Developmental medicine and child neurology, Aug 15, 2016
To identify soft neurological signs (SNS) in a population-based study of children living in remot... more To identify soft neurological signs (SNS) in a population-based study of children living in remote Aboriginal communities in the Fitzroy Valley, Western Australia, born between 2002 and 2003 and explore the relationship between SNS, prenatal alcohol exposure (PAE), and fetal alcohol spectrum disorders (FASD). The presence of SNS was assessed using the Quick Neurological Screening Test, 2nd edition (QNST-2), which has a total maximum score of 140. Higher scores indicated more SNS. 'Severe discrepancy' was defined as scores less than or equal to the fifth centile while 'moderate discrepancy' represented scores from the sixth to the 24th centile. Children were assigned FASD diagnoses using modified Canadian FASD diagnostic guidelines. A total of 108 of 134 (80.6%) eligible children (mean age 8y 9mo, SD=6mo, 53% male) were assessed. The median QNST-2 Total Score for all participants was within the normal category (19.0, range 4-66). However, the median QNST-2 Total Score...
De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Her... more De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Herein, we define the phenotypic spectrum of SCN2A encephalopathy. Twelve patients with an SCN2A epileptic encephalopathy underwent electroclinical phenotyping. Patients were aged 0.7 to 22 years; 3 were deceased. Seizures commenced on day 1-4 in 8, week 2-6 in 2, and after 1 year in 2. Characteristic features included clusters of brief focal seizures with multiple hourly (9 patients), multiple daily (2), or multiple weekly (1) seizures, peaking at maximal frequency within 3 months of onset. Multifocal interictal epileptiform discharges were seen in all. Three of 12 patients had infantile spasms. The epileptic syndrome at presentation was epilepsy of infancy with migrating focal seizures (EIMFS) in 7 and Ohtahara syndrome in 2. Nine patients had improved seizure control with sodium channel blockers including supratherapeutic or high therapeutic phenytoin levels in 5. Eight had severe to pro...
Rett syndrome and neurodevelopmental disorders with features overlapping this syndrome frequently... more Rett syndrome and neurodevelopmental disorders with features overlapping this syndrome frequently remain unexplained in patients without clinically identified MECP2 mutations. We recruited a cohort of 11 patients with features of Rett syndrome and negative initial clinical testing for mutations in MECP2. We analyzed their phenotypes to determine whether patients met formal criteria for Rett syndrome, reviewed repeat clinical genetic testing, and performed exome sequencing of the probands. Using 2010 diagnostic criteria, three patients had classical Rett syndrome, including two for whom repeat MECP2 gene testing had identified mutations. In a patient with neonatal onset epilepsy with atypical Rett syndrome, we identified a frameshift deletion in STXBP1. Among seven patients with features of Rett syndrome not fulfilling formal diagnostic criteria, four had suspected pathogenic mutations, one each in MECP2, FOXG1, SCN8A, and IQSEC2. MECP2 mutations are highly correlated with classical Rett syndrome. Genes associated with atypical Rett syndrome, epilepsy, or intellectual disability should be considered in patients with features overlapping with Rett syndrome and negative MECP2 testing. While most of the identified mutations were apparently de novo, the SCN8A variant was inherited
Autoimmunity is being increasingly recognized as a cause of neurologic presentations both inside ... more Autoimmunity is being increasingly recognized as a cause of neurologic presentations both inside and outside the intensive care unit (ICU) setting. Pediatric autoimmune neurologic diseases likely to be seen in the ICU include autoimmune encephalitidies such as N-Methyl-D-aspartate (NMDA) receptor encephalitis, central nervous system vasculitis, demyelinating disorders, and neurologic involvement of systemic autoimmune disorders. In addition, there are conditions of suspected autoimmune etiology such as febrile infectionrelated epilepsy syndrome (FIRES) and rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) syndrome that are rare, but when they do present, it is often to the ICU. Refractory seizures, altered mental status, and disordered breathing are the most common indications for intensive care for these patients.
