Publications by authors named "Kim V Annink"

12 Publications

  • Page 1 of 1

Mammillary body atrophy and other MRI correlates of school-age outcome following neonatal hypoxic-ischemic encephalopathy.

Sci Rep 2021 Mar 3;11(1):5017. Epub 2021 Mar 3.

Department of Neonatology, UMC Utrecht Brain Centre, Wilhelmina Children's Hospital, University Utrecht, Internal Room Number KE04.123.1, Lundlaan 6, 3508AB, Utrecht, The Netherlands.

The mammillary bodies (MB) and hippocampi are important for memory function and are often affected following neonatal hypoxic ischemic encephalopathy (HIE). The aim of this study was to assess neurodevelopmental outcome in 10-year-old children with HIE with and without therapeutic hypothermia. Additional aims were to assess the associations between MB atrophy, brain volumes (including the hippocampi), white matter microstructure and neurodevelopmental outcome at school-age. Ten-year-old children with HIE were included, who were treated with therapeutic hypothermia (n = 22) or would have qualified but were born before this became standard of care (n = 28). Children completed a neuropsychological and motor assessment and MRI. Mammillary bodies were scored as normal or atrophic at 10 years. Brain volumes were segmented on childhood MRI and DTI scans were analysed using tract-based spatial statistics. Children with HIE suffered from neurocognitive and memory problems at school-age, irrespective of hypothermia. Hippocampal volumes and MB atrophy were associated with total and performance IQ, processing speed and episodic memory in both groups. Normal MB and larger hippocampi were positively associated with global fractional anisotropy. In conclusion, injury to the MB and hippocampi was associated with neurocognition and memory at school-age in HIE and might be an early biomarker for neurocognitive and memory problems.
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http://dx.doi.org/10.1038/s41598-021-83982-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930036PMC
March 2021

Glomerular Filtration Rate in Asphyxiated Neonates Under Therapeutic Whole-Body Hypothermia, Quantified by Mannitol Clearance.

Clin Pharmacokinet 2021 Feb 21. Epub 2021 Feb 21.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.

Background: Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderate-to-severe hypoxic-ischemic encephalopathy resulting from perinatal asphyxia. Despite this beneficial effect, TH may further affect drug elimination pathways such as the glomerular filtration rate.

Objectives: The objective of this study was to quantify the effect of TH in addition to asphyxia on mannitol clearance as a surrogate for the glomerular filtration rate.

Methods: The effect of asphyxia and TH (mild vs moderate/severe) on mannitol clearance was assessed using a population approach, based on mannitol observations collected in the ALBINO (ALlopurinol in addition to TH for hypoxic-ischemic Brain Injury on Neurocognitive Outcome) trial, as some were exposed to a second dose of 10 mg/kg intravenous mannitol as placebo to ensure blinding. Pharmacokinetic analysis and model development were conducted using NONMEM version 7.4.

Results: Based on 77 observations from 17 neonates (TH = 13), a one-compartment model with first-order linear elimination best described the observed data. To account for prenatal glomerular filtration rate maturation, both birthweight and gestational age were implemented as clearance covariates using an earlier published three-quarters power function and a sigmoid hyperbolic function. Our final model predicted a mannitol clearance of 0.15 L/h for a typical asphyxia neonate (39.5 weeks, birthweight 3.25 kg, no TH), lower than the reported value of 0.33 L/h for a healthy neonate of similar age and weight. By introducing TH as a binary covariate on clearance, the additional impact of TH on mannitol clearance was quantified (60% decrease).

Conclusions: Mannitol clearance was decreased by approximately 60% in neonates undergoing TH, although this is likely confounded with asphyxia severity.

Trial Registration: ClinicalTrials.gov identifier NCT03162653.
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http://dx.doi.org/10.1007/s40262-021-00991-6DOI Listing
February 2021

Pathophysiology of Cerebral Hyperperfusion in Term Neonates With Hypoxic-Ischemic Encephalopathy: A Systematic Review for Future Research.

