Optic Radiation Tractography in Pediatric Brain Surgery Applications: A Reliability and Agreement Assessment of the Tractography Method.

BACKGROUND: Optic radiation (OR) tractography may help predict and reduce post-neurosurgical visual field deficits. OR tractography methods currently lack pediatric and surgical focus. PURPOSE: We propose a clinically feasible OR tractography strategy in a pediatric neurosurgery setting and examine its intra-rater and inter-rater reliability/agreements. METHODS: Preoperative and intraoperative MRI data were obtained from six epilepsy and two brain tumor patients on 3 Tesla MRI scanners. Four raters with different clinical experience followed the proposed strategy to perform probabilistic OR tractography with manually drawing anatomical landmarks to reconstruct the OR pathway, based on fiber orientation distributions estimated from high angular resolution diffusion imaging data. Intra- and inter-rater reliabilities/agreements of tractography results were assessed using intraclass correlation coefficient (ICC) and dice similarity coefficient (DSC) across various tractography and OR morphological metrics, including the lateral geniculate body positions, tract volumes, and Meyer's loop position from temporal anatomical landmarks. RESULTS: Good to excellent intra- and inter-rater reproducibility was demonstrated for the majority of OR reconstructions (ICC = 0.70-0.99; DSC = 0.84-0.89). ICC was higher for non-lesional (0.82-0.99) than lesional OR (0.70-0.99). The non-lesional OR's mean volume was 22.66 cm3; the mean Meyer's loop position was 29.4 mm from the temporal pole, 5.89 mm behind of and 10.26 mm in front of the temporal ventricular horn. The greatest variations (± 1.00-3.00 mm) were observed near pathology, at the tract edges or at cortical endpoints. The OR tractography were used to assist surgical planning and guide lesion resection in all cases, no patient had new visual field deficits postoperatively. CONCLUSION: The proposed tractography strategy generates reliable and reproducible OR tractography images that can be reliably implemented in the routine, non-emergency pediatric neurosurgical setting.

Cost-effectiveness of epileptic surgery compared with medical treatment in children with drug-resistant epilepsy.

BACKGROUND: Epilepsy surgery is an alternative to continued antiepileptic drugs (AEDs) in children with drug-resistant epilepsy (DRE). OBJECTIVE: The objective of the study was to measure, model, and compare the medical costs and impacts on health-related quality of life (HRQL) of epilepsy surgery versus continued medical treatment with AEDs in children with DRE. METHODS: A decision analytic model was created to estimate the cost-effectiveness of epilepsy surgery relative to continued medical treatment with AEDs. The model was based on costing and effectiveness data collected from 105 children with DRE who were operated on at the Royal Children's Hospital, Melbourne, Australia. The mean cost of conducting epilepsy surgery was AU$ 61,417 per person. Effectiveness of continued medical treatment was sourced from best available literature. In the absence of published utility values for pediatric patients with epilepsy and ethical approval to contact patients directly, HRQL was estimated by four clinicians using the Child Health Utility 9 Dimension (CHU9D). Outcome measures were seizure freedom and quality-adjusted life years (QALYs). RESULTS: The costs over 7.6 years of follow-up were AU$ 219,297 for the surgical treatment group compared with AU$ 170,583 for the medical treatment group. The incremental cost-effectiveness ratio (ICER) for surgically vs medical treatment was AU$ 76,538 per additional patient attaining seizure freedom and AU$ 75,541 per additional QALY gained. CONCLUSION: Epilepsy surgery resulted in a greater reduction of seizures and improvement in HRQL but was more expensive than continued medical treatment with AEDs. Including benefits outside of a healthcare perspective would likely lead to a more compelling cost-effective argument.

A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy.

OBJECTIVE: The severe epilepsies of infancy (SEI) are a devastating group of disorders that pose a major care and economic burden on society; early diagnosis is critical for optimal management. This study sought to determine the incidence and etiologies of SEI, and model the yield and cost-effectiveness of early genetic testing. METHODS: A population-based study was undertaken of the incidence, etiologies, and cost-effectiveness of a whole exome sequencing-based gene panel (targeted WES) in infants with SEI born during 2011-2013, identified through electroencephalography (EEG) and neonatal databases. SEI was defined as seizure onset before age 18 months, frequent seizures, epileptiform EEG, and failure of ≥2 antiepileptic drugs. Medical records, investigations, MRIs, and EEGs were analyzed, and genetic testing was performed if no etiology was identified. Economic modeling was performed to determine yield and cost-effectiveness of investigation of infants with unknown etiology at epilepsy onset, incorporating targeted WES at different stages of the diagnostic pathway. RESULTS: Of 114 infants with SEI (incidence = 54/100 000 live births/y), the etiology was determined in 76 (67%): acquired brain injuries (n = 14), focal cortical dysplasias (n = 14), other brain malformations (n = 17), channelopathies (n = 11), chromosomal (n = 9), metabolic (n = 6), and other genetic (n = 5) disorders. Modeling showed that incorporating targeted WES increased diagnostic yield compared to investigation without targeted WES (48/86 vs 39/86). Early targeted WES had lower total cost ($677 081 U.S. dollars [USD] vs $738 136 USD) than late targeted WES. A pathway with early targeted WES and limited metabolic testing yielded 7 additional diagnoses compared to investigation without targeted WES (46/86 vs 39/86), with lower total cost ($455 597 USD vs $661 103 USD), lower cost per diagnosis ($9904 USD vs $16 951 USD), and a dominant cost-effectiveness ratio. SIGNIFICANCE: Severe epilepsies occur in 1 in 2000 infants, with the etiology identified in two-thirds, most commonly malformative. Early use of targeted WES yields more diagnoses at lower cost. Early genetic diagnosis will enable timely administration of precision medicines, once developed, with the potential to improve long-term outcome.

