a case study of frozen shoulder

• Introduction
• Conclusions
• Article Information

A, The size of the circles denotes the contribution of participants in each intervention and the thickness of the lines between circles represents the contribution of studies comparing the two interventions. B, The bar graph shows the probability of the 6 interventions ranking from best to worst based on their effectiveness. IA indicates intra-articular.

eTable 1. Explanation of the Components of the GRADE Tool and How They Were Assessed

eTable 2. Risk of Bias Assessments

eTable 3. Results of Comparisons of Interventions Assessed by Fewer Than 3 Studies and Were Not Pooled Qualitatively or Quantitatively

eTable 4. Results of Grading of the Certainty of Evidence According to the GRADE Tool for Each Comparison of Interventions

eTable 5. Results of Statistical Inconsistency Assessment for Each Pairwise Meta-analysis

eFigure 1. Results of Pairwise Meta-analyses with Respective Mean Differences for Early Short-term Outcomes

eFigure 2. Results of Pairwise Meta-analyses With Respective Mean Differences for Late Short-term Outcomes

eFigure 3. Results of Pairwise Meta-analyses With Respective Mean Differences for Mid-term Outcomes

eFigure 4. Results of Pairwise Meta-analyses With Respective Mean Differences for Function

eFigure 5. TSA Results for IA Corticosteroid vs No Treatment or Placebo for Early Short-term Pain

eFigure 6. TSA Results for IA Corticosteroid vs No Treatment or Placebo for Late Short-term Pain

eFigure 7. Network Forest Plots With Consistency Test for Late Short-term Pain

eFigure 8. Network Forest Plots With Consistency Test for Mid-term Pain

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Challoumas D , Biddle M , McLean M , Millar NL. Comparison of Treatments for Frozen Shoulder : A Systematic Review and Meta-analysis . JAMA Netw Open. 2020;3(12):e2029581. doi:10.1001/jamanetworkopen.2020.29581

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Comparison of Treatments for Frozen Shoulder : A Systematic Review and Meta-analysis

• 1 Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Scotland, United Kingdom

Question   Are any treatment modalities for frozen shoulder associated with better outcomes than other treatments?

Findings   In this meta-analysis of 65 studies with 4097 participants, intra-articular corticosteroid was associated with increased short-term benefits compared with other nonsurgical treatments, and its superiority appeared to last for as long as 6 months. The addition of a home exercise program and/or electrotherapy or passive mobilizations may be associated with added benefits.

Meaning   The results of this study suggest that intra-articular corticosteroid should be offered to patients with frozen shoulder at first contact.

Importance   There are a myriad of available treatment options for patients with frozen shoulder, which can be overwhelming to the treating health care professional.

Objective   To assess and compare the effectiveness of available treatment options for frozen shoulder to guide musculoskeletal practitioners and inform guidelines.

Data Sources   Medline, EMBASE, Scopus, and CINHAL were searched in February 2020.

Study Selection   Studies with a randomized design of any type that compared treatment modalities for frozen shoulder with other modalities, placebo, or no treatment were included.

Data Extraction and Synthesis   Data were independently extracted by 2 individuals. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Random-effects models were used.

Main Outcomes and Measures   Pain and function were the primary outcomes, and external rotation range of movement (ER ROM) was the secondary outcome. Results of pairwise meta-analyses were presented as mean differences (MDs) for pain and ER ROM and standardized mean differences (SMDs) for function. Length of follow-up was divided into short-term (≤12 weeks), mid-term (>12 weeks to ≤12 months), and long-term (>12 months) follow-up.

Results   From a total of 65 eligible studies with 4097 participants that were included in the systematic review, 34 studies with 2402 participants were included in pairwise meta-analyses and 39 studies with 2736 participants in network meta-analyses. Despite several statistically significant results in pairwise meta-analyses, only the administration of intra-articular (IA) corticosteroid was associated with statistical and clinical superiority compared with other interventions in the short-term for pain (vs no treatment or placebo: MD, −1.0 visual analog scale [VAS] point; 95% CI, −1.5 to −0.5 VAS points; P  < .001; vs physiotherapy: MD, −1.1 VAS points; 95% CI, −1.7 to −0.5 VAS points; P  < .001) and function (vs no treatment or placebo: SMD, 0.6; 95% CI, 0.3 to 0.9; P  < .001; vs physiotherapy: SMD 0.5; 95% CI, 0.2 to 0.7; P  < .001). Subgroup analyses and the network meta-analysis demonstrated that the addition of a home exercise program with simple exercises and stretches and physiotherapy (electrotherapy and/or mobilizations) to IA corticosteroid may be associated with added benefits in the mid-term (eg, pain for IA coritocosteriod with home exercise vs no treatment or placebo: MD, −1.4 VAS points; 95% CI, −1.8 to −1.1 VAS points; P  < .001).

Conclusions and Relevance   The findings of this study suggest that the early use of IA corticosteroid in patients with frozen shoulder of less than 1-year duration is associated with better outcomes. This treatment should be accompanied by a home exercise program to maximize the chance of recovery.

Adhesive capsulitis, also known as frozen shoulder, is a common shoulder concern manifesting in progressive loss of glenohumeral movements coupled with pain. 1 It is a fibroproliferative tissue fibrosis, and although the immunobiological advances in other diseases have helped dissect the pathophysiology of this condition, overall, the molecular mechanisms underpinning it remain poorly understood. 2 - 5

Frozen shoulder manifests clinically as shoulder pain with progressive restricted movement, both active and passive, along with normal radiographic scans of the glenohumeral joint. 6 It classically progresses prognostically through 3 overlapping stages of pain (stage 1, lasting 2-9 months), stiffness (stage 2, lasting 4-12 months), and recovery (stage 3, lasting 5-24 months). 7 However, this is an estimated time frame, and many patients can still experience symptoms at 6 years. 8 A primary care–based observational study estimated its incidence as 2.4 per 100 000 individuals per year, 9 with prevalence varying from less than 1% to 2% of the population. 10

A true evidence-based model for its medical management has not been defined, with a wide spectrum of operative and nonoperative treatments available. From the international to departmental level, management strategies vary widely, reflecting the lack of good-quality evidence. 11 The British Elbow and Shoulder Society/British Orthopaedic Association (BESS/BOA) has published recommendations in a patient care pathway for frozen shoulder, with a step-up approach in terms of invasiveness advised. 12 The UK Frozen Shoulder Trial, a randomized parallel trial comparing the clinical and cost-effectiveness of early structured physiotherapy, manipulation under anesthetic (MUA), and arthroscopic capsular release (ACR) is currently under way. 13 The aim of this systematic review is to present the available evidence relevant to treatment and outcomes for frozen shoulder with the ultimate objective of guiding clinical practice, both in primary and secondary care.

The present systematic review has been conducted and authored according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses ( PRISMA ) reporting guideline. 14 Our patient, intervention, comparison, and outcome (PICO) was defined as follows: patients, patients with frozen shoulder of any etiology, duration, and severity; intervention, any treatment modality for frozen shoulder; comparison, any other treatment modality, placebo, or no treatment; and outcome, pain and function (primary outcomes) and external rotation range of movement (ER ROM) (secondary outcome) in the short term, midterm, or long term.

Included studies had a randomized design of any type and compared treatment modalities for frozen shoulder with other treatment modalities, placebo, or no treatment. Additionally, at least 1 of our preset outcome measures needed to be included in the study. Studies that compared different types, regimens, dosages, or durations of the same intervention were excluded (eg, different doses of corticosteroid or different exercise types). Those assessing the effectiveness of the same modality applied in different anatomical sites (eg, subacromial vs intra-articular [IA] corticosteroid) were included. Participants had to be older than 18 years with a clinical diagnosis of adhesive capsulitis. No formal diagnostic criteria were used to define frozen shoulder; however, the use of inappropriate or inadequate diagnostic criteria was taken into account in risk-of-bias assessments. Duration of the condition was not a criterion nor were previous treatments and follow-up. Inclusion of patients with specific conditions (eg, diabetes) was not an exclusion criterion, and it was not taken into account in analyses, provided that their proportion in the treatment groups was comparable.

Nonrandomized comparative studies, observational studies, case reports, case series, literature reviews, published conference abstracts, and studies published in languages other than English were excluded. Studies including patients with the general diagnosis of shoulder pain were also excluded even if a proportion of them had frozen shoulder. Studies assessing the effectiveness of different types of physiotherapy-led interventions, exercise, or stretching regimens were also excluded.

A thorough literature search was conducted by 3 of us (D.C., M.B., and M.M.) via Medline, EMBASE, Scopus, and CINAHL in February 2020, with the following Boolean operators in all fields: ( adhesive capsulitis OR frozen shoulder OR shoulder periarthritis ) AND ( treatment OR management OR therapy ) AND randomi* ). Relevant review articles were screened to identify eligible articles that may have been missed at the initial search. Additionally, reference list screening and citation tracking in Google Scholar were performed for each eligible article.

From a total of 73 299 articles that were initially identified, after exclusion of duplicate and noneligible articles, title and abstract screening, and the addition of missed studies identified subsequently, 65 studies were found to fulfil the eligibility criteria. Figure 1 illustrates the article screening process.

The internal validity (freedom from bias) of each included study was assessed with the Cochrane Collaboration’s tool for assessing risk of bias in randomized trials separately by 2 of us (D.C. and M.B.), and a third independent opinion (M.M.) was sought when disagreements existed. 15 Studies were characterized as having low, high, or unclear overall risk of bias based on the following formula: low overall risk studies had high risk of bias in 2 or fewer domains; high overall risk studies had high risk of bias in more than 2 domains; unclear overall risk studies had unclear risk of bias in more than 2 domains, unless they also had high risk of bias in more than 2 domains, in which case they were labeled as high overall risk. Risk of bias was assessed separately for outcome measures that included patient reporting (pain, function) and those that did not (ROM); all studies with nonmasked participants were labeled as high risk in the masking of outcome measures domain for patient-reported outcomes given that the assessors were the participants themselves.

Certainty of evidence was graded with the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool (eTable 1 in the Supplement ). 16 The scale starts with high, and depending on how many of the 5 possible limitations used in the GRADE tool were present in each comparison, the study could be downgraded to moderate, low, and very low. Grading of evidence was performed by 2 authors (D.C. and M.B.) independently and any disagreements were resolved by discussion and involvement of a third assessor (M.M.). Each outcome measure within each comparison had its own evidence grade. Our recommendations for clinical practice were based on results of either high or moderate quality evidence with both clinical and statistical significance.

Two of us (D.C. and M.B.) performed data extraction. The key characteristics of each eligible article were extracted and inserted in tables in Microsoft Word version 16.43 (Microsoft Corp) to facilitate analysis and presentation. For missing data, attempts were made to contact the original investigators for included studies published less than 10 years ago.

For the presentation of results, outcomes were divided into short-term (≤12 weeks), mid-term (>2 weeks to ≤12 months), and long-term (>12 months) follow-up. When sufficient data existed, short-term follow-up was subdivided into early short-term (2-6 weeks) and late short-term (8-12 weeks). All short-term follow-up points were converted to weeks, and all mid-term follow-up points to months for consistency and easier analysis.

Comparisons of interventions reported by fewer than 3 studies were included in the supplementary results table and were not analyzed or included in the article. When 3 or more studies contributed data for outcome measures at similar follow up times (ie, 2-6 weeks, 8-12 weeks, and 4-6 months), pairwise meta-analyses were conducted. Raw mean differences (MDs) with their accompanying 95% CIs were calculated and used in the tests for each comparison of pain and ER ROM because the tools used across studies were the same. Standardized mean differences (SMDs) were used for function because different functional scores were used.

When pain results were reported in different settings (eg, at rest, at night, with activity) in studies, only pain at rest was used in results. When both active and passive ROM were used as outcome measures, passive ROM was used in our results to increase homogeneity given that most studies used passive ROM. Results for the following outcome measures were recorded in tables and combined qualitatively only based on direction of effect to yield an overall effect for each comparison: abduction ROM, flexion ROM, and quality of life. However, these were not included in the results nor was the quality of the relevant evidence graded.

Additionally, comparisons that yielded both clinically and statistically significant results (ie, greater than or equal to the minimal clinically relevant difference and P  < .05) underwent trial sequential analysis (TSA) to rule out a type I error and further reinforce our recommendations for clinical practice. TSA is a quantitative method applying sequential monitoring boundaries to cumulative meta-analyses in a similar fashion as the application of group sequential monitoring boundaries in single trials to decide whether they could be terminated early because of a sufficiently small P value. TSA is considered an interim meta-analysis; it helps control for type I and II errors and clarifies whether additional trials are needed by considering required information size. 17 The TSA graph includes 2 horizontal lines, representing the conventional thresholds for statistical significance ( Z  = 1.96; P  < .05); 1 vertical line, representing required information size; a curved red line, representing the TSA boundaries (ie, thresholds for statistical significance); and a blue line showing the cumulative amount of information as trials are added. A significant result is denoted by a crossing of the curved blue and red lines.

Finally, a network meta-analysis was conducted for treatments used by 3 or more studies for the primary outcome (pain) at late short-term (8-12 weeks) and mid-term (4-6 months) follow-up. Both direct and indirect comparisons were included in the model, and treatment rank probabilities were produced for the 2 follow-up time periods. The certainty of evidence deriving from network meta-analyses was not graded. Subgroup analyses for the effect of home exercise, different physiotherapy interventions, and chronicity of frozen shoulder were conducted when possible.

