Broad-spectrum efficacy of zonisamide at 12 months in children with intractable epilepsy

In a retrospective study of 35 children (ages 8 months to 22 years; mean age 9 years) with intractable epilepsy, seizure frequency was determined before and after 12 months of zonisamide therapy. Charts were reviewed for seizure type (focal, generalized, or mixed), cognitive function (no special education versus special education), concomitant anticonvulsant medications, and the number of previous anticonvulsant drugs. Good to excellent seizure control (50-100% reduction) was attained in seven (54%) patients with generalized seizures, two (40%) patients with focal seizures, five (35%) patients with mixed seizures, and one (33%) patient with infantile spasms. In this group of children, the efficacy of zonisamide was comparable for focal, generalized, and mixed seizures. The efficacy of zonisamide was independent of cognitive status.Adverse effects were not associated with a higher mean dose. This could be attributable to different rates of metabolism or represent idiosyncratic responses to the medication. Our finding that those children taking the combination of zonisamide and levetiracetam had a significantly worse outcome than those on levetiracetam and a different drug warrants further study, both clinically and from the standpoint of mechanisms of action of zonisamide and levetiracetam and/or their pharmacodynamic interactions.     

Clinical experience with zonisamide monotherapy and adjunctive therapy in children with epilepsy at a tertiary care referral center

We evaluated our clinical experience with zonisamide, a broad-spectrum antiepileptic drug, in a group of children with predominantly medically refractory epilepsy. A retrospective chart review was conducted on patients at our tertiary referral center following Institutional Review Board approval. Observers documented reports of seizure frequency, and seizure types were identified either clinically or by prior video-electroencephalography monitoring. We identified 68 patients (age range 1.9-18.1 years [median 6.9 years]; male to female ratio 1.3:1) treated with zonisamide for 0.7 to 28.9 months; at the last visit, 22% and 78% were on monotherapy and adjunctive therapy, respectively. The median duration of treatment and maintenance dose at the end of the follow-up were 11.2 months and 8.0 mg/kg/day, respectively. Seizure types included generalized (primary generalized tonic-clonic, myoclonic, tonic, atonic, absence) and partial (simple, complex, and secondarily generalized tonic-clonic seizures); 10 (15%) patients had both partial and generalized seizures. Sixteen (25.8%) patients were seizure free, although five of them were already in remission prior to starting zonisamide. Thirteen (21.0%) patients had a > 50% seizure reduction, 10 (16.1%) patients had a < 50% seizure reduction, 14 (22.6%) had no improvement in baseline seizures, and 9 (14.5%) reported having increased seizures. The latter were mostly associated with dosage alterations in concomitant antiepileptic drugs. Common side effects were central nervous system related, including behavioral or psychiatric (23.5%), cognitive dysfunction (12.0%), and sedation (10.3%). Eleven (16.2%) patients ultimately discontinued zonisamide, but only five were strictly due to side effects. Zonisamide is clinically effective against multiple seizure types in a significant proportion of children with epilepsy across a broad age range. Drug discontinuation as a result of side effects is uncommon.     

Efficacy and safety of zonisamide monotherapy in a cohort of children with epilepsy

The aim of this study was to evaluate the efficacy and safety of zonisamide monotherapy in a cohort of children and adolescents with various types of epilepsy. Retrospective review of charts of our institution from 2001 through 2004 identified 69 children (19 males and 50 females, mean age 13.2 years) with epilepsy on zonisamide monotherapy. Seizure count and side effect profile were maintained during therapy. Sixty-one percent had idiopathic generalized epilepsy, 4% symptomatic generalized epilepsy, and 35% partial-onset epilepsy. Zonisamide was the first-line and second-line monotherapy for 32% and 68% of patients, respectively. The mean duration of follow-up on treatment was 22 months (range 3-48 months). The overall efficacy of zonisamide was 75.4% (> or = 50% seizure frequency reduction: good responders). Sixty-seven percent of good responders became seizure-free. Seventy-nine percent of patients with partial epilepsy and 71% with generalized epilepsy were good responders, of whom 79% and 63% were free of seizure, respectively. Eighteen (26%) patients developed side effects: weight loss (9), cognitive impairment (3), sleepiness (3), dizziness (2), and decreased appetite (1). In seven patients (10%), zonisamide had to be discontinued: four due to side effects and three because of poor seizure control. Zonisamide was demonstrated to be effective as monotherapy in children with epilepsy.     

