Quinidine therapy and therapeutic drug monitoring in four patients with KCNT1 mutations

Aims. Several recent studies have reported potassium sodium‐activated channel subfamily T member 1 (KCNT1) mutations in epilepsy patients on quinidine therapy. The efficacy and safety of quinidine for epilepsy treatment, however, remains controversial. Methods. We herein report the cases of four patients with KCNT1 mutations treated with quinidine. Results. A reduction in seizures of more than 50% after quinidine treatment was observed in one patient with epilepsy of infancy with migrating focal seizures (EIMFS), whereas two patients with EIMFS and one with focal epilepsy did not achieve apparent seizure reduction. The relationship between quinidine dose and serum quinidine concentration was inconsistent, particularly at high quinidine doses. One patient with EIMFS developed ventricular tachycardia the day after an increase in quinidine dose from 114 to 126 mg/kg/day. The serum trough quinidine concentration and the corrected QT interval (QTc) before arrhythmia onset were 2.4 μg/ml and 420 ms, respectively, and peak serum quinidine concentration after arrhythmia onset was 9.4 μg/ml. Another patient with EIMFS showed aberrant intraventricular conduction with a quinidine dose of 74.5 mg/kg/day and a serum trough concentration of 3.2 μg/ml. Conclusions. Given that serum quinidine levels may elevate sharply after a dose increase, careful monitoring of electrocardiographs and serum concentrations is required. Based on a review of previous reports and our experience with this case, quinidine should be considered as a promising drug for patients with EIMFS harbouring KCNT1 mutations, however, its efficacy remains controversial due to the limited number of cases, and more information on optimal serum concentrations and appropriate titration methods is required.     

De novo KCNT1 mutations in early‐onset epileptic encephalopathy

KCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1‐targeted next‐generation sequencing (207 samples) and/or whole‐exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0.56%), and one of 66 unclassified EOEE cases (1.52%). KCNT1 mutations occurred de novo in 10 patients, and one was transmitted from the patient's mother who carried a somatic mosaic mutation. The mutations accumulated in transmembrane segment 5 (2/9, 22.2%) and regulators of K⁺ conductance domains (7/9, 77.8%). Five of nine mutations were recurrent. Onset ages ranged from the neonatal period (<1 month) in five patients (5/11, 45.5%) to 1–4 months in six patients (6/11, 54.5%). A generalized attenuation of background activity on electroencephalography was seen in six patients (6/11, 54.5%). Our study demonstrates that the phenotypic spectrum of de novo KCNT1 mutations is largely restricted to EIMFS.     

A quinidine non responsive novel KCNT1 mutation in an Indian infant with epilepsy of infancy with migrating focal seizures

Epilepsy of infancy with migrating focal seizures {a.k.a malignant migrating partial seizures of infancy (MMPSI)} is an uncommon epileptic encephalopathy with a poor prognosis. Migrating focal seizures with autonomic features, developmental stagnation and refractoriness to treatment are its key features. It is caused by genetic defects in various ion channels, most common being sodium activated potassium channel (KCNT1), found in up to 50% of cases. With advent of genetic diagnosis and precision medicine, many targeted therapies have been identified. Antagonist of KCNT1 coded ion channel like Quinidine has shown promising results in MMPSI. Here we report first mutation proven case of MMPSI from India. This child had a novel heterozygous missense mutation in exon10 of the KCNT1 gene (chr9:138650308; c.808C?>?C/G (p.Q270E)) which was pathogenic. Neither quinidine nor ketogenic diet could control his seizures. Ultimately, the child succumbed to his illness at nine months of age.     

Targeted treatment of migrating partial seizures of infancy with quinidine

Migrating partial seizures of infancy is an early onset epileptic encephalopathy syndrome that is typically resistant to treatment. The most common cause is a gain of function mutation in the potassium channel KCNT1. The antiarrhythmic drug quinidine is a partial antagonist of KCNT1 and hence may be a candidate drug for treatment of this condition. We report the case of a child with migrating partial seizures of infancy secondary to an activating mutation in KCNT1 treated with quinidine. Treatment with quinidine was correlated with a marked reduction in seizure frequency and improved psychomotor development. Ann Neurol 2014;76:457–461     

Characterization of two de novo KCNT1 mutations in children with malignant migrating partial seizures in infancy

