Role of zonisamide in advanced Parkinson's disease: a randomized placebo-controlled study.

BACKGROUND: Zonisamide (ZNS) has shown some efficacy in motor symptoms of PD; however, more evidence is lacking, and its effects on nonmotor symptoms (NMSs) and quality of life (QoL) remain to be investigated. This randomized double-blinded placebo-controlled crossover study investigated the effect of ZNS on motor and NMS symptoms and QoL in advanced PD. METHODS: PD patients with Hoehn and Yahr stage ≥ 2 ("On" state) and at least 2 h off time daily were randomized to groups: ZNS 25 mg, ZNS 50 mg and placebo. Groups were assessed at baseline and at the 1- and 3-month follow-ups. The primary endpoint was the change in the total MDS-UPDRS III "On", while the secondary endpoint was the change in the total and parts I and IV MDS-UPDRS, Nonmotor Symptoms Scale and Parkinson's disease questionnaire-39 at the final assessment. RESULTS: Sixty-nine patients were assessed for efficacy at the 1-month follow-up, and 58 patients were assessed at the 3-month follow-up. The primary endpoint showed significant improvement in the ZNS 25 mg group compared to the placebo group (p = 0.009). At the final assessment, the ZNS 25 mg group showed significant improvement of total and part VI MDS-UPDRS, bradykinesia, tremor and functional impact of fluctuations compared to placebo. There was no change in dyskinesia, NMSs, QoL or side effects except for sedation. CONCLUSION: ZNS has a favourable effect on motor symptoms in patients with wearing off as adjunctive therapy with other dopaminergic drugs, with no exacerbation of dyskinesia and a limited impact on NMSs and QoL. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04182399, in 24/11/2019.

A retrospective study of the efficacy of zonisamide in controlling seizures in 57 cats.

BACKGROUND: Evidence-based recommendations for antiepileptic drug selection in cats beyond phenobarbital are limited, and additional studies are needed for cats where seizures remain inadequately controlled by administration of phenobarbital alone or for cats that cannot safely receive phenobarbital. OBJECTIVE: To compare seizure frequency in cats before and after oral administration of zonisamide and describe adverse clinical or clinicopathologic effects in this cohort. ANIMALS: Fifty-seven cats with a history of seizures. METHODS: Multicenter, retrospective study. Median number of seizures per month and number of seizure days per month were compared before and after administration of zonisamide in all cats, a subgroup of cats with idiopathic epilepsy (IE), and a subgroup of cats receiving zonisamide as sole therapy. Clinical and clinicopathologic adverse effect data were also reported. RESULTS: A median decrease of 1 (P = .001, 95% confidence interval (CI) [-1.0, -0.5]) seizure per month, and 1 (P = .003, 95% CI [-1.5, -0.2]) seizure days per month was found across all cats after oral administration of zonisamide. The subgroup with IE showed median decreases of 1 (P = .03, 95% CI [-2.0, -0.5]) and 2 (P = .01, 95% CI [-2.5, -1.0]), respectively. The most common clinical adverse effects were sedation (17%), ataxia (11%), hyporexia (17%), and emesis (5%). One cat developed mild nonregenerative anemia, 2 cats developed mild metabolic acidosis, and 6 cats showed mild increases in ALT and ALP. CONCLUSION: Zonisamide was well tolerated and efficacious in controlling seizure activity in most cats.

Switching from zonisamide to perampanel improved the frequency of seizures caused by hyperthermia in Dravet syndrome: a case report.

