Clomiphene Citrate and Enclomiphene Hydrochloride Exposure Is Associated With Interfrontal Suture Fusion in Zebrafish

Background: The last several decades have witnessed an increase in metopic craniosynostosis incidence. Population-based studies suggest that pharmacological exposure in utero may be responsible. This study examined effects of the fertility drug clomiphene citrate (CC) on calvarial development in an established model for craniofacial development, the zebrafish Danio rerio. Results: Zebrafish larvae were exposed to clomiphene citrate or its isomer enclomiphene for five days at key points during calvarial development. Larvae were then raised to adulthood in normal rearing water. Zebrafish were analyzed using whole-mount skeletal staining. We observed differential effects on survivability, growth and suture formation depending on the treatment. Treatments with CC or enclomiphene at 5.5 mm SL led to increased fusion of the interfrontal suture (p < .01) compared to controls. Conclusions: Exposure to fertility drugs appears to affect development of the cranial vault, specifically the interfrontal suture, in zebrafish. Further research is required to identify the signaling mechanisms at play. This work suggests that fertility drug treatment may contribute to the increased incidence of metopic craniosynostosis observed globally.

“Validation of Artificial Intelligence Severity Assessment in Metopic Craniosynostosis”

Objective Several severity metrics have been developed for metopic craniosynostosis, including a recent machine learning-derived algorithm. This study assessed the diagnostic concordance between machine learning and previously published severity indices. Design Preoperative computed tomography (CT) scans of patients who underwent surgical correction of metopic craniosynostosis were quantitatively analyzed for severity. Each scan was manually measured to derive manual severity scores and also received a scaled metopic severity score (MSS) assigned by the machine learning algorithm. Regression analysis was used to correlate manually captured measurements to MSS. ROC analysis was performed for each severity metric and were compared to how accurately they distinguished cases of metopic synostosis from controls. Results In total, 194 CT scans were analyzed, 167 with metopic synostosis and 27 controls. The mean scaled MSS for the patients with metopic was 6.18 ± 2.53 compared to 0.60 ± 1.25 for controls. Multivariable regression analyses yielded an R-square of 0.66, with significant manual measurements of endocranial bifrontal angle (EBA) (P = 0.023), posterior angle of the anterior cranial fossa (p < 0.001), temporal depression angle (P = 0.042), age (P < 0.001), biparietal distance (P < 0.001), interdacryon distance (P = 0.033), and orbital width (P < 0.001). ROC analysis demonstrated a high diagnostic value of the MSS (AUC = 0.96, P < 0.001), which was comparable to other validated indices including the adjusted EBA (AUC = 0.98), EBA (AUC = 0.97), and biparietal/bitemporal ratio (AUC = 0.95). Conclusions The machine learning algorithm offers an objective assessment of morphologic severity that provides a reliable composite impression of severity. The generated score is comparable to other severity indices in ability to distinguish cases of metopic synostosis from controls.

Rate of craniometric change following suture release in patients with metopic and sagittal craniosynostosis

OBJECTIVE Craniosynostosis is a congenital disorder resulting from the premature fusion of cranial sutures in the infant skull. This condition results in significant cosmetic deformity and can impede neurodevelopment, if left untreated. Currently, rates of craniometric change following minimally invasive surgery have only been examined for sagittal craniosynostosis. A better understanding of postoperative skull adaptations in other craniosynostosis subtypes is needed to objectively categorize surgical outcomes and guide length of cranial orthosis therapy. METHODS Eleven patients with sagittal and 8 with metopic craniosynostosis treated using endoscopic strip craniectomy and postoperative helmet orthoses were retrospectively reviewed. Using semiautomated image analysis of top-down orthogonal 2D photographs, the following craniometrics were recorded before surgery and at postoperative visits: cephalic index (CI), cranial vault asymmetry index (CVAI), anterior arc angle (AAA), posterior arc angle (PAA), anterior-middle width ratio (AMWR), anterior-posterior width ratio (APWR), left-right height ratio (LRHR), sagittal Hu moment (Sag-Hu), and brachycephaly Hu moment (Brachy-Hu). These craniometrics were then normalized to photograph-based measurements of normocephalic patients and the rates of change between metopic and sagittal craniosynostoses were compared. RESULTS Patients with sagittal craniosynostosis exhibited significantly lower CI, lower PAA, higher AMWR, higher APWR, lower Sag-Hu, and higher Brachy-Hu preoperatively compared to patients with normocephalic craniosynostosis. Patients with metopic craniosynostosis exhibited lower AAA and AMWR preoperatively compared to normocephalic subjects. Sagittal and metopic patients had a rapid initial change in normalized CI or AAA, respectively. Craniometric rates of change that significantly differed between metopic and sagittal patients were found in AAA (p < 0.001), AMWR (p < 0.001), and APWR (p < 0.0001). Metopic patients had a prolonged AAA change with a significantly different rate of change up to 6 months postoperatively (median at 3 months = 0.027 normalized units/day, median at 6 months = 0.017 normalized units/day, and median at > 6 months = 0.007 normalized units/day), while sagittal CI rate of change at these time points was not significantly different. CONCLUSIONS Patients with metopic craniosynostosis have a prolonged rate of change compared to patients with sagittal craniosynostosis and may benefit from longer helmet use and extended postoperative follow-up. Categorizing craniometric changes for other craniosynostosis subtypes will be important for evaluating current treatment guidelines.

