Intraventricular haemorrhage and posthaemorrhagic ventricular dilatation remain an important challenge in the management of prematurity and are associated with significant permanent morbidity. ...Progressive ventricular dilatation causes white matter injury by pressure, distortion, free radical injury and inflammation. Therapeutic interventions include serial lumbar punctures, only useful when the ventricles remain in communication with the lumbar subarachnoid space, and repeated aspiration through a ventricular access device. Reduction of cerebrospinal fluid production by acetazolamide and frusemide in a large multicentre randomised trial showed a worse outcome in the treated arm. A trial of drainage, irrigation and fibrinolytic therapy did not demonstrate a reduced need for permanent cerebrospinal fluid diversion, but did show a significant reduction in severe cognitive disability at two years. Ventriculoperitoneal shunting is indicated when the ventricles continue to enlarge at a body weight of around 2.5 kg and cerebrospinal fluid protein levels are below 1.5 g /L. This review summarises current concepts on the pathophysiology and management of posthaemorrhagic ventricular dilatation, underlining clinical challenges and ongoing research. Although the percentage of small preterm infants developing intraventricular haemorrhage (IVH) has been greatly reduced in the last three decades, increased survival of very immature infants has meant that large IVH with subsequent posthaemorrhagic ventricular dilatation is still a serious unsolved problem.
Objective
To investigate whether inhaling 50% xenon during hypothermia (HT) offers better neuroprotection than xenon or HT alone.
Methods
Ninety‐eight newborn pigs underwent a 45‐minute global ...hypoxic‐ischemic insult severe enough to cause permanent brain injury, and 12 pigs underwent sham protocol. Pigs then received intravenous anesthesia and were randomized to 6 treatment groups: (1) normothermia (NT; rectal temperature 38.5°C, n = 18); (2) 18 hours 50% xenon with NT (n = 12); (3) 12 hours HT (rectal temperature 33.5°C, n = 18); (4) 24 hours HT (rectal temperature 33.5°C, n = 17); (5) 18 hours 50% xenon with 12 hours HT (n = 18); and (6) 18 hours 50% xenon with 24 hours HT (n = 17). Fifty percent xenon was administered via a closed circle with 30% oxygen and 20% nitrogen. After 10 hours rewarming, cooled pigs remained normothermic until terminal perfusion fixation at 72 hours. Global and regional brain neuropathology and clinical neurological scores were performed.
Results
Xenon (p = 0.011) and 12 or 24 hours HT (p = 0.003) treatments offered significant histological global, and regional neuroprotection. Combining xenon with HT yielded an additive neuroprotective effect, as there was no interaction effect (p = 0.54). Combining Xenon with 24 hours HT offered 75% global histological neuroprotection with similarly improved regional neuroprotection: thalamus (100%), brainstem (100%), white matter (86%), basal ganglia (76%), cortical gray matter (74%), cerebellum (73%), and hippocampus (72%). Neurology scores improved in the 24‐hour HT and combined xenon HT groups at 72 hours.
Interpretation
Combining xenon with HT is a promising therapy for severely encephalopathic infants, doubling the neuroprotection offered by HT alone. ANN NEUROL 2010
Context:
Fifty percent of pediatric low-grade gliomas affect the optic pathway, hypothalamus, and suprasellar areas (OP/HSGs), resulting in significant long-term neuroendocrinopathy.
Objective:
This ...study aimed to dissect tumor- from treatment-related risk factors for OP/HSG-associated neuroendocrinopathy.
Design:
This was a retrospective case notes analysis of 166 children with newly diagnosed OP/HSGs at our quaternary center between 1980 and 2010 by multivariate Cox, linear, and logistic regression.