Anecdotal reports suggest that high-risk drinking in pregnancy is common in some remote Australia... more Anecdotal reports suggest that high-risk drinking in pregnancy is common in some remote Australian communities. Alcohol is teratogenic and may cause a range of lifelong conditions termed 'fetal alcohol spectrum disorders' (FASD). Australia has few diagnostic services for FASD, and prevalence of these neurodevelopmental disorders remains unknown. In 2009, Aboriginal leaders in the remote Fitzroy Valley in North Western Australia identified FASD as a community priority and initiated the Lililwani Project in partnership with leading research organisations. This project will establish the prevalence of FASD and other health and developmental problems in school-aged children residing in the Fitzroy Valley, providing data to inform FASD prevention and management. This is a population-based active case ascertainment study of all children born in 2002 and 2003 and residing in the Fitzroy Valley. Participants will be identified from the Fitzroy Valley Population Project and Communica...
Journal of paediatrics and child health, Jan 15, 2015
Aboriginal leaders concerned about high rates of alcohol use in pregnancy invited researchers to ... more Aboriginal leaders concerned about high rates of alcohol use in pregnancy invited researchers to determine the prevalence of fetal alcohol syndrome (FAS) and partial fetal alcohol syndrome (pFAS) in their communities. Population-based prevalence study using active case ascertainment in children born in 2002/2003 and living in the Fitzroy Valley, in Western Australia (April 2010-November 2011) (n = 134). Socio-demographic and antenatal data, including alcohol use in pregnancy, were collected by interview with 127/134 (95%) consenting parents/care givers. Maternal/child medical records were reviewed. Interdisciplinary assessments were conducted for 108/134 (81%) children. FAS/pFAS prevalence was determined using modified Canadian diagnostic guidelines. In 127 pregnancies, alcohol was used in 55%. FAS or pFAS was diagnosed in 13/108 children, a prevalence of 120 per 1000 (95% confidence interval 70-196). Prenatal alcohol exposure was confirmed for all children with FAS/pFAS, 80% in the...
To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) t... more To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%).…
SummaryObjectiveReports of studies evaluating rufinamide as an add‐on therapy in children and ado... more SummaryObjectiveReports of studies evaluating rufinamide as an add‐on therapy in children and adolescents with refractory epilepsy are restricted to a few publications. Prospective multicenter studies including children and adults have yielded important information about several types of epilepsies and syndromes. We evaluated the use of rufinamide in a single pediatric center with a large cohort and long‐term follow‐up period.MethodsWe retrospectively included patients taking rufinamide from November 2008 to March 2013. Response was defined by a seizure reduction of ≥50% compared to baseline.ResultsThree hundred patients with a median age of 9.1 years (range 0.4–29.6 years) were reviewed. Median follow‐up was 9 months (range 1–37 months). Epilepsy etiology was classified as genetic (23.7%), structural/metabolic (41%), and unknown cause (35.3%). Overall, rufinamide treatment led to a median seizure frequency reduction of 59.2% from responders to baseline. Seizure reduction was greate...
Alcohol is a common human teratogen that, when ingested by a pregnant woman, can produce a wide a... more Alcohol is a common human teratogen that, when ingested by a pregnant woman, can produce a wide array of fetal complications. The fetus's developing brain seems most sensitive to prenatal alcohol exposure: Alcohol-related brain damage can be quite diffuse, ...
Plant Cell, Tissue and Organ Culture (PCTOC), 2013
ABSTRACT The sugar alcohol mannitol is a carbohydrate with well-documented roles in both metaboli... more ABSTRACT The sugar alcohol mannitol is a carbohydrate with well-documented roles in both metabolism and osmoprotection in plants and fungi. In addition, however, mannitol is an antioxidant, and current research suggests that pathogenic fungi can secrete mannitol into the plant’s extracellular spaces during infection to suppress reactive oxygen-mediated host defenses. In response to pathogen attack, plants have been shown to secrete the normally symplastic enzyme, mannitol dehydrogenase (MTD). Given that MTD converts mannitol to the sugar mannose, extracellular MTD may be an important defense against mannitol-secreting fungal pathogens. Previous work demonstrated that overexpression of MTD in tobacco did, in fact, provide increased resistance to the mannitol-secreting fungal pathogen Alternaria alternata. In the present work we demonstrate that the fungal pathogen Botrytis cinerea also can secrete mannitol, and that overexpression of MTD in zonal geranium (Pelargonium × hortorum) in turn provides increased resistance to B. cinerea. These results are not only an important validation of previous work, but support the idea that MTD-overexpression might be used to engineer a broad variety of plants for resistance to mannitol-secreting fungal pathogens like B. cinerea for which specific resistance is lacking.
