Kumar, Rahul

Abstract Cerebrospinal fluid (CSF) is the biofluid most proximal to the central nervous system (CNS), yet its proteomic organization across neurological disease remains unresolved. We assembled a meta-atlas of 35 CSF proteomic datasets (2016–2026) comprising 10,560 quality-controlled samples spanning neurodegenerative, neuroinflammatory, neuro-oncological, infectious and structural-injury contexts. Meta-analysis of cross-cohort detection defined a 747-protein core mass-spectrometry-accessible CSF proteome that generalizes to held-out cohorts. We derived thirteen consensus meta-programs that transfer across independent cohorts and span the major neural, barrier, immune and plasma compartments. Unexpectedly, these programs are dominated by a single axis of variation opposing complement- and plasma-associated inflammation against neuronal-synaptic homeostasis. This injury–homeostasis axis is diagnosis-spanning and tracks clinical severity and disease activity across diverse neurological conditions. We show that a two-protein C5–NRCAM model can approximate the injury–homeostasis axis, bridging deep proteomic profiling toward bedside assessment.

BACKGROUND AND OBJECTIVES: Ventriculoperitoneal shunt (VPS) placement is a common treatment for idiopathic normal pressure hydrocephalus (iNPH), but patients may require VPS revision. This study aims to evaluate the effectiveness of a standardized VPS placement protocol by comparing indications and rates of shunt revision compared with a historical institutional cohort. METHODS: All patients treated with VPS for “suspected” iNPH at a tertiary care center between January 2000 and January 2023 were retrospectively reviewed and divided into temporally distinct historical (before 2017) and standardized (after 2017) cohorts. Cumulative incidence and timing of VPS revision were compared using competing risks analyses. RESULTS: A total of 561 patients (median age 75.0 years) were identified with 324 (57.8%) in the historical and 237 (42.2%) in the standardized cohorts. Significant variations in surgical technique and shunt hardware were noted between the cohorts. With a median follow-up of 11.4 months for historical and 12.4 months for standardized cohort, shunt revisions occurred in 19.4% and 8.4% of patients in the historical and standardized cohorts, respectively ( P < .001). Revision indications also varied significantly with lower rates of overdrainage ( P < .001), infection ( P < .001), and proximal malfunction ( P = .042) but higher rate of distal malfunction ( P = .03) in the standardized cohort. Notably, no infections were noted in the standardized cohort. CONCLUSION: Risk of shunt revision among iNPH patients may be associated with modifiable factors related to surgical technique and shunt hardware selection. Importantly, no short-term complications such as hemorrhage, infection, or catheter malposition were observed with the standardized protocol. Development and refinement of standardized shunt protocols for iNPH patients should be commonplace to facilitate tracking, identification, and modification of modifiable technical risk factors.

BACKGROUND AND OBJECTIVES: Anterior lumbar interbody fusion (ALIF) is a powerful procedure for sagittal correction and indirect decompression in the lumbar spine, though aggressive correction can cause stretch neuropraxia and implant subsidence. The aim of this study was to identify radiographic and clinical predictors of segmental correction, as well as to evaluate the degree to which segmental correction on supine intraoperative radiographs translates to postoperative upright alignment changes. METHODS: We identified patients treated with 1- or 2-level ALIF at a tertiary care center and extracted data on demographics, spinopelvic parameters, and surgical details. Patients treated with isolated ALIF and ALIF with supplementary posterior instrumentation were compared on pre- and postoperative intradiscal lordosis (IDL) and change in IDL. Multivariable linear regression was performed to identify independent predictors of postoperative IDL. RESULTS: We included 204 patients (median age 57 years, 55.4% male) treated at 258 levels, of whom 114 (55.9%) underwent supplementary posterior fixation and 150 (73.5%) underwent single-level implantation. Across all patients, postoperative IDL was significantly greater than preoperative segmental lordosis (25.4° vs 15.3°; P < .001). Standalone ALIF achieved less ΔIDL than circumferential fusion for L5/S1 procedures (7.4° vs 11.6°; P < .001), though ΔIDL for L3/4 and L4/5 was similar between the standalone and circumferential groups. Multivariable analysis showed postoperative IDL to be predicted by greater preoperative IDL (β = 0.26° per degree; [0.15, 0.36]; P < .001), L5/S1 [vs L4/5] implantation (β = 3.97°; [2.72, 5.21]; P < .001), use of supplementary posterior fixation (β = 1.80°; [0.70, 2.89]; P < .001), and greater implant lordosis (β = 0.62° per degree; [0.44, 0.79]; P < .001). CONCLUSION: Postoperative IDL after 1- or 2-level ALIF is best predicted by placement of larger interbody sizes, L5/S1 implantation, greater baseline IDL, and use of adjunct posterior fixation. Patients with higher preoperative lordosis experienced smaller postoperative increases in IDL, though this was likely influenced by a treatment bias.

