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Papers by gayatri annapurna vadlamani

Frontiers in Neurology, Jul 14, 2022

We report the genetic analysis of two consanguineous pedigrees of Pakistani ancestry in which two... more We report the genetic analysis of two consanguineous pedigrees of Pakistani ancestry in which two siblings in each family exhibited developmental delay, epilepsy, intellectual disability and aggressive behavior. Whole-genome sequencing was performed in Family 1, and we identified ∼80,000 variants located in regions of homozygosity. Of these, 615 variants had a minor allele frequency ≤ 0.001, and 21 variants had CADD scores ≥ 15. Four homozygous exonic variants were identified in both affected siblings: PDZD7 (c.1348_1350delGAG, p.Glu450del), ALG6 (c.1033G>C, p.Glu345Gln), RBM20 (c.1587C>G, p.Ser529Arg), and CNTNAP2 (c.785G>A, p.Gly228Arg). Sanger sequencing revealed co-segregation of the PDZD7, RBM20, and CNTNAP2 variants with disease in Family 1. Pathogenic variants in PDZD7 and RBM20 are associated with autosomal recessive non-syndromic hearing loss and autosomal dominant dilated cardiomyopathy, respectively, suggesting that these variants are unlikely likely to contribute to the clinical presentation. Gene panel analysis was performed on the two affected siblings in Family 2, and they were found to also be homozygous for the p.Gly228Arg CNTNAP2 variant. Together these families provide a LOD score 2.9 toward p.Gly228Arg CNTNAP2 being a completely penetrant recessive cause of this disease. The clinical presentation of the affected siblings in both families is also consistent with previous reports from individuals with homozygous CNTNAP2 variants where at least one allele was a nonsense variant, frameshift or small deletion. Our data suggests that homozygous CNTNAP2 missense variants can also contribute to disease, thereby expanding the genetic landscape of CNTNAP2 dysfunction.

European Journal of Paediatric Neurology, Jun 1, 2017

100,000 person-years) with unadjusted HR 1.41(1.10e1.82) for ID. Conclusion: The risk of hospital... more 100,000 person-years) with unadjusted HR 1.41(1.10e1.82) for ID. Conclusion: The risk of hospital-treated injury is higher among children with epilepsy than in controls. The risk is further elevated among children with comorbid ID.

Journal of pediatric neurology, Jun 1, 2016

The diagnosis of pediatric metabolic disease is complicated and markers of dysfunction are often ... more The diagnosis of pediatric metabolic disease is complicated and markers of dysfunction are often key in directing appropriate genetic testing. We present a 4-year-old girl with developmental regression following an episode of chicken pox at 7 months. She lost her ability to sit, roll over, or babble. Investigations revealed high plasma lactate at 3.7 mmol/L (normal: NDUFV1 mutation, predicted to result in mitochondrial complex I deficiency, and was subsequently confirmed by molecular genetic analysis. Coincidentally, she had raised oxalate and glycolate on repeated urine examination with raised urine oxalate: creatinine ratio. Genetic testing confirmed a pathological mutation in AGXT , consistent with primary hyperoxaluria type 1. NDUFV1 mutations result in variable phenotypes including Leigh syndrome, infantile lactic acidosis, cardiomyopathy, leukoencephalopathy, and the majority are described to be progressive and rapidly fatal in some cases. After the initial episode and now aged 4 years, our index case continues to make developmental progress without further episodes of regression, although speech and language delay persists. This case helps broaden our understanding of genotype–phenotype correlations associated with recessively inherited NDUFV1 mutations and highlights that they can be associated with less severe phenotypes. Moreover, there may be coexisting conditions, particularly in consanguineous pedigrees, which careful analysis of their clinical and biochemical data may allude to.

