- Email: [email protected]
Zonisamide for refractory juvenile absence epilepsy
Accepted Manuscript Title: Zonisamide for Refractory Juvenile Absence Epilepsy Author: Reana Velizarova Arielle Crespel Pierre Genton Anna Serafini Philippe Gelisse PII: DOI: Reference:
S0920-1211(14)00126-0 http://dx.doi.org/doi:10.1016/j.eplepsyres.2014.04.010 EPIRES 5145
To appear in:
Epilepsy Research
Received date: Revised date: Accepted date:
19-1-2014 31-3-2014 27-4-2014
Please cite this article as: VELIZAROVA, R., CRESPEL, A., GENTON, P., SERAFINI, A., GELISSE, P.,Zonisamide for Refractory Juvenile Absence Epilepsy, Epilepsy Research (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.04.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Zonisamide for Refractory Juvenile Absence Epilepsy
Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France. Centre Saint Paul-H. Gastaut, Marseille, France.
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1 1 2 1 Reana VELIZAROVA, Arielle CRESPEL, Pierre GENTON, Anna SERAFINI, 1 Philippe GELISSE
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Address correspondence and reprint requests to Dr. Dr Philippe Gelisse, Epilepsy Unit, Hôpital Gui de Chauliac, 80 avenue Fliche, 34295 Montpellier cedex 05, France. Fax: +33 4 67 33 61 00; E-mail address [email protected]
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Character and word counts: Title: 51 characters including spaces and punctuation Abstract: 246 words. Paper: 1332 words (excluding references).
Figure: 0 Table: 1 References: 11
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Page 1 of 15
Abstract
Purpose To examine the clinical effect of zonisamide (ZNS) in patients with drug-
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resistant Juvenile Absence Epilepsy (JAE). Methods Between 2006 and 2010, 13 JAE patients were successively treated with add-on
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ZNS. Safety and efficacy were assessed according to the patient and caregiver reports at
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visits every 3 months. Response rate was defined as a 50% or greater reduction in seizure frequency.
an
Results Mean age was 42 years. No patient had been seizure free for a period >12 months before ZNS. The mean follow-up was 34 months. The mean dosage of ZNS was
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388 mg. ZNS was effective for absence seizures (AS) in all patients (more than 50% AS reduction). Four patients reached seizure reduction on 550-600 mg/day. Three (23%) had
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a reduction in AS frequency > 75% and five (38,5%) between 50%-75%. Seizure
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freedom was achieved in five patients (38,5%) (3 patients with AS only and two with AS
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plus generalized tonic-clonic seizures (GTCS)). Before ZNS, four patients had AS evolving to absence status. After ZNS, three of them were in the seizure-free group, the later never experienced this type of complication. Among 7 patients with AS plus GTCS, two of them did not report any improvement in the frequency of GTCS (29%). Conclusion This observational post-marketing study confirms the broad-spectrum activity of ZNS that includes GTCS, myoclonic seizures and now AS. This study provides evidence that add-on ZNS is efficient and well tolerated in adult patients with refractory JAE, even at high doses.
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Keywords: Juvenile Absence Epilepsy; Zonisamide; Drug resistance; Absence seizures; Antiepileptic drugs
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Introduction Juvenile absence epilepsy (JAE) is an idiopathic generalized epilepsy (IGE) with onset around puberty. Seizures are typical absences in 100%, generalized tonic-clonic
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seizures (GTCS) in 80% and sporadic myoclonic jerks in 20%. JAE is estimated at
cr
around 10% of IGE and between 1.5-2% of all epilepsies (Gelisse et al., 2012). Valproate (VPA) is very effective in JAE; in case of side effects, or in women of childbearing age,
us
lamotrigine (LTG) can be used (Gelisse et al., 2012). Ethosuximide (ESM), a T-type calcium channel blocker is the drug of choice in chilhood absence epilepsy (Glauser et
an
al., 2013), but is not recommended in monotherapy in JAE due to existence of GTCS. JAE is not considered a severe condition but in some patients, absence seizures (AS) and
M
GTCS may resist first-line drugs. Experimental studies indicate that zonisamide (ZNS)
d
could be a blocker of T-type voltage-gated calcium channel (Mac Donald, 2002; Matar et
Ac ce p
JAE patients.
te
al., 2009). In this study, we examined the clinical effect of add-on ZNS in drug-resistant
Patients and Methods
All patients referred to the epilepsy Unit of Montpellier (tertiary center
specialized in epilepsy for adolescent and adults) were included prospectively since 2001 in a computerized database. Database includes the gender, the medical history, the type of epilepsy, the onset of seizures, the types and the frequency of seizures at each visit and the antiepileptic drugs. In our center, benign and easily treatable forms of epilepsy tend to
4
Page 4 of 15
be underrepresented.
