For the first time, this study examined PCF morphometrics and the overall health impact of ICTE in the general pediatric population. Previous pediatric morphometrics studies have been limited in terms of both the morphometrics measures examined and how subjects were selected [32-34]. Perhaps because of this, results have been mixed. In comparing CMI to controls, Trigylidas et al. [34] found differences, while Furtado et al. did not [32]. Khalsa et al. compared asymptomatic to symptomatic CMI across ten morphometrics measures and found no differences, implying that structurally ICTE may be similar to symptomatic CMI. However, Khalsa et al. used hospital-based images, which raises the question of whether the finding of TP > 5mm is strictly incidental since each patient presented at the hospital with sufficient concern to justify head and neck MRI acquisition [33]. The present study used the ABCD data repository to identify the ICTE and control pediatric subjects. All ABCD participants were screened for major health and neurological issues, ensuring that all subjects were healthy, and thus, all subjects found with TP > 5mm were strictly incidental. In addition, the size of the ABCD repository enabled the selection of a carefully matched control group by race, ethnicity, gender, age, BMI, all factors that can affect morphometric evaluation [37]. Finally, 22 morphometrics measures were selected representing cranial, tissue, PCF lengths, areas, and angles that together comprise an extensive assessment of the PCF morphometrics. This incidental tonsillar ectopia study is highly unique because of the careful screening of the ABCD participants, the fact that the ABCD participants were volunteering and not seeking medical care, and because the control group was precisely matched to the ICTE group.
PCF Morphometrics
The present pediatric results were compared with adult CMI PCF morphometrics reported previously [31, 36, 37]. Specifically, Houston et al. looked at >115 adult female CMI subjects compared to matched controls and found 14 significant differences they grouped as PCF structure heights, clivus angulation, and odontoid process irregularities [31, 36]. In a smaller follow-up study, Houston et al. examined the same PCF morphometrics in 26 male symptomatic CMI subjects and matched controls and found largely similar results as with females, but that the male differences were larger in magnitude [37]. In a study using many of the same subjects as Houston et al., Biswas et al. found that adult female CMI subjects exhibited larger cerebellum (in the PCF space) and reduced CSF spaces below the FM [36]. Our study has found pediatric ICTE subjects, both male and female, demonstrate similar differences to controls as adult symptomatic CMI cases do in terms of reduced PCF structure heights and crowding, but not in terms of clivus angulation or odontoid process irregularities. In addition, we found several gender-based differences in comparing ICTEs to controls.
PCF Structure Heights
Houston et al. found that in adults (females and males), the distances from the fastigium, pons, and corpus callosum to the McRae line were ~3mm shorter in CMI subjects compared to controls, meaning the entire hindbrain sits lower [31, 37]. Pediatric ICTE subjects were also found to have a ~3mm shortening of the distance from the McRae line to these hindbrain structures, implying a similar type of hindbrain sagging as seen in adult CMI. However, the clivus bone in adult CMI has also been found to be significantly shorter compared to controls, with a larger reduction in men than women (5.4 vs. 3 mm, respectively) [29, 31, 37]. In the present study, the differences in clivus length between ICTE and controls were not as dramatic (1.15 and 2.15 mm, for females and males, respectively), with only the male difference reaching statistical significance. This could be an indication of ICTE versus symptomatic CMI in females as it is similar to what Nwotchouang et al. found in comparing symptom-free female adults with low-lying tonsils (TP < 5 mm) to healthy controls. They reported that the clivus lengths were similar between the two groups (0.3 mm difference, p=0.79 [38]. However, it could also be due to the relatively young age of the ICTE subjects, as the closure of the synchondrosis between the basisphenoid and basioccipital regions of the clivus does not start in girls until 12-13 years, in boys at 14-15 years, and is not complete until 17-18 years [39, 40].