Efficacy and safety of levetiracetam in infants and young children with refractory epilepsy.

The aim of this multicentric, retrospective, and uncontrolled study was to evaluate the efficacy and safety of levetiracetam (LEV) in 81 children younger than 4 years with refractory epilepsy. At an average follow-up period of 9 months, LEV administration was found to be effective in 30% of patients (responders showing more than a 50% decrease in seizure frequency) of whom 10 (12%) became seizure free. This efficacy was observed for focal (46%) as well as for generalized seizures (42%). In addition, in a group of 48 patients, we compared the initial efficacy (evaluated at an average of 3 months of follow-up) and the retention at a mean of 12 months of LEV, with regard to loss of efficacy (defined as the return to the baseline seizure frequency). Twenty-two patients (46%) were initial responders. After a minimum of 12 months of follow-up, 9 of 48 patients (19%) maintained the improvement, 4 (8%) of whom remained seizure free. A loss of efficacy was observed in 13 of the initial responders (59%). Maintained LEV efficacy was noted in patients with focal epilepsy and West syndrome. LEV was well tolerated. Adverse events were seen in 18 (34%) patients. The main side effects were drowsiness and nervousness. Adverse events were either tolerable or resolved in time with dosage reduction or discontinuation of the drug. We conclude that LEV is safe and effective for a wide range of epileptic seizures and epilepsy syndromes and, therefore, represents a valid therapeutic option in infants and young children affected by epilepsy.     

Levetiracetam monotherapy in children with epilepsy

Although levetiracetam has shown efficacy in children with epilepsy, when used as adjunctive therapy, limited data are available regarding its use as monotherapy. The objective of this study is to evaluate the efficacy and tolerability of levetiracetam monotherapy in a cohort of pediatric patients with epilepsy. A retrospective analysis of pediatric epilepsy patients receiving levetiracetam at a single institution was performed over a 3-year period. Eighty-one patients were identified, 18 of whom received levetiracetam as monotherapy (mean age, 9.6 years). Epilepsy types were partial in 14 and generalized in 4. Conversion to levetiracetam monotherapy occurred in 16 patients due to lack of efficacy or adverse events, and 2 patients were initially started on monotherapy. Dose range of levetiracetam was 14-60 mg/kg, and duration of therapy ranged from 2-24 months. Eleven patients became seizure free on levetiracetam, one had at least 50% reduction in seizures, and six others had no change in seizure frequency. Adverse events included worsening of behavior, irritability, and possible cognitive changes, seen in 4 patients. Levetiracetam was discontinued in seven patients overall. Levetiracetam monotherapy appeared to be effective and well tolerated in this group of children with epilepsy and warrants further investigation in a well-controlled, prospective study.     

Nonlesional frontal lobe epilepsy (FLE) of childhood: clinical presentation, response to treatment and comorbidity

RATIONALE: Few studies have looked at long-term epileptic and cognitive outcome of frontal lobe epilepsy (FLE) in children. Most are limited by inclusion of lesional and nonlesional patients. GOAL: To define the epileptic and functional outcome of children with nonlesional FLE. METHODS: We reviewed medical records and neuropsychological evaluations of patients with nonlesional FLE diagnosed between 1994 and 2004. We included children with either focal or regional frontal EEG and/or functional imaging abnormalities. We reviewed their charts for seizure and neuropsychological outcome. RESULTS: We included 21 children. Twelve (57.1%) presented with daily seizures. Seizures were nocturnal in 8 of 21, secondarily generalized in 6 of 21, adversive in 5 of 21, and focal motor in 6 of 21. Although, initial seizure control was poor in 14 of 21, long-term control was achieved in 10 of 21 after 14.6+/-22.3 months. Early development was normal in 12 of 21 but at later formal neuropsychological evaluation only 3 of 12 still had a normal profile. The majority of children had learning difficulties requiring special education prior to seizure onset (6 of 10). A clearly defined regression after seizure onset was observed in three children. The majority exhibited attention deficit and hyperactivity or impulsivity (14 of 21), behavioral problems (8 of 21), and cognitive impairments (10 of 21). Early seizure control was associated with a better cognitive outcome. CONCLUSION: Nonlesional FLE is associated with poor seizure and behavioral outcomes. Whether this is secondary to MRI-silent developmental lesions or to the progressive repercussion of seizures on frontal lobe functions remains uncertain. A prospective study with early neuropsychological assessment could help confirm the latter.     

