Physical Therapy in Women with Early Stage Lipedema: Potential Impact of Multimodal Manual Therapy, Compression, Exercise, and Education Interventions

Abstract

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.

Introduction

Lipedema is a distinct adipose disorder from obesity, yet remains clinically under-recognized despite a high reported prevalence of 10%–18% in adolescent and adult women.^1,2 Lipedema is described as a loose connective tissue disease³ and typically presents during puberty, pregnancy, or menopause. The condition presents with disproportionately larger lower body compared with upper body habitus,⁴ with more limited or negligible upper extremity⁵ and central nervous system⁶ abnormalities, and is commonly misidentified as behavior-induced weight gain or obesity.⁷ The affected extremities in persons with lipedema exhibit bilateral swelling due to excess fluid in the extracellular matrix³ and abnormal accretion of subcutaneous adipose tissue (SAT)⁸ that is associated with physical morbidities impacting functional mobility and quality of life (QoL).^9–12 Lipedema SAT does not reduce as expected in response to diet, exercise, and bariatric surgeries,^10,13 thus necessitating a different management approach from what is employed in simple obesity (i.e., nonlipedema adipose tissue). Less recognized lipedema-related symptoms include pain with light touch or pressure,¹⁴ easy bruising associated with capillary fragility,¹⁵ orthostatic swelling,⁴ joint hypermobility,^16,17 and muscle weakness¹⁸ in the affected areas. These symptoms may critically impact function and QoL if they are ignored in early disease stages, such as orthostatic swelling progressing to chronic lymphedema (i.e., lipolymphedema).¹⁹ However, persons with lipedema typically experience delayed referral to therapy until overt signs of lymphedema present.²⁰ Furthermore, it remains unclear whether treatment will benefit symptoms of pain or function in patients with lipedema, particularly in the earlier disease stages.

Although complete decongestive therapy (CDT) improves physical functioning and QoL in women with lymphedema,^21,22 including subclinical and early stage lymphedema,²³ the investigation of similar conservative therapy approaches in women with lipedema is limited and remains controversial.^24,25 Additionally, a limited understanding of conservative treatment potential for women with early stage lipedema persists in the absence of confounding factors from metabolic disease or advanced lymphatic impairment.

A necessary prerequisite to a definitive, randomized clinical trial of therapy in females with early stage lipedema is a study to understand whether such therapy has an impact on established radiological indicators of lipedema pathophysiology and symptomatology. To address this unmet need, we performed sequential sodium magnetic resonance imaging (MRI) and symptomatology assessments in a proof-of-principle trial to investigate the possible utility of physical therapy, a patient-tailored approach, including components of the CDT model, in well-characterized participants with early stage lipedema. Sodium MRI was incorporated as it has recently been shown to provide an objective, internal marker of lipedema compared with body mass index (BMI)-matched females without lipedema.²⁶ The overarching hypothesis is that a 6-week course of physical therapy reduces clinical symptoms of pain, improves patient-reported functional QoL measures, and modifies tissue sodium deposition in the treated lower extremities of women with early stage lipedema.

Methods

Demographics

All volunteers provided informed, written consent in accordance with the Institutional Review Board to participate for this prospective study (ClinicalTrials.gov ID NCT03634462). Research procedures were performed at the Vanderbilt University Institute of Imaging Science. Inclusion criteria were sex = female, age = 20–60 years, early stage lipedema (Lipedema Stage = 1–2) without late-stage lymphedema (Lymphedema Stage ≤1), BMI <35 kg/m², and availability to participate in 6 weeks of therapy. Exclusion criteria were history of cancer, immune disease, hypertension, and reported injury or infection within 1 month. Lipedema stage and type¹⁰ and lymphedema stage derived from the International Society of Lymphology (ISL)^27,28 criteria were identified for each participant and confirmed by a certified lymphedema therapist (P.M.C.D.; 14 years experience). Lymphedema Stage 0 was assigned to participants without overt signs of swelling yet had subjective symptoms of heaviness in the limb and/or detected altered fluid composition using bioimpedance, volume or imaging measurements. Lymphedema Stage 0 is commonly utilized in the cancer treatment literature and was adopted in this study as well for consistency. Lymphedema Stage 1 was assigned when participants had evidence of edema at the time of examination where their symptoms are reversible and fall within the mild category of edema.

