National survey of patient symptoms and therapies among 707 women with a lipedema phenotype in the United States.

BACKGROUND: National survey data exploring the patient experience with lipedema are lacking. METHODS: We conducted national surveys from 2016 to 2022 of women with lipedema as well as female controls. Surveys collected information on symptomatology, pain, and therapies. We performed logistic regression comparing symptoms among those with lipedema versus controls adjusting for age and BMI. RESULTS: A total of 707 women with lipedema and 216 controls completed the surveys. Those with lipedema had a mean age of 48.6 years and mean BMI of 40.9 kg/m2. Lipedema symptom onset occurred frequently at puberty (48.0%) or pregnancy (41.2%). Compared to controls, women with lipedema were more likely to report leg swelling in heat (odds ratio [OR], 66.82; 95% CI, 33.04-135.12; p < 0.0001), easy bruising (OR, 26.23; 95% CI, 15.58-44.17; p < 0.0001), altered gait (OR, 15.54; 95% CI, 7.58-31.96; p < 0.0001), flu-like symptoms (OR, 12.99; 95% CI, 4.27-39.49; p < 0.0001), joint hypermobility (OR, 12.88; 95% CI, 6.68-24.81; p < 0.0001), cool skin (OR, 12.21; 95% CI, 5.20-28.69; p < 0.0001), varicose veins (OR, 11.29; 95% CI, 6.71-18.99; p < 0.0001), and fatigue (OR, 9.59; 95% CI, 6.10-15.09; p < 0.0001). Additionally, 70.3% had upper arm involvement, 21.2% reported foot swelling, and 16.6% reported foot pain. Most (52.2%) reported no symptom improvement with diet or exercise. Common therapies used included compression therapy (45.0%), gastric bypass (15.7%), and lower-extremity liposuction (14.0%). CONCLUSION: In a large, national, symptom survey, women with lipedema reported excess pain, swelling, and fat in the legs along with numerous symptoms beyond those classically described. Symptom responses to common therapies remain understudied.

High tissue-sodium associates with systemic inflammation and insulin resistance in obese individuals.

BACKGROUND AND AIMS: High sodium intake is associated with obesity and insulin resistance, and high extracellular sodium content may induce systemic inflammation, leading to cardiovascular disease. In this study, we aim to investigate whether high tissue sodium accumulation relates with obesity-related insulin resistance and whether the pro-inflammatory effects of excess tissue sodium accumulation may contribute to such association. METHODS AND RESULTS: In a cross-sectional study of 30 obese and 53 non-obese subjects, we measured insulin sensitivity determined as glucose disposal rate (GDR) using hyperinsulinemic euglycemic clamp, and tissue sodium content using 23Na magnetic resonance imaging. Median age was 48 years, 68% were female and 41% were African American. Median (interquartile range) BMI was 33 (31.5, 36.3) and 25 (23.5, 27.2) kg/m2 in the obese and non-obese individuals, respectively. In obese individuals, insulin sensitivity negatively correlated with muscle (r = -0.45, p = 0.01) and skin sodium (r = -0.46, p = 0.01). In interaction analysis among obese individuals, tissue sodium had a greater effect on insulin sensitivity at higher levels of high-sensitivity C-reactive protein (p-interaction = 0.03 and 0.01 for muscle and skin Na+, respectively) and interleukin-6 (p-interaction = 0.024 and 0.003 for muscle and skin Na+, respectively). In interaction analysis of the entire cohort, the association between muscle sodium and insulin sensitivity was stronger with increasing levels of serum leptin (p-interaction = 0.01). CONCLUSIONS: Higher muscle and skin sodium are associated with insulin resistance in obese patients. Whether high tissue sodium accumulation has a mechanistic role in the development of obesity-related insulin resistance through systemic inflammation and leptin dysregulation remains to be examined in future studies. CLINICALTRIALS: gov registration: NCT02236520.

Semiautomated segmentation of lower extremity MRI reveals distinctive subcutaneous adipose tissue in lipedema: a pilot study.

Purpose: Lipedema is a painful subcutaneous adipose tissue (SAT) disease involving disproportionate SAT accumulation in the lower extremities that is frequently misdiagnosed as obesity. We developed a semiautomatic segmentation pipeline to quantify the unique lower-extremity SAT quantity in lipedema from multislice chemical-shift-encoded (CSE) magnetic resonance imaging (MRI). Approach: Patients with lipedema (n=15) and controls (n=13) matched for age and body mass index (BMI) underwent CSE-MRI acquired from the thighs to ankles. Images were segmented to partition SAT and skeletal muscle with a semiautomated algorithm incorporating classical image processing techniques (thresholding, active contours, Boolean operations, and morphological operations). The Dice similarity coefficient (DSC) was computed for SAT and muscle automated versus ground truth segmentations in the calf and thigh. SAT and muscle volumes and the SAT-to-muscle volume ratio were calculated across slices for decades containing 10% of total slices per participant. The effect size was calculated, and Mann-Whitney U test applied to compare metrics in each decade between groups (significance: two-sided P<0.05). Results: Mean DSC for SAT segmentations was 0.96 in the calf and 0.98 in the thigh, and for muscle was 0.97 in the calf and 0.97 in the thigh. In all decades, mean SAT volume was significantly elevated in participants with versus without lipedema (P<0.01), whereas muscle volume did not differ. Mean SAT-to-muscle volume ratio was significantly elevated (P<0.001) in all decades, where the greatest effect size for distinguishing lipedema was in the seventh decade approximately midthigh (r=0.76). Conclusions: The semiautomated segmentation of lower-extremity SAT and muscle from CSE-MRI could enable fast multislice analysis of SAT deposition throughout the legs relevant to distinguishing patients with lipedema from females with similar BMI but without SAT disease.

