Muraszko, Karin M.

OBJECTIVE The objective of this study was to understand the natural history of scoliosis in patients with Chiari malformation type I (CM-I) with and without syringomyelia. METHODS A retrospective review of data was conducted. Patients with CM-I were identified from a cohort of 14,118 individuals age 18 years or younger who had undergone MRI over an 11-year period at the University of Michigan. Patients eligible for study inclusion had a coronal curve ≥ 10° on radiography, associated CM-I with or without syringomyelia, and at least 1 year of clinical follow-up prior to any surgery. Curve magnitude at initial diagnosis, prior to posterior fossa decompression (PFD; if applicable), and at the last follow-up (prior to any surgical correction of scoliosis) was recorded, and clinical and radiographic characteristics were noted. The change in curve magnitude by 10° was defined as curve progression (increase by 10°) or regression (decrease by 10°). RESULTS Forty-three patients met the study inclusion criteria and were analyzed. About one-third (35%) of the patients presented with symptoms attributed to their CM-I. The mean degree of scoliosis at presentation was 32.6° ± 17.7°. Twenty-one patients (49%) had an associated syrinx. The mean tonsil position below the level of the foramen magnum was 9.8 ± 5.8 mm. Patients with a syrinx were more likely to have a curve > 20° (86% vs 41%, p = 0.002). Curve magnitude remained stable (≤ ±10°) in 77% of patients (33/43), progressed in 16% (7/43), and regressed in 7% (3/43). Mean age was higher (14.8 ± 0.59 years) among patients with regressed curves (p = 0.026). All regressed curves initially measured ≤ 20° (mean 14° ± 5.3°), and none of the patients with regressed curves had a syrinx. The change in curve magnitude was statistically similar in patients with (7.32° ± 17.7°) and without (5.32° ± 15.8°) a syrinx (p = 0.67). After a mean follow-up of 3.13 ± 2.04 years prior to surgery, 27 patients (63%) ultimately underwent posterior fossa or scoliosis correction surgery. For those who eventually underwent PFD only, the rate of change in curve magnitude prior to surgery was 0.054° ± 0.79°. The rate of change in curve magnitude was statistically similar before (0.054° ± 0.79°) and after (0.042° ± 0.33°) surgery (p = 0.45) for patients who underwent PFD surgery only. CONCLUSIONS The natural history of scoliosis in the presence of CM-I is variable, though most curves remained stable. All curves that regressed were ≤ 20° at initial diagnosis, and most patients in such cases were older at scoliosis diagnosis. Patients who underwent no surgery or PFD only had similar profiles for the change in curve magnitude, which remained relatively stable overall, as compared to patients who underwent PFD and subsequent fusion, who demonstrated curve progression. Among the patients with a syrinx, no curves regressed, most remained stable, and some progressed. Understanding this variability is a first step toward building a prediction model for outcomes for these patients.

Abstract Purpose: Pediatric high-grade glioma (pHGG) diagnosis portends poor prognosis and therapeutic monitoring remains difficult. Tumors release cell-free tumor DNA (cf-tDNA) into cerebrospinal fluid (CSF), allowing for potential detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of cf-tDNA with a handheld platform (Oxford Nanopore MinION) could quantify patient-specific CSF cf-tDNA variant allele fraction (VAF) with improved speed and limit of detection compared with established methods. Experimental Design: We performed ultra-short fragment (100–200 bp) PCR amplification of cf-tDNA for clinically actionable alterations in CSF and tumor samples from patients with pHGG (n = 12) alongside nontumor CSF (n = 6). PCR products underwent rapid amplicon-based sequencing by Oxford Nanopore Technology (Nanopore) with quantification of VAF. Additional comparison to next-generation sequencing (NGS) and droplet digital PCR (ddPCR) was performed. Results: Nanopore demonstrated 85% sensitivity and 100% specificity in CSF samples (n = 127 replicates) with 0.1 femtomole DNA limit of detection and 12-hour results, all of which compared favorably with NGS. Multiplexed analysis provided concurrent analysis of H3.3A (H3F3A) and H3C2 (HIST1H3B) mutations in a nonbiopsied patient and results were confirmed by ddPCR. Serial CSF cf-tDNA sequencing by Nanopore demonstrated correlation of radiological response on a clinical trial, with one patient showing dramatic multi-gene molecular response that predicted long-term clinical response. Conclusions: Nanopore sequencing of ultra-short pHGG CSF cf-tDNA fragments is feasible, efficient, and sensitive with low-input samples thus overcoming many of the barriers restricting wider use of CSF cf-tDNA diagnosis and monitoring in this patient population.

OBJECT There is currently no consensus on the safety of sports participation for patients with Chiari I malformation (CM-I). The authors' goal was to define the risk of sports participation for children with the imaging finding of CM-I. METHODS A prospective survey was administered to 503 CM-I patients at 2 sites over a 46-month period. Data were gathered on imaging characteristics, treatment, sports participation, and any sport-related injuries. Additionally, 81 patients completed at least 1 subsequent survey following their initial entry into the registry and were included in a prospective group, with a mean prospective follow-up period of 11 months. RESULTS Of the 503 CM-I patients, 328 participated in sports for a cumulative duration of 4641 seasons; 205 of these patients participated in contact sports. There were no serious or catastrophic neurological injuries. One patient had temporary extremity paresthesias that resolved within hours, and this was not definitely considered to be related to the CM-I. In the prospective cohort, there were no permanent neurological injuries. CONCLUSIONS No permanent or catastrophic neurological injuries were observed in CM-I patients participating in athletic activities. The authors believe that the risk of such injuries is low and that, in most cases, sports participation by children with CM-I is safe.