Abstract
Objectives:
To set age-specific normal reference values for brainstem, cerebellar vermis, and peduncles measurements and characterize values’ variations according to gender, age, and age by gender interaction.
Methods:
565 normal brain magnetic resonance examinations with normal anatomy and signal intensity of the supra- and infratentorial structures were categorized into six age groups (infant, child, adolescent, young adult, middle-age adult, and old aged adults). Patients with congenital malformations, gross pathology of the supra- or infratentorial brain, brain volume loss, developmental delay, metabolic disorders, and neuropsychological disorders (n = 2.839) were excluded. On midsagittal T1 weighted and axial T2 weighted images specific linear diameters and ratios of the brainstem, cerebellar vermis, and peduncles were attained. Two observers assessed a random sample of 100 subjects to evaluate the inter- and intraobserver reproducibility. Intraclass correlation coefficients, means ± standard deviation, one and two-way analysis of variance tests were used in the statistical analysis.
Results:
Good to excellent inter- and intraobserver measurements’ reproducibility were observed, except for the transverse diameter of the midbrain, the anteroposterior diameter of the medulla oblongata at the pontomedullary and cervicomedullary junctions, cerebellar vermis anteroposterior diameter, and thickness of the superior cerebellar peduncle. Age-specific mean values of the investigated measurements were established. A significant gender-related variation was recorded in the anteroposterior diameter of the basis pontis (p = 0.044), the anteroposterior diameter of the medulla oblongata at the cervicomedullary junction (p = 0.044), and cerebellar vermis height (p = 0.018). A significant age-related change was detected in all measurements except the tectal ratio. Age by gender interaction had a statistically significant effect on the tectal ratio, inferior, and middle cerebellar peduncles’ thickness (p = 0.001, 0.022, and 0.028, respectively).
Conclusion:
This study provides age-specific normal mean values for various linear dimensions and ratios of the posterior fossa structures with documentation of measurements’ variability according to gender, age, and their interaction.
Advances in knowledge:
It provides a valuable reference in the clinical practice for easier differentiation between physiological and pathological conditions of the posterior fossa structures especially various neurodegenerative diseases and congenital anomalies.
Introduction
Knowledge about the normal size of the posterior fossa structures, specifically brainstem, cerebellar vermis, and peduncles, is important to understand the physiological variance, evaluate pathological changes occurring in neoplastic and several neurodegenerative disorders,1–3 and interpret congenital malformations.
Many studies had worked upon MR-based volumetric measurements of the normal posterior fossa structures.4–11 However, this method is time-consuming, not feasible for routine work, and requires specific MRI software for processing. The linear measurement method is rapid, requires no additional software, more suitable for daily practice, and easily acquired on the hardcopy of images.2 Several researches had investigated linear measurements of the normal posterior fossa structures, characterized the effect of gender and age differences, and documented normal values; however, they were limited by the small sample sizes, extreme age groups or narrow range of ages.1–3,12–15 Moreover, to our knowledge, no previous study had investigated the cerebellar peduncles measurements in normal subjects.
Non-significant gender-related effect on the diameters of the normal posterior fossa structures had been reported.2,3,12–15 On the contrary, age is a principal factor when considering changes in the size of the posterior fossa structures.2–9,11,13–15 Therefore, age-specific standard values and ranges of the diameters of the posterior fossa structures are necessary for diagnostic purposes. However, current normal reference values are deficient, variable, and based on studies with relatively small samples size; hence large-scale studies are needed.
Furthermore, the effect of age on the size of posterior fossa structures might differ by gender. Data on the effect of age by gender interaction on the normal measurements of the posterior fossa structures are scarce.
Consequently, this large-scale study was implemented to provide age-specific normative values for various linear dimensions and ratios of the brainstem, cerebellar vermis, and peduncles that would add to the normative database of the posterior fossa structures and further clarify the variability of these measurements according to gender, age, and age by gender interaction.
Patients and methods
Ethical statement
The Research Ethics Committee approved this study and written informed consent was waived by the Institutional Review Board. The study was held based on the ethical principles of the Declaration of Helsinki.
Study population
During the period from January 2019 to February 2020, the hospital databases of the three sharing institutions were searched for non-contrast-enhanced brain MRI examinations that showed normal anatomy and signal intensity of the brain and posterior fossa structures in any age group to be included in the study. Patients were admitted for MRI for complaints of poor feeding or fever in neonates and short stature, fever, acute trauma, headache or blurring of vision in older age groups. Exclusion criteria included brain MRI examinations showing congenital malformations (n = 71), or gross pathology of the supra- or infratentorial brain (n = 2.158), or volume loss (n = 274) manifested with prominent ventricular system, cortical brain sulci, and cerebellar folia, or images with deficient quality. We also excluded MRI examinations of patients with a history of prematurity (birth before 37 weeks of gestation) (n = 12), developmental delay (n = 57), metabolic disorders (n = 29), epilepsy (n = 195), and neuropsychological disorders (n = 43) including developmental causes as autism, learning and attention disorders, schizophrenia, and dementia. In total, 565 brain MR studies were eligible for participation in the research. The age of the involved subjects ranged from 23 days to 69 years. The study subjects were categorized into six age groups: Group 1: neonate & infant (0 - ≤ 1 y), Group 2: child (>1y - ≤ 12 y), Group 3: adolescent (>12 y - ≤ 18 y), Group 4: young adult (>18 - < 40 y), Group 5: middle-age adult (≥40 - < 60 y), Group 6: old aged adults (≥60 y) (Table E1).