European Journal of Paediatric Neurology, May 1, 2015

Objective To describe an unusual clinical and EEG phenotype of Hashimoto's encephalopathy. Me... more Objective To describe an unusual clinical and EEG phenotype of Hashimoto's encephalopathy. Methods A case report and discussion. Results Hashimoto's encephalopathy is rare progressive or relapsing encephalopathy syndrome associated with cognitive decline, seizures and myoclonus. We describe a six year old previously well girl who presented with gradual cognitive decline over a number of months. Work up for this revealed significantly raised thyroid peroxidase antibodies consistent with autoimmune thyroiditis. Therefore a diagnosis of Hashimoto's encephalopathy was made. She had no clinical seizures at presentation or follow up which is unusual for the described phenotype of paediatric Hashimoto's encephalopathy. Her MRI scans revealed global atrophy with multi-focal T2 white matter hyperintensities with no diffusion restriction. An EEG showed spike and polyspike wave complexes with background slowing and photo-paroxysmal responses at multiple frequencies. Other investigations including CSF, VLCFA's, ceruloplasmin, white cell enzymes and urine for organic acids were normal. She was commenced on steroids for Hashimoto's. She showed improvement and of note her previous EEG abnormalities had normalised as well as having no abnormal responses to photic stimulation. Conclusion The absence of prominent seizures is an unusual phenotype of Hashimoto's and presence of photo-paroxysmal responses has been described only in a few other cases in the literature. Our case illustrates that children presenting with Hashimoto's with evidence of CNS involvement should have an EEG including photic stimulation as this represents a potentially treatable entity within Hashimoto's even in those with no overt clinical seizures

Cochrane Database of Systematic Reviews, 2005

Epilepsy is a disorder with recurrent epileptic seizures. Corticosteroids have been used in the t... more Epilepsy is a disorder with recurrent epileptic seizures. Corticosteroids have been used in the treatment of children with epilepsy and have significant adverse effects. Their efficacy and tolerability have not been not clearly established. To determine the efficacy of corticosteroids in terms of seizure control, improvements in cognition and in quality of life and tolerability of steroids compared to placebo or other antiepileptic drugs. We searched the following databases: The Cochrane Epilepsy Group Specialized Register (September 2006); Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library Issue 2, 2006); MEDLINE (1966 - April 2004); EMBASE (1966 - December 2004); Database of Abstracts of Reviews of Effectiveness (DARE) (December 2004). We checked the reference lists of retrieved studies for additional reports of relevant studies. All randomized controlled trials of administration of corticosteroids to children (less than 16 years) with epilepsy. Three review authors independently selected trials for inclusion and extracted data. Outcomes included cessation of seizures, reduction in seizure frequency, improvement in cognition, quality of life and adverse effects of steroids. A single RCT was included that recruited five patients in double blind crossover trial. One was withdrawn prematurely from the study and another had infantile spasms and hence was excluded from further analysis. ACTH 4-9 was administered. The overall reduction in seizure frequency of more than 25% and less than 50% occurred in one child at low dose and in two children at higher dose. One child did not show any reduction in seizure frequency. No adverse effects were reported. No evidence was found for the efficacy or safety of corticosteroids in treating childhood epilepsies. Clinicians using steroids in childhood epilepsies, other than for epileptic spasms, should take this into account before using these agents.

Epilepsy Research, 2019

This is a repository copy of Assessing evidence quality in research reporting neurocognitive outc... more This is a repository copy of Assessing evidence quality in research reporting neurocognitive outcomes following paediatric temporal lobe surgery for epilepsy.

Neurology. Genetics, 2017

To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-... more To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, alt...

Human Mutation, 2019

This is the author manuscript accepted for publication and undergone full peer review but has not... more This is the author manuscript accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

Seizure, Jan 7, 2017

A review of all published evidence for mapping eloquent (motor, language and memory) cortex using... more A review of all published evidence for mapping eloquent (motor, language and memory) cortex using advanced functional neuroimaging (functional magnetic resonance imaging [fMRI] and magnetoencephalography [MEG]) for paediatric epilepsy surgery candidates has not been conducted previously. Research in this area has predominantly been in adult populations and applicability of these techniques to paediatric populations is less established. A review was performed using an advanced systematic search and retrieval of all published papers examining the use of functional neuroimaging for paediatric epilepsy surgery candidates. Of the 2724 papers retrieved, 34 met the inclusion criteria. Total paediatric participants identified were 353 with an age range of 5 months-19 years. Sample sizes and comparisons with alternative investigations to validate techniques are small and variable paradigms are used. Sensitivity 0.72 (95% CI 0.52-0.86) and specificity 0.60 (95% CI 0.35-0.92) values with a Pos...

