Recognition of Intracranial Hypertension in Children with Craniosynostosis using Handheld OCT: A Diagnostic Accuracy Study

Recognition of Intracranial Hypertension in Children with Craniosynostosis using Handheld OCT: A Diagnostic Accuracy Study | Research Square Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Recognition of Intracranial Hypertension in Children with Craniosynostosis using Handheld OCT: A Diagnostic Accuracy Study Sohaib R. Rufai, Ravi Purohit, Richard Bowman, Irene Gottlob, and 17 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8977346/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 15 You are reading this latest preprint version Abstract Craniosynostosis is often associated with intracranial hypertension (IH), which can damage the brain and vision if unaddressed. This prospective, multicentre diagnostic accuracy study evaluated the diagnostic accuracy of handheld optical coherence tomography (OCT) in recognising IH in craniosynostosis. Handheld OCT was performed in children with craniosynostosis at the time of gold-standard overnight intracranial pressure (ICP) monitoring. Mixed model regression assessed for associations with ICP. Qualitative OCT signs of IH were raised cup and rim, cup obliteration, anterior displacement of Bruch’s membrane and severe optic atrophy. Primary quantitative OCT measures were disc width, cup width, rim width, and retinal nerve fibre layer (RNFL) thickness (nasal/temporal). Of 37 eligible children, handheld OCT was successful in 36 (97%). Eighteen children (50%) were female. Eleven children (31%) had syndromic craniosynostosis. Median age at examination was 76 months (range: 14–205 months; IQR: 46–105 months). When defining IH as mean ICP ≥ 20mmHg +/- prolonged ICP spikes, qualitative OCT sensitivity was 89% (95% CI: 65–99) and specificity was 63% (95% CI: 38–84). Anterior displacement of Bruch’s membrane delivered 100% specificity for IH. Area under the ROC curve (AUC) was 0.78 (95% CI: 0.67–0.89) for disc width, 0.81 (95% CI: 0.71–0.91;) for rim width, and 0.74 (95% CI: 0.62–0.86;) for nasal RNFL thickness; all three were significantly associated with IH (P < 0.004, P < 0.001 and P = 0.014, respectively). In conclusion, handheld OCT can recognise IH in craniosynostosis, and could improve early intervention and clinical outcomes. Health sciences/Diseases Health sciences/Medical research Health sciences/Neurology Biological sciences/Neuroscience Handheld optical coherence tomography handheld OCT optical coherence tomography OCT intracranial pressure ICP intracranial hypertension papilloedema Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Craniosynostosis is characterised by the premature, pathological fusion of the cranial sutures. Its estimated prevalence is 5.9 per 10,000 live births. 1 Craniosynostosis is commonly associated with raised intracranial pressure (ICP), termed intracranial hypertension (IH), which affects 17–47% of cases depending on subgroup. 2 – 4 IH can damage the brain and vision, and can be fatal if untreated. 5 Craniosynostosis is often associated with neurodevelopmental and cognitive delay. 6 Recognising IH in children with craniosynostosis is challenging. The gold standard test is overnight, invasive ICP monitoring, which involves hospital admission, general anaesthesia and risk of complications, including haemorrhage, infections and mechanical failure. 7 Furthermore, there is no universal consensus over which ICP threshold constitutes IH in craniosynostosis. 8 An ideal surrogate test for IH should be non-invasive, objective, highly sensitive, and child-friendly, such that serial testing can be performed. Existing surrogate tests, including fundoscopy 9 , ocular ultrasound 10 and radiography 11 , deliver inadequate sensitivity to be employed as reliable surveillance tools. Optical coherence tomography (OCT) is a non-invasive imaging modality that achieves ultrahigh resolution, cross-sectional images of the optic nerve and retina, within seconds. OCT can recognise optic nerve changes due to IH in adults. 