BACKGROUND: Dravet syndrome is a severe epilepsy disorder characterized by drug-resistant seizures and cognitive dysfunction, often caused by SCN1A gene mutations. It leads to neurodevelopmental delays and motor, behavioral, and cognitive impairments, with a high mortality rate. Treatment options include sodium valproate, clobazam, and newer agents such as cannabidiol and fenfluramine. Zonisamide, which is used in some cases, can cause hyperthermia and oligohydrosis. Herein, we present a case of a patient with Dravet syndrome whose seizures were controlled by treating infections and switching from zonisamide to perampanel. CASE PRESENTATION: A 24-year-old Japanese man with Dravet syndrome presented to our department with aspiration pneumonia. The patient had been treated with valproate, sodium bromide, and zonisamide for a long time. His seizures were triggered by hyperthermia. The patient was experiencing a sustained pattern of hyperthermia caused by infection, zonisamide, and persistent convulsions, which caused a vicious cycle of further seizures. In this case, the control of infection and switching from zonisamide to perampanel improved seizure frequency. CONCLUSION: Dravet syndrome usually begins with generalized clonic seizures in its infancy because of fever and progresses to various seizure types, often triggered by fever or seizure-induced heat due to mutations in the SCN1A gene that increases neuronal excitability. Seizures usually diminish with age, but the heat sensitivity remains. In this case, seizures were increased by repeated infections, and hyperthermia was induced by zonisamide, resulting in status epilepticus. Perampanel, an aminomethylphosphonic acid receptor antagonist, decreased seizures but caused psychiatric symptoms. It was effective in suppressing seizures of Dravet syndrome in this patient.

Zonisamide attenuates pressure overload-induced myocardial hypertrophy in mice through proteasome inhibition.

Myocardial hypertrophy is a pathological thickening of the myocardium which ultimately results in heart failure. We previously reported that zonisamide, an antiepileptic drug, attenuated pressure overload-caused myocardial hypertrophy and diabetic cardiomyopathy in murine models. In addition, we have found that the inhibition of proteasome activates glycogen synthesis kinase 3 (GSK-3) thus alleviates myocardial hypertrophy, which is an important anti-hypertrophic strategy. In this study, we investigated whether zonisamide prevented pressure overload-caused myocardial hypertrophy through suppressing proteasome. Pressure overload-caused myocardial hypertrophy was induced in mice by trans-aortic constriction (TAC) surgery. Two days after the surgery, the mice were administered zonisamide (10, 20, 40 mg·kg-1·d-1, i.g.) for four weeks. We showed that zonisamide administration significantly mitigated impaired cardiac function. Furthermore, zonisamide administration significantly inhibited proteasome activity as well as the expression levels of proteasome subunit beta types (PSMB) of the 20 S proteasome (PSMB1, PSMB2 and PSMB5) and proteasome-regulated particles (RPT) of the 19 S proteasome (RPT1, RPT4) in heart tissues of TAC mice. In primary neonatal rat cardiomyocytes (NRCMs), zonisamide (0.3 µM) prevented myocardial hypertrophy triggered by angiotensin II (Ang II), and significantly inhibited proteasome activity, proteasome subunits and proteasome-regulated particles. In Ang II-treated NRCMs, we found that 18α-glycyrrhetinic acid (18α-GA, 2 mg/ml), a proteasome inducer, eliminated the protective effects of zonisamide against myocardial hypertrophy and proteasome. Moreover, zonisamide treatment activated GSK-3 through inhibiting the phosphorylated AKT (protein kinase B, PKB) and phosphorylated liver kinase B1/AMP-activated protein kinase (LKB1/AMPKα), the upstream of GSK-3. Zonisamide treatment also inhibited GSK-3's downstream signaling proteins, including extracellular signal-regulated kinase (ERK) and GATA binding protein 4 (GATA4), both being the hypertrophic factors. Collectively, this study highlights the potential of zonisamide as a new therapeutic agent for myocardial hypertrophy, as it shows potent anti-hypertrophic potential through the suppression of proteasome.

Efficacy evaluation of a commercially available MCT enriched therapeutic diet on dogs with idiopathic epilepsy treated with zonisamide: a prospective, randomized, double-blinded, placebo-controlled, crossover dietary preliminary study.