OBJECTIVE Lordotic devices have garnered increased attention for improving the segmental lordosis (SL) achieved with transforaminal lumbar interbody fusion (TLIF). However, it is unclear the degree to which surgeons maximize the "ideal" or listed lordosis of the interbody device. METHODS Patients undergoing one- or two-level TLIF for degenerative pathologies were identified and data were extracted on demographics, baseline lumbopelvic radiographic parameters, and TLIF details. The primary outcome of interest was the degree to which postoperative SL approximated the listed cage lordosis (Δtarget). Change in SL was a secondary outcome. Linear mixed-effects modeling was used to identify significant predictors of the percentage of ideal lordosis achieved. RESULTS A total of 239 treated levels were included (median patient age 66.6 years; 56.9% female); 151 levels were part of single-level TLIF constructs. The median segmental corrections were a 2.8° increase in SL and 2.8 mm in disc height. The median difference between listed cage lordosis and postoperative SL (Δtarget) was 0.5°. However, only 56.1% of levels achieved at least the listed cage lordosis. Linear mixed-effects modeling found that independent predictors of Δtarget were lower implant lordosis (estimate −1.01° [95% CI −1.15° to −0.87°] per degree, p < 0.001), greater preoperative SL (estimate 0.38° [95% CI 0.28°–0.48°] per degree, p < 0.001), greater preoperative PI (estimate 0.06° [95% CI 0.02°–0.11°] per degree, p = 0.007), and closer approximation of the anterior apophyseal ring of the caudal vertebrae (estimate −0.27° [95% CI −0.39° to −0.15°] per mm, p < 0.001). Similarly, independent predictors of postoperative SL were larger implant lordosis (estimate 0.16° [95% CI 0.05°–0.27°] per degree, p = 0.004), lower preoperative SL (estimate −0.70° [95% CI −0.79° to −0.62°] per degree, p < 0.001), greater preoperative PI (estimate 0.08° [95% CI 0.04°–0.12°] per degree, p < 0.001), and closer approximation of the anterior apophyseal ring of the cranial vertebrae (estimate −0.15° [95% CI −0.28° to −0.03°] per mm, p = 0.014). CONCLUSIONS The present results suggest that while lordosing, only 56% TLIF operations obtain the listed interbody lordosis ("target" lordosis). Anterior placement within the disc space is the only modifiable intraoperative technical factor for maximizing lordosis for a given interbody, highlighting the importance of effective disc space exenteration.

