Children had increased risks of impaired motor and visual-motor skills after prenatal exposure to opioid maintenance therapy.

AIM: Preschool children prenatally exposed to opioid maintenance therapy (OMT) have an increased risk of neurodevelopmental impairments. We aimed to investigate long-term motor and visual-motor integration outcome in children aged 5-13 Years, born to mothers in OMT. METHODS: From January 2018 to June 2021, 63 children prenatally exposed to OMT and 63 comparison children matched for age and gender, were examined at two Norwegian hospitals. Motor skills were assessed by the Movement-ABC test and visual-motor integration by the Beery VMI test. A motor function neurological assessment test was used to examine neuromotor soft signs. RESULTS: In the OMT-exposed group, 16% had motor impairment, 35% had motor problems and 19% had visual-motor integration problems. Forty-three percent of the exposed children had neuromotor soft signs. Strabismus had some influence on motor and visual-motor outcomes but could not explain the group differences. CONCLUSION: Children prenatally exposed to opioid maintenance therapy have an increased risk of long-term motor impairment and visual-motor problems. In addition, they exhibit significantly more neuromotor soft signs, which may affect general well-being, leisure activities and school performance.

Temperature-dependent autoactivation associated with clinical variability of PDGFRB Asn666 substitutions.

Ocular pterygium-digital keloid dysplasia (OPDKD) presents in childhood with ingrowth of vascularized connective tissue on the cornea leading to severely reduced vision. Later the patients develop keloids on digits but are otherwise healthy. The overgrowth in OPDKD affects body parts that typically have lower temperature than 37°C. We present evidence that OPDKD is associated with a temperature sensitive, activating substitution, p.(Asn666Tyr), in PDGFRB. Phosphorylation levels of PDGFRB and downstream targets were higher in OPDKD fibroblasts at 37°C but were further greatly increased at the average corneal temperature of 32°C. This suggests that the substitution cause significant constitutive autoactivation mainly at lower temperature. In contrast, a different substitution in the same codon, p.(Asn666Ser), is associated with Penttinen type of premature aging syndrome. This devastating condition is characterized by widespread tissue degeneration, including pronounced chronic ulcers and osteolytic resorption in distal limbs. In Penttinen syndrome fibroblasts, equal and high levels of phosphorylated PDGFRB was present at both 32°C and 37°C. This indicates that this substitution causes severe constitutive autoactivation of PDGFRB regardless of temperature. In line with this, most downstream targets were not affected by lower temperature. However, STAT1, important for tissue wasting, did show further increased phosphorylation at 32°C. Temperature-dependent autoactivation offers an explanation to the strikingly different clinical outcomes of substitutions in the Asn666 codon of PDGFRB.

Norwegian paediatric habilitation centres judge their own competence on cerebral visual impairment as limited.

AIM: Cerebral visual impairment (CVI), a frequently occurring functional impairment in children with neurodevelopmental disorders, leads to communicative, social and academic challenges. In Norway, children with neurodevelopmental disorders are assessed at paediatric habilitation centres. Our aims were to explore how CVI is identified, how paediatric habilitation centres assess their CVI competence and the reported prevalence of CVI among children with cerebral palsy. METHODS: An electronic questionnaire was sent to all 19 Norwegian paediatric habilitation centre leaders in January 2022. The results were analysed quantitatively and qualitatively. The prevalence of CVI among children with cerebral palsy was estimated using register-based data. RESULTS: The questionnaire was answered by 17. Only three judged their habilitation centre as having sufficient competence on CVI. None of the centres used screening questionnaires systematically, and 11 reported that CVI assessment was not good enough. Awareness that a child may have CVI typically occurred during examinations for other diagnoses. The prevalence of CVI among children with cerebral palsy was only 8%, while CVI status was unknown in 33%. CONCLUSION: Better knowledge and assessment of CVI at Norwegian paediatric habilitation centres are needed. CVI appears to be often overlooked in children with neurodevelopmental disorders.

