Association of patient-reported cognitive impairment with quality of life and employment in multiple sclerosis.

BACKGROUND: Cognition is frequently affected in persons with multiple sclerosis (MS). Cognitive impairment (CI) is associated with decreased quality of life (QOL) and employment status. Yet, CI assessed using patient-reported outcome measures is not as well studied and is thought to be influenced by other symptoms. Health Utilities Index 3 (HUI3) is a multi-attribute health-status classification system that assesses 8 different single attributes, including cognition. METHODS: The North American Consortium of Multiple Sclerosis (NARCOMS) Registry, a voluntary, self-report registry for persons with MS, Spring 2019 survey collected the HUI3 and self-reported assessment of health-related QOL (RAND-12), cognitive status, depression, fatigue, disability, employment, disease-modifying therapy use, and sociodemographic data. We assessed the relationship between patient-reported cognitive CI from the HUI3 (HUI-C), QOL, and employment while adjusting for factors previously associated with the outcomes. For employment outcomes, the cohort was limited to participants 65 years of age or younger. RESULTS: Of the 6,227 respondents, 56.4 % reported cognitive difficulty with the HUI-C. After adjusting for multiple covariates, cognitive difficulty was associated with 1.2 point lower physical QOL for each 0.1 decrease in HUI-C (p < 0.0001). Mental QOL decreased by 2 points for each 0.1 decrease in HUI-C (p < 0.0001). Cognitive difficulty was associated with a 10 % decreased odds of employment in the multivariable model (p < 0.0001). DISCUSSION: Patient-reported CI was associated with lower health-related and vocational outcomes for MS patients, even after accounting for age, income, depression, fatigue, and disability associated with cognition. The HUI-C is a single attribute score derived from the HUI3 that may facilitate the evaluation of CI in MS.

Investigating the Prevalence of Comorbidity in Multiple Sclerosis Clinical Trial Populations.

BACKGROUND AND OBJECTIVES: Comorbidity is common in multiple sclerosis (MS) with the most prevalent conditions being depression, anxiety, hypertension, and hyperlipidemia. Limited information regarding the representation of comorbidity status is available from phase III clinical trials in MS leading to concern about the potential underrepresentation of individuals with comorbidity in clinical trials. The objective was to estimate the prevalence of comorbidities in MS clinical trial populations. METHODS: Individual-level data from multiple sponsors were requested for a 2-stage meta-analysis of phase III clinical trials of MS disease-modifying therapies. To ensure consistency of our approach across trials, we followed the Maelstrom retrospective harmonization guidelines. Chronic comorbidities at clinical trial enrollment recommended by the International Advisory Committee on Clinical Trials in MS were considered (depression, anxiety, hypertension, hyperlipidemia, migraine, diabetes, chronic lung disease). Additional comorbidities were also classified. Classification was based on medical history data. Individual comorbidities were summed and categorized as 0, 1, 2, or ≥3. We report the pooled prevalence (95% confidence interval [95% CI]) of comorbidity. The pooled prevalence and prevalence ratios across age, sex, race, disability level, and treatment were also reported. Heterogeneity was assessed using the I2 statistic. RESULTS: Seventeen trials involving 17,926 participants were included. Fourteen trials enrolled participants with relapsing MS (RMS) while 3 enrolled participants with progressive MS (PMS). The distributions of sex, age, and disability level were generally consistent within RMS and PMS trials. When pooled, almost half of trial participants (46.5%) had ≥1 comorbidity (1: 25.0%, 95% CI 23.0-27.0, I2 = 89.9; 2: 11.4% [9.3-14.0], I2 = 96.3; ≥3: 6.0% [4.2-8.4], I2 = 97.7). Depression (16.45% [12.96-20.88], I2 = 98.3) was the most prevalent comorbidity reported, followed by hypertension (10.16% [8.61-11.98], I2 = 93.2). Heterogeneity was high across trials. Older age and female participants were associated with increased number of comorbidities. Older individuals and male participants had a higher prevalence of hyperlipidemia, while older individuals and female participants had a higher prevalence of depression and anxiety. DISCUSSION: Individuals with comorbidities are included in clinical trials, although they may still be underrepresented compared with the general MS population. Given the comorbidity prevalence in the trial populations and studies suggesting an association of comorbidities with disease activity, comorbidity may influence outcomes in clinical trials.

Diffusion basis spectrum imaging and diffusion tensor imaging predict persistent black hole formation in multiple sclerosis.

