Use Of Zonisamide Research Articles

Incidence trends and risk factors for hyponatremia in epilepsy patients: A large-scale real-world data study

ObjectiveThis study aimed to evaluate the annual incidence and risk factors of hyponatremia in pediatric, adult, and older adult patients with epilepsy. MethodsWe enrolled 26,179 patients: 8598 pediatric patients (aged 0–15 years), 16,476 adults (aged 16–64 years), and 1105 older adults (aged ≥65 years). Patients were included if their serum sodium levels were measured between January 2006 and December 2020. Moderate-severe hyponatremia was defined as a serum sodium level of less than 130 mEq/L. ResultsFrom 2006 to 2020, 677 patients (2.6%) developed moderate-severe hyponatremia. The incidence of hyponatremia per 1000 person-years was 3.1 in the pediatric group, 19.8 in the adult group, and 50.4 in the older adult group. The incidence increased markedly from 36.8 in 2007 to 58.5 in 2020 in the older adult group but remained unchanged in the adult group and tended to decrease in the pediatric group. In the multiple logistic regression model, use of carbamazepine, valproate, phenytoin, phenobarbital, benzodiazepines, and antipsychotics was found to be a significant risk factor for hyponatremia. In adult patients, carbamazepine, benzodiazepine, and antipsychotics induced hyponatremia in a dose-dependent manner. Concomitant use of zonisamide reduced the risk of hyponatremia. SignificanceHyponatremia will become an increasingly important concern in clinical settings because the population of epilepsy patients is aging. Serum sodium levels should be monitored carefully when patients are receiving first-generation antiseizure medications or antipsychotics or combinations of these drugs. Our findings may help to minimize the risk of hyponatremia in epilepsy patients.

How accurately do adult patients report their absence seizures?

We depend upon self-reporting to determine seizure frequency for epilepsy management decisions, but people often misreport their seizures. Here, we determined misreporting rates in adults with absence seizures, undergoing inpatient video-EEG telemetry (VET) or outpatient ambulatory electroencephalography (aEEG). Under-reporting rates were based on VET data, where behavior could be assessed, whilst over-reporting was assessed using both VET and aEEG. Forty-two patients (31 female and 11 males, median age 28.5 years) and 759 reported absence seizures were included in this study. Overall, only 24% of the 759 reported seizures had an associated EEG correlate, indicating a high over-reporting rate, which occurred in 57% of patients. Age, sex, time of epilepsy, VET versus aEEG, epilepsy syndrome, or medication were not significant predictors of over-reporting. In the VET group in which we could assess both over- and under-reporting (22 patients), only 2 patients correctly reported their seizures, and patients were predominantly over-reporters or under-reporters, not both. Only 26% of 423 absence seizures were reported. Use of zonisamide or valproate was associated with under-reporting, possibly through an impact on attention. These findings indicate that self-reported absence seizures are a poor measure to use for treatment decisions due to both over- and under-reporting.

Zonisamide's Efficacy and Safety on Parkinson's Disease and Dementia with Lewy Bodies: A Meta-Analysis and Systematic Review.