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Between 2006 and 2010, of the 38 JAE patients, 13 (34%) (7 males, 6 females) were treated successively with ZNS in add-on therapy because they were difficult to
cr
control with other drugs. The diagnosis of JAE was based on the criteria of the
us
International Classification of Epilepsies (Comission, 1989). All patients had been treated at least once with VPA, LTG or ESM but these drugs were stopped in some patients
an
because of side effects or lack of efficacy. ZNS was started at 50 mg/day with increase of 50 mg every one or two weeks. The titration schedule was individualized for each patient
M
based on the tolerability. Safety and efficacy were assessed according to the patient and caregiver reports at visits every 3 months. Responders were defined as experiencing a
te
d
50% or greater reduction in seizure frequency. The total daily dose was adjusted for each patient according to the efficacy and tolerability. The maximal daily dose was 600
Ac ce p
mg/day.
Results
The demographic data and clinical characteristics of the patients are presented on
Table 1. Mean age of the patients at the time of inclusion in the study was 42 years (range 22-64 years). The mean age at onset of seizures was 15.6 years (range 5-35 years). The mean duration of epilepsy was 29.7 years (range 16-59). Before ZNS, the baseline frequency of GTCS was 1-2 annually in four (pat. 2-4, 8), monthly in two (pat. 6, 11),
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Page 5 of 15
and weekly in one (pat. 12). The AS frequency was monthly in 4 (pat. 2, 5, 13), weekly in 5 (pat. 1, 3, 4, 6, 8, 11) and daily in four (pat. 7, 9, 10, 12). Three patients had 3-4 episodes of absence status per year (pat 4, 5, 12), and one every month (pat. 9). No
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patient had been seizure-free before ZNS therapy for a period >12 months. One patient
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(Pat 10) had vagus nerve stimulation.
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The mean follow-up period was 34 months (range 22-51 months). ZNS was stopped in patient 7 after 24 months because of tremor in spite of reduction of AS
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frequency (> 50%). The other patients tolerated ZNS and the drug was continued. The
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mean dosage of ZNS was 388 mg/day (range 150-600 mg/day).
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ZNS was effective for AS in all patients (more than 50% absence reduction).
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Three (23%) had a reduction in AS frequency > 75% (pat. 2, 3, 13) and five (38.5%) between 50%-75% (pat. 6-8, 10, 12). Seizure freedom was achieved in five patients
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(38.5%) (3 patients with AS only (pat. 1, 5, 9) and two with AS plus GTCS (pat. 4, 11) with a mean follow-up of 30 months (range: 22 to 45 months). All patients with absence status before ZNS never experienced this type of complication after the introduction of the drug. After ZNS, three of them were in the seizure free group. The later had more than 50% seizure reduction and never experienced this type of complication. Among the 7 patients with AS plus GTCS, two of them did not report a decrease in the seizure frequency of GTCS (29%) (pat. 2, 6).
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Page 6 of 15
Patient 11 was treated in monotherapy with carbamazepine (CBZ) when he was referred because a wrong diagnosis of focal epilepsy was made. However, he was previously treated with valproate, ethosuximide, lamotrigine and phenobarbital but these
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drugs were not well tolerated and the patient continued to have frequent seizures. CBZ was proposed by his neurologist and was quite effective against GTCS during several
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months but reappeared progressively. AS were present every weeks. When ZNS was
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introduced, he became seizure free and CBZ was progressively stopped.