Anticonvulsant effects of zonisamide and phenytoin on seizure activity of the feline visual cortex

The acute anticonvulsant effects of zonisamide (ZNS) and phenytoin (PHT) on seizure activity produced by electrical stimulation of the feline visual cortex were studied. The intravenous administration of ZNS 60 mg/kg reduced kindled generalized seizures into partial seizures, with marked reduction in the afterdischarge duration. ZNS also suppressed focal seizure activity of the visual cortex and produced a dose-related increase in the afterdischarge threshold. The anticonvulsant effect of ZNS (60 mg/kg) was comparable to that of PHT (15 mg/kg) and was observed in the absence of neurological toxicity and background EEG changes. The present findings demonstrated that ZNS possesses potent anticonvulsant action against focal seizure and its secondary generalization from the visual cortex.     

Effectiveness and tolerability of zonisamide in children with epilepsy: A retrospective review

PurposeTo evaluate the effectiveness and tolerability of zonisamide in children with epilepsy.MethodRetrospective case note review of young people (less than 19 years) with epilepsy from three UK tertiary centres who received treatment with zonisamide and were followed up for a minimum of 12 months.ResultsFifty-seven children were included, aged 1.5–18.5 (median, 12) years. Thirty-three (57.9%) patients had generalised epilepsy, 21 (36.8%) focal epilepsy, and three (5.3%) a mixed, generalised and focal, epilepsy. Fifty-six of the 57 patients had been refractory to at least three previous antiepileptic drugs. The maintenance dose of zonisamide was [range (median)] 0.7–14 (5) mg/kg/day. The median duration of treatment for all patients was 12 (range 0.25–35) months. After 2 months of treatment, 51 patients remained on zonisamide, 18 (35.3%) of whom demonstrated a ≥50% reduction in seizure frequency. At the end of the follow-up period, there was a loss of effect for some patients. Thirteen (25.5%) of the 51 patients continued to demonstrate a ≥50% reduction in seizure frequency whilst two who had become seizure-free started having seizures again. Six (11.8%) had <50% reduction, twenty-four (47%) had no change, and eight (15.7%) had increasing seizures. Twenty-five (43.9%) patients reported unwanted effects although this contributed to the withdrawal of zonisamide in only ten (17.6%) patients.ConclusionsZonisamide appeared to be a reasonably effective and generally well-tolerated antiepileptic drug in a heterogeneous group of 57 children with poorly controlled epilepsy and provides another treatment option for children with refractory seizures.     

Anticonvulsant efficacy of gabapentin and levetiracetam in phenytoin-resistant kindled rats