Seizure, 2017

Objective: The systematic review aimed to assess the neuropsychological outcomes of temporal lobe... more Objective: The systematic review aimed to assess the neuropsychological outcomes of temporal lobe resections for epilepsy in children. Additional objectives included determining whether earlier age at surgery leads to better neuropsychological outcomes; the relationships between and predictors of these outcomes. Methods: Using advanced search terms, a systematic review of electronic databases was conducted, comprising MEDLINE, Embase, PsycINFO, Global Health, Web of Science and CINAHL. Included studies reported on outcome following neurosurgical treatment for epilepsy. Specifically, studies were included if they reported neuropsychological outcomes and were concerned only with temporal lobe resection. Results: 73 studies met inclusion criteria. For reported neuropsychological outcomes, the majority of participants remained stable after surgery; some declined and some improved. There was some evidence for increased material-specific memory deficits after temporal lobe surgery based on resection side, and more positive cognitive outcome for those with lower pre-surgical ability level. Significance: Retrieved evidence highlights the need for improvements to quality of methodology and reporting. Appropriately designed prospective multicentre trials should be conducted with adequate follow-up for long-term outcomes to be measured. Core outcome measures should be agreed between centres. This would permit higher quality evidence so that clinicians, young people and their families may make better informed decisions about whether or not to proceed with surgery and likely post-operative profile.

Child's Nervous System, 2015

The demand for paediatric epilepsy surgery in the UK greatly exceeds the number of operations per... more The demand for paediatric epilepsy surgery in the UK greatly exceeds the number of operations performed. Hence, Children's Epilepsy Surgery Service (CESS) was commenced in 2012. This study is aimed to characterise the changes in service delivery in the North East of England Paediatric Neuroscience Network and nationally. A retrospective cohort study of paediatric epilepsy surgery in Leeds between 2005 and 2012 is presented followed by analysis of British Paediatric Neurosurgical Group (BPNG) data before and after CESS commissioning. During the study period, 42 children underwent epilepsy surgery in Leeds. The commonest aetiologies were neoplasm (33 %), focal cortical dysplasia (19 %) and mesial temporal sclerosis (19 %). Seizure outcome was 71 % EngelI and 83 % EngelI+II. Complications included one infection (2 %), two temporary (5 %) and one permanent (2 %) motor deficits, three new/worsened visual field deficits (7 %). There were six re-craniotomies (14 %). The BPNG data show a 48 % increase in paediatric epilepsy surgery in England between 2009 (90 cases) and 2012 (133 cases), and a 20 % fall in 2013 (106 cases)-the first calendar year for CESS. On average, 64 % of all operations were performed in London. The number of children receiving surgery for epilepsy in England had increased annually up to, and declined after, the establishment of CESS centres. The yearly caseload in neurosurgical units outside of London is small. The outcomes from Leeds are comparable to those published elsewhere. Other UK units are encouraged to publish outcomes to facilitate patient, commissioner and provider decision making.

Epilepsia, 2010

The 2007 UK National Institute for Health and Clinical Excellence (NICE) guidelines for epilepsy ... more The 2007 UK National Institute for Health and Clinical Excellence (NICE) guidelines for epilepsy recommend disclosing the risk of sudden unexpected death in epilepsy (SUDEP) to patients. This recommendation is not undertaken routinely, and considerable variation in individual physician practice exists. Literature indicates wariness of causing distress and anxiety, particularly to children/young people and their families through disclosing a nonpreventable risk. There has been no systematic pediatric study examining parent/guardian information needs and beliefs for risk of SUDEP and its impact on seizure management. It is important to first address these concerns before routinely imparting SUDEP information to parents following NICE recommendations. Two questionnaire surveys: a questionnaire examining the provision by pediatric neurologists of SUDEP information, and questionnaires examining parental beliefs and implications at two time points regarding SUDEP information provided in a leaflet. Participants were included in the study if their child had an established diagnosis of epilepsy. Factors for exclusion were single unprovoked seizure, absence seizures, patients in remission, and active discontinuation of treatment. The majority (74%) of pediatric neurologists provided SUDEP information only to a select group of children with epilepsy and were uncertain about the effect such information would have upon the parent and child. Conversely, 91% of parents expected the pediatric neurologist to provide SUDEP risk information. The provision of this information did not have a significant immediate and longer-term negative impact. The majority of parents wanted to know about SUDEP and its associated risks. Whenever possible, SUDEP information should be given by the physician accompanied by an information leaflet.