Crowding
Compared to controls, adult female CMI patients have been found to have a significantly smaller PCF area on average combined with an 8.4% larger cerebellum (even without considering the herniated tonsils), resulting in crowding of the PCF [36]. In addition, compared to controls, adult female CMI have reduced CSF spaces below the FM (25 and 20% on the posterior and anterior sides, respectively). Unfortunately, similar morphometrics measurements are not available for adult male CMI subjects in the literature. We found that both female and male pediatric ICTE subjects showed significant reductions in anterior PCF and PCF areas relative to controls and increased cerebellum area inside the PCF of 13 and 15%, respectively. While this increase in cerebellum size is larger than seen in adults, it should be noted that total cerebellar volume has been found to follow an inverted U course with age, peaking at around 12 years for females and 15-16 years for males [41]. Regardless, both male and female ICTE subjects clearly showed crowding of the PCF area similar to what is seen in symptomatic adult CMI.
In terms of crowding below the FM, the posterior CSF space was significantly reduced by 24% for pediatric ICTE females and 19% for pediatric ICTE males compared to controls, similar to the adult female CMI finding. However, the anterior CSF space was only significantly reduced for ICTE females (19%) and not males. Since this morphometric is not available for adult male CMI, this finding's implications are not clear. It is interesting to note that it could contribute to the fact that females far outnumber males in adult symptomatic CMI prevalence [42-44].
Clivus Angulation
Adult CMI subjects on average demonstrate a flattening of the clivus bone indicative of cranial settling as reflected in a significant increase in the Boogard angle (3° for females, 6° for males) and a significant decrease in the Wackenheim angle (6° for females, 8° for males) [31, 37]. For this study, the Boogard angle showed similar differences between the ICTE and control groups (4° for females and 5° for males), but the Wackenheim angle did not (3° for females and 1° for males). This may be due to the age of the subjects, but it also could have implications for the pathogenesis of CMI symptoms. Since Boogard angle and Wackenheim angle overlap via the clivus, this implies that the alignment of the odontoid, C1 and C2 may be different in adult symptomatic CMI compared to incidental cases. This is supported by the fact that Houston et al. also found that the odontoid angle was significantly smaller in adult female CMI compared to controls (3°), but in this study, the odontoid angle was not significantly different between the ICTE groups and controls. It could be that misalignment of the upper cervical spine of even just a few degrees plays a role in adult CMI symptomatology, perhaps through subtle instability. Goel et al. has recently proposed that cervical instability plays a primary role in CMI symptoms and that the cerebellar tonsils herniate to cushion from mechanical pinching, but his theory does not account for the preponderance of ICTE compared to symptomatic CMI [45]. It seems more likely that upper cervical misalignment, even if subtle, is one of several factors which, in concert, contribute to the development of CMI symptoms.
Normative Values
Although the control subject group was not selected randomly or with purposeful distribution by race and ethnicity, it still represents a large sample of healthy 9–10 year-olds. As such, this study established for the first-time normative PCF morphometric values for that age range in both males and females, which can be used as the basis for future comparative studies.
Health Metrics
No significant differences were found between either female or male ICTE and the associated control groups for any of the physical, mental and behavioral health instruments. Given the breadth of assessments, it is reasonable to conclude that ICTE in and of itself does not have a measurable impact on the overall health of 9-10 year old pediatric subjects.
In addition, the health instruments contained a number of elements that would be indicative of unrecognized CMI symptoms. Headaches have been found to affect 40-78% of pediatric symptomatic CMI cases, yet the Medical History Questionnaire revealed no significant difference between either the male or female ICTE groups and the associated control groups in terms of headache history (Table 4) [1, 5]. Similarly, both vision problems - such as nystagmus, strabismus, diplopia, and blurred vision – and sensorineural hearing loss have been linked to pediatric CMI, but again, the Medical History Questionnaire showed no difference between the ICTE and control groups [3, 6, 9] in these areas. Although less common, seizures have also been linked by some to pediatric CMI, but the Medical History showed no differences in this regard either [46, 47].
The health instruments included a Parent Sleep Disturbance Scale for Children. Using polysomnography, Amin et al. found that 49% of 68 pediatric CMI cases exhibited sleep-disordered breathing. In a review, Abel et al. and Tahir et al. concluded that sleep-disordered breathing is highly prevalent in pediatric CMI [2, 8]. In contrast, we found no significant difference in reports of difficulty breathing during sleep, gasping for air, snoring, or overall sleep patterns between the ICTE and control groups.