MR examination
Brain MR examinations were performed by 1.5 T MRI systems (Achieva-class IIa, Philips Medical System, North America Co. Philips, 22100 Bothell Everett Hwy, Bothell, WA 98021-8431) using a standard head coil or neonate head coil (according to examined age group). Needed MRI fast spin-echo sequences were; sagittal T1 (TE = 10–12 ms, TR = 400–600 ms) and axial T2 weighted images (TE = 70–90 ms, TR = 2800–3500 ms), done with a flip angle of 90°, NEX = 1, slice thickness 2–3 mm, gap 1 mm, FOV 24–30 cm, and matrix 512 × 512.
Image analysis
Two consultant neuroradiologists (with 10 and 12 years of experience) blinded to the subjects' gender and age, independently reviewed all MR examinations, and calculated the investigated measurements. MR image analysis was performed centrally on a dedicated platform Extended Brilliance Workstation (Philips Medical System, Best, The Netherlands), or PACS system (Paxera Ultima- paxeramed). All measurements for each MRI examination were performed in 10–15 min. The adopted MR-based measurement method included:
Specification of the midsagittal T1WI as the reference image for localization of the brainstem parts and vermis, and measurement of the considered sagittal diameters depending on the modification of the brainstem segmentation method proposed by Oba et al16 and Luft et al8 (Figure 1).
Specification of the axial T2WI for measuring the transverse diameters (Figure 2).
Figure 1.
MRI mid-sagittal non-enhanced T1WI. (a) demonstrates the modification of Oba’s method for midbrain and pons segmentation via four demarcating lines (I, II, III, and IV), line I representing the upper boundary of the midbrain connecting the mammillary body anteriorly to the superior boundary of the quadrigeminal plate posteriorly, line II separating between midbrain and pons, connecting superior pontine notch anteriorly to the inferior boundary of the quadrigeminal plate posteriorly, line III separating pons and medulla oblongata, drawn parallel to line II passing through the inferior pontine notch. Addition of line IV as a demarcation of the medullocervical junction drawn parallel to line III at the level of the foramen magnum. (b) demonstrates the vertical measurements, including line I for the vertical diameter of the tectum, line II for the vertical diameter of the midbrain, line III for the vertical diameter of the pons, line IV for cerebellar vermis height. (c) demonstrates the AP measurements as follows: line I for AP diameter of the tectum, line II for AP diameter of the midbrain, line III AP diameter of the basis pontis, line IV for AP diameter of the pons, line V for cerebellar vermis AP diameter. AP, anteroposterior; T2WI, T2weighted imaging.
Figure 2.
MRI axial T2WI. (a) Dotted line expresses the transverse diameter of the midbrain, star points to the level of the superior colliculus. (b) Black arrow points to the line that expresses the thickness of the superior cerebellar peduncle, white arrow points to the level of the inferior colliculus. (c) Line expresses the transverse diameter of the pons, the dotted line refers to the thickness of the middle cerebellar peduncle, arrow points to the trigeminal nerve. (d) Black line refers to the transverse diameter of the medulla oblongata, black arrows point to the inferior olivary nucleus. (e) Black line refers to the thickness of the inferior cerebellar peduncle.
Table 1 demonstrates the acquired diameters and the level of measurements.
Table 1.