Developmental Medicine & Child Neurology, 2006

The possibility that so-called anti-epileptic drugs (AEDs) may aggravate epilepsy must always be ... more The possibility that so-called anti-epileptic drugs (AEDs) may aggravate epilepsy must always be borne in mind by the clinician. Many reports of such aggravation of seizures have been published. Most such reports are anecdotal and speculative, and suggest that many such reactions are idiosyncratic. However, for some there is a sufficient body of evidence to suggest that some AEDs used in certain epilepsies may consistently cause worsening of seizures. Seizure aggravation may include increase in the frequency or severity of existing seizures, emergence of new types of seizure, or the occurrence of status epilepticus. The pathophysiology of seizure aggravation is poorly understood including non-specific effects such as those associated with sedation, drug-induced encephalopathy, and paradoxical or inverse pharmacodynamic effects. For some epilepsies the choice of AEDs may be inappropriate, and although the mechanism of seizure aggravation is not clear, its occurrence may be fairly predictable. This is best documented for the use of carbamazepine in idiopathic generalized and myoclonic epilepsies. Most other AEDs have been reported occasionally to cause seizure aggravation. The lowest risk of seizure aggravation appears to be with valproate. Risk factors for worsening of seizures are epileptic encephalopathy, polytherapy, high frequency of seizures, and cognitive impairment. Advances in pharmacogenomics may in the future enable such adverse effects to be predicted for individual patients. Meanwhile, a systematic approach to reporting AED-induced seizure aggravation should be developed.

European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 2016

To establish the efficacy and tolerability of inhaled 5% carbon dioxide/95% oxygen as a treatment... more To establish the efficacy and tolerability of inhaled 5% carbon dioxide/95% oxygen as a treatment for paediatric non-convulsive status epilepticus (NCSE). In an open label clinical trial, children in NCSE were given high flow inhaled 5% carbon dioxide/95% oxygen by face mask for 120 s under EEG control. Six children (five male; ages 3-13; all with severe underlying epilepsy and disability) were recruited. Inhalation was well tolerated in all cases. Capillary blood gasses showed no significant derangements at the end of the inhalation. Effects on EEG normalisation were limited and transient, and no clinical improvements were noted. No adverse effects occurred. Inhaled 5% carbon dioxide/95% oxygen has been suggested as a potent, well tolerated anticonvulsant. An anticonvulsant without sedating and respiration-depressing effects would be particularly welcome in the management of NCSE where the justification for aggressive anticonvulsant therapy is often uncertain, however it appears th...

The 2007 UK National Institute for Health and Clinical Excellence (NICE) guidelines for epilepsy ... more The 2007 UK National Institute for Health and Clinical Excellence (NICE) guidelines for epilepsy recommend disclosing the risk of sudden unexpected death in epilepsy (SUDEP) to patients. This recommendation is not undertaken routinely, and considerable variation in individual physician practice exists. Literature indicates wariness of causing distress and anxiety, particularly to children/young people and their families through disclosing a nonpreventable risk. There has been no systematic pediatric study examining parent/guardian information needs and beliefs for risk of SUDEP and its impact on seizure management. It is important to first address these concerns before routinely imparting SUDEP information to parents following NICE recommendations. Methods: Two questionnaire surveys: a questionnaire examining the provision by pediatric neurologists of SUDEP information, and questionnaires examining parental beliefs and implications at two time points regarding SUDEP information provided in a leaflet. Participants were included in the study if their child had an established diagnosis of epilepsy. Factors for exclusion were single unprovoked seizure, absence seizures, patients in remission, and active discontinuation of treatment. Results: The majority (74%) of pediatric neurologists provided SUDEP information only to a select group of children with epilepsy and were uncertain about the effect such information would have upon the parent and child. Conversely, 91% of parents expected the pediatric neurologist to provide SUDEP risk information. The provision of this information did not have a significant immediate and longer-term negative impact. Discussion: The majority of parents wanted to know about SUDEP and its associated risks. Whenever possible, SUDEP information should be given by the physician accompanied by an information leaflet.

The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth d... more The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects

Objective: To establish the efficacy and tolerability of inhaled 5% carbon dioxide/95% oxygen as ... more Objective: To establish the efficacy and tolerability of inhaled 5% carbon dioxide/95% oxygen as a treatment for paediatric non-convulsive status epilepticus (NCSE). Methods: In an open label clinical trial, children in NCSE were given high flow inhaled 5% carbon dioxide/95% oxygen by face mask for 120 s under EEG control. Results: Six children (five male; ages 3e13; all with severe underlying epilepsy and disability) were recruited. Inhalation was well tolerated in all cases. Capillary blood gasses showed no significant derangements at the end of the inhalation. Effects on EEG normalisation were limited and transient, and no clinical improvements were noted. No adverse effects occurred. Conclusion: Inhaled 5% carbon dioxide/95% oxygen has been suggested as a potent, well tolerated anticonvulsant. An anticonvulsant without sedating and respiration-depressing effects would be particularly welcome in the management of NCSE where the justification for aggressive anticonvulsant therapy is often uncertain, however it appears that 5% carbon dioxide is of limited efficacy in this context.