Sensory processing differences are reported in a high proportion of children with fetal alcohol s... more Sensory processing differences are reported in a high proportion of children with fetal alcohol spectrum disorders (FASD), but how these problems impact caregiver burden has not been investigated. Linear regression was used to examine the association between parenting stress and problems in sensory processing, along with other child and family characteristics, among 52 children aged 5 to 12 years with FASD. Participants also had clinically significant problem behaviors. Higher levels of child-related parenting stress were moderately correlated with more parent-reported sensory processing problems ( r = −.60). Regression findings revealed that parent-reported problems in children's behavior regulation, an aspect of executive function, and sensory processing deficits were the strongest predictors of child-related parenting stress, together accounting for 62% of variance. Children's sensory processing deficits and executive function impairments affect the parent—child system an...
Journal of Speech, Language, and Hearing Research, 2007
Purpose To evaluate classification accuracy and clinical feasibility of a narrative analysis tool... more Purpose To evaluate classification accuracy and clinical feasibility of a narrative analysis tool for identifying children with a fetal alcohol spectrum disorder (FASD). Method Picture-elicited narratives generated by 16 age-matched pairs of school-aged children (FASD vs. typical development [TD]) were coded for semantic elaboration and reference strategy by judges who were unaware of age, gender, and group membership of the participants. Receiver operating characteristic (ROC) curves were used to examine the classification accuracy of the resulting set of narrative measures for making 2 classifications: (a) for the 16 children diagnosed with FASD, low performance ( n = 7) versus average performance ( n = 9) on a standardized expressive language task and (b) FASD ( n = 16) versus TD ( n = 16). Results Combining the rates of semantic elaboration and pragmatically inappropriate reference perfectly matched a classification based on performance on the standardized language task. More im...
A comprehensive neuropsychological/psychiatric, MR imaging, (MRI), MR spectroscopy (MRS), and fun... more A comprehensive neuropsychological/psychiatric, MR imaging, (MRI), MR spectroscopy (MRS), and functional MRI (fMRI) assessment was administered to children with fetal alcohol spectrum disorders (FASD) to determine if global and/or focal abnormalities could be identified, and distinguish diagnostic subclassifications across the spectrum. The four study groups included: 1. FAS/Partial FAS; 2. Static Encephalopathy/Alcohol Exposed (SE/AE); 3. Neurobehavioral Disorder/Alcohol Exposed (ND/AE); and 4. healthy peers with no prenatal alcohol exposure. fMRI outcomes are reported here. The neuropsychological/psychiatric, MRI, and MRS outcomes are reported separately. fMRI was used to assess activation in seven brain regions during performance of N-back working memory tasks. Children across the full spectrum of FASD exhibited significant working memory deficits and altered activation patterns in brain regions that are known to be involved in working memory. These results demonstrate the potent...
Maternal alcohol consumption during pregnancy is a significant social problem associated with dev... more Maternal alcohol consumption during pregnancy is a significant social problem associated with developmental difficulties in young children. Child developmental and behavioral characteristics were examined from the 9-month data point of the Early Childhood Longitudinal Studies—Birth Cohort, a prospective nationally representative study. Several findings indicate linear patterns between the amount of prenatal alcohol dosage and sensory regulation, mental, and motor development outcomes. Undesirable social engagement and child interaction were found to be statistically significant at the prenatal alcohol level of one to three drinks per week. Children exposed to four or more drinks per week showed statistically significant and clinically passive behavior on three sensory regulation variables.