The KCNT1 gene encodes for subunits contributing to the Na⁺-activated K⁺ current (K_Na), expressed in many cell types. Mutations in KCNT1 have been found in patients affected with a wide spectrum of early-onset epilepsies, including Malignant Migrating Partial Seizures in Infancy (MMPSI), a severe early-onset epileptic encephalopathy characterized by pharmacoresistant focal seizures migrating from one brain region or hemisphere to another and neurodevelopment arrest or regression, resulting in profound disability. In the present study we report identification by whole exome sequencing (WES) of two de novo, heterozygous KCNT1 mutations (G288S and, not previously reported, M516V) in two unrelated MMPSI probands. Functional studies in a heterologous expression system revealed that channels formed by mutant KCNT1 subunits carried larger currents when compared to wild-type KCNT1 channels, both as homo- and heteromers with these last. Both mutations induced a marked leftward shift in homomeric channel activation gating. Interestingly, the KCNT1 blockers quinidine (3–1000 μM) and bepridil (0.03–10 μM) inhibited both wild-type and mutant KCNT1 currents in a concentration-dependent manner, with mutant channels showing higher sensitivity to blockade. This latter result suggests two genotype-tailored pharmacological strategies to specifically counteract the dysfunction of KCNT1 activating mutations in MMPSI patients.     

Quinidine therapy for West syndrome with KCNTI mutation: A case report

The KCNT1 gene encodes the sodium-dependent potassium channel, with quinidine being a partial antagonist of the KCNT1 channel. Gain-of-function KCNT1 mutations cause early onset epileptic encephalopathies including migrating partial seizures of infancy (MPSI). At 5 months of age, our patient presented with epileptic spasms and hypsarrhythmia by electroencephalogram. Psychomotor retardation was observed from early infancy. The patient was diagnosed with West syndrome. Consequently, various anti-epileptic drugs, adrenocorticotropic hormone therapy (twice), and ketogenic diet therapy were tried. However, the epileptic spasms were intractable. Whole exome sequencing identified a KCNT1 mutation (c.1955G>T; p.G652V). At 2 years and 6 months, the patient had daily epileptic spasms despite valproate and lamotrigine treatment, and was therefore admitted for quinidine therapy. With quinidine therapy, decreased epileptic spasms and decreased epileptiform paroxysmal activity were observed by interictal EEG. Regarding development, babbling, responsiveness, oral feeding and muscle tone were ameliorated. Only transient diarrhea was observed as an adverse effect. Thus, quinidine therapy should be attempted in patients with West syndrome caused by KCNT1 mutations, as reported for MPSI.     

De novo gain‐of‐function variants in KCNT2 as a novel cause of developmental and epileptic encephalopathy

Variants in several potassium channel genes have been found in developmental and epileptic encephalopathies (DEE). We report on 2 females with de novo variants in KCNT2 with West syndrome followed by Lennox‐Gastaut syndrome or with DEE with migrating focal seizures. After in vitro analysis suggested quinidine‐responsive gain‐of‐function effects, we treated 1 of the girls with quinidine add‐on therapy and achieved marked clinical improvements. This suggests that the new spectrum of KCNT2‐related disorders do not only share similar phenotypic and in vitro functional and pharmacological features with previously known KCNT1‐related disorders, but also represents a further example for possible precision medicine approaches. Ann Neurol 2018;83:1198–1204     

Lacosamide monotherapy for the treatment of childhood epilepsy with centrotemporal spikes

ObjectiveChildhood epilepsy with centrotemporal spikes (CECTS) is known as age-limited focal epilepsy syndrome in childhood. Lacosamide is a third-generation antiepileptic drug. This study aimed to evaluate the efficacy of lacosamide monotherapy for the treatment of CECTS.MethodsWe enrolled 18 patients (6 girls and 12 boys) who met the following criteria: 1) the age of onset of the seizures was between 3 and 13 years of age; 2) showing at least hemifacial and/or oropharyngeal seizures; 3) interictal discharges in central and/or middle temporal electrodes; 4) no intellectual disability; 5) treatment duration of lacosamide monotherapy over 6 months. We retrospectively collected and analyzed clinical data and treatment information. We evaluated the seizure occurrences during 0–3, 4–6, and 7–12 months from the treatment initiation and the last 6 months of the follow-up. We also evaluated the outcomes as seizure-free if the patients developed no seizures both over 6 months and 3 times of pretreatment mean seizure interval at the last follow-up.ResultsOf the patients, 39%, 67% and 72% were seizure-free during 0–3, 4–6, and 7–12 months from treatment initiation, respectively. Finally, 83% of the patients achieved seizure freedom. Seizure freedom was achieved in 72% during the first 4 months of treatment. All patients continued lacosamide monotherapy during the study, although four patients showed transient fatigue or somnolence.ConclusionsLacosamide showed good efficacy for controlling seizures with fewer adverse effects, and therefore may be a good candidate as a first-line medication for the treatment of new-onset CECTS.     

