Publications by authors named "Lakshmi Nagarajan"

43 Publications

Seizures in the neonate: A review of etiologies and outcomes.

Seizure 2021 Feb 4;85:48-56. Epub 2021 Jan 4.

Department of Neuropediatrics, University Children's Hospital Zurich, Switzerland. Electronic address:

Neonatal seizures occur in their majority in close temporal relation to an acute brain injury or systemic insult, and are accordingly defined as acute symptomatic or provoked seizures. However less frequently, unprovoked seizures may also present in the neonatal period as secondary to structural brain abnormalities, thus corresponding to structural epilepsies, or to genetic conditions, thus corresponding to genetic epilepsies. Unprovoked neonatal seizures should be thus considered as the clinical manifestation of early onset structural or genetic epilepsies that often have the characteristics of early onset epileptic encephalopathies. In this review, we address the conundrum of neonatal seizures including acute symptomatic, remote symptomatic, provoked, and unprovoked seizures, evolving to post-neonatal epilepsies, and neonatal onset epilepsies. The different clinical scenarios involving neonatal seizures, each with their distinct post-neonatal evolution are presented. The structural and functional impact of neonatal seizures on brain development and the concept of secondary epileptogenesis, with or without a following latent period after the acute seizures, are addressed. Finally, we underline the need for an early differential diagnosis between an acute symptomatic seizure and an unprovoked seizure, since it is associated with fundamental differences in clinical evolution. These are crucial aspects for neonatal management, counselling and prognostication. In view of the above aspects, we provide an outlook on future strategies and potential lines of research in this field.
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http://dx.doi.org/10.1016/j.seizure.2020.12.023DOI Listing
February 2021

Acute symptomatic neonatal seizures, brain injury, and long-term outcome: The role of neuroprotective strategies.

Expert Rev Neurother 2021 Feb 6;21(2):189-203. Epub 2020 Dec 6.

Child Neurology Unit, Department of Paediatrics, Azienda USL-IRCCS Di Reggio Emilia , Reggio Emilia, Italy.

Introduction: Neonatal seizures are frequent but underdiagnosed manifestations of acute brain dysfunction and an important contributor to unfavorable outcomes. Etiology and severity of brain injury are the single strongest outcome determinants.

Areas Covered: The authors will discuss the prognostic role of acute symptomatic seizures versus brain injury and the main neuroprotective and neurorestorative strategies for full-term and preterm infants.

Expert Opinion: Prolonged acute symptomatic seizures likely contribute to long-term outcomes by independently adding further brain injury to initial insults. Correct timing and dosing of therapeutic interventions, depending on etiology and gestational ages, need careful evaluation. Although promising strategies are under study, the only standard of care is whole-body therapeutic hypothermia in full-term newborns with hypoxic-ischemic encephalopathy.
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http://dx.doi.org/10.1080/14737175.2021.1848547DOI Listing
February 2021

Why do neonates receive antiseizure medications?

J Matern Fetal Neonatal Med 2020 Sep 14:1-5. Epub 2020 Sep 14.

Department of Neurology, Children's Neuroscience Service, Perth Children's Hospital, Perth, Australia.

Background: Continuous conventional video-electroencephalography (cVEEG), the gold standard, is not routinely available for monitoring neonatal seizures in Australia. Therefore, seizures are monitored with clinical observation and amplitude-integrated electroencephalography (aEEG), which may result in under- or over-treatment with antiseizure medications (ASMs). We aimed to investigate ASM usage and its relation to the "cVEEG-confirmed seizures" (cVEEG seizures) in the at-risk infants admitted to a tertiary referral neonatal intensive care unit (NICU).

Methods: The study was a part of a diagnostic study comparing cVEEG with aEEG for the detection of neonatal seizures. Thirty-six infants ≥35 weeks gestational age and at risk of seizures and admitted to NICU were recruited after informed parental consent. The infants were monitored and treated with ASMs based on clinical observation and aEEG findings. A simultaneous cVEEG, not available for clinical decision making, was recorded for 24-h and interpreted at a later date. Data regarding ASM usage and seizure burden on cVEEG were collected. Spearman's Rho coefficient was used to assess the correlation between the number of doses of ASMs administered and seizure burden on cVEEG.

Results: cVEEG recordings of 35 infants were available for analysis. The gestational age of the infants ranged from 36 to 42 weeks, and the most common diagnosis was hypoxic-ischemic encephalopathy. Twelve infants received ASMs during the 24-h study period, of which five (42%) did not have cVEEG seizures. Maximum cVEEG seizure burden was 8.3 h, and maximum number of ASMs used was three. The correlation between the number of doses of ASMs administered in an infant and the seizure burden on cVEEG was low (Spearman's Rho: 0.44;  = .148).

Conclusion: Treatment of neonatal seizures based on clinical observation and aEEG, without cVEEG, results in unnecessary or inadequate exposure to ASMs for many infants.
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http://dx.doi.org/10.1080/14767058.2020.1819976DOI Listing
September 2020

Biotinidase deficiency presenting as Neuromyelitis Optica Spectrum Disorder.

Brain Dev 2020 Nov 31;42(10):762-766. Epub 2020 Jul 31.

