Pathophysiology and Treatment of Syringomyelia

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Genetics of Chiari I Malformation (CM1) Syringomyelia (SM) is often associated with Chiari I malformation (CM1). Ectopia of the cerebellar tonsils through the skull's foramen magnum is the defining characteristic of CM1. CM1 develops through various processes, including decreased volume of the posterior fossa or the posterior fossa region around the foramen magnum (1). This year, we published an article on the relationship between Chiari Malformation, Types 0 and 1, and a small posterior fossa [1]. In families with multiple members with CM1, abnormal posterior fossa development is a transmitted phenotypic trait. In a clinical study of families with CM1 in multiple members, we used magnetic resonance imaging of the brain to evaluate CM1 and measure the size of the bony structures and volume of the posterior fossa. After phenotyping, we collected DNA specimens to genotype family members as affected or unaffected with CM1 or small posterior fossa traits. In collaboration with Associate Investigator Joan Bailey-Wilson, M.D., Ph.D., we sent DNA samples of affected and control individuals for Whole Exome Sequence (WES) under the NHGRI NISC-funded flagship project. The samples originated from Russian and United States families with CM1. This data set consisted of whole-exome data from 10 extended families with 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 findings of a genome-wide significant signal on chromosomes 1q43-44 (HLOD = 3.5) and 12q23 (HLOD = 3.3) in both linkage analyses. Most interesting was that single (different) families drove both signals. Both regions held several linked exonic variants, including rare ones 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 found linkage to chromosomal regions in 2 families, but not specific gene variants associated with CM1. We performed whole genome sequencing (WGS) from these two families to find specific gene variants and confirm the causality of the linkage signals. Finding one or more genetic loci associated with CM1 would increase understanding of CM1 etiology. Natural History and Treatment of Syringomyelia We began a natural history study of patients with syringomyelia 15 years ago. Patients are monitored annually for five years with neurological examinations, standard scales of pain and function, and brain and spine MRI. Patients receive specialized care, including surgery if necessary. This study will better define the outcome of patients with SM and supply 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 finished follow-up in 2024. We have various subgroups in the study. In 2024, we published a prospective, longitudinal study of clinical outcomes and morphometric posterior fossa changes after craniocervical decompression for symptomatic Chiari I malformation. We also published our description of the audiovestibular phenotype of a 24-patient cohort with CM1 expressly referred for dizziness. We found that hearing and auditory brainstem tract function were essentially normal. This year, we contributed to a study comparing the presentations of pediatric and adult Chiari I malformation patients [2]. The adult CM1 patient population requiring surgical intervention had a greater proportion of female patients than the CM1 pediatric population. At the initial clinical presentation, syringomyelia and scoliosis had a higher incidence in pediatric patients than in adult patients with CM1. However, adults more often presented with signs and symptoms of headaches, ocular findings, and bulbar symptoms than children. After suboccipital decompression procedures for CM1, 94.4% of pediatric patients reported symptomatic relief compared with 75% of adults [2]. In 2025, we assisted Dr. Jian, an external collaborator, in his group's publication of a longitudinal cohort study on the natural history of patients with Chiari I malformation and syringomyelia [3]. The non-Chiari-related SM surgery subgroup of the syringomyelia natural history study includes patients with chronic adhesive spinal arachnoiditis (SA), a complex disease process resulting in SM, spinal cord tethering, CSF flow blockage, intradural adhesions, and spinal cord edema. The disease responds to open surgical approaches when focal or restricted to fewer than three spinal segments. Extensive arachnoiditis extending beyond four spinal segments has a much worse surgical prognosis, inadequate adhesion removal, and a higher propensity for postoperative scarring and retethering. This year we performed laboratory studies of arachnoid scar and cerebrospinal fluid (CSF) from patients with spinal arachnoiditis and syringomyelia to identify inflammatory and fibrotic biomarkers involved in arachnoiditis pathogenesis. We have also been studying flexible neuroendoscopy as a minimalist approach to extend the longitudinal range of the surgical field. Endoscopic dissection of extensive arachnoiditis revealed 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. Pathophysiology of Syringomyelia We previously evaluated the morphology of the cerebellum and medulla before and 3-6 months after surgery in patients with CM1 and SM. After surgically expanding the posterior fossa, the abnormally shaped cerebellum and medulla in CM1 adopted a more normal appearance. This morphologic finding supports CM1 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 SM. SM also resolved after removing the CSF pathway obstruction in Chiari I-type SM, suggesting that SM 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.