Prenatal alcohol exposure can lead to significant neurodevelopmental disabilities, now recognized... more Prenatal alcohol exposure can lead to significant neurodevelopmental disabilities, now recognized as fetal alcohol spectrum disorders (FASD). This includes both fetal alcohol syndrome, a lifelong birth defect, and a wider range of enduring learning and behavior deficits often called alcoholrelated neurodevelopmental disorder (ARND). Diagnostic classification systems have been developed to identify children with FASD, and early interventionists from multiple disciplines can be central in identification and referral for diagnosis, and in providing the known protective influence of intervention early in life. With the recent federal mandates to better address needs of children born prenatally affected by substances, or those impacted by abuse and/or neglect, by referring them for screening and possible early intervention services, there is heightened need for providers to understand FASD. There is a growing body of research data describing the teratogenic effects of alcohol on central nervous system function and physical development, the diversity of children with prenatal alcohol exposure and their families, and the developmental and behavioral characteristics of this clinical population. This article reviews the latest research evidence, bearing in mind what is important to early intervention. This article also gives practical guidance on FASD prevention, methods for early screening, and referral of young children for diagnosis of FASD (and referral for needed services once diagnosed), and how to provide education, support, advocacy assistance, and anticipatory guidance for families raising children with FASD.
Distal partial trisomies involving the region 1q32 have been associated with dysmorphic features ... more Distal partial trisomies involving the region 1q32 have been associated with dysmorphic features and developmental delay.[1-11] To further define the critical region for developmental delay and to investigate the genotype-phenotype association of 1q trisomy syndrome, we report two patients with much smaller (3 Mb and 3.5 Mb in size) trisomic regions on 1q32.1. The two microduplications largely overlap and both patients exhibited cognitive and motor delays. Case 1 is a 5-year-old boy with global developmental delay, behavioral problems, pervasive developmental disorder not otherwise specified (PDD-NOS), staring spells, headaches, and paresthesias. Case 2 is a 14-year-old girl with seizures, cognitive and motor difficulties, and minor dysmorphic features. These two cases suggest that 1q32.1 region on distal arm of 1q and genes involved are critical to cognitive and motor development in a gene dosage sensitive manner and that other neurological features are variable within this syndrome.
The purpose of this study was to determine the safety and efficacy of rufinamide for treatment of... more The purpose of this study was to determine the safety and efficacy of rufinamide for treatment of epileptic spasms. Methods: We retrospectively reviewed patients treated with rufinamide for epileptic spasms from January 2009 to March 2010. Age, presence of hypsarrhythmia, change in seizure frequency following rufinamide initiation, and side effects were assessed. Patients who had a ≥ 50% reduction in spasm frequency were considered responders. Results: Of all 107 children treated with rufinamide during the study period, 38 (36%) had epileptic spasms. Median patient age was 7 years (range: 17 months to 23). One patient had hypsarrhythmia at the time of treatment with rufinamide, and 9 other patients had a history of hypsarrhythmia. Median starting dose of rufinamide was 9 mg/kg/day (range: 2-18) and median final treatment dose was 39 mg/kg/day (range: 8-92). All patients were receiving concurrent antiepileptic drug therapy, with the median number of antiepileptic drugs being 3 (range: 2-6). Median duration of follow-up since starting rufinamide was 171 days (range: 10-408). Responder rate was 53%. Median reduction in spasm frequency was 50% (interquartile range =-56 to 85%, P b 0.05). Two patients (5%) achieved a N 99% reduction in spasms. Rufinamide was discontinued in 7 of 38 patients (18%) because of lack of efficacy, worsening seizures, or other side effects. Minor side effects were reported in 14 of 38 patients (37%). Conclusions: Rufinamide appears to be a well-tolerated and efficacious adjunctive therapeutic option for children with epileptic spasms. A prospective study is warranted to validate our observations.
SummaryPurposeThe 2005 diagnostic criteria for Rasmussen encephalitis (RE) are based on seizures,... more SummaryPurposeThe 2005 diagnostic criteria for Rasmussen encephalitis (RE) are based on seizures, clinical deficits, electroencephalography (EEG), neuroimaging, and pathology (Brain, 128, 2005, 451). We applied these criteria to patients evaluated for RE and epilepsy surgery controls to determine the sensitivity, specificity, and positive and negative predictive values (PPVs, NPVs) using pathology as the gold standard.MethodsWe identified patients evaluated for RE based on medical records from 1993 to 2011. Fifty‐two control patients with refractory epilepsy, unilateral magnetic resonance imaging (MRI) changes, and biopsies were selected from an epilepsy surgery database from matching years. Patients meeting all three of group A and/or two of three group B criteria were classified as meeting full criteria (positive). Patients not meeting full criteria were classified as negative. When available, pathology findings were re‐reviewed with neuropathologists, and MRI imaging was re‐revie...
