Quantitative detection and follow-up of intracranial hypertension in craniosynostosis: an optical coherence tomography study.

BACKGROUND/PURPOSE: To evaluate in craniosynostosis: 1) the diagnostic accuracy of fundoscopy and optical coherence tomography (OCT) to detect intracranial hypertension (ICH); 2) the time course of retinal thickness after treatment of ICH; and 3) the relation between high hyperopia (HH) and fundoscopy/OCT scan findings. METHODS: Syndromic, multisuture, unicoronal, unilambdoid and sagittal synostosis patients visiting our national center were included in this longitudinal cohort study and formed a consecutive series. Retinal layers on OCT, OCT fundus image and fundoscopy were evaluated. ICH was scored according to presence of abnormal intracranial pressures, hydrocephalus, progressive cerebellar tonsillar herniation or fingerprinting and growth arrest. Diagnostic accuracy of OCT, fundoscopy and fundus image, the time course of retinal thickness after ICH and interference of HH were analyzed using linear mixed models. RESULTS: 577 OCT scans in 307 patients were included. ICH was found in 7.2%. Combining total retinal thickness (TRT), OCT fundus image and fundoscopy resulted in a sensitivity of 76% and 81% specificity to detect signs of ICH. TRT was increased in patients who have had signs of ICH versus patients who never had signs of ICH (ß+44.9 µm in patients who have had ICH, 95%CI 9.0-80.8,P=0.01). TRT decreased to normal in the years after surgery (ß -3.6 µm/year, 95%CI -7.2 - -0.05, P=0.047). There were greater odds of having increased TRT in patients with HH (OR 2.9, 95%CI 1.1-7.6,P=0.03). CONCLUSIONS: The correlation between TRT, OCT fundus image, fundoscopy and particularly for the combination of these parameters with ICP surrogate markers is fair. Increased TRT in the presence of a clinical suspicion of ICH warrants further screening.

The use of OCT to detect signs of intracranial hypertension in patients with sagittal suture synostosis: Reference values and correlations.

PURPOSE: To obtain pediatric normative reference values and determine whether optical coherence tomography (OCT) corresponds better with clinical signs of intracranial hypertension (ICH) compared to the traditional screening method fundoscopy in a large cohort of one type of single suture craniosynostosis. METHODS: Control subjects without optic nerve diseases and isolated sagittal synostosis patients aged 3-10 years who underwent fundoscopy and OCT were included in this prospective cohort study. Normative reference values were obtained through bootstrap analysis. Main outcome was the association between peripapillary total retinal thickness (TRT) and total retinal volume (TRV) and appearance on fundoscopy. Signs and symptoms suggestive of ICH, including skull growth arrest, fingerprinting, and headache, were scored. RESULTS: Sixty-four healthy controls and 93 isolated sagittal synostosis patients were included. Normative cut-off values for mean TRT are < 256 µm and > 504 µm and for mean TRV < 0.21 mm3 and > 0.39 mm3. TRT was increased in 16 (17%) and TRV in 15 (16%) of 93 patients, compared to only 4 patients with papilledema on fundoscopy (4%). Both parameters were associated with papilledema on fundoscopy (OR = 16.7, p = 0.02, and OR = 18.2, p = 0.01). Skull growth arrest was significantly associated with abnormal OCT parameters (OR = 13.65, p < 0.01). CONCLUSIONS: The established cut-off points can be applied to screen for ICH in pediatrics. The present study detected abnormalities with OCT more frequent than with fundoscopy, which were associated with skull growth arrest. Therefore, a combination of OCT, fundoscopy, and skull growth arrest can improve clinical decision-making in craniosynostosis.

Cerebral cortex maldevelopment in syndromic craniosynostosis.