Front Pediatr 2021 2;9:631258. Epub 2021 Feb 2.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Worldwide neonatal hypoxic-ischemic encephalopathy (HIE) is a common cause of mortality and neurologic disability, despite the implementation of therapeutic hypothermia treatment. Advances toward new neuroprotective interventions have been limited by incomplete knowledge about secondary injurious processes such as cerebral hyperperfusion commonly observed during the first 1-5 days after asphyxia. Cerebral hyperperfusion is correlated with adverse neurodevelopmental outcome and it is a process that remains poorly understood. In order to provide an overview of the existing knowledge on the pathophysiology and highlight the gaps in current understanding of cerebral hyperperfusion in term animals and neonates with HIE, we performed a systematic research. We included papers scoping for study design, population, number of participants, study technique and relevant findings. Methodological quality was assessed using the checklist for cohort studies from The Joanna Briggs Institute. Out of 2,690 results, 34 studies were included in the final review-all prospective cohort studies. There were 14 studies of high, 17 moderate and 3 of low methodological quality. Data from the literature were analyzed in two main subjects: (1) Hemodynamic Changes subdivided into macro- and microscopic hemodynamic changes, and (2) Endogenous Pathways which was subdivided into N-methyl-D-aspartate/Mitogen activated protein kinase (NDMA/MAPK), Nitric Oxide (NO), prostanoids and other endogenous studies. Cerebral hyperperfusion in term neonates with HIE was found to be present 10-30 min after the hypoxic-ischemic event and was still present around day 10 and up to 1 month after birth. Cerebral hyperperfusion was also characterized by angiogenesis and cerebral vasodilation. Additionally, cerebral vasodilation was mediated by endogenous pathways such as MAPK through urokinase Plasminogen Activator (uPA), by neuronal NO synthase following NMDA and by prostanoid synthesis. Future research should elucidate the precise role of NMDA, MAPK and prostanoids in cerebral hyperperfusion. Moreover, research should focus on possible interventions and the effect of hypothermia on hyperperfusion. These findings should be taken into account simultaneously with brain imagining techniques, becoming a valuable asset in assessing the impact in neurodevelopmental outcome.
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http://dx.doi.org/10.3389/fped.2021.631258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884860PMC
February 2021

Cerebellar injury in term neonates with hypoxic-ischemic encephalopathy is underestimated.

Pediatr Res 2020 Sep 23. Epub 2020 Sep 23.

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht Brain Center, University Utrecht, Utrecht, The Netherlands.

Background: Postmortem examinations frequently show cerebellar injury in infants with severe hypoxic-ischemic encephalopathy (HIE), while it is less well visible on MRI. The primary aim was to investigate the correlation between cerebellar apparent diffusion coefficient (ADC) values and histopathology in infants with HIE. The secondary aim was to compare ADC values in the cerebellum of infants with HIE and infants without brain injury.

Methods: ADC values in the cerebellar vermis, hemispheres and dentate nucleus (DN) of (near-)term infants with HIE (n = 33) within the first week after birth were compared with neonates with congenital non-cardiac anomalies, normal postoperative MRIs and normal outcome (n = 22). Microglia/macrophage activation was assessed using CD68 and/or HLA-DR staining and Purkinje cell (PC) injury using H&E-stained slices. The correlation between ADC values and the histopathological measures was analyzed.

Results: ADC values in the vermis (p = 0.021) and DN (p < 0.001) were significantly lower in infants with HIE compared to controls. ADC values in the cerebellar hemispheres were comparable. ADC values in the vermis were correlated with the number and percentage of normal PCs; otherwise ADC values and histology were not correlated.

Conclusion: Histopathological injury in the cerebellum is common in infants with HIE. ADC values underestimate histopathological injury.

Impact: ADC values might underestimate cerebellar injury in neonates with HIE. ADC values in the vermis and dentate nucleus of infants with HIE are lower compared to controls, but not in the cerebellar hemispheres. Abnormal ADC values are only found when cytotoxic edema is very severe. ADC values in the vermis are correlated with Purkinje cell injury in the vermis; furthermore, there were no correlations between ADC values and histopathological measures.
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http://dx.doi.org/10.1038/s41390-020-01173-zDOI Listing
September 2020

The development and validation of a cerebral ultrasound scoring system for infants with hypoxic-ischaemic encephalopathy.

Pediatr Res 2020 03;87(Suppl 1):59-66

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: Hypoxic-ischaemic encephalopathy (HIE) is an important cause of morbidity and mortality in neonates. When the gold standard MRI is not feasible, cerebral ultrasound (CUS) might offer an alternative. In this study, the association between a novel CUS scoring system and neurodevelopmental outcome in neonates with HIE was assessed.

Methods: (Near-)term infants with HIE and therapeutic hypothermia, a CUS on day 1 and day 3-7 after birth and available outcome data were retrospectively included in cohort I. CUS findings on day 1 and day 3-7 were related to adverse outcome in univariate and the CUS of day 3-7 also in multivariable logistic regression analyses. The resistance index, the sum of deep grey matter and of white matter involvement were included in multivariable logistic regression analyses. A comparable cohort from another hospital was used for validation (cohort II).

Results: Eighty-three infants were included in cohort I and 35 in cohort II. The final CUS scoring system contained the sum of white matter (OR = 2.6, 95% CI 1.5-4.7) and deep grey matter involvement (OR = 2.7, 95% CI 1.7-4.4). The CUS scoring system performed well in cohort I (AUC = 0.90) and II (AUC = 0.89).

