The effect of seizure type and medication on cognitive and behavioral functioning in children with idiopathic epilepsy

Antiepileptic drugs have been reported to have a variety of adverse effects on behavior and performance in children with epilepsy. Previous studies investigating these side effects, however, have not controlled for the baseline status of the child (e.g. underlying neurological condition, seizure type, socioeconomic status, family variables), making it difficult to determine whether changes in function are attributable to the use of medication. We investigated the cognitive and behavioral profiles of 43 children, aged from 4 to 16 years, with new onset, idiopathic seizures. Twenty-six of these children participated in a 6-month follow-up study, and 12 in a 12-month follow-up study, investigating the effects of antiepileptic medications on psychological functioning. The children were of average intelligence (mean 1Q108) and had not previously been treated with antiepileptic medication. Children were classified as having either generalized convulsive, generalized non-convulsive (absence), simple partial, or complex partial seizures. Prior to the initiation of treatment, children with partial seizures were found to perform better than children with generalized seizures on measures of cognitive functioning. Children with convulsive seizures obtained significantly higher cognitive scores than those with non-convulsive seizures. Children with generalized non-convulsive seizures had lower cognitive scores than subjects with other types of seizure. No differences were found between groups at baseline prior to the initiation of antiepileptic medications. Analysis of subjects' performance after 6 and 12 months of antiepileptic therapy showed no significant deterioration attributable to medication. The differences in cognitive performance of the four seizure groups at baseline were not apparent at the time of follow-up. These results indicate that intrinsic and environmental variables may play a more significant role in predisposing certain children to cognitive and learning problems than do antiepileptic medications.     

Emergency department admission of children with unprovoked seizure: recurrence within 24 hours

Little is known about acute recurrence of seizures, and children with unprovoked seizure tend to be admitted for observation on the basis of the risk factors known for epilepsy. The purpose of this study is to define the clinical profile of pediatric seizure patients who are likely to be admitted and to analyze the incidence and the risk factors of acute recurrence of seizures in the admitted patients within 24 hours after admission. A retrospective chart review was performed on pediatric patients who arrived to the Schneider Children's Hospital Emergency Department because of an unprovoked seizure who were not on antiepileptic medication. Fifty-nine percent of children who arrived to the emergency department were admitted. Emergency department physicians tend to admit children with younger age (P<0.01), multiple seizures (P<0.001), and children who were treated in the emergency department (P<0.001). Twenty percent of admitted patients had one or more seizures within 24 hours. Multiple seizures before the emergency department arrival was a significant risk factor for acute recurrence (33%, P<0.05). Based on our findings that 20% of admitted children had one or more seizures within 24 hours, we think it is justified to admit and observe the children with seizures who are not on antiepileptic medications if the follow-up cannot be ensured.     

When to start and stop anticonvulsant therapy in children.

A large body of evidence has accrued in recent years, allowing a more precise estimate of the risk of seizure recurrence for children with new-onset seizures and for children who stop therapy once they are seizure-free. The primary goal for children with epilepsy is not solely freedom from seizures, but an optimal quality of life. Unless the physician can predict a recurrence risk at the extremes (0% or 100%), the nonmedical factors that affect quality of life will usually dominate the family's decision making. Together, the physician and family should weigh the risks and benefits of treatment against the risks and benefits of withholding or stopping therapy. Antiepileptic drug treatment should be withheld from most children until they have had a second seizure. Most children who receive antiepileptic drug treatment should attempt to taper their medications after 2 years without seizures.     

Open study of clobazam in refractory epilepsy

Clobazam is a 1,5-benzodiazepine reported to have a wide spectrum of antiepileptic activity and is associated with less neurotoxicity than the 1,4-benzodiazepines, nitrazepam and clonazepam. The effect of clobazam on seizure control and neurologic behavior was examined prospectively in 115 children (average age: 8.4 years) with intractable seizures. Eighteen children (16%) became seizure free and a further 35 (31%) demonstrated a greater than 90% decrease in seizure frequency. Tolerance to the antiepileptic effect of clobazam was observed in 30 of 79 children (38%) who demonstrated an initial improvement in seizure control. Complete tolerance was observed in 9 patients, partial tolerance in 9, and partial tolerance that responded to an increased dose of clobazam in 12. Seventy-two percent of patients reported improvement and 26% worsening in at least one parameter of neurologic function after beginning clobazam. The improvement in neurologic function correlated poorly with change in seizure control. Patients who discontinued 1,4-benzodiazepine (n = 37) had a greater improvement in attention span, alertness, balance, drooling, and mood compared to the remainder of the group. These data suggest that clobazam is effective in the treatment of children with a wide range of epilepsies and seizure types and support the clinical impression that clobazam is associated with less neurotoxicity than the 1,4-benzodiazepines.     

