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Efficacy and tolerability of zonisamide in idiopathic generalized epilepsy Volume 11, issue 1, March 2009

Auteur(s) : Ainhoa Marinas1, Vicente Villanueva2, Beatriz G Giráldez1, Albert Molins3, Javier Salas-Puig4, Jose M Serratosa1

1Fundación Jiménez Díaz, Madrid
2Hospital La Fe, Valencia
3Hospital Josep Trueta, Girona
4Hospital Central de Asturias, Oviedo, Spain

Article reçu le 14 Août 2008, accepté le 22 Decembre 2008

The idiopathic generalized epilepsies (IGEs) are a group of common epilepsies that affect mainly children and adolescents and have a significant impact on their quality of life. The idiopathic generalized epilepsies (IGEs) are estimated to account for 15-20% of all epilepsies (Jallon and Latour 2005). Response to antiepileptic drugs (AEDs) is usually good, but pharmacoresistance occurs in 10-20% of patients (Benbadis 2005). The classic choice of AEDs includes valproic acid (VPA), clonazepam (CZP) and ethosuximide. Recently, lamotrigine (LTG), topiramate (TPM) and levetiracetam (LEV) have been shown to also be effective in some generalized seizures in patients with IGE. However, in case of lack of efficacy or of adverse events, new AEDs may be needed.

Zonisamide (ZNS) is an AED with proven efficacy as adjunctive therapy in patients with partial seizures (Brodie et al. 2005, Faught et al. 2001, Sackellares et al. 2004, Schmidt et al. 1993). To date, no double-blind, randomised, controlled trial has evaluated its efficacy in idiopathic generalized epilepsy (French et al. 2004a, b). However, evidence from long and extensive clinical use of ZNS in Japan, and data from trials conducted prior to registration, post-marketing surveillance studies and independent reports indicate that ZNS is also efficacious in treating generalized-onset seizures both in adult and paediatric patients, showing response rates of 66-78% in patients with IGEs and 58-87.5% for different types of generalized seizures (Ohtahara 2006, Yagi and Seino 1992, Yamauchi and Aikawa 2004). Better responses were found when ZNS was administered as monotherapy (Yagi and Seino 1992, Yamauchi and Aikawa 2004). There are also some case reports, observational studies and a few open-label studies that suggest that ZNS may be effective for the treatment of IGEs (Kothare et al. 2004, Wilfong and Schultz 2005, Kothare et al. 2006, O’Rourke et al. 2007).

One of the mechanisms of action of ZNS that supports its efficacy in generalized seizures is blockage of the low-threshold T-type calcium channel, which may confer efficacy against absence seizures (Suzuki et al. 1992, Kito et al. 1996, Futatsugi and Riviello 1998, Kim et al. 2001).

To advance our knowledge of the efficacy of ZNS for the treatment of IGEs, we retrospectively analyzed 13 patients with different types of idiopathic generalized epilepsy that were treated with ZNS. The objective of this study was to evaluate the efficacy and safety of ZNS for the treatment of IGEs.

Patients and methods

All patients with IGE from four hospitals in Spain who were treated with ZNS between the years 2006 and 2008 were identified. The accuracy of the diagnosis of IGE and subtypes was reviewed and assessed according to ILAE criteria (Commission 1989). Patient charts were reviewed for demographic characteristics, seizure types and frequency, date of onset for each type of seizure, electroencephalographic findings, reason for introducing ZNS (pharmacoresistancy or intolerance to other AEDs), previous and concomitant antiepileptic drug therapy, ZNS dosage, duration of ZNS therapy, subjective patient reports of ZNS efficacy and adverse events. Safety, efficacy and tolerability were assessed at months 6 and 12. Data were analysed using descriptive statistics. Efficacy was assessed by comparing monthly seizure frequency during the last 3 months (6 month follow-up group) and last 9 months (12 month follow-up group) with the seizure frequency during the first pre-ZNS year. Response was defined as a 50% or greater reduction in seizure frequency.