Anesthetic challenges involved in successful resuscitation of a child from cardiac arrest secondary to massive hemorrhage and possible venous air embolism while undergoing fronto-orbital advancement surgery for metopic craniosynostosis

A one year 3 month old child undergoing fronto-orbital advancement surgery for metopic craniosynostosis had severe bleeding when the surgeon attempted to remove bone flap. Head-end elevation was given at the surgeon’s request to reduce bleeding. Immediately there was a drastic fall in end tidal carbon dioxide (ETCO) and arterial saturation (SpO). Considering air embolism, fraction of inspired oxygen (FiO) was increased to 100% and the surgeon filled the field with saline and covered the area with wet gauze. The operating table was leveled. The child continued to deteriorate with the cardiac rhythm changing to pulseless electrical activity and asystole. Incremental bolus doses of adrenaline, blood products transfusion, fluid bolus and infusion of inotropes were given. Chest compression was not done as the endotracheal tube was fixed to the chest of the patient. Tube dislodgement without access to the head-end of the patient would have been a disaster. The child became hemodynamically stable, the surgery continued and the child was extubated the next day. Other than focal seizures which responded to levetiracetam, the child had no neurological deficits.

Quantitative and qualitative comparison of morphometric outcomes after endoscopic and conventional correction of sagittal and metopic craniosynostosis versus control groups

OBJECTIVE Surgical correction for sagittal and metopic craniosynostosis (SCS and MCS) aims to alter the abnormal cranial shape to resemble that of the normal population. The achieved correction can be assessed by morphometric parameters. The purpose of the presented study was to compare craniometric parameters of control groups to those same parameters after endoscopic and conventional (open) correction. METHODS The authors identified 4 groups of children undergoing surgical treatment for either SCS or MCS, with either endoscopic (SCS, n = 17; MCS, n = 16) or conventional (SCS, n = 29; MCS, n = 18) correction. In addition, normal control groups of nonaffected children who were 6 (n = 30) and 24 (n = 18) months old were evaluated. For all groups, several craniometric indices calculated from 3D photographs were compared for quantitative analysis. For qualitative comparison, averages of all 3D photographs were generated for all groups and superimposed to visualize relative changes. RESULTS For children with SCS, the cephalic index and coronal circumference index significantly differed preoperatively from those of the 6-month normal controls. The respective postoperative values were similar to those of the 24-month normal controls after both endoscopic and conventional correction. Similarly, for children with MCS, indices for circumference and diagonal dimension that were significantly different preoperatively became nonsignificantly different from those of 24-month normal controls after both endoscopic and conventional correction. The qualitative evaluation of superimposed average 3D head shapes confirmed changes toward normal controls after both treatment modalities for SCS and MCS. However, in SCS, the volume gain, especially in the biparietal area, was more noticeable after endoscopic correction, while in MCS, relative volume gain of the bilateral forehead was more pronounced after conventional correction. The average 3D head shapes matched more homogeneously with the average of normal controls after endoscopic correction for SCS and after conventional correction for MCS. CONCLUSIONS This quantitative analysis confirms that the performed surgical techniques of endoscopic and conventional correction of SCS and MCS alter the head shape toward those of normal controls. However, in a qualitative evaluation, the average head shape after endoscopic technique for SCS and conventional correction for MCS appears to be closer to that of normal controls than after the alternative technique. This study reports on morphometric outcomes after craniosynostosis correction. Only an assessment of the whole multiplicity of outcome parameters based on multicenter data acquisition will allow conclusions of superiority of one surgical technique.

Minimally invasive strip craniectomy for metopic craniosynostosis using a lighted retractor

Surgical options for metopic craniosynostosis include the traditional open approach or a minimally invasive approach that typically involves an endoscopy-assisted strip craniectomy. The minimally invasive approach has been associated with less blood loss and operative time, a lower transfusion rate, and a shorter length of stay. Additionally, it is more cost-effective than open reconstruction, despite the need for a postoperative cranial orthosis and multiple follow-up visits. The authors describe a variation of the minimally invasive approach using a lighted retractor to perform a strip craniectomy of the metopic suture in a 2-month-old patient with metopic craniosynostosis. The video can be found here: https://vimeo.com/511237503.

A Case Series of the Use of Piezosurgery Instrument for Minimally Invasive Metopic Suturectomy

BACKGROUND Minimal invasive suturectomy is one of the many surgical approaches to treat isolated single suture craniosynostosis. This approach can be technically challenging in metopic craniosynostosis given the narrow corridor and steep angle of the forehead. New instruments such as the Piezosurgery device (Mectron) have the potential to improve the ability to safely perform minimal invasive surgery in metopic craniosynostosis. OBJECTIVE To demonstrate the safety and efficacy of Piezosurgery technology in minimal invasive suturectomy for nonsyndromic metopic suture craniosynostosis and to describe our technique. METHODS A retrospective chart review was performed of all the single metopic suturectomies performed at our single institution from March 2018 to November 2019. Pre-, intra-, and postoperative data were collected to assess the safety of Piezosurgery. RESULTS The cohort consisted of 12 patients with an average of 95.25 d old and an average weight of 6.2 kg. A total of 91.7% were male, and 91.7% were Caucasian. There were no intraoperative or postoperative Piezosurgery device-related complications in the entire cohort. CONCLUSION The use of the Piezosurgery instrument was safe in this cohort of minimal invasive metopic suturectomy. This device has greatly increased the ease of this procedure in our hands.