A new hypothesis for the pathophysiology of symptomatic adult Chiari malformation Type I.

Chiari malformation Type I (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum. The pathophysiology of CMI is not well elucidated; however, the prevailing theory focuses on the underdevelopment of the posterior cranial fossa which results in tonsillar herniation. Symptoms are believed to be due to the herniation causing resistance to the natural flow of cerebrospinal fluid (CSF) and exerting a mass effect on nearby neural tissue. However, asymptomatic cases vastly outnumber symptomatic ones and it is not known why some people become symptomatic. Recently, it has been proposed that CMI symptoms are primarily due to instability of either the atlanto-axial (AA) or the atlanto-occipital (AO) joint and the cerebellar tonsils herniate to prevent mechanical pinching. However, only a small percentage of patients exhibit clinical instability and these theories do not account for asymptomatic herniations. We propose that the pathophysiology of adult CMI involves a combination of craniocervical abnormalities which leads to tonsillar herniation and reduced compliance of the cervical spinal canal. Specifically, abnormal AO and/or AA joint morphology leads to chronic cervical instability, often subclinical, in a large portion of CMI patients. This in turn causes overwork of the suboccipital muscles as they try to compensate for the instability. Over time, the repeated, involuntary activation of these muscles leads to mechanical overload of the myodural bridge complex, altering the mechanical properties of the dura it merges with. As a result, the dura becomes stiffer, reducing the overall compliance of the cervical region. This lower compliance, combined with CSF resistance at the same level, leads to intracranial pressure peaks during the cardiac cycle (pulse pressure) that are amplified during activities such as coughing, sneezing, and physical exertion. This increase in pulse pressure reduces the compliance of the cervical subarachnoid space which increases the CSF wave speed in the spinal canal, and further increases pulse pressure in a feedback loop. Finally, the abnormal pressure environment induces greater neural tissue motion and strain, causing microstructural damage to the cerebellum, brainstem, and cervical spinal cord, and leading to symptoms. This hypothesis explains how the combination of craniocervical bony abnormalities, anatomic CSF restriction, and reduced compliance leads to symptoms in adult 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.

An examination of pain, disability, and the psychological correlates of Chiari Malformation pre- and post-surgical correction.

BACKGROUND: 50% of patients with Chiari Malformation (CM) report a history of depression; however, rates of other psychological symptoms are unknown. Further, it is unclear whether surgical correction impacts pain, disability, and psychological symptoms. OBJECTIVE: /Hypothesis: We examined rates of symptoms in a nationwide sample of CM patients who had (n = 639) and had not (n = 551) undergone surgical correction. We hypothesized lower symptom severity in the latter group. METHODS: Participants completed assessments and submitted pre-surgical MRI scans online (n = 286). Informed by the Fear-Avoidance Model of pain, we controlled for psychological symptoms when assessing pain/disability, and pain/disability when assessing psychological symptoms. RESULTS: Overall, high rates of depression (44% moderate-severe) and anxiety (60% moderate-severe) were reported. Groups (surgery vs. no-surgery) did not differ in the proportion of patients meeting cutoff scores for current disability; however, the no-surgery group was more likely to meet cutoffs for anxiety (χ2 = 11.26, p < .05), stress (χ2 = 14.63, p < .01) and health anxiety (χ2 = 4.63, p < .05). The surgery group reported lower levels of continuous affective pain F(1, 1065) = 10.28, p < .001), anxiety F(1,1026) = 4.96, p < .05) and stress F(1, 978) = 5.67, p < .05) although effect sizes were small (η2s ranging from 0.010 to 0.006, Cohen's D ranging from 0.17 to 0.25). CONCLUSION: CM patients experience high rates of psychological symptomatology regardless of surgical status, suggesting that all CM patients may benefit from evidence-based interventions to address anxiety and depression.

Three-Dimensional CT Morphometric Image Analysis of the Clivus and Sphenoid Sinus in Chiari Malformation Type I.

This study evaluated three-dimensional (3D) volumetric image reconstructions to identify morphological differences of the clivus and sphenoid sinus on computed tomography (CT) scans of Chiari malformation type I (CMI) and control subjects. Axial CT images of adult females for 30 CMI subjects and 30 age and body mass index (BMI) matched controls were used for this retrospective study. 3D volumetric reconstructions were created from the bone windows of axial data following image registration for position and orientation correction of the head. The volume, surface area, linear dimensions and spatial position in the x, y, and z-axes were computed separately for the clivus and the sphenoid sinus for each subject. Eleven parameters were found to be significantly different between CMI subjects compared to controls. Most notably, clivus volume was reduced by 31% on average in CMI subjects. In contrast, we found that the sphenoid sinus volume was 38% greater on average in CMI subjects. Moreover, clivus length, height, width, and thickness were 3.7, 2.8, 3.0 and 9.4 mm reduced, respectively, in CMI subjects. This is the first study to demonstrate cephalometric differences in the 3D morphology of the clivus and sphenoid sinus between CMI subjects and controls.

National Institutes of Health Chiari Research Conference: state of the research and new directions.

OBJECTIVE: To establish the current Chiari knowledge base and develop recommendations for future research. METHODS: Chiari malformation: state of the research and new directions was a two-day, National Institutes of Health sponsored conference. The agenda included review presentations and working groups tasked with developing specific, achievable research recommendations. Content for both the review presentations and working groups was divided into six areas: pathophysiology, symptoms and diagnosis, engineering and imaging analysis, treatment, pediatric issues, and related conditions. RESULTS: The articles in this issue represent the knowledge base that was developed at the conference, plus subsequent literature reviews. There are significant gaps in the understanding of Chiari malformation, including a clinically relevant definition of Chiari, confusing terminology, subjective diagnostic criteria, and a well-accepted standard of care. These knowledge gaps are not surprising given the relative lack of Chiari research compared to similar neurological conditions and the preponderance of case reports in the published Chiari literature. The lack of understanding, and research, regarding Chiari translates directly into negative patient experiences and outcomes. CONCLUSIONS: Implementation of the recommendations developed at the conference would not only further expand the current understanding of the condition, but would likely have a significant, positive impact on patient experiences and outcomes.