AIM: To assess the relationship of surface area of the cerebral cortex to intracranial volume (ICV) in syndromic craniosynostosis. METHOD: Records of 140 patients (64 males, 76 females; mean age 8y 6mo [SD 5y 6mo], range 1y 2mo-24y 2mo) with syndromic craniosynostosis were reviewed to include clinical and imaging data. Two hundred and three total magnetic resonance imaging (MRI) scans were evaluated in this study (148 patients with fibroblast growth factor receptor [FGFR], 19 patients with TWIST1, and 36 controls). MRIs were processed via FreeSurfer pipeline to determine total ICV and cortical surface area (CSA). Scaling coefficients were calculated from log-transformed data via mixed regression to account for multiple measurements, sex, syndrome, and age. Educational outcomes were reported by syndrome. RESULTS: Mean ICV was greater in patients with FGFR (1519cm3 , SD 269cm3 , p=0.016) than in patients with TWIST1 (1304cm3 , SD 145cm3 ) or controls (1405cm3 , SD 158cm3 ). CSA was related to ICV by a scaling law with an exponent of 0.68 (95% confidence interval [CI] 0.61-0.76) in patients with FGFR compared to 0.81 (95% CI 0.50-1.12) in patients with TWIST1 and 0.77 (95% CI 0.61-0.93) in controls. Lobar analysis revealed reduced scaling in the parietal (0.50, 95% CI 0.42-0.59) and occipital (0.67, 95% CI 0.54-0.80) lobes of patients with FGFR compared with controls. Modified learning environments were needed more often in patients with FGFR. INTERPRETATION: Despite adequate ICV in FGFR-mediated craniosynostosis, CSA development is reduced, indicating maldevelopment, particularly in parietal and occipital lobes. Modified education is also more common in patients with FGFR.

Does the association between abnormal anatomy of the skull base and cerebellar tonsillar position also exist in syndromic craniosynostosis?

PURPOSE: Cerebellar tonsillar herniation (TH) occurs frequently in syndromic craniosynostosis; however, the exact pathogenesis is unknown. This study evaluates the association between skull base deformities and TH in syndromic craniosynostosis. METHODS: Retrospective study MRI study comparing syndromic craniosynostosis to controls. Measured parameters included clivus length, skull base angle, Boogard's angle, foramen magnum area, and cerebellar tonsillar position (TP). The association between skull base parameters and TP was evaluated with linear mixed models, correcting for age and risk factors for TH in craniosynostosis (hydrocephalus, intracranial hypertension, craniocerebral disproportion, and lambdoid synostosis). RESULTS: Two hundred and eighty-two scans in 145 patients were included, and 146 scans in 146 controls. The clivus was smaller at birth, and its growth was retarded in all syndromes. The skull base angle was smaller at birth in Apert and Crouzon syndromes, and the evolution through time was normal. Boogard's angle was smaller at birth in Apert syndrome, and its evolution was disturbed in Apert and Saethre-Chotzen syndromes. The foramen magnum was smaller at birth in Crouzon and Saethre-Chotzen syndromes, and its growth was disturbed in Apert, Crouzon, and Saethre-Chotzen syndromes. TP was higher at birth in Apert syndrome, but lowered faster. In Crouzon syndrome, TP was lower at birth and throughout life. A smaller clivus and larger foramen magnum were associated with a lower TP in controls (p<0.001, p=0.007), and in Crouzon syndrome, this applied to only foramen magnum size (p=0.004). CONCLUSION: The skull base and its growth are significantly different in syndromic craniosynostosis compared to controls. However, only foramen magnum area is associated with TP in Crouzon syndrome.

Saethre-Chotzen syndrome: long-term outcome of a syndrome-specific management protocol.