BACKGROUND: Idiopathic epilepsy (IE) is a common, chronic brain dysfunction in dogs. Recently, the effect of feeding a diet enriched with medium-chain triglycerides (MCTs) on seizure frequency has been evaluated in several studies in dogs with IE. However, most dogs with IE in previous studies were treated with phenobarbital as the main antiseizure medication (ASM). In Japan, zonisamide (ZNS) is the most prescribed ASM for dogs with IE. The interaction between ZNS and various nutrients including MCTs and the potential effects on treatment efficacy resulting from combining these therapies have not been previously studied. A prospective, randomized, double-blinded, placebo-controlled, crossover dietary study was conducted. Dogs (n = 7) treated with ZNS were fed either a placebo diet (PL) or Purina ProPlan Veterinary Diet NeuroCare (NC) for 3 months, after which treatments were crossed over and continued for another 3 months. Seizure frequency (seizures/month; sz/m), blood tests including concentrations of ZNS and ß-hydroxybutyric acid, and owner's visual analogue scale score were collected from all dogs for both treatment periods. RESULTS: There was no significant difference in the seizure frequency between PL (2.95 ± 0.80 sz/m) and NC (1.90 ± 0.57 sz/m) during the 6 months of trial. Three of 7 dogs showed ≥ 50% seizure reduction, and 1 of those 3 dogs achieved seizure freedom in NC period. However, 2 of 7 dogs had no changes in epileptic seizure frequency, 2 of 7 dogs had a deterioration in seizure frequency in the NC period. Feeding the MCT diet concurrent with ZNS showed no apparent adverse effects and did not affect ZNS concentration. CONCLUSIONS: This study indicated that the commercially available MCT-enriched diet (NC) can be safely used concurrently with ZNS for dogs with IE.

Evaluation of antiseizure medications including zonisamide in feline idiopathic epilepsy at a referral hospital in Japan.

Background: Idiopathic epilepsy in cats is a more common disease than previously thought, but little information is available about the medical treatment of feline idiopathic epilepsy. Aim: To assess the therapeutic efficacy and safety of antiseizure medication (ASM) for a minimum of 6 months, including zonisamide (ZNS), in feline idiopathic epilepsy at a referral hospital in Japan. Methods: Twenty cats diagnosed with idiopathic epilepsy treated with ASMs were retrospectively included. Results: Nine cats that were finally treated with phenobarbital (PB) monotherapy reached the primary goal (the seizure frequency after the treatment intervention was less than one seizure every 3 months). Three cats were treated with ZNS monotherapy and two reached the primary goal. Eight cats finally received combination therapy. Two of the three cats receiving PB and ZNS therapy achieved the primary goal, but one was considered no responder. Five cats [PB + diazepam (DZP), ZNS + DZP, and ZNS + levetiracetam + DZP] decreased the seizure frequency and reached the primary goal in all but one cat reached the secondary goal. Adverse events were observed in eight patients, but these were curable. Two patients had vomiting after ZNS monotherapy, one had diarrhea, and another was an increase in sleeping hours. Conclusion: PB was frequently used and seemed effective as both monotherapy and combination therapy. Some cats were treated with ASM protocols containing ZNS. ZNS may be available to treat idiopathic epilepsy in cats. However, ZNS administration may cause adverse events, such as gastrointestinal toxicity, in cats.

Efficacy of Adjunctive Therapy with Zonisamide Versus Increased Dose of Levodopa for Motor Symptoms in Patients with Dementia with Lewy Bodies: The Randomized, Controlled, Non-Inferiority DUEL Study.

BACKGROUND: In patients with dementia with Lewy bodies (DLB), it is unknown whether adjunct zonisamide is as effective and safe as increasing levodopa dose when levodopa has inadequate efficacy on parkinsonism. OBJECTIVE: To compare adjunct zonisamide 25 mg/day versus an increased levodopa dose (increased by 100 mg/day) in patients with DLB treated with levodopa ≤300 mg/day for parkinsonism. METHODS: The DUEL study was a multicenter, randomized, controlled, open-label, parallel-group, interventional, non-inferiority trial. During the observation period, levodopa was administered at ≤300 mg/day for 4 weeks. Subsequently, patients were randomized to receive adjunct zonisamide 25 mg/day or levodopa increased by 100 mg/day. RESULTS: Respective adjusted mean changes in MDS-UPDRS Part III total score at 16 and 24 weeks (primary endpoint) were -6.3 and -4.4 in the zonisamide add-on and -0.8 and 2.0 in the levodopa increase groups. The adjusted mean difference at 24 weeks was -6.4 (95% confidence interval [CI] -13.5, 0.7); the upper limit of the 95% CI (0.7) was lower than the non-inferiority margin (3.0). No significant between-group differences were observed in total scores of the MDS-UPDRS Part II, Eating Questionnaire, EuroQol-5 dimension-5 level, Zarit Caregiver Burden Interview, or other secondary endpoints. No notable between-group differences were observed in adverse event incidences. CONCLUSION: Adjunct zonisamide 25 mg/day may yield moderate improvement in motor symptoms in patients with DLB when the levodopa effect is insufficient, but it could not be verified that the zonisamide 25 mg/day was as effective as levodopa 100 mg/day because levodopa showed no sufficient efficacy as assumed.

