolerability profile (Glauser et al, 2006; Specchio et al., 2006; Berkovic et al., 2007; Striano et al., 2007) and all patients who completed the trial are still on levetiracetam. The effect of AEDs on EEG abnormalities should be assessed by specific studies. Notably, the correlation between EEG changes and treatment outcome after levetiracetam trial was not primarily explored in this trial. However, we observed an improvement in EEG paroxysmal response either to eye closure or photosensitivity in most of the responders, in line with that reported in previous studies (Kasteleijn-Nolst Trenite et al, 1996; Gallagher et al., 2004; Striano et al., 2007). The results of this trial should be regarded as preliminary and be interpreted with caution due to the open-label design and the limited follow-up. The limits of the uncontrolled trial include a possible “Hawthorne effect” (i.e., the general idea that results of a trial may be affected by

subjects’ awareness of participating in the trial itself) and lack of systematic intervention. Nevertheless, the significant reduction in seizures in 80% of patients from our series suggests that levetiracetam is a promising and easyto-test drug in this epileptic syndrome and further broadens the efficacy spectrum of this AED. Larger randomized placebo-controlled studies should confirm these data. Furthermore, the investigation of the effect of AEDs in a specific epileptic syndrome is an interesting approach aimed to identify new subgroups of patients who respond to a drug.

ACKNOWLEDGMENTS We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The authors thank Dr Judith Martin for editing the manuscript and Dr Bruno Ferr`o for the helpful comments. We also thank Dr Amedeo Bianchi and the Italian League Against Epilepsy (LICE) for supporting the research on EMA. Conflict of interest: The authors have no conflicts of interest to declare.

R EFERENCES Appleton E, Panayiotopoulos CP, Acomb BA and Beirne M. (1993) Eyelid myoclonia with typical absences: an epilepsy syndrome. J Neurol Neurosurg Psychiatry 56:1312–1316. Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U; on behalf of the Levetiracetam N01057 Study Group. (2007) Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology 69:1751–1760. Capovilla G, Rubboli G, Striano S, Zara F. (2006) Study proposal of electroclinical features in eyelid myoclonia with absences (EMA). Italian League Against Epilepsy (LICE) Website (http://www.lice.it/commissioni/genetica/comunicazioni.html#2). Crest C, Dupont S, Leguern E, Adam C, Baulac M. (2004) Levetiracetam in progressive myoclonic epilepsy: an exploratory study in 9 patients. Neurology 62:640–643. Destina Yalcin A, Forta H, Kilic E. (2006) Overlap cases of eyelid myoclonia with absences and juvenile myoclonic epilepsy. Seizure 15:359–365. Di Bonaventura C, Fattouch J, Mari F, Egeo G, Vaudano AE, Prencipe M, Manfredi M, Giallonardo AT. (2005) Clinical experience with levetiracetam in idiopathic generalized epilepsy according to different syndrome subtypes. Epileptic Disord 7:231–235. Engel J Jr. (2001) A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE task force on classification and terminology. Epilepsia 42:796–803. Gallagher MJ, Eisenman LN, Brown KM, Erbayat-Altay E, Hecimovic H, Fessler AJ, Attarian HP, Gilliam FG. (2004) Levetiracetam reduces spike-wave density and duration during continuous EEG monitoring in patients with idiopathic generalized epilepsy. Epilepsia 45:90–91. Gelisse P, Crespel A, Genton P, Baldy-Moulinier M. (2003) Dramatic effect of levetiracetam on epileptic negative myoclonus. Acta Neurol Scand 107:302–303. Giannakodimos S, Panayiotopoulos CP. (1996) Eyelid myoclonia with absences in adults: a clinical and video-EEG study. Epilepsia 37:36– 44. Glauser TA, Ayala R, Elterman RD, Mitchell WG, Van Orman CB, Gauer LJ, Lu Z; N159 Study Group. (2006) Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 66:1654–1660. Incorpora G, Sofia V, Pavone P, Biondi R, Barone B, Parano E. (2002). Clinical heterogeneity in eyelid myoclonia, with absences, and epilepsy. Eur J Pediatr 161:175–177. Jeavons PM. (1977) Nosological problems of myoclonic epilepsies in childhood and adolescence. Dev Med Child Neurol 19:3–8. Epilepsia, 49(3):425–430, 2008 doi: 10.1111/j.1528-1167.2007.01524.x