BACKGROUND AND OBJECTIVES: Diffusion basis spectrum imaging (DBSI) extracts multiple anisotropic and isotropic diffusion tensors, providing greater histopathologic specificity than diffusion tensor imaging (DTI). Persistent black holes (PBH) represent areas of severe tissue damage in multiple sclerosis (MS), and a high PBH burden is associated with worse MS disability. This study evaluated the ability of DBSI and DTI to predict which acute contrast-enhancing lesions (CELs) would persist as T1 hypointensities (i.e. PBHs) 12 months later. We expected that a higher radial diffusivity (RD), representing demyelination, and higher DBSI-derived isotropic non-restricted fraction, representing edema and increased extracellular space, of the acute CEL would increase the likelihood of future PBH development. METHODS: In this prospective cohort study, relapsing MS patients with ≥1 CEL(s) underwent monthly MRI scans for 4 to 6 months until gadolinium resolution. DBSI and DTI metrics were quantified when the CEL was most conspicuous during the monthly scans. To determine whether the CEL became a PBH, a follow-up MRI was performed at least 12 months after the final monthly scan. RESULTS: The cohort included 20 MS participants (median age 33 years; 13 women) with 164 CELs. Of these, 59 (36 %) CELs evolved into PBHs. At Gd-max, DTI RD and AD of all CELs increased, and both metrics were significantly elevated for CELs which became PBHs, as compared to non-black holes (NBHs). DTI RD above 0.74 conferred an odds ratio (OR) of 7.76 (CI 3.77-15.98) for a CEL becoming a PBH (AUC 0.80, CI 0.73-0.87); DTI axial diffusivity (AD) above 1.22 conferred an OR of 7.32 (CI 3.38-15.86) for becoming a PBH (AUC 0.75, CI 0.66-0.83). DBSI RD and AD did not predict PBH development in a multivariable model. At Gd-max, DBSI restricted fraction decreased and DBSI non-restricted fraction increased in all CELs, and both metrics were significantly different for CELs which became PBHs, as compared to NBHs. A CEL with a DBSI non-restricted fraction above 0.45 had an OR of 4.77 (CI 2.35-9.66) for becoming a PBH (AUC 0.74, CI 0.66-0.81); a CEL with a DBSI restricted fraction below 0.07 had an OR of 9.58 (CI 4.59-20.02) for becoming a PBH (AUC 0.80, 0.72-0.87). CONCLUSION: Our findings suggest that greater degree of edema/extracellular space in a CEL is a predictor of tissue destruction, as evidenced by PBH evolution.

Severity and worsening of fatigue among individuals with multiple sclerosis.

Background: Fatigue is associated with reduced quality of life and social participation, and poor employment outcomes. However, most studies examining fatigue are limited by small sample sizes or short follow-up periods. Objective: To characterize the natural history of fatigue. Methods: The North American Research Committee on Multiple Sclerosis Registry participants with ≥7 years of longitudinal data between 2004 and 2019 and a relapsing disease course were included. A subset of participants enrolled within 5 years of diagnosis was identified. The Fatigue Performance Scale assessed fatigue and ≥1-point increase in Fatigue Performance Scale sustained at the next survey defined fatigue worsening. Results: Of 3057 participants with longitudinal data, 944 were within 5 years of multiple sclerosis diagnosis. Most participants (52%) reported fatigue worsening during follow-up. Median time to fatigue worsening ranged from 3.5 to 5 years at lower levels of index fatigue. Fatigue worsening was associated with lower annual income, increasing disability, lower initial fatigue level, taking injectable disease-modifying therapies and increasing depression levels in the relapsing multiple sclerosis participants. Conclusion: Most multiple sclerosis participants early in their disease suffer from fatigue and at least half reported fatigue worsening over time. Understanding factors associated with fatigue may help to identify populations most at risk of fatigue worsening will be informative for the overall management of patients with multiple sclerosis.

Physical activity as a correlate of symptoms, quality of life, comorbidity, and disability status in Hispanics with multiple sclerosis.

BACKGROUND: Hispanics with multiple sclerosis (MS) experience disproportionate rates of mobility disability compared to non-Hispanic Whites with MS. Physical activity (PA) is highlighted as a potential adjuvant therapy for improving MS symptoms and disease progression, however less than 30% of Hispanics with MS report sufficient levels of PA. OBJECTIVES: The current study aimed to examine the correlates of PA behavior among Hispanics with MS in the North American Research Committee on Multiple Sclerosis Registry (NARCOMS). METHODS: In Spring 2015, 136 NARCOMS participants identified as Hispanic and completed the International Physical Activity Questionnaire (IPAQ). IPAQ scores were converted to Health Contribution Scores (HCS) for estimating PA. The association between the HCS scores and MS symptoms (i.e., mobility, cognition, fatigue, spasticity, hand function, bowel/bladder, sensory, tremors, depression, and pain), quality of life (QOL), comorbid conditions, and disability status were evaluated using Pearson or Spearman correlation coefficients with follow-up multivariable regression analyses. RESULTS: The mean age among participants was 58 years and 79% identified as female. The mean MS disease duration was 20 years and 68% reported relapsing disease course. The mean HCS score among participants was 15.6 ± 20.9. HCS was moderately associated with disability status (rs = -0.39), mobility (rs = -0.37), bowel/bladder function (rs = -0.33), and physical health related QOL (r = 0.32). There were small associations between HCS and hand function (rs = -0.29), fatigue (rs = -0.20), and tremor (rs = -0.25). Multivariable regression analyses indicated that disability status, mobility, bowel/bladder function, and physical health related QOL were all associated with HCS but did not independently contribute to the models when controlling for age, sex, and employment. CONCLUSIONS: This study highlights correlates of PA behavior among Hispanics with MS. Researchers and clinicians may consider disability status, mobility, and physical health related QOL in future studies examining PA among Hispanics with MS.

