Graft subsidence and reoperation after lateral lumbar interbody fusion: a propensity score-matched and cost analysis of polyetheretherketone versus 3D-printed porous titanium interbodies.

OBJECTIVE: Lumbar interbody cage subsidence has a multifactorial etiology. Cage material, although well studied after transforaminal lumbar interbody fusion, has not been investigated as a contributing factor to subsidence after lateral lumbar interbody fusion (LLIF). In this study the authors compared rates of subsidence and reoperation after LLIF between polyetheretherketone (PEEK) and 3D-printed porous titanium (pTi) in an institutional propensity score-matched and cost analysis. METHODS: This is a retrospective observational cohort analysis of adult patients who underwent LLIF with pTi versus PEEK between 2016 and 2020. Demographic, clinical, and radiographic characteristics were collected. Propensity scores were calculated and 1:1 matching without replacement of surgically treated levels was performed. The primary outcome of interest was subsidence. The Marchi subsidence grade was determined at the time of last follow-up. Chi-square or Fisher's exact tests were used to compare subsidence and reoperation rates between lumbar levels treated with PEEK versus pTi. Modeling and cost analysis were performed using TreeAge Pro Healthcare. RESULTS: The authors identified a total of 192 patients; 137 underwent LLIF with PEEK (212 levels) and 55 had LLIF with pTi (97 levels). After propensity score matching, a total of 97 lumbar levels remained in each treatment group. After matching, there were no statistically significant differences between groups in baseline characteristics. Levels treated with pTi were significantly less likely to exhibit subsidence (any grade) compared to those treated with PEEK (8% vs 27%, p = 0.001). Five (5.2%) levels treated with PEEK required reoperation for subsidence, but only 1 (1.0%) level treated with pTi required reoperation for subsidence (p = 0.12). Given subsidence and revision rates experienced in the cohorts in this study, the pTi interbody device is economically superior to PEEK in a single-level LLIF as long as its cost is at least $1185.94 lower than that of PEEK. CONCLUSIONS: The pTi interbody device was associated with less subsidence, but statistically similar revision rates after LLIF. pTi is potentially a superior economic choice at this study's reported revision rate.

Development of a clinical model to predict vagus nerve stimulation response in pediatric patients with drug-resistant epilepsy.

OBJECTIVE: Epilepsy impacts 470,000 children in the United States. For patients with drug-resistant epilepsy (DRE) and unresectable seizure foci, vagus nerve stimulation (VNS) is a treatment option. Predicting response to VNS has been historically challenging. The objective of this study was to create a clinical VNS prediction tool for use in an outpatient setting. METHODS: The authors performed an 11-year retrospective cohort analysis with 1-year follow-up. Patients < 21 years of age with DRE who underwent VNS (n = 365) were included. Logistic regressions were performed to assess clinical factors associated with VNS response (≥ 50% seizure frequency reduction after 1 year); 70% and 30% of the sample were used to train and validate the multivariable model, respectively. A prediction score was subsequently developed. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated. RESULTS: Variables associated with VNS response were < 4-year epilepsy duration before VNS (p = 0.008) and focal motor seizures (p = 0.037). The variables included in the clinical prediction score were epilepsy duration before VNS, age at seizure onset, number of pre-VNS antiseizure medications, if VNS was the patient's first therapeutic epilepsy surgery, and predominant seizure semiology. The final AUCs were 0.7013 for the "fitted" sample and 0.6159 for the "validation" sample. CONCLUSIONS: The authors developed a clinical model to predict VNS response in a large sample of pediatric patients treated with VNS. Despite the large sample size, clinical variables alone were not able to accurately predict VNS response. This score may be useful after further validation, although its predictive ability underscores the need for more robust biomarkers to predict treatment response.

Investigation of the effectiveness of vagus nerve stimulation for pediatric drug-resistant epilepsies secondary to nonaccidental trauma.