12 Young children have been largely deprived of OCT technology, as conventional OCT machines are table-mounted and not designed for young children. However, we have found that handheld OCT 13 , 14 and portable OCT 15 devices are feasible in unsedated children with craniosynostosis. Furthermore, we have demonstrated that the optic nerve is morphologically different in craniosynostosis, thus special considerations should be applied when evaluating optic nerve OCT images in this patient population. 16 No study has yet evaluated the diagnostic accuracy of handheld OCT in detecting IH in craniosynostosis, using gold standard overnight ICP monitoring. Here, we conducted a diagnostic accuracy study using handheld OCT as an index test, and gold standard overnight ICP monitoring as the reference standard. We hypothesise that handheld OCT can recognise IH in craniosynostosis with high sensitivity. MATERIALS AND METHODS Study Design and Participants This was a multi-centre, prospective diagnostic accuracy study that took place at Great Ormond Street Hospital for Children (GOSH), London, UK, and the John Radcliffe Hospital, Oxford, UK, conducted according to our published protocol. 17 Patients were recruited between September 3rd 2020 and July 21st 2022. This study adhered to the tenets of the Declaration of Helsinki. Ethical approval was granted by the East Midlands Nottingham 2 Research Ethics committee (UOL0348/IRAS 105137). This study was reported according to the Standards for Reporting Diagnostic Accuracy (STARD) guidelines. 18 Inclusion criteria were as follows: clinical/genetic diagnosis of craniosynostosis, age 0–18 years, overnight ICP bolt monitoring, and handheld/portable OCT imaging acquired at the time of ICP bolt monitoring. At both centres, all patients listed for ICP bolt monitoring were consecutively recruited from the surgical admissions ward. Parents/guardians were provided with a patient information leaflet and had opportunities to ask questions prior to providing informed consent. Participants without an available parent/guardian to provide consent were excluded. OCT image acquisition and analysis This study utilised two handheld spectral-domain OCT devices: the Envisu C2300 handheld OCT (Leica Microsystems, Wetzlar, Germany) and the Spectralis Flex (Heidelberg Engineering, Heidelberg, Germany). The Envisu C2300 and Spectralis Flex deliver 3.3-µm and 3.9-µm axial resolution, respectively. The majority of OCT examinations were performed without sedation, with a minority (n = 5) performed under general anaesthesia immediately prior to ICP bolt insertion, due to logistical reasons. The Envisu C2300 protocol used a 12 mm × 8 mm (approximately 42° × 28°) scanning window with an acquisition time of 1.9 seconds, enabling rapid image acquisition without compromising quality to avoid measurement bias; the three-dimensional raster scan protocol included 80 B-scans, where each B-scan line comprised 600 A-scans. The Spectralis protocol used a 55° × 30° scanning window with a 0.8-second acquisition time, where the 3D raster included 73 B-scans, each with 768 A-scans. Our imaging protocol involved scanning the right eye followed by the left eye. Imaging sessions lasted up to 10 minutes, aiming to acquire bilateral optic nerve head images of sufficient quality, which was defined as a tomogram wherein the disc margins and full cup profile were clearly visualised. Visual fixation devices, such as toys and cartoons on tablets/smartphones, were utilised to minimise movement during OCT imaging. The en-face view was used to identify the optic nerve head, which was navigated frame by frame until the central slice featuring the deepest point of the optic cup was identified for analysis. Figure 1 displays the quantitative OCT measures used in this study. The five primary quantitative measures, determined a priori , were disc width, cup width, rim width, and RNFL thickness (nasal and temporal), encompassing the main anatomical portions of the ONH. All other OCT measures were exploratory, expanding upon the primary measures rather than representing independent measures. Quantitative analysis was performed by the lead investigator (SRR) using ImageJ 1.4815 (National Institutes of Health, Bethesda, MD); 19 the ABSnake plugin 