Subcutaneous Adipose Tissue Edema in Lipedema Revealed by Noninvasive 3T MR Lymphangiography.

BACKGROUND: Lipedema exhibits excessive lower-extremity subcutaneous adipose tissue (SAT) deposition, which is frequently misidentified as obesity until lymphedema presents. MR lymphangiography may have relevance to distinguish lipedema from obesity or lymphedema. HYPOTHESIS: Hyperintensity profiles on 3T MR lymphangiography can identify distinct features consistent with SAT edema in participants with lipedema. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Participants (48 females, matched for age [mean = 44.8 years]) with lipedema (n = 14), lipedema with lymphedema (LWL, n = 12), cancer treatment-related lymphedema (lymphedema, n = 8), and controls without these conditions (n = 14). FIELD STRENGTH/SEQUENCE: 3T MR lymphangiography (nontracer 3D turbo-spin-echo). ASSESSMENT: Review of lymphangiograms in lower extremities by three radiologists was performed independently. Spatial patterns of hyperintense signal within the SAT were scored for extravascular (focal, diffuse, or not apparent) and vascular (linear, dilated, or not apparent) image features. STATISTICAL TESTS: Interreader reliability was computed using Fleiss Kappa. Fisher's exact test was used to evaluate the proportion of image features between study groups. Multinomial logistic regression was used to assess the relationship between image features and study groups. The odds ratio (OR) and 95% confidence interval (CI) of SAT extravascular and vascular features was reported in groups compared to lipedema. The threshold of statistical significance was P < 0.05. RESULTS: Reliable agreement was demonstrated between three independent, blinded reviewers (P < 0.001). The frequency of SAT hyperintensities in participants with lipedema (36% focal, 36% diffuse), LWL (42% focal, 33% diffuse), lymphedema (62% focal, 38% diffuse), and controls (43% focal, 0% diffuse) was significantly distinct. Compared with lipedema, SAT hyperintensities were less frequent in controls (focal: OR = 0.63, CI = 0.11-3.41; diffuse: OR = 0.05, CI = 0.00-1.27), similar in LWL (focal: OR = 1.29, CI = 0.19-8.89; diffuse: OR = 1.05, CI = 0.15-7.61), and more frequent in lymphedema (focal: OR = 9.00, CI = 0.30-274.12; diffuse: OR = 5.73, CI = 0.18-186.84). DATA CONCLUSION: Noninvasive MR lymphangiography identifies distinct signal patterns indicating SAT edema and lymphatic load in participants with lipedema. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Intermuscular adipose tissue in patients with systemic lupus erythematosus.

OBJECTIVE: Patients with SLE frequently have debilitating fatigue and reduced physical activity. Intermuscular adipose tissue (IMAT) accumulation is associated with reduced physical exercise capacity. We hypothesised that IMAT is increased in patients with SLE and associated with increased fatigue, reduced physical activity and increased inflammation. METHODS: In a cross-sectional study, 23 patients with SLE and 28 control participants were evaluated. IMAT was measured in the calf muscles using sequential T 1-weighted MRI. Patient-reported physical activity and fatigue were measured and a multiplex proteomic assay was used to measure markers and mediators of inflammation. RESULTS: IMAT accumulation (percentage of IMAT area to muscle area) was significantly higher in SLE versus control participants (7.92%, 4.51%-13.39% vs 2.65%, 1.15%-4.61%, median, IQR, p<0.001) and remained significant after adjustment for age, sex, race and body mass index (p<0.001). In patients with SLE, IMAT accumulation did not differ significantly among corticosteroid users and non-users (p=0.48). In the study cohort (patients and controls), IMAT was positively correlated with self-reported fatigue score (rho=0.52, p<0.001) and inversely correlated with self-reported walking distance (rho=-0.60, p<0.001). Several markers of inflammation were associated with IMAT accumulation in patients with SLE, and gene ontology analysis showed significant enrichment for pathways associated with macrophage migration and activation in relation to IMAT. CONCLUSION: Patients with SLE have greater IMAT accumulation than controls in the calf muscles. Increased IMAT is associated with greater fatigue and lower physical activity. Future studies should evaluate the effectiveness of interventions that improve muscle quality to alleviate fatigue in patients with SLE.