PURPOSE: Epilepsy following non-accidental trauma (NAT) occurs in 18% of pediatric patients. About 33% of patients with epilepsy develop drug-resistant epilepsy. For these patients, vagus nerve stimulation (VNS) is a palliative treatment option. We aimed to investigate the effectiveness of VNS among pediatric NAT-related epilepsy patients compared to those with non-NAT-related epilepsy. METHODS: We performed an 11-year retrospective analysis of VNS implantations for drug-resistant epilepsy at UPMC Children's Hospital of Pittsburgh. Patients were split into two groups: NAT vs. non-NAT. The primary outcome was the attainment of ≥ 50% seizure frequency reduction at 1-year post-VNS implantation. Fisher's exact tests and Wilcoxon rank-sum tests were used to compare groups. Significance was assessed at the alpha = 0.05 level. RESULTS: This analysis included data from 370 pediatric VNS patients, of whom 9 had NAT-related epilepsy. NAT patients had a significantly younger age of epilepsy onset than non-NAT patients (0.3 years vs. 3.3 years). Otherwise, there were no statistically significant baseline differences between groups, including patient sex and quantity of antiseizure medications pre-VNS. Overall, 71% of NAT patients experienced ≥ 50% seizure frequency reduction compared to 48% of non-NAT patients (p = 0.269). CONCLUSION: VNS may allow a higher proportion of pediatric patients with NAT-related epilepsy to achieve ≥ 50% seizure frequency reduction compared to other epilepsy etiologies. While the results of this study were not statistically significant, the effect size was large. Our results underscore the need for larger, multi-center studies to validate the effectiveness of VNS for this patient population.

Stereotactic radiosurgery as the initial management option for small-volume hypothalamic hamartomas with intractable epilepsy: a 35-year institutional experience and systematic review.

OBJECTIVE: Young patients with hypothalamic hamartomas (HHs) often present with intractable epilepsy. Currently there are no established management guidelines for HH. The authors retrospectively reviewed their single-institution experience to delineate the role of stereotactic radiosurgery (SRS). METHODS: Seven patients with HHs (4 females; median age 13.7 years, range 2.5-25 years) with no prior resection underwent SRS between 1987 and 2022. The clinical history, epilepsy profile, radiographic findings, and neurological outcomes were characterized. HH topographical types were classified according to the Régis classification. Outcome measures included Engel seizure classification, HH response, and the need for additional surgical interventions. RESULTS: All patients had Engel class IV epilepsy. A Leksell Gamma Knife was used to deliver a median margin dose of 18 Gy (range 16-20 Gy) to a median hamartoma volume of 0.37 cm3 (range 0.20-0.89 cm3). Seizure reduction was confirmed in 6 patients, and 2 patients had regression of their hamartoma. Two patients underwent resection and/or laser interstitial thermal therapy after SRS. At follow-up, 1 patient was seizure free, 4 patients achieved Engel class II, 1 patient had Engel class III, and 1 patient had Engel class IV seizure outcomes. CONCLUSIONS: SRS as the initial management option for HH was associated with a low risk of adverse effects. In this institutional series reviewing small-volume HHs treated with SRS, no adverse radiation effect was detected, and the majority of patients experienced seizure reduction. SRS should be considered as the first-line treatment for seizure control in patients with small-volume HHs.

The longitudinal volumetric response of vestibular schwannomas after Gamma Knife radiosurgery.