Frontiers in Neurology, Jul 14, 2022

We report the genetic analysis of two consanguineous pedigrees of Pakistani ancestry in which two... more We report the genetic analysis of two consanguineous pedigrees of Pakistani ancestry in which two siblings in each family exhibited developmental delay, epilepsy, intellectual disability and aggressive behavior. Whole-genome sequencing was performed in Family 1, and we identified ∼80,000 variants located in regions of homozygosity. Of these, 615 variants had a minor allele frequency ≤ 0.001, and 21 variants had CADD scores ≥ 15. Four homozygous exonic variants were identified in both affected siblings: PDZD7 (c.1348_1350delGAG, p.Glu450del), ALG6 (c.1033G>C, p.Glu345Gln), RBM20 (c.1587C>G, p.Ser529Arg), and CNTNAP2 (c.785G>A, p.Gly228Arg). Sanger sequencing revealed co-segregation of the PDZD7, RBM20, and CNTNAP2 variants with disease in Family 1. Pathogenic variants in PDZD7 and RBM20 are associated with autosomal recessive non-syndromic hearing loss and autosomal dominant dilated cardiomyopathy, respectively, suggesting that these variants are unlikely likely to contribute to the clinical presentation. Gene panel analysis was performed on the two affected siblings in Family 2, and they were found to also be homozygous for the p.Gly228Arg CNTNAP2 variant. Together these families provide a LOD score 2.9 toward p.Gly228Arg CNTNAP2 being a completely penetrant recessive cause of this disease. The clinical presentation of the affected siblings in both families is also consistent with previous reports from individuals with homozygous CNTNAP2 variants where at least one allele was a nonsense variant, frameshift or small deletion. Our data suggests that homozygous CNTNAP2 missense variants can also contribute to disease, thereby expanding the genetic landscape of CNTNAP2 dysfunction.

European Journal of Paediatric Neurology, Jun 1, 2017

100,000 person-years) with unadjusted HR 1.41(1.10e1.82) for ID. Conclusion: The risk of hospital... more 100,000 person-years) with unadjusted HR 1.41(1.10e1.82) for ID. Conclusion: The risk of hospital-treated injury is higher among children with epilepsy than in controls. The risk is further elevated among children with comorbid ID.

Journal of pediatric neurology, Jun 1, 2016

The diagnosis of pediatric metabolic disease is complicated and markers of dysfunction are often ... more The diagnosis of pediatric metabolic disease is complicated and markers of dysfunction are often key in directing appropriate genetic testing. We present a 4-year-old girl with developmental regression following an episode of chicken pox at 7 months. She lost her ability to sit, roll over, or babble. Investigations revealed high plasma lactate at 3.7 mmol/L (normal: NDUFV1 mutation, predicted to result in mitochondrial complex I deficiency, and was subsequently confirmed by molecular genetic analysis. Coincidentally, she had raised oxalate and glycolate on repeated urine examination with raised urine oxalate: creatinine ratio. Genetic testing confirmed a pathological mutation in AGXT , consistent with primary hyperoxaluria type 1. NDUFV1 mutations result in variable phenotypes including Leigh syndrome, infantile lactic acidosis, cardiomyopathy, leukoencephalopathy, and the majority are described to be progressive and rapidly fatal in some cases. After the initial episode and now aged 4 years, our index case continues to make developmental progress without further episodes of regression, although speech and language delay persists. This case helps broaden our understanding of genotype–phenotype correlations associated with recessively inherited NDUFV1 mutations and highlights that they can be associated with less severe phenotypes. Moreover, there may be coexisting conditions, particularly in consanguineous pedigrees, which careful analysis of their clinical and biochemical data may allude to.