Specific fetal malformations following intrauterine exposure to antiseizure medication.

OBJECTIVE: To investigate in the Australian Pregnancy Register of Antiepileptic Drugs patterns of fetal malformation associated with intrauterine exposure to particular currently available antiseizure medications taken by women with epilepsy. RESULTS: There was statistically significant evidence (P < 0.05) of an increased hazard of fetal malformation associated with exposure to valproate, carbamazepine, topiramate, zonisamide, and with conception after assisted fertilization, but a reduced hazard in the offspring of women who continued to smoke during pregnancy. Valproate exposure was associated with malformations in a wide range of organs and organ systems, carbamazepine and topiramate with hydronephrosis, topiramate also with hypospadias, zonisamide with spina bifida and assisted fertilization with heart and great vessel maldevelopment. CONCLUSIONS: Prenatal valproate exposure appears to interfere with the development of many if not all, fetal tissues. It seems likely that prenatal exposure to carbamazepine and topiramate, and possibly exposure to zonisamide, but also some process related to in vitro fertilization, may more selectively affect the normal development of particular fetal tissues or organs.

Comparison of caregivers' assessments of clinical outcome in dogs with idiopathic epilepsy administered levetiracetam, zonisamide, or phenobarbital monotherapy.

OBJECTIVE: To investigate caregivers' assessments of outcome in dogs with idiopathic epilepsy (IE) administered levetiracetam (LEV), zonisamide (ZNS), or phenobarbital (PB) monotherapy. ANIMALS: 100 dogs with IE administered LEV (n = 34), ZNS (31), or PB (35) monotherapy between January 1, 2003, and February 6, 2019, and survey responses from their caregivers. PROCEDURES: Information on duration of therapy, adverse effects (AEs), and outcome was obtained from medical record review and caregiver questionnaire. RESULTS: A significant improvement in mean quality of life score was reported during monotherapy (7.7; SD, 2.14) compared to before treatment (6.25; SD, 2.63; P < .0001), with no difference identified between monotherapy groups. Compared to ZNS monotherapy, dogs prescribed PB monotherapy had a significantly younger median age at seizure onset (2.6 vs 4.3 years; P = .024). A significant relationship was identified between the occurrence of reported AEs and monotherapy group, with a higher prevalence in the PB group (77% [27/35]) and a lower prevalence in the ZNS group (39% [12/31]; P = .0066). Treatment failure rates for PB, LEV, and ZNS monotherapy were 51%, 35%, and 45%, respectively, with failure attributed most commonly to inadequate seizure control. No significant difference was identified between groups with respect to rate of or time to failure. CLINICAL RELEVANCE: Most caregivers reported a favorable outcome with administration of LEV, ZNS, or PB monotherapy to dogs with IE. Phenobarbital is associated with the highest prevalence of AEs but no difference in quality of life score. Prospective controlled studies are needed to further compare the efficacy and safety of these monotherapies in dogs with IE.

An Update on Nondopaminergic Treatments for Motor and Non-motor Symptoms of Parkinson's Disease.

Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its symptoms. Therefore, nondopaminergic receptors are key targets for developing novel preparations for the management of motor and non-motor symptoms in PD, without the potential adverse events of dopamine replacement therapy. We reviewed English-written articles and ongoing clinical trials of nondopaminergic treatments for PD patients till 2014 to summarize the recent findings on nondopaminergic preparations for the treatment of PD patients. The most promising research area of nondopaminergic targets is to reduce motor complications caused by traditional dopamine replacement therapy, including motor fluctuations and levodopa-induced dyskinesia. Istradefylline, Safinamide, and Zonisamide were licensed for the management of motor fluctuations in PD patients, while novel serotonergic and glutamatergic agents to improve motor fluctuations are still under research. Sustained- release agents of Amantadine were approved for treating levodopa induced dyskinesia (LID), and serotonin 5HT1B receptor agonist also showed clinical benefits to LID. Nondopaminergic targets were also being explored for the treatment of non-motor symptoms of PD. Pimavanserin was approved globally for the management of hallucinations and delusions related to PD psychosis. Istradefylline revealed beneficial effect on daytime sleepiness, apathy, depression, and lower urinary tract symptoms in PD subjects. Droxidopa may benefit orthostatic hypotension in PD patients. Safinamide and Zonisamide also showed clinical efficacy on certain non-motor symptoms of PD patients. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs may lead to new approaches with positive clinical implications.