Physical therapy

Each participant received physical therapy by the same therapist (P.M.C.D.). Treatment lasted 6 weeks with a total of nine sessions (Fig. 1). The 60-minute therapy sessions consisted of manual therapy, tailored exercise guidance for a home program, education, and compression needs. The majority of each session was spent on manual therapy focused on the lower quadrant and bilateral legs. The manual techniques (hand and instrument assisted) incorporated manual lymphatic drainage (MLD) for stimulation of lymphatic clearance along with myofascial releases and soft tissue mobilization to address tissue tenderness, restricted movement of the lower body and legs, overt swelling (if present), and feelings of leg heaviness and fatigue. A graded negative pressure device was utilized to mobilize the tissue directionally opposite (negative pressure) from what hands-on techniques (positive pressure) provides to together achieve a wider tissue release. Negative pressure was customized to participant tolerance (range = 80–300 mmHg; pull/release ratio of 4:1 seconds; treatment cup size varied, predominantly using the large size). As tissue tenderness reduced, participant tolerance increased allowing for greater negative pressure pull as well as increased tolerance for combined orthogonal and rotational tissue stretches during the pull phase. Additionally, education and guided reinforcement was provided throughout on posture, joint protection, movement and exercise, compression needs, diaphragmatic breathing, and healthy eating. Compression recommendations were tailored to meet the needs of each person to essentially prevent swelling or symptoms of leg heaviness and fatigue following the guidelines for standard of care for lipedema in the United States.³ Tailored exercise programs addressed lower body strengthening, flexibility, and conditioning with a focus on long-term adherence given their individual interests.

FIG. 1.

Intervention timeline consisting of nine therapy visits for 6 weeks, as well as study intake measures before, after, and during therapy. MRI, magnetic resonance imaging; VAS, visual analog scale.

Physical and symptomatology measures

Immediately before treatment and within 10 days following the last treatment visit (Fig. 1), portable biophysical measures were performed, and symptomology questionnaires were administered. Participants' height, weight, waist and hip circumference measurement, blood pressure, and pulse (Invivo, Gainesville, FL) were obtained. Pain Visual Analog Scale (VAS 0–10) of the legs was measured at every therapy visit. The patient-specific functional scale (PSFS) monitoring patient-identified functional impairment was acquired. The PSFS score ranges from 0 to 10, where 0 indicates inability to perform a self-selected functional task and 10 indicates task performance at the individual's premorbid baseline. The clinically significant change for PSFS measured in chronic pain is a 2-point reduction when scaling 3 patient-selected activities,²⁹ and across all body regions is defined as 1.3 (small), 2.3 (medium), and 2.7 (large).³⁰ The RAND-36 was administered as a secondary health questionnaire supporting the PSFS and pain VAS. RAND-36 is a self-reported health questionnaire with 36 items, where the total score is 0 (poor health) to 100 (good health) incorporating subcategories of general health, pain, and physical, social, and emotional functioning. A clinically significant change in the RAND-36 total score is 3–5 points.³¹

Magnetic resonance imaging

All participants underwent a MRI protocol before and after the 6 weeks of treatment on the same day the biophysical and symptomatology measures were obtained (Fig. 1). Imaging was performed at 3.0 Tesla (3.0T, Philips Ingenia; Philips Healthcare, Best, The Netherlands) using a protocol incorporating multinuclear sodium (²³Na-MRI) and conventional proton T₁-weighted imaging (Fig. 2). Given the relatively poor discriminatory capacity of standard anatomical proton MRI for lipedema pathology,^5,26 sodium MRI, which has previously been shown to be elevated in the lower extremities of persons with lipedema,²⁶ was performed in one leg and the ipsilateral arm at the widest girth of the participant's calf and forearm, respectively. The extremity was centered over four standard sodium solutions (aqueous NaCl in the physiologic range of tissue sodium content [TSC] 10–40 mmol/L) embedded in a platform in the coil resting for 10 minutes before acquisition of the sodium image. Sodium imaging was acquired with a three-dimensional gradient echo sequence (repetition time/echo time [TR/TE] = 130/0.99 mseconds, field-of-view [FOV] = 192 × 192 mm², acquired matrix size = 64 × 64, slice thickness = 30 mm) and a quadrature knee coil tuned for sodium signal reception (Rapid Biomedical GmbH, Rimpar, Germany).³² Proton MRI for high spatial resolution anatomical localization was acquired with the Dixon method (TR = 200 mseconds, TE₁ = 1.15 mseconds, TE₂ = 2.30 mseconds, matrix size = 192 × 192, in-plane spatial resolution = 1 × 1 mm², slice = 6; slice thickness = 5 mm) in the identical in-plane FOV as the sodium image.