Results

The characteristics of the patients and follow-up data are summarized in table 1. Thirteen patients were identified (four males and nine females with a mean age of 28; ranging between 10-53 years). Three patients had childhood absence epilepsy (CAE), two had juvenile absence epilepsy (JAE), six had juvenile myoclonic epilepsy (JME) and two idiopathic generalized epilepsy (IGE) with generalized tonic-clonic (GTC) seizures only. Mean age at seizure onset was 12.4 years old (ranging between 7-19 years). Nine patients were pharmacoresistant and presented frequent seizures: one patient presented at least one seizure per day (absences), seven patients presented at least one seizure per month (two patients with absences, two with myoclonic seizures, one with generalized tonic-clonic seizures, one with generalized tonic-clonic and absence seizures, one with generalized tonic-clonic and myoclonic seizures), and one patient presented at least one seizure every two months (myoclonic seizures). Four patients were seizure free with VPA treatment. In these patients ZNS was added to replace VPA due to intolerable adverse events. One of these four patients was switched to ZNS. For the other three patients the dose of VPA was reduced with the objective of complete withdrawal.

ZNS was introduced at a starting daily dose of 25-100 mg/day. The mean daily dose was 319 mg (range 100-500 mg/day). ZNS was initially administered as add-on therapy in all patients. However, during follow-up two patients were switched to ZNS monotherapy. Concomitant AEDs included VPA, LTG, LEV, TPM and CZP. During ZNS therapy changes in patients’ concomitant AED regimens were performed.

Patients were exposed to ZNS for two to 22 months (mean duration of exposure being 12 months). Twelve patients (92.3%) continued with ZNS at month 6 (one patient withdrew due to adverse events) and 11 (84.6%) at month 12 (two patients withdrew due to adverse events).

Efficacy

Response was achieved at month 6 in eight of the 12 patients (66.6%) that continued with ZNS, of which seven (58.3%) were seizure-free. At month 12, eight of the 11 (72.7%) patients that continued with ZNS were responders, of which six (63.6%) were seizure-free. Four patients were seizure-free at baseline with VPA monotherapy. Three of these four remained seizure-free after receiving ZNS (one switched to ZNS, and two continued to be seizure-free with less than half the dose of VPA). In one of the four patients ZNS was withdrawn at month 2 because of adverse events and efficacy was not assessed.

At the end of the study two patients with JME were on monotherapy with ZNS: one became seizure-free after switching to ZNS and the other one, previously seizure-free on VPA, remained seizure-free.

According to seizure types, response was observed for absences in 3/5 patients (60%) at month 6 and 4/5 (80%) at month 12. For generalized tonic-clonic seizures, response was obtained in 7/10 patients (70%) at months 6 and 12, and for myoclonic seizures, in 3/5 patients (60%) at months 6 and 12.

With regards to epilepsy syndromes, two of the three patients with CAE (66.6%) were seizure-free after 12 months with ZNS. One of two patients with JAE experienced a reduction of more than 50% in absence seizure frequency. Three of the five patients with JME (60%) that continued with ZNS at month 6 were seizure-free, and for two, no change in seizure frequency was observed. Three of the four patients with JME (75%) that continued at month 12 were seizure-free, and one showed no change in seizure frequency. Both patients with IGE with GTCs only, remained seizure-free at months 6 and 12.

In one patient with CAE a five hour video-EEG monitoring was performed before the introduction of ZNS. Very frequent generalized spike-wave discharges during wakefulness and sleep and numerous typical absence seizures were recorded. A 24 hour video-EEG monitoring performed one month later showed no absence seizures and no epileptiform discharges. Video-EEG Monitoring was also performed in patient 5, eight months before receiving ZNS. Frequent generalized epileptiform activity was observed during wakefulness and sleep. A second video-EEG monitoring was performed five months after initiating ZNS treatment. This second study showed an improvement with generalized epileptiform activity only during sleep and not during the awake state.
Table 1 Characteristics of the patients and follow-up data.