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 Sudden Unexplained Death Syndrome in Epilepsy: Demographic, Clinical, and Postmortem Features

Sudden unexplained death syndrome (SUDS) accounts for about 10% of deaths in patients with epilepsy. It is associated with subtherapeutic postmortem serum antiepileptic drug (AED) levels but no anatomic cause of death on autopsy. The mechanisms of death are not known. We investigated 44 cases of SUDS for details of seizure history, treatment, medical and psychological history, events at the time of death, and postmortem findings. Cases of status epilepticus, drowning or other identifiable causes of death were excluded. Two groups emerged: five children with uncontrolled seizures receiving multiple AEDs and good compliance with medications, and 39 adults with less frequent seizures, often receiving monotherapy, but noncompliant with medications. Four children (80%) but only one adult (3%) had fully therapeutic postmortem AED levels. Sixty-three percent of adults recently had experienced an unusually stressful life event. Investigation of the circumstances at the time of death suggested two possible modes of death: (a) a seizure with an immediately fatal arrhythmia, or, (b) a seizure, recovery, then delayed secondary respiratory arrest or arrhythmia. Even though the mechanisms of death are unknown, the risk of SUDS may be reduced by encouraging patients to be compliant with medications, especially in times of unusual life stress.     

Initiation and discontinuation of antiepileptic drugs

The issues of when to initiate and discontinue antiepileptic drugs (AEDs) are reviewed using an approach that emphasizes weighing the relative risks and benefits of the therapeutic decisions. The majority of children and adults who present with a first unprovoked seizure will not experience further seizures. Treatment reduces recurrence risk but does not alter long-term prognosis. Treatment should be deferred until a second seizure has occurred. The majority of children and adults who are seizure free for two or more years on medications will remain so when medications are withdrawn. The risk of reoccurrence is somewhat higher in adults. The consequences of recurrence are much more significant in adults. Most children who are seizure free on medications should have at least one attempt at medication withdrawal. In adults, the decisions need to be individualized based on a variety of factors including age, sex, occupation, and the presence or absence of risk factors for reoccurrence.     

Focal status epilepticus as atypical presentation of pyridoxine-dependent epilepsy

Pyridoxine-dependent epilepsy usually presents in the neonatal period or even in utero, is refractory to antiepileptic medications, and is treatable with lifelong administration of pyridoxine. The seizures are typically generalized tonic-clonic, although myoclonic seizures or infantile spasms have been described. We report an infant who presented at 5 months of age with a right-sided clonic seizure with fever. Subsequently, she had recurrent right focal or generalized seizures despite sequential treatment with various antiepileptic medications. At 7 months, she was hospitalized with status epilepticus, which was finally controlled with pyridoxine. After she became seizure free, she continued to have a strong left arm preference with mild weakness of the right arm and delayed language skill. Eventually, she outgrew these symptoms. This case illustrates that pyridoxine-dependent epilepsy, although rare, must be included in the differential diagnosis of focal seizures, especially when the seizures are refractory to traditional antiepileptic drugs.     

Discontinuing Medication in Epileptic Children: A Study of Risk Factors Related to Recurrence

We studied 70 children who had experienced at least two seizures before age 12 years, excluding febrile seizures, neonatal seizures, or seizures occurring during a metabolic, or infectious insult to the central nervous system (CNS) and who had been seizure free for at least 2 years. Twenty children (28.5%) experienced a recurrence, 75% during antiepileptic (AED) drug discontinuation or less than 6 months after discontinuation. Risk factors statistically related to seizure recurrence were greater than 10 seizures before seizure control, an abnormal EEG in the year before AED discontinuation, presence of focal neurologic signs and/or mental retardation, and presence of a mixed seizure pattern. Fourteen children (70%) with recurrence had two or more risk factors, whereas 36 (72%) without recurrence had no risk factor or only one. We conclude that a selected group of epileptic children who remain seizure-free for a period of at least 2 years can have AEDs discontinued based on presence or absence of risk factors.     