Placental histology predicted adverse outcomes in extremely premature neonates in Norway-population-based study.

AIM: We evaluated the role of placental pathology in predicting adverse outcomes for neonates born extremely preterm (EPT) before 28 weeks of gestation. METHODS: This was a prospective observational study of 123 extremely preterm singletons born in a hospital in western Norway, and the placentas were classified according to the Amsterdam criteria. The associations between histologic chorioamnionitis (HCA), by the presence or the absence of a foetal inflammatory response (FIR+ or FIR-), maternal vascular malperfusion (MVM) as a whole and adverse neonatal outcomes were evaluated by logistic regression analyses. Adverse outcomes were defined as perinatal death, necrotising enterocolitis (NEC), bronchopulmonary dysplasia (BPD), brain pathology by magnetic resonance imaging at term-equivalent age, retinopathy of prematurity and early-onset neonatal sepsis. The results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: HCA was associated with NEC (OR 12.2, 95% CI 1.1 to 137.1). HCA/FIR+ was associated with BPD (OR 14.9, 95% CI 1.8-122.3) and brain pathology (OR 9.8, 95% CI 1.4-71.6), but HCA/FIR- was not. The only neonatal outcome that MVM was associated with was low birthweight. CONCLUSION: Placental histology provided important information when assessing the risk of adverse neonatal outcomes following EPT birth.

Short-term effects on ocular variables immediately after hyperbaric oxygen exposures.

PURPOSE: To determine ocular refraction, corneal thickness, corneal radius, corneal power, corneal astigmatism and intraocular pressure in patients before and immediately after repeated hyperbaric oxygen (HBO2) exposures twice a week during six weeks of HBO2 therapy. METHODS: 23 patients received HBO2 therapy at 2.4 ATA for 90 minutes daily in monoplace chambers for six weeks, five days a week. The Topcon TRK-1P instrument was installed next to the hyperbaric chambers to record the ocular measurements. RESULTS: A gross myopic shift developed at -0.95 ± 0.54 D (P ⟨ 0.001) in the right eye and -0.95 ± 0.53 D (P ⟨ 0.001) in the left eye during the six weeks of treatment. Myopic shift reversion, corneal thinning and reduced intraocular pressure appeared as immediate effects after a single HBO2 exposure, but resolved before the patients attended for the next measurement visit. CONCLUSIONS: Ocular variables were influenced by both cumulative and transient short-term effects during the HBO2 therapy. The short-term effects showed that the point of time for performing the ocular measurements after HBO2 exposure might influence the result and must be considered before making relevant comparisons among studies.

Visual impairment in children and adolescents in Norway. / Nedsatt syn hos barn og unge i Norge.

BACKGROUND Due to failures in reporting and poor data security, the Norwegian Registry of Blindness was closed down in 1995. Since that time, no registration of visual impairment has taken place in Norway. All the other Nordic countries have registries for children and adolescents with visual impairment. The purpose of this study was to survey visual impairments and their causes in children and adolescents, and to assess the need for an ophthalmic registry.MATERIAL AND METHOD Data were collected via the county teaching centres for the visually impaired in the period from 2005 - 2010 on children and adolescents aged less than 20 years with impaired vision (n = 628). This was conducted as a point prevalence study as of 1 January 2004. Visual function, ophthalmological diagnosis, systemic diagnosis and additional functional impairments were recorded.RESULTS Approximately two-thirds of children and adolescents with visual impairment had reduced vision, while one-third were blind. The three largest diagnostic groups were neuro-ophthalmic diseases (37 %), retinal diseases (19 %) and conditions affecting the eyeball in general (14 %). The prevalence of additional functional impairments was high, at 53 %, most often in the form of motor problems or cognitive impairments.INTERPRETATION The results of the study correspond well with similar investigations in the other Nordic countries. Our study shows that the registries associated with teaching for the visually impaired are inadequate in terms of medical data, and this underlines the need for an ophthalmic registry of children and adolescents with visual impairment.

Myopic Shift during Hyperbaric Oxygenation Attributed to Lens Index Changes.