AIM: To assess the long-term outcomes of our management protocol for Saethre-Chotzen syndrome, which includes one-stage fronto-orbital advancement. METHOD: All patients born with Saethre-Chotzen syndrome between January 1992 and March 2017 were included. Evaluated parameters included occipital frontal head circumference (OFC), fundoscopy, neuroimaging (ventricular size, tonsillar position, and the presence of collaterals/an abnormal transverse sinus), polysomnography, and ophthalmological outcomes. The relationship between papilledema and its associated risk factors was evaluated with Fisher's exact test. RESULTS: Thirty-two patients (21 females, 11 males) were included. Median (SD) age at first surgery was 9.6 months (3.1mo) for patients who were primarily referred to our center (range: 3.6-13.0mo), the median (SD) age at last follow-up was 13 years (5y 7mo; range: 3-25y). Seven patients had papilledema preoperatively, which recurred in two. Two patients had papilledema solely after first surgery. Second cranial vault expansion was indicated in 20%. Thirteen patients had an OFC deflection, indicating restricted skull growth, one patient had ventriculomegaly, and none developed hydrocephalus. Eleven patients had emissary veins, while the transverse sinus was aberrant unilaterally in 13 (hypoplastic n=10 and absent n=3). Four patients had mild tonsillar descent, one of which was a Chiari type I malformation. Four patients had obstructive sleep apnoea (two mild, one moderate, and one severe). An aberrant transverse sinus was associated with papilledema (p=0.01). INTERPRETATION: Single one-stage fronto-orbital advancement was sufficient to prevent intracranial hypertension for 80% of our patients with Saethre-Chotzen syndrome. Follow-up should focus on OFC deflection and venous anomalies.

Intracranial hypertension and cortical thickness in syndromic craniosynostosis.

AIM: To evaluate the impact of risk factors for intracranial hypertension (ICH) on cerebral cortex thickness in syndromic craniosynostosis. METHOD: ICH risk factors including papilloedema, hydrocephalus, obstructive sleep apnea (OSA), cerebellar tonsillar position, occipitofrontal circumference (OFC) curve deflection, age, and sex were collected from the records of patients with syndromic craniosynostosis (Apert, Crouzon, Pfeiffer, Muenke, Saethre-Chotzen syndromes) and imaging. Magnetic resonance images were analysed and exported for statistical analysis. A linear mixed model was developed to determine correlations with cerebral cortex thickness changes. RESULTS: In total, 171 scans from 107 patients (83 males, 88 females [including repeated scans], mean age 8y 10mo, range 1y 1mo-34y, SD 5y 9mo) were evaluated. Mean cortical thickness in this cohort was 2.78mm (SD 0.17). Previous findings of papilloedema (p=0.036) and of hydrocephalus (p=0.007) were independently associated with cortical thinning. Cortical thickness did not vary significantly by sex (p=0.534), syndrome (p=0.896), OSA (p=0.464), OFC (p=0.375), or tonsillar position (p=0.682). INTERPRETATION: Detection of papilloedema or hydrocephalus in syndromic craniosynostosis is associated with significant changes in cortical thickness, supporting the need for preventative rather than reactive treatment strategies. WHAT THIS PAPER ADDS: Papilloedema is associated with thinning of the cerebral cortex in syndromic craniosynostosis, independently of hydrocephalus.

Hipertensión intracraneal y grosor cortical en craneosinostosis sindrómica OBJETIVO: Evaluar el impacto de los factores de riesgo de hipertensión intracraneal (HIC) en el grosor de la corteza cerebral en la craneosinostosis sindrómica. MÉTODO: La neuroimagen, y, los factores de riesgo para HIC que incluyeron papiledema, hidrocefalia, apnea obstructiva del sueño (SAOS), posición de la tonsila cerebelosa, edad de desviación de la curva de circunferencia occipitofrontal (CFO) y el sexo, se recogieron de los registros de pacientes con craneosinostosis sindrómica (Apert, Crouzon, Pfeiffer, Muenke, Saethre-Chotzensis). Las imágenes de resonancia magnética fueron analizadas y exportadas para análisis estadístico. Se desarrolló un modelo mixto lineal para determinar las correlaciones con los cambios en el espesor de la corteza cerebral. RESULTADOS: En total se evaluaron 171 exploraciones de 107 pacientes (83 varones, 88 mujeres [incluyendo escaneos repetidos], edad media 8 años 10 meses, rango 1 año 1 mes - 34 años, DE 5 años 9 meses). El espesor medio cortical en esta cohorte fue de 2,78 mm (DS 0,17). Los hallazgos anteriores de papiledema (p=0,036) y de hidrocefalia (p=0,007) se asociaron de forma independiente con el adelgazamiento cortical. El grosor cortical no varió significativamente por sexo (p=0,534), síndrome (p=0,896), SAOS (p=0,464), CFO (p=0,375), o posición tonsilar (p=0,682). INTERPRETACIÓN: La detección de papiledema o hidrocefalia en la craneosinostosis sindrómica, se asocia con cambios significativos en el grosor cortical. Esto apoya la necesidad de estrategias de tratamiento preventivo en lugar de tratamientos reactivos.