20 enabled semi-automated identification of the internal limiting membrane contour, which was manually corrected where required. Measurements were scaled from Spectralis to Envisu using scale factors published by Folgar et al 21 : lateral scaling, 0.989; axial scaling, 0.975; our recent cross-sectional study 22 demonstrated that OCT measurements are comparable between these two OCT machines in craniosynostosis using these scale factors. Lateral distance measurements were corrected to account for smaller paediatric axial lengths, using age-specific conversions published by Maldonado et al. 23 Fig. 2 displays the qualitative OCT signs used in this study. OCT image analysis was performed at least 6 months after recruitment by the lead investigator (SRR), who was masked to the ICP results at the time of OCT analysis, to avoid confirmation bias. Intracranial pressure measurement Patients underwent hospital admission for gold standard, overnight ICP monitoring using the RAUMEDIC ICP bolt system (RAUMEDIC AG, Helmbrechts, Germany) in both study centres. The ICP bolt system was surgically inserted by consultant neurosurgeons, masked to the OCT findings to avoid confirmation bias. The ICP traces were interpreted in craniofacial multidisciplinary team meetings as per standard procedure, where the teams were masked to OCT findings. As there is no consensus on what constitutes IH in children with craniosynostosis, the following two IH definitions were used, as per our protocol 17 : • Definition 1 • Grand mean ICP ≥ 20 mmHg, or ICP traces with ≥ 2 ICP spikes at least double the baseline ICP and ≥ 20 mm Hg for ≥ 5 min. • Definition 2 • Grand mean ICP ≥ 15 mmHg, or ICP traces with ≥ 2 ICP spikes at least double the baseline ICP and ≥ 15 mm Hg for ≥ 5 min. Statistical analysis Statistical analysis was conducted using SPSS Statistics 22.0. (IBM Corp., Armonk, NY). Demographic data for diagnoses, sex and age were summarised using descriptive statistics. With respect to the quantitative analysis, OCT data were analysed against ICP using linear mixed model regression, including age and eye recorded (right/left) in the model. No adjustment for multiple testing was required as only five primary OCT measures were used, and all exploratory OCT measures expanded upon these. Receiver operating characteristic (ROC) curves were plotted for quantitative OCT measures demonstrating statistically significant association with IH. An available case analysis was conducted for OCT outcome measures, as only a small minority of OCT parameters were missing. With respect to the qualitative analysis, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy (proportion of true test results amongst all evaluated cases) were reported in confusion matrices. Diagnostic accuracy using any positive OCT signs (where at least one sign is present), and presence of any OCT sign except the raised cup and rim sign, were analysed using IH Definitions 1 and 2 . Fisher’s Exact test was employed to determine whether there was significant difference between the OCT and ICP groups. A sample of at least 22 children was required to demonstrate at least 79% sensitivity, representing a 57% improvement in sensitivity compared with 22% reported for fundoscopy by Tuite et al 9 (McNemar’s Z-test: n = 22; power = 80%, α = 0.05). This level of sensitivity would be equal to that demonstrated by maximal RNFL thickness (79%) in a similar study by Swanson et al. 24 RESULTS Baseline characteristics Twenty-four eligible children were recruited from GOSH and 13 recruited from Oxford. Of the total 37 children eligible for inclusion, OCT was successful in 36 children (97%). Seven patients were imaged under general anaesthesia, two patients were napping but unsedated, and the remaining 28 patients were imaged whilst awake. Handheld OCT was technically unsuccessful in one child with sagittal synostosis due to pinpoint pupils and upward eyerolling – this was secondary to opiate administration by the anaesthetist. One child had two ICP monitoring episodes at GOSH 12 months apart, with successful bilateral imaging in both episodes, hence both episodes were included in the analysis to