Results:
Patients were of median (range) age 4.9 (0.2–15.4) years at diagnosis and followed up for 8.3 (0.04–26.8) years. Despite high 20-year overall survival (81.0%), progression-free and endocrine event-free survival (EEFS) were 47.2 and 20.8%, respectively. EEFS declined up to 15 years post-diagnosis, with hypothalamic involvement (P < .001) being implicated more than radiotherapy (P = .008) in earlier endocrinopathy; the reverse being true of its density (radiotherapy P < .001; hypothalamic involvement P = .006). GH deficiency (GHD) was most common (40.3%), followed by central precocious puberty (CPP, 26.0%), gonadotropin (GnD; 20.4%), TSH (13.3%), and ACTH (13.3%) deficiencies. GHD increased with later treatment eras (P < .01), but replacement did not increase progression. CPP was associated with future GnD (P < .05). Posterior pituitary dysfunction (PPD; 7.2%) occurred in 57.9% after only biopsies or shunt procedures, and was associated with 6/13 deaths; 50.2% became obese. Tumor extent, surgery, and increased endocrinopathy, rather than radiotherapy, predicted visuocognitive morbidity.
Conclusions:
This first longitudinal OP/HSG-specific study demonstrates that hypothalamo-pituitary dysfunction evolves hierarchically over decades. Tumor location predicts its speed of onset and radiotherapy its density. GnD can evolve from previous CPP, whereas life-threatening PPD can occur after any surgery. Our data suggest that recent radiation-avoiding chemotherapeutic strategies have increased GHD without improving survival.
Tumors of the central nervous system comprise nearly a quarter of all childhood cancers and are the most frequent solid tumor in the pediatric population. The most common location is in the posterior ...fossa, but tumors can occur anywhere intracranially. The spectrum of lesions encountered varies, from being completely benign and requiring surveillance alone to being highly malignant and requiring aggressive treatment in the form of surgery and adjuvant therapy. The extent of resection plays a crucial role in the oncological outcome of many of these tumors. A variety of surgical approaches are available for the spectrum of lesions encountered. This review focuses on summarizing the location, types, and neurosurgical management strategies for pediatric brain intracranial brain tumors. Here, we discuss neurosurgical approaches for a variety of brain tumors and regions, including the management of tumors of the posterior fossa, brainstem, pineal region, intraventricular region, sellar and suprasellar regions, optic pathway and hypothalamus, and supratentorial hemispheres.
Hypoxic/ischemic (HI) brain injury affects 1 to 6 per 1000 live human births, with a mortality of 15% to 20%. A quarter of survivors have permanent disabilities. Hypothermia is the only intervention ...that improves outcome; however, further improvements might be obtained by combining hypothermia with additional treatments. Xenon is a noble anesthetic gas with an excellent safety profile, showing great promise in vitro and in vivo as a neuroprotectant. We investigated combinations of 50% xenon (Xe(50%)) and hypothermia of 32 degrees C (HT(32 degrees C)) as a post-HI therapy.
An established neonatal rat HI model was used. Serial functional neurologic testing into adulthood 10 weeks after injury was performed, followed by global and regional brain histopathology evaluation.
In the combination Xe(50%)HT(32 degrees C) group, complete restoration of long-term functional outcomes was seen. Hypothermia produced improvement on short- (P<0.001) and long- (P<0.001) term functional testing, whereas Xe(50%) alone predominantly improved long-term function (P<0.05), suggesting that short-term testing does not always predict eventual outcome. Similarly, the Xe(50%)HT(32 degrees C) combination produced the greatest (71%) improvement in global histopathology scores, a pattern mirrored in the regional scores, whereas Xe(50%) and HT(32 degrees C) individually produced smaller improvements (P<0.05 and P<0.001, respectively). The interaction between the 2 treatments was additive.
The xenon/hypothermia combination additively confers greater protection after HI than either treatment alone. The functional improvement is almost complete, is sustained long term, and is accompanied by greatly improved histopathology. The unique safety profile differentiates xenon as an attractive combination therapy with hypothermia to improve the otherwise bleak outcome from neonatal HI.