Department of Neurology, Perth Children's Hospital, Nedlands, WA, Australia; School of Medicine , University of Western Australia, Perth, WA, Australia; Telethon Kids Institute, Perth Children's Hospital, Perth, WA, Australia. Electronic address:

Biotinidase deficiency disorder is a rare inherited metabolic disorder with typical neurological manifestations of hypotonia, developmental delay, rashes, seizures, hearing and vision impairment. We present two cases with different and unusual clinical profiles, whose neuroimaging resembled Neuromyelitis Optica Spectrum Disorder. Case 1 was initially treated with immunomodulation with steroids and intravenous immunoglobulins, with partial improvement. However reinvestigation for worsening of symptoms showed more extensive changes on spine magnetic resonance imaging. Raised lactate and alanine levels on repeat cerebrospinal fluid testing resulted in further investigations that revealed a biotinidase deficiency. Case 2 presented mainly with respiratory symptoms: a barium swallow suggested bulbar dysfunction. Neuroimaging of brain and spine was similar to that in case 1 and the child was promptly investigated for and confirmed to have biotinidase deficiency. Both cases responded to biotin supplementation. It is important to be cognisant of atypical neurological presentations of biotinidase deficiency including those that mimic immune mediated neurodemyelination disorders, as biotinidase deficiency is potentially treatable.
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http://dx.doi.org/10.1016/j.braindev.2020.07.007DOI Listing
November 2020

Neuronal ceroid lipofuscinosis type 2: an Australian case series.

J Paediatr Child Health 2020 Aug 24;56(8):1210-1218. Epub 2020 Apr 24.

Genetic Metabolic Disorders Service, The Sydney Children's Hospitals Network, Sydney, New South Wales, Australia.

Aim: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare neurodegenerative disorder presenting in children aged 2-4 years with seizures and loss of motor and language skills, followed by blindness and death in late childhood. Initial presenting features are similar to a range of common epilepsies. We aim to highlight typical clinical and radiological features that may prompt diagnosis of CLN2 disease in early disease stages.

Methods: We present a series of 13 Australian patients with CLN2 disease, describing clinical features, disease evolution, neuroimaging, electroencephalogram, biochemical and genetic results. Expert neuroradiological magnetic resonance imaging (MRI) analysis was retrospectively performed on 10 cases.

Results: Twelve patients presented with seizures, with initial seizures being focal (n = 4), generalised tonic-clonic (n = 3), absence (n = 3) and febrile (n = 2). Eleven patients (85%) had a language delay before the onset of seizures. Cerebellar or cerebral atrophy was noted in all patients on centralised MRI review, with abnormalities of the brain-stem, ventricles, corpus callosum and hippocampi.

Conclusions: Early language delay with the onset of seizures at 2-4 years of age is the hallmark of CLN2 disease. MRI findings of early subtle atrophy in the cerebellum or posterior cortical regions should hasten testing for CLN2 disease to enable early initiation of enzyme replacement therapy.
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http://dx.doi.org/10.1111/jpc.14890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497200PMC
August 2020

Gastrostomy and quality of life in children with intellectual disability: a qualitative study.

Arch Dis Child 2020 10 8;105(10):969-974. Epub 2020 Apr 8.

Telethon Kids Institute, Centre for Child Health Research, The University of Western Australia, Perth, Nedlands, Western Australia, Australia

Objective: Children with intellectual disability and marked feeding difficulties may undergo gastrostomy insertion to assist with their nutritional and medication needs. Use has increased recently for younger children, and it is intended to provide long-term support. This study explored the perceived value of gastrostomy for the quality of life (QOL) of children with intellectual disabilities and their families.

Methods: Twenty-one primary caregivers of children with intellectual disability aged 2-18 years participated in semistructured telephone interviews. Data were analysed using directed content analysis, and data were coded to existing QOL domains relevant to children with intellectual disability and their families.

Results: Benefits in each of the child and family QOL domains were represented in the interview data. For children, the impacts of gastrostomy for the physical health domain were predominant, supplemented by experiences of value for emotional well-being, social interactions, leisure activities and independence. For families, gastrostomy was integrated into multiple aspects of QOL relating to family interactions, parenting, resources and supports, health and safety, and advocacy support for disability. Shortcomings related to difficulties with equipment and complications.

Conclusions: Our comprehensive overview of the value of gastrostomy for children with intellectual disability and their families was classified within a QOL framework. Gastrostomy was mainly supportive over long time periods across many QOL domains. Findings will be of use to patient counselling and education and the development of family support resources.
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http://dx.doi.org/10.1136/archdischild-2020-318796DOI Listing
October 2020

Inter-rater reliability of amplitude-integrated EEG for the detection of neonatal seizures.

Early Hum Dev 2020 04 4;143:105011. Epub 2020 Mar 4.

Neonatal Clinical Care Unit, King Edward Memorial Hospital and Perth Children's Hospital, Perth, Australia; Centre for Neonatal Research and Education, Medical School, University of Western Australia, Australia.

Background: Amplitude-integrated electroencephalogram (aEEG) is being used increasingly for seizure detection in neonates. However, data regarding inter-rater reliability among neonatologists for the use of aEEG for the detection of neonatal seizures is lacking.

Methods: Term and late-preterm infants at risk of seizures were monitored simultaneously with 24-h video-electroencephalography (vEEG) and aEEG. vEEG was interpreted by an experienced neurologist. Five neonatologists with experience in aEEG interpretation from four different neonatal units interpreted aEEG recordings independently. The Brennan and Prediger kappa coefficient and Intra-class Correlation Coefficients (ICC) were used to assess inter-rater reliability between the neonatologists.