Predictors of Clinical Outcomes of Pharmacomechanical Catheter-Directed Thrombolysis for Acute Iliofemoral Deep Vein Thrombosis: Analysis of a Multicenter Randomized Trial.

PURPOSE: To identify the baseline patient characteristics that predict who will benefit from pharmacomechanical catheter-directed thrombolysis (PCDT) of acute iliofemoral deep vein thrombosis (DVT). MATERIALS AND METHODS: In the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) multicenter randomized trial, 381 patients with acute iliofemoral DVT underwent PCDT and anticoagulation or anticoagulation alone. The correlations between baseline factors and venous clinical outcomes were evaluated over 24 months using post hoc regression analyses. Interaction terms were examined to evaluate for differential effects by treatment arm. RESULTS: Patients with clinically severe DVT (higher baseline Villalta score) experienced greater effects of PCDT in improving 24-month venous outcomes, including moderate or severe postthrombotic syndrome (PTS) (odds ratios [ORs] and 95% confidence intervals [CIs] per unit increase in the baseline Villalta scores were as follows: for PCDT, OR, 1.08 [95% CI, 1.01-1.15]; for control, OR, 1.20 [95% CI, 1.12-1.29]; Pinteraction = .03), PTS severity (between-arm differences in the Villalta [Pinteraction = .004] and Venous Clinical Severity Scale [VCSS] [Pinteraction = .002)] scores), and quality of life (between-arm difference in the Venous Insufficiency Epidemiological and Economic Study Quality of Life score; Pinteraction = .025). Patients with previous DVT had greater effects of PCDT on 24-month PTS severity than those in patients without previous DVT (mean [95% CI] between-arm difference in the Villalta score, 4.2 [1.56-6.84] vs 0.9 [-0.44 to 2.26], Pinteraction = .03; mean [95% CI] between-arm difference in the VCSS score, 2.6 [0.94-4.21] vs 0.3 [-0.58 to 1.14], Pinteraction = .02). The effects of PCDT on some but not all outcomes were greater in patients presenting with left-sided DVT (Villalta PTS severity, Pinteraction = .04; venous ulcer, Pinteraction = .0499) or a noncompressible popliteal vein (PTS, Pinteraction = .02). The effects of PCDT did not vary by sex, race, ethnicity, body mass index, symptom duration, hypertension, diabetes, or hypercholesterolemia. CONCLUSIONS: In patients with acute iliofemoral DVT, greater presenting clinical severity (higher baseline Villalta score) and a history of previous DVT predict enhanced benefits from PCDT.

Qualitative imaging features of pancreatic neuroendocrine neoplasms predict histopathologic characteristics including tumor grade and patient outcome.

OBJECTIVES: To identify PanNEN imaging features associated with tumor grade and aggressive histopathological features. METHODS: Associations between histopathological and imaging features of resected PanNEN were retrospectively tested. Histopathologic features included WHO grade, lymphovascular invasion (LVI), growth pattern (infiltrative, circumscribed), and intratumoral fibrosis (mature, immature). Imaging features included size, degree/uniformity of enhancement, progressive enhancement, contour, infiltrative appearance (infiltrativeim), calcifications, cystic components, tumor thrombus, vascular occlusion (VO), duct dilatation, and atrophy. Multinomial logistic regression analyses evaluated the magnitude of associations. Association of variables with outcome was assessed using Cox-proportional hazards regression. RESULTS: 133 patients were included. 3 imaging features (infiltrativeim, ill-defined contour [contourill], and VO) were associated with all histopathologic parameters and poor outcome. Increase in grade increased odds of contourill by 15.6 times (p = 0.0001, 95% CI 3.8-64.4). PanNEN with VO were 51.1 times (p = 0.0002, 6.5-398.6) more likely to demonstrate LVI. For PanNEN with contourill, infiltrative growth pattern was 51.3 times (p < 0.0001, 9.1-288.4), and fibrosis was 14 times (p = 0.0065, 2.1-93.7) more likely. Contourill was associated with decreased recurrence-free survival (p = 0.0003, HR 18.29, 3.83-87.3) and VO (p = 0.0004, HR6.08, 2.22-16.68) with decreased overall survival. CONCLUSIONS: Infiltrativeim, contourill, and VO on imaging are associated with higher grade/histopathological parameters linked to tumor aggression, and poor outcome.

