Baseline cognition, behavior, and motor skills in children with new-onset, idiopathic epilepsy

Aim  Epilepsy is associated with difficulties in cognition and behavior in children. These problems have been attributed to genetics, ongoing seizures, psychosocial issues, underlying abnormality of the brain, and/or antiepileptic drugs. In a previous study, we found baseline cognitive differences between children with partial versus generalized and convulsive versus non-convulsive seizures. Measures in that study focused primarily on IQ scores. In the present study, we assessed baseline function with respect to new learning, attention, and memory, thus providing a more comprehensive profile than our previous study.
Method  We examined 57 children (42 females, 15 males), aged 6 to 17 years (mean 10y 1mo, SD 2y 9mo), with new-onset, idiopathic epilepsy, using tests of cognitive function reflective of new learning, memory, and attention. Seizures were classified as generalized convulsive ( n =5), generalized non-convulsive ( n =18), or focal ( n =34). Focal seizures were divided into unilateral versus bilateral independent foci, and presence versus absence of secondary generalization.
Results  Attention was a particular area of weakness across all groups. The Vocabulary score of an intelligence screen was higher for the focal seizure groups ( p =0.012), primarily because of a difference between the unilateral focal and the primary generalized groups ( p <0.047). Children with generalized, non-convulsive seizures performed significantly worse than the focal group on a measure of short-term auditory memory ( p =0.019). All groups performed poorly on a test of visual–motor speed.
Interpretation  These findings suggest intrinsic abnormalities in children with new-onset, idiopathic epilepsy at baseline.     

Beneficial effects of antiepileptic medication on absence seizures and cognitive functioning in children

In this prospective clinical study, the effects on cognitive functioning of absence seizures, epileptiform EEG discharges, and their abolishment by antiepileptic medication were evaluated in patients newly diagnosed with childhood absence epilepsy or juvenile absence epilepsy. Eleven children in the study group and ten age- and gender-matched controls with mild asthma underwent combined video/EEG and neurocognitive assessment (IQ, fine-motor fluency, attention, visual and spatial memory). The neuropsychological assessment was repeated after the introduction of antiepileptic medication. Ten children with absence epilepsy became clinically seizure free. The study group improved in attention, fine-motor fluency, and visual memory. The controls improved only in fine-motor and attention skills. Duration of generalized 3-Hz spike-wave discharges and clinical absence seizures was negatively correlated with performance on the visual memory task. Cessation of seizures induced by antiepileptic medication may support neurocognitive functioning in children.     

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

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

Interictal cognitive changes in epilepsy

There is little evidence for significant intellectual deterioration in well-controlled seizure disorders. With recurrent convulsive seizures, the picture is less clear and depends on severity, type, age of onset, and frequency of toxic levels of antiepileptic drugs (see Table 1). In the interictal state, deficits in verbal language and memory have been observed, especially in patients with complex partial seizure foci in the left (dominant) hemisphere. The memory deficits appear to affect new learning and retention of material; the verbal deficits are more subtle, affecting word-finding, verbal fluency, and comprehension abilities. Both of these changes may either go unnoticed by the patient in day to day activities or be attributed to the effects of antiepileptic medication. Antiepileptic drugs can also affect interictal cognitive functioning. The worst of these appears to be phenobarbital; phenytoin has an intermediate effect; valproic acid and carbamazepine as single agents seem to produce fewer adverse effects. However, individual patients may be particularly sensitive to cognitive side effects of certain drugs. Finally, attention deficits and slowing of cognitive processes, either chronically or intermittently, appear to affect all seizure patients to some extent. The syndrome is more prominent in frontal or generalized seizure patterns. The intermittent nature of these disturbances has been emphasized in recent research on subclinical interictal spike-wave electrical phenomena.     

Dravet syndrome and SCN1A gene mutation related-epilepsies: cognitive impairment and its determinants

Some studies have demonstrated that cognitive decline occurs in Dravet syndrome, starting shortly after the onset of seizures, rapidly progressing and then plateauing within a few years. It is unclear whether children that develop the syndrome had entirely normal cognitive skills before seizure onset, since subtle impairment easily escapes recognition in small infants. It is also difficult to demonstrate whether a recognisable profile of cognitive impairment or a definite behavioural phenotype exists. No clear-cut imaging or neuropathological marker or substrate has been recognised for cognitive impairment in this syndrome. However, there are different potentially causative factors, including the specific effects on the Nav1.1 channels caused by the underlying genic or genomic defect; frequent and prolonged convulsive and non-convulsive seizures or status epilepticus; recurrent subtle ictal phenomena, such as that accompanying pronounced visual sensitivity; the use of antiepileptic drugs with cognitive side effects, especially in heavy multiple-drug therapy; and the restrictions that children with severe epilepsy inevitably undergo.     