Results: Thirty-five infants at risk of seizure with gestational age at birth 35-42 weeks were recruited for the study after informed parental consent. vEEG detected seizures in seven infants with a total of 169 individual seizure episodes. Neonatologists detected seizures in 10 to 15 infants on aEEG. The sensitivities for the detection of individual seizures by neonatologists ranged from 18% to 38%. The inter-rater reliability for detection of: individual seizure was "fair" (kappa = 0.37; 95% CI: 0.32-0.42), infant with seizure was "moderate" (kappa = 0.60; 95% CI: 0.44-0.75), duration of individual seizure (ICC: 0.22; 95% CI: 0.18-0.28) and total duration of seizures in an infant (ICC: 0.46; 95% CI: 0.30-0.63) was "poor". The neonatologists missed 77-90% of the duration of seizures.

Conclusion: The inter-rater reliability of aEEG for the detection of neonatal seizures was suboptimal. Even when interpreted by experienced and trained clinicians, seizure detection with aEEG has limitations and can miss large number and duration of seizures.
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http://dx.doi.org/10.1016/j.earlhumdev.2020.105011DOI Listing
April 2020

Risk of Hospitalizations Following Gastrostomy in Children with Intellectual Disability.

J Pediatr 2020 02 4;217:131-138.e10. Epub 2019 Dec 4.

Telethon Kids Institute, Center for Child Health Research, The University of Western Australia, Perth, Australia; School of Physiotherapy and Exercise Science, Curtin University, Perth, Australia. Electronic address:

Objective: To examine the frequency of hospital admissions before and after gastrostomy insertion in children with severe intellectual disability.

Study Design: We conducted a retrospective cohort study using linked health administrative and disability data from Western Australia (WA) and New South Wales (NSW). Children born between 1983 and 2009 in WA and 2002 and 2010 in NSW who had a gastrostomy insertion performed (n = 673 [WA, n = 325; NSW, n = 348]) by the end of 2014 (WA) and 2015 (NSW) were included. Conditional Poisson regression models were used to evaluate the age-adjusted effect of gastrostomy insertion on acute hospitalizations for all-cause, acute lower respiratory tract infections (LRTI), and epilepsy admissions.

Results: The incidence of all-cause hospitalizations declined at 5 years after procedure (WA cohort 1983-2009: incidence rate ratio, 0.70 [95% CI, 0.60-0.80]; WA and NSW cohort 2002-2010: incidence rate ratio, 0.63 [95% CI, 0.45-0.86]). Admissions for acute LRTI increased in the WA cohort and remained similar in the combined cohort. Admissions for epilepsy decreased 4 years after gastrostomy in the WA cohort and were generally lower in the combined cohort. Fundoplication seemed to decrease the relative incidence of acute LRTI admissions in the combined cohort.

Conclusions: Gastrostomy was associated with health benefits including reduced all-cause and epilepsy hospitalizations, but was not protective against acute LRTI. These decreases in hospitalizations may reflect improved delivery of nutrition and medications.
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http://dx.doi.org/10.1016/j.jpeds.2019.10.020DOI Listing
February 2020

Intraoperative neurophysiology monitoring in scoliosis surgery in children.

Clin Neurophysiol Pract 2019 25;4:11-17. Epub 2019 Jan 25.

Dept. of Anaesthetics, Perth Children's Hospital, Hospital Avenue, Nedlands, WA 6009, Australia.

Objective: Intraoperative neurophysiology monitoring (INM) is thought to reduce the risk of postoperative neurological deficits in children undergoing scoliosis and spine deformity surgery. INM is being used increasingly despite conflicting opinions, varied results, non-standard alarm criteria and concern regarding cost effectiveness. In this paper we present our experience with INM in scoliosis and spine deformation surgery in children, propose alert criteria and preferred anaesthetics in clinical practice.

Methods: We retrospectively analysed our experience with INM in 56 children who had 61 scoliosis and spine deformity surgeries.

Results: INM was successfully undertaken with transcranial electrical motor evoked potentials (TcMEP) and somatosensory evoked potentials. There were no injuries due to INM. Four children had 5 alerts during 4 surgeries. A postoperative deficit was seen in one child only. No new postoperative deficits were seen in any child who did not have an alert during INM. Total intravenous anaesthesia was better for INM compared to inhalational anaesthetics.

Conclusions: INM is useful in scoliosis surgery; it is likely to mitigate the risk of new deficits following surgery. We recommend alert criteria for TcMEPs that include multiple facets - amplitude, stimulus paradigm, morphology. We recommend propofol and remifentanil, in preference to sevoflurane and remifentanil for anaesthesia during INM.

Significance: Our study adds to the literature supporting the role of INM in scoliosis surgery in children. We provide guidelines for alarm criteria in clinical practice and recommend the use of total intravenous anaesthesia as the preferred anaesthetic option.
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http://dx.doi.org/10.1016/j.cnp.2018.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383123PMC
January 2019

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance.

Mol Genet Genomic Med 2019 02 4;7(2):e00507. Epub 2019 Jan 4.

Curtin Health Innovation Research Institute and Sarich Neuroscience Institute, Curtin University, Crawley, Western Australia, Australia.

Background: Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region.

Methods: We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues.