A propensity-matched comparison of long-term disability worsening in patients with multiple sclerosis treated with dimethyl fumarate or fingolimod.

BACKGROUND: Although the aggregate of data among patients with multiple sclerosis (MS) have shown similar efficacy between dimethyl fumarate (DMF) and fingolimod (FTY), most studies have not assessed long-term worsening of disability. We compared long-term disability worsening over 5 years, as assessed by the Patient-Determined Disease Steps (PDDS), among participants with MS treated with DMF or FTY. METHODS: We identified individuals in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry who had relapsing-remitting MS (RRMS), residing in the United States (Spring 2011 to Spring 2018), who initiated treatment with DMF (n = 689) or FTY (n = 565) and had ⩾1 year follow-up on index treatment. Participants receiving DMF who were previously treated with FTY and those on FTY previously treated with DMF were excluded. Propensity score matching at baseline was used to match FTY-treated to DMF-treated participants. Time to 6-month confirmed disability worsening (⩾1-point increase on PDDS, sustained for ⩾6 months) was estimated using Cox regression. A sensitivity analysis was conducted to account for differences in the duration of index exposure between DMF and FTY groups. RESULTS: After propensity score matching, 468 DMF-treated participants were matched with 468 FTY-treated participants. Median treatment duration was 3.0 years for DMF and 4.0 years for FTY. At 5 years, 68.3% [95% confidence interval (CI): 62.4-73.5] of DMF-treated participants and 63.3% (95% CI: 59.6-70.1) treated with FTY were free from 6-month confirmed PDDS worsening [hazard ratio (HR) 1.01 (95% CI: 0.79-1.28); p = 0.95]. Results were similar in the sensitivity analysis: 70.5% (95% CI: 61.8-77.6) of DMF-treated participants and 72.7% (95% CI: 65.4-78.6) of FTY-treated participants were free from 6-month confirmed PDDS worsening [HR: 1.04 (95% CI: 0.71-1.51); p = 0.84]. CONCLUSIONS: In participants with MS from the NARCOMS registry, there was no significant difference in confirmed disability (PDDS) worsening over 5 years between those treated with DMF versus FTY.

Clinical Outcomes of a Pharmacomechanical Catheter-Directed Venous Thrombolysis Strategy that Included Rheolytic Thrombectomy in a Multicenter Randomized Trial.

PURPOSE: To describe the clinical outcomes of a pharmacomechanical catheter-directed venous thrombolysis (PCDT) strategy that included AngioJet rheolytic thrombectomy. METHODS: In the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis multicenter randomized trial, physicians at 33 sites designated AngioJet as their preferred device for PCDT. In these sites, 364 patients with acute proximal lower-extremity deep vein thrombosis (DVT) were randomized to a strategy of PCDT that incorporated either AngioJet along with anticoagulation or anticoagulation alone. Relief from presenting DVT symptoms was evaluated over 30 days of follow-up. Postthrombotic syndrome (PTS), quality of life (QOL), recurrent venous thromboembolism (VTE), and safety were evaluated over 24 months of follow-up. RESULTS: Within 30 days, AngioJet-PCDT led to a greater improvement in leg swelling (mean difference calf circumference 0.55 cm, P = .009), venous QOL (mean difference 6.5 Venous Insufficiency Epidemiologic and Economic Study [VEINES]-QOL points, P = .0073), and venous symptoms (mean difference 5.6 VEINES-symptoms points, P = .0134) than control, with differences most apparent in iliofemoral DVT. AngioJet-PCDT reduced PTS at 6 months (24% with AngioJet-PCDT vs 40% with control, P = .003) but did not influence PTS or QOL between 12 and 24 months. Major bleeding, pulmonary embolism, renal failure, and bradycardia were infrequent with AngioJet-PCDT (<2% each), but 24-month VTE recurrence may have been more frequent (13.9% with AngioJet-PCDT vs 6.8% with control, P = .03) CONCLUSIONS: In patients with acute proximal DVT, a treatment strategy that included first-line AngioJet-PCDT was reasonably safe and led to an improved symptom status and venous QOL at 1 month and reduced PTS at 6 months compared with anticoagulation alone. However, AngioJet-PCDT did not influence PTS or the QOL beyond 6 months and may have increased recurrent VTE.

Characterizing Long-term Disability Progression and Employment in NARCOMS Registry Participants with Multiple Sclerosis Taking Dimethyl Fumarate.

