Treatment evaluation by volumetric segmentation in pediatric optic pathway glioma: evaluation of the effect of bevacizumab on intra-tumor components.

PURPOSE: Progressive pediatric optic pathway gliomas (OPGs) are treated by diverse systemic antitumor modalities. Refined insights on the course of intra-tumoral components are limited. METHODS: We performed an exploratory study on the longitudinal volumetric course of different (intra-)tumor components by manual segmentation of MRI at the start and after 3, 6 and 12 months of bevacizumab (BVZ) treatment. RESULTS: Thirty-one patients were treated with BVZ (median 12 months, range: 2-39 months). During treatment the total tumor volume decreased with median 19.9% (range: - 62.3 to + 29.7%; n = 30) within the first 3 months, decreased 19.0% (range: - 68.8 to + 96.1%; n = 28) between start and 6 months and 27.2% (range: -73.4 to + 36.0%; n = 21) between start and 12 months. Intra-tumoral cysts were present in 12 OPGs, all showed a decrease of volume during treatment. The relative contrast enhanced volume of NF1 associated OPG (n = 11) showed an significant reduction compared to OPG with a KIAA1549-BRAF fusion (p < 0.01). Three OPGs progressed during treatment, but were not preceded by an increase of relative contrast enhancement. CONCLUSION: Treatment with BVZ of progressive pediatric OPGs leads to a decrease of both total tumor volume and cystic volume for the majority of OPGs with emphasis on the first three months. NF1 and KIAA1549-BRAF fusion related OPGs showed a different (early) treatment effect regarding the tumor enhancing component on MRI, which did not correlate with tumor volume changes. Future research is necessary to further evaluate these findings and its relevance to clinical outcome parameters.

Tocilizumab for the fifth progression of cystic childhood craniopharyngioma-a case report.

We present the case of a 15-year-old girl, with a fifth cystic progression of an adamantinomatous craniopharyngioma after multiple surgeries and previous local radiotherapy. She had severe visual impairment, panhypopituitarism including diabetes insipidus, and several components of hypothalamic damage, including morbid obesity and severe fatigue. To prevent further late effects hampering her quality of survival, she was treated biweekly with intravenous tocilizumab, an anti-interleukin-6 agent, which stabilized the cyst for a prolonged time. Based on the biology of adamantinomatous craniopharyngioma, this immune-modulating treatment seems promising for the treatment of this cystic tumor in order to reduce surgery and delay or omit radiotherapy.

Diagnostic accuracy of retinal optical coherence tomography in children with a newly diagnosed brain tumour.

PURPOSE: To estimate the diagnostic accuracy of circumpapillary retinal nerve fibre layer (RNFL) thickness and macular ganglion cell layer-inner plexiform layer (GCL-IPL) thickness measurements to discriminate an abnormal visual function (i.e. abnormal age-based visual acuity and/or visual field defect) in children with a newly diagnosed brain tumour. METHODS: This cross-sectional analysis of a prospective longitudinal nationwide cohort study was conducted at four hospitals in the Netherlands, including the national referral centre for paediatric oncology. Patients aged 0-18 years with a newly diagnosed brain tumour and reliable visual acuity and/or visual field examination and optical coherence tomography were included. Diagnostic accuracy was evaluated with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Of 115 patients included in the study (67 [58.3%] male; median age 10.6 years [range, 0.2-17.8 years]), reliable RNFL thickness and GCL-IPL thickness measurements were available in 92 patients (80.0%) and 84 patients (73.0%), respectively. The sensitivity for detecting an abnormal visual function was 74.5% for average RNFL thickness and 41.7% for average GCL-IPL thickness at a specificity of 44.5% and 82.9%, respectively. The PPV and NPV were 33.0% and 82.6% for the average RNFL thickness and 57.1% and 82.2% for the average GCL-IPL thickness. CONCLUSION: An abnormal visual function was discriminated correctly by using the average RNFL thickness in seven out of ten patients and by using the average GCL-IPL thickness in four out of ten patients. The relatively high NPVs signified that patients with normal average RNFL thickness and average GCL-IPL thickness measurements had a relative high certainty of a normal visual function.