OBJECTIVE: Gamma Knife radiosurgery (GKRS) is an effective treatment for vestibular schwannomas (VSs) and has been used in > 100,000 cases worldwide. In the present study the authors sought to define the serial volumetric tumor response of Koos grade I-IV VS after radiosurgery. METHODS: A total of 201 consecutive VS patients underwent GKRS at a single institution between 2015 and 2019. All patients had a minimum follow-up of 18 months and at least 2 interval postprocedure MRI scans. The contrast-enhanced tumor volumes were contoured manually and compared between pre- and post-GKRS imaging. The percentages of tumor volume change at 18 months (short-term follow-up) and up to 5 years after GKRS (long-term follow-up) were compared with the baseline tumor volume. An increase of 20% was considered a significant increase of tumor volume. Trends of tumor volume over time were assessed with linear models using time as a continuous variable. A test for linear trend was evaluated according to the initial Koos tumor classification. RESULTS: Koos grade II VS was the most frequently occurring tumor (n = 74, 36.8%), followed by grade III (n = 57, 28.4%), grade I (n = 41, 20.4%), and grade IV (n = 29, 14.4%). The mean tumor volume at the time of GKRS was 2.12 ± 2.82 cm3 (range 0.12-18.77 cm3) and the median margin dose was 12 Gy. Short-term follow-up revealed that tumor volumes transiently increased in 34.2% and 28.4% of patients at 6 and 18 months, respectively, regardless of Koos grade. Linear regression analysis of Koos grade II, III, and IV tumors showed a significant longitudinal volume decrease on long-term follow-up. At last follow-up (median 30 months, range 18-54 months), 19 patients (9.4%) showed a persistent increase of tumor volume. Five patients received additional management after GKRS. CONCLUSIONS: Although selected VS patients demonstrate an early and measurable transient volumetric increase after GKRS, > 90% have stable or reduced tumor volumes over an observed period of up to 5 years. Volumetric regression is most pronounced in Koos grade II, III, and IV tumors and may not be fully detectable until 3 years after GKRS.

Predictors of vagus nerve stimulation complications among pediatric patients with drug-resistant epilepsy.

OBJECTIVE: Complications from vagus nerve stimulator (VNS) procedures are common and can have important implications for morbidity and seizure control, yet predictors of complications are poorly understood. The objective of this study was to assess clinical factors associated with minor and major complications from VNS procedures among pediatric patients with drug-resistant epilepsy. METHODS: The authors performed an 11-year retrospective review of patients who underwent VNS procedures for drug-resistant epilepsy at age < 21 years. The primary outcome was complications (minor or major) following VNS surgery. Preoperative and surgery characteristics were compared between patients who developed versus those who did not develop complications. Multivariable Poisson regression was performed to determine the association between preoperative characteristics and infection. RESULTS: Of 686 surgeries, 48 complications (7.0%) developed; there were 7 minor complications (1.0%) and 41 major complications (6.0%). Surgeries with minor complications were an average of 68 minutes longer than those without minor complications (p < 0.001). The incidence rate of infection was 1 per 100 person-years, with 3% of procedures complicated by infection. Poisson regression revealed that after adjusting for age at surgery, duration of surgery, and primarily motor seizure semiology, the incident rate of infection for revision surgeries preceded by ≥ 2 procedures was 19 times that of first-time revisions. CONCLUSIONS: The overall minor complication rate was 1% and the overall major complication rate was 6% for VNS procedures. Longer surgery duration was associated with the development of minor complications but not major complications. Repeat incisions to the VNS pocket may be associated with higher incident rate of infection, highlighting a need for longer-lasting VNS pulse generator models.

Revision Pharyngoplasty in Cleft Palate and Velopharyngeal Insufficiency: Management and Outcomes.