PURPOSE: To examine ocular lens parameters and structural changes to elucidate mechanisms underlying the myopic shift and cataract-related changes that occur in some patients during hyperbaric oxygen (HBO) therapy. METHODS: Scheimpflug images (Nidek EAS-1000) of the crystalline lens, measurements of scattered light, objective refraction, keratometry, tonometry, and axial length of the eye were obtained after the first day of HBO therapy and repeated when patients had completed 19 days of the treatment. RESULTS: Significant reduction in mean (± SD) optical density was found in the lens nucleus, -2.8 (± 4.3) units (p = 0.009) and -2.2 (± 4.1) units (p = 0.027) within circular and oval areas, respectively. Significant decrease in mean (± SD) backward scattered light was measured, -0.4 (± 0.8) units (p = 0.022). Mean (± SD) myopic shift was -0.58 (± 0.39) diopters (p < 0.001), whereas cortical optical density, forward scattered light, lenticular parameters, keratometry, tonometry, anterior chamber depth, and axial length of the eye appeared unchanged. CONCLUSIONS: Transient myopic shift reported in patients during HBO therapy is attributed to changes in the refractive index of the lens. No changes in lens curvatures or thickness were found after treatment.

Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19.

A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy. Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis. WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport. We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis. Our results suggest that isolated nephronophthisis, Jeune, and Sensenbrenner syndromes are clinically overlapping disorders that can result from a similar molecular cause.

Ocular pterygium--digital keloid dysplasia.

We describe an adolescent Peruvian male with marked, aggressive ingrowth of conjunctiva (pterygium-like) over the cornea associated with keloid formation on his distal limbs. He has in addition camptodactyly of all fingers and to some extent of his toes, and unusual skin pigmentations. He resembles an earlier described family from Norway in which a mother and two children showed a similar combination of signs. We present the follow-up of the Norwegian family. The entity resembles the Penttinen syndrome but can be differentiated due to the early aging in the latter, which is lacking in the presently reported entity. We suggest naming this entity ocular pterygium-digital keloid dysplasia. The condition follows likely an autosomal dominant pattern of inheritance.

Posterior segment changes of the eye during hyperbaric oxygen therapy.

PURPOSE: To examine central retinal thickness, retinal and vitreo-retinal structures, and ocular blood flow during a standard protocol of hyperbaric oxygen (HBO2) therapy. METHODS: Retinal thickness and color scans of the vitreo-retinal structures were obtained before and after 19 days of HBO2 therapy in 15 patients by optical coherence tomography (OCT). Pulsatile ocular blood flow was measured by ocular blood flow tonometry. Ocular refraction and axial length of the eye were monitored for control. RESULTS: Significant reduction was found in mean retinal thickness, -1.7 ± 1.6 µm (range -3.9 to 1.1 µm) (p < 0.001) in nine subfields within the 6-mm-diameter circle around the central macula. An insignificant decrease in pulsatile ocular blood flow of -19.0 ± 148.8 µl/minute was measured. No morphological changes were seen in retinal and vitreo-retinal structures. A mean myopic shift of -0.62 ± 0.39 D (p < 0.001) developed while axial length of the eye remained unchanged. CONCLUSIONS: A small decrease in central retinal thickness was seen during the study period, but the changes were not correlated to the myopic shift. No significant changes in vitreo-retinal structures or ocular pulsatile blood flow occurred.

Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia.