Impact of Bevacizumab on Visual Function, Tumor Size, and Toxicity in Pediatric Progressive Optic Pathway Glioma: A Retrospective Nationwide Multicentre Study.

BACKGROUNDS: Bevacizumab (BVZ) is used as a subsequent line of treatment for pediatric optic pathway glioma (OPG) in the case of progression. Data on the treatment effect concerning tumor progression and visual function are scarce and nationwide studies are lacking. METHODS: We performed a retrospective, nationwide, multicentre cohort study including all pediatric patients with OPG treated with BVZ in the Netherlands (2009-2021). Progression-free survival, change in visual acuity and visual field, MRI-based radiologic response, and toxicity were evaluated. RESULTS: In total, 33 pediatric patients with OPG were treated with BVZ (median 12 months). Visual acuity improved in 20.5%, remained stable in 74.4%, and decreased in 5.1% of 39 of all analysed eyes. The monocular visual field improved in 73.1%, remained stable in 15.4%, and decreased in 7.7% of 25 analysed eyes. Radiologic response at the end of therapy showed a partial response in 7 patients (21.9%), minor response in 7 (21.9%), stable disease in 15 (46.9%), and progressive disease in 3 (9.3%). Progression-free survival at 18 and 36 months after the start of BVZ reduced from 70.9% to 38.0%. Toxicity (≥grade 3 CTCAE) during treatment was observed in five patients (15.2%). CONCLUSION: Treatment of BVZ in pediatric patients with OPG revealed stabilisation in the majority of patients, but was followed by progression at a later time point in more than 60% of patients. This profile seems relatively acceptable given the benefits of visual field improvement in more than 70% of analysed eyes and visual acuity improvement in more than 20% of eyes at the cessation of BVZ.

Ophthalmological Findings in Youths With a Newly Diagnosed Brain Tumor.

Importance: Visual impairment is an irreversible adverse effect in individuals who experienced a childhood brain tumor. Ophthalmological evaluation at diagnosis enables early detection of vision loss, decision-making about treatment, and when applicable, the timely use of visual interventions. However, awareness of visual impairment in clinical practice is suboptimal, and adherence to ophthalmological evaluation needs to be improved. Objective: To assess the prevalence and types of abnormal ophthalmological findings in youths with a newly diagnosed brain tumor. Design, Setting, and Participants: In this nationwide, prospective cohort study, youths aged 0 to 18 years with a newly diagnosed brain tumor between May 15, 2019, and August 11, 2021, were consecutively enrolled in 4 hospitals in the Netherlands, including the dedicated tertiary referral center for pediatric oncology care. Exposures: A standardized and comprehensive ophthalmological examination, including orthoptic evaluation, visual acuity testing, visual field examination, and ophthalmoscopy, was performed within 4 weeks from brain tumor diagnosis. Main Outcomes and Measures: The main outcomes were prevalence and types of visual symptoms and abnormal ophthalmological findings at brain tumor diagnosis. Results: Of 170 youths included in the study (96 [56.5%] male; median age, 8.3 years [range, 0.2-17.8 years]), 82 (48.2%) had infratentorial tumors; 53 (31.2%), supratentorial midline tumors; and 35 (20.6%), cerebral hemisphere tumors. A total of 161 patients (94.7%) underwent orthoptic evaluation (67 [41.6%] preoperatively; 94 [58.4%] postoperatively); 152 (89.4%), visual acuity testing (63 [41.4%] preoperatively; 89 [58.6%] postoperatively); 121 (71.2%), visual field examination (49 [40.4%] preoperatively; 72 [59.6%] postoperatively); and 164 (96.5%), ophthalmoscopy (82 [50.0%] preoperatively; 82 [50.0%] postoperatively). Overall, 101 youths (59.4%) presented with visual symptoms at diagnosis. Abnormal findings were found in 134 patients (78.8%) during ophthalmological examination. The most common abnormal findings were papilledema in 86 of 164 patients (52.4%) who underwent ophthalmoscopy, gaze deficits in 54 of 161 (33.5%) who underwent orthoptic evaluation, visual field defects in 32 of 114 (28.1%) with reliable visual field examination, nystagmus in 40 (24.8%) and strabismus in 32 (19.9%) of 161 who underwent orthoptic evaluation, and decreased visual acuity in 13 of 152 (8.6%) with reliable visual acuity testing. Forty-five of 69 youths (65.2%) without visual symptoms at diagnosis had ophthalmological abnormalities on examination. Conclusions and Relevance: The results of this study suggest that there is a high prevalence of abnormal ophthalmological findings in youths at brain tumor diagnosis regardless of the presence of visual symptoms. These findings support the need of standardized ophthalmological examination and the awareness of ophthalmologists and referring oncologists, neurologists, and neurosurgeons for ophthalmological abnormalities in this patient group.