European Journal of Paediatric Neurology, May 1, 2015

Objective To describe an unusual clinical and EEG phenotype of Hashimoto's encephalopathy. Me... more Objective To describe an unusual clinical and EEG phenotype of Hashimoto's encephalopathy. Methods A case report and discussion. Results Hashimoto's encephalopathy is rare progressive or relapsing encephalopathy syndrome associated with cognitive decline, seizures and myoclonus. We describe a six year old previously well girl who presented with gradual cognitive decline over a number of months. Work up for this revealed significantly raised thyroid peroxidase antibodies consistent with autoimmune thyroiditis. Therefore a diagnosis of Hashimoto's encephalopathy was made. She had no clinical seizures at presentation or follow up which is unusual for the described phenotype of paediatric Hashimoto's encephalopathy. Her MRI scans revealed global atrophy with multi-focal T2 white matter hyperintensities with no diffusion restriction. An EEG showed spike and polyspike wave complexes with background slowing and photo-paroxysmal responses at multiple frequencies. Other investigations including CSF, VLCFA's, ceruloplasmin, white cell enzymes and urine for organic acids were normal. She was commenced on steroids for Hashimoto's. She showed improvement and of note her previous EEG abnormalities had normalised as well as having no abnormal responses to photic stimulation. Conclusion The absence of prominent seizures is an unusual phenotype of Hashimoto's and presence of photo-paroxysmal responses has been described only in a few other cases in the literature. Our case illustrates that children presenting with Hashimoto's with evidence of CNS involvement should have an EEG including photic stimulation as this represents a potentially treatable entity within Hashimoto's even in those with no overt clinical seizures

Cochrane Database of Systematic Reviews, 2005

Epilepsy is a disorder with recurrent epileptic seizures. Corticosteroids have been used in the t... more Epilepsy is a disorder with recurrent epileptic seizures. Corticosteroids have been used in the treatment of children with epilepsy and have significant adverse effects. Their efficacy and tolerability have not been not clearly established. To determine the efficacy of corticosteroids in terms of seizure control, improvements in cognition and in quality of life and tolerability of steroids compared to placebo or other antiepileptic drugs. We searched the following databases: The Cochrane Epilepsy Group Specialized Register (September 2006); Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library Issue 2, 2006); MEDLINE (1966 - April 2004); EMBASE (1966 - December 2004); Database of Abstracts of Reviews of Effectiveness (DARE) (December 2004). We checked the reference lists of retrieved studies for additional reports of relevant studies. All randomized controlled trials of administration of corticosteroids to children (less than 16 years) with epilepsy. Three review authors independently selected trials for inclusion and extracted data. Outcomes included cessation of seizures, reduction in seizure frequency, improvement in cognition, quality of life and adverse effects of steroids. A single RCT was included that recruited five patients in double blind crossover trial. One was withdrawn prematurely from the study and another had infantile spasms and hence was excluded from further analysis. ACTH 4-9 was administered. The overall reduction in seizure frequency of more than 25% and less than 50% occurred in one child at low dose and in two children at higher dose. One child did not show any reduction in seizure frequency. No adverse effects were reported. No evidence was found for the efficacy or safety of corticosteroids in treating childhood epilepsies. Clinicians using steroids in childhood epilepsies, other than for epileptic spasms, should take this into account before using these agents.

Epilepsy Research, 2019

This is a repository copy of Assessing evidence quality in research reporting neurocognitive outc... more This is a repository copy of Assessing evidence quality in research reporting neurocognitive outcomes following paediatric temporal lobe surgery for epilepsy.

Neurology. Genetics, 2017

To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-... more To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, alt...

Human Mutation, 2019

This is the author manuscript accepted for publication and undergone full peer review but has not... more This is the author manuscript accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

Seizure, Jan 7, 2017

A review of all published evidence for mapping eloquent (motor, language and memory) cortex using... more A review of all published evidence for mapping eloquent (motor, language and memory) cortex using advanced functional neuroimaging (functional magnetic resonance imaging [fMRI] and magnetoencephalography [MEG]) for paediatric epilepsy surgery candidates has not been conducted previously. Research in this area has predominantly been in adult populations and applicability of these techniques to paediatric populations is less established. A review was performed using an advanced systematic search and retrieval of all published papers examining the use of functional neuroimaging for paediatric epilepsy surgery candidates. Of the 2724 papers retrieved, 34 met the inclusion criteria. Total paediatric participants identified were 353 with an age range of 5 months-19 years. Sample sizes and comparisons with alternative investigations to validate techniques are small and variable paradigms are used. Sensitivity 0.72 (95% CI 0.52-0.86) and specificity 0.60 (95% CI 0.35-0.92) values with a Pos...