We evaluated the anticonvulsant efficacy of the new antiepileptic drugs (AEDs) gabapentin and levetiracetam in amygdala kindled rats that had been preselected with respect to their response to phenytoin. Anticonvulsant response was tested by determining the afterdischarge threshold (ADT), i.e. a sensitive measure for drug effects on focal seizure activity. By repeated testing with the phenytoin prodrug fosphenytoin, three groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (phenytoin responders), rats which showed no anticonvulsant response (phenytoin nonresponders), and rats with variable responses (variable phenytoin responders). The latter, largest group was used to evaluate at which doses gabapentin and levetiracetam exerted significant anticonvulsant effects on ADT 1 h after i.p. drug administration. Effective doses were then used for drug testing in phenytoin responders and nonresponders. Both gabapentin and levetiracetam proved to be effective anticonvulsant drugs in the kindling model by significantly increasing the ADT. In addition, both drugs markedly decreased seizure severity recorded at ADT currents, indicating that these drugs affect seizure threshold in the epileptic focus and seizure spread from the focus in the kindling model. When the threshold for secondary generalized seizures (GST) was determined in addition to ADT, gabapentin and levetiracetam strikingly increased this threshold compared to predrug control. In phenytoin nonresponders, gabapentin and levetiracetam significantly increased ADT and GST, which is in line with their proven efficacy in patients with refractory partial epilepsy in whom older AEDs have failed. In phenytoin responders, gabapentin tended to be more efficacious in increasing ADT and GST than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. In contrast to gabapentin, levetiracetam was more efficacious in increasing ADT in nonresponders than in responders. The data of this study substantiate that phenytoin nonresponders are a unique model for the search of new AEDs with improved efficacy in refractory partial epilepsy.     

Efficacy of zonisamide: our experience

The current overview of zonisamide use and effectiveness is based on both a long-term prospective postmarketing survey and current zonisamide use at the Saitama Medical College, Department of Neuropsychiatry. Survey data, which were collected from individual physicians and 23 survey groups throughout Japan, assessed the effectiveness of zonisamide in 1631 patients. Zonisamide was highly effective for treating partial seizures, with 70% of patients reporting improvement. More than half of patients with generalized seizures (58%) and half of patients with myoclonic and atypical absence seizures showed improvement with zonisamide treatment. Among the different epileptic syndromes, zonisamide was highly effective in treating generalized idiopathic epilepsy (≥78% improvement) and partial epilepsy (≥58% improvement). However, only 28% of patients with West syndrome or Lennox-Gastaut syndrome showed improvement. Among 60 outpatients treated with zonisamide at our facility as of October 1998, most had partial seizures or generalized seizures subsequent to partial seizures. The majority of patients received zonisamide in combination with other antiepilepsy drugs. Patients receiving zonisamide monotherapy showed greater improvement than did patients receiving polytherapy. We conclude that zonisamide is highly effective for partial seizures and generalized seizures, and that there appears to be no decrease in efficacy with long-term use.     

A paradoxical effect of levetiracetam may be seen in both children and adults with refractory epilepsy.

The aim of this prospective, uncontrolled clinical study was to evaluate the tolerability and the efficacy of levetiracetam as add-on treatment in 78 adults and 44 children with intractable epilepsy. The patients' seizure frequency in the 8 weeks baseline period was compared to their seizure frequency after a mean follow-up of 8 months of treatment.A greater than 50% reduction in seizure frequency was achieved in 31 adults (40%) and 9 children (20%), of whom 7 adults (9%) and 3 children (7%) became seizure free. Most often levetiracetam was well tolerated, somnolence being the most frequently reported side effect (18% in adults and 7% in children). However, in 14 adults (18%) and 19 children (43%) levetiracetam was associated with an increase (>25%) in seizure frequency. Such a paradoxical effect, including the development of status epilepticus in three adults and four children, appeared most often in mentally retarded patients during the first 2 months of treatment, and on relatively high doses. Two children developed status epilepticus after 5 and 7 months, respectively.In conclusion, levetiracetam is usually well tolerated as add-on treatment in patients with difficult-to-treat partial onset seizures. By using a lower initial dose and a slower dose escalation than recommended by the manufacturer, a paradoxical effect may perhaps be avoided. In children, doses >20 mgkg(-1) per day should be introduced with caution.     