Objective Clinical data has recently shown an association between Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and zonisamide. The purpose of this study was to thoroughly evaluate the efficacy and safety of zonisamide in PD and DLB. MethodsPubmed, the Cochrane Library, Web of Science, and Embase databases were searched for all randomized clinical trials (RCTS) on the role of zonisamide in PD and DLB that were completed by April 18, 2022. UPDRS II (off) total score, UPDRS III total score, Daily “off” time, and UPDRS Part IV, Nos. 32, 33, and 34 were used as clinical efficacy endpoints. Adverse events reported in the RCTs will be considered in the final safety analysis. To better understand the effect of zonisamide on the efficacy and safety of PD and DLB, the UPDRS III total score and the six overlapping adverse events were examined in subgroups. Either a fixed effects model analysis (OR) or a random effects model analysis (MD) is used to figure out the mean difference (MD) and the relative risk. Results Seven articles involving 1749 patients (916 PD and 833 DLB) were included in this study. Compared to the control group, zonisamide could significantly reduce the UPDRS III total score in patients with PD and DLB (WMD-2.27 [95% CI: -3.06, -1.48], p < 0.0001). For patients with PD, compared to the control group, zonisamide could significantly reduce the UPDRS II (off) total score (WMD-0.81 [95% CI: -1.36, -0.26], p = 0.004), daily “off” time (WMD-0.67 [95% CI: -1.10, 0.24], p = 0.002), and UPDRS part IV, No. 32 worsen (OR-3.48 [95% CI: 1.20, 10.10], p = 0.02). In terms of safety, compared with the control group, for patients with DLB, zonisamide could significantly increase the incidence of contusion (OR-0.60 [95% CI: 0.38, 0.96], p = 0.03) and may increase the probability of reduced appetite (OR-3.13 [95% CI: 1.61, 6.08], p = 0.0008). And for patients with PD, zonisamide may increase the probability of somnolence (OR-2.17 [95% CI: 1.25, 3.76], p = 0.006). Conclusions For the analysis of the current study results, our results show that zonisamide could improve the motor function in patients with PD and DLB and improve the activities of daily living (off) and wearing off and decrease the duration of dyskinesia in patients with PD. In terms of safety, the use of zonisamide significantly increases the probability of contusion in patients with DLB and may increase the probability of reduced appetite in patients with DLB and somnolence in patients with PD. Zonisamide appears to be a new treatment option for patients with PD and DLB. However, the effectiveness and safety of zonisamide in the treatment of PD and DLB need to be further investigated.

Zonisamide attenuates the severity of levodopa-induced dyskinesia via modulation of the striatal serotonergic system in a rat model of Parkinson's disease

Glutamate, GABA, acetylcholine, dopamine, and serotonin interact with each other to regulate the flow of neural information in the striatum. Serotonin type 1A receptor (5HT1A) is primarily expressed on glutamatergic nerve terminals, and 5HT1B is expressed on GABAergic medium spiny neurons (MSNs). Zonisamide (ZNS) reportedly improves the off period without worsening levodopa-induced dyskinesia (LID) in patients with advanced Parkinson's disease. In this study, LID model rats were prepared by administrating levodopa to unilaterally 6-OHDA-lesioned rats. We analyzed changes in serotonergic neurotransmission of LID model rats to elucidate the relationship between LID and the serotonergic system and pathomechanism of the anti-dyskinetic effects of ZNS. Abnormal involuntary movements (AIMs) were most severe in intermittently levodopa-treated rats but milder in rats intermittently medicated with levodopa and ZNS. Continuously levodopa-infused rats or intermittently ZNS-injected rats did not develop AIMs, and no differences in the expression of brain-derived neurotrophic factor, 5-HT transporter, 5HT1A, and 5HT1B mRNA between the lesioned striatum and normal side were observed. Expression of 5HT1B mRNA was elevated in the lesioned striatum of intermittently levodopa-treated rats, but this elevation was normalized by concomitant use of ZNS. The severity of AIMs was correlated with the ratio of 5HT1B to 5HT1A mRNA expression in the lesioned striatum, indicating that the anti-LID effect of ZNS is based on inhibition via 5HT1B receptors to direct pathway MSNs sensitized by intermittent levodopa treatment. Selectively acting serotonergic drugs, especially those that lower the 5HT1B to 5HT1A ratio, are promising new therapeutic agents to attenuate LID development.

Efficacy, tolerability, and safety of zonisamide in children with epileptic spasms: A systematic review and meta-analysis.