The term physiotherapy was used for any supervised, physiotherapist-led, noninvasive treatment (mobilizations, application of ice and heat, diathermy, electrotherapy modalities). These were grouped and analyzed together. Exercises and stretching that were performed by the participants at home (home exercise program) or under a physiotherapist’s supervision were not included in physiotherapy. Acupuncture and extracorporeal shock wave therapy (ESWT) were regarded as a separate intervention to physiotherapy. Interventions that had accompanying physiotherapy were grouped and analyzed separately from those that did not, regardless of intensity and frequency. For example, studies with a treatment group who received IA corticosteroid plus physiotherapy (eg, ice packs and diathermy) were included in the intervention category IA corticosteroid plus physiotherapy; those with a treatment group receiving only IA corticosteroid (with or without a home exercise program) were included in the IA corticosteroid category. Patients in the following groups were considered control groups and were analyzed together: no treatment, placebo, sham procedures, IA normal saline or lidocaine, simple analgesia, and home exercise alone.

The following tools and questionnaires that were found in included studies represented our function outcome measure: Shoulder Pain and Disability Index, American Shoulder and Elbow Surgeons shoulder score, Constant-Murley, and the Strengths and Difficulties Questionnaire. All patient-reported pain and function scales were uniformly converted to a scale from 0 to 10 and a scale from 0 to 100, respectively.

The Review Manager version 5 (RevMan) software was used for pairwise meta-analyses and their accompanying forest plots and heterogeneity tests (χ 2 and I 2 ). TSA software version 0.9β (Copenhagen Trial Unit) was used for TSAs; random-effect models with 5% type I error and 20% power and O’Brien-Fleming α-spending function were used for all TSA analyses. The required information size was estimated by the software based on the power (20%), mean difference, variance, and heterogeneity. Stata version 16.1 (StataCorp) with the mvmeta extension (multivariate random-effects meta-regression) was used for network meta-analyses (frequentist approach). 18

When exact mean and SD values were not reported in the included articles, approximate values (to the nearest decimal place) were derived from the graphs. When only interquartile ranges (IQRs) were reported, the SD was calculated as IQR divided by 1.35. When only the median was reported, the mean was assumed to be the same. When CIs of means were reported, SDs were calculated by dividing the length of the CI by 3.92 and then multiplying by the square root of the sample size. When SEs of mean were given, these were converted to SDs by multiplying them by the square root of the sample size. In studies in which only means and the population were given, the SD was imputed using the SDs of other similar studies using the prognostic method (ie, calculating the mean of all SDs). 19 Pooled means were calculated by adding all the means, multiplied by their sample size, and then dividing this by the sum of all sample sizes. Pooled SDs were calculated with the following formula: SD pooled  = √(SD 1 2 [ n 1 -1]) + (SD 2 2 [ n 2 -1]) + … + (SD k 2 [ n k -1]) / ( n 1  +  n 2  + … +  n k  –  k ), where n indicates sample size and k , the number of samples. The following formula was used for the sample size calculation as part of GRADE’s assessment for imprecision 20 :

In which N indicates the sample size required in each of the groups; ( x 1  –  x 2 ) indicates the minimal clinically relevant difference (MCRD), defined as 1 point for VAS pain, effect size of 0.45 for functional scores, and 10° for ER ROM; SD 2 indicates the population variance, calculated using pooled SD from our treatment groups; a  = 1.96, for 5% type I error; and b  = 0.842, for 80% power.

The MCRD for function on functional scales would have been set at 10 points. However, because SMDs were used, which produce effect sizes, rather than MDs, the 10 points were divided by the population SD (ie, 22) that was used to calculate the optimal information size (effect sizes can be converted back to functional scores when multiplied by SD).

Potential publication bias was evaluated by Egger test for asymmetry of the funnel plot in comparisons including more than 10 studies. Expecting wide-range variability in studies’ settings, a random-effects metasynthesis was employed in all comparisons.

Subgroup analyses were conducted with independent samples t tests in Graphpad version 8 (Prism) comparing pooled means and SDs. All statistical significance levels were set at P  < .05, tests were 2-tailed, and clinical significance was defined as a MD or SMD being equal or higher than our predefined MCRD.

Of the 65 eligible studies, a total of 34 studies 21 - 54 were included in pairwise meta-analyses with a total of 2402 participants with frozen shoulder. Duration of symptoms ranged from 1 month to 7 years and length of follow-up from 1 week to 2 years, with most follow-up occurring at 6 weeks, 12 weeks, and 6 months.

Table 1 summarizes the main characteristics of the included studies. 21 - 87 eTable 2 in the Supplement shows the results of the risk-of-bias assessment.

Table 2 summarizes the findings of the present review. Where feasible (ie, results at similar follow-up times in at least 3 studies), pairwise meta-analyses were conducted. The results of abduction ROM, flexion ROM, and quality of life were pooled only based on direction of effect, and their certainty of evidence was not graded. eTable 3 in the Supplement summarizes the results of comparisons reported by 1 or 2 studies only. eTable 4 in the Supplement demonstrates how the strength of evidence for each outcome measure within each comparison was derived for all follow-up time categories, per GRADE. eTable 5 in the Supplement shows the heterogeneity for each comparison ( I 2 statistic) and where studies were removed to reduce heterogeneity based on sensitivity analyses.

We conducted pairwise meta-analysis comparing the effectiveness of each intervention with other interventions (or placebo/no treatment) in the short-term (early, 2-6 weeks; late, 8-12 weeks) and mid-term (4-6 months). Data for long-term follow-up (>12 months) were inadequate for analyses. Numerical data are only presented for the statistically significant comparisons; those for nonsignificant comparisons appear in the forest plots (eFigure 1, eFigure 2, and eFigure 3 in the Supplement ).

IA corticosteroid appeared to be associated with superior outcomes compared with control for early short-term pain (moderate certainty; MD, −1.4 visual analog scale [VAS] points; 95% CI, −1.8 to −0.9 VAS points; P  < .001), ER ROM (high certainty; MD, 4.7°; 95% CI, 2.7° to 6.6°; P  < .001), and function (high certainty; SMD, 0.6; 95% CI, 0.3 to 0.9; P  < .001) and late short-term pain (moderate certainty; MD, −1.0 VAS points; −1.5 to −0.5 VAS points; P  < .001), ER ROM (high certainty; MD, 6.8°; 95% CI, 3.4° to 10.2°; P  < .001), and function (moderate certainty; SMD, 0.6; 95% CI, 0.3 to 0.8; P  < .001).

IA corticosteroid was associated with better outcomes than control only for function (moderate certainty; SMD, 0.3; 95% CI, 0.1 to 0.5; P  = .01). However, effects for pain and ER ROM were similar (moderate certainty for both).

Physiotherapy was found to be associated with improved outcomes compared with control in the early short-term for ER ROM (moderate certainty; MD, 11.3°; 95% CI, 8.6°-14.0°; P  < .001). Data for other follow-up time periods were insufficient for quantitative analysis.

Combined treatment with IA corticosteroid plus physiotherapy was associated with superior outcomes vs control for early short-term ER ROM (high certainty; MD, 17.9°; 95% CI, 12.1°-23.7°; P  < .001). Data for other follow-up periods were insufficient for quantitative analysis.

IA corticosteroid was associated with significant benefits compared with physiotherapy for early short-term function (moderate certainty; MD, 0.5; 95% CI, 0.2 to 0.7; P  < .001) and late short-term pain (high certainty; MD, −1.1 VAS points; 95% CI, −1.7 to −0.5 VAS points; P  < .001) only. Differences for early short-term pain (moderate certainty), late short-term function (moderate certainty), and early and late short-term ER ROM (moderate and high certainty, respectively) were insignificant.

IA corticosteroid was associated with better outcomes than physiotherapy for ER ROM (moderate certainty; MD, 4.6°; 95% CI, 0.7°-8.6°; P  = .02). However, no significant differences in pain (low certainty) or function (moderate certainty) were observed.

Compared with IA corticosteroid alone, combined treatment with IA corticosteroid plus physiotherapy was only associated with superior outcomes for early short-term ER ROM (moderate certainty; MD, 11.6°; 95% CI, 3.7°-19.4°; P  = .004). Pain and function in the early short-term (moderate and low certainty, respectively) and late short-term function (high certainty) were similar between groups.

No significant differences were found between the groups in pain, function, or ER ROM. These results had high, moderate, and high certainty, respectively.

Combined therapy with IA corticosteroid plus physiotherapy was associated with significant benefits compared with physiotherapy alone only for early short-term function (low certainty; SMD, 0.7; 95% CI, 0.3-1.0; P  < .001). Differences for early short-term pain and ER ROM and late short-term function were not significant (moderate certainty for all).

No significant differences were found between the groups for pain, function, or ER ROM. These comparisons had moderate, low, and high certainty, respectively.

Compared with subacromial administration, administering corticosteroid intra-articularly was only associated with superior outcomes for early short-term pain (moderate certainty; MD, −0.6 VAS points; 95% CI, −1.1 to −0.1 VAS points; P  = .02) and late short-term function (moderate certainty; SMD, 0.3; 95% CI, 0 to 0.6; P  = .03). Improvements in late short-term pain (moderate certainty) and ER ROM (high certainty) and early short-term function (high certainty) were similar with the 2 interventions.

No significant differences were found between the groups for pain or ER ROM. These comparisons had moderate and high certainty, respectively.

Adding arthrographic distension to IA corticosteroid appeared to be associated with greater improvements in early and late short-term pain (early: high certainty; MD, −0.9 VAS points; −1.3 to −0.4 VAS points; P  < .001; late: high certainty; MD, −0.8 VAS points; 95% CI, −1.1 to −0.5 VAS points; P  < .001). Early and late short-term function (moderate and high certainty, respectively) and early and late short-term ER ROM (high certainty for both) were similar with or without distension.

No differences were found with the addition of acupuncture to physiotherapy for early short-term pain and ER ROM. These comparisons had low and high certainty, respectively.

Despite several statistically significant differences in pairwise comparisons, most did not reach the threshold for MCRD. Only IA corticosteroid vs no treatment or placebo for early and late short-term pain and function, physiotherapy with and without IA corticosteroid vs no treatment or placebo for early short-term ER ROM, IA corticosteroid vs physiotherapy for early short-term function and late short-term pain, and combination therapy with IA corticosteroid plus physiotherapy compared with IA corticosteroid for early short-term ER ROM and with physiotherapy for early short-term function reached MCRD.

For the primary outcome measure, the clinically and statistically significant results underwent TSA, which confirmed the results ruling out a type I error in 2 comparisons (IA corticosteroid vs no treatment or placebo for early and late short-term pain) but not in the comparison of IA corticosteroid vs physiotherapy for late short-term pain. This suggests that more studies may be needed to confirm the benefit of IA corticosteroid compared with physiotherapy with more confidence.

eFigures 1 to 3 in the Supplement illustrate the results of the pairwise meta-analyses and associated forest plots for early short-term, late short-term, and mid-term follow up for pain and ER ROM. eFigure 4 in the Supplement illustrates the forest plots for function, and eFigure 5 and eFigure 6 in the Supplement illustrate the TSA graphs.

Figure 2 and Figure 3 show the network maps and treatment rank probabilities for the primary outcome measure (pain) for late short-term (8-12 weeks) and mid-term (4-6 months) follow-up, respectively. eFigure 7 and eFigure 8 in the Supplement illustrates the network forests with their consistency tests.

In the late short-term, arthrographic distension plus IA corticosteroid had the highest probability (96%) of being the most effective treatment. IA corticosteroid had the highest probability (85%) of being the second most effective. Physiotherapy was the least effective treatment, followed by no treatment or placebo. No data existed in the late short-term for combined treatment with IA corticosteroid plus physiotherapy ( Figure 2 B).

In the mid-term, combined treatment with IA corticosteroid plus physiotherapy had the highest probability (43%) of being the best treatment with physiotherapy. IA corticosteroid had the highest probability (34%) of being the second best treatment. No treatment or placebo followed by subacromial corticosteroid had the highest probability of being the worst interventions ( Figure 3 B).

The potential benefit of home exercise was assessed by comparing the mean improvement in pain in patients who received (1) IA corticosteroid plus a home exercise program vs IA corticosteroid without home exercise, and (2) no treatment or placebo plus home exercise vs no treatment/placebo without home exercise. For the first comparison, a statistically significant (but clinically small) mean benefit of home exercise on pain improvement was identified at 8 to 12 weeks (MD, −0.5 VAS points; 95% CI, −0.9 to −0.1 VAS points; P  = .01). The benefit of home exercise was much more substantial (clinically and statistically) in those receiving no treatment or placebo (MD, −1.4 VAS points; 95% CI, −1.8 to −1.1 VAS points; P  < .001). Both results are based on 10 studies 22 , 24 , 25 , 28 , 42 , 43 , 45 , 46 , 48 , 49 with low overall risk of bias.

Similarly, we assessed for an effect of IA placebo by comparing samples who received IA placebo and no treatment from the IA corticosteroid vs no treatment or placebo comparison. Both subgroups received a home exercise program. Based on 9 studies 22 , 24 , 25 , 28 , 42 , 43 , 45 , 46 , 49 with high overall risk of bias, IA placebo was associated with statistically and clinically significant effects on pain compared with no treatment (MD, −1.6 VAS points; 95% CI, −2.1 to −1.1 VAS points; P  < .001).

