DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY
COMMENTARIES
Does epilepsy in childhood affect cognitive development? CASSIE KARLSSON 1
| DAVID DUNN 1,2
1 Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN; 2 Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA. doi: 10.1111/dmcn.12447 This commentary is on the original article by Rathouz et al. on pages 635–641 of this issue.
The relationship between epilepsy and cognitive development remains poorly understood despite increased interest in this area in recent years. Rathouz et al. 1 present one of the first prospective studies examining the trajectory of cognitive development in children with a recent diagnosis of epilepsy. While cognitive abnormalities have long been linked to epilepsy diagnosis, there has been considerable debate in the literature regarding the impact of epilepsy on further cognitive development and achievement. The authors have provided an important addition to this growing body of literature. Their study confirms previous findings of cognitive impairment at or near the time of initial epilepsy diagnosis, but also demonstrates that abnormalities present at the time of diagnosis remain static over the 5-year to 6-year follow-up period, even when measured over multiple cognitive domains. Previous studies have proposed that lower IQ can be independently linked to a diagnosis of epilepsy.2 This study suggests a relatively weak relationship between epilepsy and overall intelligence, instead finding specific domains had more impact than others, namely motor and psychomotor speed, attention and inhibition, and arithmetic computation skills. These findings echo past studies linking higher rates of attention-deficit–hyperactivity disorder and specific learning disorders in children diagnosed with epilepsy.3 Utilization of a comprehensive psychometric test battery is a strength of the paper by Rathouz et al., representing a more objective measurement of ability than some past studies relying on grade level retention, inclusion in special education classes, and teacher rating scales as measures of ability and achievement.3 What remains unclear is whether these objective measures alone relate to academic success. While these findings reflect static changes in cognitive functioning, it is not yet understood whether this will carry forward in regard to long-term achievement. This study has limitations when generalizing the results to larger populations with epilepsy. The findings are limited to children with normal intelligence, neurological examination, and imaging studies, and with onset of epilepsy during school age (8–18y). The study does not look at children of an early age at seizure onset who may be at increased risk of cognitive difficulties. Many of the epi© 2014 Mac Keith Press
leptic encephalopathies start early in life and have been associated with decline in cognitive function.4 One small study of children with tuberous sclerosis was able to assess cognition before and after the onset of seizures. They found a decline in intellectual development after onset of infantile spasms but not in children with other seizure types.5 Other studies have suggested that early onset seizures may have a more negative impact on subsequent academic performance than later onset seizures.6 However, the evidence for cognitive decline with seizures other than the epileptic encephalopathies is still weak. It is still unknown whether younger children with epilepsy experience a more severely affected trajectory of cognitive development over time. There is no general consensus in the literature regarding the use of antiepileptic medications and their impact on cognitive development. Antiepileptic drugs such as phenobarbital, topiramate, and valproic acid have adversely affected attention and might secondarily have a negative impact on academic achievement.7 Although participants in the current study diagnosed with idiopathic/ genetic epilepsy were older at seizure onset, they were also more likely to be on antiepileptic medication. When differences in cognitive ability did exist between the groups, those with idiopathic/genetic epilepsy were more severely affected. Questions remain whether pharmacotherapy plays a role in cognitive deficits, and whether this is consistent over time. Further research is needed to understand premorbid cognitive functioning in children diagnosed with epilepsy, as the majority of current studies point to correlations between epilepsy and cognitive deficits, but fail to establish cause and effect – a difficult task. It remains to be seen whether specific impairments in cognitive domains are linked to different forms of epilepsy – including forms which may be considered more severe, of earlier onset, or requiring antiepileptic medication therapy. Additionally, rates of psychiatric comorbidity are higher in children with epilepsy when compared to healthy controls.3 Understanding the role of psychiatric comorbidity and subjective reports of cognitive impairment in conjunction with measured cognitive changes will be key when looking at long-term outcomes. This paper strengthens the argument that routine cognitive screening is important in children with new onset epilepsy, even in cases formerly considered ‘benign’ and without additional neurological, psychiatric, or known developmental/intellectual delays. One could argue that children with epilepsy may benefit from additional support prior to clear academic or psychosocial deficits to promote long-term academic, social, and career success. Questions remain whether interventions initiated at the time of 605
epilepsy diagnosis can affect the trajectory of cognitive development in this population, an area which has the
potential to hold numerous implications for our patients and their families.