Mutations in the gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase (PDE6C) have been recently reported in patients with autosomal recessive inherited achromatopsia (ACHM) and early-onset cone photoreceptor dysfunction. Here we present the results of a comprehensive study on PDE6C mutations including the mutation spectrum, its prevalence in a large cohort of ACHM/cone dysfunction patients, the clinical phenotype and the functional characterization of mutant PDE6C proteins. Twelve affected patients from seven independent families segregating PDE6C mutations were identified in our total patient cohort of 492 independent families. Eleven different PDE6C mutations were found including two nonsense mutations, three mutations affecting transcript splicing as shown by minigene assays, one 1 bp-insertion and five missense mutations. We also performed a detailed functional characterization of six missense mutations applying the baculovirus system to express recombinant mutant and wildtype chimeric PDE6C/PDE5 proteins in Sf9 insect cells. Purified proteins were analyzed using Western blotting, phosphodiesterase (PDE) activity measurements as well as inhibition assays by zaprinast and Pγ. Four of the six PDE6C missense mutations led to baseline PDE activities and most likely represent functional null alleles. For two mutations, p.E790K and p.Y323N, we observed reduction in PDE activity of approximately 60% and 80%, respectively. We also observed differences for Pγ inhibition. The p.E790K mutant, with an IC50 value of 2.7 nm is 20.7-fold more sensitive for Pγ inhibition, whereas the p.Y323N mutant with an IC50 of 158 nm is 3-fold less sensitive when compared with the wildtype control.

Visual function in Norwegian children aged 5-13 years with prenatal exposure to opioid maintenance therapy: A case-control study.

PURPOSE: To assess various aspects of visual function in school children prenatally exposed to opioid maintenance therapy (OMT) and to explore possible outcome differences between prenatal methadone and buprenorphine exposure. METHODS: In a cross-sectional case-control study, 63 children aged 5-13 years with prenatal OMT exposure were compared with 63 age- and gender-matched, non-exposed controls regarding important visual parameters, such as visual acuity, orthoptic status, refractive state, colour vision, and visual field. RESULTS: The OMT-exposed children had significantly poorer visual acuity, both for the best eye, the worst eye and binocularly. Two children had mild visual impairment. Manifest strabismus was more frequent in the OMT group, 30%, vs. 4.8% in the control group. The most frequent types of strabismus were accommodative esotropia and intermittent exotropia. Manifest nystagmus was present in 10 (16%) of the exposed children compared to one among the non-exposed children. The accommodative amplitude was decreased in the OMT group compared to the controls. After adjusting for polydrug exposure and SGA (small-for-gestational-age), the between-group differences in visual acuity, strabismus, and nystagmus remained. The methadone-exposed children had poorer visual acuity, increased frequency of strabismus and a higher percentage of nystagmus, hypermetropia and astigmatism compared to the buprenorphine-exposed children. CONCLUSIONS: School-age children exposed to methadone or buprenorphine in utero had a higher prevalence of strabismus and nystagmus, and a lower visual acuity and accommodation amplitude. Buprenorphine exposure was associated with more favourable results than methadone exposure on most visual outcome measures and should be the preferred substance in OMT.

Bag-in-the-lens intraocular lens in paediatric cataract surgery: intraoperative and postoperative outcomes.

PURPOSE: To report intra- and postoperative surgical outcome using the bag-in-the-lens (BIL) technique in paediatric cataract surgery. METHODS: In a retrospective case series, we studied the outcomes of children aged <12 years operated for cataract with the bag-in-the-lens intraocular lens (IOL), with a minimum of 6 months of follow-up. RESULTS: Since 2013, 50 eyes in 30 patients <12 years (20 bilateral and 10 unilateral) have been operated at our department with the BIL technique, with a median follow-up time of 33.5 months (range 6-77). Median age at surgery was 49.5 months (4-139). In one case, the IOL luxated through the capsulorhexes to the vitreous, but could be secured and repositioned as planned without further difficulties. Anterior vitrectomy was necessary in one case due to prolapse of vitreous to the anterior chamber during surgery. No other intraoperative complications occurred. Visual axis opacification (VAO) developed in four eyes (8%). So far, only one of these has needed a reoperation with clearing of the secondary cataract. A complete absence of VAO was thus seen throughout the study period in 92%. In two eyes, postoperative iris capture occurred. In both cases, surgical repositioning of the iris was needed. No eyes developed secondary glaucoma during the study period. CONCLUSION: The BIL technique seems to be a safe surgical procedure in paediatric cataract, with significantly less complications and need for additional surgery compared with the conventional lens-in-the-bag technique.