There was insufficient data for a similar subgroup analysis at mid-term follow-up. Subgroup analyses for the effect of chronicity on the effectiveness of treatment modalities could not be evaluated because studies including patients with mixed stages and chronicity of frozen shoulder did not include subgroup data. Finally, subgroup analyses according to physiotherapeutic interventions were not possible because of high clinical heterogeneity (various combinations of modalities and treatment durations used). Most studies used electrotherapy modalities (transcutaneous electrical nerve stimulation, therapeutic ultrasound, diathermy) combined with mobilizations, stretching, or exercises with or without heat and ice packs.

To our knowledge, this is the first systematic review and network meta-analysis to comprehensively analyze all nonsurgical randomized clinical trials pertaining to the treatment of frozen shoulder as well as the largest systematic review ever published in the field. Based on the available evidence, it appears that the use of an IA corticosteroid for patients with frozen shoulder of duration less than 1 year is associated with greater benefits compared with all other interventions, and its benefits may last as long as 6 months. This has important treatment ramifications for the general and specialist musculoskeletal practitioner, providing them with an accessible, cost-effective, 88 and evidence-based treatment to supplement exercise regimes, which we anticipate will inform national guidelines on frozen shoulder treatments moving forward.

In the short-term, IA corticosteroid appeared to be associated with better outcomes compared with no treatment in all outcome measures. Adding arthrographic distension to IA corticosteroid may be associated with positive effects that last at least as long as 12 weeks compared with IA corticosteroid alone; however, these benefits are probably not clinically significant. Compared with physiotherapy, IA corticosteroid seemed to be associated with better outcomes, with clinically significant differences. Combination therapy with IA corticosteroid plus physiotherapy may be associated with significant benefits compared with IA corticosteroid alone or physiotherapy alone for ER ROM and function, respectively, at 6 weeks. Compared with control, combined IA corticosteroid plus physiotherapy appeared to be associated with an early benefit in ER ROM (as long as 6 weeks), with clinical significance. Subacromial administration of corticosteroid appeared to be as efficacious as IA administration. The addition of acupuncture to physiotherapy did not seem to be associated with any added benefits. Based on the network meta-analysis, arthrographic distension with IA corticosteroid was probably the most effective intervention for pain at 12 weeks follow-up. IA corticosteroid alone ranked second, and as demonstrated by the pairwise meta-analysis, the benefit of adding distension appeared clinically nonsignificant.

Most compared interventions appeared to be associated with similar outcomes at 6-month follow up, without significant differences. The only intervention that was associated with mid-term statistically significant benefits compared with control and physiotherapy (without reaching clinical significance) was IA corticosteroid for function and ER ROM. No mid-term data exist assessing the effectiveness of adding arthrographic distension to IA corticosteroid and acupuncture to physiotherapy or comparing physiotherapy (with or without IA corticosteroid) with no treatment. Our network meta-analysis found that combined therapy with IA corticosteroid and physiotherapy, physiotherapy alone, and IA corticosteroid alone were the most effective interventions for pain at 6 months follow-up. However, according to our pairwise meta-analyses, their clinical benefit compared with other treatments (or even no treatment) appeared very small.

A home exercise program with simple ROM exercises and stretches administered with or without IA corticosteroid appeared to be associated with short-term pain benefits. This was statistically significant but clinically nonsignificant compared with no treatment when accompanied by IA corticosteroid. It was both clinically and statistically significant on its own.

Several systematic reviews have been published assessing the effectiveness of therapeutic interventions for frozen shoulder. Sun et al 89 looked at the effectiveness if IA corticosteroid by comparing it with no treatment, and their findings were similar to ours, reporting that IA corticosteroid may be associated with benefits on pain, function, and ROM that are most pronounced in the short-term and can last as long as 6 months. The systematic review of both randomized and observational studies by Song et al 90 is also in agreement with our results, showing a possible early benefit of IA corticosteroid, which likely diminishes in the mid-term. An earlier systematic review by Maund et al, 88 which was only based on limited evidence (meta-analyses of 2 and 3 studies), was largely inconclusive, demonstrating possible benefits of IA corticosteroid (with and without physiotherapy) in conjunction with a home exercise program. A Cochrane review on arthrographic distension 91 was also in agreement with our results, showing that arthrographic distension with IA corticosteroid may be associated with short-term benefits in pain, ROM, and function. Their comparison of combined treatment vs IA corticosteroid alone yielded no significant differences; however, it was only based on 2 studies. A 2018 systematic review by Saltychev et al 92 also supports our findings, having demonstrated a small but clinically insignificant benefit of the addition of arthrographic distension to IA corticosteroid. In their systematic review, Catapano et al 93 reported that the addition of arthrographic distension to IA corticosteroid may be associated with a clinically significant benefit at 3 months; however, no quantitative analyses were conducted. Finally, a Cochrane review investigating the effects of manual therapy and exercise 94 concluded that they are probably associated with worse outcomes compared with IA corticosteroid in the short-term, which is in accordance with the findings of the present review, and another study 95 investigating the effectiveness of electrotherapy modalities was inconclusive because of lack of sufficient evidence.

In this review we aimed to assess the comparative effectiveness of all interventions for frozen shoulder, both surgical and nonsurgical; however, conclusions on the former could not be reached given that included studies did not assess the same interventions, which precluded pooling their results. The existing literature is conflicting regarding the superiority of arthroscopic capsular release (ACR) over nonoperative modalities; De Carli et al 62 reported no short-term or long-term benefits of ACR plus MUA compared with IA corticosteroid plus physiotherapy in function or ROM. Conversely, Mukherjee et al 75 found that ACR was associated with significant improvements in pain, function, and ROM compared with IA corticosteroid in the short-term and mid-term. Gallacher et al 63 demonstrated mixed results, concluding that compared with IA corticosteroid plus arthrographic distension, combined treatment with ACR and IA corticosteroid may be associated with improved function, external rotation, and flexion ROM but not quality of life and abduction ROM in the short-term and mid-term. The risk of complications, where reported, was not higher in the surgical groups. 63 The existing evidence on MUA, which is not a surgical procedure per se although it is administered under general anesthesia, is more consistent, suggesting its lack of long-term superiority compared with other commonly used nonsurgical treatments or even no treatment. 65 , 71 , 76

Because of the paucity of robust evidence, no firm recommendations exist for clinical practice. The National Institute of Health and Care Excellence (NICE) guidelines, 96 influenced in turn by the BESS/BOA recommendations, recommend a stepped approach, starting with physiotherapy and only considering IA corticosteroid if there is no, or slow, progress. 96 With our review, we provide convincing evidence that IA corticosteroid is associated with better short-term outcomes than other treatments, with possible benefits extending in the mid-term; therefore, we recommend its early use with an accompanying home exercise program. This can be supplemented with physiotherapy to further increase the chances of resolution of symptoms by 6 months.

Most patients in the included studies had duration of symptoms of less than 1 year; therefore, our management recommendations are strongest for this subgroup, which includes patients most commonly encountered in clinical practice. Based on the underlying pathophysiology of the condition, usual practice is to only administer IA corticosteroid in the painful and not freezing phase (also advised by NICE guidance 95 ); however, this is not backed up by evidence. In our review, studies that included patients with symptoms for more than 1 year reported equally substantial improvements in outcome measures including ROM and function; therefore, the benefits of corticosteroids may also apply to the freezing phase of frozen shoulder. 48 , 79

Despite the comprehensiveness and rigor of our methods, which include thorough risk of bias assessments and grading of evidence, we do recognize its limitations. Frozen shoulder of all chronicity was analyzed together; therefore; conclusions about specific stages and their most effective management could not be drawn. Most studies included a home exercise program, but its frequency, intensity, and duration were not taken into account in comparisons nor were separate analyses made adjusting for it. Finally, physiotherapy interventions, regardless of nature and duration, were grouped and analyzed together to minimize imprecision; in reality, some might be more effective than others. However, we only present findings that derived from thorough quantitative analyses, which were in turn substantially reinforced by the TSA, minimizing the risk for type I errors; most previous similar meta-analyses did not use TSA. Additionally, we present the first network meta-analysis including all conservative treatments for frozen shoulder. Furthermore, we based our recommendations on both statistically and clinically significant results.

Based on the findings of the present review, we recommend the use of IA corticosteroid for patients with frozen shoulder of duration less than 1 year because it appeared to have earlier benefits than other interventions; these benefits could last as long as 6 months. We also recommend an accompanying home exercise program with simple ROM exercises and stretches. The addition of physiotherapy in the form of an electrotherapy modality and supervised mobilizations should also be considered because it may add mid-term benefits and can be used on its own, especially when IA corticosteroid is contra-indicated. Implicated health care professionals should always emphasize to patients that frozen shoulder is a self-limiting condition that usually lasts for a few months but can sometimes take more than 1 year to resolve and its resolution may be expedited by IA corticosteroid. This should be offered at first contact, and an informed decision should be made by the patient after the risks and alternative therapies are presented to them. In the future, other interventions that have shown promising results and currently have inadequate evidence for definitive conclusions (eg, MUA, ACR, specific types of electrotherapy and mobilizations) should be assessed with large, well-designed randomized studies. Finally, future studies should include subgroup analyses assessing the effectiveness of specific interventions on frozen shoulder of different chronicity and stage.

Accepted for Publication: October 22, 2020.

Published: December 16, 2020. doi:10.1001/jamanetworkopen.2020.29581

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2020 Challoumas D et al. JAMA Network Open .

Corresponding Author: Neal L. Millar, MD, PhD, Institute of Infection, Immunity, and Inflammation, College of Medicine, Veterinary and Life Sciences University of Glasgow, 120 University Ave, Glasgow G12 8TA, United Kingdom ( [email protected] ).

Author Contributions: Dr. Challoumas had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Challoumas, McLean, Millar.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Challoumas, Millar.

Statistical analysis: Challoumas.

Obtained funding: Millar.

Administrative, technical, or material support: Challoumas, McLean.

Supervision: Challoumas, Millar.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was funded by grant MR/R020515/1 from the Medical Research Council UK.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Adhesive capsulitis: a case study

Affiliation.

• 1 Brooke Army Medical Center at Fort Sam, Houston, TX, USA.
• PMID: 20016342
• DOI: 10.1097/NOR.0b013e3181c01227

Adhesive capsulitis (AC), also known as frozen shoulder, is a common and painful musculoskeletal disorder. The shoulder is a complex joint comprising 3 bones and multiple muscle groups, ligaments, and tendons. Accompanying the inflammation of the joint is stiffness that greatly restricts the patient's motion and strength. AC is a treatable condition requiring months of daily physical therapy. The reports that 1 in 7 Americans has a musculoskeletal impairment including shoulder problems that accounted for 14 million visits to physicians' offices in 2003. It is imperative that practitioners accurately assess and diagnose the patient with shoulder pain to facilitate an appropriate plan of care. This paper will discuss the case of a patient with AC including differential diagnoses, pathophysiology, and treatment options.

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• Research article
• Open access
• Published: 04 April 2022

Living with a frozen shoulder – a phenomenological inquiry

• Suellen Anne Lyne 1 , 2 ,
• Fiona Mary Goldblatt 1 , 2 &
• Ernst Michael Shanahan   ORCID: orcid.org/0000-0001-8309-3289 1 , 2  

BMC Musculoskeletal Disorders volume  23 , Article number:  318 ( 2022 ) Cite this article

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Frozen shoulder (adhesive capsulitis) is an inflammatory condition affecting the capsule of the glenohumeral joint. It is characterised by a painful restricted range of passive and active movement in all planes of motion. The impact of frozen shoulder on affected individuals remains poorly characterised. In this study we sought to better understand the lived experience of people suffering from frozen shoulder to characterise the physical, psychological and socioeconomic impact of the condition.

A qualitative study using a phenomenological approach was undertaken. Purposeful sampling was used to identify individuals for interview. Semi-structured interviews were performed and continued until saturation was achieved. A biopsychosocial framework was used during the analysis in order to generate themes which best described the phenomenon and reflected the lived experience of individuals’ suffering from this condition.

Ten interviews were conducted, and five main themes emerged including; the severity of the pain experience, a loss of independence, an altered sense of self, the significant psychological impact, and the variable experience with healthcare providers.

Conclusions

These findings offer an insight into the lived experience of individuals with frozen shoulder, both on a personal and sociocultural level. The pain endured has profound impacts on physical and mental health, with loss of function resulting in a narrative reconstruction and altered sense of self. Our findings illustrate that frozen shoulder is much more than a benign self-limiting musculoskeletal condition and should be managed accordingly.

Trial registration

ANZCTR 12620000677909 Registered 28/04/2020 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379719&isReview=true

Peer Review reports

Frozen shoulder is often poorly diagnosed and inadequately managed, and this study adds important insights on the lived experience of individuals suffering from frozen shoulder.

The severity and pervasiveness of the pain endured, a loss of independence and patients’ altered sense of self are profound representations of living with a frozen shoulder.

This study challenges us to reconsider whether our current treatment targets for frozen shoulder are appropriate.

An emphasis on early and effective pain management and on managing the psychological sequelae of the disease emerge from this study as key treatment targets.

Frozen shoulder is a common but often under-recognised condition. It is an inflammatory and fibrosing condition affecting the glenohumeral joint capsule, characterised by shoulder pain and stiffness with significant resultant disability [ 1 , 2 ]. The aetiology is unknown, however a number of risk factors have been identified including diabetes and shoulder trauma [ 1 , 3 ]. Frozen shoulder is considered primary if it occurs spontaneously, or secondary if there is an antecedent event such as trauma. The combined prevalence is estimated between 3 and 5% in the general population, but rates as high as 20% are reported in people with diabetes [ 4 , 5 ]. Peak age of onset is 40–60 years and women are affected slightly more often than men [ 6 , 7 ]. Given frozen shoulder typically affects those of working age, there are resultant economic impacts, both on a personal and societal level [ 8 ].