Impact of systemic anticancer therapy in pediatric optic pathway glioma on visual function: A systematic review.

Pediatric optic pathway glioma (OPG) can seriously decrease visual function in the case of progression. Systemic anticancer therapy (SAT) is considered the treatment of first choice for unresectable OPG. New SAT modalities for the treatment of progressive OPG have been introduced in the last decade, including VEGF and MAPK pathway inhibition. This systematic review evaluated the effect of SAT on change in visual acuity and visual field in OPG. A systematic review was performed on SAT for OPG (January 1990 to August 2020). MEDLINE and EMBASE (Ovid) were searched for studies reporting on change in visual acuity and visual field after treatment with SAT for OPG. Overall, 11 series, including 358 patients, fulfilled the eligibility criteria. After follow-up of median 3.7 years (range: cessation of SAT- 8.2 years), improvement in binocular VA was found in 0-45% of studies, stability in 18-77% and a decrease in 0-82%. Two studies reported on change in visual field (improvement in 19% and 71% of patients), although either the change was not defined or the testing strategy was lacking. Considerable heterogeneity was present among the included studies, such as variety in the combinations of SAT administered, status of neurofibromatosis type 1, definition regarding change in visual acuity, 1- or 2-eye analysis, diversity in anatomic location, and extent of follow-up, all of which made meta-analysis inappropriate. This systematic review suggests that the impact of SAT in OPG on visual function is still unclear. The wide ranges reported on the efficacy of SAT and the observed heterogeneity highlight the need for prospective studies with uniform definitions of outcome parameters.

Optical coherence tomography to measure the progression of myelopathy in adrenoleukodystrophy.

OBJECTIVE: To prospectively determine the value of optical coherence tomography (OCT) as a surrogate outcome measure for the progression of myelopathy in males with adrenoleukodystrophy. METHODS: Retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness were measured at baseline, 1- and 2-year follow-up in patients and age-matched controls. We assessed the severity of myelopathy with clinical parameters: Expanded Disability Status Scale (EDSS), Severity Scoring system for Progressive Myelopathy (SSPROM), and timed up-and-go. Linear mixed model analysis was used to compare changes in retinal layer thickness of patients to controls. In addition, we correlated changes in retinal layer thickness with changes in clinical parameters. RESULTS: Longitudinal data were available for 28 patients and 29 controls. Peripapillary RNFL (pRNFL) thickness decreased significantly in patients compared to controls (-1.75µm, p = 0.001), whereas change in macular GCL and RNFL was not different between groups. Analysis of the symptomatic subgroup showed that, apart from a similar decrease in pRNFL thickness, GCL thickness decreased significantly (-0.55 µm, p = 0.014). There were moderately strong correlations between changes in retinal layer thickness and changes in clinical parameters of severity of myelopathy. INTERPRETATION: This prospective study demonstrates the potential of OCT-measured retinal neurodegeneration as a surrogate outcome measure for the progression of myelopathy in adrenoleukodystrophy. As differences were small, our findings need to be confirmed with longer follow-up and/or in a larger patient sample.

Increase in treatment of retinopathy of prematurity in the Netherlands from 2010 to 2017.