Polysomnographic and Clinical Parameters before and after Zonisamide Therapy for Parkinson's Disease.

Objective Sleep disturbance is a common nonmotor symptom associated with a decreased quality of life in patients with Parkinson's disease (PD). In this study, we evaluated the effects of zonisamide on motor and non-motor symptomology in patients with PD, especially with respect to objective sleep assessments conducted via polysomnography. Methods We conducted a 12-week, open-label study to assess the effects of zonisamide. The patients received 25 mg/day of zonisamide and underwent overnight polysomnography prior to and after 12 weeks of zonisamide treatment. They were assessed for their cognitive function (Mini-Mental State Examination and the Japanese version of the Montreal Cognitive Assessment), gait function (Timed Up-and-Go Test, 10-m Gait Walk Test), Parkinson's symptomology (Movement Disorder Society Revision of the Unified Parkinson's Disease Rating Scale parts 2 and 3), and self-reported sleep (Epworth Sleepiness Score, Parkinson's Disease Sleep Scale-2). Results Six patients completed the study. Polysomnographic data revealed a statistically significant increase in the percentage of time spent in sleep stage N2 (10.8%±9.2%, p=0.031) and a declining trend in the percentage of time spent in sleep stage N1 (-8.9%±12.7%, p=0.063). Although none of the patients had sleep stage N3 at baseline, 3 of the 6 patients experienced sleep stage N3 (1.1-5.4%) after 12 weeks of zonisamide treatment. The other polysomnographic parameters and clinical scores showed no statistically significant differences. Conclusions This preliminary study demonstrated that zonisamide improved objective sleep parameters measured by polysomnography in patients with PD.

Comparative efficacy and safety of monoamine oxidase type B inhibitors plus channel blockers and monoamine oxidase type B inhibitors as adjuvant therapy to levodopa in the treatment of Parkinson's disease: a network meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: The monoamine oxidase type B inhibitors plus channel blockers (MAO-BIs plus) are a new class of antiparkinsonian drug with additional mechanisms of action for their property as ion channel blockers. The present study aimed to compare the efficacy and safety of MAO-BIs plus and conventional MAO-BIs, as well as their corresponding doses, as adjuvant therapy to levodopa in the treatment of Parkinson's disease (PD). METHOD: Randomized controlled trials enrolling PD patients treated with selegiline, rasagiline, safinamide or zonisamide as adjuvant therapy to levodopa were identified. Bayesian network meta-analysis was conducted. RESULTS: Thirty-one randomized controlled trials comprising 7142 PD patients were included. Compared with levodopa monotherapy, the combination therapy of MAO-BIs and levodopa was significantly more effective, with a mean difference of 2.74 (1.26-4.18) on the Unified Parkinson's Disease Rating Scale (UPDRS) III score change for selegiline, 2.67 (1.45-3.87) for safinamide, 2.2 (0.98-3.64) for zonisamide and 2.04 (1.24-2.87) for rasagiline. No significant difference was detected amongst MAO-BIs. The surface under the cumulative ranking results showed that safinamide 100 mg and rasagiline 1 mg ranked first in improving UPDRS III and UPDRS II, respectively. Zonisamide 100 mg ranked first in reducing OFF time. For safety outcomes, rasagiline was associated with a higher incidence of adverse events than placebo and safinamide. MAO-BIs plus had a higher probability of being safer agents compared to conventional MAO-BIs. CONCLUSIONS: Monoamine oxidase type B inhibitors plus, conventional MAO-BIs and the corresponding doses are similar in efficacy in PD treatment. MAO-BIs plus might be safer than conventional MAO-BIs. Head-to-head comparisons are needed for further investigation.

Breastfeeding while on treatment with antiseizure medications: a systematic review from the ILAE Women Task Force

We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short- and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.

Bidirectionality of antiseizure and antipsychotic treatment: A population-based study.