Pt

Sex

Age

Age at seizure onset

Type/s of epilepsy

Seizure type

Seizure frequency

EEG

Therapy at the onset

Current therapy

Current ZNS daily dose mg

Follow-up duration

  • Seizure reduction (%)
  • 6 months


  • Seizure reduction (%)
  • 12 months


Adverse events

1

F

10

9

CAE

Absence

Absence-daily

GSW

VPA

VPA + ZNS

100

16 months

Seizure free

Seizure free

2

M

43

7

JAE

Absence, GTC

  • GTC-monthly
  • Absence-monthly


GSW, PSW

LTG + LEV

LTG + LEV + ZNS

400

22 months

> 50% reduction

  • 50% reduction GTC.
  • >50% reduction absences


3

F

53

17

JME

Myoclonic, GTC

  • Myoclonic-monthly.
  • GTC-free


BFSW, PSW

VPA + LTG + TPM + CZP

VPA + LTG + CZP + ZNS

300

14 months

No change

No change

Yes

4

F

47

7

CAE

Absence, GTC

Absence-monthly GTC-free

PSW

VPA + LEV

VPA + LEV + ZNS

300

14 months

Seizure free

Seizure free

5

F

32

17

JAE

Absence, GTC

  • Absence-monthly
  • GTC-every two months


GSW, PSW

CBZ + CZP

ZNS + CZP

500

15 months

No change GTC. Worsening absences

Worsening GTC. >50% reduction absences

6

M

15

13

JME

Myoclonic, GTC

Myoclonic every two months GTC-free

PSW

VPA

ZNS

300

12 months

Seizure free

Seizure free

7

M

29

11

IGE

GTC-only

GTC-free

PSW

VPA

VPA + ZNS

300

12 months

Continued seizure free

Continued seizure free

Yes

8

F

48

12

IGE

GTC-only

GTC-free

Normal

VPA

VPA + ZNS

400

12 months

Continued seizure free

Continued seizure free

9

F

18

14

JME

Myoclonic

Myoclonic-free

GSW, PSW

VPA

ZNS

400

12 months

Continued seizure free

Continued seizure free

10

F

18

15

JME

Myoclonic

Myoclonic-free

GSW, PSW

VPA

VPA + ZNS

200

2 months. Withdrawal adverse events

_

_

Yes. Withdrawal

11

F

21

7

CAE

  • GTC,
  • Absence


  • GTC-monthly
  • Absence -annual


GSW

LTG + LEV

LTG + ZNS

400

16 months

GTC free. Worsening absences

GTC free. Absences no change

12

F

26

19

JME

Myoclonic, GTC

Myoclonic-monthly. GTC-every two months

GSW, PSW

TPM + LEV

TPM + ZNS

300

12 months

Seizure free

Seizure free

13

M

23

13

JME

Myoclonic, GTC

Myoclonic-weekly. GTC monthly

GSW, PSW

VPA + CZP

VPA + CZP + ZNS

150

8 months. Withdrawal adverse events and inefficacy

No change

_

Yes. Withdrawal

Tolerability

Four patients out of 13 (30.7%) experienced adverse events. There were no severe adverse events. The most common adverse events were loss of appetite and weight loss in 3/13 patients. One patient (1/13) experienced headaches, somnolence and irritability. In two patients (15.3%), adverse events led to ZNS withdrawal with remission of the symptoms. These two patients received concomitant AED treatment of either VPA or VPA and CZP.

Discussion

There are few open-label studies and anecdotal case reports in the literature supporting the effectiveness of ZNS for the treatment of the idiopathic generalized epilepsies, however, there is a lack of controlled studies. Data from registration trials in Japan, which included 286 patients with generalized epilepsies (both children and adults), showed responses to ZNS of 66% in this group of patients (≥ 50% reduction in baseline seizure frequency; Ohtahara 2006, Yagi and Seino 1992). In the post-marketing surveillance study in Japan, the responder rates were 78% for patients with IGEs and 58-75% for different types of generalized seizures (similar rates for the subgroup of children; Ohtahara 2006, Yamauchi and Aikawa 2004, Iinuma and Haginoya 2004). Higher response rates have been observed in patients with generalized seizures with ZNS monotherapy (83-93%; Yamauchi and Aikawa 2004, Yagi and Seino 1992). Additional independent studies in children have shown a wide range of responder rates from 18% in small series of children on ZNS polytherapy to 50-90% in children with ZNS monotheraphy (Ohtahara 2006, Glauser and Pellock 2002, Seki et al. 2004, Kothare et al. 2006). In our study, 66.6-70% of patients treated with ZNS showed a good response (≥ 50% seizure reduction) after 12 months of follow-up, and 58.3-60% were seizure-free at month 12.

The dose of ZNS in this study ranged from 100 to 500 mg/day, similar to the dose published for adults and children (Ohtahara 2006, Kothare et al. 2006, Wilfong and Schultz 2005, Kothare et al. 2004, Glauser and Pellock 2002).

Most patients in our study presented with JME. In this group of patients, three of five patients (60%) that continued in the study at month 6 were seizure-free and three of four patients (75%) were seizure-free at month 12. Two patients remained seizure-free with ZNS monotherapy at month 12. A study by Kothare et al. (2004), in 15 patients with JME receiving ZNS for 2-24 months, showed similar results; 50% or greater reduction in seizure frequency was observed for 50% of the patients with polytherapy and 80% of the patients with monotherapy.