Background: Valproate, levetiracetam, benzodiazepines, and topiramate are antiseizure medications (ASMs) considered to have definite efficacy in reducing the frequency of epileptic spasm frequency, apart from ketogenic dietary therapies. Although zonisamide has also been shown to have efficacy as second-line ASM for epileptic spasms, various studies have conflicting results in literature. This systematic review aims to summarize clinical studies regarding the efficacy of zonisamide for epileptic spasms. Methods: We conducted a systematic literature search collating all available literature. The primary objective was to determine efficacy in terms of proportion with complete spasm resolution, we also intended to determine proportion with at least 50% spasm reduction, hypsarrhythmia resolution, and nature/frequency of adverse effects. All prospective/retrospective, controlled/uncontrolled studies describing the use of zonisamide with epileptic spasms were included in the qualitative review excluding case reports, but for metanalysis pertaining to key outcomes, we included studies with at least 10 participants. Results: A total of nineteen publications were found eligible for inclusion in the qualitative review, out of 101 search items. A total of 401 children with epileptic spasms were tried up to a maximum of 9.9-35 mg/kg/day dose with only mild adverse effects in a few patients. Total 20.8% (95% CI-11.4%-29.2%) and 23.4% (95% CI-17.8%-29.1%) patients had complete cessation of spasms and at least a 50% reduction in total spasm frequency as compared to baseline after starting zonisamide. Similarly, 20.3% (95% CI-10.1%-30.5%) had resolution of hypsarrhythmia in EEG after starting zonisamide. Conclusion: Zonisamide can reduce spasms in 21% of children with epileptic spasms, without major adverse effects. But there are only limited studies on epileptic spasms of sufficient quality to give high confidence in meta-analysis. Large controlled trials are needed in this regard to provide high-quality evidence favoring/disfavoring its use in patients with epileptic spasms.

Zonisamide safety in pregnancy: Data from the UK and Ireland epilepsy and pregnancy register

BackgroundAnimal data suggest teratogenic effects with zonisamide use and risk of pregnancy losses. Human data following zonisamide exposure are presently limited, but suggest low risk of malformation with elevated risk of low birth weight. ObjectiveTo calculate the major congenital malformation (MCM) rate of zonisamide in human pregnancy and assess for a signal of any specific malformation pattern and associations with birth weight. Methods and materialsData were obtained from the UK and Ireland Epilepsy and Pregnancy register (UKIEPR) which is an observational, registration, and follow up study from December 1996 to July 2020. Eligibility criteria were use of zonisamide and to have been referred to the UKIEPR before the outcome of the pregnancy was known. Primary outcome was evidence of MCM. ResultsFrom December 1996 through July 2020 there were 112 cases of first trimester exposure to zonisamide, including 26 monotherapy cases. There were 3 MCM for monotherapy cases (MCM rate 13.0% (95% confidence interval 4.5–32.1)), and 5 MCM for polytherapy cases (MCM rate 6.9% (95% confidence interval 3.0–15.2)). While the median birth weight was on 71st and 44th centile for monotherapy and polytherapy cases respectively, there was a high rate of infants born small for gestational age (21% for both). ConclusionThese data raise concerns about a signal for potential teratogenicity with zonisamide in human pregnancy. Given the low numbers reported, further data will be required to adequately counsel women who use zonisamide in pregnancy.

Comparison of zonisamide with non-levodopa, anti-Parkinson's disease drugs in the incidence of Parkinson's disease-relevant symptoms

IntroductionPatients with Parkinson's disease (PD) experience various symptoms, both from the disease progression itself and the medication. Few large-scale studies have investigated the associations between zonisamide and these symptoms. This study compared zonisamide and other anti-PD drugs by analyzing their associations with the incidence of PD-relevant symptoms. MethodsThis was a cohort study based on claims data from Diagnosis Procedure Combination hospitals between 2008 and 2014 in Japan. Patients were included in the cohort if they were diagnosed with PD, aged ≥40 years, and were prescribed anti-PD drugs from the same single class without switching to/combination use with other classes excepting levodopa. The outcomes were the incidence of PD-relevant symptoms from the following categories; mental/psychiatric, autonomic nervous system, motor-related, and gastric symptoms. The associations between the incidence of these symptoms and the prescriptions of 8 different classes of anti-PD drugs were explored by the survival analysis. ResultsIn the final cohort, 9157 patients were included. The zonisamide use was significantly associated with a lower risk of dementia, insomnia, and gastric ulcers than 3 of 7 other classes without levodopa (p < .05). ConclusionThere may be a potential clinical impact of zonisamide on some of the PD-relevant symptoms.