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Discussion
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JAE is not considered severe. The response to therapy is usually good,
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approximately 80% of cases become seizure-free with the traditional drugs such as
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ethosuximide and valproate (Gelisse et al., 2012). But in the study of Bartolomei et al. (1997), which included 27 cases of JAE, the results were not quite as good since GTCS or AS persisted in about 40% of the patients. This study was performed in a center specialized in epilepsy for children and adults with moderate or severe epilepsies. Our center is also specialized in difficult-to treat patients that explain why about one third of our JAE patients were not controlled with classical drugs. This is the reason why we choose to treat these patients with ZNS in add-on therapy.
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Page 7 of 15
ZNS is effective against focal seizures and GTCS in patients with localizationrelated epilepsy (Zaccara et al., 2009). Some reports suggest that ZNS may be effective in myoclonic epilepsies such as juvenile myoclonic epilepsy and progressive myoclonic
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epilepsies (Zaccara et al., 2009). Different studies have shown a positive effect in the
treatment of AS but these studies included heterogeneous group of patients with different
cr
types of generalized epilepsies and with a clear predominance of children (Zaccara et al.,
us
2009). The efficacy of ZNS on AS has been shown for the first time in a small series of patients in a prospective study (Yagi and Sieno, 1992). Later, Yamauchi and Aikawa
an
(2004) in their post-marketing surveillance study reported that the responder rate (proportion of patients with at least 50% seizure reduction) was 87.5% (n=8) for typical
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absences and 46.3% (n=54) for atypical absences. Wilfong and Schultz (2005) examined
d
efficacy of ZNS in a group of young patients (n=45) with AS and found remarkable
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absence reduction.
te
results. Seizure freedom achieved 51.1% of the patients and 35.5 % had more than 50%
Our population includes drug-resistant JAE patients with a long evolution. All had
been treated with adequate drugs for JAE at one time of their life with incomplete control. ZNS was given as an adjunctive therapy. All patients were responders, including more than 1/3 seizure free and 23% with at least 75% absence seizure reduction from baseline. The mean dosage of ZNS was 388 mg/day which is in agreement with the therapeutic dosage reported in other studies (Wilfong and Schultz, 2005; Ohtahara, 2006). Four of our patients reached seizure reduction on 550-600 mg/d ZNS, which is higher than the recommended dose of 500 mg/d. They did not report side effects.
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Page 8 of 15
In conclusion, ZNS may be used with benefit as add-on therapy in adult patients with refractory JAE. Patients treated with ZNS have a decrease in seizure frequency. Five
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patients became seizure-free and the patients with a history of absence status never experienced this type of seizure again. The tolerance was good even in patients treated
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with high doses. This observational post-marketing study confirms a broad spectrum
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activity of ZNS, also now against typical absences. Add-on ZNS can be used in JAE,
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even at high doses.
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Page 9 of 15
References
Bartolomei F, Roger J, Bureau M, Genton P, Dravet C, Viallat D, Gastaut JL. Prognostic
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factors for childhood and juvenile absence epilepsies. Eur Neurol 1997;37:169-75.
Commission on Classification and Terminology of the International League Against
us
Epilepsy: proposal for the classification of epilepsy and epileptic syndromes. Epilepsia
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1989;30:389-99.
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Gelisse P, Wolf P, Inoue Y. Juvenile absence epilepsy. In: Bureau M, Genton P, Dravet C, Delgado-Escueta A, Tassinari P, Thomas P, Wolf P (Eds). Epileptic Syndromes in
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Infancy, Childhood and Adolescence. 5th Ed. Montrouge: John Libbey Eurotext Ltd,
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2012:329-339.
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Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Adamson PC; Childhood Absence Epilepsy Study Team. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia 2013;54:141-55.
Mac Donald RL. Zonisamide: Mechanisms of action. In: Levy RH, Mattson RH, Meldrum BS, Perucca E. Antiepileptic drugs. 5th Ed. Philadelphia: Lippincott Williams & Wilkins 2002:838-851.
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Matar N, Jin W, Wrubel H, Hescheler J, Schneider T, Weiergraber M. Zonisamide block of cloned human T-type voltage-gated calcium channels. Epilepsy Res 2009;83:224-34.
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Ohtahara S. Zonisamide in the management of epilepsy-Japanese experience. Epilepsy
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Res 2006;68 (Suppl 2):25-33.
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Wilfong A, Schultz R. Zonisamide for absence seizures. Epilepsy Res. 2005;64:31-34.