FIG. 2.

Multimodal water and sodium MRI. (A) Sagittal T₁-weighted localizer with the green line demarcating the water and sodium slice and (B) corresponding high spatial resolution T₁-weighted axial slice showing fat and water. (C) Dixon-MRI water-weighted image with standards below, and (D) quantitative map of TSC with standards below (mM/L). Sodium MRI regions of interest were selected from the (E) SAT defined as the area between the inner border of the skin and outer border of the muscle, and (F) skin. The SAT and skin are isolated from the tissue sodium map. (G) Example of Lipedema Stage 1 Type 3 participant with subtle ankle cuff and no clinical comorbidity of lymphedema or obesity. Tendency to lock knees into full extension and right ankle pronation can be appreciated. SAT, subcutaneous adipose tissue; TSC, tissue sodium content.

Standardized TSC maps were calculated in the arm and leg. First, the mean signal intensity was measured in the standard sodium solutions included in the FOV, and a linear model fit was identified for each image. Model parameters were used to calculate TSC (mmol/L) from magnitude signal intensity (arbitrary units) voxel wise. TSC maps were interpolated to match the in-plane spatial resolution (1 × 1 mm²) of the Dixon image. Next, TSC was measured in three regions of interest (ROIs): skin, SAT, and muscle. ROIs were manually drawn on the central slice of the Dixon water-weighted image and overlaid on the TSC map. The posterior semiperimeter of the skin region was segmented given this region is subject to fewer partial volume effects than the anterior extremity.

Statistical considerations

Statistical analysis was performed in R version 3.6.3 and MATLAB 2018 (Mathworks, Natick, MA). Descriptive statistics, including means, standard deviations, and ranges for continuous parameters, were calculated, as well as frequencies for categorical parameters. Cohen's d effect size with 95% confidence interval for paired samples (e.g., pre- vs. post-treatment) was used to evaluate treatment effects in this proof-of-principle study. The treatment effect size is equal to the mean difference divided by standard deviation of the paired difference. Interpretation of these effect sizes is as follows: |d| < 0.2 represents a negligible effect size, |d| < 0.5 represents a small effect size, |d| < 0.8 represents a medium effect size, and |d| > 0.8 represents a large effect size.³³ The 95% confidence interval for the primary variables of interest for QoL, pain, and TSC were presented as alternative to post hoc power analysis.

Results

Demographics

Female volunteers with lipedema (n = 5, age = 38.4 ± 13.4 years, BMI = 27.2 ± 4.3 kg/m²) satisfying the study inclusion and exclusion criteria were enrolled and completed all study components (Fig. 1). Table 1 summarizes participant characteristics and Supplementary Table S1 provides characteristic details for each participant. Participants exhibited either Lipedema Stage 1 (n = 3) or Stage 2 (n = 2) and Lymphedema Stage 0 (n = 4) or Stage 1 (n = 1).

Table 1.

Participant Characteristic Data

Characteristic	N = 5a
Lipedema stage
1	2 (40%)
2	3 (60%)
Lipedema leg type
2	2 (40%)
3	3 (60%)
Lipedema arm
Yes	4 (80%)
Lymphedema stage
0	4 (80%)
1	1 (20%)
Age (years)	38.4 ± 13.4
BMI (kg/m2)	27.2 ± 4.3
Waist circumference (cm)	79.5 ± 10.2
Hip circumference (cm)	110.2 ± 13.5
Systolic blood pressure (mmHg)	117.8 ± 11.7
Diastolic blood pressure (mmHg)	75.6 ± 5.3
Heart rate (bpm)	67.4 ± 6.7

All participants are female, right-handed, white race, and of non-Hispanic ethnicity.

^a Column denotes N (%) or mean ± standard deviation.

BMI, body mass index.