INTRODUCTION: Velopharyngeal insufficiency (VPI), a stigmatizing hallmark of palatal dysfunction, occurs in a wide spectrum of pediatric craniofacial conditions. The mainstays for surgical correction include palate repair and/or pharyngeal surgery. However, primary pharyngoplasty has a failure rate of 15% to 20%. Although revision pharyngoplasty may be necessary in those with persistent VPI, little is known regarding the indications for and outcomes after such procedures. The purpose of this study is to describe the authors' experience with indications for and outcomes after revision pharyngoplasty. METHODS: A single-center retrospective review was performed of all patients undergoing revision pharyngoplasty between 2002 and 2019. Demographic data and Pittsburgh Weighted Speech Scores, diagnoses, comorbidities, and complications were tabulated. Two-tailed Student t test was used, and a P value of 0.05 or less was considered statistically significant. RESULTS: Thirty-two patients (65.6% male) met inclusion criteria for this study. The most common diagnoses included cleft palate (68.8%), submucous cleft palate (SMCP, 18.8%), and congenital VPI (6.3%, likely occult SMCP). Most patients (84.4%) underwent palatoplasty before their initial pharyngoplasty. The primary indication for initial pharyngoplasty was VPI (mean age 7.1 ± 4.6 years). The most common indication for revision pharyngoplasty (mean age 11.2 ± 5.1 years) included persistent VPI (n = 22), followed by obstructive sleep apnea (OSA) (n = 11). Persistent VPI (n = 8) and OSA (n = 6) were the most common complications after secondary pharyngoplasty. Thirteen patients (40.6%) within the revision pharyngoplasty cohort required additional surgical intervention: 4 underwent tertiary pharyngoplasty, 4 underwent takedown for OSA (n = 3) or persistent VPI (n = 1), 3 underwent takedown and conversion Furlow for persistent VPI (n = 2), OSA (n = 2) and/or flap dehiscence (n = 1), and 2 underwent palatal lengthening with buccal myomucosal flaps for persistent VPI. Of the 4 patients who required a tertiary pharyngoplasty, the mean age at repair was 6.6 ± 1.1 years and their speech scores improved from 13.5 to 2.3 after tertiary pharyngoplasty (P = 0.11). The overall speech score after completion of all procedures improved significantly from 19 to 3.3. CONCLUSION: Patients who fail primary pharyngoplasty represent a challenging population. Of patients who underwent secondary pharyngoplasty, nearly half required a tertiary procedure to achieve acceptable speech scores or resolve complications.

Subsidence after lateral lumbar interbody fusion using a 3D-printed porous titanium interbody cage: single-institution case series.

OBJECTIVE: Cage subsidence is a well-known phenomenon after lateral lumbar interbody fusion (LLIF), occurring in 10%-20% of cases. A 3D-printed porous titanium (pTi) cage has a stiffness that mimics the modulus of elasticity of native vertebrae, which reduces stress at the bone-hardware interface, lowering the risk of subsidence. In this study, the authors evaluated their institutional rate of subsidence and resultant reoperation in patients who underwent LLIF using a 3D-printed pTi interbody cage. METHODS: This is a retrospective case series of consecutive adult patients who underwent LLIF using pTi cages from 2018 to 2020. Demographic and clinical characteristics including age, sex, bone mineral density, smoking status, diabetes, steroid use, number of fusion levels, posterior instrumentation, and graft size were collected. The Marchi subsidence grade was determined at the time of last follow-up. Outcome measures of interest were subsidence and resultant reoperation. Univariable logistic regression analysis was performed to assess the extent to which clinical and operative characteristics were associated with Marchi grade I-III subsidence. Significance was assessed at p < 0.05. RESULTS: Fifty-five patients (38 with degenerative disc disease and 17 with adult spinal deformity) were treated with 97 pTi interbody cages with a mean follow-up of 18 months. The mean age was 63.6 ± 10.1 years, 60% of patients were female, and 36% of patients had osteopenia or osteoporosis. Patients most commonly underwent single-level LLIF (58.2%). Sixteen patients (29.1%) had posterior instrumentation. The subsidence grade distribution was as follows: 89 (92%) grade 0, 5 (5%) grade I, 2 (2%) grade II, and 1 (1%) grade III. No patients who were active or prior smokers and no patients with posterior instrumentation experienced graft subsidence. No clinical or operative characteristics were significantly associated with graft subsidence. One patient (1.8%) required reoperation because of subsidence. CONCLUSIONS: In this institutional case series, subsidence of pTi intervertebral cages after LLIF occurred in 8% of operated levels, 3% of which were grade II or III. Only 1 patient required reoperation. These reported rates are lower than those reported for polyetheretherketone implants. Further studies are necessary to compare the impact of these cage materials on subsidence after LLIF.