Early‐onset epileptic encephalopathy with migrating focal seizures associated with a FARS2 homozygous nonsense variant

Epilepsy of infancy with migrating focal seizures (EIMFS) is now a well‐recognized early‐onset syndrome included in the ILAE classification of the epilepsies. KCNT1 gain‐of‐function variants are identified in about half of patients. In the remaining cases, the underlying genetic component is far more heterogeneous with sporadic mutations occasionally reported in SCN1A, SCN2A, SLC12A5, TBC1D24, PLCB1, SLC25A22, and KCNQ2. Here, we report, for the first time, a homozygous deleterious variant in the FARS2 gene, identified using a 115‐gene panel for monogenic epilepsies, in a patient with EIMFS. This boy was the second child born to healthy consanguineous parents. The first seizures occurred at six weeks of age. The patient rapidly developed severe epilepsy with focal discharges on EEG, migrating from one brain region to another, highly suggestive of EIMFS. At five months of age, he had daily multifocal clonic seizures and erratic myoclonic fits, which were not consistently related to spikes or spike‐and‐wave discharges. Neurological status was severely abnormal from onset and the patient died at 10 months of age from respiratory distress. Using the gene panel, a homozygous missense variant of FARS2 was identified, at Chr6 (GRCh37):g.5404829C>T, c.667C>T (NM_001318872.1), inherited from both parents, leading to an arginine‐to‐cysteine substitution, p.(Arg223Cys). FARS2 is a member of the mitochondrial aminoacyl tRNA transferase (ARS) enzymes. ARS variants are increasingly recognized causes of early‐onset epileptic and neurodevelopmental encephalopathies, however, the associated epileptic phenotype is not completely described. This case shows that FARS2‐related seizures can mimic EIMFS in the early stage of the disease. Furthermore, in the setting of migrating focal seizures of infancy, FARS2 should be considered as a further candidate gene, and increased lactate level and occurrence of refractory myoclonic seizures are possible key features to suspect FARS deficiency.     

Epilepsy of infancy with migrating focal seizures: Six patients treated with bromide

PurposeWe present six patients with epilepsy of infancy with migrating focal seizures (EIMFS) and provide a comprehensive evaluation of potassium bromide therapy.MethodBetween February 1, 2007 and July 31, 2012, six patients who met the diagnostic criteria of EIMFS were treated with potassium bromide. Potassium bromide was added to other antiepileptic drugs (AEDs) in doses ranging from 30 to 80 mg/kg/day. Plasma bromide concentration was monitored. A therapeutic bromide concentration between 75 and 125 mg/dL was considered to be ideal.ResultsFour of six children responded well to bromide. One of these patients became seizure free, but remained severely mentally impaired. Two boys, currently 4 and 6 years of age, respectively, have monthly seizures as well as axial hypotonia and severe language impairment. The fourth child responded well to bromide, having only weekly seizures and moderate psychomotor retardation. The patient who became seizure free improved visual contact and head control. In the other three patients with good control, the seizures became focal without secondary generalization and status epilepticus and hospital admission was not required. The remaining two patients did not respond well to bromide. Adverse effects were seen in three cases: vomiting in one, drowsiness in another, and acneiform eruption in the face in the remaining patient. Adverse effects resolved with dose reduction.ConclusionEarly treatment with bromides should be considered in EIMFS to control the seizures and status epilepticus and to avoid progressive cognitive impairment. Potassium bromide is an old AED. Plasma concentration monitoring should be considered.     