Zonisamide for Cluster Headache Prophylaxis: A Case Series.

There is very little literature surrounding the prophylactic use of zonisamide in cluster headaches. The study aims to evaluate the effectiveness of zonisamide for prophylaxis of cluster headache in patients with chronic or episodic cluster headache. Both chronic and episodic cluster headaches are debilitating disorders which are often refractory to multiple prophylactic medication regimens. There is a scarcity of research in this area, and current prophylactic options for patients are fairly limited, which is troublesome for affected patients. Zonisamide is an established antiepileptic with a multifactorial mechanism of action which has shown to be useful in other headache disorders such as migraine. Twenty cluster headache patients, both episodic (n=12; ICHD 3.1.1) and chronic (n=8; ICHD 3.1.2), who had been or currently were treated with zonisamide, were retrospectively evaluated. Effectiveness of the medication was assessed and identified as headache remission or a reduction in severity or frequency of cluster headache of greater than 50%. Responder status, side effects, and dosage were recorded. Fourteen (70%) patients responded to zonisamide treatment, while 6 (30%) did not. Recorded effective plasma zonisamide levels ranged from 10.2 to 31.9μg/mL. Of the 6 non-responders, 2 stopped the medication due to ineffectiveness, while 4 discontinued the medication secondary to intolerable side effects ranging from gastrointestinal upset to malaise. No more serious adverse events occurred. Eight patients total experienced weight loss/anorexia which many perceived as a positive effect; they lost an average of 10.5% of their body weight in the first 6months of therapy. Zonisamide appears to be an effective prophylactic treatment for patients with chronic and episodic cluster headache disorders. Further research in this area is clearly warranted.

Zonisamide cotreatment delays striatal dopamine transporter reduction in Parkinson disease: A retrospective, observational cohort study

This study examined whether zonisamide (ZNS) cotreatment delays dopamine transporter (DAT) reduction on SPECT in Parkinson disease (PD) patients. The study participants met the following criteria: (i) age ≥ 40 years; (ii) HY stage = 2 or 3; (iii) average specific binding ratio (SBR) ≥2.00; (iv) levodopa administration without a prior history of ZNS use before the first DAT-SPECT (baseline). Attending physicians initially determined whether ZNS (25 mg/day) should be used or not. Levodopa and other anti-PD medications were not restricted. The second DAT-SPECT (endpoint) was conducted 1.2 ± 0.2 years after the first DAT-SPECT. Clinicoradiological changes of HY stage, UPDRS parts II to IV, dyskinesia subscore, and SBR were calculated. Statistical differences were analyzed by Student's t-test, ANOVA, or multilogistic analysis. ZNS cotreatment improved wearing off and prevented the development of dyskinesia without additional administration of selegiline, entacapone, and dopamine receptor agonists. The endpoint SBR reduced significantly in the non-ZNS group compared to the baseline (P < .01). The SBR decline rate reduced significantly in the ZNS group (P < .01). ZNS was an independent preventive factor for SBR reduction. These results suggested a beneficial potential that ZNS preserves striatal presynaptic DAT expression and slows disease progression in early-stage PD.

Efficacy of zonisamide on interictal electroencephalography in familial spontaneous epileptic cats.