Computed Tomography Hounsfield Units as a Predictor of Reoperation and Graft Subsidence After Standalone and Multilevel Lateral Lumbar Interbody Fusion.

BACKGROUND: Standalone single and multilevel lateral lumbar interbody fusion (LLIF) have been increasingly applied to treat degenerative spinal conditions in a less invasive fashion. Graft subsidence following LLIF is a known complication and has been associated with poor bone mineral density (BMD). Previous research has demonstrated the utility of computed tomography (CT) Hounsfield units (HUs) as a surrogate for BMD. In the present study, we investigated the relationship between the CT HUs and subsidence and reoperation after standalone and multilevel LLIF. METHODS: A prospectively maintained single-institution database was retrospectively reviewed for LLIF patients from 2017 to 2020, including single and multilevel standalone cases with and without supplemental posterior fixation. Data on demographics, graft parameters, BMD determined by dual-energy x-ray absorptiometry, preoperative mean segmental CT HUs, and postoperative subsidence and reoperation were collected. We used 36-in. standing radiographs to measure the preoperative global sagittal alignment and disc height and subsidence at last follow-up. Subsidence was classified using the Marchi grading system corresponding to disc height loss: grade 0, 0%-24%; grade I, 25%-49%; grade II, 50%-74%; and grade III, 75%-100%. RESULTS: A total of 89 LLIF patients had met the study criteria, with a mean follow-up of 19.9 ± 13.9 months. Of the 54 patients who had undergone single-level LLIF, the mean segmental HUs were 152.0 ± 8.7 for 39 patients with grade 0 subsidence, 136.7 ± 10.4 for 9 with grade I subsidence, 133.9 ± 23.1 for 3 with grade II subsidence, and 119.9 ± 30.9 for 3 with grade III subsidence (P = 0.032). Of the 96 instrumented levels in the 35 patients who had undergone multilevel LLIF, 85, 9, 1, and 1 level had had grade 0, grade I, grade II, and grade III subsidence, with no differences in the HU levels. On multivariate logistic regression, increased CT HU levels were independently associated with a decreased risk of reoperation after both single-level and multilevel LLIF (odds ratio, 0.98; 95% confidence interval, 0.97-0.99; P = 0.044; and odds ratio, 0.97; 95% confidence interval, 0.94-0.99; P = 0.017, respectively). Overall, the BMD determined using dual-energy x-ray absorptiometry was not associated with graft subsidence or reoperation. Using a receiver operating characteristic curve to separate the patients who had and had not required reoperation, the threshold HU level determined for single-level and multilevel LLIF was 131.4 (sensitivity, 0.62; specificity 0.65) and 131.0 (sensitivity, 0.67; specificity, 0.63), respectively. CONCLUSIONS: Lower CT HUs were independently associated with an increased risk of graft subsidence after single-level LLIF. In addition, lower CT HUs significantly increased the risk of reoperation after both single and multilevel LLIF with a critical threshold of 131 HUs. The determination of the preoperative CT HUs might provide a more robust gauge of local bone quality and the likelihood of graft subsidence requiring reoperation following LLIF than overall BMD.

Comparison of traditional and closed loop vagus nerve stimulation for treatment of pediatric drug-resistant epilepsy: A propensity-matched retrospective cohort study.