Quinidine in the treatment of KCNT1‐positive epilepsies

We report 2 patients with drug‐resistant epilepsy caused by KCNT1 mutations who were treated with quinidine. Both mutations manifested gain of function in vitro, showing increased current that was reduced by quinidine. One, who had epilepsy of infancy with migrating focal seizures, had 80% reduction in seizure frequency as recorded in seizure diaries, and partially validated by objective seizure evaluation on EEG. The other, who had a novel phenotype, with severe nocturnal focal and secondary generalized seizures starting in early childhood with developmental regression, did not improve. Although quinidine represents an encouraging opportunity for therapeutic benefits, our experience suggests caution in its application and supports the need to identify more targeted drugs for KCNT1 epilepsies. Ann Neurol 2015;78:995–999     

SCN2A mutation in an infant presenting with migrating focal seizures and infantile spasm responsive to a ketogenic diet

SCN2A mutations have been identified in various encephalopathy phenotypes, ranging from benign familial neonatal-infantile seizure (BFNIS) to more severe forms of epileptic encephalopathy such as Ohtahara syndrome or epilepsy of infancy with migrating focal seizure (EIMFS). Thus far, no particularly effective treatment is available for severe epileptic encephalopathy caused by SCN2A mutations in children.We present the case of a boy who developed seizures on the third day of life and received a diagnosis of EIMFS based on his clinical presentations and electroencephalography reports. Antiepileptic drugs, namely oxcarbazepine, phenytoin, valproate, levetiracetam, and clonazepam, as well as adrenocorticotropic hormone therapy failed to reduce the severity of the seizures. Seizure pattern changed to infantile spasm with extensor thrust since 5?months of age. A ketogenic diet consisting of a medium-chain triglyceride recipe was introduced at 8?months of age and the seizures were resolved in the following 10?months. A de novo mutation in SCN2A (c.573G?>?T; p.W191C) was proven through next-generation sequencing.     

Anticonvulsant Efficacy in Sturge-Weber Syndrome

ObjectiveWe analyzed individuals with epilepsy due to Sturge-Weber syndrome to determine which anticonvulsants provided optimal seizure control and which resulted in the fewest side effects.MethodsOne-hundred-eight records from a single center were retrospectively analyzed for Sturge-Weber syndrome brain involvement, epilepsy, Sturge-Weber syndrome neuroscores, and currently used anticonvulsants.ResultsOf the fourteen anticonvulsants that had been employed, the most often used agents were oxcarbazepine or carbamazepine, and levetiracetam. Individuals whose seizures at the most recent visit were fully controlled (seizure-free) for 6 months or longer were more likely to have ever tried, or currently used, oxcarbazepine or carbamazepine than those with uncontrolled seizures. Thirty-nine of 69 individuals (56.5%) were seizure-free with oxcarbazepine or carbamazepine history versus 11 of 35 individuals (31.4%) who had not taken these agents (P < 0.05); 38 of 62 patients (61.3%) were seizure-free while currently taking these anticonvulsants versus 12 of 42 (28.6%) not taking them (P < 0.01). Patients with seizure control for 6 months or longer were less likely to have ever tried, or to currently be taking, levetiracetam than those without control. Sixteen of 56 individuals (28.6%) were seizure-free with levetiracetam history versus 34 of 48 (70.8%) without it (P < 0.001); 14 of 43 individuals (32.6%) were seizure-free and currently taking levetiracetam versus 36 of 61 (59.0%) not taking it (P < 0.01). When topiramate was added as second-line medication, five of nine patients (55.6%) experienced decreased seizure severity, and worsening of glaucoma was not reported.ConclusionsCarbamazepine and oxcarbazepine were associated with better seizure control than levetiracetam in this Sturge-Weber syndrome cohort and so may be preferred as the initial therapy. When used as adjunctive therapy, topiramate was effective in this limited analysis without a clear increased incidence of glaucoma.     

Repetitive transcranial magnetic stimulation to treat benign epilepsy with centrotemporal spikes

ObjectivesTo investigate the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) on patients with benign epilepsy with centrotemporal spikes (BECTS).MethodsIn this open pilot study, we enrolled four BECTS patients who had frequent seizures (at least 3 seizures during the 3-month baseline). After localizing sources of interictal epileptiform discharges (IEDs) with magnetoencephalography, IEDs-source-rTMS (1 Hz) with 500 pulses at 90% of resting motor threshold was applied for 10 weekdays in each patient. The primary outcome measure was the seizure-reduction rate after rTMS. Other outcome measures were the spike-wave index (SWI), behavioral evaluation, and adverse effects.ResultsAll four patients received at least 3 months seizure-free after rTMS. Compared with baseline, SWI decreased significantly after rTMS in three patients (patient 1, 3 and 4) (P = .002, P = .007, and P < .001, respectively). Attention deficit identified in two patients in baseline recovered to the normal range after rTMS. No adverse effect was observed.DiscussionOur preliminary observation provides a promising approach to reducing clinical seizures for BECTS with frequent seizures. Of importance, our data may provide a potentially novel method for the high prevalence of behavioral problems in BECTS patients via decreasing cortical hyperexcitability.     