Illustration of the investigated midsagittal and axial diameters
| The acquired measurements | Site of maximum dimension |
|---|---|
| Anteroposterior diameter of the midbrain | Extends from the anterior surface of the midbrain to its posterior surface |
| Vertical diameter of the midbrain | Extends from the superior surface of the midbrain to the pontomesencephalic junction parallel to the long axis of the midbrain. |
| Anteroposterior diameter of the tectum | Midway between the superior and inferior colliculi. |
| Vertical diameter of the tectum | Extends from the superior colliculus to the lower border of the inferior colliculus parallel to the long axis of the tectum. |
| Anteroposterior diameter of the pons | Extends from the anterior surface of the basis pontis to the posterior surface of the pontine tegmentum perpendicular to the long axis of the fourth ventricle. |
| Vertical diameter of the pons | Extends from the superior to inferior pontine notch parallel to the long axis of the pons. |
| Anteroposterior diameter of the basis pontis | Extends from the ventral surface of the basis pontis to its dorsal surface |
| Anteroposterior diameter of the medulla oblongata at the pontomedullary junction | Extends from the anterior surface of the medulla oblongata to its posterior surface at the level of the pontomedullary junction |
| Anteroposterior diameter of the medulla oblongata at the cervicomedullary junction | Extends from the anterior surface of the medulla oblongata to its posterior surface at the level of the foramen magnum |
| Cerebellar vermis height | Craniocaudal length of the vermis excluding cerebellar tonsil |
| Cerebellar vermis anteroposterior diameter | Extends from the posterior surface of the cerebellar vermis to the inner surface of the fastigium cerebelli perpendicular to the long axis of the fourth ventricle |
| Transverse diameter of the midbrain | Measured at the level of the superior colliculus extending between the outer portions of the right and left cerebral peduncles |
| Transverse diameter of the pons | Measured at the level just posterior to the root of the trigeminal nerve |
| Transverse diameter of the medulla oblongata | Measured at the level of the inferior olivary nucleus |
| Thickness of the superior cerebellar peduncle | Measured at the level of the inferior colliculus |
| Thickness of the middle cerebellar peduncle | Measured at the level of the trigeminal nerve |
| Thickness of the inferior cerebellar peduncle | Measured at the level of connection between the cerebellum and the medulla |
Brainstem ratios calculation: tectal ratio: vertical diameter of the tectum/anteroposterior diameter of the tectum; basis pontis ratio: vertical diameter of the pons/anteroposterior diameter of the basis pontis; pons to midbrain ratio: anteroposterior diameter of the pons/anteroposterior diameter of the midbrain; pons to medulla oblongata ratio 1: anteroposterior diameter of the pons/anteroposterior diameter of the medulla oblongata at the pontomedullary junction; pons to medulla oblongata ratio 2: anteroposterior diameter of the pons/anteroposterior diameter of the medulla oblongata at the cervicomedullary junction.
Reproducibility of measurements
The interobserver reproducibility of the investigated measurements was determined by the repetition of all measurements on a random sample of 100 subjects by the two observers. To evaluate the intraobserver reproducibility, the measurements were repeated 1 month after the initial evaluation to reduce recall bias.
Statistical analysis
Statistical analysis of data was done using SPSS v. 26 (IBM, Armonk, NY). Normal distribution of the data was evaluated and confirmed using Kolmogorov–Smirnov test. Continuous variables were expressed as mean ± SD and range, while categorical variables were presented as number and percentage. Means ± SD and ranges of the investigated measurements were calculated for each age group to set up the normal reference values. Intra- and interobserver reliability was assessed by intraclass correlation coefficients (ICCs) with 95% confidence interval and was interpreted as follows: <0.5= poor reliability, 0.5–0.75 = moderate reliability, 0.75–0.9 = good reliability, and >0.90 = excellent reliability. A comparison of the mean values of the age groups was performed by one way analysis of variance (ANOVA) with the Games Howell post-hoc multiple comparisons test. For the simultaneous assessment of the effect of age, gender, and age by gender interaction, two-way ANOVA with Bonferroni’s correction of multiple comparisons and Bonferroni post-hoc test was conducted. All tests were two-tailed, and the p-value was significant at ≤0.05. The post-hoc multiple comparisons were performed to evaluate the differences between every pair of age groups. For Bonferroni corrected multiple comparisons, to keep the familywise error rate of 0.05 throughout all comparisons, a Bonferroni corrected p-value was calculated (α = 0.05/number of comparisons = 5); consequently, the mean difference between each pair of age groups was significant at p˂0.01. Moreover, mean plots were generated and analyzed.
Results
Study subjects comprised 273 males (48.3%) and 292 females (51.7%), their ages ranged from 23 days to 69 years, the mean age was 34.6 ± 17.7 years for males and 33.7 ± 15.4 years for females. The study subjects were classified into six distinct age groups (Table E1).
Normal reference values
Table 2 shows age-specific normal values (means ± SD) and ranges (minimum–maximum) of the considered measurements in six distinct age groups.
Table 2.