BACKGROUND: Delayed-release dimethyl fumarate (DMF) is effective in relapsing-remitting multiple sclerosis (RRMS), but long-term effects of DMF on disability and disease progression in clinical settings are unknown. We evaluated disability and employment outcomes in persons with RRMS treated with DMF for up to 5 years. METHODS: This longitudinal study included US North American Research Committee on Multiple Sclerosis (NARCOMS) Registry participants with RRMS reporting DMF initiation in fall 2013 through spring 2018 with 1 year or more of follow-up. Time to 6-month confirmed disability progression (≥1-point increase in Patient-Determined Disease Steps [PDDS] score) and change in employment status were evaluated using Kaplan-Meier analysis. Participants were censored at last follow-up or at DMF discontinuation, whichever came first. RESULTS: During the study, 725 US participants with RRMS had at least 1 year of DMF follow-up data, of whom most were female and White. At year 5, 69.9% (95% CI, 65.4%-73.9%) of these participants were free from 6-month confirmed disability progression, and 84.7% (95% CI, 78.6%-89.2%) were free from conversion to secondary progressive MS. Of 116 participants with data at baseline and year 5, most had stable or improved PDDS and Performance Scales scores over 5 years. Of 322 participants 62 years and younger and employed at the index survey, 66.0% (95% CI, 57.6%-73.1%) were free from a negative change in employment type over 5 years. CONCLUSIONS: Most US NARCOMS Registry participants treated up to 5 years with DMF remained free from 6-month confirmed disability progression and conversion to secondary progressive MS and had stable disability and employment status. These results support the long-term stability of disability and work-related outcomes with disease-modifying therapy.

Correlation between Post-Procedure Residual Thrombus and Clinical Outcome in Deep Vein Thrombosis Patients Receiving Pharmacomechanical Thrombolysis in a Multicenter Randomized Trial.

PURPOSE: To evaluate relationships between immediate venographic results and clinical outcomes of pharmacomechanical catheter-directed thrombolysis (PCDT). MATERIALS AND METHODS: Venograms from 317 patients with acute proximal deep vein thrombosis (DVT) who received PCDT in a multicenter randomized trial were reviewed. Quantitative thrombus resolution was assessed by independent readers using a modified Marder scale. The physician operators recorded their visual assessments of thrombus regression and venous flow. These immediate post-procedure results were correlated with patient outcomes at 1, 12, and 24 months. RESULTS: PCDT produced substantial thrombus removal (P < .001 for pre-PCDT vs. post-PCDT thrombus scores in all segments). At procedure end, spontaneous venous flow was present in 99% of iliofemoral venous segments and in 89% of femoral-popliteal venous segments. For the overall proximal DVT population, and for the femoral-popliteal DVT subgroup, post-PCDT thrombus volume did not correlate with 1-month or 24-month outcomes. For the iliofemoral DVT subgroup, over 1 and 24 months, symptom severity scores were higher (worse), and venous disease-specific quality of life (QOL) scores were lower (worse) in patients with greater post-PCDT thrombus volume, with the difference reaching statistical significance for the 24-month Villalta post-thrombotic syndrome (PTS) severity score (P = .0098). Post-PCDT thrombus volume did not correlate with 12-month valvular reflux. CONCLUSIONS: PCDT successfully removes thrombus in acute proximal DVT. However, the residual thrombus burden at procedure end does not correlate with the occurrence of PTS during the subsequent 24 months. In iliofemoral DVT, lower residual thrombus burden correlates with reduced PTS severity and possibly also with improved venous QOL and fewer early symptoms.

Outcomes of Yttrium-90 Radioembolization for Unresectable Combined Biphenotypic Hepatocellular-Cholangiocarcinoma.

PURPOSE: To evaluate outcomes of yttrium-90 radioembolization in patients with combined biphenotypic hepatocellular-cholangiocarcinoma (cHCC-CC). MATERIALS AND METHODS: A retrospective review of patients with biopsy-confirmed cHCC-CC treated with yttrium-90 radioembolization between 2012 and 2018 was performed. Twenty-two patients with cHCC-CC (mean age 65.6 y, 17 men, 5 women) underwent 29 radioembolization treatments (5 resin, 24 glass microspheres). Survival data were available in 21 patients, and hepatic imaging response data were available in 20 patients. Hepatic imaging response to radioembolization was assessed on follow-up CT or MR imaging using modified Response Evaluation Criteria In Solid Tumours criteria. Univariate stepwise Cox regression analysis was used to evaluate the association between demographic and clinical factors and survival. Logistic regression evaluated associations between clinical factors and response to treatment, overall response, and disease control. RESULTS: Hepatic imaging response was as follows: 15% complete response, 40% partial response, 10% stable disease, and 35% progressive disease (55% response rate, 65% disease control rate). Two patients were downstaged or bridged to transplant, and 1 patient was downstaged to resection. Median overall survival was 9.3 mo (range, 2.5-31.0 mo) from time of radioembolization. Nonreponse to treatment, bilobar disease, presence of multiple tumors, and elevated carbohydrate antigen 19-9 before treatment were associated with reduced survival after radioembolization. CONCLUSIONS: Radioembolization is a viable option for locoregional control of cHCC-CC with good response and disease control rates.