Efficacy of the ketogenic diet in focal versus generalized seizures

Most reports of the ketogenic diet have focused on its efficacy for generalized seizures. Few data are available regarding its effect on focal seizures. We retrospectively studied patients (mean = 7.5 years of age) with medically intractable epilepsy treated by the ketogenic diet. The predominant seizure types in each patient were classified as generalized (100 patients) or focal (34 patients) based on ictal electroencephalograms (EEGs) or seizure semiology and interictal EEG. A seizure reduction of more than 50% compared with baseline was seen in nine patients (27%) with focal seizures and 46 patients (46%) with generalized seizures at 3 months, in 10 patients (30%) with focal seizures and 46 patients (46%) with generalized seizures at 6 months, and in eight patients (24%) with focal seizures and 42 patients (42%) with generalized seizures at 12 months. Differences were not significant. Outcome tended to be better in patients younger than 12 years of age compared with the older age group, but the difference was significant at 6 months only. Our results suggest that some patients with intractable focal epilepsy may respond favorably to the ketogenic diet and that this option should be considered if epilepsy surgery is not possible.     

Efficacy and tolerability of adjunctive therapy with zonisamide in childhood intractable epilepsy

Purpose: This study investigated the efficacy and safety of zonisamide (ZNS) adjunctive therapy in children with intractable epilepsy to existing antiepileptic drugs (AEDs). Methods: A clinical retrospective study was performed from 2003 to 2005 at two tertiary epilepsy centers. We reviewed the data from 163 children (107 boys and 56 girls) who experienced more than four seizures per month, whose seizures were intractable to an initial 2 or more AEDs, and could be followed up for at least 6 months after ZNS adjunctive therapy initiation. Efficacy was estimated by seizure reduction rate according to seizure types including infantile spasms, and adverse events were also measured. Results: Seventy-nine patients (48.5%) out of 163 patients experienced a reduction in seizure frequency of more than 50%, and 25 patients (15.3%) became seizure-free. The rate of seizure reduction greater than 50% in children with partial seizures was 40.5% (17/42) and in children with generalized seizures was 51.2% (62/121). Of 36 patients who manifested mainly myoclonic seizures, 20 patients (55.6%) showed a seizure reduction of more than 50% and 9 patients (25.0%) were seizure-free. Mean maintenance dosage of drug was 8.2 mg/kg/day (range 5.0-16.0 mg/kg/day). Adverse events were documented in 15 children (9.2%), including somnolence (8 patients), fatigue, and anorexia, but all were transient and successfully managed. One patient discontinued ZNS therapy due to acute pancreatitis. Conclusion: ZNS adjunctive therapy is an effective and safe treatment in various childhood intractable epilepsy.     

A pilot study transitioning children onto levetiracetam monotherapy to improve language dysfunction associated with benign rolandic epilepsy

Benign rolandic epilepsy (BRE) and Landau-Kleffner syndrome (LKS) are similar epilepsy syndromes with sleep-accentuated epileptiform activity, sporadic seizures, and language dysfunction. Levetiracetam has been associated with improved language function in LKS and seizure reduction in BRE. We hypothesized levetiracetam would improve language function in children with BRE. A pilot study was performed with six children (aged 6-12) with BRE and evidence of impaired auditory comprehension and verbal memory. Children were transitioned from their current anticonvulsant to 40 mg/kg/day levetiracetam over a 2-week period and retested at 6 months. At 6 months, three of four children with baseline auditory comprehension impairments performed normally (P=0.06), and five had improved auditory verbal memory (P=0.08). Seizures improved in five, decreasing from 2.7 to 1.0 seizure per 6 months (P=0.11). Results from this pilot study suggest that levetiracetam may have a beneficial effect on language in children with BRE.     

Lacosamide treatment of juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy is the most common form of idiopathic generalized epilepsy with onset at puberty or late teenage years. About 80-90% of patients with juvenile myoclonic epilepsy respond to appropriate antiepileptic treatment and achieve seizure freedom, and about 15% of patients become intractable. Valproic acid, levetiracetam, lamotrigine, topiramate and zonisamide are used as first line or adjunctive therapy of this disorder. Lacosamide is approved for adjunctive treatment of partial onset epilepsies. The role of lacosamide in treatment of idiopathic generalized epilepsy including juvenile myoclonic epilepsy is unknown. We present three patients with classic clinical and electrographic features of juvenile myoclonic epilepsy that were maintained on lacosamide (one on monotherapy and two as adjuvant therapy). There were no special pharmacodynamic actions causing exacerbation or worsening of myoclonic jerks or generalized seizures in these three patients. In conclusion, although, the data from our three patients' suggest that lacosamide may be effective in the treatment of juvenile myoclonic epilepsy, larger studies are needed to explore efficacy and role of lacosamide in the treatment of this disorder.     

Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review

OBJECTIVE: To undertake a systematic review and meta-analysis of placebo controlled add-on trials of levetiracetam, oxcarbazepine, remacemide and zonisamide for patients with drug resistant localization related epilepsy. METHODS: We searched Medline, The Cochrane Library and contacted the relevant pharmaceutical companies. Outcomes were 50% or greater reduction in seizure frequency and treatment withdrawal for any reason. Data were synthesised in a meta-analysis. The effect of dose was explored in regression models for levetiracetam and remacemide. RESULTS: We found four trials (1023 patients) of levetiracetam, two (961) of oxcarbazepine, two (388) of remacemide and three (499) of zonisamide. Ignoring dose, the relative risks (95% CI) for a 50% response were 3.78 (2.62-5.44), 2.51 (1.88-3.33), 1.59 (0.91-2.97) and 2.46 (1.61-3.79), respectively. There was evidence for increasing effect with increasing dose for levetiracetam, oxcarbazepine and remacemide. The relative risks for treatment withdrawal were 1.21 (0.88-1.66), 1.72 (1.35-2.18), 1.90 (1.00-3.60) and 1.64 (1.02-2.62), respectively. CONCLUSIONS: These data suggest a useful effect for levetiracetam, oxcarbazepine and zonisamide. Levetiracetam has the more favourable 'responder-withdrawal ratio' followed by zonisamide and oxcarbazepine.     

Gabapentin as add-on therapy in children with refractory partial seizures: a 24-week, multicentre, open-label study

The efficacy and safety of gabapentin as add-on therapy for refractory partial seizures in 237 children, aged 3 to 12 years were evaluated over a 6-month period. All children received gabapentin at 24 to 70 mg/kg/day. Efficacy variables included the percent change in seizure frequency and the responder rate (defined as those patients who showed >50% reduction in seizure frequency). For all partial seizures, the median percent change in seizure frequency was -34% and the overall responder rate was 34%. Simple partial seizures showed a median reduction of -53%; complex partial seizures, -38%; and secondarily generalized tonic-clonic seizures, -35%. Thirteen patients (5%) withdrew during the 6-month period because of adverse events. Concurrent antiepileptic medication remained unchanged in 185 patients (78%), was decreased in 27 (11%), and increased in 25 (11%) patients. This 6-month follow-up study has demonstrated that gabapentin was well tolerated and appeared to show a sustained efficacy in a large population of children with refractory partial and secondarily generalized tonic-clonic seizures.     

Levetiracetam monotherapy in newly diagnosed cryptogenic West syndrome

The combination of axial spasms in clusters, hypsarrhythmia, and psychomotor delay beginning in the first year of life defines West syndrome. Adrenocorticotrophic hormone remains the choice of treatment for many neurologists. Recent controlled studies support vigabatrin as first-line therapy, and open-label studies suggest that topiramate, lamotrigine, and zonisamide may be useful in treating spasms. Studies regarding the efficacy and safety of such treatments often come from small, uncontrolled trials and are often inconclusive. Levetiracetam is effective for treating localization-related epilepsy, but it is uncertain whether it is effective for treating West syndrome. To evaluate the efficacy of levetiracetam monotherapy in newly diagnosed cryptogenic West syndrome, levetiracetam was used initially in the treatment of five patients with cryptogenic West syndrome. On admission, levetiracetam (30 mg/kg) tablets were crushed and administered via nasogastric tube. Two patients were seizure free, two patients experienced a 50% reduction in seizure frequency, and one patient had no improvement in seizure frequency. There were no relapses in the two patients at 6 months after the cessation of seizures. It appears that levetiracetam may be effective in the initial treatment of selected patients with cryptogenic West syndrome.