Frozen shoulder is predominantly a clinical diagnosis. Restriction of movement occurs in all planes of motion, both passive and active, and there is insufficient joint degeneration to account for the restricted movement [ 9 ]. The pathognomonic feature is almost complete loss of external rotation [ 7 ]. Additional investigations are usually non-contributory but can be useful in ruling out other pathologies. The natural history of frozen shoulder remains poorly understood [ 10 ], but the most commonly accepted description of disease progression is defined by three overlapping clinical phases. Phase one manifests as severe shoulder pain, typically worse at night, with concurrent progressive loss of motion. This phase can last 2–9 months and is known as the painful phase . Phase two, the frozen phase , lasts 4–12 months and is characterised by gradual reduction in pain, but persistent and considerable restriction in movement. Phase three, termed the resolution or thawing phase, and can last 12–36 months [ 3 ]. Few effective treatments are available which significantly alter the natural history of disease [ 2 ]. The extent of recovery is variable, with some reporting persistent pain and residual limitation of movement. In one large case series 35% of people had mild to moderate and 6% had severe symptoms, at a mean follow up of 4.4 years [ 11 ]. Recurrence is uncommon, although the contralateral shoulder can become affected in 6–17% of patients within the first 5 years [ 11 ]. In current practice the management of frozen shoulder has been primarily undertaken by orthopaedic surgeons and physical therapists who emphasise biomechanics and restoration of range of motion. This approach has tended to shape our understanding of the condition and influence treatment targets.

The clinical picture of frozen shoulder is well described but the impact on individual suffering is poorly characterised. Some people describe difficulties with basic activities of daily living, such as showering, dressing and cooking [ 8 ]. The pain is reported to interfere with sleep, which further intensifies the pain and impacts one’s ability to engage with domestic, social and occupational activities [ 12 , 13 ]. What remains poorly described is the experience of protracted and debilitating shoulder pain which has the potential for profound physical, psychological and socioeconomic consequences [ 14 ]. A recent systematic review of patients’ experiences with shoulder disorders in general concluded that patients contend with considerable disruption to their lives, impacting sleep, cognitive function and emotional wellbeing [ 12 ]. However, there is very limited data reporting the impact of frozen shoulder. One paper focused on patients’ experiences with conventional care pathways [ 8 ] and another examined patients’ experience of a specific treatment, Bowen’s technique [ 15 ]. To our knowledge, there have been no papers describing a holistic exploration of the lived experience of frozen shoulder.

Despite its prevalence, treatment outcomes for frozen shoulder continue to be modest [ 2 ]. Given this reality, it is important to ask why our treatments appear to be missing the mark. Is it possible our therapeutic targets are not the most appropriate for this poorly understood condition? Little is reported about the experience of individuals suffering from frozen shoulder, so in this paper we set out to better understand the lived experience. We believe this work to be important in helping to better manage this common medical condition. By improving understanding of the impact on the individual, we aim to increase practitioner awareness of the disease and its severity, facilitate earlier diagnosis and better design therapies which improve outcomes that are important to patients [ 16 ].

A qualitative study using a phenomenological approach was employed to explore the lived experience of a group of individuals suffering from frozen shoulder. Participants were identified from a group of patients with a recent diagnosis of frozen shoulder based on assessment by a specialist Rheumatologist. Inclusion criteria included male and female participants, aged over 18 years. There were no exclusion criteria. Patients were referred to the Southern Adelaide Local Health Network (SALHN) rheumatology outpatient clinic from community and hospital settings, including general practice, physiotherapists and specialty services, with the exception of one participant who was not previously known to the service. Purposive sampling was used to select individuals for interview. Patients who reported significant psychosocial impact from their frozen shoulder were invited to participate.

Interviews took place either in person at the rheumatology outpatient clinic or via audio and video telehealth, between June and August 2020. In-depth, semi-structured interviews were conducted using an interview guide (Supplementary File  1 ) Following an introduction to orientate participants, the interviewer asked the interviewee to describe the impact of the frozen shoulder on their life. Questions were “directed to the participants’ experiences, feelings, beliefs and convictions about the theme in question” [ 17 ]. An iterative approach was used for the interviews, meaning that knowledge acquired in each interview helped guide questioning for interviews of subsequent participants and enabled identification of emergent themes [ 18 ]. The audio-recorded interviews were transcribed and data de-identified. Each transcript was given to the respective interviewee to read, and an opportunity provided to amend or add any material they felt relevant. Interviews were conducted by a single researcher, SL, who had no involvement in the participants’ medical care prior to study commencement, minimising risk of bias. SL is a rheumatologist who had professional knowledge of the condition and was trained in qualitative interview techniques. Interviewing was continued until saturation was achieved, that is until interviewees introduced no new perspectives, no new themes emerged, and no further coding was possible [ 19 , 20 ]. The SALHN Human Research Ethics Committee approved the study (OFR number: 81.20, ANZCTR 12620000677909).

A phenomenological approach was deemed the most appropriate enquiry method because the research sought to understand the participants’ conscious experience; their judgments, perceptions and emotions [ 21 , 22 , 23 ]. The philosophy of Husserl and methods described by Colaizzi were applied to analyse the interviews [ 21 , 24 ]. This involves reading the interviews in their entirety, repeatedly if necessary, in order to become familiar with the data set and develop a holistic sense of the interview, the “gestalt” [ 25 ]. The researchers attempt to bracket out their own prejudices and presuppositions to avoid prejudging the data and therefore allow true realisation of the essence of the experience in order to “enter the unique world of the informant/participant” [ 26 , 27 ]. Coding was conducted using NVivo 12 Qualitative Data Analysis Software [ 28 ]. Coding was performed by the three authoring researchers and all interviews were at least dual coded. The authors are rheumatologists with experience in qualitative research. Codes were collated and sorted, and units of meaning delineated, taking into account the literal content, the number of times the unit of meaning arose, and how the meaning was delivered. Themes were derived from the data rather than being identified in advance. Themes emerged as units of meaning were clustered, bringing together recurrent experience and its variant manifestations, in order to get to the essence of the phenomenon and elucidate the “lived experience” [ 29 , 30 ].

Of the 16 individuals invited, ten agreed to participate (Eight female and two male, age range 32–72). No participants were excluded, and all provided written informed consent. Four did not respond to our invitation and two others expressed interest but we not formally recruited before saturation was achieved. Nine interviewees had recovered from their frozen shoulder, having been diagnosed within the preceding 2 years, while one was still in the resolution phase. Two participants had suffered two frozen shoulders, affecting each shoulder at different time points, whereas the remainder had only one arm affected. Data analysis resulted in identification of five main themes; the severity of the pain experience, a loss of independence, an altered sense of self, the significant psychological impact, and the variable experience with healthcare providers.

The severity of the pain experience

The intractable nature and intensity of the pain dominated the participants’ experience of frozen shoulder. The pain was severe and the timing unpredictable, although most often precipitated by movement. Participants used vivid descriptors of pain, such as “horrible”, “excruciating”, “debilitating” and “unbearable” to illustrate their experience.

“You see the Western movies [where] they forge the steel and … plunge it into the cold water … that’s what it feels like, hot, molten lava encapsulated by metal, dragging your shoulder down”

The pain affected all facets of life, impacting work, sleep, personal hygiene, interpersonal relationships and independence. The prolonged duration and inescapable nature of the pain made it both debilitating and demoralising. It was consistently recognised that above all else, participants wanted the pain to go away. Pain was the priority and was considered far more significant than the loss of movement:

“All I wanted was for the pain to go away”.

Resolution of the pain had a major positive psychological impact on participants:

“Once the pain was alleviated, then I could cope with everything else”.

Improvement in pain enabled participants to engage more effectively in physical therapies and begin their recovery.

A loss of Independence

The degree and impact of the disability and loss of independence was another prominent theme. There were implications both at home and in the workplace. Activities such as dressing, driving, shopping and personal hygiene were limited, or near impossible for some, occasionally with resultant loss of income. This was particularly evident for those whose dominant arm was affected.

“It's hard to describe how much it limits you. You can't do anything”.

Many participants felt that the severity of their illness and consequent disability was underappreciated by others due to the ‘invisible’ nature of frozen shoulder. Often a sense of stoicism was expressed as people tried to cope as though nothing was wrong, while simultaneously becoming frustrated by others’ inability to appreciate their incapacity. Many struggled to accept their disability, and were reluctant to rely on others:

“I felt like I was abusing my friends … to ask them again or to rely on them again, that was stupid”.

Meanwhile, others exhibited a greater sense of acceptance and self-kindness. There was an apparent sense of fear associated with loss of independence; fear of being judged, of being a burden, of resentment, and of loss of income. This fear was compounded by social isolation and a sense of hopelessness, particularly for those with limited social supports and inadequate access to services.

An altered sense of self

The loss of independence, in combination with intractable pain, prompted an identity narrative reconstruction for some participants, resulting in an altered sense of self. In the context of the severe pain and physical limitation, individuals struggled to meet their own expectations, and also the expectations of those around them.

“I was supposed to be the one that could cope and do everything”

This resulted in a growing separation between their private sense of self and their public social identity, causing a paradigm shift in their self-concept [ 30 , 31 , 32 ]. Pain was a constant reminder of disability. Their disability prevented them for undertaking activities of daily living, as well as activities that brought joy, such as sport and playing with children or grandchildren. Inability to drive or catch public transport caused their world to shrink. Interrupted sleep caused fatigue and irritability, as well as an inability to function at full capacity at work. The fear of being a burden and lack of understanding from others resulted in social isolation:

I didn't want anybody around me because I didn't want anybody to see me the way I was”

Cumulatively, these factors challenged the sufferers’ perception of self and often resulted in social withdrawal. For some, this altered sense of self was enduring, and in others it was transient. Resilience and strong supportive social networks were recognised as important factors in preventing such a loss in sense of self.

The psychological impact

Living with a frozen shoulder often had profound psychological effects including anxiety, irritability, depression and even the contemplation of suicide. The unrelenting pain, as well as interrupted sleep, were key determinants of mood:

“When the world is crumbling and you’re in pain … it’s a dark time”

Furthermore, patients often felt they weren’t believed about the severity of their pain, with a lack of empathy and understanding emanating from family, friends, colleagues and members of the medical profession. People reported feeling frustrated at their lost independence and lack of understanding from others. This frustration manifest itself as irritability.

“people see me as more cantankerous than they’d ever been seen before.”

Depression was frequently reported.

“I’d had enough, I couldn’t handle it and my depression got really bad”

Two participants had even contemplated suicide as a means of ending their pain.

“had I woken up the next morning … still in the same sort of pain, then yes, I may not still be here”

A lack of recognition of the individuals’ mental health issues by treating health professionals was reported, and may have contributed to the psychological impacts being poorly managed.

The healthcare approach

Medical and allied health professionals often appeared to lack awareness of this condition. At times, this resulted in prolonged delays to diagnosis, inappropriate investigation and inadequate treatment.

“I’d seen 3 or 4 GP’s up to that point and none of them, they’re all sending me off to have an ultrasound for bursitis and no one, and I’d even mentioned frozen shoulder and, and they were all like “No we don’t think it’s that” you know, and so I felt very disempowered from the medical profession and very not understood.”

There were many differing interpretations by the health professionals of what “frozen shoulder” actually meant and why people get it. On reflection, participants became aware of this knowledge gap over time. An apparent lack of compassion and empathy was sometimes noted as members of the healthcare team trivialised the severity of symptoms and failed to acknowledge their impact.

“[They] never ever asked me how things, how was I managing at home”

The severity of the pain was also underappreciated by certain practitioners, as demonstrated by the lack of compassion when asked to perform exercises:

“She grabbed my arm, and she used all her force to pull my arm all the way up, I screamed like you had no idea.”

Participants expressed concerns about the overall knowledge and experience of many of their healthcare providers and suggested a need to improve this through further education. In contrast, participants described a sense of relief when a health practitioner was able to identify and confidently manage their frozen shoulder. The knowledge of being understood provided a sense of relief, and instilled patients with new hope.

“I almost burst into tears. I can feel it now. I was like

Oh my God, someone understands me”

The formation of a therapeutic relationship and established treatment targets was evidently important in the overall healing process.

To our knowledge, this is the first qualitative study to describe the phenomenon of living with a frozen shoulder. Jones et al. explored the perceptions of people living with frozen shoulder and their priorities for treatment [ 8 ] however, while this work emphasised the loss of function and unacceptable delays to treatment, there was little evaluation of the subjective experience and psychological impact of the pain.

The aetiology and pathophysiology of frozen shoulder remains poorly understood and is postulated by some to be an algoneurodystrophic process, on the same spectrum as chronic regional pain syndrome [ 33 , 34 ]. It is difficult to delineate the role of tissue damage and nociceptive stimulation in perception of pain from frozen shoulder. According to Moseley, pain experience does not correlate directly with the state of the tissues and many factors across somatic, psychological and social domains influence pain modulation [ 35 ]. In the absence of a clear pathological process and inadequate direction from health practitioners, the sufferer’s consciousness is held accountable for their own condition [ 36 , 37 ]. The complexity of musculoskeletal pain has been extensively studied and there is an ever-growing body of evidence which explores the modern concept of chronic pain [ 35 , 38 , 39 , 40 ]. It has been consistently demonstrated that expectations and pre-existing personality traits influence one’s experience of pain. For example, catastrophising and health-related anxiety are associated with heightened pain experience, whereas resilience and strong social supports help ameliorate pain [ 40 , 41 ]. Given the burden of psychological distress expressed by some of our participants, it is imperative that patient expectations, social isolation and health related anxiety be acknowledged and addressed early when managing frozen shoulder.