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Yagi K, Seino M. Methodological requirements for clinical trials in refractory epilepsiesour experience with zonisamide. Prog Neuropsychopharmacol Biol Psychiatry
d
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1992;16:79-85.
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1):41-48.
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Yamauchi T, Aikawa H. Efficacy of zonisamide: our experience. Seizure 2004;13 (Suppl
Zaccara G, Specchio LM. Long-term safety and effectiveness of zonisamide in the treatment of epilepsy: a review of the literature. Neuropsychiatr Dis Treat 2009;5:249-59.
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Disclosure Dr Velizarova reports no conflicts of interest.
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Dr Crespel received support for teaching programs from Sanofi-Aventis, UCB, GSK and served as advisory board member for Eisai-France for zonisamide and presently serves as advisory board member for Eisai-France for perampenel.
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Dr Genton received speaker honoraria from Sanofi-Aventis, Novartis, GSK, Pfizer, Janssen-Cilag, UCB, Eisai and received support for teaching programs from SanofiAventis and UCB.
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Dr Serafini reports no conflicts of interest.
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Dr Gelisse received support for teaching programs from Sanofi-Aventis, UCB, Psicofarma. He received a research grant form the French League Against Epilepsy and the Janssen-Cilag company. He worked as consultant for Eisai-France in 2011.
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Individual contribution
Dr. Velizarova - Acquisition of data - Analysis and interpretation - Critical revision of the manuscript for important intellectual content
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Dr. Crespel- Study concept and design- Acquisition of data- Critical revision of the manuscript for important intellectual content
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Dr Serafini- Acquisition of data - Analysis and interpretation
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Dr. Genton- Critical revision of the manuscript for important intellectual content
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Dr Gelisse- Study concept and design - Acquisition of data- Analysis and interpretation Critical revision of the manuscript for important intellectual content - Study supervision
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i cr us
Sex M
Age 22
Onset of epilepsy (years) 6
2
F
28
8
VPA, LTG
3 4
M F
26 32
10 14
VPA, LTG VPA, LTG
5
F
64
5
6
M
26
7
F
8
Concomitant AED at referral VPA, LTG
FU (months) 36
ZNS (mg/d) 200
48
Seizure free
400
GTCS 1-2 annually, AS monthly
No change GTCS, AS reduction >75%
48 25
400 300
GTCS 1-2 annually, AS weekly GTCS 1-2 annually, AS weekly, ASE 3/year
GTCS free, AS reduction >75% Seizure free
LTG, LEV
45
150
AS monthly, ASE 4/year
Seizure free
10
VPA, LEV
24
400
GTCS monthly, AS weekly
No change GTCS, AS reduction >50%
52
35
PB, LTG, CNZ
24
400
AS daily
AS reduction >50%
F
43
9
LTG, LEV
37
600
GTCS 1-2 annually, AS weekly
No change GTCS, AS reduction >50%
9
M
56
14
24
300
AS daily, ASE monthly
Seizure free
10
M
46
14
VPA, LEV, CNZ VPA, PB, LTG and VNS
24
600
AS daily
ABS reduction > 50%
11
M
51
11
CBZ
22
600
GTCS monthly, AS weekly
Seizure free leading to stop CBZ
12
F
48
14
LTG
51
550
GTCS weekly, AS daily, ASE every 2-3 months
GTCS and AS reduction > 50%, ASE free
13
F
52
9
VPA, LTG
36
150
AS monthly
AS reduction >75%
Ac
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Baseline seizure type and frequency AS weekly
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Pat. 1
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Table 1 Demographic and clinical characteristic of the patients before and after zonisamide
Effect of ZNS
AS: absence seizures; ASE: absence status epilepticus; AED: antiepileptic drugs; FU: Follow-up; GTCS: Generalized tonic-clonic seizure; MJ: myoclonic jerks; CBZ: carbamazepine; CNZ: clonazepam; LTG; lamotrigine ; LEV: levetiracetam; PB: Phenobarbital; VNS: vagus nerve stimulation; VPA: valproate; ZNS: zonisamide
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Highlights Observational post-marketing study. Broad-spectrum activity of zonisamide that includes now typical absences. Zonisamide is efficient in adult patients with refractory juvenile absence epilepsy.