Results: We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects.

Conclusion: Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.
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http://dx.doi.org/10.1002/mgg3.507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393688PMC
February 2019

Epidemiology of gastrostomy insertion for children and adolescents with intellectual disability.

Eur J Pediatr 2019 Mar 15;178(3):351-361. Epub 2018 Dec 15.

Telethon Kids Institute, Centre for Child Health Research, The University of Western Australia, PO Box 855, West Perth, Western Australia, 6872, Australia.

The largest group of recipients of pediatric gastrostomy have neurological impairment with intellectual disability (ID). This study investigated trends in first gastrostomy insertion according to markers of disadvantage and ID etiology. Linked administrative and health data collected over a 32-year study period (1983-2014) for children with ID born between 1983 and 2009 in Western Australia were examined. The annual incidence rate change over calendar year was calculated for all children and according to socioeconomic status, geographical remoteness, and Aboriginality. The most likely causes of ID were identified using available diagnosis codes in the linked data set. Of 11,729 children with ID, 325 (2.8%) received a first gastrostomy within the study period. The incidence rate was highest in the 0-2 age group and there was an increasing incidence trend with calendar time for each age group under 6 years of age. This rate change was greatest in children from the lowest socioeconomic status quintile, who lived in regional/remote areas or who were Aboriginal. The two largest identified groups of ID were genetically caused syndromes (15.1%) and neonatal encephalopathy (14.8%).Conclusion: Gastrostomy is increasingly used in multiple neurological conditions associated with ID, with no apparent accessibility barriers in terms of socioeconomic status, remoteness, or Aboriginality. What is Known: • The use of gastrostomy insertion in pediatrics is increasing and the most common recipients during childhood have neurological impairment, most of whom also have intellectual disability (ID). What is New: • Nearly 3% of children with ID had gastrostomy insertion performed, with the highest incidence in children under 3 years of age. • Gastrostomy use across different social groups was equitable in the Australian setting.
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http://dx.doi.org/10.1007/s00431-018-3304-xDOI Listing
March 2019

Paediatric new-onset seizure clinic in Australia: Experience and lessons learnt.

J Paediatr Child Health 2019 Jul 8;55(7):789-794. Epub 2018 Nov 8.

Department of Neurology, Children's Neuroscience Service, Princess Margaret Hospital for Children, Perth, Western Australia, Australia.

Aim: A new-onset seizure clinic (NOSC) was established at our hospital in 2011, with the aim to provide accurate diagnosis and appropriate management to children with new-onset seizures or seizure mimics.

Methods: We report on the data analysis of the first 200 children seen in NOSC. A paediatric neurologist or paediatric/neurology trainee under supervision of a neurologist reviewed all the children. A detailed history and clinical examination were undertaken. Electroencephalogram (EEGs) were undertaken prior to clinic review in most emergency departments. Children were classified as 'epilepsy positive' (EP+) or 'epilepsy negative' (EP-) after the first consultation.

Results: Of 200 patients, 109 were classified as EP+: generalised epilepsy in 57 of 109, focal in 36, childhood seizure susceptibility syndrome in 26 and epileptic encephalopathy in 5. EEG was available in 192: in 117, it was abnormal - 23 with background abnormalities and 109 with epileptiform activity. Of the 109 patients, 80 were commenced on anti-epileptic drugs (AEDs): 12 were able to come off medication after seizure-free period, 61 were controlled on AEDs and 7 were refractory. Children were followed up for 12-48 months. None of the children had diagnosis revised on follow-up.

Conclusions: This is the first Australian study to report on a large cohort of children from a NOSC. An EEG and a paediatric neurologist assessment is a good combination to enable diagnostic accuracy: In the first 200 patients seen, there were no revisions of the initial diagnosis on follow-up.
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http://dx.doi.org/10.1111/jpc.14290DOI Listing
July 2019

Evolving Trends of Gastrostomy Insertion Within a Pediatric Population.

J Pediatr Gastroenterol Nutr 2018 11;67(5):e89-e94

Telethon Kids Institute, Centre for Child Health Research, The University of Western Australia.

Objective: Gastrostomy insertion in pediatrics is usually used in children with complex needs and severe disability. The accessibility and acceptance of the procedure is increasing but population-based occurrence data are lacking and there is limited understanding of its use in clinical subgroups.

Methods: This birth cohort study investigated the trends in first gastrostomy insertion among a pediatric population born between 1983 and 2009 in Western Australia using linked administrative and health data collected over a 32-year period (1983-2014). Indications were identified using diagnosis codes from linked hospitalization data and grouped according to a refined classification system. Age and birth cohort patterns of first gastrostomy use, over calendar year and age respectively, were described.

Results: Of the 690,688 children born between 1983 and 2009, 466 underwent a gastrostomy insertion. Overall, the prevalence was approximately 7 cases per 10,000 births. New gastrostomy insertions were increasingly performed in children during the preschool years over calendar years and in successive birth cohorts. Children with a neurological disorder constituted the largest group receiving gastrostomy (n = 372; 79.8) including 325 (87.4%) with comorbid intellectual disability.

Conclusions: New gastrostomy insertion among children who require long-term enteral feeding support increased over the study period. The procedure is most often performed in the context of severe neurological disability, including intellectual disability, and offers families potential for long-term home-based management of feeding difficulties.
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http://dx.doi.org/10.1097/MPG.0000000000002042DOI Listing
November 2018

A novel, homozygous mutation in () in a 46, XY patient with dysgenetic testes presenting with primary amenorrhoea: a case report.

