Pathophysiology and Treatment of Syringomyelia

脊髓空洞症的病理生理学和治疗

基本信息

批准号：
10915973
负责人：
John Heiss
金额：
$ 105.3万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10915973
关键词：
Adhesions Adhesives Adopted Affect Appearance Arachnoiditis Auditory Automobile Driving Brain Brain Stem Brain imaging Candidate Disease Gene Caring Cerebellar tonsil Cerebellum Cerebrospinal Fluid Cerebrospinal Fluid Pressure Characteristics Chest Chromosomes Chronic Cicatrix Clinical Research Collaborations Communication Complex Congenital Disorders Cyst Cytolysis DNA Data Data Set Development Diagnosis Disease Dissection Dizziness Doctor of Medicine Doctor of Philosophy Dorsal Dura Mater Dyes Edema Effectiveness Endoscopes Endoscopy Enrollment Equilibrium Etiology Excision Extended Family Family Family Study Family member Functional disorder Funding Future Genetic Genotype Hearing Individual Infection Laminectomy Link Liquid substance Magnetic Resonance Imaging Maps Measures Membrane Mesenchymal Microscopic Morphology Myelography National Human Genome Research Institute Natural History Neck Pain Nervous System Physiology Neuroendoscopy Neurologic Dysfunctions Neurologic Examination Obstruction Operative Surgical Procedures Outcome Measure Paralysed Pathway interactions Patient Monitoring Patient-Focused Outcomes Patients Phenotype Physical shape Posterior Fossa Postoperative Period Posture Process Prognosis Publishing Research Personnel Resolution Russia Sampling Sensory Shapes Signal Transduction Specialist Specimen Spinal Spinal Cord Spinal Cord Diseases Structure Subarachnoid Space Subgroup Syndrome Syringes Syringomyelia Testing Tonsil Trauma United States Update Variant Vertebral column Visual cerebrospinal fluid flow cohort cranium data cleaning exome exome sequencing flexibility follow-up foramen magnum genetic linkage analysis genetic variant genome sequencing genome-wide genomic locus improved malformation member neural pain scale programs somatosensory standard measure technique development trait transmission process tumor whole genome

项目摘要

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).

