Background: Lipedema and Dercum's disease (DD) are incompletely characterized adipose tissue diseases, and objective measures of disease profiles are needed to aid in differential diagnosis. We hypothesized that fluid properties, quantified as tissue water bioimpedance in the upper and lower extremities, differ regionally between these conditions. Methods and Results: Women (cumulative n = 156) with lipedema (n = 110), DD (n = 25), or without an adipose disease matched for age and body mass index to early stage lipedema patients (i.e., controls n = 21) were enrolled. Bioimpedance spectroscopy (BIS) was applied to measure impedance values in the arms and legs, indicative of extracellular water levels. Impedance values were recorded for each limb, as well as the leg-to-arm impedance ratio. Regression models were applied to evaluate hypothesized relationships between impedance and clinical indicators of disease (significance criteria: two-sided p < 0.05). Higher extracellular water was indicated (i) in the legs of patients with higher compared with lower stages of lipedema (p = 0.03), (ii) in the leg-to-arm impedance ratio in patients with lipedema compared with patients with DD (p ≤ 0.001), and (iii) in the leg-to-arm impedance ratio in patients with stage 1 lipedema compared with controls (p ≤ 0.01). Conclusion: BIS is a noninvasive portable modality to assess tissue water, and this device is available in both specialized and nonspecialized centers. These findings support that regional bioimpedance measures may help to distinguish lipedema from DD, as well as to identify early stages of lipedema.
Lipedema is a disease with abnormally increased adipose tissue deposition and distribution. Pain sensations have been described in the clinical evaluation of lipedema, but its etiology remains poorly understood. We hypothesized that pain sensitivity measurements and ex vivo quantitation of neuronal cell body distribution in the skin would be lipedema stage-dependent, and could, thus, serve to objectively characterize neuropathic pain in lipedema. The pain was assessed by questionnaire and peripheral cutaneous mechanical sensitization (von-Frey) in lipedema (n = 27) and control (n = 23) consenting female volunteers. Dermal biopsies from (n = 11) Stages 1–3 lipedema and control (n = 10) participants were characterized for neuronal cell body and nociceptive neuropeptide calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) distribution. Stage 2 or 3 lipedema participants responded positively to von Frey sensitization in the calf and thigh, and Stage 3 participants also responded in the arm. Lipedema abdominal skin displayed reduced Tuj-1+ neuronal cell body density, compared to healthy controls, while CGRP and NGF was significantly elevated in Stage 3 lipedema tissues. Together, dermal neuronal cell body loss is consistent with hyper-sensitization in patients with lipedema. Further study of neuropathic pain in lipedema may elucidate underlying disease mechanisms and inform lipedema clinical management and treatment impact.
Lipedema is a loose connective tissue disease predominantly in women identified by increased nodular and fibrotic adipose tissue on the buttocks, hips and limbs that develops at times of hormone, weight and shape change including puberty, pregnancy, and menopause. Lipedema tissue may be very painful and can severely impair mobility. Non-lipedema obesity, lymphedema, venous disease, and hypermobile joints are comorbidities. Lipedema tissue is difficult to reduce by diet, exercise, or bariatric surgery.This paper is a consensus guideline on lipedema written by a US committee following the Delphi Method. Consensus statements are rated for strength using the GRADE system.Eighty-five consensus statements outline lipedema pathophysiology, and medical, surgical, vascular, and other therapeutic recommendations. Future research topics are suggested.These guidelines improve the understanding of the loose connective tissue disease, lipedema, to advance our understanding towards early diagnosis, treatments, and ultimately a cure for affected individuals.
Lipedema is a painful connective tissue disease involving excessive subcutaneous adipose tissue (SAT) accumulation in the lower extremities. Lipedema remains poorly recognized as a unique clinical entity and is often misdiagnosed as obesity. Whole-body magnetic resonance imaging (MRI) acquisitions could provide insight into the unique body composition of lipedema, yet methodologies for multi-slice analyses are lacking. In this work, a semi-automated processing workflow was developed to segment and quantify adiposity from whole-leg chemical-shift encoded (CSE) MRI to distinguish lipedema. Patients with lipedema (N=15) and controls (N=13) matched for age and body mass index underwent a CSE MRI exam in eight stacks from the head-to-ankles. Slices from thighs-to-ankles were segmented via Chan-Vese segmentation, clustering, and morphological techniques to separate SAT and skeletal muscle. SAT and muscle volume per slice and the SAT-to-muscle volume ratio were recorded in decades of slices and compared between groups using Mann-Whitney U test with two-sided significance criteria p<0.05. SAT volume was significantly elevated in participants with lipedema in all decades (p<0.001), while muscle volume was not significantly different. SAT-to-muscle volume ratio was elevated in lipedema compared to controls (p<0.001), with the greatest effect size (rrb = 0.74) observed in the eighth decade corresponding to the mid-thigh region. These findings reveal SAT distribution is uniquely elevated throughout the legs of participants with lipedema as discerned from whole-leg CSE MRI. CSE MRI and analysis methods developed herein for SAT quantification could inform the diagnosis of lipedema, which suffers from few objective strategies to differentiate the disease from obesity.