OBJECTIVE: For epilepsy patients with drug-resistant, unresectable epilepsy, vagus nerve stimulation (VNS) is an option for seizure control. Approximately 40-70% of patients will achieve ≥50% seizure reduction with VNS. New closed loop VNS models detect ictal tachycardia and responsively stimulate the vagus nerve. The effectiveness of closed loop VNS compared to traditional VNS for pediatric epilepsy is unknown. METHODS: An 11-year retrospective electronic medical record review at Children's Hospital of Pittsburgh was performed. Patients with drug-resistant epilepsy who underwent VNS implantation were included. Patients were divided into groups based on VNS model: traditional versus closed loop. Those who transitioned from traditional to closed loop VNS were excluded. Given potential for selection bias, propensity scores matching was utilized to compare traditional to closed loop VNS patients. Patients with focal versus generalized epilepsy were also separately analyzed. The primary outcome was "VNS response", defined as at least 50% seizure frequency reduction from baseline. RESULTS: A total of 320 patients were included in this sample. The percentage of matched patients (total n = 220: n = 179 traditional VNS, n = 41 closed loop VNS) who responded to VNS after one year of therapy was 43% for traditional VNS and 39% for closed loop VNS (p = 0.64). After two years of therapy, a higher proportion of closed loop VNS patients than traditional VNS patients responded to VNS among all subgroups, though no differences were statistically significant (p>0.05). Notably, for those with generalized epilepsy, 73% of closed loop patients responded to VNS compared to only 46% of traditional patients (p = 0.10). After two years of VNS therapy, patients were taking approximately the same quantity of antiseizure medications as baseline (change of +0.074 +/- 0.90 ) with no difference between VNS models (p = 0.87). SIGNIFICANCE: Among pediatric patients with drug-resistant epilepsy, closed loop VNS trends towards a higher rate of VNS response after two years of treatment, especially among generalized epilepsy patients. Neither model of VNS allows patients to reduce antiseizure medication quantity after two years.

Inflammatory signals and network connections implicate cell-mediated immunity in chronic venous insufficiency.

BACKGROUND: The role of inflammation in superficial venous reflux in varicose veins (VVs) is unknown. Computational network modeling has deduced inflammation in experimental and clinical settings. We measured immune mediators in plasma from competent and incompetent leg veins inferring the role of cellular immunity based on cytokine networks. METHODS: Temperature was assessed using infrared thermography (IRT) to measure inflammation. Blood was obtained during sclerotherapy or endovenous thermal ablation for VVs. Control subjects underwent phlebotomy from saphenous and forearm veins. Vein segments were harvested during surgery. Demographics, clinical, etiology, anatomy and pathophysiology classification, venous clinical severity scores (VCSSs), and body mass index (BMI) were collected. Twenty-five mediators were measured in serum and vein segments. Means were compared using Mann-Whitney U test. Pearson correlations equaling or exceeding a threshold prompted connections among nodes, and mapped as networks. Spearman correlations were performed between interleukin (IL)-17A and both granulocyte macrophage colony stimulation factor, and IL-10 as indicators of pathogenic and nonpathogenic Th17 cell involvement. RESULTS: Age, BMI, and VCSSs differed significantly between groups. Temperatures were higher over diseased veins. Plasma concentrations of 20 cytokines differed between control and patient subjects (P<0.05), and most were lower in patients. C-X-C motif chemokine ligand-9 (aka monokine-induced by gamma interferon), C-X-C motif chemokine ligand 10 (aka IFNγ induced protein 10), and soluble IL-2 receptor-alpha were higher in patients, but not connected to other mediators in networks. In contrast, IL-17A, IL-12p70, and interferon gamma were the only mediators that were more highly interconnected in venous insufficiency. IL-17A and granulocyte macrophage colony stimulating factor (GM-CSF) were highly correlated in chronic venous insufficiency (CVI) but not in controls. In tissue, refluxing VVs significantly higher IL-15 expression than competent saphenous veins. CONCLUSIONS: Venous insufficiency associates with age, BMI, skin temperature, and plasma cytokines associated with interferon gamma and possibly IL-17A signaling. The vein wall may be a source of activation of cellular activation, given elevated IL-15 expression. Correlations between IL-17A and GM-CSF suggested a potential role for pathogenic Th17 cells in VVs. Differentially expressed inflammatory networks induced by venous hypertension may reflect or drive venous damage and ulceration.