Seizure, 2017

Objective: The systematic review aimed to assess the neuropsychological outcomes of temporal lobe... more Objective: The systematic review aimed to assess the neuropsychological outcomes of temporal lobe resections for epilepsy in children. Additional objectives included determining whether earlier age at surgery leads to better neuropsychological outcomes; the relationships between and predictors of these outcomes. Methods: Using advanced search terms, a systematic review of electronic databases was conducted, comprising MEDLINE, Embase, PsycINFO, Global Health, Web of Science and CINAHL. Included studies reported on outcome following neurosurgical treatment for epilepsy. Specifically, studies were included if they reported neuropsychological outcomes and were concerned only with temporal lobe resection. Results: 73 studies met inclusion criteria. For reported neuropsychological outcomes, the majority of participants remained stable after surgery; some declined and some improved. There was some evidence for increased material-specific memory deficits after temporal lobe surgery based on resection side, and more positive cognitive outcome for those with lower pre-surgical ability level. Significance: Retrieved evidence highlights the need for improvements to quality of methodology and reporting. Appropriately designed prospective multicentre trials should be conducted with adequate follow-up for long-term outcomes to be measured. Core outcome measures should be agreed between centres. This would permit higher quality evidence so that clinicians, young people and their families may make better informed decisions about whether or not to proceed with surgery and likely post-operative profile.

Child's Nervous System, 2015

The demand for paediatric epilepsy surgery in the UK greatly exceeds the number of operations per... more The demand for paediatric epilepsy surgery in the UK greatly exceeds the number of operations performed. Hence, Children's Epilepsy Surgery Service (CESS) was commenced in 2012. This study is aimed to characterise the changes in service delivery in the North East of England Paediatric Neuroscience Network and nationally. A retrospective cohort study of paediatric epilepsy surgery in Leeds between 2005 and 2012 is presented followed by analysis of British Paediatric Neurosurgical Group (BPNG) data before and after CESS commissioning. During the study period, 42 children underwent epilepsy surgery in Leeds. The commonest aetiologies were neoplasm (33 %), focal cortical dysplasia (19 %) and mesial temporal sclerosis (19 %). Seizure outcome was 71 % EngelI and 83 % EngelI+II. Complications included one infection (2 %), two temporary (5 %) and one permanent (2 %) motor deficits, three new/worsened visual field deficits (7 %). There were six re-craniotomies (14 %). The BPNG data show a 48 % increase in paediatric epilepsy surgery in England between 2009 (90 cases) and 2012 (133 cases), and a 20 % fall in 2013 (106 cases)-the first calendar year for CESS. On average, 64 % of all operations were performed in London. The number of children receiving surgery for epilepsy in England had increased annually up to, and declined after, the establishment of CESS centres. The yearly caseload in neurosurgical units outside of London is small. The outcomes from Leeds are comparable to those published elsewhere. Other UK units are encouraged to publish outcomes to facilitate patient, commissioner and provider decision making.

Epilepsia, 2010

The 2007 UK National Institute for Health and Clinical Excellence (NICE) guidelines for epilepsy ... more The 2007 UK National Institute for Health and Clinical Excellence (NICE) guidelines for epilepsy recommend disclosing the risk of sudden unexpected death in epilepsy (SUDEP) to patients. This recommendation is not undertaken routinely, and considerable variation in individual physician practice exists. Literature indicates wariness of causing distress and anxiety, particularly to children/young people and their families through disclosing a nonpreventable risk. There has been no systematic pediatric study examining parent/guardian information needs and beliefs for risk of SUDEP and its impact on seizure management. It is important to first address these concerns before routinely imparting SUDEP information to parents following NICE recommendations. Two questionnaire surveys: a questionnaire examining the provision by pediatric neurologists of SUDEP information, and questionnaires examining parental beliefs and implications at two time points regarding SUDEP information provided in a leaflet. Participants were included in the study if their child had an established diagnosis of epilepsy. Factors for exclusion were single unprovoked seizure, absence seizures, patients in remission, and active discontinuation of treatment. The majority (74%) of pediatric neurologists provided SUDEP information only to a select group of children with epilepsy and were uncertain about the effect such information would have upon the parent and child. Conversely, 91% of parents expected the pediatric neurologist to provide SUDEP risk information. The provision of this information did not have a significant immediate and longer-term negative impact. The majority of parents wanted to know about SUDEP and its associated risks. Whenever possible, SUDEP information should be given by the physician accompanied by an information leaflet.