Page 15 of 15
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S0920-1211(14)00126-0 http://dx.doi.org/doi:10.1016/j.eplepsyres.2014.04.010 EPIRES 5145
To appear in:
Epilepsy Research
Received date: Revised date: Accepted date:
19-1-2014 31-3-2014 27-4-2014
Please cite this article as: VELIZAROVA, R., CRESPEL, A., GENTON, P., SERAFINI, A., GELISSE, P.,Zonisamide for Refractory Juvenile Absence Epilepsy, Epilepsy Research (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.04.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Zonisamide for Refractory Juvenile Absence Epilepsy
Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France. Centre Saint Paul-H. Gastaut, Marseille, France.
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1 1 2 1 Reana VELIZAROVA, Arielle CRESPEL, Pierre GENTON, Anna SERAFINI, 1 Philippe GELISSE
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Address correspondence and reprint requests to Dr. Dr Philippe Gelisse, Epilepsy Unit, Hôpital Gui de Chauliac, 80 avenue Fliche, 34295 Montpellier cedex 05, France. Fax: +33 4 67 33 61 00; E-mail address [email protected]
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Character and word counts: Title: 51 characters including spaces and punctuation Abstract: 246 words. Paper: 1332 words (excluding references).
Figure: 0 Table: 1 References: 11
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Page 1 of 15
Abstract
Purpose To examine the clinical effect of zonisamide (ZNS) in patients with drug-
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resistant Juvenile Absence Epilepsy (JAE). Methods Between 2006 and 2010, 13 JAE patients were successively treated with add-on
cr
ZNS. Safety and efficacy were assessed according to the patient and caregiver reports at
us
visits every 3 months. Response rate was defined as a 50% or greater reduction in seizure frequency.
an
Results Mean age was 42 years. No patient had been seizure free for a period >12 months before ZNS. The mean follow-up was 34 months. The mean dosage of ZNS was
M
388 mg. ZNS was effective for absence seizures (AS) in all patients (more than 50% AS reduction). Four patients reached seizure reduction on 550-600 mg/day. Three (23%) had
d
a reduction in AS frequency > 75% and five (38,5%) between 50%-75%. Seizure
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freedom was achieved in five patients (38,5%) (3 patients with AS only and two with AS
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plus generalized tonic-clonic seizures (GTCS)). Before ZNS, four patients had AS evolving to absence status. After ZNS, three of them were in the seizure-free group, the later never experienced this type of complication. Among 7 patients with AS plus GTCS, two of them did not report any improvement in the frequency of GTCS (29%). Conclusion This observational post-marketing study confirms the broad-spectrum activity of ZNS that includes GTCS, myoclonic seizures and now AS. This study provides evidence that add-on ZNS is efficient and well tolerated in adult patients with refractory JAE, even at high doses.
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Page 2 of 15
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Keywords: Juvenile Absence Epilepsy; Zonisamide; Drug resistance; Absence seizures; Antiepileptic drugs
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Page 3 of 15
Introduction Juvenile absence epilepsy (JAE) is an idiopathic generalized epilepsy (IGE) with onset around puberty. Seizures are typical absences in 100%, generalized tonic-clonic
ip t
seizures (GTCS) in 80% and sporadic myoclonic jerks in 20%. JAE is estimated at
cr
around 10% of IGE and between 1.5-2% of all epilepsies (Gelisse et al., 2012). Valproate (VPA) is very effective in JAE; in case of side effects, or in women of childbearing age,
us
lamotrigine (LTG) can be used (Gelisse et al., 2012). Ethosuximide (ESM), a T-type calcium channel blocker is the drug of choice in chilhood absence epilepsy (Glauser et
an
al., 2013), but is not recommended in monotherapy in JAE due to existence of GTCS. JAE is not considered a severe condition but in some patients, absence seizures (AS) and
M
GTCS may resist first-line drugs. Experimental studies indicate that zonisamide (ZNS)
d
could be a blocker of T-type voltage-gated calcium channel (Mac Donald, 2002; Matar et
Ac ce p
JAE patients.