Hipertensão intracrianiana e espessura cortical na craniossinostose sindrômica OBJETIVO: Avaliar o impacto de fatores de risco para hipertensão intracraniana (HIC) na espessura cortical em craniossinostose sindrômica. MÉTODO: Fatores de risco para HIC incluindo papiloedema, hidrocefalia, apnéia obstrutiva do sono (AOS), posição das tonsilas do cerebelo, idade de deflexão da curva da circunferência occipitofrontal (COF), e sexo foram coletados dos registros de pacientes com craniossinostose sindrômica (síndromes de Apert, Crouzon, Pfeiffer, Muenke, Saethre-Chotzen) e imagens. As imagens de ressonância magnética foram analisadas e exportadas para análise estatística. Um modelo linear misto foi desenvolvido para determinar correlações com mudanças na espessura do córtex cerebral. RESULTADOS: No total, 171 imagens de 107 pacientes (83 do sexo masculino, 88 do sexo feminino [incluindo varreduras repetidas], média de idade 8a 10m, variação 1a 1m-34a, DP 5a 9m) foram avaliados. A espessura cortical média nesta coorte foi 2,78mm (DP 0,17). Achados prévios de papiloedema (p=0,036) e de hidrocefalia (p=0,007) foram independentemente associados com a redução cortical. A espessura cortical não variou significativamente com o sexo (p=0,534), síndrome (p=0,896), AOS (p=0,464), COF (p=0,375), ou posição tonsilar (p=0,682). INTERPRETAÇÃO: A detecção do papiloedema ou hidrocefalia na craniossinostose sindrômica se associa com mudanças significativas na espessura cortical, sustentando a necessidade de estratégias de tratamento preventivas e não reativas.

Dural sinus volume in children with syndromic craniosynostosis and intracranial hypertension.

OBJECTIVE: Intracranial hypertension is a major concern in children with syndromic craniosynostosis (sCS). Cerebral venous hypertension caused by cerebral venous outflow obstruction is believed to contribute to intracranial hypertension. The authors therefore hypothesized that cerebral venous volume would be increased in those children with sCS and intracranial hypertension. METHODS: In a case series of 105 children with sCS, of whom 32 had intracranial hypertension, cerebral MRI techniques were used to quantify the volume of the superior sagittal sinus, straight sinus (StrS), and both transverse sinuses. RESULTS: Linear regression showed that total cerebral venous volume increased by 580.8 mm3 per cm increase in occipitofrontal head circumference (p < 0.001). No significant difference was found between the intracranial hypertension group and the nonintracranial hypertension group (p = 0.470). Multivariate ANOVA showed increased StrS volume (as a proportion of total volume) in the intracranial hypertension group (8.5% vs 5.1% in the nonintracranial hypertension group, p < 0.001). Multivariate logistic regression showed that a 100-mm3 increase in StrS volume is associated with increased odds of having intracranial hypertension by 60% (OR 1.60, 95% CI 1.24-2.08). CONCLUSIONS: Although intracranial hypertension was not associated with total cerebral venous volume increase, it was associated with an isolated increase in StrS volume. Hence, it is unlikely that general cerebral venous outflow obstruction is the mechanism of intracranial hypertension in sCS. Rather, these findings indicate either a central cerebral vulnerability to intracranial hypertension or a mechanism involving venous blood redistribution.