Developmental medicine and child neurology, Aug 15, 2016
To identify soft neurological signs (SNS) in a population-based study of children living in remot... more To identify soft neurological signs (SNS) in a population-based study of children living in remote Aboriginal communities in the Fitzroy Valley, Western Australia, born between 2002 and 2003 and explore the relationship between SNS, prenatal alcohol exposure (PAE), and fetal alcohol spectrum disorders (FASD). The presence of SNS was assessed using the Quick Neurological Screening Test, 2nd edition (QNST-2), which has a total maximum score of 140. Higher scores indicated more SNS. 'Severe discrepancy' was defined as scores less than or equal to the fifth centile while 'moderate discrepancy' represented scores from the sixth to the 24th centile. Children were assigned FASD diagnoses using modified Canadian FASD diagnostic guidelines. A total of 108 of 134 (80.6%) eligible children (mean age 8y 9mo, SD=6mo, 53% male) were assessed. The median QNST-2 Total Score for all participants was within the normal category (19.0, range 4-66). However, the median QNST-2 Total Score...
De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Her... more De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Herein, we define the phenotypic spectrum of SCN2A encephalopathy. Twelve patients with an SCN2A epileptic encephalopathy underwent electroclinical phenotyping. Patients were aged 0.7 to 22 years; 3 were deceased. Seizures commenced on day 1-4 in 8, week 2-6 in 2, and after 1 year in 2. Characteristic features included clusters of brief focal seizures with multiple hourly (9 patients), multiple daily (2), or multiple weekly (1) seizures, peaking at maximal frequency within 3 months of onset. Multifocal interictal epileptiform discharges were seen in all. Three of 12 patients had infantile spasms. The epileptic syndrome at presentation was epilepsy of infancy with migrating focal seizures (EIMFS) in 7 and Ohtahara syndrome in 2. Nine patients had improved seizure control with sodium channel blockers including supratherapeutic or high therapeutic phenytoin levels in 5. Eight had severe to pro...
Rett syndrome and neurodevelopmental disorders with features overlapping this syndrome frequently... more Rett syndrome and neurodevelopmental disorders with features overlapping this syndrome frequently remain unexplained in patients without clinically identified MECP2 mutations. We recruited a cohort of 11 patients with features of Rett syndrome and negative initial clinical testing for mutations in MECP2. We analyzed their phenotypes to determine whether patients met formal criteria for Rett syndrome, reviewed repeat clinical genetic testing, and performed exome sequencing of the probands. Using 2010 diagnostic criteria, three patients had classical Rett syndrome, including two for whom repeat MECP2 gene testing had identified mutations. In a patient with neonatal onset epilepsy with atypical Rett syndrome, we identified a frameshift deletion in STXBP1. Among seven patients with features of Rett syndrome not fulfilling formal diagnostic criteria, four had suspected pathogenic mutations, one each in MECP2, FOXG1, SCN8A, and IQSEC2. MECP2 mutations are highly correlated with classical Rett syndrome. Genes associated with atypical Rett syndrome, epilepsy, or intellectual disability should be considered in patients with features overlapping with Rett syndrome and negative MECP2 testing. While most of the identified mutations were apparently de novo, the SCN8A variant was inherited
Autoimmunity is being increasingly recognized as a cause of neurologic presentations both inside ... more Autoimmunity is being increasingly recognized as a cause of neurologic presentations both inside and outside the intensive care unit (ICU) setting. Pediatric autoimmune neurologic diseases likely to be seen in the ICU include autoimmune encephalitidies such as N-Methyl-D-aspartate (NMDA) receptor encephalitis, central nervous system vasculitis, demyelinating disorders, and neurologic involvement of systemic autoimmune disorders. In addition, there are conditions of suspected autoimmune etiology such as febrile infectionrelated epilepsy syndrome (FIRES) and rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) syndrome that are rare, but when they do present, it is often to the ICU. Refractory seizures, altered mental status, and disordered breathing are the most common indications for intensive care for these patients.