Conclusion: This validated CUS scoring system is associated with neurodevelopmental outcome in neonates with HIE.
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http://dx.doi.org/10.1038/s41390-020-0782-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098882PMC
March 2020

Brain temperature of infants with neonatal encephalopathy following perinatal asphyxia calculated using magnetic resonance spectroscopy.

Pediatr Res 2020 08 2;88(2):279-284. Epub 2020 Jan 2.

Department of Radiology, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.

Background: Little is known about brain temperature of neonates during MRI. Brain temperature can be estimated non-invasively with proton Magnetic Resonance Spectroscopy (H-MRS), but the most accurate H-MRS method has not yet been determined. The primary aim was to estimate brain temperature using H-MRS in infants with neonatal encephalopathy (NE) following perinatal asphyxia. The secondary aim was to compare brain temperature during MRI with rectal temperatures before and after MRI.

Methods: In this retrospective study, brain temperature in 36 (near-)term infants with NE was estimated using short (36 ms) and long (288 ms) echo time (TE) H-MRS. Brain temperature was calculated using two different formulas: formula of Wu et al. and a formula based on phantom calibration. The methods were compared. Rectal temperatures were collected <3 hours before and after MRI.

Results: Brain temperatures calculated with the formula of Wu et al. and the calibrated formula were similar as well as brain temperatures derived from short and long TE H-MRS. Rectal temperature did not differ before and after MRI.

Conclusions: Brain temperature can be measured using H-MRS in daily clinical practice using the formula of Wu et al. with both short and long TE H-MRS. Brain temperature remained within physiological range during MRI.
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http://dx.doi.org/10.1038/s41390-019-0739-3DOI Listing
August 2020

Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III).

BMC Pediatr 2019 06 27;19(1):210. Epub 2019 Jun 27.

University Hospital Tuebingen, Calwerstr. 7, 72076, Tuebingen, Germany.

Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia.

Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion.

Discussion: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia.

Trial Registration: NCT03162653, www.ClinicalTrials.gov , May 22, 2017.
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http://dx.doi.org/10.1186/s12887-019-1566-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595623PMC
June 2019

The long-term effect of perinatal asphyxia on hippocampal volumes.

Pediatr Res 2019 01 17;85(1):43-49. Epub 2018 Jul 17.

Department of Neonatology, Brain Center Rudolf Magnus, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: Hypoxic-ischemic encephalopathy (HIE) in term-born infants can lead to memory problems. The hippocampus is important for long-term episodic memory. The primary aim was to investigate the effect of HIE on hippocampal volumes in 9- to 10-year-old children. The secondary aim was to investigate the association between hippocampal volumes and previously found impaired memory and cognitive functions in the current cohort.

Methods: In total 26 children with mild HIE, 26 with moderate HIE, and 37 controls were included. The intelligence quotient (IQ) and memory were tested. A 3D-volumetric MRI was obtained. Brain segmentation was performed for hippocampal volumes and intracranial volume. The differences in hippocampal volumes, memory, and IQ between the groups were determined. Multivariable linear regression analyses were performed, including hippocampal volume as a percentage of intracranial volume as a dependent variable.

Results: Smaller hippocampal volumes were found in moderate HIE (p < 0.001), with a trend toward smaller volumes in mild HIE, compared to controls. In multivariable linear regression analysis, hippocampal volume as a percentage of intracranial volume was significantly associated with long-term visuospatial memory.

Conclusion: Children with moderate HIE had smaller hippocampal volumes than controls, with a trend toward smaller volumes following mild HIE. Reduced hippocampal volumes were associated with poorer long-term visuospatial memory.
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http://dx.doi.org/10.1038/s41390-018-0115-8DOI Listing
January 2019

Allopurinol: Old Drug, New Indication in Neonates?

Curr Pharm Des 2017 ;23(38):5935-5942

Department of Neonatology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Netherlands.

Background: Hypoxic-ischemic encephalopathy (HIE) is an important cause of neonatal mortality and neurological morbidity, even despite hypothermia treatment. Neuronal damage in these infants is partly caused by the production of superoxides via the xanthine-oxidase pathway and concomitant free radical formation. Allopurinol is a xanthine-oxidase inhibitor and can potentially reduce the formation of these superoxides that lead to brain damage in HIE.

Methods: The aim of this review is to provide an overview of the animal and clinical data about the neuroprotective effect of allopurinol in HIE and the relevant mechanisms leading to brain injury in HIE.