Physical therapy is considered by many as first line therapy for frozen shoulder despite multiple studies and a recent Cochrane review demonstrating little evidence to support physical therapy [ 34 , 42 , 43 , 44 ]. Our work has highlighted that the patients’ priority is pain management, above all else. Patient-centred care involves listening to patients’ priorities [ 16 ] and empowering patients to effectively critique and provide feedback on the quality and appropriateness of healthcare services [ 45 ]. In our study, pain management clearly was prioritised by the patients over range of movement. By treating the pain effectively, participants said that they would be better able to cope psychologically with their incapacity and engage better with physical therapies.

Our data showed that being understood by healthcare professionals and others also played a therapeutic role. Participants reported feeling frustrated and disempowered by the lack of understanding and empathy offered by health professionals. This sentiment has been echoed by other qualitative work exploring chronic pain, even in specialist pain clinics, where it seems the clinician’s ability to truly understand the patients’ experience is “outside their lexicon of knowledge” [ 8 , 14 ]. If a patient’s experience is misrepresented or trivialised by the health practitioner, this may propagate a negative self-image with resultant shame, distress and altered sense of self [ 46 ]. Such feelings promote resentment and helplessness and are counterproductive to the therapeutic relationship, while also increasing risk of anxiety and depression [ 38 ]. This in turn magnifies the individual’s experience of pain. Conversely, if a patient feels their struggle is understood, there are profound positive impacts. It validates the individual’s experience, which instils a sense of relief and hope, reaffirms their functioning as a social individual and diminishes their sense of spoiled identity [ 14 ]. There is a large body of evidence which supports the need for a strong therapeutic alliance when managing chronic musculoskeletal pain, based on a shared understanding of the symptomatology and treatment targets, and the management of frozen shoulder is no different [ 47 , 48 ].

The findings in this research have allowed us to reconceptualise the treatment targets for frozen shoulder and a number of issues have been identified which may improve patient care. Firstly, a clearer focus on early and effective pain management is imperative, as is improved management of the psychological sequelae. These findings align with an increasing body of evidence that explores the impact of pain and pain-related behaviours on outcomes in frozen shoulder [ 49 , 50 , 51 ]. Treatment of chronic musculoskeletal pain is complex, requiring a multifaceted biopsychosocial approach. While targeting nociceptive signals with analgesia and neural blockade may be helpful, educating patients about the mechanisms of chronic musculoskeletal pain is also of great importance [ 52 ]. Enquiring about a patient’s coping strategies and acknowledging their struggle are simple measures to provide improved psychological support. In Australia, there is a paucity of services available for patients with short term incapacity, however, referral to a psychologist and advocating for access to community support services may be beneficial. Education is required to enable practitioners to better recognise and manage frozen shoulder. Equally, the language chosen by clinicians needs to be reconsidered in order to foster a constructive therapeutic alliance [ 53 ]. Given that frozen shoulder is so painful and slow to improve, early patient education is critical to ameliorate apprehension and help formulate realistic treatment targets [ 4 ]. We believe that addressing the above short fallings will reduce pain severity, lessen the sense of spoiled identity and help minimise rates of anxiety and depression.

There are a number of strengths to our study. The use of bracketing and dual coding has minimised potential bias. Employing phenomenology as the methodology in this study has allowed the voice of individuals’ experiences to be clear. Some limitations to this study also need to be considered. Participants’ experiences were historical, having recovered from their frozen shoulder some weeks or months prior and it is therefore possible that themes may have differed in participants with active disease. Recall bias must also be taken into consideration. Because of public health restriction in place at the time of our study, interviews were conducted in person, and via audio and video telehealth. Use of different communication platforms may have impacted rapport and limit translatability. Furthermore, this was a small study which included mostly patients from a single tertiary centre and limited geographical area.

This study has focused on the experience of living with a frozen shoulder. It has provided new insight into the severity of the pain and the subsequent impact on physical and mental health, with loss of function resulting in a narrative reconstruction and altered sense of self. Insights from this research align with recent studies that emphasise the importance of pain-perception and pain-related behaviours in patients with frozen shoulder. Increased practitioner awareness of patient experience helps facilitate earlier diagnosis and refocuses treatment approaches based on patient priorities. A clearer emphasis on early and effective pain management and on managing the psychological sequelae of the disease are two clear opportunities which emerge from this study.

Availability of data and materials

De identified original interviews available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank all the patients who participated in the interview process. We would also like to thank Narelle Goldie, who transcribed the audio-recordings and Liz Briggs who assisted with patient recruitment.

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Suellen Anne Lyne, Fiona Mary Goldblatt & Ernst Michael Shanahan

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The manuscript has been read and approved by all the authors. Contributions for each author are as follows; S.A.L. responsible for participant recruitment, conducting interviews, data analysis through coding and authorship of article; F. M G. responsible for dual coding of interviews and co-authorship; E.M.S. who is the principal investigator, responsible for study design, patient recruitment, dual coding of interviews and co-authorship. The final manuscript has been read and approved by all authors.

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Lyne, S.A., Goldblatt, F.M. & Shanahan, E.M. Living with a frozen shoulder – a phenomenological inquiry. BMC Musculoskelet Disord 23 , 318 (2022). https://doi.org/10.1186/s12891-022-05251-7

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• Marta Karbowiak , trauma and orthopaedics core trainee 1 ,
• Thomas Holme , trauma and orthopaedics registrar 2 ,
• Maisum Mirza , general practitioner 3 ,
• Nashat Siddiqui , consultant orthopaedic and upper limb surgeon 2
• 1 Royal Hampshire County Hospital, Winchester, UK
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What you need to know

Patients with diabetes are at higher risk of developing frozen shoulder and having bilateral symptoms than the general population

Recovery times vary, but can be years, and some patients are left with residual pain or functional impairment

Physiotherapy is the most commonly used intervention and can be supplemented by intra-articular steroid injections

Treatments offered in secondary care include joint manipulation under anaesthesia, arthroscopic capsular release, and hydrodilatation

The UK FROST trial compared manipulation under anaesthetic, arthroscopic capsular release, and early structured physiotherapy with intra-articular corticosteroid injections, and found that none of the interventions were clinically superior

Frozen shoulder is a common and often debilitating condition that lacks a clear consensus on management, partly owing to a lack of high quality evidence on the various treatments options. In this clinical update, we offer an overview of the latest evidence on management of frozen shoulder, incorporating the clinical implications of recently published research, including the UK FROST study—the largest randomised controlled trial in this field to date, which compares surgical treatments with early structured physiotherapy and intra-articular corticosteroid injections.

What is frozen shoulder?

Frozen shoulder is a condition that results in development of thickened, fibrosed joint capsule, contraction of the joint, and reduced intra-articular volume. 1 The exact cause of these changes is unknown, with several possible processes suggested in the literature. 1 Over the years, uncertainty has surrounded the definition and classification of this condition, leading to inconsistencies in both clinical practice and scientific studies. 2 This is partially owing to the wide spectrum of clinical presentations, with patients experiencing different levels and combinations of symptoms. This also means their lives can be affected in many different ways, depending on the severity of the condition and their daily activities.

Who gets it?

The age of onset is usually in the fifth decade of life, with peak incidence between …

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• Original Paper
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• Published: 18 November 2020

The puzzling pathophysiology of frozen shoulders – a scoping review

• T. Kraal   ORCID: orcid.org/0000-0003-4377-6901 1 , 2 ,
• J. Lübbers 3 ,
• M. P. J. van den Bekerom 4 ,
• J. Alessie 5 ,
• Y. van Kooyk 3 ,
• D. Eygendaal 6 &
• R. C. T. Koorevaar 7  

Journal of Experimental Orthopaedics volume  7 , Article number:  91 ( 2020 ) Cite this article

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The pathophysiology of frozen shoulders is a complex and multifactorial process. The purpose of this review is to scope the currently available knowledge of the pathophysiology of frozen shoulders.

A systematic search was conducted in Medline, Embase and the Cochrane library. Original articles published between 1994 and October 2020 with a substantial focus on the pathophysiology of frozen shoulders were included.

Out of 827 records, 48 original articles were included for the qualitative synthesis of this review. Glenohumeral capsular biopsies were reported in 30 studies. Fifteen studies investigated were classified as association studies. Three studies investigated the pathophysiology in an animal studies. A state of low grade inflammation, as is associated with diabetes, cardiovascular disease and thyroid disorders, predisposes for the development of frozen shoulder. An early immune response with elevated levels of alarmins and binding to the receptor of advance glycation end products is present at the start of the cascade. Inflammatory cytokines, of which transforming growth factor-β1 has a prominent role, together with mechanical stress stimulates Fibroblast proliferation and differentiation into myofibroblasts. This leads to an imbalance of extracellular matrix turnover resulting in a stiff and thickened glenohumeral capsule with abundance of type III collagen.

This scoping review outlines the complexity of the pathophysiology of frozen shoulder. A comprehensive overview with background information on pathophysiologic mechanisms is given. Leads are provided to progress with research for clinically important prognostic markers and in search for future interventions.

Level of evidence

Introduction.

Frozen Shoulder (FS) is a common cause of shoulder pain associated with restricted active and passive range of motion. Although this condition has been recognized as a clinical disease entity for about 150 years, we still have not unraveled the pathophysiology yet. FS has often been described as a self-limiting condition, with recovery within two to three years for the majority of patients [ 1 ]. However, symptoms of mild to moderate pain and stiffness are reported in 27–50% of patients at long term [ 2 , 3 , 4 ]. Even in patients with a favorable natural course of the condition, there is still an extensive period to deal with pain, and functional limitations.

Current surgical interventions, such as manipulation under anesthesia or arthroscopic capsular release, are aimed at the advanced stage of the disease, when the fibrotic cascade has already had its effect. To optimize treatment the treatment of FS, it is of fundamental importance to get a better understanding of the pathophysiology. With advancing knowledge, it might become possible to intervene early on in the disease process.

The aim of this scoping review is to systematically collate the currently available knowledge that we have about the pathophysiology of FS. The histologic findings and the mechanism of tissue fibrosis on a cellular level are addressed. The purpose is to give and apprehensible overview which aids clinicians in the understanding of the pathophysiology and to translate this to clinical implications.

Materials and methods

A systematic search in Medline, Embase and the Cochrane library was conducted in all three databases on the fifth of October 2020. The search was build including the following terms; “frozen shoulder”, or (“shoulder” AND “adhesive capsulitis”), “pathophysiology”, (“etiology” or “aetiology”) and (“histology” or “anatomy and histology”). Publications had to be original papers published in English after the first of January 1994. The limit of 1994 was chosen since the techniques to analyze tissue samples of more than 25 years ago are most likely outdated and therefore not relevant anymore. Articles were eligible for inclusion if the there was a substantial focus on the pathophysiology of FS. All studies on tissue samples from FS patients were eligible for inclusion. Association studies between medical co-morbidities and FS were only eligible if the pathophysiologic mechanism between the investigated condition and FS was discussed. Basic science studies (in vitro or animal model studies) were eligible for inclusion if the aim of the article was to clarify the pathophysiology of FS. Reviews, case reports and imaging studies were excluded.

A number of 1088 potential relevant studies were identified in the searches. After removal of duplicates, titles and abstracts were screened from a total of 827 studies. A low threshold was used to verify if the full text articles included unique or relevant information on the pathophysiology of FS. This resulted in 48 original studies eligible for inclusion in the qualitative synthesis of this review. A PRISMA flow chart of the review process is presented in Fig.  1 . (Fig.  1 ).

PRISMA flow diagram

The 48 included articles are categorized by study design in three tables, in a chronological order. The most relevant finding for each article is given. Table one shows all 30 original articles wherein tissue samples from the glenohumeral joint were analyzed. These are mostly case control studies with a small number of patients. The controls were usually patients undergoing arthroscopy for different shoulder pathology like instability or rotator cuff surgery. The number of FS patients, controls, biopsy location and used method for tissue analysis is described for each study.(Table 1 ) Table two shows 15 association studies wherein the pathologic mechanism between a certain co-morbidity (e.g. diabetes, thyroid disorder) and FS is discussed. This includes studies investigating the association between FS and serum levels in peripheral blood, for example hormones, lipids or gene polymorphism.(Table 2 ) Table three displays three animal (rats) studies investigating the pathophysiologic pathways in FS in detail. (Table 3 ).