produce a total of 37 cases. Of 37 included cases, the Envisu handheld OCT was used in 21 examinations (57%) and the Spectralis Flex in 16 examinations (43%). There were no adverse events caused by OCT or ICP monitoring. Baseline characteristics Included patients Syndromic craniosynostosis diagnoses, n Apert Crouzon Muenke Noonan Pfeiffer Saethre-Chotzen Sotos Total syndromic 2 1 1 1 2 3 1 11 Non-syndromic craniosynostosis diagnoses, n Sagittal Multisuture Total non-syndromic 16 9 25 Sex, n Male Female 18 18 Age at OCT (months), median (range; IQR) 76 (14-205; 46-105) Table 1: Baseline characteristics Key: IQR = interquartile range; n = number of patients. Of the 36 included children, 18 (50%) were female and 18 (50%) were male. The median age at examination was 76 months (range: 14-205 months; IQR: 46-105 months). Diagnostic accuracy using qualitative signs Confusion matrices (2×2 tables) were used to evaluate diagnostic accuracy for both IH definitions. All 37 cases were included. All confusion matrices with diagnostic accuracy test results for qualitative OCT signs of IH are detailed in Table 2. The STARD patient flowchart is displayed in Supplemental Figure 1. Confusion matrices IH Sensitivity, % (95% CI) Specificity, % (95% CI) PPV, % (95% CI) NPV, % (95% CI) Accuracy, % (95% CI) Present Absent IH Definition 1, any OCT signs 89 (65-99) 63 (38-84) 70 (55-81) 86 (61-96) 76 (59-88) OCT+ 16 7 OCT- 2 12 IH Definition 1, any OCT signs excl. raised rim + cup 67 (41-87) 84 (60-97) 80 (57-92) 73 (57-84) 76 (59-88) OCT+ 12 3 OCT- 6 16 IH Definition 2, any OCT signs 75 (53-90) 62 (32-86) 78 (64-88) 57 (37-75) 70 (53-84) OCT+ 18 5 OCT- 6 8 IH Definition 2, any OCT signs excl. raised rim + cup 58 (37-78) 85 (55-98) 88 (65-96) 52 (39-65) 68 (50-82) OCT+ 14 2 OCT- 10 11 Table 2: Confusion matrices for both IH definitions IH Definition 1: mean ICP ≥20mmHg and/or prolonged ICP spikes. IH Definition 2: mean ICP ≥15mmHg and/or prolonged ICP spikes. Key: CI = confidence interval; excl. = excluding; IH = intracranial hypertension; NPV = negative predictive value; OCT = optical coherence tomography; OCT+ = positive OCT findings; OCT- = negative OCT findings; PPV = positive predictive value. The highest sensitivity and overall accuracy was achieved using any qualitative OCT signs for IH Definition 1, whereby sensitivity for IH was 89%, specificity was 63%, PPV was 70%, NPV was 86% and overall accuracy was 76%. Fisher’s exact test demonstrated significant differences between the OCT groups (positive/negative) and IH groups (present/absent) for IH Definition 1 using any qualitative OCT signs (P=0.002), IH Definition 1 excluding the raised cup and rim sign (P=0.003), IH Definition 2 using any OCT signs (P=0.040) and IH definition 2 excluding raised cup and rim (P=0.017). Supplemental Table 1 displays confusion matrices for individual OCT signs using IH Definition 1; notably, all ten patients demonstrating anterior displacement of Bruch’s membrane had IH, delivering 100% specificity and 100% PPV. With respect to the two patients missed using any OCT signs and IH Definition 1, neither patient had globally raised ICP (i.e. raised day and night), but were categorised as IH due to ICP spikes. One patient had known optic disc drusen and normal ICP using both definitions, causing false positive results for raised cup and rim, and cup obliteration. One patient had a previous history of right central artery occlusion and secondary longstanding right severe optic atrophy, causing a false positive result for severe optic atrophy as the ICP was normal. Diagnostic accuracy using quantitative measures Quantitative OCT analysis was performed using both IH definitions. Using IH Definition 1, IH was significantly associated with increased disc width, nasal RNFL, rim width, all 11 exploratory rim measures, and nasal retinal thickness (p<0.05) as detailed in Supplemental Table 2. Using IH Definition 2, IH was not significantly associated with any of the primary OCT measures, but was statistically significantly associated with temporal rim edge and temporal BMO-MRW (P<0.05). Figure 3 displays receiver operating characteristic (ROC) curves based