Cerebral blood flow in children with syndromic craniosynostosis: cohort arterial spin labeling studies.

OBJECTIVE: In comparison with the general population, children with syndromic craniosynostosis (sCS) have abnormal cerebral venous anatomy and are more likely to develop intracranial hypertension. To date, little is known about the postnatal development change in cerebral blood flow (CBF) in sCS. The aim of this study was to determine CBF in patients with sCS, and compare findings with control subjects. METHODS: A prospective cohort study of patients with sCS using MRI and arterial spin labeling (ASL) determined regional CBF patterns in comparison with a convenience sample of control subjects with identical MRI/ASL assessments in whom the imaging showed no cerebral/neurological pathology. Patients with SCS and control subjects were stratified into four age categories and compared using CBF measurements from four brain lobes, the cerebellum, supratentorial cortex, and white matter. In a subgroup of patients with sCS the authors also compared longitudinal pre- to postoperative CBF changes. RESULTS: Seventy-six patients with sCS (35 female [46.1%] and 41 male [53.9%]), with a mean age of 4.5 years (range 0.2-19.2 years), were compared with 86 control subjects (38 female [44.2%] and 48 male [55.8%]), with a mean age of 6.4 years (range 0.1-17.8 years). Untreated sCS patients < 1 year old had lower CBF than control subjects. In older age categories, CBF normalized to values observed in controls. Graphical analyses of CBF by age showed that the normally expected peak in CBF during childhood, noted at 4 years of age in control subjects, occurred at 5-6 years of age in patients with sCS. Patients with longitudinal pre- to postoperative CBF measurements showed significant increases in CBF after surgery. CONCLUSIONS: Untreated patients with sCS < 1 year old have lower CBF than control subjects. Following vault expansion, and with age, CBF in these patients normalizes to that of control subjects, but the usual physiological peak in CBF in childhood occurs later than expected.

Improvement in Sleep Architecture is associated with the Indication of Surgery in Syndromic Craniosynostosis.

Children with syndromic craniosynostosis (sCS) often suffer from obstructive sleep apnea (OSA) and intracranial hypertension (ICH). Both OSA and ICH might disrupt sleep architecture. However, it is unclear how surgically treating OSA or ICH affects sleep architecture. The aim of this study was twofold: to explore the usefulness of sleep architecture analysis in detecting disturbed sleep and to determine whether surgical treatment can improve it. METHODS: Eighty-three children with sCS and 35 control subjects, who had undergone a polysomnography (PSG), were included. Linear-mixed models showed the effects of OSA and ICH on sleep architecture parameters. In a subset of 19 patients, linear regression models illustrated the effects of OSA-indicated and ICH-indicated surgery on pre-to-postoperative changes. RESULTS: An increase in obstructive-apnea/hypopnea index (oAHI) was significantly associated with an increase in N2-sleep, arousal index, and respiratory-arousal index and a decrease in REM-sleep, N3-sleep, sleep efficiency, and sleep quality. ICH and having sCS were not related to any change in sleep architecture. OSA-indicated surgery significantly increased the total sleep time and sleep efficiency and decreased the arousal index and respiratory-arousal index. ICH-indicated surgery significantly decreased REM-sleep, N1-sleep, sleep efficiency, and sleep quality. CONCLUSIONS: For routine detection of disturbed sleep in individual subjects, PSG-assessed sleep architecture is currently not useful. OSA does disrupt sleep architecture, but ICH does not. OSA-indicated surgery improves sleep architecture, which stresses the importance of treating OSA to assure adequate sleep. ICH-indicated surgery affects sleep architecture, although it is not clear whether this is a positive or negative effect.

