Quantification of changes in brain morphology following posterior fossa decompression surgery in women treated for Chiari malformation type 1

Eppelheimer, Maggie S.; Biswas, Dipankar; Braun, Audrey M.; Houston, James R.; Allen, Philip A.; Bapuraj, Jayapalli Rajiv; Labuda, Richard; Loth, Dorothy; Frim, David M.; Loth, Francis

doi:10.1007/s00234-019-02206-z

Cited by 22 publications

(21 citation statements)

References 43 publications

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“…Classical CM-1 occurs because of a smaller and shallower posterior cranial fossa (PCF), as a consequence of a change in the length and slope of the basilar part of the occipital bone (basiocciput) [ 5 , 32 , 33 ]. However, other mechanisms can also lead to a small PCF, such as craniosynostosis (Crouzon’s syndrome or Apert syndrome).…”

Section: Discussionmentioning

confidence: 99%

Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1

et al. 2021

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Chiari Malformation Type 1 (CM-1) is characterized by herniation of the cerebellar tonsils below the foramen magnum and the presence of headaches and other neurologic symptoms. Cranial bone constriction is suspected to be the most common biologic mechanism leading to CM-1. However, other mechanisms may also contribute, particularly in the presence of connective tissue disorders (CTDs), such as Ehlers Danlos Syndrome (EDS). Accumulating data suggest CM-1 with connective tissue disorders (CTD+) may have a different patho-mechanism and different genetic risk factors than CM-1 without CTDs (CTD-). To identify CM-1 genetic risk variants, we performed whole exome sequencing on a single large, multiplex family from Spain and targeted sequencing on a cohort of 186 unrelated adult, Caucasian females with CM-1. Targeted sequencing captured the coding regions of 21 CM-1 and EDS candidate genes, including two genes identified in the Spanish family. Using gene burden analysis, we compared the frequency of rare, functional variants detected in CM-1 cases versus publically available ethnically-matched controls from gnomAD. A secondary analysis compared the presence of rare variants in these genes between CTD+ and CTD- CM-1 cases. In the Spanish family, rare variants co-segregated with CM-1 in COL6A5, ADGRB3 and DST. A variant in COL7A1 was present in affected and unaffected family members. In the targeted sequencing analysis, rare variants in six genes (COL7A1, COL5A2, COL6A5, COL1A2, VEGFB, FLT1) were significantly more frequent in CM-1 cases compared to public controls. In total, 47% of CM-1 cases presented with rare variants in at least one of the four significant collagen genes and 10% of cases harbored variants in multiple significant collagen genes. Moreover, 26% of CM-1 cases presented with rare variants in the COL6A5 gene. We also identified two genes (COL7A1, COL3A1) for which the burden of rare variants differed significantly between CTD+ and CTD- CM-1 cases. A higher percentage of CTD+ patients had variants in COL7A1 compared to CTD+ patients, while CTD+ patients had fewer rare variants in COL3A1 than did CTD- patients. In summary, rare variants in several collagen genes are particularly frequent in CM-1 cases and those in COL6A5 co-segregated with CM-1 in a Spanish multiplex family. COL6A5 has been previously associated with musculoskeletal phenotypes, but this is the first association with CM-1. Our findings underscore the contribution of rare genetic variants in collagen genes to CM-1, and suggest that CM-1 in the presence and absence of CTD symptoms is driven by different genes.

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Section: Discussionmentioning

confidence: 99%

Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1

et al. 2021

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“…Twenty-two 2D measurements were performed by a single operator (DML) using MorphPro [35] and CerePro [36], a custom in-house software developed in MATLAB (MathWorks, Natick, MA) at the University of Akron [35,36] (Figure 1). The methodology used for the morphometric measures has been described in previous studies [30,31,36]. Each morphometric measurement, brie y described in Table 1, was compared between the ICTE and control groups for both males and females (see Figure 1 for visual examples).…”