Predicting antiepileptic drug response in children with epilepsy

In clinical practice, after diagnosis and when treatment has begun, it is important to predict as soon as possible which children will become seizure-free and which are likely to develop medically intractable seizures. This article summarizes factors predicting seizure remission in childhood-onset epilepsy treated with antiepileptic drugs (AEDs). Sustained seizure remission can be expected in over 90% of idiopathic epilepsies of childhood and in neurologically normal children with epilepsy having infrequent seizures showing early remission after starting treatment with AEDs. Even in the presence of symptomatic etiology of epilepsy--focal seizures and syndromes; high seizure frequency prior to or during treatment; seizure clustering; and poor or delayed response to first adequate drug therapy--up to 60% of children with treated epilepsy are able to enter long-term remission. However, remission can be expected in only 30% or less of those with catastrophic epilepsies of childhood.     

Childhood absence epilepsy requiring more than one medication for seizure control

INTRODUCTION: Absence epilepsy is the most common primary generalized epilepsy syndrome encountered in pediatric practice. Treatment is pharmacologically specific and usually successful with a single medication. The objective of this study was to identify any clinical or electroencephalographic features at initial presentation in a consecutive cohort of children with absence epilepsy that may be associated with the need for a second medication. METHODS: A computerized pediatric neurology database (1991-2007 inclusive) was retrospectively searched for all patients with typical absence seizures, 3 Hz spike and wave on EEG and no apparent symptomatic etiology who were over the age of two years at seizure onset with at least one year of follow-up. All such children were then divided into two groups; a) those requiring a single medication for seizure control (Group 1), and b) those requiring two medications for seizure control despite optimal management with the initial medication as determined by serum drug monitoring (Group 2). Clinical and electrographic features evident at diagnosis were then contrasted between Group 1 and 2. RESULTS: Seventy-five children with absence seizures were initially identified with 52 meeting the study's inclusion and none of the exclusion criteria. Of these 52 children, 43 required a single medication for seizure control (Group 1), while 9 required two or more medications for seizure control (Group 2). A significant difference (p < 0.05) was apparent between Group 1 and 2 with respect to gender (16/43 males vs 8/9 males) and mean age of diagnosis (8.19 years +/- 3.00 vs 6.06 years +/- 2.22). Age of onset of seizures, interval duration of seizures prior to treatment initiation, duration of seizures, presence of automatisms, family history, presence of co-morbid conditions and EEG findings were not found to be significantly different between the two Groups. CONCLUSIONS: Male gender and an earlier age of diagnosis is associated with the need for two medications for seizure control in children with absence epilepsy. This observation may suggest the need for more intensive early programmatic follow-up for young male children with newly diagnosed absence epilepsy to effect more rapid attainment of seizure control.     

Levetiracetam monotherapy for elderly patients with epilepsy.

We retrospectively identified 14 elderly patients with a history of partial seizures who received levetiracetam (LEV) monotherapy. Patients began LEV either as first line therapy (n=5) or were converted to LEV monotherapy (n=9) after failing prior antiepileptic medications (AEDs). Thirteen patients continued on LEV monotherapy for at least 6 months. One patient was lost to follow-up. Eight patients (61.5%) became seizure free. Four patients who began LEV as a first line therapy became seizure free, whereas the remaining four patients who converted to LEV after they failed their previous AEDs became seizure free. Four patients (30.7%) had more than a 50% seizure reduction of seizures. Only one patient had no significant change in seizure frequency after started on LEV. The total dosages used to control seizures were 500-3000 mg/day, (mean 1839.2 mg/day). LEV monotherapy can be effective and well tolerated in this group of patients. A prospective, larger, double blind monotherapy study is needed to confirm this finding.     

Discontinuing antiepileptic drugs in children with epilepsy: A prospective study

In a prospective study, antiepileptic drugs were discontinued in 264 children with epilepsy after a mean seizure-free interval of 2.9 years. They were then followed for a mean of 58 months to ascertain whether seizures recurred. Seizures recurred in 95 (36%) of the children. Etiology was a significant predictor of outcome (relative risk [RR] = 1.81). On multivariable analysis, significant factors in the idiopathic group included age at onset above 12 years (RR = 5.4), a family history of seizures (RR = 3.1), the presence of slowing on the electroencephalogram prior to medication withdrawal (RR = 2.4), and a history of atypical febrile seizures (RR = 2.8). Specific epileptic syndromes such as juvenile myoclonic epilepsy and benign rolandic epilepsy were also significant predictors of outcome. In the remote symptomatic group, significant predictors of outcome included age at onset older than 12 years (RR = 3.6), moderate to severe mental retardation (IQ < 50) (RR = 2.8), a history of atypical febrile seizures (RR = 2.0), and a history of absence seizures (RR = 0.4). The majority of children with epilepsy in remission while on antiepileptic drug therapy will remain seizure free when medications are withdrawn. A few readily available parameters distinguish those with a good prognosis from those in whom seizures are likely to recur. These data provide the framework for the clinical decision making for withdrawal of medications in these children.     