430 P. Striano et al. Kasteleijn-Nolst Trenite DG, Marescaux C, Stodieck S, Edelbroek PM, Oosting J. (1996) Photosensitive epilepsy: a model to study the effects of antiepileptic drugs. Evaluation of the piracetam analogue, levetiracetam. Epilepsy Res 25:225–230. Kasteleijn-Nolst Trenite DG, Binnie CD, Harding GF, Wilkins A, Covanis T, Eeg-Olofsson O, Goosens L, Henriksen O, Kr¨amer G, Leyten F, Da Silva FH, Da Silva AM, Naquet R, Pedersen B, Ricci S, Rubboli G, Spekreijse H, Waltz S. (1999) Medical technology assessment photic stimulation–standardization of screening methods. Neurophysiol Clin 29:318–324. Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, Fuks B. (2004) The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA 101:9861–9866. Magaudda A, Gelisse P, Genton P. (2004) Antimyoclonic effect of levetiracetam in 13 patients with Unverricht-Lundborg disease: clinical observations. Epilepsia 45:678–681. Panayiotopoulos CP, Agathonikou A, Koutroumanidis M, Giannakodimos S, Rowlinson S, Carr CP. (1996) Eyelid myoclonia with absences: the symptoms. In Duncan JS, Panayiotopoulos CP (Eds) Eyelid myoclonia with absences, John Libbey Ltd, London, pp. 17–26. Richens A. (1996) Treatment of eyelid myoclonia with absences. In Duncan JS, Panayiotopoulos CP (Eds) Eyelid myoclonia with absences, John Libbey Ltd, London, pp. 17–26.

Epilepsia, 49(3):425–430, 2008 doi: 10.1111/j.1528-1167.2007.01524.x

Sevgi EB, Saygi S, Ciger A. (2007) Eye closure sensitivity and epileptic syndromes: a retrospective study of 26 adult cases. Seizure 16:17–21. Specchio LM, Gambardella A, Giallonardo AT, Michelucci R, Specchio N, Boero G, La Neve A. (2006) Open label, long-term, pragmatic study on levetiracetam in the treatment of juvenile myoclonic epilepsy. Epilepsy Res 71:32–39. Striano S, Fels A, Vacca G, Cardona AM. (1979) Epileptic seizures on closing the eyes and upon the sudden disappearance of light. Acta Neurol (Naples) 34:443–451. Striano S, Striano P, Nocerino C, Boccella P, Bilo L, Meo R, Ruosi P. (2002) Eyelid myoclonia with absences: an overlooked epileptic syndrome? Neurophysiol Clin 32:287–296. Striano P, Manganelli F, Boccella P, Perretti A, Striano S. (2005) Levetiracetam in patients with cortical myoclonus: a clinical and electrophysiological study. Mov Disord 20:1610–1614. Striano P, Coppola A, Pezzella M, Ciampa C, Specchio N, Ragona F, Mancardi MM, Gennaro E, Beccaria F, Capovilla G, Rasmini P, Besana D, Coppola GG, Elia M, Granata T, Vecchi M, Vigevano F, Viri M, Gaggero R, Striano S, Zara F. (2007) An open-label trial of levetiracetam in severe myoclonic epilepsy of infancy. Neurology 69:250– 254. UCB/N166 study. Levetiracetam as Add-on Treatment of Myoclonic Jerks in Adolescents + Adults. Available at ClinicalTrials.gov (http://clinicaltrials.gov/show/NCT00150774).