A Color Flow Tract in Ultrasound-Guided Random Renal Core Biopsy Predicts Complications.

OBJECTIVES: To determine patient and procedural risk factors for major complications in ultrasound (US)-guided random renal core biopsy. METHODS: Random renal biopsies performed by radiologists in the US department at a single institution between 2014 and 2018 were retrospectively reviewed. The patient's age, sex, race, and estimated glomerular filtration rate (eGFR) were recorded. The biopsy approach, needle gauge, length of cores, number of throws, and presence of a color flow tract were recorded. Outcome data included minor and major complications. Associations between variables were tested with χ2 analyses and univariable/multivariable logistic regression models. RESULTS: A total of 231 biopsies (167 native and 64 allografts) were reviewed. There was no significant difference in the sex, age, race, or eGFR between native and allograft groups. The overall rate for any complication was 18.2%, with a 4.3% rate of major complications, which was significantly greater in native compared to allograft biopsies (6% versus 0%; P = .045). A risk analysis in native biopsies only showed that major complications were significantly associated with a low eGFR such that patients with stage 4 or 5 kidney disease had higher odds of complications (odds ratio [95% confidence interval]: stage 4, 9.405 [1.995-44.338]; P = .0393; stage 5, 10.749 [2.218-52.080]; P = .0203) than patients with normal function (eGFR >60 mL/min). The presence of a color flow tract portended a 10.7 times greater risk of having any complication (95% confidence interval, 4.595-24.994; P < .001). Other procedural factors were not significantly associated with complications. CONCLUSIONS: There is an increased risk of major complications in US-guided random native kidney biopsy in patients with a low eGFR (<30 mL/min) and a patent color flow tract in the immediate postbiopsy setting.

Turning is an important marker of balance confidence and walking limitation in persons with multiple sclerosis.

The standard functional tool for gait assessment in multiple sclerosis (MS) clinical trials has been the 25-Foot Timed Walk Test, a measure of gait speed. Straight-line gait assessment may not reflect adequately upon balance and coordination. Walking tests with turns may add additional information towards understanding gait and balance status, and be more reflective of ambulation in the community. Understanding the impact of turn parameters on patient-reported outcomes of balance and walking would help MS clinicians better formulate treatment plans for persons with gait limitations. In this study, ninety-one persons with MS (Expanded Disability Status Score; EDSS, range: 0-6.5) were enrolled in an initial cross-sectional study. Twenty-four subjects (EDSS, range:1.0-6.0) completed a follow-up visit an average of 12 months later. Spatiotemporal gait analysis was collected at both visits using APDM Opal wireless body-worn sensors while performing the Timed-Up-and-Go (TUG) and 6-Minute Walk Test (6MWT). For both cross-sectional and longitudinal data, regression analyses determined the impact on the addition of turning parameters to stride velocity (SV), in the prediction of self-reported balance confidence (Activities-Specific Balance Confidence Scale (ABC)) and walking limitation (12-item Multiple Sclerosis Walking Scale (MSWS-12)). The addition of 6MWT peak turn velocity (PTV) to 6MWT SV increased the predictive power of the 6MWT for the ABC from 20% to 33%, and increased the predictive power from 28% to 41% for the MSWS-12. TUG PTV added to TUG SV also strengthened the relationship of the TUG for the ABC from 19% to 28%, and 27% to 36% for the MSWS-12. For those with 1 year follow-up, percent change in turn number of steps (TNS%Δ) during the 6MWT added to 6MWT SV%Δ improved the modeling of ABC%Δ from 24% to 33%. 6MWT PTV%Δ added to 6MWT SV%Δ increased the predictive power of MSWS-12%Δ from 8% to 27%. Conclusively, turn parameters improved modeling of self-perceived balance confidence and walking limitations when added to the commonly utilized measure of gait speed. Tests of longer durations with multiple turns, as opposed to shorter durations with a single turn, modeled longitudinal change more accurately. Turn speed and stability should be qualitatively assessed during the clinic visit, and use of multi-faceted tests such as the TUG or 6MWT may be required to fully understand gait deterioration in persons with MS.

Intensity ratio to improve black hole assessment in multiple sclerosis.