Mean values and ranges of the investigated measurements in different age groups
| Variables | All Subjects (n = 565) | ||||||
|---|---|---|---|---|---|---|---|
| Group 1(0 – ≤ 1 y) Mean ± SD (min.–max.) | Group 2(>1y – ≤ 12 y) Mean ± SD (min.–max.) | Group 3(12 – ≤ 18 y) Mean ± SD (min.–max.) | Group 4(>18 – < 40 y) Mean ± SD (min.–max.) | Group 5(≥40 – < 60 y) Mean ± SD (min.–max.) | Group 6(≥60 y) Mean ± SD (min.–max.) | *P–value | |
| Anteroposterior diameter of the midbrain | 1.28 ± 0.11 | 1.61 ± 0.15 | 1.75 ± 0.19 | 1.77 ± 0.14 | 1.7 ± 0.16 | 1.56 ± 0.11 | <0.001 |
| (1.1–1.5) | (1.1–1.96) | (1.5–2.3) | (1.34–2.4) | (1.2–2.4) | (1.22–1.8) | ||
| Vertical diameter of the midbrain | 1.04 ± 0.17 | 1.27 ± 0.18 | 1.37 ± 0.13 | 1.4 ± 0.14 | 1.33 ± 0.14 | 1.21 ± 0.12 | <0.001 |
| (0.8–1.45) | (0.89–1.8) | (1.17–1.65) | (1–1.89) | (0.98–2) | (0.9–1.5) | ||
| Anteroposterior diameter of the tectum | 0.3 ± 0.08 | 0.37 ± 0.06 | 0.4 ± 0.04 | 0.4 ± 0.07 | 0.38 ± 0.06 | 0.35 ± 0.05 | <0.001 |
| (0.2–0.48) | (0.25–0.5) | (0.3–0.48) | (0.23–0.63) | (0.25–0.6) | (0.28–0.5) | ||
| Vertical diameter of the tectum | 0.95 ± 0.10 | 1.23 ± 0.15 | 1.31 ± 0.13 | 1.33 ± 0.14 | 1.31 ± 0.15 | 1.2 ± 0.1 | <0.001 |
| (0.75–1.15) | (0.9–1.7) | (1.05–1.5) | (1–1.8) | (1–1.8) | (1–1.5) | ||
| Anteroposterior diameter of the pons | 1.45 ± 0.22 | 2.04 ± 0.20 | 2.15 ± 0.11 | 2.23 ± 0.15 | 2.23 ± 0.15 | 2.17 ± 0.14 | <0.001 |
| (1.1–2) | (1.5–2.5) | (1.9–2.4) | (1.95–2.6) | (1.9–2.6) | (1.9–2.5) | ||
| Vertical diameter of the pons | 1.48 ± 0.30 | 2.17 ± 0.31 | 2.33 ± 0.21 | 2.4 ± 0.20 | 2.4 ± 0.21 | 2.34 ± 0.19 | <0.001 |
| (1.07–2.05) | (1.06–2.8) | (2.06–3) | (1.9–2.88) | (2–2.9) | (2.07–2.8) | ||
| Anteroposterior diameter of the basis pontis | 1.1 ± 0.14 | 1.33 ± 0.12 | 1.54 ± 0.08 | 1.61 ± 0.11 | 1.58 ± 0.11 | 1.54 ± 0.13 | <0.001 |
| (0.9–1.4) | (1.1–1.5) | (1.4–1.7) | (1.4–1.9) | (1.4–1.9) | (1.45–1.75) | ||
| Anteroposterior diameter of the medullo oblongata at the pontomedullary junction | 0.92 ± 0.18 | 1.30 ± 0.14 | 1.45 ± 0.08 | 1.38 ± 0.14 | 1.34 ± 0.11 | 1.24 ± 0.11 | <0.001 |
| (0.6–1.26) | (0.8–1.6) | (1.3–1.6) | (1–1.8) | (1.1–1.7) | (1–1.5) | ||
| Anteroposterior diameter of the medulla oblongata at the cervicomedullary junction | 0.8 ± 0.12 | 1.11 ± 0.13 | 1.25 ± 0.12 | 1.2 ± 0.12 | 1.15 ± 0.13 | 1.07 ± 0.11 | <0.001 |
| (0.6–1.09) | (0.6–1.4) | (1–1.5) | (0.86–1.5) | (0.8–1.45) | (0.8–1.4) | ||
| Transverse diameter of the midbrain | 2.4 ± 0.35 | 3 ± 0.35 | 3.25 ± 0.23 | 3.28 ± 0.31 | 3.25 ± 0.31 | 3 ± 0.37 | <0.001 |
| (1.7–3) | (2.10–3.8) | (2.7–3.78) | (2.4–3.97) | (2.5–4) | (2.5–4) | ||
| Transverse diameter of the pons | 1.91 ± 0.47 | 2.9 ± 0.45 | 3.13 ± 0.50 | 3.28 ± 0.36 | 3.32 ± 0.35 | 3.14 ± 0.41 | <0.001 |
| (1.22–3) | (1.8–3.8) | (2–4.3) | (2.2–4.3) | (2.8–4.4) | (2.68–4.2) | ||