Pain

Leg pain (VAS 0–10 scale) improved following treatment (pretreatment mean = 4.6 ± 1.8 vs. post-treatment mean = 0.0 ± 0.0, p = 0.005). This reduction in pain reflects a large treatment effect size (Table 2, Cohen's d = −2.5) with the negative effect size indicating pain reduction. The mean pain VAS steadily reduced with subsequent therapy visits (Fig. 3) and all participants reported 0/10 pain score by visit 8 (Supplementary Table S2).

Table 2.

Primary Symptomatology Study Measures Pre- and Post-Treatment

Study measure	Pre (n = 5)a	Post (n = 5)a	Differenceb	95% CI of differenceb	p b	Effect size (95% CI)c
PSFS total score	4.5 ± 0.5	8.3 ± 1.0	3.8	2.7 to 4.9	<0.001	4.4 (1.0 to 7.7)
Pain (VAS 0–10)	4.6 ± 1.8	0.0 ± 0.0	−4.6	−6.9 to −2.3	0.005	−2.5 (−4.6 to −0.4)
Leg skin sodium (mM/L)	14.2 ± 1.7	13.0 ± 2.2	−1.2	−2.5 to 0.1	0.059	−1.2 (−2.5 to 0.2)
Leg SAT sodium (mM/L)	10.5 ± 1.4	9.7 ± 1.5	−0.8	−1.8 to 0.3	0.12	−0.9 (−2.1 to 0.3)

^a Mean ± standard deviation.

^b Paired t-test.

^c Effect size Cohen's d (95% CI); effect size = mean difference/standard deviation of the paired difference.

CI, confidence interval; PSFS, patient-specific functional scale; SAT, subcutaneous adipose tissue; VAS, visual analog scale.

FIG. 3.

(A, B) Boxplot with paired (pre- and post- treatment) data points for each participant for the PSFS and pain VAS. Box plots represent the group median (central bar), the upper and lower quartiles (upper and lower bars), and minimum and maximum data points (whiskers with 1.5 IQR). (C) The mean pain VAS at each therapy visit. Note that all participants report no pain (0/10) at visits 8 and 9. Error bars denote the standard deviation from the mean. IQR, interquartile range; PSFS, patient-specific functional scale.

Function and QoL

Primary symptomatology measures of function using PSFS revealed a clinically significant mean change of 3.8 pre- versus post-treatment (4.5 ± 0.5 vs. 8.3 ± 1.0, p ≤ 0.001, Fig. 3) and a large treatment effect (Cohen's d = 4.4, Table 2). Each participant's change in PSFS score indicates a clinically meaningful improvement (Supplementary Table S3). The mean RAND-36 total score pre- versus post-treatment (69.3 ± 26.0 vs. 79.4 ± 18.2, p = 0.10) indicates a large treatment effect (Cohen's d = 1.0) and an individual clinically meaningful improvement in four of the five participants (80%), see Supplementary Table S4. The RAND-36 subcategories (social, emotional, and physical functioning and pain) reveal medium-to-large treatment effects of 0.7, 2.3, 1.4, and 1.1, respectively. Specifically, the RAND-36 pain subset reveals a large treatment effect of reduced pain (Cohen's d = 1.1) consistent with the large treatment effect noted in pain VAS. For RAND-36, an impactful treatment effect is positive since higher scores indicate improvement.

Sodium MRI results

Objective disease-related imaging measures of leg skin sodium showed a trend for a reduction (pretreatment =14.2 ± 1.7 mmol/L vs. post-treatment = 13.0 ± 2.2 mmol/L, 9% reduction, p = 0.059, Fig. 4) and a large treatment effect size (Cohen's d = −1.2, Table 2). A similarly large effect size was observed for leg SAT sodium (pre = 10.5 ± 1.4 mmol/L vs. post = 9.7 ± 1.5 mmol/L, 8% reduction, p = 0.12, Cohen's d = −0.9) with the negative effect sizes indicating reduction in tissue sodium. A representative case example of sodium MRI pre- versus post-treatment is presented in Figure 4. Compared with the treated legs, tissue sodium remained more consistent in the untreated ipsilateral arms pre- versus post-treatment (Supplementary Table S3).

FIG. 4.