Anecdotal reports suggest that high-risk drinking in pregnancy is common in some remote Australia... more Anecdotal reports suggest that high-risk drinking in pregnancy is common in some remote Australian communities. Alcohol is teratogenic and may cause a range of lifelong conditions termed 'fetal alcohol spectrum disorders' (FASD). Australia has few diagnostic services for FASD, and prevalence of these neurodevelopmental disorders remains unknown. In 2009, Aboriginal leaders in the remote Fitzroy Valley in North Western Australia identified FASD as a community priority and initiated the Lililwani Project in partnership with leading research organisations. This project will establish the prevalence of FASD and other health and developmental problems in school-aged children residing in the Fitzroy Valley, providing data to inform FASD prevention and management. This is a population-based active case ascertainment study of all children born in 2002 and 2003 and residing in the Fitzroy Valley. Participants will be identified from the Fitzroy Valley Population Project and Communica...
Journal of paediatrics and child health, Jan 15, 2015
Aboriginal leaders concerned about high rates of alcohol use in pregnancy invited researchers to ... more Aboriginal leaders concerned about high rates of alcohol use in pregnancy invited researchers to determine the prevalence of fetal alcohol syndrome (FAS) and partial fetal alcohol syndrome (pFAS) in their communities. Population-based prevalence study using active case ascertainment in children born in 2002/2003 and living in the Fitzroy Valley, in Western Australia (April 2010-November 2011) (n = 134). Socio-demographic and antenatal data, including alcohol use in pregnancy, were collected by interview with 127/134 (95%) consenting parents/care givers. Maternal/child medical records were reviewed. Interdisciplinary assessments were conducted for 108/134 (81%) children. FAS/pFAS prevalence was determined using modified Canadian diagnostic guidelines. In 127 pregnancies, alcohol was used in 55%. FAS or pFAS was diagnosed in 13/108 children, a prevalence of 120 per 1000 (95% confidence interval 70-196). Prenatal alcohol exposure was confirmed for all children with FAS/pFAS, 80% in the...
To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) t... more To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%).…
SummaryObjectiveReports of studies evaluating rufinamide as an add‐on therapy in children and ado... more SummaryObjectiveReports of studies evaluating rufinamide as an add‐on therapy in children and adolescents with refractory epilepsy are restricted to a few publications. Prospective multicenter studies including children and adults have yielded important information about several types of epilepsies and syndromes. We evaluated the use of rufinamide in a single pediatric center with a large cohort and long‐term follow‐up period.MethodsWe retrospectively included patients taking rufinamide from November 2008 to March 2013. Response was defined by a seizure reduction of ≥50% compared to baseline.ResultsThree hundred patients with a median age of 9.1 years (range 0.4–29.6 years) were reviewed. Median follow‐up was 9 months (range 1–37 months). Epilepsy etiology was classified as genetic (23.7%), structural/metabolic (41%), and unknown cause (35.3%). Overall, rufinamide treatment led to a median seizure frequency reduction of 59.2% from responders to baseline. Seizure reduction was greate...
Alcohol is a common human teratogen that, when ingested by a pregnant woman, can produce a wide a... more Alcohol is a common human teratogen that, when ingested by a pregnant woman, can produce a wide array of fetal complications. The fetus's developing brain seems most sensitive to prenatal alcohol exposure: Alcohol-related brain damage can be quite diffuse, ...
Plant Cell, Tissue and Organ Culture (PCTOC), 2013
ABSTRACT The sugar alcohol mannitol is a carbohydrate with well-documented roles in both metaboli... more ABSTRACT The sugar alcohol mannitol is a carbohydrate with well-documented roles in both metabolism and osmoprotection in plants and fungi. In addition, however, mannitol is an antioxidant, and current research suggests that pathogenic fungi can secrete mannitol into the plant’s extracellular spaces during infection to suppress reactive oxygen-mediated host defenses. In response to pathogen attack, plants have been shown to secrete the normally symplastic enzyme, mannitol dehydrogenase (MTD). Given that MTD converts mannitol to the sugar mannose, extracellular MTD may be an important defense against mannitol-secreting fungal pathogens. Previous work demonstrated that overexpression of MTD in tobacco did, in fact, provide increased resistance to the mannitol-secreting fungal pathogen Alternaria alternata. In the present work we demonstrate that the fungal pathogen Botrytis cinerea also can secrete mannitol, and that overexpression of MTD in zonal geranium (Pelargonium × hortorum) in turn provides increased resistance to B. cinerea. These results are not only an important validation of previous work, but support the idea that MTD-overexpression might be used to engineer a broad variety of plants for resistance to mannitol-secreting fungal pathogens like B. cinerea for which specific resistance is lacking.