PURPOSE: Compare patients treated for Retinopathy of Prematurity (ROP) in two consecutive periods. METHODS: Retrospective inventory of anonymized neonatal and ophthalmological data of all patients treated for ROP from 2010 to 2017 in the Netherlands, subdivided in period (P)1: 1-1-2010 to 31-3-2013 and P2: 1-4-2013 to 31-12-2016. Treatment characteristics, adherence to early treatment for ROP (ETROP) criteria, outcome of treatment and changes in neonatal parameters and policy of care were compared. RESULTS: Overall 196 infants were included, 57 infants (113 eyes) in P1 and 139 (275 eyes) in P2, indicating a 2.1-fold increase in ROP treatment. No differences were found in mean gestational age (GA) (25.9 ± 1.7 versus 26.0 ± 1.7 weeks, p = 0.711), mean birth weight (791 ± 311 versus 764 ± 204 grams, p = 0.967) and other neonatal risk factors for ROP. In P2, the number of premature infants born <25 weeks increased by factor 1.23 and higher oxygen saturation levels were aimed at in most centres. At treatment decision, 59.6% (P1) versus 83.5% (P2) (p = 0.263) infants were classified as Type 1 ROP (ETROP classification). Infants were treated with laser photocoagulation (98 versus 96%) and intravitreal bevacizumab (2 versus 4%). Retreatment was necessary in 10 versus 21 (p = 0.160). Retinal detachment developed in 6 versus 13 infants (p = 0.791) of which 2 versus 6 bilateral (p = 0.599). CONCLUSION: In period 2, the number of infants treated according to the ETROP criteria (Type 1) increased, the number of ROP treatments, retinal detachments and retreatments doubled and the absolute number of retinal detachments increased. Neonatal data did not provide a decisive explanation, although changes in neonatal policy were reported.

Correction to: Optical coherence tomography shows neuroretinal thinning in myelopathy of adrenoleukodystrophy.

The original version of this article unfortunately contained a mistake.

Optical coherence tomography shows neuroretinal thinning in myelopathy of adrenoleukodystrophy.

BACKGROUND: Progressive myelopathy is the main cause of disability in adrenoleukodystrophy (ALD). Development of therapies is hampered by a lack of quantitative outcome measures. In this study, we investigated whether myelopathy in ALD is associated with retinal neurodegeneration on optical coherence tomography (OCT), which could serve as a surrogate outcome measure. METHODS: Sixty-two patients (29 men and 33 women) and 70 age-matched and sex-matched controls (33 men and 37 women) were included in this cross-sectional study. We compared retinal nerve fiber layer (RNFL), ganglion cell layer (GCL) and peripapillary retinal nerve fiber layer (pRNFL) thickness between ALD patients and controls. In addition, we correlated these OCT measurements with clinical parameters of severity of myelopathy. RESULTS: Patients had significantly thinner RNFL (male group, p < 0.05) and pRNFL superior and temporal quadrant [both male (p < 0.005) and female (p < 0.05) groups] compared to controls. Comparing three groups (symptomatic patients, asymptomatic patients and controls), there were significant differences in RNFL thickness (total grid and peripheral ring) in the male group (p ≤ 0.002) and in pRNFL thickness (superior and temporal quadrant) in both male (p ≤ 0.02) and the female (p ≤ 0.02) groups. Neuroretinal layer thickness correlated moderately with severity of myelopathy in men (correlation coefficients between 0.29-0.55, p < 0.02), but not in women. CONCLUSIONS: These results suggest that neurodegeneration of the spinal cord in ALD is reflected in the retina of patients with ALD. Therefore, OCT could be valuable as an outcome measure for the myelopathy of ALD. Additional longitudinal studies are ongoing.

A prospective multicentre randomized placebo-controlled superiority trial in patients with suspected bacterial endophthalmitis after cataract surgery on the adjuvant use of intravitreal dexamethasone to intravitreal antibiotics.