(A) Representative patient example (LIP04) showing the T₁-weighted image and quantified TSC images pre- and post-treatment. Reductions in TSC can be observed in the skin (arrow heads) and SAT (arrows). (B, C) Boxplot with paired (pre- and post-treatment) data points for SAT and skin sodium. Box plots represent the group median (central bar), the upper and lower quartiles (upper and lower bars), and minimum and maximum data points (whiskers with 1.5 IQR).

Discussion

Management and treatment of lipedema symptoms are essential to improving the function and QoL of those afflicted. However, effective treatment strategies remain unclear, in particular for early stage disease. In this well-characterized group of participants with early stage lipedema (Stage 1–2) and early symptoms of lymphatic impairment (Lymphedema Stage ≤1), assessments for pain and QoL revealed pretreatment impairment, yet this population is not routinely referred for therapy to mitigate pain, and referral is delayed until later-stage lymphedema presents. These study findings reveal a positive treatment impact, which reduced pain and increased function in persons with early stage lipedema following nine therapy visits. Furthermore, objective imaging biomarkers of tissue sodium deposition (evaluated at the calf level in this study) reduced in treated limbs, including those with lipedema Type II (upper leg and buttocks), thereby motivating a larger treatment trial for early stage lipedema.

Manual therapies reduce pain

Lipedema is becoming increasingly appreciated as an independent disease from obesity and is largely refractory to commonly prescribed diet and exercise regimens. Indications of lymphatic impairment in persons with lipedema have raised the question of whether lipedema symptoms respond to decongestive therapies. In this study, manual techniques, including MLD, were utilized to reduce sensitivity to touch and stimulate the lymphatics, which were applied in combination with negative pressure to assist with tissue mobilization for addressing pain, soft tissue restrictions, and lymphatic clearance.³⁴ Results indicate that these manual techniques, commonly applied as an effective therapy in patients with lymphedema and tissue restrictions, had a large treatment effect size for reduced pain in the participants where all reported 0/10 pain VAS by the eighth visit (Supplementary Table S2). During a single session and throughout therapy, on average, participants experienced decreased pain in the legs.

Findings of pain reduction with manual intervention reinforces the results of other studies. Manual techniques, including MLD, have demonstrated abilities to modify lipedema symptoms of edema and pain,^{14,15,25,35–37} yet others have suggested that MLD approaches should be minimized or avoided²⁴ owing to the disagreement regarding lymphatic impairment in lipedema. This proof-of-principle study provides support for a large therapeutic treatment effect when including the incorporation of MLD techniques, which may be attributable to (1) a controlled implementation whereby all treatments were performed by a single therapist, (2) added use of negative pressure, and (3) objective radiological endpoints used for confirming efficacy. Since the lymphatics are responsible for removal of toxins and cellular waste in addition to maintaining fluid homeostasis, such as through extracellular sodium regulation,^38,39 the incorporation of lymphatic stimulation with manual techniques is logical, and its efficacy was also supported here through demonstration of a reduction in sodium level after treatment.

Potential for a lymphedema surveillance model in lipedema

This study focused on early stage lipedema, yet reported symptoms and clinical presentation were consistent with subclinical or Lymphedema Stage 1, which is also consistent with the growing literature that suggests lymphatic insufficiency in the lipedema population.^40–42 Recent lymphoscintigraphy studies provided internal evidence of lymphatic involvement and fluid retention in lipedema, including early stages.⁴⁰ Taken together with the current results, these findings highlight the potential utility of monitoring and managing early subclinical lymphatic insufficiency in patients with lipedema, similar to the lymphedema surveillance models used following cancer therapies²³ and more recently with vascular insufficiencies.^43,44

Tailoring treatment recommendations to an individual's impairment level may also benefit persons with lipedema. In this study, all participants reported aching and fatigue in the legs, yet four out of five participants (80%) were without overt signs of lymphedema, rather expressed symptoms consistent with occasional fluctuation from Lymphedema Stage 0 to Stage 1. Thus, we provided tailored education on early lymphedema management, which involved use of appropriate compression to mitigate feelings of leg heaviness or swelling. Importantly, the degree of compression used followed recommendations for managing Lymphedema Stage 0 or Stage 1. The compression recommendations were based on the patient's individual needs for adequate containment. Two participants benefitted from daily use of compression and the others were on an “as-needed basis” based on activities that tended to result in their achiness, heaviness, and/or swelling without compression. Four of five patients were quick to follow recommendations for compression frequency and one patient took a few weeks before incorporating compression during specific situations as recommended. Once using compression, this participant noted improvement in her symptom management.