Int J Pediatr Endocrinol 2018 2;2018. Epub 2018 Mar 2.

1Department of Endocrinology and Diabetes, Princess Margaret Hospital, Subiaco, WA Australia.

Background: () mutations have been described in only a limited number of individuals with 46, XY disorders of sex development (DSD) presenting as either partial or complete gonadal dysgenesis. Gonadal tumours and peripheral neuropathy have been associated with mutations. Herein we report a novel, homozygous mutation of identified through a targeted, massively parallel sequencing (MPS) DSD panel, in a patient presenting with partial gonadal dysgenesis. This novel mutation is two amino acids away from a previously described mutation in a patient who presented with complete gonadal dysgenesis. Adding to the complexity of work-up, our patient also expressed gender identity concern.

Case Presentation: A 14-year-old, phenotypic female presented with primary amenorrhoea and absent secondary sex characteristics. Investigations revealed elevated gonadotrophins with low oestradiol, testosterone of 0.6 nmol/L and a 46, XY karyotype. Müllerian structures were not seen on pelvic ultrasound or laparoscopically and gonadal biopsies demonstrated dysgenetic testes without neoplasia (partial gonadal dysgenesis). The patient expressed gender identity confusion upon initial notification of investigation findings. Formal psychiatric evaluation excluded gender dysphoria. Genetic analysis was performed using a targeted, MPS DSD panel of 64 diagnostic and 927 research candidate genes. This identified a novel, homozygous mutation in exon 2 of (DHH:NM_021044:exon2:c.G491C:p.R164P). With this finding our patient was screened for the possibility of peripheral neuropathy which was not evident clinically nor on investigation. She was commenced on oestrogen for pubertal induction.

Conclusion: The evaluation of patients with DSD is associated with considerable psychological distress. Targeted MPS enables an affordable and efficient method for diagnosis of 46, XY DSD cases. Identifying a genetic diagnosis may inform clinical management and in this case directed screening for peripheral neuropathy. In addition to the structural location of the mutation other interacting factors may influence phenotypic expression in homozygous mutations.
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http://dx.doi.org/10.1186/s13633-018-0056-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834851PMC
March 2018

Amplitude Integrated Electroencephalography Compared With Conventional Video EEG for Neonatal Seizure Detection: A Diagnostic Accuracy Study.

J Child Neurol 2017 08 8;32(9):815-822. Epub 2017 May 8.

3 Telethon Institute of Child Health and Research, Perth, Australia.

This diagnostic accuracy study compared the accuracy of seizure detection by amplitude-integrated electroencephalography with the criterion standard conventional video EEG in term and near-term infants at risk of seizures. Simultaneous recording of amplitude-integrated EEG (2-channel amplitude-integrated EEG with raw trace) and video EEG was done for 24 hours for each infant. Amplitude-integrated EEG was interpreted by a neonatologist; video EEG was interpreted by a neurologist independently. Thirty-five infants were included in the analysis. In the 7 infants with seizures on video EEG, there were 169 seizure episodes on video EEG, of which only 57 were identified by amplitude-integrated EEG. Amplitude-integrated EEG had a sensitivity of 33.7% for individual seizure detection. Amplitude-integrated EEG had an 86% sensitivity for detection of babies with seizures; however, it was nonspecific, in that 50% of infants with seizures detected by amplitude-integrated EEG did not have true seizures by video EEG. In conclusion, our study suggests that amplitude-integrated EEG is a poor screening tool for neonatal seizures.
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http://dx.doi.org/10.1177/0883073817707411DOI Listing
August 2017

Rare pattern of relapse to the pancreas and bilateral extraocular muscles in paediatric alveolar rhabdomyosarcoma.

J Paediatr Child Health 2017 04 13;53(4):419-421. Epub 2017 Mar 13.

Department of Haematology and Oncology, Princess Margaret Hospital for Children, Perth, Western Australia, Australia.

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http://dx.doi.org/10.1111/jpc.13497DOI Listing
April 2017

Opsoclonus-Myoclonus Syndrome, Neuroblastoma, and Insulin-Dependent Diabetes Mellitus in a Child: A Unique Patient.

Pediatr Neurol 2016 Feb 23;55:68-70. Epub 2015 Oct 23.

Department of Neurology, Princess Margaret Hospital, Perth, Western Australia, Australia; School of Paediatrics and Child Health, University of Western Australia, Princess Margaret Hospital, Perth, Western Australia, Australia. Electronic address:

Aim: We present a new and unique association of opsoclonus-myoclonus-ataxia syndrome with neuroblastoma and type 1 diabetes mellitus.

Patient Description: This 17-month-old child presented with opsoclonus-myoclonus-ataxia syndrome. Investigations revealed a thoracic neuroblastoma. Eleven days later, she re-presented with diabetic ketoacidosis. The neuroblastoma was resected, and she was given immunotherapy. At 12 months' follow-up, her neurological signs and symptoms have significantly improved, but she continues to be insulin dependent.

Discussion: This child expands the clinical spectrum of autoimmune disorders associated with opsoclonus-myoclonus-ataxia syndrome.
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http://dx.doi.org/10.1016/j.pediatrneurol.2015.09.021DOI Listing
February 2016

Amplitude-integrated EEG for detection of neonatal seizures: a systematic review.