on IH Definition 1 for the following quantitative OCT parameters: disc width, rim width and nasal RNFL thickness. The qualitative OCT signs delivered a greater combined sensitivity and specificity compared to any of the quantitative measures. Area under the ROC curve (AUC) 0.78 (95% CI: 0.67-0.89) for disc width, 0.81 (95% CI: 0.71-0.91) for rim width, and 0.74 (95% CI: 0.62-0.86) for nasal RNFL thickness. DISCUSSION Main findings Our study has demonstrated that handheld OCT can detect IH in children with craniosynostosis. Using IH Definition 1 (mean ICP ≥ 20mmHg and/or prolonged ICP spikes) and any positive OCT signs, high sensitivity (89%) and reasonable specificity (67%) were delivered. Of the primary OCT measures, greater disc width, rim width and nasal RNFL thickness were significantly associated with IH as per Definition 1 . ROC curve analyses demonstrated that the qualitative OCT signs delivered higher combined sensitivity and specificity than quantitative OCT measurements. This study shed light on particularly useful OCT signs and parameters. Anterior displacement of Bruch’s membrane was a valuable ‘red flag’ sign, delivering 100% specificity and PPV. This suggests that children demonstrating this sign may not require invasive ICP monitoring, and could receive their surgery to reduce ICP sooner, reducing overall treatment burden and potentially improving clinical outcomes. The raised cup and rim sign was the most sensitive of the qualitative OCT signs and may represent an early sign in IH; however, this delivered many false positive results. Serial OCT imaging may help identify early evolving changes in the ONH, improving diagnostic accuracy overall. Post-hoc analysis demonstrated an improved specificity (71%) and PPV (76%) after excluding two rationalised false positive results, using IH Definition 1 . One patient had longstanding drusen causing the appearance of cup obliteration, and another had longstanding severe optic atrophy due to central retinal artery occlusion. Furthermore, Neither of the two ‘false negative’ cases demonstrated globally raised ICP on invasive monitoring, according to IH Definition 1 . Both were classified as IH due to prolonged ICP spikes. Had these patients had longer periods of raised ICP and/or globally raised ICP, they may have demonstrated optic nerve head changes detectable on OCT. With respect to the IH definitions, when using IH Definition 1 , three primary OCT measures and twelve secondary OCT measures were significantly associated with IH, as opposed to no primary measures and only two exploratory measures using IH Definition 2 . Whilst IH Definition 1 appears to be more appropriate for this cohort, clinical judgment remains paramount and certain patients may still require surgical intervention to reduce ICP at lower ICP levels, potentially reflecting a disturbance in ICP compliance. Research in context As per our recent systematic review 25 and further literature review, to the best of our knowledge, this represents the first prospective diagnostic accuracy study using handheld OCT to detect IH in children, using gold standard ICP monitoring. Our literature review has revealed three diagnostic accuracy studies for OCT in craniosynostosis, all supporting the role of OCT as a surrogate measure for ICP. In the 2017 Children’s Hospital of Philadelphia (CHOP) study, Swanson et al 24 used the iVue OCT system for on-table OCT imaging, in 79 children under general anaesthesia (craniosynostosis, n = 40; hydrocephalus, n = 5; controls, n = 34). They evaluated three OCT measurements: maximal RNFL thickness, maximal retinal thickness and maximal anterior retinal projection. Single, subdural measures of ICP were used as the reference standard and obtained under general anaesthesia. Though this is not considered the gold standard measure of ICP, a standardised protocol was followed to minimise measurement bias. 24 Swanson et al found that their combined OCT parameters delivered a sensitivity of 89% and specificity of 62%, similar to the qualitative signs in our study (89% and 63%, respectively). In the more recent 2022 CHOP study by Kalmar et al 26 , two thresholds for intracranial hypertension were analysed (15mmHg and 20mmHg), similar to this study due to the lack of consensus over what constitutes elevated ICP in children with craniosynostosis. 