Potential delays in referral and assessment for epilepsy surgery in children with drug-resistant, early-onset epilepsy.

OBJECTIVE: To study potential delays in epilepsy surgery in children with drug-resistant epilepsy (DRE) of early-onset. METHODS: Medical records were reviewed from 87 children with DRE and seizure onset before age 3 years who underwent epilepsy surgery between 2006 and 2015. Information was obtained about each child's epilepsy, treatment and specific time points in management. Time intervals along diagnostic, investigative, treatment and referral pathways were calculated. RESULTS: Median ages at seizure onset, when seen in the epilepsy surgery program and surgery were 5.9 (IQR 10), 19 (IQR 29) and 36 (IQR 67) months; the median delay from seizure onset to surgery was 30 (IQR 67) months. Most children were promptly diagnosed, treated, investigated and seen by a pediatric neurologist. Focal abnormalities were reported on initial EEGs and MRIs in most children, and DRE developed within a median of 6.3 months from commencement of medication. There were median durations of 6.2 months between seeing a neurologist and being seen in the epilepsy surgery program, and then 6.1 months in determining surgical candidacy. Median durations from potential indications for a surgical evaluation to agreed surgical candidacy were 10 (DRE), 12 (focal MRI) and 17 (focal EEG) months. Children received a median of six antiepileptic drugs prior to surgery. Median interval from agreed surgical candidacy to surgery was only 3 months. There were longer durations from seizure onset to surgery in children needing PET (p = 0.001) and in children with seizure-free periods (p < 0.001), and shorter durations in children with a history of infantile spasms (p = 0.01). SIGNIFICANCE: Delays in referral of children for epilepsy surgery are reported. Delays in assessment may be specific to centralized children's hospitals in public health systems.

Limited role for routine EEG in the assessment of staring in children with autism spectrum disorder.

AIM: The assessment of staring episodes in children with autism spectrum disorder (ASD) is difficult due to the range of diagnostic possibilities, the increased frequency of epileptiform activity on electroencephalogram (EEG), and the inability of normal EEG to exclude seizures. We reviewed the diagnostic use of routine EEG in this setting. METHOD: The routine EEG database of the Royal Children's Hospital, Melbourne was searched for recordings during 2005-2010 in children with ASD below 16 years of age who were referred for staring. EEG reports and recordings were reviewed and epileptiform activity was characterised. RESULTS: Ninety-two EEGs in children with ASD were requested for episodes of staring. No child had absence or focal dyscognitive seizures confirmed on EEG. Findings were normal or showed non-epileptiform abnormalities in 80 children. Interictal epileptiform abnormalities were recorded in 12 children, but were judged potentially significant in only three. Seven children had epileptiform activity typical of benign focal epilepsy of childhood, such discharges seen not uncommonly in developmentally normal and delayed children without seizures. INTERPRETATION: Given the difficulties of performing EEG in children with ASD, the low yield of positive diagnostic findings and the high frequency of insignificant abnormalities, we suggest that EEG should be undertaken judiciously when evaluating children with ASD and staring episodes.

The ketogenic diet in refractory childhood epilepsy.

OBJECTIVE: To report the efficacy and tolerability of the ketogenic diet (KD) in refractory paediatric epilepsy. METHODS: Twenty-six consecutive children were treated with the classical KD from 1996 to 2001. The epilepsy syndromes included symptomatic generalized epilepsy (15), idiopathic generalized epilepsy (4), symptomatic partial epilepsy (1) and unclassified epilepsy (6). One child was lost to follow up. RESULTS: Median age at initiation of the KD was 6.1 years. Median duration of the treatment was 9 months. Twelve children (48%) were treated for >12 months; one still remains on the KD. Four children (16%) became seizure-free. Five children (20%) had 50-99% reduction in seizures, seven (28%) had <50% reduction in seizures and eight (36%) had no improvement. Age, seizure-type and aetiology did not predict response. The medications were decreased in 33% of the children. The KD was discontinued in 64% of the children because of poor efficacy and in 12% because of side-effects. Problems during initiation of the KD included asymptomatic hypoglycaemia (24%) and vomiting (12%). Later complications included poor growth (20%), hyperlipidaemia (16%), hypercalcuria (8%), hypocarnitaemia (8%), constipation (8%), pancreatitis (4%) and decreased bone density (4%). There were no deaths. A 3-month trial of the KD costs A3879 dollars. The first 12 months cost A7275 dollars with a cost of A4528 dollars each year, thereafter. CONCLUSIONS: The KD is an effective treatment for some children with refractory epilepsy, being generally well tolerated and rarely associated with side-effects. Response is not necessarily predicted by age, syndrome or aetiology. A prospective study of the KD is presently underway.