Relationship of Morphometrics and Symptom Severity in Female Type I Chiari Malformation Patients with Biological Resilience.

In the present study we report the relationship among MRI-based skull and cervical spine morphometric measures as well as symptom severity (disability-as measured by Oswestry Head and Neck Pain Scale and social isolation-as measured by the UCLA Loneliness scale) on biomarkers of allostatic load using estrogen, interleukin-6, C-reactive protein, and cortisol in a sample of 46 CMI patients. Correlational analyses showed that McRae line length was negatively associated with interleukin-6 and C-reactive protein levels, and Analysis of Variance (ANOVA) showed joint effects of morphometric measures (McRae line length, anterior CSF space) and symptom severity (disability and loneliness) on estrogen and intereukin-6 levels. These results are consistent with allostatic load. That is, when the combination of CSF crowding and self-report symptom (disability and loneliness) severity exceed the capacity of biological resilience factors, then biomarkers such as neuroprotective estrogen levels drop, rather than rise, with increasing symptom severity.

Pain and Depression Account for More Than One Half of the Neck Disability Variance Among Adult Women with Chiari I.

OBJECTIVE: We sought to quantify the neck-related disability in adult women with Chiari malformation type I and identify the significantly related variables. METHODS: A total of 70 variables were selected from the self-report history questionnaires (12 variables; n = 474), standardized scales (15 variables; n = 474), and morphometric data (43 variables; n = 293-474) of adult women with Chiari malformation type I. The variables were tested independently to identify those with a significant relationship to the Neck Disability Index (NDI; P < 0.00071) and those that might be associated with the NDI (P < 0.05). A forward selection regression model was constructed to identify the variables contributing unique variance to the NDI. In addition, a mediation analysis was performed to determine whether depression mediated the relationship between pain and disability. RESULTS: Overall, 79.5% of the patients had scored at a moderate level of disability or higher. Independent testing identified 16 significant variables, including symptom duration, tonsillar position, and measures of psychological distress. The short-form McGill pain questionnaire-2 (r = 0.69; P < 0.00001) and CES-D scale for depression (r = 0.56; P < 0.00001) exhibited the highest correlations with the NDI. The forward selection regression model produced an R2 of 0.6178. Pain and depression accounted for more than one half of the NDI variance. CONCLUSIONS: We found that high levels of disability are common among adult women with Chiari malformation type I, independent of surgical status. Pain and depression were the primary factors related to this disability. Depression mediated the relationship between pain intensity and disability at a modest level (5%). Patients who had experienced symptoms for >2 years before diagnosis had had, on average, 77% higher NDI scores, highlighting the importance of a timely diagnosis.

The importance of precise plane selection for female adult Chiari Type I malformation midsagittal morphometrics.

INTRODUCTION: Morphometric assessment of Chiari malformation type I (CMI) is typically performed on a midsagittal MRI. However, errors arising from an imprecise selection of the midsagittal plane are unknown. We define absolute parasagittal error as the absolute difference between morphometric measurements at the midsagittal and parasagittal planes. Our objective was to determine the absolute parasagittal error at various lateral distances for morphometric parameters commonly used in CMI research. METHODS: Sagittal T1-weighted MRI scans of 30 CMI adult female subjects were included. Image sets were evaluated to assess 14 CMI morphometric parameters in the midsagittal plane and four parasagittal planes located 1 and 2 mm lateral (left and right). Comparisons between measurements at the midsagittal and parasagittal planes were conducted to determine the mean individual absolute and mean group parasagittal errors for all 14 parameters. RESULTS: The mean individual absolute parasagittal error was > 1 unit (1 mm for lengths and 1 degree for angles) for 9/14 parameters within a lateral distance of 2 mm. No significant group parasagittal errors were seen in 14/14 parameters, including tonsillar position within a lateral distance of 2 mm. CONCLUSION: Our results show that the absolute errors for imprecise midsagittal plane selection may impact the clinical assessment of an individual patient. However, the impact on group measurements, such as in a research setting, will be minimal.

Factors Associated With Patient-Reported Postsurgical Symptom Improvement in Adult Females with Chiari Malformation Type I: A Report from the Chiari1000 Dataset.

OBJECTIVE: The goal of this study was to assess if a broad array of factors is predictive of patient-reported surgical impact on symptoms. METHODS: Sixty-five presurgical factors were selected from the self-report history questionnaires (12 variables, N = 653), standardized scales (14 variables, N = 494-581), and morphometric measurements from magnetic resonance imaging (39 variables, N = 137) data of adult women in the Chiari1000 dataset. The factors were tested independently to identify those that were either significantly different in terms of, or significantly related to, patient-reported surgical impact on symptoms (P < 0.05). These results were then used to build a forward selection regression model. RESULTS: Overall, 74.4% of the patients reported either some level of improvement or complete resolution of symptoms. Independent testing identified 12 significant factors, including having a family member diagnosed with Chiari malformation type I (CMI), Ehlers-Danlos syndrome, migraines, duration of symptoms >2 years, multiple surgeries, symptom severity, depression, anxiety, stress, and loneliness. Depression showed the highest correlation (r = 0.36; P < 0.00001) with a negative outcome. The regression model produced an R2 = 0.346 and identified 5 factors with significant unique variance. CONCLUSIONS: The regression model accounted for more than a third of the surgical impact variance. Having a family member diagnosed with CMI contributed the largest unique variance to the model, suggesting that hereditary CMI may represent a unique subset of patients with poorer outcomes. Independent testing showed that psychological factors, such as depression and anxiety, were significant negative predictors, indicating that presurgical screening and treatment for these psychological conditions may improve outcomes.