Results: A possible neuroprotective effect of allopurinol has been suggested based on several preclinical studies in rats, piglets and sheep. Allopurinol seemed to inhibit the formation of superoxide and to scavenge free radicals directly, but the effect on brain damage was inconclusive in these preclinical trials. The neuroprotective effect was also investigated in neonates with HIE. In three small studies, in which, allopurinol was administered postnatally and a pilot and one multi-center study, in which, allopurinol was administered antenatally, a possible beneficial effect was found. After combining the data of 2 postnatal allopurinol studies, long-term follow-up was only beneficial in infants with moderate HIE, therefore, large-scale studies are needed. Additionally, safety, pharmacokinetics and the neuroprotective effect of allopurinol in other neonatal populations are discussed in this review.

Conclusion: The available literature is not conclusive whether allopurinol is a neuroprotective add-on therapy in infants with HIE. More research is needed to establish the neuroprotective effect of allopurinol especially in combination with hypothermia.
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http://dx.doi.org/10.2174/1381612823666170918123307DOI Listing
June 2019

Response to: 'Autoinflammatory disease damage index (ADDI): a possible newborn also in hidradenitis suppurativa daily practice' by Damiani .

Ann Rheum Dis 2017 08 2;76(8):e26. Epub 2017 Jan 2.

Department of Paediatrics, University Medical Centre Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1136/annrheumdis-2016-210918DOI Listing
August 2017

Development of the autoinflammatory disease damage index (ADDI).

Ann Rheum Dis 2017 May 3;76(5):821-830. Epub 2016 Nov 3.

Department of Paediatrics, University Medical Centre Utrecht, Utrecht, The Netherlands.

Objectives: Autoinflammatory diseases cause systemic inflammation that can result in damage to multiple organs. A validated instrument is essential to quantify damage in individual patients and to compare disease outcomes in clinical studies. Currently, there is no such tool. Our objective was to develop a common autoinflammatory disease damage index (ADDI) for familial Mediterranean fever, cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic fever syndrome and mevalonate kinase deficiency.

Methods: We developed the ADDI by consensus building. The top 40 enrollers of patients in the Eurofever Registry and 9 experts from the Americas participated in multiple rounds of online surveys to select items and definitions. Further, 22 (parents of) patients rated damage items and suggested new items. A consensus meeting was held to refine the items and definitions, which were then formally weighted in a scoring system derived using decision-making software, known as 1000minds.

Results: More than 80% of the experts and patients completed the online surveys. The preliminary ADDI contains 18 items, categorised in the following eight organ systems: reproductive, renal/amyloidosis, developmental, serosal, neurological, ears, ocular and musculoskeletal damage. The categories renal/amyloidosis and neurological damage were assigned the highest number of points, serosal damage the lowest number of points. The involvement of (parents of) patients resulted in the inclusion of, for example, chronic musculoskeletal pain.

Conclusions: An instrument to measure damage caused by autoinflammatory diseases is developed based on consensus building. Patients fulfilled a significant role in this process.
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http://dx.doi.org/10.1136/annrheumdis-2016-210092DOI Listing
May 2017

Health-related quality of life in children with newly diagnosed immune thrombocytopenia.

Haematologica 2014 Sep 20;99(9):1525-31. Epub 2014 Jun 20.

Department of Pediatric Hematology and Oncology, University Medical Center/Wilhelmina's Children Hospital, Utrecht, the Netherlands.

Despite its generally transient and benign course, childhood immune thrombocytopenia has a large impact on health-related quality of life. Recently published guidelines state that quality of life should be taken into account while making decisions on management in childhood immune thrombocytopenia. We, therefore, assessed health-related quality of life in children with newly diagnosed immune thrombocytopenia in a prospective multicenter study. One hundred and seven children aged 6 months-16 years (mean age 5.57 years) were included. We used Pediatric Quality of Life Inventory™ and Kids' ITP Tools questionnaires at diagnosis and during standardized follow-up. Scores on the Pediatric Quality of Life Inventory™ Core Scales were compared with those of healthy children. Relationships between health-related quality of life scores and treatment modality, bleeding tendency and course of the disease were examined. Kids' ITP Tools proxy reports and parent self-reports showed significant higher health-related quality of life scores in children who recovered than in children with persistent immune thrombocytopenia (at 3 months: Kids' ITP Tools parent self-report score 80.85 for recovered patients (n=69) versus 58.98 for patients with persistent disease (n=21), P<0.001). No significant differences in health-related quality of life were found between children with mild or moderate bleeding or between children who received intravenous immunoglobulin or children who were carefully observed. In conclusion, health-related quality of life of children with newly diagnosed immune thrombocytopenia is not influenced by treatment modality or bleeding severity, but only by clinical course of the disease. (Dutch Trial Register identifier: NTR TC1563).
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http://dx.doi.org/10.3324/haematol.2014.106963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562543PMC
September 2014