Clinical characteristics of KCNQ2 encephalopathy

PurposeKCNQ2 mutations are associated with benign familial neonatal epilepsy (BFNE) or developmental and epileptic encephalopathy (DEE). In this study, we aimed to delineate the phenotype of KCNQ2 encephalopathy and evaluate the treatment response.MethodsThirteen patients of KCNQ2 encephalopathy were included in the study. Characteristics of KCNQ2 mutations, electroclinical features, clinical course, and response to the treatment were analyzed.ResultsAge range of the thirteen patients was between 3 months and 20.9 years. The onset of seizures in 11 patients ranged from 1 to 3 days of age, while in the other two patients it was 7 and 40 days, respectively. Most common initial seizure types were tonic seizures. Initial EEGs were suppression burst pattern in seven patients and slow and disorganized background with multifocal epileptiform discharges in six patients. Initial epilepsy syndrome was Ohtahara syndrome in seven patients, neonatal focal seizure in five patients, and focal epilepsy beyond neonatal period in one patient. Sodium channel blockers including oxcarbazepine (OXC) (n = 3), lamotrigine (LTG) (n = 3), phenytoin (PHT) (n = 2), topiramate (TPM) (n = 2), and zonisamide (ZNS) (n = 1) were tried and found effective in eleven patients. Ultimately, 12 of 13 patients became seizure-free. However, developmental outcomes were poor.ConclusionsSodium channel blockers are effective in seizure control in these patients with KCNQ2 encephalopathy. Early recognition of KCNQ2 encephalopathy and early use of sodium channel blockers might be helpful in seizure control.     

Postsurgical outcome in patients with olfactory auras and drug-resistant epilepsy

ObjectivesWe investigated the clinical features associated with olfactory auras in patients with drug-resistant epilepsy and also hypothesized that this type of aura may predict worse postsurgical outcome in patients with drug-resistant temporal lobe epilepsy (TLE).MethodsIn this retrospective analysis, data from all patients with drug-resistant epilepsy who underwent epilepsy surgery were reviewed. Patients were prospectively registered in a database from 1986 through 2016. We assessed outcome in the first 5 years after surgery to produce a Kaplan–Meier estimate of seizure recurrence. Post-surgical outcome was classified into two groups; 1) seizure-free, with or without auras; or 2) relapse of complex partial or secondarily generalized seizures. We also investigated the clinical features of patients with TLE and olfactory auras compared with those without olfactory auras.ResultsWe studied 1186 patients. Thirty-seven patients (3.1%) reported olfactory auras with their seizures. Thirty-two patients had temporal lobe surgery. Intracranial video-EEG recording was performed in four patients. Three patients with lateral temporal neocortical seizures reported olfactory auras with their seizures; two of them were seizure-free after surgery. There were no significant clinical differences between patients with TLE and olfactory auras compared with those without. Seizure outcome after surgery was not significantly different between these two groups (p = 0.3; Cox–Mantel test).ConclusionThe rarity of olfactory auras makes it difficult to propose new diagnostic and treatment strategies. A multicenter approach, which can enroll more patients, is needed to devise better therapies for patients with drug-resistant epilepsy and this symptom.     

