Absence seizures in children Search date July 2013 Ewa Posner ABSTRACT INTRODUCTION: About 10% of seizures in children with epilepsy are typical absence seizures. Absence seizures have a significant impact on quality of life. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for typical absence seizures in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 18 RCTs or systematic reviews of RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: clonazepam, ethosuximide, gabapentin, lamotrigine, and valproate.
QUESTIONS What are the effects of treatments for typical absence seizures in children?. . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 INTERVENTIONS TREATMENTS FOR TYPICAL ABSENCE SEIZURES Trade off between benefits and harms Ethosuximide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Unknown effectiveness Clonazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Valproate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Key points • Absence seizures are characterised by sudden, brief, frequent periods of unconsciousness, which may be accompanied by automatic movements. They may occur alone, or may coexist with other types of seizures in a child with other epileptic syndromes. Absence seizures have a typical spike and wave pattern on the EEG. Atypical absence seizures have different EEG changes and clinical manifestations, and have a different natural history and response to treatment. Absence seizures can be differentiated from complex partial seizures by their abrupt ending and lack of a postictal phase. About 10% of seizures in children with epilepsy are typical absence seizures, with genetic factors considered to be the main cause. Where they are the only manifestation of epilepsy, they generally resolve spontaneously by the age of 12 years. • Lamotrigine increases the likelihood of being seizure-free compared with placebo, but it seems to be less effective than valproate and ethosuximide at reducing seizures in children with absence seizures of new onset, and can cause serious skin reactions and aseptic meningitis. • Ethosuximide seems to be more effective than lamotrigine at reducing seizure frequency in childhood absence seizures of new onset. Ethosuximide is rarely associated with aplastic anaemia, skin reactions, and renal and hepatic impairment. • There is consensus that valproate is beneficial in childhood absence seizures, although we don't know this for sure. We don't know how effective valproate and ethosuximide are, compared with each other, at reducing seizure rate in children with absence seizures. Valproate is rarely associated with behavioural and cognitive abnormalities, liver necrosis, and pancreatitis. • We don't know whether clonazepam or gabapentin reduces the frequency of absence seizures. Clinical context
GENERAL BACKGROUND Absence seizures in children are brief, recurrent episodes of unconsciousness often accompanied by simple automatisms, or clonic, atonic, or autonomic components. There are two types of absence seizure: typical and atypical. Typical absence seizures usually occur in children with normal development and intelligence. They last for approximately 10 seconds and display characteristic regular symmetrical generalised spike and wave complexes with a frequency of 3 Hz that are diagnostic of the condition. If untreated, absence seizures have a significant impact on a child’s physical safety, education capacity and quality of life. The majority of typical absence seizures respond to treatment with anticonvulsant medication. © BMJ Publishing Group Ltd 2013. All rights reserved.
..................... 1 .....................
Clinical Evidence 2013;12:317
Child health
..................................................
FOCUS OF THE REVIEW This review refers to typical absence seizures only. The effectiveness and safety of the following anticonvulsant agents is evaluated: clonazepam, ethosuximide, gabapentin, lamotrigine, and valproate. Selection of anticonvulsant medication is guided by clinician preference and adverse effects profile.
COMMENTS ON EVIDENCE Ethosuximide and valproate have been used for the management of absence seizures for many years and, with lamotrigine, are widely regarded as first-line treatments as these anticonvulsants have the largest evidence-base showing their efficacy in absence seizures.
SEARCH AND APPRAISAL SUMMARY The update literature search for this review was carried out from the date of the last search, October 2007, to July 2013. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved 74 studies. After deduplication and removal of conference abstracts, 37 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 21 studies and the further review of 16 full publications. Of the 16 full articles evaluated, one systematic review and two RCTs were included at this update.
ADDITIONAL INFORMATION As episodes of unconsciousness may occur at any time and without warning, absence seizures have a significant impact on quality of life. Children should take precautions to prevent injury during absences by avoiding activities that would place them at risk in the event of a seizure (such as unsupervised swimming, climbing heights, or cycling on busy roads). If left untreated, most children will have many episodes per day and the absences can have a detrimental impact on schooling as recurrent episodes of unconsciousness during class result in the child missing a significant amount of what is being taught. Typical absence seizures generally cease spontaneously by 12 years of age or sooner. DEFINITION
Absence seizures are sudden, frequent episodes of unconsciousness lasting a few seconds, and are often accompanied by simple automatisms or clonic, atonic, or autonomic components. The differentiation into typical versus atypical seizures is important, as the natural history and response to treatment vary between the two groups. Interventions for atypical absence seizures or for absence seizures secondary to structural lesions are not included in this review. Typical absence seizures display a characteristic EEG showing regular symmetrical generalised spike and wave complexes with a frequency of 3 Hz, and usually occur in children with normal development and intelligence. Typical absence seizures are often confused with complex partial seizures, especially in cases of prolonged seizure with automatisms. However, the abrupt ending of typical absence seizures, without a postictal phase, is the most useful clinical feature in distinguishing the two types. Typical absence seizures should not be confused with atypical absence seizures, which differ markedly in EEG findings and ictal behaviour, and are usually present with other seizure types in a child with [1] a background of learning disability and severe epilepsy.