te
al., 2009). In this study, we examined the clinical effect of add-on ZNS in drug-resistant
Patients and Methods
All patients referred to the epilepsy Unit of Montpellier (tertiary center
specialized in epilepsy for adolescent and adults) were included prospectively since 2001 in a computerized database. Database includes the gender, the medical history, the type of epilepsy, the onset of seizures, the types and the frequency of seizures at each visit and the antiepileptic drugs. In our center, benign and easily treatable forms of epilepsy tend to
4
Page 4 of 15
be underrepresented.
ip t
Between 2006 and 2010, of the 38 JAE patients, 13 (34%) (7 males, 6 females) were treated successively with ZNS in add-on therapy because they were difficult to
cr
control with other drugs. The diagnosis of JAE was based on the criteria of the
us
International Classification of Epilepsies (Comission, 1989). All patients had been treated at least once with VPA, LTG or ESM but these drugs were stopped in some patients
an
because of side effects or lack of efficacy. ZNS was started at 50 mg/day with increase of 50 mg every one or two weeks. The titration schedule was individualized for each patient
M
based on the tolerability. Safety and efficacy were assessed according to the patient and caregiver reports at visits every 3 months. Responders were defined as experiencing a
te
d
50% or greater reduction in seizure frequency. The total daily dose was adjusted for each patient according to the efficacy and tolerability. The maximal daily dose was 600
Ac ce p
mg/day.
Results
The demographic data and clinical characteristics of the patients are presented on
Table 1. Mean age of the patients at the time of inclusion in the study was 42 years (range 22-64 years). The mean age at onset of seizures was 15.6 years (range 5-35 years). The mean duration of epilepsy was 29.7 years (range 16-59). Before ZNS, the baseline frequency of GTCS was 1-2 annually in four (pat. 2-4, 8), monthly in two (pat. 6, 11),
5
Page 5 of 15
and weekly in one (pat. 12). The AS frequency was monthly in 4 (pat. 2, 5, 13), weekly in 5 (pat. 1, 3, 4, 6, 8, 11) and daily in four (pat. 7, 9, 10, 12). Three patients had 3-4 episodes of absence status per year (pat 4, 5, 12), and one every month (pat. 9). No
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patient had been seizure-free before ZNS therapy for a period >12 months. One patient
cr
(Pat 10) had vagus nerve stimulation.
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The mean follow-up period was 34 months (range 22-51 months). ZNS was stopped in patient 7 after 24 months because of tremor in spite of reduction of AS
an
frequency (> 50%). The other patients tolerated ZNS and the drug was continued. The
M
mean dosage of ZNS was 388 mg/day (range 150-600 mg/day).
d
ZNS was effective for AS in all patients (more than 50% absence reduction).
te
Three (23%) had a reduction in AS frequency > 75% (pat. 2, 3, 13) and five (38.5%) between 50%-75% (pat. 6-8, 10, 12). Seizure freedom was achieved in five patients
Ac ce p
(38.5%) (3 patients with AS only (pat. 1, 5, 9) and two with AS plus GTCS (pat. 4, 11) with a mean follow-up of 30 months (range: 22 to 45 months). All patients with absence status before ZNS never experienced this type of complication after the introduction of the drug. After ZNS, three of them were in the seizure free group. The later had more than 50% seizure reduction and never experienced this type of complication. Among the 7 patients with AS plus GTCS, two of them did not report a decrease in the seizure frequency of GTCS (29%) (pat. 2, 6).
6
Page 6 of 15
Patient 11 was treated in monotherapy with carbamazepine (CBZ) when he was referred because a wrong diagnosis of focal epilepsy was made. However, he was previously treated with valproate, ethosuximide, lamotrigine and phenobarbital but these
ip t
drugs were not well tolerated and the patient continued to have frequent seizures. CBZ was proposed by his neurologist and was quite effective against GTCS during several
cr
months but reappeared progressively. AS were present every weeks. When ZNS was
an
us
introduced, he became seizure free and CBZ was progressively stopped.
M
Discussion
d
JAE is not considered severe. The response to therapy is usually good,
te
approximately 80% of cases become seizure-free with the traditional drugs such as
Ac ce p
ethosuximide and valproate (Gelisse et al., 2012). But in the study of Bartolomei et al. (1997), which included 27 cases of JAE, the results were not quite as good since GTCS or AS persisted in about 40% of the patients. This study was performed in a center specialized in epilepsy for children and adults with moderate or severe epilepsies. Our center is also specialized in difficult-to treat patients that explain why about one third of our JAE patients were not controlled with classical drugs. This is the reason why we choose to treat these patients with ZNS in add-on therapy.