Regarding seizure types, our study showed slightly better responses for absences and GTC seizures. In the post-marketing study in Japan, ZNS showed higher efficacy against absences, followed by clonic and tonic-clonic seizures (Ohtahara 2006, Yamauchi and Aikawa 2004, Iinuma and Haginoya 2004). Kothare et al. (2004) found better responses for GTC and myoclonic seizures than for absences in the group of JME patients. However, O’Rourke et al. (2007) showed better response rates for myoclonic and absence seizures than for GTC seizures in a small series of JME patients.

In our study, response was observed for typical absences in 3/5 (60%) patients at month 6 and 4/5 (80%) at month 12. These data are consistent with those published in some series with a small number of patients suggesting that ZNS may be efficacious in treating typical absence seizures. For these small series studies (n = 4-8) responder rates were of 50-87.5% (Yamauchi and Aikawa 2004, Iinuma and Haginoya 2004, Yagi and Seino 1992). Wilfong and Schultz (2005) reported a 100% reduction in absence seizure frequency in 51% of 45 young patients. However, there are no details regarding whether the absences were typical or atypical.

In one patient with CAE, 24 hour video-EEG recording was performed before and one month after introducing ZNS. No absence seizures and epileptiform discharges were found after treatment with ZNS. Szaflarski (2004) also reported a patient with JME that had a significant improvement in the EEG recording after introducing ZNS. Video-EEG monitoring was also performed in patient 5, eight months before starting ZNS treatment. Frequent generalized epileptiform activity was observed during wakefulness and sleep. A second video-EEG monitoring was performed five months after initiating ZNS treatment. This second study showed an improvement with generalized epileptiform activity only during sleep and not during the awake state.

ZNS has been shown to have a well-defined safety profile. In Japan, where an extensive clinical experience has been accumulated (for a review see Arzimanoglou and Rahbani, 2006) ZNS has been shown to be well tolerated. In the post-marketing surveillance study in Japan, 31.5% of patients receiving ZNS for up to three years reported adverse events. This percentage was lower for children (26.2%) than for adults (39.9%; Ohtahara and Yamatogi 2004). Other studies in children on ZNS treatment have reported adverse events in 24-42.2% of patients (Iinuma and Haginoya 2004, Kothare et al. 2006, Seki et al. 2004, Wilfong and Schultz 2005). The incidence of adverse events is lower among patients on ZNS monotherapy than for those on polytherapy (Ohtahara and Yamatogi 2004, Iinuma and Haginoya 2004). In the study on JME by Kothare et al. (2004), adverse events were reported in 20% of the patients. Central nervous system (CNS)-related adverse events (cognitive impairment, somnolence, decreased spontaneity, etc) have been the most commonly reported, followed by gastrointestinal adverse events (mainly anorexia and weight loss; Ohtahara 2006; Kothare et al. 2006, Seki et al. 2004, Wilfong and Schultz 2005, Kothare et al. 2004). In our series, 30.7% of patients experienced adverse effects and these were usually mild leading to withdrawal in only two patients. As previously published, the main adverse effects were gastrointestinal and neurological.

The limitations of this study include a small sample size and a short period of follow-up. Although 6 -12 months is not a long follow-up period for IGEs, the high frequency of seizures prior to the introduction of ZNS (monthly in most patients) allowed us to assess efficacy during this period of time. Other studies reported similar follow-up periods of two to 24 months (Kothare et al. 2004, Wilfong and Schultz 2005). Response was evaluated in patients that continued in the study and this could explain the better responses at month 12 than month 6. However, improvement over time has already been described (O’Rourke et al. 2007). For four patients, the dose of concomitant AED varied. Except for two patients, it may be that the previous drug worsened the epilepsy (in on patient an attempt to withdraw TPM failed due to seizure worsening and the other one was on a very low dose of carbamazepine). Although four patients were seizure-free when ZNS was introduced, they remained seizure-free even when the dose of the concomitant AED was reduced by more than half (two remained seizure-free on ZNS monotherapy). Most patients in this study were refractory and received polytherapy. As other authors have reported (Yamauchi and Aikawa 2004, Yagi and Seino 1992), lower responses were found in patients receiving polytherapy compared with those receiving ZNS monotherapy, and a better response may be expected in IGE patients receiving ZNS monotherapy.

In conclusion, in this retrospective study, ZNS showed efficacy and was a well-tolerated therapeutic option in patients with IGE. Prospective randomized, double-blind studies are needed to confirm these data.

Disclosures

All authors have received speaker or consulting fees from one or more of the following compagnies : GSK, Pfizer, Esai, Johnson and Johnson, UCB and Novartis.