Initial findings in traumatic peripheral nerve injury and repair with diffusion tensor imaging.

OBJECTIVE: Management of peripheral nerve injuries requires physicians to rely on qualitative measures from patient history, electromyography, and physical exam. Determining a successful nerve repair can take months to years for proximal injuries, and the resulting delays in clinical decision-making can lead to a negative impact on patient outcomes. Early identification of a failed nerve repair could prevent permanent muscle atrophy and loss of function. This study aims to test the feasibility of performing diffusion tensor imaging (DTI) to evaluate injury and recovery following repair of wrist trauma. We hypothesize that DTI provides a noninvasive and reliable assessment of regeneration, which may improve clinical decision-making and alter the clinical course of surgical interventions. METHODS: Clinical and MRI measurements from subjects with traumatic peripheral nerve injury, carpal tunnel syndrome, and healthy control subjects were compared to evaluate the relationship between DTI metrics and injury severity. RESULTS: Fractional anisotropy from DTI was sensitive to differences between damaged and healthy nerves, damaged and compressed nerves, and injured and healthy contralateral nerves. Longitudinal measurements in two injury subjects also related to clinical outcomes. Implications of other diffusion measures are also discussed. INTERPRETATION: DTI is a sensitive tool for wrist nerve injuries and can be utilized for monitoring nerve recovery. Across three subjects with nerve injuries, this study has shown how DTI can detect abnormalities between injured and healthy nerves, measure recovery, and determine if re-operation was successful. Additional comparisons to carpal tunnel syndrome and healthy nerves show that DTI is sensitive to the degree of impairment.

Length-dependent MRI of hereditary neuropathy with liability to pressure palsies.

OBJECTIVE: Hereditary neuropathy with liability to pressure palsies (HNPP) is caused by heterozygous deletion of the peripheral myelin protein 22 (PMP22) gene. Patients with HNPP present multifocal, reversible sensory/motor deficits due to increased susceptibility to mechanical pressure. Additionally, age-dependent axonal degeneration is reported. We hypothesize that length-dependent axonal loss can be revealed by MRI, irrespective of the multifocal phenotype in HNPP. METHODS: Nerve and muscle MRI data were acquired in the proximal and distal leg of patients with HNPP (n = 10) and matched controls (n = 7). More specifically, nerve magnetization transfer ratios (MTR) were evaluated to assay proximal-to-distal gradients in nerve degeneration, while intramuscular fat percentages (Fper ) were evaluated to assay muscle fat replacement following denervation. Neurological disabilities were assessed via the Charcot-Marie-Tooth neuropathy score (CMTNS) for correlation with MRI. RESULTS: Fper values were elevated in HNPP proximal muscle (9.8 ± 2.2%, P = 0.01) compared to controls (6.9 ± 1.0%). We observed this same elevation of HNPP distal muscles (10.5 ± 2.5%, P < 0.01) relative to controls (6.3 ± 1.1%). Additionally, the amplitude of the proximal-to-distal gradient in Fper was more significant in HNPP patients than controls (P < 0.01), suggesting length-dependent axonal loss. In contrast, nerve MTR values were similar between HNPP subjects (sciatic/tibial nerves = 39.4 ± 2.0/34.2 ± 2.5%) and controls (sciatic/tibial nerves = 37.6 ± 3.8/35.5 ± 1.2%). Proximal muscle Fper values were related to CMTNS (r = 0.69, P = 0.03), while distal muscle Fper and sciatic/tibial nerve MTR values were not related to disability. INTERPRETATION: Despite the multifocal nature of the HNPP phenotype, muscle Fper measurements relate to disability and exhibit a proximal-to-distal gradient consistent with length-dependent axonal loss, suggesting that Fper may be a viable biomarker of disease progression in HNPP.

Spreading activation in emotional memory networks and the cumulative effects of somatic markers.

The theory of spreading activation proposes that the activation of a semantic memory node may spread along bidirectional associative links to other related nodes. Although this theory was originally proposed to explain semantic memory networks, a similar process may be said to exist with episodic or emotional memory networks. The Somatic Marker hypothesis proposes that remembering an emotional memory activates the somatic sensations associated with the memory. An integration of these two models suggests that as spreading activation in emotional memory networks increases, a greater number of associated somatic markers would become activated. This process would then result in greater changes in physiological functioning. We sought to investigate this possibility by having subjects recall words associated with sad and happy memories, in addition to a neutral condition. The average ages of the memories and the number of word memories recalled were then correlated with measures of heart rate and skin conductance. The results indicated significant positive correlations between the number of happy word memories and heart rate (r = .384, p = .022) and between the average ages of the sad memories and skin conductance (r = .556, p = .001). Unexpectedly, a significant negative relationship was found between the number of happy word memories and skin conductance (r = -.373, p = .025). The results provide partial support for our hypothesis, indicating that increasing spreading activation in emotional memory networks activates an increasing number of somatic markers and this is then reflected in greater physiological activity at the time of recalling the memories.