Ongoing research is warranted to elicit a better understanding of the development of lymphatic impairment in lipedema and the clinical necessity of a lymphedema surveillance model in this population.

Sodium MRI as a measure of intervention response in lipedema

Compared with healthy females with similar BMI but without lipedema, emerging MRI studies show that the skin and underlying SAT in women with all stages of lipedema contain higher sodium levels. Sodium is also a hallmark biomarker for inflammation²⁶ and such elevated sodium is associated with leg pain in women with lipedema.⁵ This study is the first to evaluate changes in skin and SAT sodium in the lower extremities following a therapy for lipedema. Reduction in both tissue sodium and pain provide additional support for a mechanistic link between tissue sodium and pain in persons with lipedema.

In this study design, the arm was used as an internal control by not receiving treatment and demonstrated no substantial changes in arm sodium, particularly skin sodium, following the intervention. Participants engaged in full-body exercise and conditioning as a component of their home program, which may account for the small treatment effect size reduction in arm SAT sodium. Future research should investigate the treatment impact on arms to determine if similar or different effects on pain, upper extremity function, or sodium reduction are possible for the affected upper extremities in lipedema as observed in the legs.

Water and sodium MRI hold potential as objective methodologies for evaluating lipedema treatments in randomized clinical trials. These measures can be performed noninvasively in vivo in approximately 20–30 minutes, thereby making MRI a promising candidate for evaluating immediate treatment effects while obviating concerns for exogenous agents and associated dose considerations. Future work may also investigate the possibility of triaging persons with lipedema for therapies based on personalized tissue or lymphatic profiles obtained from noninvasive imaging.

Limitations and future directions

Owing to limited data on therapies in early stage lipedema, this study was designed as a proof-of-principle study in five well-characterized patients rather than as a large, randomized trial that would be difficult to justify without having preliminary data, as provided here. However, it is important not to overinterpret the results given the small sample size. Despite having a well-characterized participant group who were treated by the same therapist, study limitations include a small sample size, lack of intervention on affected regions in the arms, and a lack of placebo intervention to assess whether personal contact would impact a participant's perception of symptoms. Furthermore, since four of five participants (80%) never had physical therapy to address their pain, this proof-of-principle study suggests the value of early referrals to address disease-related pain, inflammatory tissue sodium, and functional QoL.

The intent of this study was to investigate a short course of physical therapy with a primary focus on manual techniques. Future research is necessary to understand the dosing, frequency, and long-term duration of the treatment effect, and how it may differ based on lipedema staging and phenotypes. Additionally, therapy commonly utilizes a multimodal approach to address multiple impairments. Study designs to test specific or combined interventions, self-management strategies, and multidisciplinary approaches would be useful in further identifying methodologies with the greatest potential treatment impact.

Conclusions

Results support the potential relevance of physical therapy to reduce pain and increase function in persons living with early stage lipedema, including those without overt signs of lymphedema. Abnormal tissue sodium accumulation in the legs, a previously established imaging biomarker of lipedema, was reduced following therapy visits in persons with lipedema. This work motivates a future larger trial of early therapy in persons with lipedema.

Author Disclosure Statement

M.J.D. is a paid consultant for Pfizer, Inc., Global Blood Therapeutics, and LymphaTouch, Inc.; is a paid advisory board member for bluebird bio and Novartis; and receives research-related support from Philips North America and research funding from Pfizer, Inc. P.M.C.D. is a paid consultant for PureTech Health and Tactile Medical and has received clinical and imaging grants from LymphaTouch, Inc. All other authors have no competing financial interests.

Funding Information

Funding was provided by the Lipedema Foundation (Award 12). Imaging experiments were performed in the Vanderbilt Human Imaging Core, using research resources supported by the National Institutes of Health (NIH) grant 1S10OD021771-01. Recruitment through www.ResearchMatch.org and services at the Clinical Research Center are supported by the National Center for Advancing Translational Sciences (NCATS) Clinical Translational Science Award (CTSA) Program awards UL1TR002243-03 and UL1 TR000445.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4