| Transverse diameter of the medulla | 0.96 ± 0.15 | 1.33 ± 0.15 | 1.46 ± 0.18 | 1.4 ± 0.18 | 1.36 ± 0.19 | 1.19 ± 0.16 | <0.001 |
| (0.75–1.3) | (0.8–1.6) | (1.03–1.8) | (0.96–1.8) | (0.95–1.8) | (0.9–1.5) | ||
| Tectal ratio | 3.29 ± 0.87 | 3.31 ± 0.72 | 3.16 ± 0.43 | 3.4 ± 0.64 | 3.5 ± 0.65 | 3.4 ± 0.62 | 0.061 |
| (2–4.5) | (1.8–5.6) | (2.5–4.3) | (2–5.4) | (2–5.4) | (2.4–5) | ||
| Basis Pontis ratio | 1.4 ± 0.13 (1.23–1.62) | 1.78 ± 0.18 | 1.58 ± 0.12 (1.36–1.75) | 1.54 ± 0.14 | 1.55 ± 0.09 | 1.54 ± 0.16 | 0.001 |
| (1.5–2) | (1.3–1.85) | (1.4–1.78) | (1.3–1.66) | ||||
| Pons/midbrain ratio | 1.13 ± 0.13 | 1.25 ± 0.11 | 1.23 ± 0.10 | 1.28 ± 0.14 | 1.35 ± 0.17 | 1.38 ± 0.16 | <0.001 |
| (0.9–1.4) | (1–1.6) | (1–1.4) | (1–1.9) | (1.1–2.1) | (1.2–2.4) | ||
| Pons/medulla Ratio 1 | 1.6 ± 0.23 | 1.56 ± 0.18 | 1.47 ± 0.13 | 1.6 ± 0.15 | 1.7 ± 0.15 | 1.74 ± 0.15 | <0.001 |
| (1.27–2) | (1.27–1.96) | (1.26–1.7) | (1-2) | (1.3–2) | (1.5–2) | ||
| Pons/medulla Ratio 2 | 1.79 ± 0.24 | 1.82 ± 0.21 | 1.72 ± 0.23 | 1.86 ± 0.19 | 1.95 ± 0.23 | 2 ± 0.21 | <0.001 |
| (1.4–2.4) | (1.2–2.4) | (1.4–2.3) | (1.4–2.68) | (1.6–2.8) | (1.6–2.75) | ||
| Cerebellar vermis height | 3 ± 0.70 | 4.2 ± 0.42 | 4.3 ± 0.20 | 4.5 ± 0.38 | 4.6 ± 0.38 | 4.2 ± 0.32 | <0.001 |
| (2– 4) | (2.8–4.98) | (4–4.8) | (3.6–5.7) | (3.8–5.5) | (3.5–5) | ||
| Cerebellar vermis anteroposterior diameter | 1.9 ± 0.42 | 2.67 ± 0.40 | 2.8 ± 0.21 | 2.8 ± 0.41 | 2.6 ± 0.42 | 2.36 ± 0.27 | <0.001 |
| (1.2–2.5) | (1–3.8) | (2.2–3) | (2- 4) | (2-4) | (2-3) | ||
| Thickness of the superior cerebellar peduncle | 1 ± 0.24 | 1.8 ± 0.45 | 2 ± 0.32 | 2.3 ± 0.38 | 2.2 ± 0.43 | 2.2 ± 0.46 | <0.001 |
| (0.5–1.7) | (0.9–3) | (1–2.4) | (2– 4) | (2– 4) | (1.2–4) | ||
| Thickness of the middle cerebellar peduncle | 0.92 ± 0.18 | 1.34 ± 0.16 | 1.5 ± 0.20 | 1.5 ± 0.19 | 1.4 ± 0.21 | 1.3 ± 0.18 | <0.001 |
| (0.68–1.28) | (0.9–1.7) | (1.3–2) | (1–2.3) | (1–2.2) | (0.9–1.7) | ||
| Thickness of the inferior cerebellar peduncle | 0.36 ± 0.11 | 0.55 ± 0.14 | 0.67 ± 0.11 | 0.6 ± 0.12 | 0.6 ± 0.12 | 0.5 ± 0.12 | <0.001 |
| (0.2–0.6) | (0.2–0.7) | (0.4–0.8) | (0.33–0.9) | (0.3–0.8) | (0.2–0.7) | ||
All measurement units were expressed in (cm) except the thickness of superior cerebellar peduncle that was expressed in (mm)
One-way ANOVA test, the mean difference is significant at p ≤ 0.05
Reproducibility
Table 3 shows good to excellent intra- and interobserver reproducibility of all measured diameters (0.752–0.986 and 0.789–0.961, respectively), except the transverse diameter of the midbrain, anteroposterior diameter of the medulla oblongata at the pontomedullary junction, anteroposterior diameter of the medulla oblongata at the cervicomedullary junction, cerebellar vermis anteroposterior diameter, and thickness of the superior cerebellar peduncle.
Table 3.