Seizure 2015 Dec 26;33:90-8. Epub 2015 Sep 26.

Department of Neonatology, King Edward Hospital for Women and Princess Margaret Hospital for Children, Subiaco, Western Australia 6008, Australia; Center for Neonatal Research and Education, School of Pediatrics and Child Health, University of Western Australia, Crawley, Western Australia 6009, Australia. Electronic address:

Purpose: Amplitude-integrated electroencephalogram (aEEG) is being used increasingly for monitoring seizures in neonatal units. Its accuracy, compared with "the gold-standard" conventional elecroencephalogram (cEEG) is still not well established. We aimed to conduct a systematic review to evaluate the diagnostic accuracy of aEEG when compared with cEEG, for detection of neonatal seizures.

Method: A systematic review was conducted using the Cochrane methodology. EMBASE, CINAHL and PubMed databases were searched in September 2014. Studies comparing simultaneous recordings of cEEG and aEEG for detection of seizures in neonatal population were included. QUADAS 2 tool was used to examine "risk of bias" and "applicability".

Results: Ten studies (patient sample 433) were included. Risk of bias was high in five studies, unclear in one and low in four. For the detection of individual seizures, when "aEEG with raw trace" was used, median sensitivity was 76% (range: 71-85), and specificity 85% (range: 39-96). When "aEEG without raw trace" was used, median sensitivity was 39% (range: 25-80) and specificity 95% (range: 50-100). Detailed meta-analysis could not be done because of significant clinical/methodological heterogeneity. Seizure detection was better when interpreted by experienced clinicians. Seizures with low amplitude/brief duration and those occurring away from aEEG leads were less likely to be detected.

Conclusion: Studies included in the systematic review showed aEEG to have relatively low and variable sensitivity and specificity. Based on the available evidence, aEEG cannot be recommended as the mainstay for diagnosis and management of neonatal seizures. There is an urgent need of well-designed studies to address this issue definitively.
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http://dx.doi.org/10.1016/j.seizure.2015.09.014DOI Listing
December 2015

Seizure outcomes in children with epilepsy after resective brain surgery.

Eur J Paediatr Neurol 2015 Sep 12;19(5):577-83. Epub 2015 Jun 12.

Children's Neuroscience Service, Department of Neurology, Princess Margaret Hospital for Children, Perth, Australia. Electronic address:

Purpose: To assess the role of resective brain surgery in childhood epilepsy.

Methodology: We retrospectively analysed the seizure outcomes in 55 children with epilepsy who had resective brain surgery between 1997 and 2012, at our centre. The children were 1.5-18 years at the time of surgery; their seizure onset was between 0.2 andto 15 years of age. 48 had refractory epilepsy. One child died of tumour progression. Follow-up duration in the survivors ranged from 2 to -16 years (mean: 9).Presurgical evaluation included clinical profiles, non-invasive V-EEG monitoring, neuroimaging with MRIs in all; SPECT and PET in selected patients. 54 had intraoperative ECoG.

Results: An Engel Class 1 outcome was seen in 78% of the cohort, with 67% being off all AEDs at the most recent follow-up. Children with tumours constituted the majority (56%), with 87% of this group showing a Class 1 outcome and 84% being off AEDs. Children with cortical dysplasia had a Class 1 outcome in 56%.

Conclusion: Resective brain surgery is an efficacious option in some children with epilepsy. We found ECoG useful to tailor the cortical resection and in our opinion ECoG contributed to the good seizure outcomes.
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http://dx.doi.org/10.1016/j.ejpn.2015.05.006DOI Listing
September 2015

Lacosamide as adjunctive therapy in treatment-resistant epilepsy in childhood.

J Paediatr Child Health 2015 Aug 12;51(8):794-7. Epub 2015 Feb 12.

Children's Neuroscience Service, Princess Margaret Hospital for Children, Perth, Western Australia, Australia.

Aims: Lacosamide (LCM) is a novel anti-epileptic drug (AED) that enhances the slow inactivation of voltage-gated sodium channels. Its efficacy as adjunctive therapy for focal seizures is confirmed in adult placebo controlled trials with >50% reduction in seizure frequency in up to 50% patients. There is paucity of data on its efficacy and tolerance in treatment-resistant epilepsy in childhood (TREC). This study aims to assess efficacy and tolerance of LCM as adjunct therapy in TREC.

Methods: Audit of medical records and seizure diaries in children with TREC on LCM. A response (RR) was defined as ≥50% reduction in seizure frequency.

Results: Forty children (age range: 2-19 years) with TREC received LCM as add-on therapy. All had abnormal electroencephalograms, and 36 had abnormal neuroimaging. All children failed >2 AED trials, nine had trialled the ketogenic diet, five had failed the vagal nerve stimulator and 11 had failed resective epilepsy surgery. Median dose and duration of LCM therapy were 5.7 mg/kg/day and 10.5 months, respectively. RR was seen in 20% with persistence of RR in 8/36, 8/30 and 8/26 children on LCM at 3-, 6- and 9-month follow-up. Two children became seizure free. Retention on LCM was 65% at 9 months. LCM was well tolerated with minor side effects in seven children; no child discontinued LCM because of side effects.