Muenke syndrome: long-term outcome of a syndrome-specific treatment protocol.

OBJECTIVE: The authors evaluated the long-term outcome of their treatment protocol for Muenke syndrome, which includes a single craniofacial procedure. METHODS: This was a prospective observational cohort study of Muenke syndrome patients who underwent surgery for craniosynostosis within the first year of life. Symptoms and determinants of intracranial hypertension were evaluated by longitudinal monitoring of the presence of papilledema (fundoscopy), obstructive sleep apnea (OSA; with polysomnography), cerebellar tonsillar herniation (MRI studies), ventricular size (MRI and CT studies), and skull growth (occipital frontal head circumference [OFC]). Other evaluated factors included hearing, speech, and ophthalmological outcomes. RESULTS: The study included 38 patients; 36 patients underwent fronto-supraorbital advancement. The median age at last follow-up was 13.2 years (range 1.3-24.4 years). Three patients had papilledema, which was related to ophthalmological disorders in 2 patients. Three patients had mild OSA. Three patients had a Chiari I malformation, and tonsillar descent < 5 mm was present in 6 patients. Tonsillar position was unrelated to papilledema, ventricular size, or restricted skull growth. Ten patients had ventriculomegaly, and the OFC growth curve deflected in 3 patients. Twenty-two patients had hearing loss. Refraction anomalies were diagnosed in 14/15 patients measured at ≥ 8 years of age. CONCLUSIONS: Patients with Muenke syndrome treated with a single fronto-supraorbital advancement in their first year of life rarely develop signs of intracranial hypertension, in accordance with the very low prevalence of its causative factors (OSA, hydrocephalus, and restricted skull growth). This illustrates that there is no need for a routine second craniofacial procedure. Patient follow-up should focus on visual assessment and speech and hearing outcomes.

First Vault Expansion in Apert and Crouzon-Pfeiffer Syndromes: Front or Back?

BACKGROUND: Children with Apert and Crouzon-Pfeiffer syndromes are at risk of intracranial hypertension. Until 2005, when the authors switched to occipital expansion, their institution's preferred treatment was fronto-orbital advancement. However, it was still unclear whether (1) occipitofrontal head circumference (i.e., intracranial volume) was greater after occipital expansion than after fronto-orbital advancement; (2) the incidences of tonsillar herniation and papilledema were lower; and (3) visual acuity was better during follow-up. In these patients, the authors therefore compared fronto-orbital advancement with occipital expansion as the first surgical procedure. METHODS: Measurements included repeated occipitofrontal head circumference as a measure for intracranial volume; neuroimaging to evaluate tonsillar herniation; funduscopy to identify papilledema; and visual acuity testing. RESULTS: The authors included 37 patients (Apert syndrome, n = 18; Crouzon-Pfeiffer syndrome, n = 19). Eighteen underwent fronto-orbital advancement and 19 underwent occipital expansion (age at surgery, 1.0 versus 1.5 years; p = 0.13). Follow-up time in both groups was 5.7 years. The increase in occipitofrontal head circumference (+1.09 SD) was greater after occipital expansion than after fronto-orbital advancement (+0.32 SD) (p = 0.03). After occipital expansion, fewer patients with Crouzon-Pfeiffer syndrome had tonsillar herniation (occipital, three of 11; fronto-orbital advancement, seven of eight; p = 0.02); for both syndromes together, fewer patients had papilledema (occipital, four of 19; fronto-orbital advancement, 11 of 18; p = 0.02). Visual acuity was similar after fronto-orbital advancement and occipital expansion (0.09 versus 0.13 logarithm of the minimum angle of resolution) (p = 0.28). CONCLUSIONS: The authors' preference for occipital expansion as the initial craniofacial procedure in Apert and Crouzon-Pfeiffer syndromes is supported by the greater increase it produces in intracranial volume (as evidenced by the occipitofrontal head circumference), which reduces the incidences of tonsillar herniation and papilledema. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.