Treatment of status epilepticus]

Status epilepticus (SE) is a condition requiring emergency care. There are convulsive SE, non-convulsive SE including complex partial status and absence status, non-convulsive electric SE and pseudostatus epilepticus, although convulsive SE is the most common. Diagnosis of status epilepticus of complex partial seizures (CPS) and absence seizures was significantly delayed because delays in seeking medical attention were common. The seizures were generalized convulsive SE in 84% and CPS status in 16%, and the overall mortality rate was 15% in 41 SE patients of our study. EEG monitoring is important to make or exclude the diagnosis of SE. Diazepam is the first choice medication and effective in the management of SE, and lately, lorazepam, midazolam, propofol and pentobarbital etc as emergency therapy. Phenytoin is also considered first-line agent in the emergency management of SE. Repetitive transcranial magnetic stimulation (rTMS) led to a prolonged latency for seizure induction after an intraperitoneal injection of pentylenetetrazol (PTZ) and effectively prevented the development of status epilepticus of PTZ-induced convulsions in the rats. Our data suggest that rTMS has suppressive effects on the neuronal excitability in rats. These effects are anticonvulsive and suggest the possibility of therapeutic use of rTMS in the patients with refractory seizures.     

How common is ictal hypoxemia and bradycardia in children with partial complex and generalized convulsive seizures?

Purpose: Autonomic effects of seizures, including cardiorespiratory abnormalities, may be involved in sudden unexpected death in epilepsy (SUDEP). The purpose of this study was to determine the prevalence and risk factors for ictal hypoxemia (oxygen saturation <90%) and ictal bradycardia (heart rate < second percentile for age) in children during recorded seizures. Methods: The medical records of children admitted to our Epilepsy Monitoring Unit (EMU) between November 1, 2007 and March 13, 2009 were reviewed. Children selected for this study had at least one partial complex or generalized convulsive seizure with recorded oximetry and/or heart rate data. Results: Forty‐nine children were identified and 225 seizures were analyzed. Ictal hypoxemia was observed in 48.9% of children and 26.8% of seizures. Ictal hypoxemia was significantly more likely to occur during generalized versus nongeneralized seizures (43.9% vs. 18.9%) and when tapering antiepileptic drugs (AEDs) (75% vs. 35.5%). For partial complex seizures, there was an association between ictal hypoxemia and prolonged seizure duration. There was no correlation between ictal hypoxemia and partial seizure onset localization or lateralization. Ictal bradycardia occurred in 8.2% of children and 3.7% of seizures. Ictal bradycardia was observed solely with partial complex seizures of extratemporal onset. Due to the low prevalence of ictal bradycardia, these findings were not statistically significant. Discussion: Ictal hypoxemia is common, particularly in the setting of generalized tonic–clonic seizures, prolonged partial complex seizures, and when AEDs are tapered. In contrast to previous ictal bradycardia studies, ictal bradycardia occurred exclusively in extratemporal partial complex seizures in this cohort.     

Effects of age of onset of partial and generalized seizures on neuropsychological performance in children

Neuropsychological performance data from 106 children with epilepsy were evaluated to determine the effects of seizure type and age of onset. The performance of children with partial seizures (N = 49) was similar to that of children with generalized seizures (N = 57). Only one of 13 tests showed a significant difference between groups, with children with partial seizures performing better on that test. The effects of age of onset were also similar in the two seizure groups. Children whose seizures began before the age of 5 years performed significantly worse than children whose seizures began later on four measures (Verbal IQ, Performance IQ, Trails A, and Trails B) and performed more poorly, but not significantly so, on the other nine measures in the battery. A breakdown of the partial group into simple partial, complex partial, and secondarily generalized partial seizure groups found a significant difference between the groups on only one variable, but there were suggestions in the data that the performance of the partial secondarily generalized group was worse than the other two groups. These results indicate that variables associated with an early onset of seizures, regardless of type, place a child at risk for cognitive dysfunction.     

