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 (1). Ectopia of the cerebellar tonsils through the foramen magnum of the skull is the defining characteristic of the Chiari I malformation. It may result from abnormal posterior fossa development (2). In a clinical study of families with Chiari I malformation in multiple members, we use 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 with the Chiari I malformation or small posterior fossa traits, we collect DNA specimens for genotyping. In collaboration with 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. After extensive data cleaning, we identified 560,134 markers, mapped them onto the Rutgers Map, and performed 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 chromosomes 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 ones located in good candidate genes. The two significantly linked regions for the small posterior fossa were the respective driving signals in the two families. Our whole exome sequencing identified linkage to chromosomal regions in 2 families but not specific gene variants associated with Chiari I malformation. We performed whole genome sequencing (WGS)from these two families to identify specific gene variants and confirm the causality of the linkage signals. Finding one or more genetic loci associated with the Chiari I malformation would increase understanding of Chiari I malformation etiology. We collaborated with Drs. Rosenblum, Pacak, Zhuang, and others in a study that found an association between EPAS1-associated syndrome and Chiari I malformation. Improper mesenchymal transition contributes to the mechanism of neuraxial dysraphism in EPAS1-associated syndrome. Abnormal posterior fossa development predisposes to the development of Chiari I malformation in this syndrome. Dr. Rosenblum also reported developmental vascular malformations in EPAS1 gain-of-function syndrome (3). In another article, Dr. Rosenblum described his multimodal atlas of the development of the murine inner ear (4). Dr. Rosenblum also developed a non-invasive method to visualize the murine cranial vasculature (5). These studies will support further investigations into the embryology and vascular anatomy of the posterior fossa relevant to Chiari I malformation. Treatment of Syringomyelia We began a natural history study of patients with syringomyelia 12 years ago. Patients are monitored annually for five years with neurological examinations, standard scales of pain and function, and MRI of the brain and spine. Patients receive specialized care, 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. The non-Chiari-related syringomyelia surgery subgroup includes patients with chronic adhesive spinal arachnoiditis (SA). SA is a complex disease process resulting in syringomyelia, spinal cord tethering, CSF flow blockage, intradural adhesions, and spinal cord edema. The disease responds well to open surgical approaches when it is focal or restricted to fewer than three spinal segments. More extensive arachnoiditis extending beyond four spinal segments has a much worse surgical prognosis, less adequate removal of adhesions, and a higher propensity for postoperative scarring and retethering. We have been studying flexible neuroendoscopy as a minimalist approach to extend the longitudinal range of the surgical field. Over three years, we treated ten patients with progressive myelopathy from extensive SA. Seven patients had syringomyelia, one spinal cord edema, and two spinal cord distortion. The surgical intervention included 2- to 5-level thoracic laminectomy, microscopic lysis of adhesions, and then lysis of adhesions at adjacent spinal levels using an endoscope. The mean follow-up was five (range 215) months. Neurological function was examined using standard measures. MRI assessed syrinx resolution. Patients underwent laminectomies averaging 3.7 (range 25) levels followed by endoscopy, which expanded exposure by an average of another 2.4 segments. Endoscopic dissection of extensive arachnoiditis proceeded through a complex network of opaque arachnoidal bands and membranes bridging from the dorsal dura mater to the spinal cord. The endoscope did not compress or injure the spinal cord. Intrathecal endoscopy allowed visual assessment and safe removal of intradural adhesions beyond the laminectomy margins. Further development of this technique should improve its effectiveness in opening the subarachnoid space and untethering the spinal cord in extensive chronic adhesive SA (6). Pathophysiology of Syringomyelia We previously evaluated the morphology of the cerebellum and medulla before and 3-6 months after surgery in patients with Chiari I malformation and syringomyelia. After surgically expanding the posterior fossa, the abnormally-shaped cerebellum and medulla in Chiari I malformation adopted a more normal appearance. This morphologic finding supports Chiari I malformation arising from reduced posterior fossa development rather than a primary neural abnormality. We also published a clinical study of the pathophysiology of primary spinal syringomyelia. The cerebrospinal fluid (CSF) pressure waves were high in this condition, superior to an associated spinal subarachnoid space obstruction. Successful surgery for primary spinal syringomyelia opened CSF pathways, reduced CSF pressure waves, and resolved syringomyelia. Syringomyelia also resolved after removing the CSF pathway obstruction in Chiari I-type syringomyelia, suggesting syringomyelia arises from the spinal subarachnoid CSF by a similar mechanism. We previously published a clinical study of CT-myelography that showed that syringes associated with obstruction of the foramen magnum or spinal subarachnoid space had significantly more accumulation of myelography dye than syringes associated with intramedullary tumors. This finding supported more communication of the subarachnoid space with syringes associated with a subarachnoid space obstruction than syringes associated with an intramedullary tumor. This study supported the concept that syrinx fluid originates from the spinal subarachnoid space in syringes associated with spinal subarachnoid space obstruction.