Sensory processing differences are reported in a high proportion of children with fetal alcohol s... more Sensory processing differences are reported in a high proportion of children with fetal alcohol spectrum disorders (FASD), but how these problems impact caregiver burden has not been investigated. Linear regression was used to examine the association between parenting stress and problems in sensory processing, along with other child and family characteristics, among 52 children aged 5 to 12 years with FASD. Participants also had clinically significant problem behaviors. Higher levels of child-related parenting stress were moderately correlated with more parent-reported sensory processing problems ( r = −.60). Regression findings revealed that parent-reported problems in children's behavior regulation, an aspect of executive function, and sensory processing deficits were the strongest predictors of child-related parenting stress, together accounting for 62% of variance. Children's sensory processing deficits and executive function impairments affect the parent—child system an...
Journal of Speech, Language, and Hearing Research, 2007
Purpose To evaluate classification accuracy and clinical feasibility of a narrative analysis tool... more Purpose To evaluate classification accuracy and clinical feasibility of a narrative analysis tool for identifying children with a fetal alcohol spectrum disorder (FASD). Method Picture-elicited narratives generated by 16 age-matched pairs of school-aged children (FASD vs. typical development [TD]) were coded for semantic elaboration and reference strategy by judges who were unaware of age, gender, and group membership of the participants. Receiver operating characteristic (ROC) curves were used to examine the classification accuracy of the resulting set of narrative measures for making 2 classifications: (a) for the 16 children diagnosed with FASD, low performance ( n = 7) versus average performance ( n = 9) on a standardized expressive language task and (b) FASD ( n = 16) versus TD ( n = 16). Results Combining the rates of semantic elaboration and pragmatically inappropriate reference perfectly matched a classification based on performance on the standardized language task. More im...
A comprehensive neuropsychological/psychiatric, MR imaging, (MRI), MR spectroscopy (MRS), and fun... more A comprehensive neuropsychological/psychiatric, MR imaging, (MRI), MR spectroscopy (MRS), and functional MRI (fMRI) assessment was administered to children with fetal alcohol spectrum disorders (FASD) to determine if global and/or focal abnormalities could be identified, and distinguish diagnostic subclassifications across the spectrum. The four study groups included: 1. FAS/Partial FAS; 2. Static Encephalopathy/Alcohol Exposed (SE/AE); 3. Neurobehavioral Disorder/Alcohol Exposed (ND/AE); and 4. healthy peers with no prenatal alcohol exposure. fMRI outcomes are reported here. The neuropsychological/psychiatric, MRI, and MRS outcomes are reported separately. fMRI was used to assess activation in seven brain regions during performance of N-back working memory tasks. Children across the full spectrum of FASD exhibited significant working memory deficits and altered activation patterns in brain regions that are known to be involved in working memory. These results demonstrate the potent...
Maternal alcohol consumption during pregnancy is a significant social problem associated with dev... more Maternal alcohol consumption during pregnancy is a significant social problem associated with developmental difficulties in young children. Child developmental and behavioral characteristics were examined from the 9-month data point of the Early Childhood Longitudinal Studies—Birth Cohort, a prospective nationally representative study. Several findings indicate linear patterns between the amount of prenatal alcohol dosage and sensory regulation, mental, and motor development outcomes. Undesirable social engagement and child interaction were found to be statistically significant at the prenatal alcohol level of one to three drinks per week. Children exposed to four or more drinks per week showed statistically significant and clinically passive behavior on three sensory regulation variables.