Patho-anatomy

The restriction in passive range of motion in FS is caused by a contracted glenohumeral capsule. The normal shoulder joint has a volume of at least 15 ml, and on average 20 ml [ 53 ]. In FS, the joint volume can be less then 5 ml [ 54 ]. Capsular stiffness is demonstrated in studies measuring intra-articular pressure while distending the capsule. Pressure volume curves show a much steeper rise in FS compared to controls and capsular rupture occurs in FS at a much lower volume with higher pressures compared to normal shoulders [ 55 , 56 , 57 ]. It has long been hypothesized that the rotator interval with the coracohumeral ligament (CHL) is involved in the pathophysiologic process of FS, and might have a pivotal role in the development of FS, and the rest of the joint capsule is involved later on in the process [ 58 , 59 , 60 , 61 ]. The CHL spans the extra-articular side of the rotator interval, is strained in external rotation, and release of the CHL is an important part of the surgical release of a FS [ 62 , 63 ]. Several other findings are reported in the literature that support a prominent role in the etiology of FS for the rotator interval. Ultrasound guided corticosteroid injections in the rotator interval and around the CHL had greater effect on pain and range of motion compared to intra-articular corticosteroid injections directed from posterior [ 61 ]. Fluorodeoxyglucose (FDG)-PET CT scans in FS demonstrate that FDG uptake is predominantly located in the rotator interval, anterior joint capsule and axillary recess [ 64 ]. Angiography studies identified neovascularization, branching of the thoracoacromial artery, in the rotator interval of FS patients [ 65 ]. Upregulation of proteins involved in collagen metabolism, cell adhesion and the immune response were identified in the rotator interval of FS patients [ 29 ]. The gliding mechanism of the biceps tendon sheat, the lateral border of the rotator interval, was involved to a variable degree [ 66 ].

Histologic findings

Several authors have studied biopsies of the rotator interval and glenohumeral capsule. Early in the disease process, inflammatory changes with subsynovial hypervascularity, synovial hyperplasia, and fibroblastic proliferation with an increased number of fibroblasts (fibroplasia) is found [ 5 ]. This is accompanied by the formation of new nerve fibers around small blood vessels. Neogangionesis is demonstrated by overexpression of hematopoietic cell marker, CD34, and vascular endothelial growth factor (VEGF) [ 9 ]. Neurogenesis is driven by an increased expression of nerve growth factor receptor p75 [ 19 ]. Besides nerve ingrowth, pro-inflammatory mediators upregulate the acid sensing ion channels that contribute to hyperalgesia [ 23 ]. Later on in the disease process, when stiffness is established, the signs of inflammation can disappear gradually [ 67 ]. In this stage, an increased number of differentiated fibroblasts into myofibroblasts are seen within an extracellular matrix (ECM) of densely packed disorganized type III collagen [ 6 ]. The increased number of contractile myofibroblasts can be picked up with alfa smooth muscle actin (α-SMA) staining, a marker for the differentiation of fibroblasts in myofibroblasts. It has been demonstrated that α-SMA staining is not that prominent yet in the early stage of the disease compared to a more mature FS [ 25 ]. To summarize, in the early stage of FS, inflammatory changes can be seen with synovial hyperplasia and subsynovial hypervascularity and neurogenesis. Whereas in the later stage inflammation usually disappears gradually and tissue fibrosis occurs with a high number of fibroblasts within an ECM of densely packed type III collagen. (Fig.  2 ).

Schematic drawing stages FS

The mechanism of tissue fibrosis

Imbalance in extracellular matrix turnover.

Fibroblasts are the primary resident cell type in connective tissues. Articular capsule consists of a thin inner synovial lining and an outer layer, which is a more fibrous layer of connective tissue. Fibroblasts are responsible for the production of the ECM, the “soil” in which the cells live and interact. Normally, type I and III collagen are the main proteins in the ECM of normal joint capsule. Type III collagen is the more immature molecule, derived from procollagen [ 11 ]. The turnover of ECM is regulated by fibroblasts together with enzymes such as Matrix Metallo Proteinases (MMPs). MMPs degrade abundant collagen and the level of activity of MMPs is counteracted by Tissue Inhibitor of Metallo Proteinases (TIMPs). The fibrotic effects of increased TIMP activity came to light when twelve patients were treated with Marimastat (British Bio- tech Ltd, Oxford, UK) , a TIMP analogue for the treatment of gastric carcinoma. Six patients developed bilateral frozen shoulders within four months [ 68 ]. The MMP/TIMP ratio has been shown to be almost ten times lower in FS patients versus healthy controls [ 37 ]. So, at least a part of the pathophysiologic process leading to fibrosis is a dysregulated collagen synthesis, in other words, an imbalance in ECM turnover.

Fibroblast contractility: the role of TGF-β1 and mechanical stress

Not only the abundancy of collagen, but also the contractility of fibroblasts in the ECM is a prerequisite to stiffening of the tissue. Myofibroblasts can contract by using a smooth muscle type actin/myosin complex. Vimentin, a cytocontractile protein and marker for contractility, has been shown to be overexpressed in capsular biopsies of FS patients [ 69 ]. Interestingly, although fibroplasia has been shown to occur in the entire joint capsule in FS, capsular contracture measured by vimentin staining was more pronounced anteriorly compared to posteriorly [ 70 ].

Transforming growth factor-β one (TGF-β1), and mechanical stress are two important factors contributing to contractility of fibroblasts [ 71 ]. TGF-β1, an inflammatory cytokine, is present in a lot of tissues throughout the human body, and can be secreted by parenchymal cells, epithelial cells, fibroblasts and by influxing immune cells [ 72 ]. The TGF-β1 signaling pathway is believed to have a central role in fibrotic diseases [ 51 , 73 ]. TGF-β1 has been shown to stimulate contractility of fibroblasts in-vitro collagen gels and can be seen as a potent activator of myofibroblasts [ 74 , 75 ]. The expression of TGF-β1 and its receptor is increased in biopsies of the joint capsule in FS patients [ 76 ]. Besides stimulating myofibroblast differentiation, TGF-β1 also influences ECM turnover by promoting collagen synthesis. Certain genetic variants of genes for the TGF-β pathway and MMPs could be identified as risk factors for the susceptibility of FS [ 49 ].

Besides chemical stimulation by cytokines like TGF-β1, mechanical stress is also an important factor in tissue fibrosis. Fibroblasts are mechano-responsive cells, which means that they can ‘sense’ mechanical stress in the ECM with their intracellular cytoskeleton, and their differentiation in to myofibroblasts is stress dependent. In-vitro studies showed that fibroblasts seem to have a threshold for mechanical stress which needs to be reached before they differentiate in to myofibroblasts [ 77 ]. Furthermore, mechanical stress has the ability to activate latent TGF-β1, hereby upregulating the process of tissue fibrosis. So, both mechanical stress and TGF-β1 are two important closely interrelated factors in the process of tissue fibrosis [ 78 ]. This process is actually a self-reinforcing process. When the tissue gets stiffer, tissue compliance decreases and the mechanical stress recorded by the fibroblasts increases inherently.

Chronic low-grade inflammation might predispose to the development of FS

Several authors have hypothesized an association with a chronic state of low grade inflammation which might predispose to the development of FS [ 79 ]. Several association studies support this theory [ 38 , 40 , 48 ]. Fasting serum cholesterol, triglycerides and plasma glucose levels are often elevated in FS [ 6 , 80 ]. Inflammatory lipoproteins such as LDL and non-HDL, associated with vascular inflammation and immune reactions, are known risk factors for atherosclerosis. However, these inflammatory lipoproteins have also been identified as independent risk factors for FS [ 48 , 81 ]. Vascular endothelial cell activation is accompanied by increased expression of intercellular adhesion molecule-1 (ICAM-1), a well-established marker of chronic inflammation. It has also been shown that ICAM-1 levels are elevated in the joint capsule and synovial fluid of FS patients compared to controls [ 82 ]. Similar to ICAM-1, is TIMP associated with chronic inflammation. Diabetes mellitus (DM), cardiovascular disorders and thyroid disorders are conditions associated with chronic inflammation and increased levels of similar pro-inflammatory cytokines as are found in FS. This is, at least partially, an explanation why DM and thyroid disorders are strong risk factors for the development of FS, and supports the theory of a chronic state of low-grade inflammation as a predisposing factor in the etiology of FS [ 83 ].

An early inflammatory response at the onset of FS

Traditionally, fibroblasts are known for their structural role in the synthesis and remodeling of ECM in connective tissue. However, fibroblast can also act like sentinel cells involved in immune responses, and thereby modulate the recruitment of immune cells and regulate their behavior [ 30 , 84 ]. A chronic inflammatory cell infiltrate with mast cells, macrophages, B- and T-cells has been shown to be present in rotator interval biopsies from FS patients [ 85 ]. Recent publications suggest that an immune response with an overexpression of inflammatory cytokines is one of the first steps in the development of a FS, preceding the cascade of tissue fibrosis [ 21 , 86 ]. Cytokines can regulate proliferation, activation and differentiation of fibroblasts, hereby dysregulating collagen synthesis [ 87 ]. Multiple studies have shown increased levels of pro-inflammatory cytokines such as TGF-β1, tumor necrosis factor-α (TNF- α), Interleukin-1 and -6 (IL-1, IL-6) and platelet derived growth factor (PDGF) in joint fluid and capsular tissue in FS [ 7 , 21 , 86 ]. Interestingly, increased levels of cytokines were also found in the subacromial bursa in FS patients [ 21 ]. When in-vitro cultured fibroblasts are stimulated with joint aspirates of FS patients, fibroblast proliferation was markedly elevated [ 36 ]. Furthermore, when fibroblasts were being activated, the inflammatory response was enhanced [ 88 ]. A recent study confirmed an elevated level of fibroblast activation markers in capsular tissue biopsies of FS patients compared to controls [ 30 ]. Persistent fibroblast activation is a potential cellular mechanism of symptoms of a prolonged frozen stage in FS.

Cytokine release and fibroblast activation is not the first step in the inflammatory response. Capsular biopsies of FS patients have shown elevated levels of several alarmins including High Mobility Group Box 1 (HMGB1) proteins, compared with controls [ 89 ]. Alarmins, or Damage-Associated Molecular Pattern (DAMP) molecules, are signal molecules released when cells are distressed, injured or ‘in danger’. Alarmins are the early activators of the immune system and have a role in amplifying the inflammatory response in many inflammatory conditions [ 90 ]. HMGB1 can be released into the ECM upon cell death or stress where it mediates an inflammatory reaction. In-vitro cultured human dermal fibroblast and lung fibroblasts stimulated by HMGB1 have been shown to produce more TGF-β1, thereby activating the TGF-β signaling pathway and subsequently significantly upregulate myofibroblast differentiation. And more, HMGB1 has the ability to bind to the receptor of AGE (Advanced Glycation End products) and to activate a pro-inflammatory response through the Nuclear Factor κB (NF-κB) pathway inducing TGF-β1 release [ 91 , 92 ]. Although an elevated level of alarmins in frozen shoulder capsular biopsies might be quite an aspecific finding, this is an indication that an inflammatory response has an important role at the onset of the pathophysiologic process of FS, triggering the inflammatory cascade leading to tissue fibrosis.

The implications of  hyperglycaemia in FS

The lifetime prevalence of FS in diabetic patients is with 10–30% much higher than 2–5% in the general population [ 93 , 94 , 95 ]. The higher the cumulative hemoglobin A 1c level, the higher the incidence of FS [ 96 ]. FS tends to be prolonged and more refractory to conservative treatment in diabetics [ 97 ]. The exact mechanism behind this is most likely multifactorial. Several authors have hypothesized an important role for AGEs. AGEs are formed by a process called non-enzymatic glycation when glucose forms covalent adducts with proteins, caused by oxidative stress. When AGEs bond to long-lived proteins they cannot be degraded by normal remodeling, and accumulate in connective tissue. This is a normal process which happens progressively with aging, can be slowed down by endurance training, but is accelerated in patients with DM [ 98 ]. A particular non-enzymatic ‘AGE’ reaction of interest is the alteration of collagen proteins by crosslinking [ 26 , 99 ]. Excessive levels of AGEs can lead to pathological collagen crosslinking and structural changes in the tissue, making the tissue less compliant [ 100 ]. The level of AGEs has been shown to be significantly higher in capsular tissue samples of FS patients compared to controls [ 26 ]. AGEs have also been shown to decrease the expression of MMPs and increasing TIMP expression in diabetic nephropathy, similar to the pathogenic mechanism of imbalance in ECM turnover in FS [ 101 ]. And more, it has been shown in diabetic retinopathy and nephropathy that AGEs accumulation can lead to an increased expression of basic fibroblast growth factor and upregulation of the expression of profibrotic cytokines as TGF-β1, PDGF and connective tissue growth factors [ 102 ]. It is hypothesized that these pro-fibrotic actions of AGEs also have their role in the pathophysiology of FS, and are part of the explanation why FS in diabetic patients have a tendency to be refractory [ 26 ].

It is outlined in this review that the pathophysiology of frozen shoulder is a rather complex process. It involves an early inflammatory response, production of pro-inflammatory cytokines, enhanced fibroblast proliferation, activation and differentiation into myofibroblasts, and an imbalance in ECM turnover with an abundance of disorganized collagen III deposition (Fig.  3 ). It is clear that there are a lot of factors involved, and we have most likely not identified all related factors yet. There are some important questions that remain unanswered.

Diagram pathophysiology of FS

What triggers the onset of a FS?

As with many diseases, it is still unclear what triggers the onset of the disease. Microtrauma has been suggested as a trigger, although this is hard to support with evidence [ 103 ]. With the identification of predisposing factors we do get a better understanding of the etiology. An increasing amount of evidence supports a chronic state of low-grade inflammation as an important predisposing factor for the development of FS [ 46 , 48 , 79 , 81 , 104 ]. Markers of chronic inflammation (ICAM-1, TIMP) are elevated in FS patients, and pro-inflammatory lipoproteins are significant risk factors for FS, similar to patients with cardiovascular disease or metabolic syndrome [ 48 , 82 ]. The incidence of FS is so much higher in patients with DM and thyroid disorders, since these conditions are associated with a chronic state of inflammation [ 20 , 83 ]. Even depressive personality traits are sometimes linked to FS, and depression is also associated with enhanced inflammatory cytokine levels [ 105 ]. It seems plausible that female hormones might be related in this context, since the peak incidence of FS is in perimenopausal women. However, a clear explanation, or a direct relationship between female hormones and FS was not found in the current literature.