INCIDENCE/ PREVALENCE
About 10% of seizures in children with epilepsy are typical absence seizures. Annual incidence has been estimated at 0.7 to 4.6/100,000 people in the general population, and 6 to 8/100,000 in [2] children aged 0 to 15 years. Prevalence is 5 to 50/100,000 people in the general population. Similar figures were found in the US (Connecticut) and in Europe-based (Scandinavia, France) [2] population studies. Age of onset ranges from 3 to 13 years, with a peak at 6 to 7 years.
[1]
AETIOLOGY/ The cause of childhood absence epilepsy is presumed to be genetic. Seizures can be triggered [3] RISK FACTORS by hyperventilation in susceptible children. Some anticonvulsants, such as phenytoin, carba[4] [5] [6] mazepine, and vigabatrin are associated with an increased risk of absence seizures. PROGNOSIS
In childhood absence epilepsy, in which typical absence seizures are the only type of seizures suffered by the child, seizures generally cease spontaneously by 12 years of age or sooner. Less than 10% of children develop infrequent generalised tonic clonic seizures, and it is rare for them [7] to continue having absence seizures. In other epileptic syndromes (in which absence seizures may coexist with other types of seizure) prognosis is varied, depending on the syndrome. Absence seizures have a significant impact on quality of life. The episode of unconsciousness may occur at any time, and usually without warning. Affected children need to take precautions to prevent injury during absences, and should refrain from activities that would put them at risk if seizures occurred (e.g., climbing heights, swimming unsupervised, or cycling on busy roads). Often, school staff members are the first to notice the recurrent episodes of absence seizures, and treatment is generally initiated because of the adverse impact on learning.
© BMJ Publishing Group Ltd 2013. All rights reserved.
........................................................... 2
Child health
Absence seizures in children
AIMS OF Cessation or decrease in the frequency of seizures, with minimum adverse effects of treatment. INTERVENTION OUTCOMES
Seizure frequency often measured as normalisation of the EEG; adverse effects of treatment. We found no RCTs assessing quality of life.
METHODS
Clinical Evidence search July 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to July 2013, Embase 1980 to July 2013, and The Cochrane Database of Systematic Reviews 2013, issue 2 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) Database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in any language, including open studies, and containing 20 or more individuals (at least 10 per arm) of whom more than 80% were followed up. The minimum length of follow-up required to include studies was 6 weeks. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food Drug Administration (FDA), the European Medicines Agency (EMA), and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 15 ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
QUESTION
What are the effects of treatments for typical absence seizures in children?
OPTION
ETHOSUXIMIDE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•
For GRADE evaluation of interventions for Absence seizures in children, see table, p 15 .
•
Ethosuximide seems to be more effective than lamotrigine at reducing seizure frequency in childhood absence seizures of new onset.
•
We don't know how effective ethosuximide and valproate are, compared with each other, at reducing seizure rate in children with absence seizures.
•
Ethosuximide is rarely associated with aplastic anaemia, skin reactions, and renal and hepatic impairment. Benefits and harms
Ethosuximide versus placebo: [8] We found three systematic reviews (search date 2005, search date 2002, search date not reported), found no RCTs.
[9]
[10]
which
Ethosuximide versus lamotrigine: [11] We found one systematic review (search date 2012), which included two RCTs, only one of which met our inclusion criteria.The double-blind RCT reported on lack of seizure control (measured by clinical report, bedside hyperventilation [12] tests, and one-hour video EEG) in subjects at 16 to 20 weeks. An open-label follow-up reported outcomes at 12 [13] months. The RCT also reported a composite outcome of treatment failure (see Further information about studies). [12]
[13]
-
© BMJ Publishing Group Ltd 2013. All rights reserved.
...........................................................