Loss of the initial efficacy of levetiracetam in patients with refractory epilepsy

PurposeThe efficacy and safety of the anti-convulsive drug levetiracetam (LEV) has been well documented but few clinical studies have investigated tolerance to LEV. The aim of this study was to evaluate the loss of the initial efficacy of LEV in adult patients with refractory partial-onset seizures.MethodsWe enrolled patients with refractory partial epilepsy who were started on add-on LEV treatment. The efficacy of LEV was evaluated every three months and the seizure frequency was decided by the average number of monthly seizures. A responder was defined as a patient with a ≥50% reduction in seizure frequency from the baseline. Seizure freedom was defined as a seizure-free status from the beginning of LEV treatment to the evaluation period. Loss of the initial efficacy was defined as a shift from responder status during the first three months of LEV treatment to non-responder status during the follow-up period.ResultsA total of 95 epilepsy patients were analyzed. During the first three months of LEV treatment, 50 (52.6%) of the 95 patients were responders with a ≥50% seizure reduction. Nine patients (18.0%) showed a loss of initial efficacy during the second three-month period. In contrast, only two (4.0%) of the non-responders during the first three months became responders during the next three months. However, this difference did not reach statistical significance (P = 0.054). Based on Kaplan–Meier survival estimates, 49.2% of the patients who initially responded to LEV treatment during the first three months were predicted to lose this response at 42 months. Loss of the initial efficacy of LEV treatment occurred mostly within 18 months.ConclusionThis study suggests that the occurrence of tolerance is more common than late gain of efficacy of treatment although larger prospective studies would have to be carried out to prove this observation.     

A multicenter trial of oxcarbazepine oral suspension monotherapy in children newly diagnosed with partial seizures: A clinical and cognitive evaluation

PurposeWe conducted a prospective, multicenter, open label trial to evaluate the effectiveness of oxcarbazepine (OXC) oral suspension as monotherapy for children newly diagnosed with partial seizures.MethodsThis trial included a two- to eight-week titration and stabilization period to achieve effective target doses and a 24-week maintenance phase. The primary outcome measure was the seizure-free rate over six months, while a secondary measure was the change in cognition and behavior from screening to the end of the maintenance phase. The effectiveness of OXC was compared in intellectually normal versus intellectually impaired children (intelligence quotient <70).ResultsWe enrolled 171 patients and analyzed 168 as the per-protocol (PP) group (3 patients had protocol violations). The mean age of the PP group was 8.4 ± 2.7 years. The maintenance dose of OXC was 24.9 ± 8.0 mg/kg/day. Of the 168 patients included in the efficacy analysis, 122 (72.6%) completed the study and 94 (56.0%) became seizure-free after the OXC treatment. Comparing the efficacy of OXC for intellectually normal and intellectually impaired patients, 79 (56.8%) of the 139 intellectually normal patients and 15 (51.7%) of the 29 intellectually impaired patients became seizure-free (P = 0.61). After treatment, intelligence scale scores improved in intellectually normal patients compared to the intellectually impaired children (P < 0.05). Social problems quantified by behavior scales improved in intellectually impaired patients compared to intellectually normal children (P < 0.05).ConclusionsOXC is effective and well-tolerated as monotherapy in children with partial seizures. There was no difference in the effectiveness of OXC between intellectually normal and intellectually impaired children.     

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.     

Clinical phenotypes within non-surgical patients with mesial temporal lobe epilepsy caused by hippocampal sclerosis based on response to antiepileptic drugs

PurposeTo evaluate evolution and elucidate clinical phenotypes related to prognosis of patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) treated exclusively with antiepileptic drugs (AED).MethodsForty-seven out of 68 MTLE-HS patients treated between January 2005 and June 2010 were retrospectively studied for demographic, clinical and outcome data. The population was divided into drug-responder and drug-resistant patients; the latter was divided, according to the duration of the seizure-free periods along their evolution, into patients with at least one seizure-free period longer than one year and those with shorter periods. Variables were compared between drug-responders vs drug-resistants and drug-resistants with long seizure-free periods vs drug-resistants without it.ResultsThere were 7 (15%) drug-responders, 39 (83%) drug-resistants and 1 patient (2%) with an undetermined response. Eighteen (46%) drug-resistant individuals had seizure-free periods longer than one year, with mean duration of 46 months (3.8 years). Since no factor was statistically associated with long seizure-free period within drug-resistants, we can clinically distinguish two phenotypes: women with left HS and late onset of seizures, with poor prognosis, and men with right HS and earlier appearance of seizures, attaining a better outcome. Twenty out of 47 (42.5%) patients followed an intermittent pattern of epilepsy.ConclusionsNon-surgical MTLE-HS drug-resistant patients can achieve long seizure-free periods with AED, but relapses are common. Female gender, left or bilateral lesion and later onset of seizures seem to be bad prognosis factors within MTLE-HS drug-resistant patients.