Chronic management of seizures in the syndromes of idiopathic generalized epilepsy

As a group, idiopathic generalized epilepsies (IGEs) have the highest rates of complete seizure control with medication. However, there are little evidence-based data to guide drug choice for treatment. Examples of IGE include absence epilepsy, generalized tonic-clonic epilepsy, and juvenile myoclonic epilepsy. Generalized epilepsies seem to be particularly vulnerable to seizure aggravation, and medications that are primarily effective against partial seizures are more commonly involved in seizure aggravation than other medications. A review of current research has shown that only a few medications can control IGE without potentially causing seizure aggravation. Broad-spectrum antiepileptic drugs such as valproate (VPA), lamotrigine, and topiramate are extremely effective at controlling a variety of seizures without causing excessive seizure aggravation. Among these drugs, VPA has the longest clinical experience history and the largest body of published data.     

Management of epilepsy in mentally retarded children using the newer antiepileptic drugs, vagus nerve stimulation, and surgery

Clusters of seizures, prolonged seizures, and status epilepticus occur more frequently in children with multiple disabilities, and chronic seizures are more likely to be refractory to treatment. In many patients, the seizures appear to contribute to the mental retardation. Thus, if the lives of these children are to improve, seizure control is essential. However, medical treatment can interfere with cognition and cause behavioral disturbances, making life very difficult for the child and the child's family. With the introduction of 10 new antiepileptic drugs in the last decade, the treatment of epilepsy in multiply handicapped children has significantly advanced. These new antiepileptic drugs may improve seizure control, medication tolerance, or both. Although the ultimate therapeutic goal is to keep children seizure free and alert, compromises regarding medication choice and dosage are still necessary in many cases. Novel treatment options, such as the vagus nerve stimulator, may decrease seizure frequency without behavioral or cognitive side effects. In carefully selected children with specific epilepsy syndromes, epilepsy surgery can provide partial or complete relief from seizures.     

The ketogenic diet for intractable epilepsy in adults: preliminary results

PURPOSE: Little is known concerning the efficacy and adverse effects of the ketogenic diet in adults with refractory epilepsy. This review reports preliminary results in 11 adults prospectively treated with the diet who had previously failed to gain seizure control with two or more medications and/or surgery. METHODS: Eleven patients nine women, two men), median age, 32.2 years (range, 19-45 years) were treated with the ketogenic diet with a 4:1 ratio with fluid restriction. Six patients had symptomatic partial epilepsy, and five had symptomatic generalized epilepsy. The diet was administered in addition to antiepileptic medication by a multidisciplinary team geared exclusively to adult patients. Medications were not changed while on the diet. Seizure frequency at 8-month follow-up was compared with frequency during a baseline period. RESULTS: At 8 months of follow-up, three patients had a 90% seizure decrease, three patients had a 50-89% decrease in seizure frequency, one patient had <50% seizure decrease, and four patients discontinued the diet. Of the four patients who discontinued the diet, two had no appreciable change in their seizures despite high ketone levels. Two patients were unable to maintain persistent ketosis at home, despite having done so in the hospital. All seizure types responded to the diet. Common adverse effects included constipation and menstrual irregularities in women. Most patients reported a subjective improvement in concentration. Serum cholesterol and triglycerides increased while on the diet as well as cholesterol high-density lipoprotein (HDL) ratios. CONCLUSIONS: The ketogenic diet shows promise in both adult generalized and partial epilepsy. Persistent ketosis was possible in adults, and the diet was tolerable for most patients. Further study assessing the efficacy of the ketogenic diet, and the cognitive and long-term effects is ongoing.     

Neuropsychological and behavioral status of children with complex partial seizures

Neuropsychological and behavioral status were examined in 57 children aged 7 to 16 years with complex partial seizures (CPS) and compared with 27 sibling control children of the same age. Epilepsy had a significant effect on both cognitive and behavioral adjustment measures. Children with CPS had significant impairment across all seven cognitive domains assessed, reflective of a profile of relatively diffuse and generalized cognitive dysfunction. Age at onset of recurrent seizures was the strongest and most consistent predictor of adequacy of cognitive functioning; earlier age at onset was associated with poorer cognitive status. Children with CPS also had more problems compared with sibling control children on measures of social and school competence and internalizing behavior problems, but not externalizing behaviors. Further, frequency of seizure activity in the past year, rather than age at seizure onset, emerged as the strongest predictor of these behavioral difficulties. These findings are discussed in the context of understanding the impact of CPS on cognition and behavioral adjustment, and identifying the contribution of various aspects of the neurodevelopmental course of CPS to these issues.     