Why only the shoulder?

How is it possible that FS is a condition unique for the shoulder without similar conditions in other joints? Pietrzak et al. hypothesized an evolutionary explanation [ 104 ]. The ability to throw accurately and forcefully is an important ability acquired during human evolution. Therefore, the shoulder is built for elastic energy storage and generation of maximal shoulder external rotation [ 106 ]. In our modern sedentary lifestyle without the need for throwing or overhead activities, parts of the anterior shoulder capsule and ligaments are probably not being exercised or stretched sufficiently. This makes the (anterior) shoulder capsule and ligaments probably more susceptible to oxidative stress, related to cytokine production and the formation of AGEs [ 104 ]. Although it is uncertain how much of this is true, this could potentially explain why FS is seen less frequently in manual laborers, and why the dominant side seems less likely to be involved [ 2 , 4 , 103 , 107 ].

It is debatable whether FS is truly unique to shoulders. Is the capsule of the shoulder so much different to that of other joints? The joint capsule has to be compliant and allows the widest range of motion of all our joints. Is this why shoulder fibroblasts are more ‘sensitive’ to inflammation or mechanical stress? There is some literature about a similar condition in hips, ankles and also knees. However, the currently available literature are mainly case reports of conditions seldomly seen in clinical practice [ 108 , 109 ]. Contractures with fibrosis do occur frequently mainly in knees and elbows, but without the potential for spontaneous recovery as FS has. We did try to find clues why and how the reversibility happens in FS, but we are not able to find an answer to this question. Apoptosis of the myofibroblasts is probably what occurs in the final stage of the condition, this is how they normally disappear from granulation tissue after wound healing [ 11 , 25 ].

Clinical implications and potential future treatment strategies

Physiotherapy and corticosteroids are the most widely used treatment modalities in FS. There is reasonable evidence for the use of intra-articular corticosteroids in the treatment of FS [ 110 ]. Corticosteroids have a general suppressive effect on the inflammatory response and hampers the differentiation of fibroblasts into myofibroblasts. Evidence of less α-SMA staining was found, indicating less myofibroblasts, in capsular biopsies in patients treated with corticosteroid injections compared to patients without corticosteroids [ 25 ]. One can also understand that the earlier in the disease process the corticosteroid injection is administered, the greater the effect on the clinical symptoms. Corticosteroids can suppress the inflammatory response, but they cannot reverse the fibrotic changes later on in the cascade. When administered in the frozen stage later on, the effect of corticosteroids is usually more temporarily [ 111 ].

The negative effect of physiotherapy including mobilization techniques beyond the threshold of pain early on in the disease is explained by the mechanosensitive properties of the fibroblasts [ 112 ]. It is hypothesized that the inflammatory response is probably sensitizing the fibroblasts more to mechanical stress. On the other hand, stretching exercises up to a tolerable level of pain resulted in an increase in MMP/TIMP ratio, hereby favoring collagen remodeling and was found to be superior to supervised neglect in the study of Lubis et al. [ 37 ] Some mechanical stress is apparently necessary for the remodeling of ECM, especially in the later stage of the condition. This is why tissue irritability, guiding treatment intensity, is implemented in physiotherapy guidelines for the treatment of FS [ 113 ].

More advanced treatment strategies have been suggested to intervene with the inflammation-fibrosis cascade in different ways. The TGF-β pathway was interrupted by silencing the Smad4 gene in rats with a FS induced by immobilization, through transfection with a lentivirus [ 51 ]. Smad proteins are mediators in the TGF-β signaling cascade. Silencing of this gene suppressed the TGF-β pathway, impairing the inflammatory response and myofibroblast differentiation. The rats with the silenced Smad4 gene had better shoulder range of motion and an increased joint volume compared to rats without Smad4 silencing [ 51 ]. Systemic inhibition of TGF-β might have unwanted side effects since it is also an important cytokine for connective tissue homeostasis involved in the proliferation epithelial cells, endothelial cells and immune cells [ 78 ]. However, TGF-β inhibitors with low toxicity is a field of intense research. There are now clinical trials with TGF-β inhibitors in cancer patients [ 114 ]. Glenohumeral intra-articular infiltration of a TGF-β inhibitor, hereby minimizing systemic effects, could perhaps be a promising suggestion to intervene early on in FS.

Calcitonin was more or less accidentally discovered as a treatment agent for FS when postmenopausal women with FS were treated with calcitonin for osteoporosis [ 33 ]. Their FS symptoms improved significantly after the use of a nasal calcitonin spray. Calcitonin is a hormone, secreted by the thyroid, known to inhibit osteoclast activity and lowering the kidney excretion of calcium. The presence of abundant calcitonin receptors in fibroblasts of the shoulder synovium and capsule could be confirmed with immunohistochemistry. Cultured fibroblast from FS patient stimulated with salmon calcitonin showed a significant decrease in the production of collagen type I and III. Synthesis of TGF-beta1 mRNA was suppressed by salmon calcitonin, and the adhesion ability of the fibroblasts decreased with if treated with salmon calcitonin. Apoptosis of the cultured fibroblasts could even be induced with high levels of salmon calcitonin. The efficacy of nasal calcitonin spray was demonstrated in a placebo controlled double blind randomized trial [ 115 ]. This might also explain why patients with thyroid disorders have an increased risk of FS, since hypothyroidism and auto-immune thyroiditis can be accompanied by calcitonin deficiency [ 116 , 117 ].

Intra-articular injections with human recombinant relaxin-2 is suggested as a potential agent for the treatment of FS [ 52 ]. Relaxin-2 is known because it is temporarily elevated to soften the cervix during child birth. In an animal study with in vitro cultured fibroblasts Relaxin-2 has been shown to up regulate MMP production, and to down regulate collagen production and expression of TIMP and TGFB-1. This results in a net breakdown of ECM proteins. Furthermore, Relaxin-2 seems to prevent fibroblast differentiation into myofibroblasts. The safety and efficacy still has to be investigated in a human clinical trial. Lee et al. suggested HMGB1 as a therapeutic target and Hinz et al. suggested to target the stress sensors of the fibroblasts, hereby rendering them blind for mechanical stress [ 78 , 91 ]. However, to what extend these options are realistic and safe options in the near future is unclear.

Limitations

The search strategy for this scoping review was designed to keep our scope wide to make sure that all available relevant articles are included. A limitation is that the main selection criteria for this scoping review (a substantial focus on pathophysiology of FS) is subjective. Furthermore, the pathophysiologic findings are dependent on the stage of the condition and most of the current research data comes from patients with a refractory frozen stage. To make progress in our understanding of the onset of FS, it might be necessary to include patients early on in the freezing stage in research with histological and immunological analysis.

Remarks for the future

There are some considerable clinical challenges for healthcare professionals dealing with FS patients. Based on just history and physical examination, it is impossible to predict what the natural course of a FS in an individual patient will be. This is relevant information, not only to inform the patient, but also for shared decision making on when to intervene. Research on prognostic factors for FS is surprisingly scarce. A worse prognosis can be expected in patients with DM and with severe symptoms on presentation [ 118 ]. Age over 60 has shown to be a favourable prognostic factor and gender is not correlated with the prognosis [ 97 ]. Immunological research seems crucial to get a better understanding of the individual variety in natural history of a FS. Perhaps immune composition in biopsies or biomarkers in synovial fluid can be used as prognostic factors to predict the natural course of FS. Collaboration of orthopedic surgeons with immunologists and rheumatologists is essential in order to move forward in this field of research.

Conclusions

The complexity of the pathophysiology of FS is outlined in this review. A state of low grade inflammation, as is associated with DM, cardiovascular disease and thyroid disorders, predisposes for the development of FS. An early immune response with elevated levels of alarmins such as HMGB1 and binding to the receptor of AGE starts the cascade of inflammation. Activation of the NF-κB pathway together with mechanical stress stimulates release of inflammatory cytokines, of which TGF-β has a prominent role. Fibroblasts proliferate, become activated and differentiate into myofibroblasts. This results in an imbalance of ECM turnover and a stiff and thickened glenohumeral capsule with abundance of type III collagen. Based on the pathophysiologic mechanism in FS it can be explained why intra-articular corticosteroid injections should be used early on in the condition and why the intensity of physiotherapy should be guided by tissue irritability. Leads are provided to progress with research for clinically important prognostic markers and in search for early interventions in FS.

Abbreviations

Acid sensing ion channel

Alfa smooth muscle actin

Advanced Glycation End products

Coracohumeral ligament

Damage-associated molecular pattern

Diabetes mellitus

Extracellular matrix

Fluorodeoxyglucose positron emission tomography/computed tomography

• Frozen shoulder

High density lipoprotein

High mobility group box 1

Intercellular adhesion molecule-1

Interleukin

Low density lipoprotein

Matrix Metallo Proteinases

Platelet derived growth factor

Rotator interval

Real time polymerase chain reaction

Transforming growth factor-beta

Tissue Inhibitor of Metallo Proteinases

Tumor necrosis factor alfa

Vascular endothelial growth factor

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Acknowledgements

This study was supported by ReumaNederland (grant 2019-1-675111)(JL).

One of the authors (JL) is financially supported by ReumaNederland (grant 2019–1-675111).

Costs of open access publication was supported by the Amphia Scientific Institute.

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Department of Orthopaedic Surgery, Amsterdam University Medical Centre, Amsterdam, the Netherlands

D. Eygendaal

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Each author believes that the manuscript represents honest work and that each author substantially contributed to the manuscript. TK is the initiator of this manuscript and drafted the manuscript. JL contributed substantially to this manuscript, mainly related to the immunological content and participated in the creation of the figures. MvdB contributed substantially to obtain all relevant articles for this review and revised the manuscript critically for important intellectual content. JA was involved in linking and translating the pathophysiological mechanisms to clinical relevant information for healthcare professionals. YvK revised the manuscript for important intellectual content. DE was involved in the conception of this work and revised the manuscript for important intellectual content. RK was involved in the conception of this work and initiated collaboration with the department of Molecular cell biology and Immunology. The authors read and approved the final manuscript.

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Kraal, T., Lübbers, J., van den Bekerom, M.P.J. et al. The puzzling pathophysiology of frozen shoulders – a scoping review. J EXP ORTOP 7 , 91 (2020). https://doi.org/10.1186/s40634-020-00307-w

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• Adhesive capsulitis
• Pathophysiology

• Patient Care & Health Information
• Diseases & Conditions
• Frozen shoulder

During the physical exam, a health care provider might ask you to move your arm in certain ways. This is to check for pain and see how far you can move your arm (active range of motion). Then you might be asked to relax your muscles while the provider moves your arm (passive range of motion). Frozen shoulder affects both active and passive range of motion.

Frozen shoulder can usually be diagnosed from signs and symptoms alone. But imaging tests — such as X-rays, ultrasound or MRI — can rule out other problems.

More Information

• Shoulder exercises

These exercises may improve your shoulder's range of motion. Let your arm hang down like a pendulum, and then gently swing it back and forth or in circles. Pretend your fingers are your feet and walk your fingers up a wall.

Most frozen shoulder treatment involves controlling shoulder pain and preserving as much range of motion in the shoulder as possible.

Medications

Pain relievers such as aspirin and ibuprofen (Advil, Motrin IB, others) can help reduce pain and inflammation associated with frozen shoulder. In some cases, a health care provider might prescribe stronger pain-relieving and anti-inflammatory drugs.

A physical therapist can teach you range-of-motion exercises to help recover your shoulder movement. Your commitment to doing these exercises is necessary to regain as much movement as possible.

Surgical and other procedures

Most frozen shoulders get better on their own within 12 to 18 months. For severe or persistent symptoms, other treatments include:

• Steroid injections. Injecting corticosteroids into the shoulder joint might help decrease pain and improve shoulder mobility, especially if given soon after frozen shoulder begins.
• Hydrodilatation. Injecting sterile water into the joint capsule can help stretch the tissue and make it easier to move the joint. This is sometimes combined with a steroid injection.
• Shoulder manipulation. This procedure involves a medication called a general anesthetic, so you'll be unconscious and feel no pain. Then the care provider moves the shoulder joint in different directions to help loosen the tightened tissue.
• Surgery. Surgery for frozen shoulder is rare. But if nothing else helps, surgery can remove scar tissue from inside the shoulder joint. This surgery usually involves making small incisions for small instruments guided by a tiny camera inside the joint (arthroscopy).
• Cortisone shots

Lifestyle and home remedies

Continue to use the shoulder and arm as much as possible given your pain and range-of-motion limits. Applying heat or cold to your shoulder can help relieve pain.

Alternative medicine

Acupuncture.

Acupuncture uses hair-thin, flexible needles put into the skin at certain points on the body. Typically, the needles remain in place for 15 to 40 minutes. The needles are not generally put in very far. Most acupuncture treatments are relatively painless.

Nerve stimulation

A transcutaneous electrical nerve stimulation (TENS) unit delivers a tiny electrical current to key points on a path that a nerve follows. The current, delivered through electrodes taped to the skin, isn't painful or harmful. It's not known exactly how TENS works. It might cause the release of molecules that curb pain (endorphins) or block fibers that carry pain.