Axillary lymph nodes (LNs) often present a reservoir for metastatic breast cancer, yet metastatic LN involvement cannot be discerned definitively using diagnostic imaging. This study investigated whether in vivo CEST may discriminate LNs with versus without metastatic involvement.
To extend a commonly used noninvasive arterial spin labeling magnetic resonance (MR) imaging method for measuring blood flow to evaluate lymphatic flow.All volunteers (n = 12) provided informed consent in accordance with institutional review board and HIPAA regulations. Quantitative relaxation time (T1 and T2) measurements were made in extracted human lymphatic fluid at 3.0 T. Guided by these parameters, an arterial spin labeling MR imaging approach was adapted to measure lymphatic flow (flow-alternating inversion-recovery lymphatic water labeling, 3 × 3 × 5 mm) in healthy subjects (n = 6; mean age, 30 years ± 1 [standard deviation]; recruitment duration, 2 months). Lymphatic flow velocity was quantified by performing spin labeling measurements as a function of postlabeling delay time and by measuring time to peak signal intensity in axillary lymph nodes. Clinical feasibility was evaluated in patients with stage II lymphedema (three women; age range, 43-64 years) and in control subjects with unilateral cuff-induced lymphatic stenosis (one woman, two men; age range, 31-35 years).Mean T1 and T2 relaxation times of lymphatic fluid at 3.0 T were 3100 msec ± 160 (range, 2930-3210 msec; median, 3200 msec) and 610 msec ± 12 (range, 598-618 msec; median, 610 msec), respectively. Healthy lymphatic flow (afferent vessel to axillary node) velocity was 0.61 cm/min ± 0.13 (n = 6). A reduction (P < .005) in lymphatic flow velocity in the affected arms of patients and the affected arms of healthy subjects with manipulated cuff-induced flow reduction was observed. The ratio of unaffected to affected axilla lymphatic velocity (1.24 ± 0.18) was significantly (P < .005) higher than the left-to-right ratio in healthy subjects (0.91 ± 0.18).This work provides a foundation for clinical investigations whereby lymphedema etiogenesis and therapies may be interrogated without exogenous agents and with clinically available imaging equipment. Online supplemental material is available for this article.
The overall goal of this work is to apply a CEST-Dixon MRI approach in the axillary lymph nodes (LNs) of women with breast cancer to test fundamental hypotheses about biochemical LN profiles with carcinoma. Mean z-spectra and corresponding significant differences in cohorts with metastatic vs. benign LNs were observed in regions of known chemical exchange for the nuclear Overhauser effect (PTR=0.087 vs. 0.051, p=0.04), hydroxyl (PTR=0.272 vs. 0.212, p=0.003), and amine (PTR=0.081 vs. 0.033, p=0.003) protons. CEST-Dixon MRI of LNs may have relevance for pre-surgical breast cancer staging and for guiding LN sparing resections to reduce risk for lymphedema.
Background: Lipedema is a distinct adipose disorder from obesity necessitating awareness as well as different management approaches to address pain and optimize quality of life (QoL). The purpose of this proof-of-principle study is to evaluate the therapeutic potential of physical therapy interventions in women with lipedema. Methods and Results: Participants with Stage 1-2 lipedema and early Stage 0-1 lymphedema (n = 5, age = 38.4 ± 13.4 years, body mass index = 27.2 ± 4.3 kg/m2) underwent nine visits of physical therapy in 6 weeks for management of symptoms impacting functional mobility and QoL. Pre- and post-therapy, participants were scanned with 3 Tesla sodium and water magnetic resonance imaging (MRI), underwent biophysical measurements, and completed questionnaires measuring function and QoL (patient-specific functional scale, PSFS, and RAND-36). Pain was measured at each visit using the 0-10 visual analog scale (VAS). Treatment effect was calculated for all study variables. The primary symptomatology measures of pain and function revealed clinically significant post-treatment improvements and large treatment effects (Cohen's d for pain VAS = -2.5 and PSFS = 4.4). The primary sodium MRI measures, leg skin sodium, and subcutaneous adipose tissue (SAT) sodium, reduced following treatment and revealed large treatment effects (Cohen's d for skin sodium = -1.2 and SAT sodium = -0.9). Conclusions: This proof-of-principle study provides support that persons with lipedema can benefit from physical therapy to manage characteristic symptoms of leg pain and improve QoL. Objective MRI measurement of reduced tissue sodium in the skin and SAT regions indicates reduced inflammation in the treated limbs. Further research is warranted to optimize the conservative therapy approach in lipedema, a condition for which curative and disease-modifying treatments are unavailable.