Developmental Medicine & Child Neurology, 2006

The possibility that so-called anti-epileptic drugs (AEDs) may aggravate epilepsy must always be ... more The possibility that so-called anti-epileptic drugs (AEDs) may aggravate epilepsy must always be borne in mind by the clinician. Many reports of such aggravation of seizures have been published. Most such reports are anecdotal and speculative, and suggest that many such reactions are idiosyncratic. However, for some there is a sufficient body of evidence to suggest that some AEDs used in certain epilepsies may consistently cause worsening of seizures. Seizure aggravation may include increase in the frequency or severity of existing seizures, emergence of new types of seizure, or the occurrence of status epilepticus. The pathophysiology of seizure aggravation is poorly understood including non-specific effects such as those associated with sedation, drug-induced encephalopathy, and paradoxical or inverse pharmacodynamic effects. For some epilepsies the choice of AEDs may be inappropriate, and although the mechanism of seizure aggravation is not clear, its occurrence may be fairly predictable. This is best documented for the use of carbamazepine in idiopathic generalized and myoclonic epilepsies. Most other AEDs have been reported occasionally to cause seizure aggravation. The lowest risk of seizure aggravation appears to be with valproate. Risk factors for worsening of seizures are epileptic encephalopathy, polytherapy, high frequency of seizures, and cognitive impairment. Advances in pharmacogenomics may in the future enable such adverse effects to be predicted for individual patients. Meanwhile, a systematic approach to reporting AED-induced seizure aggravation should be developed.

European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 2016

To establish the efficacy and tolerability of inhaled 5% carbon dioxide/95% oxygen as a treatment... more To establish the efficacy and tolerability of inhaled 5% carbon dioxide/95% oxygen as a treatment for paediatric non-convulsive status epilepticus (NCSE). In an open label clinical trial, children in NCSE were given high flow inhaled 5% carbon dioxide/95% oxygen by face mask for 120 s under EEG control. Six children (five male; ages 3-13; all with severe underlying epilepsy and disability) were recruited. Inhalation was well tolerated in all cases. Capillary blood gasses showed no significant derangements at the end of the inhalation. Effects on EEG normalisation were limited and transient, and no clinical improvements were noted. No adverse effects occurred. Inhaled 5% carbon dioxide/95% oxygen has been suggested as a potent, well tolerated anticonvulsant. An anticonvulsant without sedating and respiration-depressing effects would be particularly welcome in the management of NCSE where the justification for aggressive anticonvulsant therapy is often uncertain, however it appears th...

The 2007 UK National Institute for Health and Clinical Excellence (NICE) guidelines for epilepsy ... more The 2007 UK National Institute for Health and Clinical Excellence (NICE) guidelines for epilepsy recommend disclosing the risk of sudden unexpected death in epilepsy (SUDEP) to patients. This recommendation is not undertaken routinely, and considerable variation in individual physician practice exists. Literature indicates wariness of causing distress and anxiety, particularly to children/young people and their families through disclosing a nonpreventable risk. There has been no systematic pediatric study examining parent/guardian information needs and beliefs for risk of SUDEP and its impact on seizure management. It is important to first address these concerns before routinely imparting SUDEP information to parents following NICE recommendations. Methods: Two questionnaire surveys: a questionnaire examining the provision by pediatric neurologists of SUDEP information, and questionnaires examining parental beliefs and implications at two time points regarding SUDEP information provided in a leaflet. Participants were included in the study if their child had an established diagnosis of epilepsy. Factors for exclusion were single unprovoked seizure, absence seizures, patients in remission, and active discontinuation of treatment. Results: The majority (74%) of pediatric neurologists provided SUDEP information only to a select group of children with epilepsy and were uncertain about the effect such information would have upon the parent and child. Conversely, 91% of parents expected the pediatric neurologist to provide SUDEP risk information. The provision of this information did not have a significant immediate and longer-term negative impact. Discussion: The majority of parents wanted to know about SUDEP and its associated risks. Whenever possible, SUDEP information should be given by the physician accompanied by an information leaflet.

The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth d... more The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects

Objective: To establish the efficacy and tolerability of inhaled 5% carbon dioxide/95% oxygen as ... more Objective: To establish the efficacy and tolerability of inhaled 5% carbon dioxide/95% oxygen as a treatment for paediatric non-convulsive status epilepticus (NCSE). Methods: In an open label clinical trial, children in NCSE were given high flow inhaled 5% carbon dioxide/95% oxygen by face mask for 120 s under EEG control. Results: Six children (five male; ages 3e13; all with severe underlying epilepsy and disability) were recruited. Inhalation was well tolerated in all cases. Capillary blood gasses showed no significant derangements at the end of the inhalation. Effects on EEG normalisation were limited and transient, and no clinical improvements were noted. No adverse effects occurred. Conclusion: Inhaled 5% carbon dioxide/95% oxygen has been suggested as a potent, well tolerated anticonvulsant. An anticonvulsant without sedating and respiration-depressing effects would be particularly welcome in the management of NCSE where the justification for aggressive anticonvulsant therapy is often uncertain, however it appears that 5% carbon dioxide is of limited efficacy in this context.