Objectives The effectiveness of zonisamide (ZNS) against spontaneous epilepsy in cats has not yet been described. The purpose of this study was to investigate the effect of ZNS on interictal paroxysmal discharges (PDs) using scalp electroencephalography (EEG) in familial spontaneous epileptic cats (FSECs). Methods Eight FSECs were evaluated (six males and two females). Scalp EEG measurements were performed once a week for 3 weeks before ZNS administration (Pre-ZNS). Thereafter, administration of ZNS was started and an adjustment period was instituted until the drug in plasma achieved the steady state. When ZNS in plasma was confirmed to be within 10-40 μg/ml, scalp EEG measurements were performed once a week for 3 weeks (Post-ZNS). The number of PDs (counts/min) were compared between Pre-ZNS and Post-ZNS treatment. Results The median number of PDs for Pre-ZNS and Post-ZNS were 0.43/min (0.13-0.82/min) and 0.28/min (0.07-0.87/min), respectively. The number of PDs Post-ZNS was significantly reduced compared with Pre-ZNS ( P = 0.02). Conclusions and relevance This study showed that ZNS, within the recommended therapeutic range suggested for use in humans and dogs (10-40 µg/ml), reduced the number of PDs recorded on EEG in FSECs that are considered a model for cats with idiopathic epilepsy. Although phenobarbital is the antiepileptic drug of choice for epileptic cats, the results of this research provide evidence to support the use of ZNS in cats with phenobarbital-resistant epilepsy or for cats that cannot use phenobarbital due to adverse side effects.

The Use of Zonisamide for the Treatment of Psychiatric Disorders: A Systematic Review.

Traditional pharmacotherapy has undoubtedly improved the outcome of patients with psychiatric disorders, but partial efficacy or poor tolerability persists in a number of these subjects. Among different compounds, zonisamide has been used to address unmet needs of standard pharmacotherapy. The purpose of the present article is to provide a review about the use of zonisamide for the treatment of psychiatric conditions. A research in the main database sources has been conducted to obtain an overview of the use of zonisamide in psychiatric disorders or associated conditions (obesity and smoking cessation). Most available data indicate the possible effectiveness of zonisamide for the treatment of acute phases of bipolar disorder, binge-eating disorder (BED), alcohol misuse, and obesity. A further assessment of the safety and tolerability of zonisamide is made necessary by the fact that, with the exception of BED, for all other disorders at least some data come from studies with combined pharmacological therapies. Zonisamide may have some utility, especially as an adjunctive therapy, for the management of acute phases and weight gain in bipolar disorder and for prevention of alcohol misuse. Preliminary evidence indicates zonisamide as a candidate compound for the treatment of BED and obesity. However, open-label design and small sample sizes of most available studies prevent from drawing sound conclusions about the utility of this compound in psychiatry.

Population pharmacokinetics of zonisamide after oral administration in healthy Chinese volunteers.

To develop a population-based pharmacokinetic model for the oral antiepileptic drug zonisamide using a cohort of healthy (nonepileptic) subjects and evaluate the effect of individual factors on the pharmacokinetics of zonisamide. 30 young adults (21-39 years) in good health were randomly assigned to 3 equal groups (1:1 sex ratio) for single-dose administration of zonisamide at 200 mg, 300 mg, or 400 mg. An additional 9 subjects (22-24 years) were administered once daily zonisamide at 300 mg for 14 days, and comprised the multiple dosing group. Venous blood samples were collected for analysis prior to (baseline, 0 hours) and after (1-300 hours) drug administration, providing 607 total samples used to build the pharmacokinetic model. The population pharmacokinetic analysis was performed by ICON's nonlinear mixed-effect modeling (NONMEM) software. Validation of the final model was carried out by nonparametric bootstrapping and visual predictive check. The zonisamide pharmacokinetics was best described by a two-compartment model with first-order elimination. In the final model, the estimated value of clearance (CL) was 23.25 L/h, the volume of distribution of the central compartment (Vc) was 34.50 L, the intercompartmental clearance (Q) was 20.22 L/h, and the Ka was 0.026 h(-1). The peripheral volume of distribution (Vp) was 1,429 L for single dose and 1,003 L for multiple doses. Body weight was the significant covariate affecting CL, Vc, Vp, and Q. Otherwise, female subjects had a lower Q than male subjects. The pharmacokinetics of zonisamide after oral administration could be described using a linear first-order elimination two-compartment model, which may provide a reference for clinical use of zonisamide in Chinese adults.