8 They found 77% sensitivity and 95% specificity for detecting ICP above 15mmHg, and 90% sensitivity and 81% specificity for detecting ICP above 20mmHg. However, the CHOP studies could not check for prolonged ICP spikes, or mean ICP during overnight monitoring, as single, on-table ICP measures were used. In a 2024 Rotterdam-based study, Den Ottelander et al 27 found a combined sensitivity of 76% and specificity of 81% for OCT, fundoscopy and fundus imaging combined, in detecting IH in 307 patients with craniosynostosis aged 2.8–23.7 years. The table-mounted Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany) was used. IH was defined either by invasive ICP monitoring using 15mmHg as the IH threshold, or clinically using radiological signs and head circumference. The sole OCT measurement was total retinal thickness (TRT), where greater TRT was associated with IH. Our recent cohort study 16 found morphological differences in the optic nerve head in craniosynostosis (n = 58) with clinically normal ICP, versus healthy controls (n = 218), including disc width 6% greater (P = 0.001), temporal cup width was 13% smaller (P = 0.027), rim width was 16% greater (P < 0.001) and temporal RNFL 11% smaller (P = 0.027). Interestingly, there was no significant difference in nasal RNFL thickness in craniosynostosis versus controls. When comparing Crouzon, Apert and Pfeiffer syndromes (n = 12) to the rest of the craniosynostosis group (n = 46), disc width was 10% smaller (P = .014) and temporal cup width was 38% smaller (P = 0.044). Limitations and future research The main limitation of this study is the modest sample size (n = 37 cases), albeit our sample size calculation indicates that power was achieved. Recruitment was hampered due to the COVID-19 pandemic coinciding with the study period. A larger cohort could permit subgroup analysis by diagnosis. We have recently demonstrated that the optic nerve head in FGFR1/2-associated syndromes (Crouzon, Apert and Pfeiffer) is morphologically different to non-FGFR1/2-associated craniosynostosis, with smaller disc and temporal cup width. 16 Therefore, diagnostic accuracy could be further enhanced through subgroup analyses in a larger cohort. It would be clinically valuable to assess which ICP levels are associated with IH and poorer long-term visual outcomes across the various forms of craniosynostosis in a larger cohort, as this could improve clinical decision making and overall clinical outcomes. To the best of our knowledge, no prospective study has longitudinally assessed the time intervals involved in the evolution of OCT parameters due to IH, nor the resolution of OCT parameters following surgical reduction of ICP in craniosynostosis – such work could guide monitoring and further improve clinical decision making. Conclusions To the best of our knowledge, this represents the first diagnostic accuracy study using handheld OCT in children with craniosynostosis undergoing gold standard, invasive ICP monitoring. Handheld OCT can recognise IH in craniosynostosis. The vast majority of examinations were successful. The qualitative OCT signs demonstrated the highest combined sensitivity and specificity for IH. Anterior displacement of Bruch’s membrane demonstrated 100% specificity and PPV, and is therefore a useful ‘red flag’ sign for IH. Disc width, rim width and nasal RNFL were significantly associated with IH. These findings could improve early recognition, early intervention and clinical outcomes for children with craniosynostosis. Declarations Competing interests: All authors report no competing interests. Ethics statement: ethical approval granted by the East Midlands Nottingham 2 Research Ethics committee (UOL0348/IRAS 105137). Meeting presentations: Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, April 26 th 2023; British & Irish Paediatric Ophthalmology and Strabismus Association (BIPOSA), October 6 th 2023; Royal College of Ophthalmologists Annual Congress, May 22 nd 2024. Data