PURPOSE: To study the prevalence and directionality of comorbid epilepsy and psychosis in Norway. METHODS: The Norwegian Prescription Database (NorPD) provided individual-based information on all antiseizure medications (ASMs) and antipsychotic drugs (APDs) dispensed during 2004-2017. Subjects were ≥18 years of age at the end of the study period. Diagnosis-specific reimbursement codes from the 10th revision of the International Classification of Diseases/2nd edition of the International Classification of Primary Care (ICD-10/ICPC-2) combined with ATC codes were used as indicators of diagnosis. Subjects had collected ASMs for epilepsy or APDs for psychosis at least four times, at least once issued with an ICD-10 code from the specialist healthcare service. Directionality was analyzed in subjects receiving both treatments. To reduce prevalent comorbidity bias, we employed a four-year comorbidity-free period (2004-2007). The use of specific ASMs and APDs was analyzed. RESULTS: A total of 31,289 subjects had collected an ASM for epilepsy at least four times, 28,889 an APD for psychosis. Both the prevalence of treatment for epilepsy and of treatment for psychosis was 0.8%. Further, 891 subjects had been treated for both conditions; 2.8% with epilepsy had been treated for psychosis, and 3.1% with psychosis had been treated for epilepsy. Among 558 subjects included in the analyses of directionality, 56% had collected the first APD before an ASM, whereas 41% had collected an ASM first. During the last year prior to comorbidity onset, levetiracetam, topiramate, or zonisamide had been used for epilepsy by approximately 40%, whereas olanzapine and quetiapine were most used in patients with psychosis, and clozapine in 13%. CONCLUSION: The proportion of patients with prior antipsychotic treatment at onset of epilepsy is higher than previously acknowledged, as demonstrated in this nation-wide study. Apart from a shared neurobiological susceptibility, the bidirectionality of epilepsy and psychosis may be influenced by various environmental factors, including the interaction of pharmacodynamic effects. APDs may facilitate seizures; ASMs may induce psychiatric symptoms. In patients with combined treatment, these potential drug effects should receive ample attention, along with the psychosocial consequences of the disorders. A prudent multi-professional approach is required.

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. Methods: Pubmed, 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.

[Efficacy of zonisamide in Lafora's disease case and brief review of its use in progressive myoclonic epilepsy]. / Eficacia de la zonisamida en un caso de enfermedad de Lafora y breve revisión en la epilepsia mioclónica progresiva.

INTRODUCTION: Mioclonic progressive epilepsy (MPE) includes a clinical and genetical heterogeneous group of neuro-degenerative disorders that associate spontaneous and action-induced myoclonus as well as progressive cognitive impairment. Lafora`s disease is a subtype of MPE with autosomical recessive inheritance due to a mutation in EPM2A or EPM2B genes. Seizures, especially myoclonus, are often refractary to antiepileptic drugs (AD). CASE REPORT: In this article we report a patient with Lafora´s disease diagnosis, previously resistant to several AD tested with good and sustained response to zonisamide. Indeed, we describe a brief review about the efficacy of zonisamida in MPE. CONCLUSION: Zonisamide may be considered as a good therapeutic alternative in MPE.

TITLE: Eficacia de la zonisamida en un caso de enfermedad de Lafora y breve revisión en la epilepsia mioclónica progresiva.Introducción. La epilepsia mioclónica progresiva constituye un grupo complejo de enfermedades neurodegenerativas clínica y genéticamente heterogéneas que asocian mioclonías espontáneas o inducidas por la acción y el deterioro neurológico progresivo. Dentro de estas entidades se encuentra la enfermedad de Lafora, una patología autosómica recesiva causada por mutación en el gen responsable de la síntesis de una proteína llamada laforina (EPM2A) o el gen responsable de la síntesis de la proteína malina (EPM2B o NHLRC1). Son entidades cuyas crisis, en especial las mioclonías, son frecuentemente resistentes a los fármacos anticrisis epilépticas. Caso clínico. Presentamos el caso de una paciente con diagnóstico de enfermedad de Lafora que, tras varios regímenes terapéuticos ineficaces, presentó buena respuesta a la introducción de la zonisamida, con una respuesta favorable mantenida en el tiempo. Asimismo, hacemos una breve revisión de la eficacia de la zonisamida en cuadros de epilepsia mioclónica progresiva. Conclusión. La zonisamida puede ser una buena alternativa en el tratamiento de cuadros con epilepsia mioclónica progresiva.