Retention, dosing, tolerability and patient reported seizure outcome of Zonisamide as only add-on treatment under real-life conditions in adult patients with partial onset seizures: Results of the observational study ZOOM

PurposeZonisamide is licensed for adjunctive therapy for partial-onset seizures with or without secondary generalisation in patients 6 years and older and as monotherapy for the treatment of partial seizures in adult patients with newly diagnosed epilepsy, and shows a favourable pharmacokinetic profile with low interaction potential with other drugs. The aim of the present study was to gather real-life data on retention and modalities of zonisamide use when administered as only add-on treatment to a current AED monotherapy in adult patients with partial-onset seizures. MethodsThis multicenter observational study was performed in 4 European countries and comprised three visits: baseline, and after 3 and 6 months. Data on patients’ retention, reported efficacy, tolerability and safety, and quality of life was collected. Of 100 included patients, 93 could be evaluated. ResultsAfter 6 months, the retention rate of zonisamide add-on therapy was 82.8%. At this time, a reduction of seizure frequency of at least 50% was observed in 79.7% of patients, with 43.6% reporting seizure freedom over the last 3 months of the study period. Adverse events were reported by 19.4% of patients, with fatigue, agitation, dizziness, and headache being most frequent. Approximately 25% of patients were older than 60 years, many of whom suffered from late-onset epilepsy. Compared to younger patients, these patients showed considerable differences with regard to their antiepileptic drug regimen at baseline, and slightly higher responder and retention rates at 6 months. ConclusionsDespite limitations due to the non-interventional open-label design and the low sample size, the results show that zonisamide as only add-on therapy is well retained, indicating effectiveness in the majority of patients under real-life conditions.

The use of zonisamide as add-on therapy in refractory partial epilepsy: experience from an epilepsy referral centre in a developing country

Background: Newer anti-epileptic drugs (AEDs), with their improved efficacy and better side-effect profiles, may be useful armamentarium in controlling seizures in refractory epilepsy, especially as add-on therapy for partial seizures. Objective: We investigate the effectiveness and tolerance of zonisamide, a newer-generation AED, in the treatment of refractory epilepsy. Patients and methods: Patients with refractory partial epilepsy being followed up at the Penang General Hospital, an epilepsy referral centre in Malaysia, who were started on zonisamide were being included. Patients’ medical records were reviewed for their demography, epilepsy classification, disease duration, and seizure frequency. Results: A total of 9 patients with refractory partial epilepsy were being commenced on zonisamide. Their mean age was 34.9 years, with mean disease duration of 11 years. For epilepsy classification, 3 patients were having lesional epilepsy (mesial temporal lobe epilepsy), 4 patients were having refractory epilepsy post-CNS infection, and 2 were having cryptogenic partial epilepsy. Zonisamide was added as 3rd AED in 2 patients, as 4th AED in 6 patients, and as 5th AED in 1 patient. Seven of the 9 patients (78%) reported at least a 50% reduction in their seizure frequency after commencing zonisamide, including 1 patient who became seizure-free, after a mean duration of 10 months. None of those patients reported any side effects toward zonisamide. Conclusion: Zonisamide is useful in reducing seizure frequency in refractory partial epilepsy, including lesional epilepsy, and thus improving patients’ quality of life. This is particular useful in developing country where epilepsy surgery is not fully developed yet.