Intra- and interobserver reproducibility of the investigated dimensions
| Dimension | Intraobserver | Interobserver | ||||
|---|---|---|---|---|---|---|
| Observer 1 | Observer 2 | |||||
| ICC | 95 % CI | ICC | 95 % CI | ICC | 95 % CI | |
| Anteroposterior diameter of the midbrain | 0.928 | 0.839–0.958 | 0.953 | 0.915–0.978 | 0.961 | 0.930–0.985 |
| Vertical diameter of the midbrain | 0.889 | 0.826–0.934 | 0.831 | 0.816–0.937 | 0.803 | 0.794–0.977 |
| Anteroposterior diameter of the tectum | 0.868 | 0.847–0.917 | 0.823 | 0.808–0.933 | 0.875 | 0.853–0.888 |
| Vertical diameter of the tectum | 0.980 | 0.977–0.988 | 0.969 | 0.952–0.990 | 0.944 | 0.931–0.979 |
| Anteroposterior diameter of the pons | 0.980 | 0.937–0.991 | 0.923 | 0.853–0.966 | 0.891 | 0.669–0.954 |
| Vertical diameter of the pons | 0.789 | 0.740–0.824 | 0.752 | 0.609–0.820 | 0.809 | 0.701–0.856 |
| Anteroposterior diameter of the basis pontis | 0.942 | 0.871–0.970 | 0.975 | 0.932–0.984 | 0.893 | 0.760–0.955 |
| Anteroposterior diameter of the medulla oblongata at the pontomedullary junction | 0.502 | 0.436–0.645 | 0.445 | 0.386–0.684 | 0.417 | 0.323–0.588 |
| Anteroposterior diameter of the medulla oblongata at the cervicomedullary junction | 0.466 | 0.572–0.680 | 0.409 | 0.513–0.748 | 0.429 | 0.572–0.609 |
| Transverse diameter of the midbrain | 0.470 | 0.423–0.535 | 0.410 | 0.503–0.622 | 0.390 | 0.352–0.405 |
| Transverse diameter of the pons | 0.887 | 0.714–0.942 | 0.859 | 0.695–0.939 | 0.908 | 0.793–0.958 |
| Transverse diameter of the medulla oblongata | 0.986 | 0.969–0.992 | 0.959 | 0.908–0.988 | 0.923 | 0.839–0.965 |
| Cerebellar vermis height | 0.785 | 0.699–0.882 | 0.823 | 0.809–0.912 | 0.789 | 0.709–0.823 |
| Cerebellar vermis anteroposterior diameter | 0.423 | 0.529–0.672 | 0.388 | 0.409–0.587 | 0.353 | 0.416–0.567 |
| Thickness of the superior cerebellar peduncle | 0.387 | 0.412–0.502 | 0.279 | 0.391–0.497 | 0.455 | 0.566–0.698 |
| Thickness of the middle cerebellar peduncle thickness | 0.909 | 0.795–0.958 | 0.978 | 0.898–0.957 | 0.877 | 0.778–0.956 |
| Thickness of the inferior cerebellar peduncle | 0.958 | 0.903–0.986 | 0.912 | 0.889–0.978 | 0.924 | 0.830–0.968 |
CI, confidence interval; ICC, intraclass correlation coefficient.
Effect of gender, age, and age by gender interaction
Brainstem
There was no significant gender-related variation in the brainstem measurements except for anteroposterior diameter of the basis pontis, anteroposterior diameter of the medulla oblongata at the cervicomedullary junction, and cerebellar vermis height (p = 0.044, 0.020, and 0.018, respectively). Across the different age groups, males showed higher mean values of the aforementioned measurements than females.
A substantial age-related change in the mean diameters of the brainstem, cerebellar vermis, and peduncles was found (p < 0.05). Except for the tectal ratio (p = 0.061), the mean values of other brainstem ratios did not significantly differ among the different age groups (Table 4). Post-hoc multiple comparisons for the brainstem diameters revealed a significant difference between the mean values of several pairs of age groups.
Table 4.
The effect of gender, age, and age by gender interaction on the acquired measurements
| Variables | ap-value | ||
|---|---|---|---|
| Gender | Age | Age × gender | |
| Anteroposterior diameter of the midbrain | 0.102 | <0.001 | 0.460 |
| Vertical diameter of the midbrain | 0.810 | <0.001 | 0.744 |
| Anteroposterior diameter of the tectum | 0.576 | <0.001 | 0.012 |
| Vertical diameter of the tectum | 0.074 | <0.001 | 0.337 |
| Anteroposterior diameter of the pons | 0.521 | <0.001 | 0.557 |
| Vertical diameter of the pons | 0.274 | <0.001 | 0.473 |
| Anteroposterior diameter of the basis pontis | 0.044 | <0.001 | 0.889 |
| Anteroposterior diameter of the medullo oblongata at the pontomedullary junction | 0.267 | <0.001 | 0.538 |
| Anteroposterior diameter of the medulla oblongata at the cervicomedullary junction | 0.020 | <0.001 | 0.562 |
| Transverse diameter of the midbrain | 0.111 | <0.001 | 0.618 |
| Transverse diameter of the pons | 0.621 | <0.001 | 0.636 |
| Transverse diameter of the medulla | 0.171 | <0.001 | 0.923 |
| Tectal ratio | 0.502 | 0.146 | 0.001 |
| Basis Pontis ratio | 0.078 | <0.001 | 0.142 |
| Pons/midbrain ratio | 0.647 | <0.001 | 0.554 |
| Pons/medulla ratio 1 | 0.300 | <0.001 | 0.394 |
| Pons/medulla ratio 2 | 0.052 | <0.001 | 0.185 |
| Cerebellar vermis height | 0.018 | <0.001 | 0.911 |
| Cerebellar vermis anteroposterior diameter | 0.433 | <0.001 | 0.803 |
| Thickness of the superior cerebellar peduncle | 0.209 | <0.001 | 0.627 |
| Thickness of the middle cerebellar peduncle | 0.341 | <0.001 | 0.022 |
| Thickness of the inferior cerebellar peduncle | 0.772 | <0.001 | 0.028 |
Two-way ANOVA test, the mean difference is significant at p ≤ 0.05.