availability statement: Data available upon reasonable request Acknowledgements We thank the patients and their families for taking part in this study. We thank Akudziwe Mawere, University of Oxford DPhil Student, for assisting with Oxford ICP data curation. We thank Andrea White, GOSH, and Kathy Truscott, GOSH Clinical Nurse Specialist, for assisting with recruitment. Funding The Medical Research Council (London, UK) (grant no.: MR/N004566/1). Dr Rufai was funded by the National Institute for Health Research (NIHR) Doctoral Fellowship Award (ref. no. NIHR300155) and NIHR Clinical Lectureship (ref. no. CL-2022-11-001). This work is supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. This paper presents independent research funded by the NIHR and MRC. The views expressed are those of the author(s) and not necessarily those of the MRC, the NIHR or the Department of Health and Social Care. Author contributions Conceptualisation: SRR, RB, IG, CB, FAP, NuOJ; Methodology: SRR, RP, RB, IG, CB, FAP, NuOJ; Software: FAP; Validation: FAP; Formal analysis: SRR, CB, FAP; Investigation: SRR, RP, RB, VP, JOC, GJ, GPLT, DJD, DJ, TPL, NuOJ; Resources: RB, RHH, TPL, NuOJ; Data curation: SRR, RP; Writing – original draft: SRR; Writing – review and editing: RP, RB, IG, CB, DAT, ORM, RHH, JOC, MGT, AHDS, GJ, CKP, RH, GPLT, DJD, DJ, FAP, TPL, NuOJ; Visualisation: SRR, FAP; Project administration: SRR, TPL, NuOJ; Funding acquisition: SRR, RB, IG, CB, FAP, NuOJ. References Shlobin, N. A. et al. Global Epidemiology of Craniosynostosis: A Systematic Review and Meta-Analysis. World Neurosurg. ; 164 : (2022). 413 – 23.e3. Tamburrini, G., Caldarelli, M., Massimi, L., Santini, P. & Di Rocco, C. Intracranial pressure monitoring in children with single suture and complex craniosynostosis: a review. Childs Nerv. Syst. 21 (10), 913–921 (2005). Thompson, D. N. et al. 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[Available from: https://imagejdocu.tudor.lu/plugin/segmentation/active_contour/start Folgar, F. A., Yuan, E. L., Farsiu, S. & Toth, C. A. Lateral and axial measurement differences between spectral-domain optical coherence tomography systems. J. Biomed. Opt. 19 (1), 16014 (2014). Rufai, S. R. et al. Feasibility and reproducibility of handheld and table-mounted optical coherence tomography in children with craniosynostosis. Eye (2026). Maldonado, R. S. et al. Optimizing hand-held spectral domain optical coherence tomography imaging for neonates, infants, and children. Invest. Ophthalmol. Vis. Sci. 51 (5), 2678–2685 (2010). Swanson, J. W. et al. Evaluation of Optical Coherence Tomography to Detect Elevated Intracranial Pressure in Children. JAMA Ophthalmol. 135 (4), 320–328 (2017). Rufai, S. R., Hisaund, M., Jeelani, N. U. O. & McLean, R. J. Detection of intracranial hypertension in children using optical coherence tomography: a systematic review. BMJ Open. 11 (8), e046935 (2021). Kalmar, C. L. et al. Elevated Intracranial Pressure in Patients with Craniosynostosis by Optical Coherence Tomography. Plast. Reconstr. Surg. 149 (3), 677–690 (2022). den Ottelander, B. K. et al. Quantitative Detection and Follow-Up of Intracranial Hypertension in Craniosynostosis: An Optical Coherence Tomography Study. Plast. Reconstr. Surg. 154 (5), 970e–8e (2024). Additional Declarations No competing interests reported. Supplementary Files SupplementalTable1.docx SupplementalTable2.docx SupplementalFigure1.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 22 Jun, 2026 Reviews received at journal 24 May, 2026 Reviews received at journal 15 May, 2026 Reviewers agreed at journal 22 Apr, 2026 Reviewers agreed at journal 22 Apr, 2026 Reviewers agreed at journal 19 Apr, 2026 Reviews received at journal 31 Mar, 2026 Reviews received at journal 29 Mar, 2026 Reviewers agreed at journal 28 Mar, 2026 Reviewers agreed at journal 28 Mar, 2026 Reviewers invited by journal 17 Mar, 2026 Editor invited by journal 06 Mar, 2026 Editor assigned by journal 27 Feb, 2026 Submission checks completed at journal 27 Feb, 2026 First submitted to journal 26 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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