3
Child health
Absence seizures in children
Seizure frequency Ethosuximide compared with lamotrigine Ethosuximide seems to be more effective than lamotrigine at improving seizure control at 16 to 20 weeks in childhood absence seizures of new onset (moderate-quality evidence). Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Seizure frequency [12]
RCT 3-armed trial
453 children aged 2.5 to 13 years with childhood absence epilepsy of new onset
Lack of seizure control , 16 or 20 weeks 22/154 (14%) with ethosuximide
OR 0.19 95% CI 0.11 to 0.32 P
QUESTIONS What are the effects of treatments for typical absence seizures in children?. . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 INTERVENTIONS TREATMENTS FOR TYPICAL ABSENCE SEIZURES Trade off between benefits and harms Ethosuximide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Unknown effectiveness Clonazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Valproate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Key points • Absence seizures are characterised by sudden, brief, frequent periods of unconsciousness, which may be accompanied by automatic movements. They may occur alone, or may coexist with other types of seizures in a child with other epileptic syndromes. Absence seizures have a typical spike and wave pattern on the EEG. Atypical absence seizures have different EEG changes and clinical manifestations, and have a different natural history and response to treatment. Absence seizures can be differentiated from complex partial seizures by their abrupt ending and lack of a postictal phase. About 10% of seizures in children with epilepsy are typical absence seizures, with genetic factors considered to be the main cause. Where they are the only manifestation of epilepsy, they generally resolve spontaneously by the age of 12 years. • Lamotrigine increases the likelihood of being seizure-free compared with placebo, but it seems to be less effective than valproate and ethosuximide at reducing seizures in children with absence seizures of new onset, and can cause serious skin reactions and aseptic meningitis. • Ethosuximide seems to be more effective than lamotrigine at reducing seizure frequency in childhood absence seizures of new onset. Ethosuximide is rarely associated with aplastic anaemia, skin reactions, and renal and hepatic impairment. • There is consensus that valproate is beneficial in childhood absence seizures, although we don't know this for sure. We don't know how effective valproate and ethosuximide are, compared with each other, at reducing seizure rate in children with absence seizures. Valproate is rarely associated with behavioural and cognitive abnormalities, liver necrosis, and pancreatitis. • We don't know whether clonazepam or gabapentin reduces the frequency of absence seizures. Clinical context
GENERAL BACKGROUND Absence seizures in children are brief, recurrent episodes of unconsciousness often accompanied by simple automatisms, or clonic, atonic, or autonomic components. There are two types of absence seizure: typical and atypical. Typical absence seizures usually occur in children with normal development and intelligence. They last for approximately 10 seconds and display characteristic regular symmetrical generalised spike and wave complexes with a frequency of 3 Hz that are diagnostic of the condition. If untreated, absence seizures have a significant impact on a child’s physical safety, education capacity and quality of life. The majority of typical absence seizures respond to treatment with anticonvulsant medication. © BMJ Publishing Group Ltd 2013. All rights reserved.
..................... 1 .....................
Clinical Evidence 2013;12:317
Child health
..................................................
FOCUS OF THE REVIEW This review refers to typical absence seizures only. The effectiveness and safety of the following anticonvulsant agents is evaluated: clonazepam, ethosuximide, gabapentin, lamotrigine, and valproate. Selection of anticonvulsant medication is guided by clinician preference and adverse effects profile.
COMMENTS ON EVIDENCE Ethosuximide and valproate have been used for the management of absence seizures for many years and, with lamotrigine, are widely regarded as first-line treatments as these anticonvulsants have the largest evidence-base showing their efficacy in absence seizures.
SEARCH AND APPRAISAL SUMMARY The update literature search for this review was carried out from the date of the last search, October 2007, to July 2013. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved 74 studies. After deduplication and removal of conference abstracts, 37 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 21 studies and the further review of 16 full publications. Of the 16 full articles evaluated, one systematic review and two RCTs were included at this update.
ADDITIONAL INFORMATION As episodes of unconsciousness may occur at any time and without warning, absence seizures have a significant impact on quality of life. Children should take precautions to prevent injury during absences by avoiding activities that would place them at risk in the event of a seizure (such as unsupervised swimming, climbing heights, or cycling on busy roads). If left untreated, most children will have many episodes per day and the absences can have a detrimental impact on schooling as recurrent episodes of unconsciousness during class result in the child missing a significant amount of what is being taught. Typical absence seizures generally cease spontaneously by 12 years of age or sooner. DEFINITION
Absence seizures are sudden, frequent episodes of unconsciousness lasting a few seconds, and are often accompanied by simple automatisms or clonic, atonic, or autonomic components. The differentiation into typical versus atypical seizures is important, as the natural history and response to treatment vary between the two groups. Interventions for atypical absence seizures or for absence seizures secondary to structural lesions are not included in this review. Typical absence seizures display a characteristic EEG showing regular symmetrical generalised spike and wave complexes with a frequency of 3 Hz, and usually occur in children with normal development and intelligence. Typical absence seizures are often confused with complex partial seizures, especially in cases of prolonged seizure with automatisms. However, the abrupt ending of typical absence seizures, without a postictal phase, is the most useful clinical feature in distinguishing the two types. Typical absence seizures should not be confused with atypical absence seizures, which differ markedly in EEG findings and ictal behaviour, and are usually present with other seizure types in a child with [1] a background of learning disability and severe epilepsy.