Phakic and pseudophakic eyes in patients during hyperbaric oxygen therapy.

PURPOSE: To examine the optical components of phakic and pseudophakic eyes during hyperbaric oxygen (HBO) therapy, and to quantify their relative impact on ocular refractive changes. METHODS: HBO therapy was given to 16 phakic and six pseudophakic patients for 90 min daily at a pressure of 240 kPa, 5 d a week for 20 days. An eye examination was performed on the first day of HBO therapy and repeated when the patients had completed 19 days of the treatment. Refractive error, best-corrected visual acuity, corneal power, radius, thickness and volume, anterior chamber depth, axial length, lens opacity, and intraocular pressure were measured in all patients. Serum glucose, glycosylated hemoglobin, serum electrolytes, and protein were measured in the phakic patients. RESULTS: In the phakic group, a significant myopic shift (≥ -0.50 D) occurred in 26 (81%) single eyes during the treatment. The median myopic shift was -0.63 D (min -0.25 D/max -1.88 D) in the OD, and -0.69 D (min -0.38 D/max -2.25 D) in the OS. No myopic shift appeared in the pseudophakic patients; the median refractive changes were +0.06 D (min -0.13 D/max +0.25 D) in the OD and +0.13 D (min 0.00 D/max +0.25 D) in the OS. Intraocular pressure, serum electrolytes, glucose, and glycosylated hemoglobin remained unchanged. CONCLUSIONS: Myopic shifts occurred in phakic but not in pseudophakic eyes during HBO therapy. The myopic shifts must be attributed to changes in the crystalline lens.

A standardized recession of the inferior oblique extraocular muscle - a safe and self-grading surgical procedure for trochlear nerve palsy: a 10-year material.

PURPOSE: To evaluate the results of surgical treatment in a large group of patients with trochlear nerve palsy, with emphasis on the self-grading effect of a standardized recession of the ipsilateral inferior oblique muscle. METHODS: All patients who underwent first-time surgery for trochlear nerve palsy in the period 2005-2014 in our department (n = 114) were retrospectively evaluated regarding pre- and postoperative data, surgical procedure, and the need for reoperations. Mean follow-up time was 8.5 ± 13.8 months. RESULTS: Among the 114 patients, 73 (64.0%) had a congenital palsy, 31 (27.2%) an acquired palsy, while in 10 cases (8.8%) the type of palsy was uncertain. A standardized recession of the ipsilateral inferior oblique muscle with reattachment at the lateral border of the inferior rectus muscle was carried out in 97.3% of the congenital palsies and in 80.5% of the acquired/uncertain group. In the total patient material, further surgery was needed in 15.8%. Among the patients who underwent a single standardized recession of the inferior oblique muscle, a significant correlation between preoperative vertical angle of deviation and the postoperative change in deviation was demonstrated (correlation coefficient -0.70, p < 0.001), confirming the self-grading nature of this procedure. Subjectively, 97.1% in the congenital and 91.4% in the acquired/uncertain group reported complete/near complete resolution or significant improvement of their symptoms at the final control examination. CONCLUSION: In the majority of patients with trochlear nerve palsy, a favourable outcome may be achieved after a single, standardized recession of the ipsilateral inferior oblique muscle.

Cerebral Functional Magnetic Resonance Imaging and Multifocal Visual Evoked Potentials in a Patient with Unexplained Impairment of Visual Function: A Case Report.

We present a case of a young female with a slowly progressing visual impairment who was examined with multifocal visual evoked potentials and functional magnetic resonance imaging (fMRI) for underlying neuronal abnormality. The fMRI examination consisted of presenting black-and-white checkerboard stimuli, and her activation patterns were compared to the patterns from 4 normal-sighted subjects. The results showed clear differences in neuronal activation between the patient and the controls in the occipital and parietal lobes. Although we have shown neuronal correlates in a case of unexplained visual loss, it is still an open question as to whether this has an organic or functional cause, which should be the subject for future research.