Chiari I畸形的遗传学（CM1）色疗（SM）通常与Chiari I畸形（CM1）有关。小脑扁桃体的外生通过颅骨的孔，是CM1的定义特征。 CM1通过各种过程形成，包括后窝的体积减少或孔周围的后窝区域（1）。在患有多个受CM1成员的家庭中，异常后窝发育是一种传播的表型特征（2）。在多个成员中CM1家族的临床研究中，我们使用大脑的磁共振成像来评估CM1并测量骨结构的大小和后窝的体积。表型后，我们收集针对基因分型家族成员的DNA标本，因为该家族成员受到CM1或小后孔的影响。在与NHGRI NISC资助的旗舰项目下，与副研究员Joan Bailey-Wilson，医学博士Joan Bailey-Wilson博士合作，为整个外显子序列（WES）发送了受影响和控制个体的DNA样本。这些样品起源于多个成员的俄罗斯和美国的家庭。该数据集由来自10个有132个人的大家庭的全外观数据组成。经过广泛的数据清洁后，我们确定了560,134个标记，将它们映射到Rutgers地图上，并进行了多点分析。使用程序twopointlods进行了两点链接分析。在2019年，我们在两个链接分析中发表了关于染色体1q43-44（HLOD = 3.5）和12q23（HLOD = 3.3）的全基因组显着信号的发现。最有趣的是那个单身（不同的）家庭都开了两个信号。这两个区域都有几种连接的外显子变体，包括良好候选基因中的罕见。小窝小窝的两个显着连接的区域是两个家庭的各自的驾驶信号。我们的整个外显子组测序发现了2个家族中的染色体区域的联系，但没有与CM1相关的特定基因变体。我们从这两个家族进行了整个基因组测序（WGS），以找到特定的基因变异并确认链接信号的因果关系。找到与CM1相关的一个或多个遗传基因座将增加对CM1病因的理解。我们与Drs合作。 Rosenblum，Pacak和Zhuang在一项研究发现EPAS1相关综合征与CM1之间存在关联。间充质转变不当有助于与EPAS1相关综合征中神经异常的症机制。后窝发育异常易于该综合征中CM1的发育。自然病史和疗程的治疗我们开始了12年前血管瘤患者的自然史研究。每年通过神经检查，疼痛和功能的标准量表以及大脑和脊柱MRI对患者进行五年监测。患者接受专门护理，包括手术。这项研究将更好地定义SM患者并提供初步数据的结果，以产生假设驱动的研究的假设。这项研究在2019年达到了180名受试者的入学式上限，最终受试者将于2024年完成。我们的研究中有各种子组。我们发表了对24患者队列的有效表型的描述，该表型与CM1明确转介出头晕。我们发现听力和听觉的脑干道功能本质上是正常的。功能平衡异常是最常见的发现（40％），其次是旋转测试期间前庭异常（33％）。 CM1患者有时具有异常的感觉组织测试（SOT）的姿势稳定性评分，适用于固定的平台条件和异常的体感分析评分。扁桃体外生的程度与任何前庭/平衡结果指标无关。然而，颈部疼痛与体感感官分析评分有显着的负相关性，颈部疼痛与较低的分数相关。只有8％的患者患有前庭病。我们的发现表明，前庭和平衡评估是有价值的，可能导致转介给适当的专家进行治疗（3）。今年，我们还发表了一篇评论文章，以更新CM1的诊断和处理。与非胸腔相关的SM手术亚组包括患有慢性粘合性脊柱蛛网膜炎（SA）的患者。 SA是一个复杂的疾病过程，导致SM，脊髓束缚，CSF流动阻塞，内膜内粘附和脊髓水肿。该疾病对开放手术方法的反应良好，当时该方法是局灶性的，或仅限于三个脊柱段。延伸超过四个脊柱段的较广泛的蛛网膜炎的手术预后较差，粘附的去除不足以及术后疤痕和保留的倾向更高。我们一直在研究柔性神经内镜镜检查，是一种极简主义的方法，可以扩展手术场的纵向范围。三年多来，我们从广泛的SA治疗了十名进行性骨髓病的患者。七名患者患有SM，1例脊髓水肿和两个脊髓失真。手术干预包括2至5级胸椎椎板切除术，粘附的微观裂解，然后使用内窥镜在相邻的脊柱水平下粘附。平均随访时间为五个月（范围215）。使用标准措施检查了神经功能。 MRI评估了Syrinx分辨率。患者接受了平均3.7（范围25）水平的椎板切除术，其次是内窥镜检查，该水平平均增加了2.4个细分市场。广泛的蛛网膜炎的内窥镜解剖表明，从背杜拉植物到脊髓桥接的不透明蛛网膜带和膜的不透明蛛网膜带和膜网络。内窥镜没有压缩或伤害脊髓。内窥镜内窥镜检查可以视觉评估和安全去除层状切除术边缘以外的内膜内粘连。该技术的进一步发展应提高其在开放蛛网膜下腔空间并在广泛的慢性粘合剂SA中缠绕的脊髓（5）。脊髓杆菌的病理生理学我们先前在CM1和SM患者的手术前和手术后3-6个月之前评估了小脑和髓质的形态。在手术膨胀后窝后，CM1中异常形状的小脑和髓质的外观更正常。这一形态学发现支持CM1降低后窝发育而不是原发性神经异常。我们还发表了一项关于原发脊髓脊髓脊髓病理生理学的临床研究。在这种情况下，脑脊液（CSF）的压力波较高，优于相关的脊髓蛛网膜下腔空间阻塞。原发性脊髓疗法的成功手术打开了CSF途径，降低了CSF压力波，并解决了SM。 SM在删除了Chiari I-type SM中的CSF途径阻塞后也解决了，这表明SM通过类似的机制来自脊髓蛛网膜下腔CSF产生。我们先前发表了一项CT脊髓造影研究的临床研究，该研究表明，与骨髓造影染料的孔子或脊髓亚蛛网膜下腔空间相比，骨髓染料的积累远高于与腔内肿瘤相关的注射器的积累。这一发现支持与与髓内肿瘤相关的注射器更多地与与蛛网膜下腔障碍有关的注射器的蛛网膜下腔空间的通信。这项研究支持了Syrinx流体起源于与脊髓亚蛛网膜下腔空间阻塞相关的注射器中的脊柱亚蛛网膜下腔空间的概念。今年，我们发表了有关CM1和SM（6）中CSF流体动力学的评论文章。