Pathophysiology and Treatment of Syringomyelia

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

Genetics of Chiari I Malformation. Syringomyelia is most often associated with Chiari I malformation. Chiari I malformation develops by an unknown process. Ectopia of the cerebellar tonsils (through the foramen magnum at the base of the skull), the defining characteristic of the Chiari I malformation, may result from abnormal posterior fossa development. In a clinical study of families with multiple members affected by the Chiari I malformation, we are using magnetic resonance imaging of the brain to evaluate Chiari I malformation and measure the size of the bony structures and volume of the posterior fossa. After phenotyping family members as affected or unaffected by these traits, we collect DNA specimens from them for genotyping. In collaboration with our Associate Investigator Joan Bailey-Wilson, M.D., Ph.D., we submitted DNA samples of affected and control individuals for Whole Exome Sequence (WES) under the NHGRI NISC-funded flagship project. The samples originated from families in Russia and the United States with Chiari I malformation in multiple members. This data set consisted of whole-exome data from 10 extended families with a total of 132 individuals (including samples that were previously sequenced). After extensive data cleaning, we identified a total of 560,134 markers, which were mapped onto the Rutgers Map to perform multi-point analyses. Two-point linkage analyses were performed using the program TwoPointLods. In 2019, we published our findings of a genome-wide significant signal on chromosome 1q43-44 (HLOD = 3.5) and 12q23 (HLOD = 3.3) in both sets of linkage analyses. Most interesting was that single (different) families drove both signals. Both regions contained several linked exonic variants, including rare variants located in good candidate genes. The two significantly linked regions for the small posterior fossa were the respective driving signals in the two families. This whole-exome sequencing (WES) study identified linkage to chromosomal regions in 2 families but not the specific gene variants associated with Chiari I malformation in those families. This year, we performed whole genome sequencing (WGS) on the DNA samples from the 2 families identified by linkage analysis to identify specific gene variants and confirm the causality of the linkage signals. Functional studies of proteins of interest will later evaluate if the gene variants discovered could cause Chiari I malformation. Finding one or more genetic loci associated with the Chiari I malformation would increase understanding of Chiari I malformation etiology. Last year, we co-authored a study that found an association of EPAS1-associate syndrome and Chiari I malformation, commenting on the role abnormal posterior fossa development plays in the development of Chiari I malformation in that syndrome. Improper mesenchymal transition is part of the mechanism of neuraxial dysraphism in EPAS1-associated syndrome (1). Dr. Rosenblum subsequently also reported on finding developmental vascular malformations in EPAS1 gain-of-function syndrome (2). Dr. Rosenblum described normal tentorial venous anatomy patterns in another article (3). Finally, we developed with Dr. Rosenblum in Dr. Zhuangs laboratory in NCI and Dr. Pacaks laboratory in NICHD a multimodal atlas of the development of the murine inner ear (4). These studies of normal murine inner ear development and human intracranial venous anatomy will support further investigations into the embryology and anatomy of the posterior fossa that may be relevant to Chiari I malformation. Treatment of Syringomyelia. We began a natural history study of patients with syringomyelia 11 years ago. Patients are monitored annually for 5 years with neurological examinations, standard scales of pain and function, and MRI of the brain and spine. Patients receive specialized care for their condition, including surgery if necessary. This study will better define the outcome of patients with syringomyelia and provide preliminary data to generate hypotheses for future hypothesis-driven studies. This study reached its enrollment ceiling of 180 subjects in 2019, and the final subject will finish in 2024. We have various subgroups in the study: a) Chiari I malformation alone, observation subgroup; b) Chiari I malformation alone, surgical treatment subgroup; c) Chiari I malformation with syringomyelia, observation subgroup; d) Chiari I malformation with syringomyelia, surgery subgroup; e) non-Chiari related syringomyelia, observation subgroup; and f) non-Chiari related syringomyelia, surgery subgroup. We will evaluate and compare the natural history of the various subgroups in the study. Pathophysiology of Syringomyelia. We previously reported a study evaluating the morphologic features of the cerebellum and medulla oblongata before and 3-6 months after surgery in patients with Chiari I malformation and syringomyelia. After surgically expanding the posterior fossa, the abnormal shape of the cerebellum and medulla oblongata characteristic of the Chiari I malformation changed to a more normal appearance. These findings support the concept that the Chiari I malformation arises from a lack of development of the posterior fossa rather than a primary neural abnormality. We subsequently published a paper with Linge et al. describing the physiologic changes in CSF flow at the foramen magnum after surgical treatment in patients with Chiari I malformation. We also published a clinical study of the pathophysiology of primary spinal syringomyelia, a type of syringomyelia not associated with Chiari I malformation. We found that the spinal subarachnoid space obstruction in primary spinal syringomyelia was associated with enlarged cerebrospinal fluid (CSF) pressure waves superior to the block. Successful surgery for primary spinal syringomyelia opened CSF pathways, reduced CSF pressure waves to normal, and resolved syringomyelia. We noted similar effects after successful surgery in our studies of Chiari I-type syringomyelia. Syringomyelia resolved after removing the CSF pathway obstruction in both primary spinal syringomyelia and Chiari I-type syringomyelia, suggesting syringomyelia arises from a similar mechanism in both conditions. We previously published a clinical study of CT-myelography that showed that syringes associated with obstruction of the spinal subarachnoid space had significantly more accumulation of myelography dye than syringes associated with intramedullary tumors, supporting more communication of the subarachnoid space with syringes associated with subarachnoid space obstruction than with syringes associated intramedullary tumor. This study supported the concept that syrinx fluid originates from the spinal subarachnoid space in syringes associated with spinal subarachnoid space obstruction.