BACKGROUND: Improved imaging methods are critical to assess neurodegeneration and remyelination in multiple sclerosis. Chronic hypointensities observed on T1-weighted brain MRI, "persistent black holes," reflect severe focal tissue damage. Present measures consist of determining persistent black holes numbers and volumes, but do not quantitate severity of individual lesions. OBJECTIVE: Develop a method to differentiate black and gray holes and estimate the severity of individual multiple sclerosis lesions using standard magnetic resonance imaging. METHODS: 38 multiple sclerosis patients contributed images. Intensities of lesions on T1-weighted scans were assessed relative to cerebrospinal fluid intensity using commercial software. Magnetization transfer imaging, diffusion tensor imaging and clinical testing were performed to assess associations with T1w intensity-based measures. RESULTS: Intensity-based assessments of T1w hypointensities were reproducible and achieved > 90% concordance with expert rater determinations of "black" and "gray" holes. Intensity ratio values correlated with magnetization transfer ratios (R = 0.473) and diffusion tensor imaging metrics (R values ranging from 0.283 to -0.531) that have been associated with demyelination and axon loss. Intensity ratio values incorporated into T1w hypointensity volumes correlated with clinical measures of cognition. CONCLUSIONS: This method of determining the degree of hypointensity within multiple sclerosis lesions can add information to conventional imaging.

Quantitative visual tests after poorly recovered optic neuritis due to multiple sclerosis.

BACKGROUND: Visual dysfunction in MS can be quantified using a variety of tests. Many vision tests have not been formally evaluated among MS patients with existing visual dysfunction. OBJECTIVE: Evaluate several versions of visual acuity and contrast sensitivity tests, measures of central and peripheral vision, retina structure, electrophysiologic function, and quality of life among MS patients with moderate/severe visual dysfunction. METHODS: Cross-sectional study of 46 patients with stable, incompletely recovered optic neuritis. Testing included Snellen eye charts, several Sloan low contrast charts, Pelli Robson (PR) contrast sensitivity charts, optical coherence tomography, visual fields, Farnsworth Munsell 100-hue test, visual evoked potentials (VEP), and visual function quality of life (VFQ-25) testing. RESULTS: 98% of eyes could read two lines of the PR chart, while only 43% read the 2.5% contrast chart. Low contrast tests correlated strongly with each other and with retinal nerve fiber layer (RNFL) thickness, visual fields, and color vision but not with VEPs. For patients with RNFL <75µm, VFQ-25 scores dropped by approximately 2 points for every 1µm decrease in RNFL. CONCLUSION: Among MS patients with visual impairment due to optic neuritis, PR contrast sensitivity could be utilized as a single chart. Visual quality of life was associated with RNFL thinning below 75µm.

Detection and quantification of regional cortical gray matter damage in multiple sclerosis utilizing gradient echo MRI.

Cortical gray matter (GM) damage is now widely recognized in multiple sclerosis (MS). The standard MRI does not reliably detect cortical GM lesions, although cortical volume loss can be measured. In this study, we demonstrate that the gradient echo MRI can reliably and quantitatively assess cortical GM damage in MS patients using standard clinical scanners. High resolution multi-gradient echo MRI was used for regional mapping of tissue-specific MRI signal transverse relaxation rate values (R2(*)) in 10 each relapsing-remitting, primary-progressive and secondary-progressive MS subjects. A voxel spread function method was used to correct artifacts induced by background field gradients. R2(*) values from healthy controls (HCs) of varying ages were obtained to establish baseline data and calculate ΔR2(*) values - age-adjusted differences between MS patients and HC. Thickness of cortical regions was also measured in all subjects. In cortical regions, ΔR2(*) values of MS patients were also adjusted for changes in cortical thickness. Symbol digit modalities (SDMT) and paced auditory serial addition (PASAT) neurocognitive tests, as well as Expanded Disability Status Score, 25-foot timed walk and nine-hole peg test results were also obtained on all MS subjects. We found that ΔR2(*) values were lower in multiple cortical GM and normal appearing white matter (NAWM) regions in MS compared with HC. ΔR2(*) values of global cortical GM and several specific cortical regions showed significant (p < 0.05) correlations with SDMT and PASAT scores, and showed better correlations than volumetric measures of the same regions. Neurological tests not focused on cognition (Expanded Disability Status Score, 25-foot timed walk and nine-hole peg tests) showed no correlation with cortical GM ΔR2(*) values. The technique presented here is robust and reproducible. It requires less than 10 min and can be implemented on any MRI scanner. Our results show that quantitative tissue-specific R2(*) values can serve as biomarkers of tissue injury due to MS in the brain, including the cerebral cortex, an area that has been difficult to evaluate using standard MRI.

Gradient echo magnetic resonance imaging correlates with clinical measures and allows visualization of veins within multiple sclerosis lesions.