Use of zonisamide in twelve patients with intractable seizures refractory to common anti-epileptic regimens

This non-randomized, uncontrolled, single-center study was conducted to evaluate the effects of zonisamide on intractable epilepsy in a primarily pediatric population. Twelve patients ranging in age from 18 months to 23 years were included in the study. All patients were diagnosed with intractable seizures. Adjunctive therapy with zonisamide was initiated at 100 mg once a day and increased, if needed, by 50-100 mg after one week to reach the maximal or therapeutic dosage depending on patient age and weight. Follow-up occurred in person or by phone at two weeks, one month, and every three months. All 12 patients responded favorably to adjunctive zonisamide. Five patients had subclinical status interrupted and stopped as evidenced by clinical examinations and electroencephalographic (EEG) findings. These patients also became awake, alert, more attentive, and more interactive. An additional six patients experienced clinical and EEG improvement in their seizure frequency, duration, and severity. One patient with autonomic seizures showed EEG improvement in seizure frequency, duration, and severity; however, seizure prodrome control was not obtained. Adjunctive therapy with zonisamide benefited all patients in this study, despite the variation in symptoms and etiology. Zonisamide is thought to have multiple mechanisms of action, which may benefit more patient types than antiepileptic drugs with a single mechanism of action. Zonisamide was well tolerated by all patients.

Zonisamide in the management of epilepsy in the elderly.

Zonisamide (ZNS), a second-generation antiepileptic drug, indicated as add-on treatment of focal epilepsy, has been recently approved as monotherapy for the treatment of partial seizures in adults affected by newly diagnosed epilepsy in Europe. Evidence on the efficacy and tolerability of antiepileptic drugs in the elderly is still lacking as these patients are frequently excluded from clinical trials. Here, a comprehensive overview of available data regarding the use of ZNS in the treatment of epilepsy in elderly people is provided. In a pooled analysis conducted in patients aged ≥65 years, no new/unexpected safety findings have emerged. Few data from uncontrolled investigations suggest that ZNS may be effective and well tolerated when administered as monotherapy or adjunctive antiepileptic treatment in the elderly. However, evidence from these observational studies is less than satisfactory, and randomized controlled trials focused on these patients are still needed.

Zonisamide-induced acute kidney injury.

Zonisamide is a new generation anticonvulsant indicated for the adjunctive management of partial seizures in adults [1]. The anticonvulsant activity of zonisamide is predominantly related to the inhibition of voltage-gated sodium action potentials and reduction of T-type calcium-channel currents. Because of its broad mechanism of action, zonisamide is used for many types of epilepsy and in patients whose epilepsy is resistant to other antiepileptic drugs (AEDs) [2,3]. There is insufficient evidence to demonstrate the superior clinical effectiveness of zonisamide compared to other adjunctive AEDs; however, its long half-life of 63 h supports convenient once- or twice-daily dosing. In vitro studies have demonstrated antioxidant and neuroprotective properties at therapeutic doses, suggesting that zonisamide may protect against ischemic damage and recurrent seizure activity [4]. Therapy is generally well tolerated; the most common reported adverse events include somnolence in 17% of patients and dizziness and anorexia in 13% of patients. Zonisamide may be an alternative in some patients over agents associated with weight gain, such as valproate or pregabalin [5,6]. Zonisamide is metabolized by acetylation to N-acetyl zonisamide and reduction to 2-sulfamoylacetyl phenol (SMAP) by cytochrome P450 isoenzyme 3A4. Zonisamide primarily undergoes renal excretion with 62% recovered from urine and 3% from feces following multiple doses [1,7]. The package insert was recently updated to reflect a risk of hyperchloremic, nonanion gap metabolic acidosis due to weak inhibition of carbonic anhydrase and increased renal excretion of bicarbonate. Furthermore, according to the manufacturer's label, zonisamide is not recommended for use in patients with renal failure (defined by the manufacturer as an estimated GFR < 50 mL/min); use of this agent in patients with renal insufficiency, defined as having a GFR < 60 mL/min according to the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative, requires slower titration and more frequent clinical monitoring for toxicities and adverse effects. Avoidance of use of zonisamide in individuals with end-stage kidney disease (e.g., GFR < 15 mL/min or on dialysis) is prudent based on manufacturer recommendations. Zonisamide has been associated with a statistically significant 8% mean increase in serum creatinine and blood urea nitrogen in clinical trials; however, this effect dissipated after therapy was discontinued. Of note, a case report has demonstrated hypersensitivity syndrome with acute kidney injury due to zonisamide; however; acute kidney injury has not been previously reported as an adverse event of zonisamide [7]. We present a case report that suggests that such an association exists as demonstrated by acute kidney injury in a patient on two separate occasions.