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

PURPOSE: Incidental cerebellar tonsillar ectopia (ICTE) that meets the radiographic criterion for Chiari malformation type I (CMI) is an increasingly common finding in the clinical setting, but its significance 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: One-hundred-six subjects with ICTE and 106 matched controls without ICTE were identified 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 significantly different between the ICTE and control groups for females and males, respectively. Notably, for females, the anterior CSF space was significantly smaller (p = 0.00005) for the ICTE group than controls. For males, the clivus bone length was significantly shorter (p = 0.0002) for the ICTE group compared to controls. No significant 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.

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

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.

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

PURPOSE: While 84% of patients surgically treated for Chiari malformation type 1 (CM1) demonstrate improved quality of life after posterior fossa decompression surgery, there are many risks associated with this surgery. Surgical planning to identify candidates likely to improve postoperatively may benefit from an improved understanding of morphological changes after decompression surgery. To evaluate these changes, we quantified 59 morphological parameters on 42 CM1 adult female patients before and after CM1 decompression surgery. METHODS: Fifty-nine morphological parameters in the posterior cranial fossa, cranio-cervical, and intracranial regions in the midsagittal plane were evaluated using 42 T1-weighted magnetic resonance images of female CM1 patients before and after surgery, and 42 healthy female controls. Morphological differences before and after surgery were compared through the development of a technique to establish the opisthion location, a key reference point not present after surgery. RESULTS: In addition to the expected reduction of the cranio-caudal dimension of the cerebellum, objective analyses showed a significant increase in the area of the cerebrospinal fluid spaces, posterior (6×) and inferior (2.6×) to the cerebellum (+ 112 ± 102 and + 140 ± 127 mm2, respectively). This increased area was primarily impacted by an average reduction in the occipital bone length of 24.5 ± 7.3 mm following surgery. Based on multiple angles, results demonstrated a 2°-4° anterior rotation of the cerebellum after surgery. CONCLUSION: Our results show that decompression surgery results in significant changes in the cerebellum and cerebrospinal fluid spaces. Further investigation should determine how these morphological changes impact clinical outcomes.

A Retrospective 2D Morphometric Analysis of Adult Female Chiari Type I Patients with Commonly Reported and Related Conditions.

Purpose: Researchers have sought to better understand Chiari type I malformation (CMI) through morphometric measurements beyond tonsillar position (TP). Soft tissue and bone structures within the brain and craniocervical junction have been shown to be different for CMI patients compared to healthy controls. Yet, several morphological characteristics have not been consistently associated with CMI. CMI is also associated with different prevalent conditions (PCs) such as syringomyelia, pseudotumor, Ehlers-Danlos syndrome (EDS), scoliosis, and craniocervical instability. The goal of this study was two-fold: (1) to identify unique morphological characteristics of PCs, and (2) to better explain inconsistent results from case-control comparisons of CMI. Methods: Image, demographic, and PC information was obtained through the Chiari1000, a self-report web-accessed database. Twenty-eight morphometric measurements (MMs) were performed on the cranial MR images of 236 pre-surgery adult female CMI participants and 140 female healthy control participants. Custom software was used to measure 28 structures within the posterior cranial fossa (PCF) compartment, craniocervical junction, oral cavity, and intracranial area on midsagittal MR images for each participant. Results: Morphometric analysis of adult females indicated a smaller McRae line length in CMI participants with syringomyelia compared to those without syringomyelia. TP was reduced in CMI participants with EDS than those without EDS. Basion to posterior axial line was significantly longer in CMI participants with scoliosis compared to those without scoliosis. No additional MMs were found to differ between CMI participants with and without a specific PC. Four morphometric differences were found to be consistently different between CMI participants and healthy controls regardless of PC: larger TP and a smaller clivus length, fastigium, and corpus callosum height in CMI participants. Conclusion: Syringomyelia, EDS, and scoliosis were the only PCs that showed significant morphometric differences between CMI participants. Additionally, four midsagittal MR-based MMs were found to be significantly different between healthy controls and CMI participants regardless of the presence of one or more PCs. This study suggests that the prevalence of comorbid conditions are not strongly related to CMI morphology, and that inconsistent findings in the radiographic literature cannot be explained by varying prevalence of comorbid conditions in CMI study samples.