REFERENCES 1. Rathouz PJ, Zhao Q, Jones JE, et al. Cognitive develop-
4. Avanzini G, Depaulis A, Tassinari A, de Curtis M. Do
6. Dunn DW, Johnson CS, Perkins SM, et al. Academic
ment in children with new onset epilepsy. Dev Med
seizures and epileptic activity worsen epilepsy and dete-
problems in children with seizures: relationships with
Child Neurol. 2014; 56: 635–41.
riorate cognitive function? Epilepsia 2013; 54(Suppl. 8):
neuropsychological functioning and family variables dur-
14–21.
ing the 3 years after onset. Epilepsy Behav 2010; 19:
2. Walker NM, Jackson DC, Dabbs K, et al. Is lower IQ in children with epilepsy due to lower parental IQ: a
5. Humphrey A, MacLean C,
Ploubidis
GB, et al.
455–61.
controlled comparison. Dev Med Child Neurol 2012; 55:
Intellectual development before and after the onset of
7. Loring DW, Meador KJ. Cognitive side effects of
278–82.
infantile spasms: a controlled prospective longitudinal
antiepileptic drugs in children. Neurology 2004; 62:
3. Fastenau PS, Shen J, Dunn DW, Austin JK. Academic underachievement among children with epilepsy. J Learn
study
in
tuberous
sclerosis.
Epilepsia
2014;
55:
872–7.
108–16.
Disabil 2008; 41: 195–207.
Benign hereditary chorea: more than meets the eye JAMES RICE Paediatric Rehabilitation Department, Women’s and Children’s Hospital, Adelaide, Australia. doi: 10.1111/dmcn.12398 This commentary is on the original article by Peall et al. on pages 642– 648 of this issue.
Benign hereditary chorea (BHC) is an autosomal dominant disorder that has remained relatively poorly understood, owing, at least in part, to its rare prevalence. At the root cause of this condition is a mutation in the NKX2.1 gene, responsible for the production of thyroid transcription factor 1, which in turn regulates the activity of genes in the formation of brain, lung and thyroid tissue. First described in 1966, BHC usually presents with hypotonia in infancy and gross motor delay, with onset of chorea in early childhood and later improvement in adolescence.1 Neuroimaging is normal. Because of its non-progressive nature, this condition has generally been considered benign particularly in comparison to the distinctly different profile of chorea seen in Huntington disease. Despite this, a relatively small number of cases have been described with persistent motor impairments and features of additional movement disorders such as ataxia, dystonia, myoclonus, and spasticity.2 The phenotype of BHC has since been expanded with the identification of coexistent hypothyroidism and respiratory disease under the alternative name ‘brain-lung-thyroid’ syndrome, reflecting the implications on broader organogenesis.3 Peall et al. have continued this work in further describing the BHC picture in a larger cohort.4 They identified ten cases consistent with BHC and/or NKX2.1 mutations in paediatric movement disorder clinics which were further evaluated by clinical examination, relevant medical history, and exon gene sequencing. Beyond chorea, hypothyroidism 606 Developmental Medicine & Child Neurology 2014, 56: 605–611
and respiratory disease were encountered, as were other physical and behavioural features. A range of oral medication was used in treating chorea. From the findings of this study and that of Gras et al.5 it appears in BHC that chorea tends to remain relatively mild and resolves in most cases; however, for the majority in the current study it was associated with myoclonus and/or dystonia, both of which have been described to persist into adulthood with ongoing disability. The label ‘benign’ may therefore be a misnomer: whilst the chorea waxes and wanes, other more ominous movement disorders may take its place. Because of the relatively young age range of this patient group and the absence of prospective follow-up, we do not know whether such movement disorders inevitably cause ongoing functional impairment. A range of medications were used to treat chorea, most commonly levodopa, without significant benefit. In contrast, Gras et al. described consistent improvement from the use of low-dose tetrabenazine.5 The pharmacological treatment of chorea in childhood disorders has limited description; a finding of tetrabenazine efficacy is encouraging and warrants further evaluation, particularly with regard to any impact that early onset of treatment may have on disease process. The relatively frequent observation of coexistent lung and thyroid disease adds to the argument that the full phenotype can look far from benign. Furthermore, description of learning disorders and attention-deficit–hyperactivity disorder in BHC perhaps links the impact of NKX2.1 mutations on both the basal ganglia and associative striatum: this mechanism is also not understood. What are the implications of this study for clinical practice and future research? The nature of this rare, heterogeneous, and evolving condition ensures the need for collaborative research between institutions. Enrolling young children with BHC into a clinical register could
COMMENTARIES
Does epilepsy in childhood affect cognitive development? CASSIE KARLSSON 1
| DAVID DUNN 1,2
1 Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN; 2 Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA. doi: 10.1111/dmcn.12447 This commentary is on the original article by Rathouz et al. on pages 635–641 of this issue.