Conclusion: LCM is a well-tolerated AED with RR in 20%: in 5%, it resulted in seizure freedom. LCM may be useful even in TREC when seizures have not responded to intervention with multiple modalities.
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http://dx.doi.org/10.1111/jpc.12850DOI Listing
August 2015

Neurologic complications of influenza.

J Child Neurol 2014 Sep 26;29(9):NP49-53. Epub 2013 Sep 26.

Princess Margaret Hospital for Children, Perth, Australia

We report on a child with mild encephalopathy with reversible splenial lesion (MERS) associated with influenza infection and present a case series of neurological complications associated with influenza infections in children who presented to a tertiary children's hospital in Australia over a period of one year.
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http://dx.doi.org/10.1177/0883073813499610DOI Listing
September 2014

Leukodystrophy: when gallbladder offers a clue to diagnosis.

Pediatr Neurol 2013 Jul;49(1):68-9

Department of Neurology, Princess Margaret Hospital, Perth, Australia.

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http://dx.doi.org/10.1016/j.pediatrneurol.2013.03.019DOI Listing
July 2013

Intravenous levetiracetam for treatment of neonatal seizures.

J Clin Neurosci 2013 Aug 7;20(8):1165-7. Epub 2013 May 7.

Department of Neonatal Paediatrics, Princess Margaret Hospital for Children and King Edward Memorial Hospital for Women, Perth, Australia.

In this case series we report on eight neonates with refractory seizures who received intravenous levetiracetam when seizures did not respond to two or more conventional anticonvulsants. Six of the eight neonates had an excellent response with either cessation, or reduction in seizures by at least 80%. One neonate showed a partial response while one did not have any reduction in seizure frequency. We did not encounter any adverse effects that could be attributable to levetiracetam.
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http://dx.doi.org/10.1016/j.jocn.2012.08.014DOI Listing
August 2013

Classification of clinical semiology in epileptic seizures in neonates.

Eur J Paediatr Neurol 2012 Mar 19;16(2):118-25. Epub 2011 Dec 19.

Department of Neurology, Princess Margaret Hospital for Children, Perth, Australia.

The clinical semiology of 61 neonatal seizures with EEG correlates, in 24 babies was analysed. Most seizures (89%) had multiple features during the EEG discharge. The seizures were classified using the prominent clinical feature at onset, and all features seen during the seizure, using an extended classification scheme. Orolingual features occurred most frequently at onset (30%), whereas ocular phenomena occurred most often during the seizure (70%). Orolingual, ocular and autonomic features were seen at onset in 55% of the seizures. Seizure onsets with clonic, tonic and hypomotor features were seen in 20%, 8% and 18% respectively. Clinico-electrical correlations were as follows. The EEG discharge involved both hemispheres in 54% of all seizures, in clonic seizures this was 93%. Focal clonic seizures were associated with EEG seizure onset from the contralateral hemisphere. Majority of the clonic and hypomotor seizures had a left hemisphere ictal EEG onset. Orolingual seizures frequently started from the right hemisphere, whereas ocular and autonomic seizures arose from either hemisphere. There was no significant difference in mortality, morbidity, abnormal neuroimaging and EEG background abnormalities in babies with or without clonic seizures. This study provides insights into neuronal networks that underpin electroclinical seizures, by analysing and classifying the obvious initial clinical features and those during the seizure.
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http://dx.doi.org/10.1016/j.ejpn.2011.11.005DOI Listing
March 2012

Fast activity during EEG seizures in neonates.

Epilepsy Res 2011 Nov 1;97(1-2):162-9. Epub 2011 Sep 1.

Department of Neurology, Princess Margaret Hospital for Children, Roberts Road, Subiaco, Perth, WA 6008, Australia.

Introduction: Paroxysmal fast activity (FA) has been proposed as a marker for epileptic networks. We explore the presence and significance of ictal FA on scalp video EEG seizures (EEG Sz) recorded in neonates.

Methodology: Forty two babies had 159 EEG Szs. The seizures were analysed for ictal FA, using a low frequency filter of 30 Hz. We explored the relationship of ictal FA to the occurrence of electroclinical and electrographic seizures, the use of phenobarbitone and to neurodevelopmental outcomes.

Results: Ictal FA occurred in 62 (39%) of the 159 EEG Szs. In the 62 seizures with ictal FA, 34 (55%) were electroclinical seizures (ECSz) and 28 (45%) were electrographic (ESz). In the remaining 97 seizures without ictal FA, 27 (28%) were ECSz and 70 (72%) ESz. There was a significant correlation (p=0.0006) between ictal FA and electroclinical seizures. There was no relationship between phenobarbitone and presence of ictal FA. There was no significant difference in the background EEG, neuroimaging abnormalities, neurodevelopmental impairment or post neonatal seizures between those with and without ictal FA.

Conclusions: Ictal FA is highly correlated to the occurrence of clinical features during an EEG seizure. The presence of ictal FA does not appear to influence neurodevelopmental outcomes.
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http://dx.doi.org/10.1016/j.eplepsyres.2011.08.003DOI Listing
November 2011

Horner's syndrome in a child with otitis media: an unusual complication.

Pediatr Neurol 2011 Sep;45(3):209-10

Department of Neurology, Princess Margaret Hospital for Children, Perth, Western Australia, Australia.