The mean diameters of the midbrain and tectum gradually increased from neonates to young adults, followed by a decrease in middle and old age groups (Figure E1). Whereas pontine diameters showed a steady increase from neonates to middle age with a little subsequent reduction in the old age group (Figure E2). Medullary diameters showed their highest values in the adolescent age group with a gentle reduction from young adult to old age (FigureE3).
Although there was no significant effect of age on the mean value of the tectal ratio, the age by gender interaction had a substantial effect on it [F (5, 553)=4.379, p = 0.001] (Table 4). This effect was prominent in the neonate and infant (p < 0.001), and middle age groups (p = 0.012). Females in the neonate and infant age group had significantly higher mean values of the tectal ratio than males. Whereas males in the middle age group had significantly higher mean values of the tectal ratio than females. Post-hoc multiple comparisons for the tectal ratio showed a considerable mean difference among various pairs of age groups.
Cerebellar vermis
There was no gender-related change in the cerebellar vermis dimensions. The mean diameter of the cerebellar vermis height gradually increased from neonates to middle-aged adults with a little reduction in the old age group. In contrast, the mean diameter of the cerebellar vermis anteroposterior diameter showed a continuous increase from neonates to young adults, followed by a slight reduction in the middle and old age groups (Figure E4). Age by gender interaction did not influence the cerebellar vermis diameters (Table 4).
Cerebellar peduncles
No considerable gender-related variation existed in the thickness of the cerebellar peduncles. Both superior and middle cerebellar peduncles expressed a gradual increase in their mean thickness from neonates to young adults, and then a slight reduction was observed in middle age and old age groups. In contrast, the mean thickness of the inferior cerebellar peduncle reached its peak in the adolescent age group then significantly declined in young adult, middle age, and old age groups (Figure E5).
The age by gender interaction had a substantial effect on the mean values of the thickness of the middle cerebellar peduncle [F (5, 553)=2.653, p = 0.022] (Table 4). This effect was predominant in the young adult age group (p = 0.008).
Moreover, the age by gender interaction effect was significant on the mean values of the thickness of the inferior cerebellar peduncle [F (5, 553)=2.534, p = 0.028] (Table 4). This effect was dominant in the young adult (p = 0.038), and old age groups (p = 0.042) since young adult males had significantly higher mean values than females, while old aged females had significantly higher mean values than males. Substantial mean differences were demonstrated between many pairs of age groups on conducting post-hoc multiple comparisons for the cerebellar peduncles’ thickness.
Discussion
The current study provided age-specific normal mean values and ranges of various linear diameters and ratios of the brainstem, cerebellar vermis, and peduncles that could be a valuable reference in clinical practice for easier differentiation between physiological and pathological conditions of the posterior fossa structures especially cases with brainstem glioma, Parkinson disease, progressive supranuclear palsy, and multiple system atrophy. Moreover, this study provided valuable information about gender- and age-related differences in the size of posterior fossa structures that would add to the expanding neuroanatomical database.
Our subjects were categorized according to commonly used practical and standardized age groups with predetermined cut-points that could be concise and more informative than age ranges or extreme age groups applied in earlier studies.2,3,11–15 Each age group incorporated a reasonable number of both genders, which allowed simultaneous assessment of the effect of gender, age, and age by gender interaction.
In our study, reproducibility of the brainstem dimensions was good to excellent except for the transverse diameter of the midbrain, and anteroposterior diameters of the medulla oblongata at the pontomedullary and cervicomedullary junctions that showed poor intra- and interobserver agreement. Raininko et al2 reported good reproducibility of the sagittal diameter of the medulla oblongata and poor reproducibility of the midbrain peduncular diameter and did not recommend the application of unreliable measurements in clinical practice.