The relationship between epilepsy and cognitive development remains poorly understood despite increased interest in this area in recent years. Rathouz et al. 1 present one of the first prospective studies examining the trajectory of cognitive development in children with a recent diagnosis of epilepsy. While cognitive abnormalities have long been linked to epilepsy diagnosis, there has been considerable debate in the literature regarding the impact of epilepsy on further cognitive development and achievement. The authors have provided an important addition to this growing body of literature. Their study confirms previous findings of cognitive impairment at or near the time of initial epilepsy diagnosis, but also demonstrates that abnormalities present at the time of diagnosis remain static over the 5-year to 6-year follow-up period, even when measured over multiple cognitive domains. Previous studies have proposed that lower IQ can be independently linked to a diagnosis of epilepsy.2 This study suggests a relatively weak relationship between epilepsy and overall intelligence, instead finding specific domains had more impact than others, namely motor and psychomotor speed, attention and inhibition, and arithmetic computation skills. These findings echo past studies linking higher rates of attention-deficit–hyperactivity disorder and specific learning disorders in children diagnosed with epilepsy.3 Utilization of a comprehensive psychometric test battery is a strength of the paper by Rathouz et al., representing a more objective measurement of ability than some past studies relying on grade level retention, inclusion in special education classes, and teacher rating scales as measures of ability and achievement.3 What remains unclear is whether these objective measures alone relate to academic success. While these findings reflect static changes in cognitive functioning, it is not yet understood whether this will carry forward in regard to long-term achievement. This study has limitations when generalizing the results to larger populations with epilepsy. The findings are limited to children with normal intelligence, neurological examination, and imaging studies, and with onset of epilepsy during school age (8–18y). The study does not look at children of an early age at seizure onset who may be at increased risk of cognitive difficulties. Many of the epi© 2014 Mac Keith Press
leptic encephalopathies start early in life and have been associated with decline in cognitive function.4 One small study of children with tuberous sclerosis was able to assess cognition before and after the onset of seizures. They found a decline in intellectual development after onset of infantile spasms but not in children with other seizure types.5 Other studies have suggested that early onset seizures may have a more negative impact on subsequent academic performance than later onset seizures.6 However, the evidence for cognitive decline with seizures other than the epileptic encephalopathies is still weak. It is still unknown whether younger children with epilepsy experience a more severely affected trajectory of cognitive development over time. There is no general consensus in the literature regarding the use of antiepileptic medications and their impact on cognitive development. Antiepileptic drugs such as phenobarbital, topiramate, and valproic acid have adversely affected attention and might secondarily have a negative impact on academic achievement.7 Although participants in the current study diagnosed with idiopathic/ genetic epilepsy were older at seizure onset, they were also more likely to be on antiepileptic medication. When differences in cognitive ability did exist between the groups, those with idiopathic/genetic epilepsy were more severely affected. Questions remain whether pharmacotherapy plays a role in cognitive deficits, and whether this is consistent over time. Further research is needed to understand premorbid cognitive functioning in children diagnosed with epilepsy, as the majority of current studies point to correlations between epilepsy and cognitive deficits, but fail to establish cause and effect – a difficult task. It remains to be seen whether specific impairments in cognitive domains are linked to different forms of epilepsy – including forms which may be considered more severe, of earlier onset, or requiring antiepileptic medication therapy. Additionally, rates of psychiatric comorbidity are higher in children with epilepsy when compared to healthy controls.3 Understanding the role of psychiatric comorbidity and subjective reports of cognitive impairment in conjunction with measured cognitive changes will be key when looking at long-term outcomes. This paper strengthens the argument that routine cognitive screening is important in children with new onset epilepsy, even in cases formerly considered ‘benign’ and without additional neurological, psychiatric, or known developmental/intellectual delays. One could argue that children with epilepsy may benefit from additional support prior to clear academic or psychosocial deficits to promote long-term academic, social, and career success. Questions remain whether interventions initiated at the time of 605
epilepsy diagnosis can affect the trajectory of cognitive development in this population, an area which has the
potential to hold numerous implications for our patients and their families.