An investigation of the effects of chronic zonisamide, sultiam, lacosamide, clobazam, and rufinamide anti-seizure medications on foliculogenesis in ovarian tissue in prepubertal non-epileptic rats.

We aimed to determine the morphological and histological effects of zonisamide, sultiam, lacosamide, clobazam, and rufinamide on ovarian folliculogenesis in rats. Sixty female Wistar rats were divided into six experimental groups as control, zonisamide, sultiam, lacosamide, clobazam, and rufinamide groups; control solution and drugs were administered by gavage for 90 days. The number of healthy follicles in the control group was significantly higher than in the anti-medication groups (p < 0.001), and the number of corpus luteum was significantly lower (p < 0.001). There was a significant difference in the number of TUNEL positive apoptotic follicles between the control and drug groups (p < 0.001). With EGF, IGF-1, and GDF-9 staining, a very strong immunoreaction was observed in the ovarian multilaminar primary follicle granulosa cells and oocytes in the control group compared to the drug group (p < 0.001). Long-term anti-seizure medication with zonisamide, sultiam, lacosamide, clobazam, and rufinamide from prepubertal to adulthood causes apoptosis and disruption of folliculogenesis in the ovarian follicles of nonepileptic rats.

Comparative whole transcriptome analysis of Parkinson's disease focusing on the efficacy of zonisamide.

OBJECTIVE: Interindividual variations in responsiveness to zonisamide in patients with Parkinson's disease (PD) have been observed in clinical settings. To decipher the molecular mechanisms determining the efficacy of zonisamide, we conducted whole transcriptome sequencing analysis of patients with PD. METHODS: We selected 23 super-responders (SRs) and 25 non-responders (NRs) to zonisamide from patients with PD who had participated in a previous clinical trial for the approval of zonisamide for the treatment of 'wearing-off'. Whole transcriptome analysis of peripheral blood was conducted on samples taken before and 12 weeks after zonisamide treatment. We performed differential gene expression analysis to compare between the SRs and NRs at each time point. RESULTS: Differentially expressed genes in the pre-treatment samples were significantly enriched for glutamatergic synapses and insulin-like growth factor binding (Padj=7.8 × 10-3 and 0.029, respectively). The gene sets associated with these functions changed more dynamically by treatment in SRs than NRs (p=7.2 × 10-3 and 8.2 × 10-3, respectively). CONCLUSIONS: Our results suggest that the efficacy of zonisamide in PD patients is associated with glutamate-related synaptic modulation and p53-mediated dopaminergic neural loss. Their transcriptomic differences could be captured before treatment, which would lead to the realisation of future personalised treatment.

Antiseizure Medication Concentrations During Pregnancy: Results From the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Study.