Section: Methodsmentioning

confidence: 99%

“…While the morphometrics of adult CMI has been studied extensively, less information is available regarding pediatric CMI morphometrics. In fact, several studies have reported the limited availability of MRIs as the reason for excluding pediatric subjects [29][30][31]. The pediatric morphometric studies that exist have produced mixed results, possibly due to the di culties in acquiring gender and age-matched control images [32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Imaging and health metrics in incidental cerebellar tonsillar ectopia: findings from the Adolescent Brain Cognitive Development Study (ABCD)

et al. 2021

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Incidental cerebellar tonsillar ectopia (ICTE) that meets the radiographic criterion for Chiari malformation type I (CMI) is an increasingly common nding in the clinical setting, but its signi cance is unclear. The present study examined posterior cranial fossa (PCF) morphometrics and a broad range of health instruments of pediatric ICTE cases and matched controls extracted from the Adolescent Brain Cognitive Development (ABCD) dataset. Methods.106 subjects with ICTE and 106 matched controls without ICTE were identi ed from 11,411 anatomical MRI of healthy screened pediatric subjects from the ABCD project. Subjects were matched by sex, age, body mass index, race, and ethnicity. Twenty-two brain morphometrics and 22 health instruments were compared between the two groups to identify unrecognized CMI symptoms and assess the general health impact of ICTE. Results.Twelve and 15 measures were signi cantly different between the ICTE and control groups for females and males, respectively. Notably, for females, the anterior CSF space was signi cantly smaller (p = 0.00005) for the ICTE group than controls. For males, the clivus bone length was signi cantly shorter (p = 0.0002) for the ICTE group compared to controls. No signi cant differences were found among the 22 health instruments between the two groups. Conclusion.This study demonstrated that pediatric ICTE subjects have similar PCF morphometrics to adult CMI. ICTE alone did not appear to cause any unrecognized CMI symptoms and had no impact on the subjects' current mental, physical, or behavioral health. Still, given their cranial and brain morphology, these cases may be at risk for adult-onset symptomatic CMI.

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“…CMI is also three times more likely to be identified in women than in men. [1][2][3][4][5] While traditionally characterized by the descent of the cerebellar tonsils >3-5 mm below the foramen magnum, 6,7 additional morphological characteristics, including the lowering of PCF structures relative to the foramen magnum, the sharper angulation of the clivus in relation to the odontoid process, and the retroflexion of the odontoid process, have been identified. 1 However, individual differences in these presentations, such as the influence of age, sex, and body mass index (BMI), have received little attention and have led to two problematic consequences.…”

Section: Introductionmentioning

confidence: 99%

Evidence for sex differences in morphological abnormalities in type I Chiari malformation

et al. 2019

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Background and purpose Relatively little is known about the influence of individual difference variables on the presentation of macro-level brain morphology in type I Chiari malformation (CMI). The goal of the present study is to examine how case-control differences in Chiari are affected by patient sex. Materials and methods Patient-provided magnetic resonance images were acquired through the Chiari 1000 database. Twenty-four morphometric measurements were taken using mid-sagittal images of 104 participants (26 male CMI, 26 female CMI, 26 male controls, and 26 female controls) using internally developed and validated custom software, Morphpro. Case-control comparisons were conducted separately by sex using healthy controls matched by age and body mass index. Probability-based t-tests, effect sizes (Cohen's d), and confidence intervals were used to compare case-control differences separately by sex. Results Male and female case-control comparisons yielded largely the same trends of CMI-related morphometric abnormalities. Both groups yielded reductions in posterior cranial fossa (PCF) structure heights. However, there was evidence for greater PCF structure height reductions in male CMI patients as measured by Cohen's d. Conclusions Case-control differences indicated strong consistency in the morphometric abnormalities of CMI malformation in males and females. However, despite the higher prevalence rates of CMI in females, the results from the present study suggest that male morphometric abnormalities may be greater in magnitude. These findings also provide insight into the inconsistent findings from previous morphometric studies of CMI and emphasize the importance of controlling for individual differences when conducting case-control comparisons in CMI.

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Quantification of changes in brain morphology following posterior fossa decompression surgery in women treated for Chiari malformation type 1

Cited by 22 publications

References 43 publications

Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1

Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1

Imaging and health metrics in incidental cerebellar tonsillar ectopia: findings from the Adolescent Brain Cognitive Development Study (ABCD)

Evidence for sex differences in morphological abnormalities in type I Chiari malformation

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