INCIDENCE/ PREVALENCE
About 10% of seizures in children with epilepsy are typical absence seizures. Annual incidence has been estimated at 0.7 to 4.6/100,000 people in the general population, and 6 to 8/100,000 in [2] children aged 0 to 15 years. Prevalence is 5 to 50/100,000 people in the general population. Similar figures were found in the US (Connecticut) and in Europe-based (Scandinavia, France) [2] population studies. Age of onset ranges from 3 to 13 years, with a peak at 6 to 7 years.
[1]
AETIOLOGY/ The cause of childhood absence epilepsy is presumed to be genetic. Seizures can be triggered [3] RISK FACTORS by hyperventilation in susceptible children. Some anticonvulsants, such as phenytoin, carba[4] [5] [6] mazepine, and vigabatrin are associated with an increased risk of absence seizures. PROGNOSIS
In childhood absence epilepsy, in which typical absence seizures are the only type of seizures suffered by the child, seizures generally cease spontaneously by 12 years of age or sooner. Less than 10% of children develop infrequent generalised tonic clonic seizures, and it is rare for them [7] to continue having absence seizures. In other epileptic syndromes (in which absence seizures may coexist with other types of seizure) prognosis is varied, depending on the syndrome. Absence seizures have a significant impact on quality of life. The episode of unconsciousness may occur at any time, and usually without warning. Affected children need to take precautions to prevent injury during absences, and should refrain from activities that would put them at risk if seizures occurred (e.g., climbing heights, swimming unsupervised, or cycling on busy roads). Often, school staff members are the first to notice the recurrent episodes of absence seizures, and treatment is generally initiated because of the adverse impact on learning.
© BMJ Publishing Group Ltd 2013. All rights reserved.
........................................................... 2
Child health
Absence seizures in children
AIMS OF Cessation or decrease in the frequency of seizures, with minimum adverse effects of treatment. INTERVENTION OUTCOMES
Seizure frequency often measured as normalisation of the EEG; adverse effects of treatment. We found no RCTs assessing quality of life.
METHODS
Clinical Evidence search July 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to July 2013, Embase 1980 to July 2013, and The Cochrane Database of Systematic Reviews 2013, issue 2 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) Database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in any language, including open studies, and containing 20 or more individuals (at least 10 per arm) of whom more than 80% were followed up. The minimum length of follow-up required to include studies was 6 weeks. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food Drug Administration (FDA), the European Medicines Agency (EMA), and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 15 ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
QUESTION
What are the effects of treatments for typical absence seizures in children?
OPTION
ETHOSUXIMIDE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•
For GRADE evaluation of interventions for Absence seizures in children, see table, p 15 .
•
Ethosuximide seems to be more effective than lamotrigine at reducing seizure frequency in childhood absence seizures of new onset.
•
We don't know how effective ethosuximide and valproate are, compared with each other, at reducing seizure rate in children with absence seizures.
•
Ethosuximide is rarely associated with aplastic anaemia, skin reactions, and renal and hepatic impairment. Benefits and harms
Ethosuximide versus placebo: [8] We found three systematic reviews (search date 2005, search date 2002, search date not reported), found no RCTs.
[9]
[10]
which
Ethosuximide versus lamotrigine: [11] We found one systematic review (search date 2012), which included two RCTs, only one of which met our inclusion criteria.The double-blind RCT reported on lack of seizure control (measured by clinical report, bedside hyperventilation [12] tests, and one-hour video EEG) in subjects at 16 to 20 weeks. An open-label follow-up reported outcomes at 12 [13] months. The RCT also reported a composite outcome of treatment failure (see Further information about studies). [12]
[13]
-
© BMJ Publishing Group Ltd 2013. All rights reserved.
...........................................................
3
Child health
Absence seizures in children
Seizure frequency Ethosuximide compared with lamotrigine Ethosuximide seems to be more effective than lamotrigine at improving seizure control at 16 to 20 weeks in childhood absence seizures of new onset (moderate-quality evidence). Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Seizure frequency [12]
RCT 3-armed trial
453 children aged 2.5 to 13 years with childhood absence epilepsy of new onset
Lack of seizure control , 16 or 20 weeks 22/154 (14%) with ethosuximide
OR 0.19 95% CI 0.11 to 0.32 P