Abstract Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) is under evaluation as a liquid biopsy tool across multiple neuro-oncologic indications, including diagnosing lesions of uncertain etiology, delineating progression from pseudoprogression, and confirming suspected leptomeningeal disease (LMD). We evaluated the real-world performance of CSF cfDNA sequencing for identification of variant alleles (VA) using targeted panel sequencing (PredicineCARE) and/or copy number alterations (CNA) using low-pass whole-genome sequencing (LPWGS; PredicineSCORE) in a diverse cohort across three aforementioned indications. From 82 adult patients, 93 samples (92.4% from lumbar puncture and 7.6% from ventriculoperitoneal shunt taps) were analyzed. For CNS progression, gliomas were most frequently evaluated (60%); for LMD, metastatic disease was most common (86.7%). Median CSF volume utilized for analysis was 4.60 mL (range: 0.40-7.50 mL). Median cfDNA yield was 0.29 ng/mL (range: 0.00–1037.74 ng/mL). For lesions of uncertain etiology (n=40 patients, 1 sample/patient), VAs were identified in 10 samples (25%); an additional 10 samples had sufficient cfDNA for LPWGS (25%). 50% of samples in this indication had insufficient cfDNA for testing. For suspected progression (n=26 patients, 35 samples), VAs were identified in 6 samples (17.1%); an additional 14 samples underwent LPWGS (40%); 15 had insufficient cfDNA for further testing (42.9%). For suspected LMD (n=16 patients, 18 samples), VAs were quantifiable in 4 samples (22.2%); LPWGS could be performed in an additional 9 (50%); 5 had insufficient cfDNA (27.8%). Across indications, identification of known tumor-associated alterations in CSF, including those confirmed previously by tissue, served as a non-surgical diagnostic adjunct. In some patients, targetable mutations could be identified via CSF. Conversely, absence of such alterations and/or low cfDNA yields may lower suspicion for active neuro-oncologic disease, when evaluated alongside clinical history. Despite modest cell-free DNA yield, CSF cfDNA evaluation provides valuable information to aid clinical decision-making across neuro-oncologic indications.

Background For large vessel occlusion (LVO) ischemic strokes, three major techniques of mechanical thrombectomy (MT) have demonstrated efficacy. Here we compare the safety and efficacy of stent retrievers (SR), contact aspiration (Asp), and a combined mechanical thrombectomy (cMT) for LVO ischemic stroke. Methods Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we queried the PubMed, EMBASE, Scopus, and Web of Science databases for studies published prior to December 2024 describing patients with ischemic stroke who underwent MT using SR, Asp, or cMT. Results Twnety-four studies comprising a total of 12 845 patients were included in the analysis. Compared with cMT, Asp was associated with a lower rate of first pass effect (FPE) (risk ratio (RR) 0.67; 95% CI 0.46 to 0.96), shorter procedure duration (mean difference (MD) −13.35 min; 95% CI −20.83 to –5.87), and lower risk of arterial dissection (RR 0.50; 95% CI 0.29 to 0.87). Additionally, SR use was linked to a higher procedure duration compared with Asp (MD 13.39 min; 95% CI 5.55 to 21.22) and a lower symptomatic intracranial hemorrhage rate (RR 0.75; 95% CI 0.59 to 0.96). No significant differences were observed between groups in terms of number of passes, successful recanalization, 90-day functional outcomes, mortality, arterial perforation, or embolization to new territory. Conclusions All three techniques demonstrated similar recanalization rates and functional outcomes. However, Asp was associated with shorter procedure times and fewer arterial dissection complications, while cMT showed a higher FPE. Given the comparable overall efficacy, the choice of technique should be guided by the physician’s preference, expertise, and confidence, tailored to the individual patient’s profile.