Potential role of cannabidiol for seizure control in a patient with recurrent glioma

Glioma-related epilepsy significantly impact on patients’ quality of life, and can often be difficult to treat. Seizures cause significant morbidity for example neurocognitive deterioration, which may result from seizures themselves or due to adverse effects from antiepileptic drugs. Management of tumour with surgery, radiotherapy and chemotherapy may contribute to seizure control, but tumour related epilepsy is often refractory despite adequate treatment with standard anti-epileptic medications. Given the increasing interest in medicinal cannabis (or cannabidiol or CBD) as an anti-epileptic drug, CBD may help with seizure control in glioma patients with treatment-refractory seizures. Here we present a case of a young lady with recurrent glioma who had refractory seizures despite multiple anti-epileptic agents, who had significant benefit with CBD.     

Childhood epilepsy: Management in resource-limited setting

Objective:

To optimize the use of phenobarbital and/or phenytoin as frontline drugs for treatment of childhood epilepsy.

Design:

Before-and -after study.

Setting:

Epilepsy clinic at paediatric OPD, Sassoon General Hospital, Pune.

Materials and Methods:

Epilepsy is a condition in which seizures are triggered recurrently from within the brain. For epidemiological classification purpose epilepsy is considered to be present when two or more unprovoked seizures occur at an interval greater than twenty four hours apart. Seizures were classified as generalized and partial seizures, with underlying etiology investigated with EEG, CT scan in majority of the patients. Follow - up rate, seizure - control and antiepileptic drugs used among 151 children enrolled as on 31 March 2005 were compared with 106 children with new onset epilepsy enrolled as on February 2006. Eight children with breakthrough convulsion after a seizure free period of five to eighteen months were followed up after injection vitamin D. Nineteen children with poor control of seizures receiving polytherapy with newer antiepileptic drugs were assessed with frontline antiepileptic medication of phenobarbital and/or phenytoin. Serum calcium, phosphorus, alkaline phosphatase were done in seventy two consecutive children with seizure disorder.

Results:

During post protocol period good seizure control was achieved in 84.8% as against 80.7% and use of phenobarbital and/or phenytoin increased to 65.11% from 22.87%. Of the 8 cases with breakthrough seizures seven remained seizure free after vitamin D administration and with no dose enhancement of AED medications of the nineteen. Children receiving polytherapy thirteen children could be successfully switched to phenobarbital and/or phenytoin. Forty four (61%) children had hypocalcemia (less than 9 mg%), fifty seven (79%) children had raised alkaline phosphatase levels (more than 270 IU).

Comments:

Phenobarbital and/or phenytoin have been found to be effective frontline AED. Periodic administration of vitamin D plays a supportive role.     

About one-half of adults with active epilepsy and seizures have annual family incomes under $25,000: The 2010 and 2013 US National Health Interview Surveys

People with active epilepsy are those who reported being told that they have epilepsy or a seizure disorder and either take antiseizure medication or have had a seizure during the past 12 months. We used combined 2010 and 2013 National Health Interview Survey (NHIS) data on US adults with active epilepsy to examine whether taking medications and seizure frequency differed by sex, age, race/ethnicity, and reported or imputed annual family income. Of adults with active epilepsy, 45.5% reported taking medication and having at least one seizure, 41.3% reported taking medication and having no seizures, and 13.2% reported not taking any medication and having at least one seizure. About one-half of adults with active epilepsy and seizures have annual family incomes of less than $25,000. Promoting self-management supports and improved access to specialty care may reduce the burden of uncontrolled seizures in adults with epilepsy.     

Ketogenic diet in patients with Dravet syndrome

PURPOSE: The ketogenic diet (KD) has been used as a therapeutic alternative to antiepileptic drugs (AEDs) for refractory epilepsy. Severe myoclonic epilepsy in infants or Dravet syndrome (DS) is one of the most malignant epileptic syndromes. In this retrospective study, we evaluated the efficacy and tolerability of the KD in patients with diagnostic criteria of DS. METHODS: Between March 1, 1990, and August 31, 2004, 52 patients who met diagnostic criteria for DS were enrolled in a study at our department. Twenty of them were placed on the KD with the Hopkins protocol and followed up for a minimum of 1 year. RESULTS: Three of the 20 original children stayed on the diet for 12 months, four children for 2 years, four children for 3 years, and two children for 4 years. One year after initiating the diet, 13 (65%) of the initial patients remained on the diet. Two (15%) patients were seizure free, eight (61.7%) children had a 75-99% decrease in seizures, and the remaining three (23%) children had a 50-74% decrease in seizures. Thus 1 year after starting the diet, 10 (77%) children had achieved a >75% decrease in their seizures. Four patients have been off the diet for >2 years; one of them is seizure free, two have sporadic seizures, and one, who abandoned the diet after 2 years of adhering to it, relapsed. No differences in seizure control when compared with age, sex, or seizure type were found. CONCLUSIONS: Considering the severity and intractability of seizures in patients with DS, the fact that 10 of the 13 children who remained on the diet had a significant reduction in number of seizures shows that the KD is at present an interesting therapeutic alternative. Even in patients in whom seizure reduction was not dramatic, quality of life improved, and in all of them, the number of AEDs was reduced to one or two. We consider that children with DS should be offered the KD immediately after three adequate trials of AEDs have failed.     