IMPORTANCE: During pregnancy in women with epilepsy, lower blood concentrations of antiseizure medications can have adverse clinical consequences. OBJECTIVE: To characterize pregnancy-associated concentration changes for several antiseizure medications among women with epilepsy. DESIGN, SETTING, AND PARTICIPANTS: Enrollment in this prospective, observational cohort study, Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD), occurred from December 19, 2012, to February 11, 2016, at 20 US sites. Enrolled cohorts included pregnant women with epilepsy and nonpregnant control participants with epilepsy. Inclusion criteria were women aged 14 to 45 years, an intelligence quotient greater than 70 points, and, for the cohort of pregnant women, a fetal gestational age younger than 20 weeks. A total of 1087 women were assessed for eligibility; 397 were excluded and 230 declined. Data were analyzed from May 1, 2014, to June 30, 2021. EXPOSURE: Medication plasma concentrations in women taking monotherapy or in combination with noninteracting medications. The cohort of pregnant women was monitored through 9 months post partum, with similar time points for control participants. MAIN OUTCOMES AND MEASURES: Dose-normalized concentrations were calculated as total or unbound plasma medication concentrations divided by total daily dose. Phlebotomy was performed during 4 pregnancy study visits and 3 postpartum visits for the pregnant women and 7 visits over 18 months for control participants. The primary hypothesis was to test pregnancy changes of dose-normalized concentrations from nonpregnant postpartum samples compared with those of control participants. RESULTS: Of the 351 pregnant women and 109 control participants enrolled in MONEAD, 326 pregnant women (median [range] age, 29 [19-43] years) and 104 control participants (median [range] age, 29 [16-43] years) met eligibility criteria for this analysis. Compared with postpartum values, dose-normalized concentrations during pregnancy were decreased by up to 56.1% for lamotrigine (15.60 µg/L/mg to 6.85 µg/L/mg; P < .001), 36.8% for levetiracetam (11.33 µg/L/mg to 7.16 µg/L/mg; P < .001), 17.3% for carbamazepine (11.56 µg/L/mg to 7.97 µg/L/mg; P = .03), 32.6% for oxcarbazepine (11.55 µg/L/mg to 7.79 µg/L/mg; P < .001), 30.6% for unbound oxcarbazepine (6.15 µg/L/mg to 4.27 µg/L/mg; P < .001), 39.9% for lacosamide (26.14 µg/L/mg to 15.71 µg/L/mg; P < .001), and 29.8% for zonisamide (40.12 µg/L/mg to 28.15 µg/L/mg; P < .001). No significant changes occurred for unbound carbamazepine, carbamazepine-10,11-epoxide, and topiramate, although a decrease was observed for topiramate (29.83 µg/L/mg to 13.77 µg/L/mg; P = .18). Additionally, compared with dose-normalized concentrations from control participants, pregnancy dose-normalized median (SE) concentrations decreased significantly by week of gestational age: carbamazepine, -0.14 (0.06) µg/L/mg (P = .02); carbamazepine unbound, -0.04 (0.01) µg/L/mg (P = .01); lacosamide, -0.23 (0.07) µg/L/mg (P < .001); lamotrigine, -0.20 (0.02) µg/L/mg (P < .001); levetiracetam, -0.06 (0.03) µg/L/mg (P = .01); oxcarbazepine, -0.14 (0.04) µg/L/mg (P < .001); oxcarbazepine unbound, -0.11 (0.03) µg/L/mg (P < .001); and zonisamide, -0.53 (0.14) µg/L/mg (P < .001) except for topiramate (-0.35 [0.20] µg/L/mg per week) and carbamazepine-10,11-epoxide (0.02 [0.01] µg/L/mg). CONCLUSIONS AND RELEVANCE: Study results suggest that therapeutic drug monitoring should begin early in pregnancy and that increasing doses of these anticonvulsants may be needed throughout the course of pregnancy.

Effectiveness of zonisamide in childhood refractory epilepsy.

INTRODUCTION: Zonisamide (ZNS) is a new generation antiepileptic drug (AED) used in refractory epilepsy. This study assessed the effectiveness and reliability of ZNS in childhood refractory epilepsy. METHOD: Sixty-eight epilepsy patients who were followed up in the paediatric neurology clinic, between 2013 and 2019, and in whom add-on therapy ZNS had been added as their seizures had continued despite multiple drugs being used, were included in this retrospective study. Their demographic findings, seizure aetiology, pre-treatment and post-treatment electroencephalography findings, treatment responses and any side effects of the drugs given were assessed in these patients. RESULTS: There were 46 (67.6%) patients in the refractory generalized epilepsy (RGE) group using multiple AEDs and 22 (32.35%) patients in the refractory focal epilepsy (RFE) group. Of these patients, 12 (17.65%) were being followed up for idiopathic epilepsy and 8 (11.76%) were being followed up for epilepsy of unknown aetiology. Twenty-two (32.36%) patients were followed up for structural abnormality, 8 patients (11.77%) were followed up for genetic disease, 4 patients (5.88%) were followed up for infectious sequel, 14 patients (20.59%) were followed up for metabolic reasons. In the RGE group, a more than 50% reduction was found in the seizures of 26 (56.5%) patients, while the seizures of 7 (15.2%) patients were found to have terminated completely. In the RFE group, a more than 50% reduction was found in the seizures of 19 (86.4%) patients, while the seizures of 2 (9.1%) patients were found to have terminated completely. The termination or a more than 50% reduction in seizures in 4 of the 6 patients followed up for a diagnosis of tuberous sclerosis complex (TSC) was significant. CONCLUSION: ZNS is an effective and reliable option as an add-on therapy in paediatric refractory epilepsy, especially in focal epilepsy. It can also be considered for treatment in TSC patients.