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http://dx.doi.org/10.1016/j.pediatrneurol.2011.05.006DOI Listing
September 2011

Ictal electroencephalograms in neonatal seizures: characteristics and associations.

Pediatr Neurol 2011 Jul;45(1):11-6

Department of Neurology, Princess Margaret Hospital for Children, Perth, Western Australia, Australia.

The characteristics of ictal electroencephalograms in 160 neonatal seizures of 43 babies were correlated with mortality and neurodevelopmental outcomes. Neonatal seizures are focal at onset, most frequently temporal, and often occur during sleep. Twenty-one percent of babies with seizures died, and 76% of survivors manifested neurodevelopmental impairment during 2-6-year follow-up. A low-amplitude ictal electroencephalogram discharge was associated with increased mortality, and a frequency of <2 Hz with increased morbidity. Status epilepticus, ictal fractions, multiple foci, and bihemispheric involvement did not influence outcomes. Of 160 seizures, 99 exhibited no associated clinical features (electrographic seizures). Neonatal seizures with clinical correlates (electroclinical seizures) exhibited a higher amplitude and frequency of ictal electroencephalogram discharge than electrographic seizures. During electroclinical seizures, the ictal electroencephalogram was more likely to involve larger areas of the brain and to cross the midline. Mortality and morbidity were similar in babies with electroclinical and electrographic seizures, emphasizing the need to diagnose and treat both types. Ictal electroencephalogram topography has implications for electrode application during limited-channel, amplitude-integrated electroencephalograms. We recommend temporal and paracentral electrodes. Video electroencephalograms are important in diagnosing neonatal seizures and providing useful information regarding ictal electroencephalogram characteristics.
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http://dx.doi.org/10.1016/j.pediatrneurol.2011.01.009DOI Listing
July 2011

Brief electroencephalography rhythmic discharges (BERDs) in the neonate with seizures: their significance and prognostic implications.

J Child Neurol 2011 Dec 7;26(12):1529-33. Epub 2011 Jun 7.

Department of Neurology, Princess Margaret Hospital for Children, Perth, Australia.

We aimed to explore the significance and prognostic implications of paroxysmal brief electroencephalography (EEG) rhythmic discharges (BERDs) in neonatal seizures. The 52 neonates in this study were divided into 3 groups: (1) BERDs only: 9 neonates, (2) BERDs + conventional EEG seizures: 11 babies, (3) Conventional EEG seizures only: 32 babies. We analyzed the BERDs and compared outcomes in the 3 groups: there was no significant difference in mortality and neurodevelopmental or background EEG impairment. Similar to conventional EEG seizures, BERDs are also associated with an increased mortality, morbidity, and EEG background abnormalities. Fewer babies with BERDS appear to develop postneonatal seizures suggesting their epileptogenic potential is less. In the appropriate clinical context, BERDs should be considered as miniseizures.
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http://dx.doi.org/10.1177/0883073811409750DOI Listing
December 2011

Recombinant monomeric CD40 ligand for delivering polymer particles to dendritic cells.

Biotechnol Prog 2011 May-Jun;27(3):830-7. Epub 2011 May 2.

Dept. of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA.

Dendritic cells (DCs) are considered the most efficient antigen-presenting cells and are therefore ideal targets for in vivo delivery of antigen for vaccines. We are investigating the strategy of using CD40 ligand (CD40L) as a targeting moiety because this protein has the potential to not only target DCs, but also stimulate cell maturation, leading to more potent immune responses. We have shown that a recombinant, monomeric CD40 ligand fusion protein conjugated to polystyrene micro- and nanoparticles led to significantly enhanced uptake by DCs in vitro. This enhancement was observed for particles of both sizes and in both a murine DC cell line and primary DCs. The uptake appeared to be specifically mediated by CD40L binding to CD40 expressed on DCs. Enhanced uptake of nanoparticles in draining lymph nodes of mice was not observed, however, 48 hours after subcutaneous injection. These findings suggest that CD40 ligand may be a potentially useful targeting moiety for delivery of particulate vaccines to DCs, and that further optimization of both CD40L and the polymer carriers is necessary to achieve efficacy in vivo.
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http://dx.doi.org/10.1002/btpr.595DOI Listing
November 2011

The relationship between MECP2 mutation type and health status and service use trajectories over time in a Rett syndrome population.

Res Autism Spectr Disord 2011 Jan;5(1):442-449

Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, Western Australia.

This study aimed to investigate the trajectories over time of health status and health service use in Rett syndrome by mutation type. Data were obtained from questionnaires administered over six years to 256 participants from the Australian Rett Syndrome Database. Health status (episodes of illness and medication load) and health service use (general practitioner and specialist visits and hospital stays) were summarized into composite scores with Principal Component Analysis. Linear and mixed regression models examined effects of mutation type and other variables on these scores over time. For some mutations (such as p.R255X, p.R168X) health status was poorer at a younger age and improved over time, while for p.R133C it was better at a younger age and deteriorated with time. For those with p.R133C health service use was lowest at a younger age and highest at 25 years. With other mutations, such as p.R255X, p.R270X, p.R294X, C terminal and p.R306C, health service use was higher at a younger age, but dropped off considerably by 25 years of age. Health service use generally declined in parallel with deterioration in health status, although this pattern differed by mutation type, demonstrating important variability in the course of Rett syndrome.
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http://dx.doi.org/10.1016/j.rasd.2010.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2968739PMC
January 2011