Pathophysiology and Treatment of Syringomyelia

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

Genetics of Chiari I Malformation (CM1) Syringomyelia (SM) is often associated with Chiari I malformation (CM1). Ectopia of the cerebellar tonsils through the foramen magnum of the skull 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). In families with multiple members affected by CM1, abnormal posterior fossa development is a transmitted phenotypic trait (2). In a clinical study of families with CM1 in multiple members, we use 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 collect DNA specimens for genotyping 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 families in Russia and the United States with CM1 in multiple members. 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 our 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. We collaborated with Drs. Rosenblum, Pacak, and Zhuang in a study that found an association between EPAS1-associated syndrome and CM1. Improper mesenchymal transition contributes to the mechanism of neuraxial dysraphism in EPAS1-associated syndrome. Abnormal posterior fossa development predisposes to the development of CM1 in this syndrome. Natural History and 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 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 will be finished in 2024. We have various subgroups in the study. We 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. Abnormal functional balance was the most common finding (40%), followed by vestibular abnormalities during rotational testing (33%). Patients with CM1 sometimes had abnormal sensory organization test (SOT) postural stability scores for fixed platform conditions and abnormal somatosensory analysis scores. The extent of tonsillar ectopia was not associated with any vestibular/balance outcome measure. However, neck pain had a significant negative association with the somatosensory sensory analysis score, with neck pain associated with lower scores. Only 8% of patients had vestibulopathy. Our findings suggested that vestibular and balance assessments were of value and could lead to referral to proper specialists for treatment (3). This year, we also published a review article updating the diagnosis and treatment of CM1 (4). The non-Chiari-related SM surgery subgroup includes patients with chronic adhesive spinal arachnoiditis (SA). SA is a complex disease process resulting in SM, 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 SM, 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 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 (5). 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. This year, we published a review article on CSF hydrodynamics in CM1 and SM (6).