Both parent surveys and cognitive testing have identified that CMI can impair executive function in pediatric cases [7, 48]. We found no significant differences in either the Stroop Test or Youth Wills Problem Solving Scale between the pediatric ICTE and control groups.
Finally, although the prevalence has not been established, pediatric CMI has been linked to precocious puberty in both males and females [48, 49]. Given the focus of the ABCD study, it includes both a Pubertal Development/Menstrual Cycle Survey and a hormonal assay. Again, no significant differences were found between the ICTE and control groups for these measures.
It is important to consider that it is unknown if any of the ICTE cases will manifest symptoms later in childhood or as adults. In a natural history review, Chatrath et al. found that 5-6% of clinically identified pediatric asymptomatic CMI cases develop symptoms over the course of several years [22]. However, no study has followed pediatric ICTE cases into adulthood, and given their morphology, the adolescents identified here may be at risk for adult-onset CMI.
ICTE Prevalence
Because the false-negative rate for the methodology used to identify the ICTE subjects from the ABCD repository is unknown, establishing an accurate ICTE prevalence from this study is not possible. However, since the automatic results were manually screened for false positives, a lower bound for ICTE prevalence among 9 to 10 year olds can be determined confidently. We identified and confirmed 112 ICTE subjects out of 11,411, representing a lower bound of 0.98%. This is lower than Smith et al. found, but they utilized a hospital database as opposed to a general pediatric population [14]. A manual review of the entire ABCD repository would be required to specify the exact ICTE prevalence, but such an undertaking was beyond the scope of this study.
ICTE & Symptomatic CMI
Radiographically, the ICTE groups in this study looked remarkably similar to adult symptomatic CMI cases. The average TP for females was 9.5 mm and for males was 8.2 mm. In addition, there were 20 cases with TP > 10 mm and 4 cases with TP > 15 mm. ICTE subjects showed a reduced height of PCF structures, crowding inside the PCF, and reduced CSF spaces below the FM. Despite this, there were no indications of any unrecognized CMI symptoms, or health impact in general, of this anatomy. This calls into question the utility of TP and crowding as indicators of CMI and also the theory that symptoms arise from a mass effect and CSF restriction [50]. However, as opposed to adult CMI, the ICTE cases did show normal alignment of the upper cervical spine and odontoid. This could mean that misalignment of C1, C2, and the odontoid process plays a role in CMI symptomatology, but further research is required to establish this.
It is also possible that a subset of the identified pediatric ICTE cases will go on to develop CMI symptoms as adults. However, the prevalence of symptomatic CMI has been estimated at 0.1% [51]. The prevalence of ICTE, even among adults, is an order of magnitude higher; so how likely it is for an individual pediatric ICTE subject to develop adult-onset Chiari is not clear. In this scenario, it is also not clear why symptoms manifest in adulthood. It could be due to aging issues further affecting the PCF morphology, or it is possible that morphometrics such as TP and PCF/CSF crowding are a necessary but not sufficient component of symptomatic CMI and that physical trauma or dynamic factors, such as involving the vascular and/or CSF systems, play a role. Either way, adult CMI PCF morphometrics in adolescence is a potential risk factor for adult-onset CMI.
The ABCD study intends to follow subjects ten years into early adulthood with repeated imaging and health assessments. This provides an unprecedented opportunity to track the PCF morphological development of the ICTE and control groups as they mature. The assessments can also be used to monitor the development of any impact ICTE may have on the subjects' mental, physical, or behavioral health.
This study's primary limitation lies in interpreting the results of the morphometric differences found between pediatric ICTE and controls compared to established morphometric differences between adult CMI and controls. Ideally, a third matched group of pediatric CMI would be included for analysis rather than relying on adults. But identifying precisely matched CMI subjects in sufficient numbers was impossible. This means that the variations in the pediatric differences compared to the adult differences could be due to age and not necessarily reflective of symptomatic CMI. However, over time as repeated studies are performed on the same ICTE and control subjects into adulthood, this limitation will be mitigated. A second limitation arises from using an automated process to identify the ICTE subjects from the ABCD repository. Although the identified ICTE cases were manually verified, it is not known what portion of the total ICTE cases in the repository they represent. Some ICTE cases were likely missed, and as a result, sampling bias could have been introduced as a result of the selection program used.