Purpose
The optimum strategy for the surveillance of low-grade gliomas in children has not been established, and there is concern about the use of gadolinium-based contrast agents (GBCAs), ...particularly in children, due to their deposition in the brain. The number of surveillance scans and the use of GBCAs in surveillance of low-risk tumours should ideally be limited. We aimed to investigate the consistency and utility of our surveillance imaging and also determine to what extent the use of GBCAs contributed to decisions to escalate treatment in children with grade 1 astrocytomas.
Methods
This was a retrospective single-centre study at a tertiary paediatric hospital. All children with a new diagnosis of a non-syndromic World Health Organization (WHO) grade 1 astrocytoma between 2007 and 2013 were included, with surveillance imaging up to December 2018 included in analysis. The intervals of surveillance imaging were recorded, and imaging and electronic health records were examined for decisions related to treatment escalation.
Results
Eighty-eight patients had 690 surveillance scans in the study period. Thirty-one patients had recurrence or progression leading to treatment escalation, 30 of whom were identified on surveillance imaging. The use of GBCAs did not appear to contribute to multidisciplinary team (MDT) decisions in the majority of cases.
Conclusion
Surveillance imaging could be reduced in number and duration for completely resected cerebellar tumours. MDT decisions were rarely made on the basis of post-contrast imaging, and GBCA administration could therefore potentially be restricted in the setting of surveillance of grade 1 astrocytomas in children.
The drainage, irrigation and fibrinolytic therapy (DRIFT) trial, conducted in 2003-6, showed a reduced rate of death or severe disability at 2 years in the DRIFT compared with the standard treatment ...group, among preterm infants with intraventricular haemorrhage (IVH) and post-haemorrhagic ventricular dilatation.
To compare cognitive function, visual and sensorimotor ability, emotional well-being, use of specialist health/rehabilitative and educational services, neuroimaging, and economic costs and benefits at school age.
Ten-year follow-up of a randomised controlled trial.
Neonatal intensive care units (Bristol, Katowice, Glasgow and Bergen).
Fifty-two of the original 77 infants randomised.
DRIFT or standard therapy (cerebrospinal fluid tapping).
Primary - cognitive disability. Secondary - vision; sensorimotor disability; emotional/behavioural function; education; neurosurgical sequelae on magnetic resonance imaging; preference-based measures of health-related quality of life; costs of neonatal treatment and of subsequent health care in childhood; health and social care costs and impact on family at age 10 years; and a decision analysis model to estimate the cost-effectiveness of DRIFT compared with standard treatment up to the age of 18 years.
By 10 years of age, 12 children had died and 13 were either lost to follow-up or had declined to participate. A total of 52 children were assessed at 10 years of age (DRIFT,
= 28; standard treatment,
= 24). Imbalances in gender and birthweight favoured the standard treatment group. The unadjusted mean cognitive quotient (CQ) score was 69.3 points standard deviation (SD) 30.1 points in the DRIFT group compared with 53.7 points (SD 35.7 points) in the standard treatment group, a difference of 15.7 points, 95% confidence interval (CI) -2.9 to 34.2 points;
= 0.096. After adjusting for the prespecified covariates (gender, birthweight and grade of IVH), this evidence strengthened: children who received DRIFT had a CQ advantage of 23.5 points (
= 0.009). The binary outcome, alive without severe cognitive disability, gave strong evidence that DRIFT improved cognition unadjusted odds ratio (OR) 3.6 (95% CI 1.2 to 11.0;
= 0.026) and adjusted OR 10.0 (95% CI 2.1 to 46.7;
= 0.004); the number needed to treat was three. No significant differences were found in any secondary outcomes. There was weak evidence that DRIFT reduced special school attendance (adjusted OR 0.27, 95% CI 0.07 to 1.05;
= 0.059). The neonatal stay (unadjusted mean difference £6556, 95% CI -£11,161 to £24,273) and subsequent hospital care (£3413, 95% CI -£12,408 to £19,234) costs were higher in the DRIFT arm, but the wide CIs included zero. The decision analysis model indicated that DRIFT has the potential to be cost-effective at 18 years of age. The incremental cost-effectiveness ratio (£15,621 per quality-adjusted life-year) was below the National Institute for Health and Care Excellence threshold. The cost-effectiveness results were sensitive to adjustment for birthweight and gender.