BACKGROUND: Conventional magnetic resonance imaging (MRI) methods do not quantify the severity of multiple sclerosis (MS) white matter lesions or measure pathology within normal-appearing white matter (NAWM). OBJECTIVE: Gradient Echo Plural Contrast Imaging (GEPCI), a fast MRI technique producing inherently co-registered images for qualitative and quantitative assessment of MS, was used to 1) correlate with disability; 2) distinguish clinical MS subtypes; 3) determine prevalence of veins co-localized within lesions in WM. METHODS: Thirty subjects representing relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS) subtypes were scanned with clinical and GEPCI protocols. Standard measures of physical disability and cognition were correlated with magnetic resonance metrics. Lesions with central veins were counted for RRMS subjects. RESULTS: Tissue damage load (TDL-GEPCI) and lesion load (LL-GEPCI) derived with GEPCI correlated better with MS functional composite (MSFC) measures and most other neurologic measures than lesion load derived with FLAIR (LL-FLAIR). GEPCI correctly classified clinical subtypes in 70% subjects. A central vein could be identified in 76% of WM lesions in RRMS subjects on GEPCI T2*-SWI images. CONCLUSION: GEPCI lesion metrics correlated better with neurologic disability than lesion load derived using FLAIR imaging, and showed promise in classifying clinical subtypes of MS. These improvements are likely attributable to the ability of GEPCI to quantify tissue damage.

Spinal cord tract diffusion tensor imaging reveals disability substrate in demyelinating disease.

OBJECTIVE: This study assessed the tissue integrity of major cervical cord tracts by using diffusion tensor imaging (DTI) to determine the relationship with specific clinical functions carried by those tracts. METHODS: This was a cross-sectional study of 37 patients with multiple sclerosis or neuromyelitis optica with remote cervical cord disease. Finger vibratory thresholds, 25-foot timed walk (25FTW), 9-hole peg test (9HPT), and Expanded Disability Status Scale were determined. DTI covered cervical regions C1 through C6 with 17 5-mm slices (0.9 × 0.9 mm in-plane resolution). Regions of interest included posterior columns (PCs) and lateral corticospinal tracts (CSTs). Hierarchical linear mixed-effect modeling included covariates of disease subtype (multiple sclerosis vs neuromyelitis optica), disease duration, and sex. RESULTS: Vibration thresholds were associated with radial diffusivity (RD) and fractional anisotropy (FA) in the PCs (both p < 0.01), but not CSTs (RD, p = 0.29; FA, p = 0.14). RD and FA in PCs, and RD in CSTs were related to 9HPT (each p < 0.0001). 25FTW was associated with RD and FA in PCs (p < 0.0001) and RD in CSTs (p = 0.008). Expanded Disability Status Scale was related to RD and FA in PCs and CSTs (p < 0.0001). Moderate/severe impairments in 9HPT (p = 0.006) and 25FTW (p = 0.017) were more likely to show combined moderate/severe tissue injury within both PCs and CSTs by DTI. CONCLUSIONS: DTI can serve as an imaging biomarker of spinal cord tissue injury at the tract level. RD and FA demonstrate strong and consistent relationships with clinical outcomes, specific to the clinical modality.

Association of neuromyelitis optica with severe and intractable pain.

OBJECTIVE: To contrast differences in pain and treatment outcomes between neuromyelitis optica (NMO) and multiple sclerosis (MS). DESIGN: Retrospective, cross-sectional cohort study. SETTING: Academic MS center. PATIENTS: Complete ascertainment of an academic MS center cohort of NMO and an MS comparison sample cohort. MAIN OUTCOME MEASURES: Current pain was quantified by a 10-point scale and the McGill Pain Questionnaire.Expanded Disability Status Scale score and number of involved spinal cord levels were collected in addition to testing for cognition, fatigue, depression, and quality of life. Number and types of pain medications were tabulated. RESULTS: Current pain was more common in subjects with NMO (n=29) vs MS (n=66) (86.2% vs 40.9%; P.001)and more severe on a 10-point scale (5.38 vs 1.85;P.001). Pain remained more common after controlling for disability and number of spinal cord segments(P=.03). Prescription pain medication was used more frequently in subjects with NMO compared with subjects with MS(75.9% vs 37.8%; P.001), often requiring more than 1 medication (65.5% vs 15.2%; P.001). No subject with NMO taking pain medication (22 of 29) rated their current pain as 0 of 10, whereas almost half of those taking pain medication with MS were currently free of pain (0% vs 48%; P=.006). CONCLUSIONS: Neuromyelitis optica is frequently associated with severe pain that appears insufficiently controlled by pharmacologic interventions. Future studies should evaluate the efficacy of a multidisciplinary and multimodal approach to pain management.