REFERENCES 1. Rathouz PJ, Zhao Q, Jones JE, et al. Cognitive develop-
4. Avanzini G, Depaulis A, Tassinari A, de Curtis M. Do
6. Dunn DW, Johnson CS, Perkins SM, et al. Academic
ment in children with new onset epilepsy. Dev Med
seizures and epileptic activity worsen epilepsy and dete-
problems in children with seizures: relationships with
Child Neurol. 2014; 56: 635–41.
riorate cognitive function? Epilepsia 2013; 54(Suppl. 8):
neuropsychological functioning and family variables dur-
14–21.
ing the 3 years after onset. Epilepsy Behav 2010; 19:
2. Walker NM, Jackson DC, Dabbs K, et al. Is lower IQ in children with epilepsy due to lower parental IQ: a
5. Humphrey A, MacLean C,
Ploubidis
GB, et al.
455–61.
controlled comparison. Dev Med Child Neurol 2012; 55:
Intellectual development before and after the onset of
7. Loring DW, Meador KJ. Cognitive side effects of
278–82.
infantile spasms: a controlled prospective longitudinal
antiepileptic drugs in children. Neurology 2004; 62:
3. Fastenau PS, Shen J, Dunn DW, Austin JK. Academic underachievement among children with epilepsy. J Learn
study
in
tuberous
sclerosis.
Epilepsia
2014;
55:
872–7.
108–16.
Disabil 2008; 41: 195–207.
Benign hereditary chorea: more than meets the eye JAMES RICE Paediatric Rehabilitation Department, Women’s and Children’s Hospital, Adelaide, Australia. doi: 10.1111/dmcn.12398 This commentary is on the original article by Peall et al. on pages 642– 648 of this issue.
Benign hereditary chorea (BHC) is an autosomal dominant disorder that has remained relatively poorly understood, owing, at least in part, to its rare prevalence. At the root cause of this condition is a mutation in the NKX2.1 gene, responsible for the production of thyroid transcription factor 1, which in turn regulates the activity of genes in the formation of brain, lung and thyroid tissue. First described in 1966, BHC usually presents with hypotonia in infancy and gross motor delay, with onset of chorea in early childhood and later improvement in adolescence.1 Neuroimaging is normal. Because of its non-progressive nature, this condition has generally been considered benign particularly in comparison to the distinctly different profile of chorea seen in Huntington disease. Despite this, a relatively small number of cases have been described with persistent motor impairments and features of additional movement disorders such as ataxia, dystonia, myoclonus, and spasticity.2 The phenotype of BHC has since been expanded with the identification of coexistent hypothyroidism and respiratory disease under the alternative name ‘brain-lung-thyroid’ syndrome, reflecting the implications on broader organogenesis.3 Peall et al. have continued this work in further describing the BHC picture in a larger cohort.4 They identified ten cases consistent with BHC and/or NKX2.1 mutations in paediatric movement disorder clinics which were further evaluated by clinical examination, relevant medical history, and exon gene sequencing. Beyond chorea, hypothyroidism 606 Developmental Medicine & Child Neurology 2014, 56: 605–611
and respiratory disease were encountered, as were other physical and behavioural features. A range of oral medication was used in treating chorea. From the findings of this study and that of Gras et al.5 it appears in BHC that chorea tends to remain relatively mild and resolves in most cases; however, for the majority in the current study it was associated with myoclonus and/or dystonia, both of which have been described to persist into adulthood with ongoing disability. The label ‘benign’ may therefore be a misnomer: whilst the chorea waxes and wanes, other more ominous movement disorders may take its place. Because of the relatively young age range of this patient group and the absence of prospective follow-up, we do not know whether such movement disorders inevitably cause ongoing functional impairment. A range of medications were used to treat chorea, most commonly levodopa, without significant benefit. In contrast, Gras et al. described consistent improvement from the use of low-dose tetrabenazine.5 The pharmacological treatment of chorea in childhood disorders has limited description; a finding of tetrabenazine efficacy is encouraging and warrants further evaluation, particularly with regard to any impact that early onset of treatment may have on disease process. The relatively frequent observation of coexistent lung and thyroid disease adds to the argument that the full phenotype can look far from benign. Furthermore, description of learning disorders and attention-deficit–hyperactivity disorder in BHC perhaps links the impact of NKX2.1 mutations on both the basal ganglia and associative striatum: this mechanism is also not understood. What are the implications of this study for clinical practice and future research? The nature of this rare, heterogeneous, and evolving condition ensures the need for collaborative research between institutions. Enrolling young children with BHC into a clinical register could