Preparing for your appointment

You might first see your primary care provider. In some cases, you may be referred to a doctor who specializes in treating bones and muscles (orthopedist or physiatrist).

What you can do

Before your appointment, be prepared with:

• A complete description of your symptoms and when they began
• Information about medical problems you've had
• Information about the medical problems of your parents or siblings
• The names of all the medications and dietary supplements you take
• Questions to ask the health care provider

What to expect from your doctor

Be prepared to answer questions, such as:

• What worsens your symptoms?
• Have you ever injured that shoulder? If so, how?
• Do you have diabetes?
• Have you had recent surgeries or had to keep your shoulder still for a time?
• McMahon PJ, et al., eds. Sports medicine: Upper extremity. In: Current Diagnosis & Treatment in Orthopedics. 6th ed. McGraw Hill; 2021. https://accessmedicine.mhmedical.com. Accessed June 18, 2022.
• Frozen shoulder. American Academy of Orthopaedic Surgeons. https://orthoinfo.aaos.org/en/diseases--conditions/frozen-shoulder. Accessed June 14, 2022.
• Prestgaard TA. Frozen shoulder (adhesive capsulitis). https://www.uptodate.com/contents/search. Accessed June 14, 2022.
• Challoumas D, et al. Comparison of treatments for frozen shoulder: A systematic review and meta-analysis. JAMA Network Open. 2020; doi:10.1001/jamanetworkopen.2020.29581.
• Kim YJ. Acupuncture management for acute frozen shoulder: A case report. Clinical Case Reports. 2021; doi:10.1002/ccr3.5055.

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• Case report
• Open access
• Published: 31 August 2024

Ewing sarcoma presenting in the lung: a case report

• Mohammad Berro   ORCID: orcid.org/0009-0006-9630-2768 1 ,
• Abdulrahman Al Balkhi   ORCID: orcid.org/0009-0005-1405-3714 1 ,
• Yahia Ranjous   ORCID: orcid.org/0009-0005-1681-2198 1 ,
• Khalil Kashour 1 , 3 ,
• Mohamad Shbat 1 , 2 &
• Hussain Chaban 1 , 2  

Journal of Medical Case Reports volume  18 , Article number:  411 ( 2024 ) Cite this article

Metrics details

Ewing sarcoma is a malignant round-cell tumor that primarily affects bones in children. It can also arise in extraosseous tissues, such as the lung, kidneys, and liver. The presentation symptoms of Ewing sarcoma may include cough, dyspnea, and chest pain.

Case presentation

This report details the history of a 15-year-old Syrian boy with a previous diagnosis of Hodgkin lymphoma who presented with chronic shoulder pain. Imaging studies revealed an 80 mm mass in the apex of the left lung, which was confirmed through histopathological examination to be Ewing sarcoma following a computed-tomography-guided biopsy. The patient received multiple cycles of chemotherapy and subsequently underwent surgical resection of the remaining mass.

Conclusions

This case highlights the rare occurrence of Ewing sarcoma in the lung and the unusual clinical presentation of shoulder pain without other accompanying symptoms.

Peer Review reports

Ewing sarcoma (ES) is a rare small round-cell tumor originating from the neural crest, accounting for 10–15% of primary bone tumors and ranking as the second most common bone malignancy in children and adolescents [ 1 , 2 ]. Although ES primarily occurs in bones, it can manifest in various locations such as the lungs, kidneys, and liver [ 3 ]. The Ewing sarcoma family of tumors encompasses four different subtypes: Ewing sarcoma of the bone, peripheral primitive neuroectodermal tumor (pPNET), Askin tumor, and extraosseous Ewing sarcoma (EES) [ 4 ]. The occurrence rate of EES in pediatric cases with ES is 22%, with the thorax being the most prevalent location [ 5 ].

Primary Ewing sarcoma in the lung, first described by Hammar et al . in 1989, is a rare presentation for Ewing sarcoma, with around 55 cases reported in the last decade [ 6 , 7 ]. The clinical manifestations of pulmonary ES can vary widely, often presenting with symptoms such as dyspnea (54.3%), cough (55.3%), chest pain (50%), fever (17%), and hemoptysis (14.9%) [ 7 ]. To the best of our knowledge, only one case has reported shoulder pain accompanied by chest pain as a symptom for pulmonary Ewing sarcoma [ 7 , 8 ].

In this report, we present a case of a 15-year-old male pateint who experienced persistent shoulder pain for 7 months, without any other accompanying symptoms. Subsequent investigations unveiled the presence of an extraskeletal primary Ewing sarcoma in the lung.

In January 2023, a 15-year-old Syrian male patient presented with chronic shoulder pain for the past 7 months. The patient’s medical history revealed a previous diagnosis of Hodgkin lymphoma at the age of 7 years, for which he received chemotherapy treatment and was monitored for 5 years. Physical examination revealed dullness on percussion and decreased respiratory sounds at the apex of the left lung, without involvement of lymph nodes in the area. Computed tomography (CT) scan revealed the presence of an 80 mm mass at the apex of the left lung. On the basis of the latest information (tumor size 80 mm, intact lymph nodes, absence of metastasis), the tumor was classified as T2N0M0. Subsequently, a CT-guided needle biopsy was conducted on the left lung apex. The histology of the specimen showed necrosis and low metabolic activity in the tumor cells. On immunohistochemical staining, the tumor cells were diffusely positive for CD99 and negative for LCA and DESMIN. On the basis of these findings, the case was diagnosed as Ewing sarcoma/PNET. Chemotherapy treatment was initiated, and the patient received 14 doses, with the last one administered 6 weeks before the surgery.

A follow-up CT scan demonstrated improvement in the size of the mass (measuring 39 × 37 mm) compared with the previous scan (Fig.  1 ).

Thoracic computed tomography, illustrating the reduction in the size of the mass (measuring 39 × 37 mm)

Subsequently, a positron emission tomography (PET)-CT scan revealed an irregular density measuring 30 × 40 mm at the apex of the left lung with no metabolic activity. Therefore, the tumor was classified as T1N0M0. Consequently, in October 2023, a surgical procedure was performed to remove the mass, which had adhered to the first rib. Therefore, both the first and second ribs had to be excised (Fig.  2 ). Following the surgical intervention, the patient was transferred to the intensive care unit before being discharged from the hospital and sent home. After 5 months from the surgery, follow-up examinations showed metastasis to the left testicle. Therefore, a second surgery was performed, and the testicle was resected.

Microscopic examination of the resected mass, revealing inflammatory infiltrate, granulation tissue, fibrosis with abundant collagen, necrosis, and hemosiderin deposition

Ewing sarcoma is part of a tumor family that shares clinical and histological similarities. The two primary members of this family are Ewing sarcoma and peripheral primitive neuroectodermal tumors (PNETs). These tumors can be distinguished by their degree of neurological differentiation [ 9 ]. While Ewing sarcoma typically arises from bones, primary pulmonary Ewing sarcoma cases are rare and sparsely documented in medical literature [ 7 ]. Diagnosing Ewing sarcoma in the lung can be challenging due to its nonspecific symptoms, such as cough and dyspnea, which resemble those of other common diseases [ 10 ].

The use of fluorodeoxyglucose (FDG)-PET/CT has significantly improved tumor detection, including extraosseous Ewing sarcoma. FDG-PET/CT is highly effective in identifying rapidly enlarging masses, making it an invaluable investigative tool. However, it is essential to emphasize that pathological examination remains the primary diagnostic method, particularly immunohistochemical staining for CD-99 [ 8 ]. Pathologically, Ewing sarcoma is characterized by small round blue cells and scant eosinophilic cytoplasm. Immunohistochemical staining reveals a robust positive reaction for glycoprotein p30/32 (CD99). This protein, produced by the MIC2 gene, serves as a reliable marker for diagnosing Ewing sarcoma [ 11 ].

Intensive chemotherapy has shown promising outcomes as an adjuvant treatment before surgery, resulting in long-term survival rates of approximately 60–70%. However, recent studies have explored alternative approaches for refractory Ewing sarcomas. Among these options, pazopanib has emerged as a potential treatment when conventional therapies fail to achieve desired results [ 12 , 13 ].

After confirming the diagnosis, initiating chemotherapy is crucial to reduce tumor size. Subsequently, surgery should be performed to completely remove affected tissue due to the potential risk of tumor relapse [ 14 ].

Our case stands out due to the rare location of Ewing sarcoma in the lung and its unique presentation as shoulder pain without other accompanying symptoms. To the best of our knowledge, shoulder pain was only reported once by Ekin et al ., and it was accompanied by chest pain, unlike our case [ 7 , 8 ].

Although Ewing sarcoma/PNET tumors are primarily observed within bones, it is essential not to disregard them as potential differential diagnoses for masses occurring outside the bone, including the lungs. This consideration is particularly significant when assessing children and young adults. A comprehensive understanding of Ewing sarcoma/PNET disease and available diagnostic methods can help radiologists and clinicians accurately diagnose and effectively treat this highly malignant tumor. By remaining vigilant and considering Ewing sarcoma/PNET as a potential diagnosis, healthcare professionals can ensure prompt and appropriate management of patients affected by this condition.

Availability of data and materials

The laboratory tests and imaging results are available from the corresponding author on reasonable request.

Abbreviations

Computed tomography

Positron emission tomography

• Primitive neuroectodermal tumors

Fluorodeoxyglucose

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Berro, M., Al Balkhi, A., Ranjous, Y. et al. Ewing sarcoma presenting in the lung: a case report. J Med Case Reports 18 , 411 (2024). https://doi.org/10.1186/s13256-024-04749-z

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Assessing environmental and economic sustainability of fresh unpacked, fresh packed, and frozen carrots in austria: a case study with a life cycle assessment (lca) approach.

1. Introduction

2. materials and methods, 2.1. life cycle of carrots, 2.2. case study on austrian carrots, 2.2.1. store check.

• Country of origin: In Austrian supermarkets, 85% of the carrots are grown in Austria. In German supermarkets, 44% of carrots are grown in Germany.
• Carrot categories: Fresh packed carrots without green make up the biggest category, followed by frozen carrots and fresh unpacked carrots.
• Packaging material: A total of 75% of frozen carrots are packed in cardboard. Fresh carrots are mostly packed in plastic, especially in LDPE (n = 12) and bioplastic (n = 7) (if unspecified plastic is not considered). All carrots in bioplastic come from and are sold in Austria.
• Portion size: Frozen carrots are mainly sold in 300 g bags, while fresh carrots are sold in 1 kg bags.
• Storage duration: The mean storage duration until best before date for frozen carrots is 17 months. The average duration of fresh carrots until for sale is six days.
• Price: The option with the cheapest mean price is fresh packed carrots in LDPE at 1.52 EUR/kg, followed by carrots in bioplastic at 1.93 EUR/kg, and unpacked fresh carrots at 2.22 EUR/kg. Frozen carrots are the most expensive product, with a mean price of 7.01 EUR/kg.

2.2.2. Environmental Sustainability

2.2.3. goal and scope definition.

• Fresh unpacked carrots
• Fresh packed carrots in LDPE
• Fresh packed carrots in PLA
• Frozen carrots packed in cardboard

2.2.4. Life Cycle Inventory

2.2.5. Economic Sustainability

3. results and discussion, 3.1. environmental sustainability, 3.1.1. life cycle impact assessment.

• Climate change
• Resource use fossil

3.1.2. Classification of Results to Literature, Database, and Store Check

• Comparison of results for fresh carrots
• Comparison of results for frozen carrots

3.1.3. Cost Calculation for Transportation and Cooled Storage

4. conclusions, supplementary materials, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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Birkenmaier, F.; Schuchter, L.; Pillei, M.; Bach, K. Assessing Environmental and Economic Sustainability of Fresh Unpacked, Fresh Packed, and Frozen Carrots in Austria: A Case Study with a Life Cycle Assessment (LCA) Approach. Sustainability 2024 , 16 , 7513. https://doi.org/10.3390/su16177513

Birkenmaier F, Schuchter L, Pillei M, Bach K. Assessing Environmental and Economic Sustainability of Fresh Unpacked, Fresh Packed, and Frozen Carrots in Austria: A Case Study with a Life Cycle Assessment (LCA) Approach. Sustainability . 2024; 16(17):7513. https://doi.org/10.3390/su16177513

Birkenmaier, Franziska, Lucas Schuchter, Martin Pillei, and Katrin Bach. 2024. "Assessing Environmental and Economic Sustainability of Fresh Unpacked, Fresh Packed, and Frozen Carrots in Austria: A Case Study with a Life Cycle Assessment (LCA) Approach" Sustainability 16, no. 17: 7513. https://doi.org/10.3390/su16177513

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• J Can Chiropr Assoc
• v.44(3); 2000 Sep

Adhesive capsulitis: a case report

Adhesive capsulitis or frozen shoulder is an uncommon entity in athletes. However, it is a common cause of shoulder pain and disability in the general population. Although it is a self limiting ailment, its rather long, restrictive and painful course forces the affected person to seek treatment. Conservative management remains the mainstay treatment of adhesive capsulitis. This includes chiropractic manipulation of the shoulder, therapeutic modalities, mobilization, exercise, soft tissue therapy, nonsteroidal anti-inflammatory drugs, and steroid injections. Manipulation under anesthesia is advocated when the conservative treatment fails. A case of secondary adhesive capsulitis in a forty-seven-year-old female recreational squash player is presented to illustrate clinical presentation, diagnosis, radiographic assessment and conservative chiropractic management. The patient’s shoulder range of motion was full and pain free with four months of conservative chiropractic care.

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Selected References

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