Epilepsia y gestación. Factores asociados con la presencia de crisis en la gestación

IntroductionThe management of epilepsy during pregnancy requires optimal seizure control, avoiding the potential teratogenic effects of antiepileptic drugs.ObjectivesThis study aims to describe the clinical characteristics and perinatal outcomes of pregnant patients with epilepsy; to analyse the factors associated with seizures during pregnancy; to describe the most commonly used antiepileptic drugs in these patients; and to analyse changes in treatment regimens in 2 periods, 2000-2010 and 2011-2018.MethodsWe conducted a prospective observational study of patients with epilepsy who reported their pregnancy between 2000 and 2018. Patients were evaluated in the first and second trimesters of pregnancy, after delivery, and at one year. Data were collected on demographic variables, epilepsy, and perinatal and obstetric variables.ResultsA total of 101 pregnancies were included. Patients’ mean age was 32.6 years; 55.4% had focal epilepsy, 38.6% had generalised epilepsy, and 5.9% had undetermined epilepsy. We recorded 90 live births, 9 miscarriages, and 5 cases of congenital malformations, 4 of which were born to women who received valproate monotherapy. Forty patients (39.6%) presented seizures, with 16 (40%) presenting generalised tonic-clonic seizures. The variables associated with seizures during pregnancy were poor seizure control in the year prior to pregnancy (66.7% vs. 15.1%; P < .001), treatment with 2 or more antiepileptic drugs (30% vs. 14.8%; P < .001), and untreated epilepsy (25% vs. 0%; P < .001). The antiepileptic drugs most widely used in monotherapy were lamotrigine (n = 19; 27.1%), valproate (n = 17; 24.2%), and levetiracetam (n = 12; 17.1%). In the most recent period (2011-2018), we observed a greater proportion patients receiving monotherapy (81.5%, vs. 55.3%), as well as a decrease in the use of carbamazepine (2.3%, vs. 23.1%) and valproate (20.5%, vs. 30.8%); and a marked increase in the use of levetiracetam (27.3%, vs. 0%).ConclusionsThe factors associated with the presence of seizures during pregnancy were previous poor seizure control, treatment with 2 or more antiepileptic drugs, and lack of treatment during pregnancy. The most commonly used drugs were lamotrigine, valproate, and levetiracetam, with an increase in levetiracetam use and a decrease in valproate use being observed in the later period (2011-2018).     

Zonisamide in the management of epilepsy--Japanese experience

Zonisamide (Zonegran), a novel antiepileptic drug (AED) approved in Europe for the adjunctive treatment of refractory partial seizures in adults, has undergone extensive evaluation in pre- and post-marketing double-blind and open-label studies in Japan (where zonisamide is used widely to treat partial and generalised seizures in adults and children). These data indicate that the clinical benefit of zonisamide extends across a range of seizure types and patient ages. In an analysis based on a mixture of controlled and open studies in adults and children with partial seizures, 51-57% responded to zonisamide treatment (achieving >or=50% reduction in baseline seizure frequency). Efficacy extends across a range of generalised seizures and 22-66% of adults and children experiencing tonic-clonic, tonic, clonic, myoclonic or absence seizures responded to treatment. Even greater responder rates have been reported when zonisamide was used as monotherapy for partial seizures and generalised seizures in patients refractory to other AEDs or with newly diagnosed epilepsy. Zonisamide is also efficacious in paediatric epilepsy syndromes, including Lennox-Gastaut Syndrome, West Syndrome and Ohtahara Syndrome. Across the spectrum of epilepsy syndromes studied, zonisamide is well-tolerated with a low incidence of adverse events, which are generally mild and CNS-related. These data indicate that zonisamide represents a valuable broad-spectrum option for the treatment of epilepsy.