The main limitations are the sample size of the trial and that important characteristics were unbalanced at baseline and at the 10-year follow-up. Although the analyses conducted here were prespecified in the analysis plan, they had not been prespecified in the original trial registration.
DRIFT improves cognitive function when taking into account birthweight, grade of IVH and gender. DRIFT is probably effective and, given the reduction in the need for special education, has the potential to be cost-effective as well. A future UK multicentre trial is required to assess efficacy and safety of DRIFT when delivered across multiple sites.
Current Controlled Trials ISRCTN80286058.
This project was funded by the NIHR Health Technology Assessment programme and will be published in full in
; Vol. 23, No. 4. See the NIHR Journals Library website for further project information. The DRIFT trial and 2-year follow-up was funded by Cerebra and the James and Grace Anderson Trust.
Despite high survival, paediatric optic pathway hypothalamic gliomas are associated with significant morbidity and late mortality. Those youngest at presentation have the worst outcomes. We aimed to ...assess presenting disease, tumour location, and treatment factors implicated in the evolution of neuroendocrine, metabolic, and neurobehavioural morbidity in 90 infants/children diagnosed before their third birthday and followed-up for 9.5 years (range 0.5-25.0). A total of 52 (57.8%) patients experienced endo-metabolic dysfunction (EMD), the large majority (46) of whom had hypothalamic involvement (H+) and lower endocrine event-free survival (EEFS) rates. EMD was greatly increased by a diencephalic syndrome presentation (85.2% vs. 46%,
= 0.001)), H+ (OR 6.1 95% CI 1.7-21.7,
0.005), radiotherapy (OR 16.2, 95% CI 1.7-158.6,
= 0.017) and surgery (OR 4.8 95% CI 1.3-17.2,
= 0.015), all associated with anterior pituitary disorders. Obesity occurred in 25% of cases and was clustered with the endocrinopathies. Neurobehavioural deficits occurred in over half (52) of the cohort and were associated with H+ (OR 2.5 95% C.I. 1.1-5.9,
= 0.043) and radiotherapy (OR 23.1 C.I. 2.9-182,
= 0.003). Very young children with OPHG carry a high risk of endo-metabolic and neurobehavioural comorbidities which deserve better understanding and timely/parallel support from diagnosis to improve outcomes. These evolve in complex, hierarchical patterns over time whose aetiology appears predominantly determined by injury from the hypothalamic tumour location alongside adjuvant treatment strategies.
Purpose:
Intraoperative diffusion MRI could provide a means of visualising brain fibre tracts near a neurosurgical target after preoperative images have been invalidated by brain shift. We propose an ...atlas-based intraoperative tract segmentation method, as the standard preoperative method, streamline tractography, is unsuitable for intraoperative implementation.
Methods:
A tract-specific voxel-wise fibre orientation atlas is constructed from healthy training data. After registration with a target image, a radial tumour deformation model is applied to the orientation atlas to account for displacement caused by lesions. The final tract map is obtained from the inner product of the atlas and target image fibre orientation data derived from intraoperative diffusion MRI.
Results:
The simple tumour model takes only seconds to effectively deform the atlas into alignment with the target image. With minimal processing time and operator effort, maps of surgically relevant tracts can be achieved that are visually and qualitatively comparable with results obtained from streamline tractography.
Conclusion:
Preliminary results demonstrate feasibility of intraoperative streamline-free tract segmentation in challenging neurosurgical cases. Demonstrated results in a small number of representative sample subjects are realistic despite the simplicity of the tumour deformation model employed. Following this proof of concept, future studies will focus on achieving robustness in a wide range of tumour types and clinical scenarios, as well as quantitative validation of segmentations.
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