Association Between Inflammatory Pathways and Phenotypes of Pulmonary Dysfunction Using Cluster Analysis in Persons Living With HIV and HIV-Uninfected Individuals.

BACKGROUND: Persons living with HIV (PLWH) are at risk of developing different phenotypes of chronic lung disease, including chronic obstructive pulmonary disease. Mechanisms underlying these phenotypes are unclear. OBJECTIVE: To identify clusters of peripheral inflammatory mediators associated with pulmonary function to determine inflammatory pathways and phenotypes of chronic obstructive pulmonary disease in PLWH and HIV-uninfected individuals. METHODS: Study participants were PLWH and HIV-uninfected individuals enrolled in the Pittsburgh HIV Lung Cohort. Pulmonary function tests were performed for all participants. Chest computed tomographic scans were performed in a subset of PLWH. Plasma levels of 19 inflammatory mediators were measured by Luminex or ELISA. Clusters were identified based on the expression pattern of inflammatory mediators in PLWH and HIV-uninfected individuals, and the relationships among clinical parameters were evaluated within clusters by using cluster and network analyses. RESULTS: In PLWH, we identified a distinct cluster with higher levels of Th1, Th2, and Th17 inflammatory mediators with increased complexity of these mediators and inferred presence of pathogenic Th17 cell types. Individuals in this cluster had worse airway obstruction and more radiographic emphysema. In HIV-uninfected individuals, a cluster with high-grade systemic inflammation also had worse diffusing capacity for carbon monoxide. CONCLUSIONS: Inflammatory pathways associated with pulmonary dysfunction in PLWH suggest multifaceted immune dysregulation involved in different phenotypes of pulmonary dysfunction with a potential specific contribution of the Th17 pathway to airway obstruction in PLWH. Identification of these associations may help in development of treatments that could alter the course of the disease.

Suppressed networks of inflammatory mediators characterize chronic venous insufficiency.

OBJECTIVE: Chronic venous insufficiency (CVI) affects 25 million adults in the United States. Little emphasis has been placed on inflammatory changes associated with CVI. We hypothesize that in patients with early to mid-stage benign varicose vein disease, differences in circulating inflammatory mediators will be manifested in blood draining the involved area vs circulating blood in control subjects. METHODS: Patients undergoing either endovenous ablation or sclerotherapy for Clinical, Etiology, Anatomy, and Pathophysiology clinical class 3 to 5 disease underwent phlebotomy from regional veins at the time of the procedure. The patient's age, gender, clinical class, duration of symptoms, presence of superficial truncal reflux by duplex ultrasound, and treatment modality were recorded. Plasma from patients and banked blood samples from healthy volunteers (HVs) were subjected to Luminex (EMD Millipore, Billerica, Mass) to evaluate the expression of an established panel of 20 inflammatory mediators. Mediator concentrations were compared between patients and HVs using Mann-Whitney U tests. Importantly, computational analysis allowed us to compare not only the panel of inflammatory mediators but also the inflammatory networks connecting these mediators to one another. Principal components were analyzed to assess network robustness in each group. RESULTS: CVI venous blood revealed significantly lower levels of monokine induced by γ interferon, soluble interleukin (IL) 2 receptor α chain, IL-4, IL-6, IL-7, tumor necrosis factor α, eotaxin, and granulocyte-macrophage colony-stimulating factor than blood from controls. Inflammatory networks were significantly less complex and less robust in the CVI patients compared with HVs. Based on principal component analysis, responses among HVs were more varied than those of CVI patients. CONCLUSIONS: We demonstrate that patients with CVI have significant differences not only in blood-borne inflammatory mediators but also in the interconnectedness of these mediators with one another and in their principal inflammatory characteristics. Results suggest hypoinflammation in chronic nonhealing changes in CVI. These novel findings, if validated in larger cohorts, may help predict the risk of disease progression or response to therapy in the future and may guide mechanistic studies on tissue responses to CVI.