7
Page 7 of 15
ZNS is effective against focal seizures and GTCS in patients with localizationrelated epilepsy (Zaccara et al., 2009). Some reports suggest that ZNS may be effective in myoclonic epilepsies such as juvenile myoclonic epilepsy and progressive myoclonic
ip t
epilepsies (Zaccara et al., 2009). Different studies have shown a positive effect in the
treatment of AS but these studies included heterogeneous group of patients with different
cr
types of generalized epilepsies and with a clear predominance of children (Zaccara et al.,
us
2009). The efficacy of ZNS on AS has been shown for the first time in a small series of patients in a prospective study (Yagi and Sieno, 1992). Later, Yamauchi and Aikawa
an
(2004) in their post-marketing surveillance study reported that the responder rate (proportion of patients with at least 50% seizure reduction) was 87.5% (n=8) for typical
M
absences and 46.3% (n=54) for atypical absences. Wilfong and Schultz (2005) examined
d
efficacy of ZNS in a group of young patients (n=45) with AS and found remarkable
Ac ce p
absence reduction.
te
results. Seizure freedom achieved 51.1% of the patients and 35.5 % had more than 50%
Our population includes drug-resistant JAE patients with a long evolution. All had
been treated with adequate drugs for JAE at one time of their life with incomplete control. ZNS was given as an adjunctive therapy. All patients were responders, including more than 1/3 seizure free and 23% with at least 75% absence seizure reduction from baseline. The mean dosage of ZNS was 388 mg/day which is in agreement with the therapeutic dosage reported in other studies (Wilfong and Schultz, 2005; Ohtahara, 2006). Four of our patients reached seizure reduction on 550-600 mg/d ZNS, which is higher than the recommended dose of 500 mg/d. They did not report side effects.
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In conclusion, ZNS may be used with benefit as add-on therapy in adult patients with refractory JAE. Patients treated with ZNS have a decrease in seizure frequency. Five
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patients became seizure-free and the patients with a history of absence status never experienced this type of seizure again. The tolerance was good even in patients treated
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with high doses. This observational post-marketing study confirms a broad spectrum
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activity of ZNS, also now against typical absences. Add-on ZNS can be used in JAE,
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even at high doses.
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References
Bartolomei F, Roger J, Bureau M, Genton P, Dravet C, Viallat D, Gastaut JL. Prognostic
cr
ip t
factors for childhood and juvenile absence epilepsies. Eur Neurol 1997;37:169-75.
Commission on Classification and Terminology of the International League Against
us
Epilepsy: proposal for the classification of epilepsy and epileptic syndromes. Epilepsia
an
1989;30:389-99.
M
Gelisse P, Wolf P, Inoue Y. Juvenile absence epilepsy. In: Bureau M, Genton P, Dravet C, Delgado-Escueta A, Tassinari P, Thomas P, Wolf P (Eds). Epileptic Syndromes in
d
Infancy, Childhood and Adolescence. 5th Ed. Montrouge: John Libbey Eurotext Ltd,
te
2012:329-339.
Ac ce p
Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Adamson PC; Childhood Absence Epilepsy Study Team. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia 2013;54:141-55.
Mac Donald RL. Zonisamide: Mechanisms of action. In: Levy RH, Mattson RH, Meldrum BS, Perucca E. Antiepileptic drugs. 5th Ed. Philadelphia: Lippincott Williams & Wilkins 2002:838-851.
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Matar N, Jin W, Wrubel H, Hescheler J, Schneider T, Weiergraber M. Zonisamide block of cloned human T-type voltage-gated calcium channels. Epilepsy Res 2009;83:224-34.
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Ohtahara S. Zonisamide in the management of epilepsy-Japanese experience. Epilepsy
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Res 2006;68 (Suppl 2):25-33.
us
Wilfong A, Schultz R. Zonisamide for absence seizures. Epilepsy Res. 2005;64:31-34.