No significant gender-related difference was observed in the investigated measurements except anteroposterior diameter of the the basis pontis, anteroposterior diameter of the medulla oblongata at the cervicomedullary junction, and cerebellar vermis height. A significant age-related change was documented in all measurements except the tectal ratio. Age by gender interaction had a crucial effect on the tectal ratio, inferior and middle cerebellar peduncles measurements. To our knowledge, this is the first study investigating the gender- and age-related variability in the tectal ratio, size of the cerebellar peduncles in normal subjects, and providing normal reference values for them.
Our study was different from the prior studies that investigated the linear diameters of the normal posterior fossa structures1,3,12–15 regarding larger sample sizes, different age groups, MR image analysis, the spectrum of measurements and ratios, approach of statistical analysis, and results. Inconsistent results of earlier studies might be due to the racial differences of the study subjects.11
The current study findings correspond with previously published studies2,3,12–15 regarding the absence of gender-related effect on the posterior fossa linear measurements. Conversely, Murshed et al10 had found a larger brainstem size in males with no significant gender effect on the cerebellar vermis. Concerning the gender effect on the basis pontis anteroposterior diameter, our study endorses Oguro et al study6 reporting reduced anteroposterior diameter of the basis pontis exclusively in males >70-year-old.
Our study is concordant with the study of Elhussein et al,13 which confirmed a significant age-related impact on the brainstem linear measurements, in contrast to Suh et al12 who reported that the mean values of the brainstem sagittal diameters showed no significant difference between the different age groups. Raininko et al2 described a different age-related change in the sagittal midbrain diameters, reaching adult size early in childhood then reducing after the age of 45–50 years, and the pontine diameters which increased until adulthood with no age-related pontine atrophy coping with other volumetric studies.8,9,11
We match up with the previous studies,8,13 which stated that the age-related effect is prominent at midbrain measurements more than pontine measurements; this finding can be attributed to the degeneration of the midbrain neuronal tracts and nuclei, including substantia nigra and other nuclei.4 Elhussein et al13 and Raininko et al2 described a different pattern of medulla oblongata aging process, being decreased at the age of (41–60 years) and after 50-year-old, respectively.
Koehler et al1 reported the implication of brainstem ratios in the assessment of brainstem abnormalities, since brainstem ratios were lower than normal in brainstem atrophy and also varied in brainstem neoplasms according to the location and extension of the tumor. In agreement with earlier studies,14,15 we noticed a significant age-related variance in pons to midbrain and pons to medulla oblongata ratios. On the contrary, Kim et al17 reported a higher basis pontis ratio in males than females with no significant difference by age.
Our results coordinate with other studies10,18 considering the age-related atrophy of the cerebellar vermis, explained by the loss of Purkinje cells.19 Ahmed et al3 reported no significant age-related changes in the cerebellar vermis dimensions. Jandeaux et al20 defined a different cerebellar vermis growth pattern that stopped growing in childhood.
Our study was limited by the retrospective nature of the study that did not allow the collection of data regarding interindividual variants such as cranial size, body weight, and height, which might affect our measurements. Also, we could not involve healthy volunteers in this retrospective study, which resulted in a relatively small number of the incorporated neonates, infants, and adolescents compared with the number of other subjects and this might influence our results. Finally, no available data about patients’ past history of medications, substance use, and various systemic diseases that may influence the size of the posterior fossa structures.
In conclusion, we established age-specific normal reference values for the dimensions of the brainstem, cerebellar vermis, and peduncles through MR-based linear measurement approach, which was fast, easily applicable, and reproducible method. We also confirmed the insignificant gender-related effect and substantial age-related effect on the posterior fossa measurements and clarified the variation of age-related effect by gender.
Footnotes
Acknowledgements: The authors thank all staff members and colleagues in the Radiology Department, Zagazig University, for their helpful cooperation.
Competing interests: The authors declare that they have no competing interests.
Funding: The authors declare that this work has not received any funding.
Patient consent: written informed consent was waived by the Institutional Review Board
Ethics approval: Institutional review board’s approval was obtained.
Contributors: Guarantor of integrity of the entire study— (MM and AE). Study concepts and design—(MM and AE). Literature research—(MM, AE, GA, RF, RA). Clinical studies— (MM, AE, GA, RF, RA
and MN). Experimental studies/data analysis—(MB, MM, AE, and RF). Statistical analysis—(AE). Manuscript preparation— (MM, AE and MB). Manuscript editing—(MM and MB). All authors read and approved the final manuscript.
Contributor Information
Maha Ibrahim Metwally, Email: aleenys009@gmail.com.
Ghada Adel AbdelHamid, Email: aghada243@gmail.com.
Mohamad Gamal Nada, Email: mohammedgamalnada.mn@gmail.com.
Reham Ramadan Ali, Email: romaramadona@gmail.com.
Reem Abdel Fattah frere, Email: dr_reem_frere@yahoo.com.
Al Shaimaa Fathi Elshetry, Email: shaimaafathi2020@gmail.com.
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