Zonisamide as a Treatment for Partial Epileptic Seizures: A Systematic Review

Although the majority of people with epilepsy have a good prognosis and their seizures can be well controlled with pharmacotherapy, up to one-third of patients can develop drug-resistant epilepsy, especially those patients with partial seizures. This unmet need has driven considerable efforts over the last few decades aimed at developing and testing newer antiepileptic agents to improve seizure control. One of the most promising antiepileptic drugs of the new generation is zonisamide, a benzisoxazole derivative chemically unrelated to other anticonvulsant agents. In this article, the authors present the results of a systematic literature review summarizing the current evidence on the efficacy and tolerability of zonisamide for the treatment of partial seizures. Of particular interest within this updated review are the recent data on the use of zonisamide as monotherapy, as they might open new therapeutic avenues.

Association Between Topiramate and Zonisamide Use During Pregnancy and Low Birth Weight

To assess the possible effects of topiramate and zonisamide use during pregnancy on fetal growth. The study population was the singleton liveborns born to women who enrolled in the North American Antiepileptic Drug Pregnancy Registry between 1997 and 2012. Data were collected through telephone interviews at enrollment, 7 months of gestation, and postpartum. The prevalence of small for gestational age at birth among neonates exposed to topiramate and to zonisamide when either was used as monotherapy during pregnancy was compared with that among neonates exposed to lamotrigine monotherapy, a weight-neutral therapy, and the most common antiepileptic drug in the Registry. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated with multivariable log-binomial regression to control for potential confounders. Data were available for 347 topiramate, 98 zonisamide, and 1,581 lamotrigine-exposed neonates. The mean gestational length was 39 weeks for all comparison groups. Prenatal exposure to topiramate or zonisamide was associated with a mean lower birth weight of 221 and 202 g, respectively, and a mean lesser neonatal length of 1 cm as compared with lamotrigine exposure (p<.01). The prevalence of small for gestational age was 6.8% for lamotrigine, 17.9% for topiramate (RR 2.4, 95% CI 1.8-3.3) and 12.2% for zonisamide (RR 1.6, 0.9-2.8). Similar results were found when a group of 457 unexposed neonates was used as the reference. Topiramate and zonisamide have been shown to reduce weight in adults. Our finding of a decrease in mean birth weight and length among neonates exposed in utero raises concern. II.

Zonisamide for Weight Loss in Adolescents

Obesity in children and adolescents is a growing epidemic in the United States, and physicians are increasingly looking for safe and effective treatments. In recent years, pharmacologic treatment has been considered for severe and refractory cases of adolescent obesity. We present a case of an obese adolescent who presented to an inpatient psychiatric unit with a body mass index (BMI) of 37.8 (>98th percentile for age). He was started on zonisamide for the purposes of weight loss, and a steady decrease in weight and BMI was noted through 4 months of outpatient follow-up. During this time, the patient's weight decreased from 126.8 kg to 106.2 kg, a 20.6-kg loss, representing a 16.25% reduction in weight. His most recent BMI decreased to 31.7 (96th percentile for age). We discuss the potential use of zonisamide for weight loss in adolescents, considering the potential risks and benefits.