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Yagi K, Seino M. Methodological requirements for clinical trials in refractory epilepsiesour experience with zonisamide. Prog Neuropsychopharmacol Biol Psychiatry
d
M
1992;16:79-85.
Ac ce p
1):41-48.
te
Yamauchi T, Aikawa H. Efficacy of zonisamide: our experience. Seizure 2004;13 (Suppl
Zaccara G, Specchio LM. Long-term safety and effectiveness of zonisamide in the treatment of epilepsy: a review of the literature. Neuropsychiatr Dis Treat 2009;5:249-59.
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Disclosure Dr Velizarova reports no conflicts of interest.
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Dr Crespel received support for teaching programs from Sanofi-Aventis, UCB, GSK and served as advisory board member for Eisai-France for zonisamide and presently serves as advisory board member for Eisai-France for perampenel.
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Dr Genton received speaker honoraria from Sanofi-Aventis, Novartis, GSK, Pfizer, Janssen-Cilag, UCB, Eisai and received support for teaching programs from SanofiAventis and UCB.
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Dr Serafini reports no conflicts of interest.
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Dr Gelisse received support for teaching programs from Sanofi-Aventis, UCB, Psicofarma. He received a research grant form the French League Against Epilepsy and the Janssen-Cilag company. He worked as consultant for Eisai-France in 2011.
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Individual contribution
Dr. Velizarova - Acquisition of data - Analysis and interpretation - Critical revision of the manuscript for important intellectual content
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Dr. Crespel- Study concept and design- Acquisition of data- Critical revision of the manuscript for important intellectual content
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Dr Serafini- Acquisition of data - Analysis and interpretation
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Dr. Genton- Critical revision of the manuscript for important intellectual content
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Dr Gelisse- Study concept and design - Acquisition of data- Analysis and interpretation Critical revision of the manuscript for important intellectual content - Study supervision
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i cr us
Sex M
Age 22
Onset of epilepsy (years) 6
2
F
28
8
VPA, LTG
3 4
M F
26 32
10 14
VPA, LTG VPA, LTG
5
F
64
5
6
M
26
7
F
8
Concomitant AED at referral VPA, LTG
FU (months) 36
ZNS (mg/d) 200
48
Seizure free
400
GTCS 1-2 annually, AS monthly
No change GTCS, AS reduction >75%
48 25
400 300
GTCS 1-2 annually, AS weekly GTCS 1-2 annually, AS weekly, ASE 3/year
GTCS free, AS reduction >75% Seizure free
LTG, LEV
45
150
AS monthly, ASE 4/year
Seizure free
10
VPA, LEV
24
400
GTCS monthly, AS weekly
No change GTCS, AS reduction >50%
52
35
PB, LTG, CNZ
24
400
AS daily
AS reduction >50%
F
43
9
LTG, LEV
37
600
GTCS 1-2 annually, AS weekly
No change GTCS, AS reduction >50%
9
M
56
14
24
300
AS daily, ASE monthly
Seizure free
10
M
46
14
VPA, LEV, CNZ VPA, PB, LTG and VNS
24
600
AS daily
ABS reduction > 50%
11
M
51
11
CBZ
22
600
GTCS monthly, AS weekly
Seizure free leading to stop CBZ
12
F
48
14
LTG
51
550
GTCS weekly, AS daily, ASE every 2-3 months
GTCS and AS reduction > 50%, ASE free
13
F
52
9
VPA, LTG
36
150
AS monthly
AS reduction >75%
Ac
pt
ed
M
Baseline seizure type and frequency AS weekly
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Pat. 1
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Table 1 Demographic and clinical characteristic of the patients before and after zonisamide
Effect of ZNS
AS: absence seizures; ASE: absence status epilepticus; AED: antiepileptic drugs; FU: Follow-up; GTCS: Generalized tonic-clonic seizure; MJ: myoclonic jerks; CBZ: carbamazepine; CNZ: clonazepam; LTG; lamotrigine ; LEV: levetiracetam; PB: Phenobarbital; VNS: vagus nerve stimulation; VPA: valproate; ZNS: zonisamide
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Highlights Observational post-marketing study. Broad-spectrum activity of zonisamide that includes now typical absences. Zonisamide is efficient in adult patients with refractory juvenile absence epilepsy.
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