OBJECTIVE Idiopathic normal pressure hydrocephalus (iNPH) is characterized by gait deterioration, cognitive disturbances, and urinary incontinence. Gait deficits pose safety hazards due to frequent falls, yet objective investigations of gait improvement following ventriculoperitoneal shunt (VPS) placement are limited. Therefore, the aim of this study was to assess objective improvement in gait parameters for patients with iNPH after VPS placement. METHODS All patients treated with a VPS for iNPH by the senior author at a single tertiary care center from December 2017 to January 2023 were retrospectively reviewed. Patients who underwent detailed motion analysis testing before surgery with > 1 follow-up assessment were included. Analyzed parameters included gait velocity, gait cadence, stride length, stride width, gait stability ratio, total support, and single support. Time-dependent linear mixed-effects models and generalized additive mixed-effects models (GAMMs) were used to model short-term and longitudinal gait parameter changes, respectively. RESULTS A total of 212 patients (137 male, median age was 75.2 years) who underwent VPS placement for iNPH were included, with a total of 747 gait analyses performed at a median last-gait analysis follow-up duration of 12.0 months. Statistically significant changes in all gait parameter values were seen between the preoperative time point and first postoperative follow-up (within 3 months) time point (paired Wilcoxon p < 0.001), with a statistically significant majority of patients experiencing improvement (binominal p < 0.0001). Longitudinal analyses using a GAMM showed increased gait velocity, single support, and stride length, with decreased stability ratio, step width, and total support at early time points, while a plateau was achieved around 6 months. CONCLUSIONS A detailed gait analysis demonstrated significant improvements in objective ambulation metrics, particularly in the gait velocity, stride length, and gait stability ratio, following VPS placement in patients with iNPH. Most patients maintained marked improvement from baseline to the last follow-up assessment, although a plateau of the benefit was experienced over longer follow-up.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) is increasingly used as a primary treatment modality for intracranial meningiomas. We aim to describe clinical outcomes after single-fraction SRS for sporadic intracranial meningiomas. METHODS: A prospectively maintained database was reviewed for patients with sporadic meningiomas who underwent SRS (Gamma Knife) as primary treatment modality from April 1997 to February 2022. Primary outcomes included progression-free survival (PFS) and treatment-related complications. RESULTS: Six hundred sixteen patients (653 tumors) underwent SRS with median follow-up of 6.3 years (interquartile range [IQR] 3.1-10.5 years). The median tumor volume was 4.5 cm 3 (IQR 2.0-8.0 cm 3 ). The median margin dose was 15.0 Gy (IQR 14.0-16.0). In-field progression was noted in 7 tumors (1.1%) and marginal progression in 2 tumors (0.3%) for a raw failure rate of 1.4%. PFS estimates at 5, 10, and 15 years were 99.8%, 99.0%, and 93.2%, respectively. Factors associated with reduced PFS on univariable analysis included older age (hazards ratio [HR] 1.14, 95% CI, 1.05-1.22, P < .001), male sex (HR 5.44, 95% CI, 1.45-20.4, P = .010), increasing tumor volume (HR 1.06, 95% CI, 0.99-1.13, P = .028), and lower tumor margin dose (HR 0.65, 95% CI, 0.43-0.97, P = .006). Treatment-related complications were noted in 56 patients (9.1%), of which 45 (7.3%) were temporary, 5 (0.8%) were minor, and 6 (1.0%) were permanent and/or required intervention. Radiosurgical parameters associated with treatment-related complications included increased number of isocenters (odds ratio [OR] 1.09, 95% CI, 1.04-1.14, P < .001), higher 12-Gy volume (OR 1.06, 95% CI, 1.03-1.09, P < .001), larger tumor volume (OR 1.06, 95% CI, 1.02-1.10, P < .001), and lower maximal dose (OR 0.90, 95% CI, 0.82-0.98, P = .11). CONCLUSION: SRS is effective as a primary treatment modality for sporadic, small-volume to medium-volume intracranial meningiomas. Pre-emptive SRS should be discussed as a safe management strategy compared with observation alone for incidentally discovered meningiomas.