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

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

Predictive factors of seizure frequency and duration of antiepileptic treatment in rolandic epilepsy: a retrospective study

Factors useful to predict seizure frequency and duration of antiepileptic treatment of children with benign partial epilepsy and rolandic spikes were retrospectively evaluated in 72 patients seizure-free for at least 5 years and off antiepileptic drugs for at least 2 years. Three groups were considered: Group I, 11 patients (15%) with a single seizure: Group II, 40 patients (56%) with 2 to 6 seizures; Group III, 21 patients (29%) with over 6 seizures. Significant predictors of rare seizure frequency were: presence of convulsive generalized seizures as the sole ictal manifestation, found in 17 patients of Group II and in one patient of Group III (p less than 0.001), and longer average interval between first and second seizure in Group II than in Group III (7.8 months versus 3.5 months, p less than 0.0001). Although the average duration of the disease was significantly shorter in Group II than in Group III (1.5 years versus 4.5 years, p less than 0.00001), the duration of the antiepileptic treatment was similar in both groups. Of the 8 untreated patients, 5 had a single seizure and one had 2 seizures. Therefore, it is suggested that antiepileptic treatment be delayed without risk until the third seizure occurrence and restricted to patients with no predictor of rare seizure recurrence.     

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

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

Generalized‐onset seizures with secondary focal evolution

The international seizure classification recognizes that partial‐onset seizures can become secondarily generalized, but generalized‐onset seizures are expected to remain generalized. We report six patients who had recorded seizures with generalized onset, but subsequent evolution into a focal discharge. The clinical seizure onset was generalized absence or myoclonic, and the most common subsequent clinical pattern was prolonged behavioral arrest with mild automatisms, and then postictal confusion. The ictal discharge started with generalized spike‐and‐wave activity and then acquired a focal predominance. Interictal epileptiform activity was generalized. There were no focal magnetic resonance imaging abnormalities. Four patients were misdiagnosed with complex partial seizures. All patients were initially refractory, but three became seizure‐free and three improved after treatment with antiepileptic medications appropriate for absence or myoclonic seizures. Generalized‐onset seizures that acquire focal features are easily misdiagnosed as complex partial. These seizures have a more favorable response to medications effective against generalized absence and myoclonic seizures.     

Impact of Taking Antiepileptic Drugs at School in a Group of Children and Adolescents

The impact of epilepsy on the quality of life can be significant. Peer acceptance is important for the social adjustment of children. Even children with controlled seizures may appear different from their peers if they are required to leave the classroom to take antiepileptic drugs. The objective of this pilot study was to determine if there is a measurable effect on peer relationships in children having to leave the classroom or recess time to take antiepileptic medications in a school setting. Results of surveys mailed or distributed by a pharmacist were obtained from 47 children, aged 6 to 18 years. Children who reported poor seizure control were significantly more likely to have trouble making friends compared with those with seizures controlled (70% vs 27%, P = 0.02). Even though the majority reported good seizure control (7/8), the children who left the classroom to take medications reported that they had significantly more trouble making friends than those who did not leave the classroom (63% vs 21%, P = 0.03). Therefore, the effect of taking medication at school may be associated with a significant decrease in social and peer relationships, even in children with self-reported good seizure control.     

Efficacy of levetiracetam at 12 months in children classified by seizure type, cognitive status, and previous anticonvulsant drug use

In a retrospective study of 59 children (ages 9 months to 23 years; mean age 11 years) with intractable epilepsy, seizure frequency was determined before and after 12 months of levetiracetam therapy. Charts were reviewed for seizure type (focal, generalized, or mixed), cognitive function (no special education versus special education), concomitant anticonvulsant medications (range 0-5), and the number of previous anticonvulsant drugs (range 1-12). Good to excellent seizure control (50-100% reduction) was attained in 6 (40%) patients with focal seizures, 16 (55%) patients with generalized seizures, and 8 (61%) patients with mixed seizures; these efficacy rates were not significantly different. The efficacy of levetiracetam was independent of cognitive status. Adverse effects were not associated with higher mean doses. This could be attributable to different rates of metabolism or represent idiosyncratic responses to the medication. Our finding that those children taking the combination of levetiracetam and zonisamide had a significantly worse outcome than those on levetiracetam and a different drug warrants further study, both clinically and from the standpoint of the mechanisms of action of levetiracetam and zonisamide and/or their pharmacodynamic interactions.     

Temozolomide treatment of refractory epilepsy in a patient with an oligodendroglioma

A 40-year-old man with a left frontotemporal grade II oligodendroglioma developed seizures that were refractory to 14 antiepileptic medications, the ketogenic diet, and epilepsy surgery. With temozolomide therapy, his seizure frequency gradually changed from 30 partial seizures per day to a single simple partial seizure in 6 months. No additional therapeutic measures were introduced during this time. This reduction in seizure frequency appears attributable solely to temozolomide therapy.