PURPOSE: We aimed to determine whether intravitreal dexamethasone as an adjuvant to intravitreal antibiotics is beneficial in the treatment of suspected bacterial endophthalmitis after cataract surgery. METHODS: Randomized, placebo-controlled superiority trial in three tertiary referral centres in the Netherlands. Patients with suspected bacterial endophthalmitis within 6 weeks after cataract surgery were eligible. A diagnostic vitreous biopsy was taken for culture, and patients received intravitreal injections of 400 µg dexamethasone (without preservatives) or placebo, in addition to 0.2 mg vancomycin and 0.05 mg gentamicin. The vancomycin and dexamethasone or placebo injections were repeated once at day 3 or 4. Primary outcome measure was best-corrected visual acuity (BCVA) at 1 year. RESULTS: Between 1 November 2004 and 1 March 2014 (excluding two interruptions totalling 20 months), 324 eligible patients presented. A total of 167 patients (81 dexamethasone, 86 placebo) were available for the intention-to-treat analysis. Biopsies of 114 patients (68%) were culture-positive. Final BCVA did not differ between the dexamethasone and the placebo group (logMAR 0.31 ± 0.58 versus 0.27 ± 0.50; p = 0.90), nor did the number of patients with final vision of no light perception (LP, 7 versus 13). Pain, corneal oedema, the absence of a red fundus reflex on presentation, LP on presentation and culture of virulent pathogens from biopsy were statistically significantly associated with an unfavourable visual outcome. CONCLUSION: Intravitreal dexamethasone without preservatives as an adjuvant to intravitreal antibiotics does not improve visual acuity (VA) in patients treated for suspected bacterial endophthalmitis after cataract surgery.

A novel mutation of laminin ß2 (LAMB2) in two siblings with renal failure.

This report describes a novel mutation of LAMB2, the gene associated with Pierson syndrome (microcoria-congenital nephrosis syndrome), in two female siblings. The c.970T>C p.(Cys324Arg) mutation in the LAMB2 gene affects one of the eight highly conserved cysteine residues within the first EGF-like module of the laminin ß2 protein. These residues form disulfide bonds in order to achieve a correct 3D structure of the protein. The reported phenotype is considered a relatively mild variant of Pierson syndrome and is associated with later-onset (18 months) therapy-resistant nephrotic syndrome leading to renal failure, and ocular abnormalities consisting of high myopia, microcoria, diverse retinal abnormalities, hence a low level of visual acuity. Importantly, the reported LAMB2 mutation was associated with normal neurological development in both siblings. CONCLUSION: this report presents the variability of the renal, ocular and neurological phenotypes associated with LAMB2 mutations and underscores the importance of ophthalmologic examination in all children with unexplained renal insufficiency or nephrotic syndrome. What is known • LAMB2 mutations are associated with Pierson syndrome • Pierson syndrome is associated with congenital nephrotic syndrome, microcoria and neurological deficits What is new • A novel mutation in the LAMB2 gene in two female siblings • Genotype and clinical phenotype description of a novel LAMB2 mutation.

A prospective multicenter randomized placebo-controlled trial of dexamethasone as an adjuvant in the treatment of postoperative bacterial endophthalmitis: interim safety analysis of the study drug and analysis of overall treatment results.

PURPOSE: In an ongoing prospective multicenter randomised placebo-controlled trial we study the adjuvant use of intravitreal dexamethasone in the treatment of patients with suspected bacterial endophthalmitis after phacoemulsification. In accordance with the study protocol, a mid-inclusion interim analysis of the safety of the study drug was performed. PATIENTS AND METHODS: Patients with suspected endophthalmitis after phacoemulsification were asked to participate in this study. A diagnostic vitreous biopsy was taken and the patients received intravitreal injections of 400 micrograms dexamethasone or a placebo, plus 0.2 mg vancomycin and 0.05 mg gentamicin. Injections were repeated after 3 or 4 days. The safety analysis included: the number of eyes with an evisceration; no light perception; or a visual acuity of less than 5/200. Treatment outcome was evaluated in terms of: the percentage of patients with a visual acuity of 20/40 or more and 20/100 or more. RESULTS: The interim analysis included 81 patients with at least 1 year follow-up. Sixty-three patients (65 %) were culture-positive. Safety analysis: 7 eyes were eviscerated (3 dexamethasone, 4 placebo); 4 eyes had no light perception (2 dexamethasone, 2 placebo); and 4 eyes had less than 5/200 vision (3 dexamethasone, 1 placebo). Treatment outcome: 70 % of patients had a visual acuity of at least 20/40. CONCLUSION: The safety analysis does not warrant premature discontinuation of the study. So far, the overall outcome of our treatment regimen, consisting of merely a diagnostic biopsy instead of a vitrectomy and an optimized antibiotic dosing, compares favourably to published literature.