OBJECTIVE Transforaminal lumbar interbody fusion (TLIF) offers both indirect decompression and segmental correction through restoration of disc height. However, stresses exerted on the vertebral endplates by the interbody device can result in implant subsidence and loss of correction. The present time-to-event analysis aimed to identify predictors of interbody subsidence. METHODS Patients who underwent 1- or 2-level TLIF were identified. Data on demographics, surgical details, preoperative bone quality using CT-based Hounsfield units (HU), and pre- and postoperative lumbopelvic parameters were collected. Univariable analyses were conducted to identify predictors of subsidence (≥ 2-mm intrusion of interbody into cranial or caudal vertebrae) and significant subsidence (≥ 4-mm intrusion). Multivariable Cox regression was performed to identify independent predictors of subsidence, expressed as hazard ratios with 95% confidence intervals. RESULTS A total of 198 patients treated at 241 levels were included (median age 66.6 years, IQR 59.5, 73.7 years; 56.6% were women). In 92 levels (38.2%) there was some subsidence and in 25 (10.4%) there was significant subsidence. Implanted levels demonstrating subsidence (≥ 2 mm) were associated with lower HU in cranial and caudal vertebrae; had interbodies positioned farther from the anterior apophyseal ring; were implanted with taller, more lordotic interbodies; and underwent greater disc height restoration. Those showing significant subsidence (≥ 4 mm) were similarly associated with lower HU in the cranial and caudal vertebrae; had interbodies positioned farther from the anterior apophyseal ring of the caudal vertebrae; and underwent greater disc height restoration. Multivariable Cox regression showed that time to subsidence was predicted by greater implant height (HR 1.20/mm, 95% CI 1.05–1.38; p = 0.009), greater postoperative disc height (HR 1.21/mm, 95% CI 1.09–1.34; p < 0.001), and greater disc height restoration (HR 1.11/mm, 95% CI 1.04–1.19; p = 0.002). The time-to-subsidence analysis for significant (≥ 4 mm) subsidence showed that it was predicted by lower HU in the cranial vertebrae (HR 0.98/unit, 95% CI 0.97–0.99; p = 0.001); increasing number of levels instrumented (HR 1.26, 95% CI 1.04–1.52; p = 0.016); and greater disc height restoration (HR 1.33/mm, 95% CI 1.18–1.51; p < 0.001). CONCLUSIONS This time-to-event analysis suggests that interbody subsidence following TLIF is best predicted by implantation of a taller interbody and aggressive disc height restoration. Significant subsidence is similarly predicted by aggressive disc height restoration along with poor baseline bone quality. The results suggest the need to balance aggressive correction at the time of surgery against the increased risk of subsequent interbody subsidence.

Introduction: Bone health optimization is a key component of the preoperative management of spine surgery patients, as poor bone quality increases the odds of mechanical complications. The present study aimed to achieve the following: (1) compare the relative efficacy of current osteoporosis medications in improving bone quality; (2) identify factors influencing treatment response in preoperative spine surgery patients. Methods: Patients treated at a single, multisite institution who received osteoporosis treatment were identified. Data were gathered on pre- and post-treatment lumbar spine Hounsfield Unit (HU) measurements, patient demographics, frailty scores (modified Frailty Index/mFI, risk analysis index/RAI), and pharmacologic treatment details. The primary outcome was a ≥7 point improvement in lumbar HU, and baseline and logistic regression models were utilized to identify factors associated with this improvement. Medications were grouped as anabolic (teriparatide, romosozumab) and antiresorptive (denosumab, alendronate) therapies. Results: A total of 267 patients were included (median age: 74 years; IQR [66–81]; 67.3% female), with 127 (47.6%) improving by ≥7 HU. The treatment agents used were alendronate (95), denosumab (113), romosozumab (31), and teriparatide (28). Univariable comparisons revealed significant differences across medication groups in age (p < 0.001), sex (p < 0.001), mFI (p < 0.001), RAI (p = 0.004), BMI (p < 0.001), pre-treatment HU (p = 0.022), and treatment duration (p < 0.001). The highest HU improvement rates (ΔHU ≥ 7) were observed in patients receiving the anabolic medications romosozumab (67.7%) and teriparatide (60.7%). Univariable logistic regression identified male sex (OR 0.54, p = 0.019), higher pre-treatment HU (OR 0.99, p = 0.006), and longer treatment duration (OR 0.97, p = 0.003) as factors associated with lower odds of HU improvement. Only romosozumab was associated with significantly higher odds of HU improvement relative to alendronate (OR 3.02, p = 0.012). In our multivariable analysis, male sex (OR 0.53, p = 0.028) and higher pre-treatment HU (OR 0.99, p = 0.002) remained significant predictors of HU improvement. However, medication type was not significant in the multivariable analysis. Conclusions: Our study highlights that male sex and higher pre-treatment HU were independently associated with lower odds of HU improvement, while medication type was not a significant predictor. Additionally, anabolic agents offered superior improvement relative to antiresorptive therapies.