Prenatal alcohol exposure can lead to significant neurodevelopmental disabilities, now recognized... more Prenatal alcohol exposure can lead to significant neurodevelopmental disabilities, now recognized as fetal alcohol spectrum disorders (FASD). This includes both fetal alcohol syndrome, a lifelong birth defect, and a wider range of enduring learning and behavior deficits often called alcoholrelated neurodevelopmental disorder (ARND). Diagnostic classification systems have been developed to identify children with FASD, and early interventionists from multiple disciplines can be central in identification and referral for diagnosis, and in providing the known protective influence of intervention early in life. With the recent federal mandates to better address needs of children born prenatally affected by substances, or those impacted by abuse and/or neglect, by referring them for screening and possible early intervention services, there is heightened need for providers to understand FASD. There is a growing body of research data describing the teratogenic effects of alcohol on central nervous system function and physical development, the diversity of children with prenatal alcohol exposure and their families, and the developmental and behavioral characteristics of this clinical population. This article reviews the latest research evidence, bearing in mind what is important to early intervention. This article also gives practical guidance on FASD prevention, methods for early screening, and referral of young children for diagnosis of FASD (and referral for needed services once diagnosed), and how to provide education, support, advocacy assistance, and anticipatory guidance for families raising children with FASD.
Distal partial trisomies involving the region 1q32 have been associated with dysmorphic features ... more Distal partial trisomies involving the region 1q32 have been associated with dysmorphic features and developmental delay.[1-11] To further define the critical region for developmental delay and to investigate the genotype-phenotype association of 1q trisomy syndrome, we report two patients with much smaller (3 Mb and 3.5 Mb in size) trisomic regions on 1q32.1. The two microduplications largely overlap and both patients exhibited cognitive and motor delays. Case 1 is a 5-year-old boy with global developmental delay, behavioral problems, pervasive developmental disorder not otherwise specified (PDD-NOS), staring spells, headaches, and paresthesias. Case 2 is a 14-year-old girl with seizures, cognitive and motor difficulties, and minor dysmorphic features. These two cases suggest that 1q32.1 region on distal arm of 1q and genes involved are critical to cognitive and motor development in a gene dosage sensitive manner and that other neurological features are variable within this syndrome.
The purpose of this study was to determine the safety and efficacy of rufinamide for treatment of... more The purpose of this study was to determine the safety and efficacy of rufinamide for treatment of epileptic spasms. Methods: We retrospectively reviewed patients treated with rufinamide for epileptic spasms from January 2009 to March 2010. Age, presence of hypsarrhythmia, change in seizure frequency following rufinamide initiation, and side effects were assessed. Patients who had a ≥ 50% reduction in spasm frequency were considered responders. Results: Of all 107 children treated with rufinamide during the study period, 38 (36%) had epileptic spasms. Median patient age was 7 years (range: 17 months to 23). One patient had hypsarrhythmia at the time of treatment with rufinamide, and 9 other patients had a history of hypsarrhythmia. Median starting dose of rufinamide was 9 mg/kg/day (range: 2-18) and median final treatment dose was 39 mg/kg/day (range: 8-92). All patients were receiving concurrent antiepileptic drug therapy, with the median number of antiepileptic drugs being 3 (range: 2-6). Median duration of follow-up since starting rufinamide was 171 days (range: 10-408). Responder rate was 53%. Median reduction in spasm frequency was 50% (interquartile range =-56 to 85%, P b 0.05). Two patients (5%) achieved a N 99% reduction in spasms. Rufinamide was discontinued in 7 of 38 patients (18%) because of lack of efficacy, worsening seizures, or other side effects. Minor side effects were reported in 14 of 38 patients (37%). Conclusions: Rufinamide appears to be a well-tolerated and efficacious adjunctive therapeutic option for children with epileptic spasms. A prospective study is warranted to validate our observations.
SummaryPurposeThe 2005 diagnostic criteria for Rasmussen encephalitis (RE) are based on seizures,... more SummaryPurposeThe 2005 diagnostic criteria for Rasmussen encephalitis (RE) are based on seizures, clinical deficits, electroencephalography (EEG), neuroimaging, and pathology (Brain, 128, 2005, 451). We applied these criteria to patients evaluated for RE and epilepsy surgery controls to determine the sensitivity, specificity, and positive and negative predictive values (PPVs, NPVs) using pathology as the gold standard.MethodsWe identified patients evaluated for RE based on medical records from 1993 to 2011. Fifty‐two control patients with refractory epilepsy, unilateral magnetic resonance imaging (MRI) changes, and biopsies were selected from an epilepsy surgery database from matching years. Patients meeting all three of group A and/or two of three group B criteria were classified as meeting full criteria (positive). Patients not meeting full criteria were classified as negative. When available, pathology findings were re‐reviewed with neuropathologists, and MRI imaging was re‐revie...
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Papers by Heather Olson