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Medicine
The American Journal of Sports
http://ajs.sagepub.com/content/early/2015/10/13/0363546515605077
The online version of this article can be found at:
DOI: 10.1177/0363546515605077
published online October 13, 2015Am J Sports Med
Suzan de Jonge, Johannes L. Tol, Adam Weir, Jan H. Waarsing, Jan A.N. Verhaar and Robert-Jan de Vos
Tendinopathy but Is Not Associated With Symptoms: A Prospective Study
The Tendon Structure Returns to Asymptomatic Values in Nonoperatively Treated Achilles
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at Erasmus Univ Rotterdam on October 29, 2015ajs.sagepub.comDownloaded from at Erasmus Univ Rotterdam on October 29, 2015ajs.sagepub.comDownloaded from
The Tendon Structure Returns to
Asymptomatic Values in Nonoperatively
Treated Achilles Tendinopathy but
Is Not Associated With Symptoms
A Prospective Study
Suzan de Jonge,
*
yz
MD, PhD, Johannes L. Tol,
§||{
MD, PhD, Adam Weir,
||
MD, PhD,
Jan H. Waarsing,
y
PhD, Jan A.N. Verhaar,
y
MD, PhD, and Robert-Jan de Vos,
y
MD, PhD
Investigation performed at Department of Sports Medicine, The Hague Medical Center
Antoniushove, Leidschendam, the Netherlands
Background: Tendinopathy is characterized by alterations in the tendon structure, but there are conflicting results on the poten-
tial of tendon structure normalization and no large studies on the quantified, ultrasonographic tendon structure and its association
with symptoms.
Purpose: To determine whether the tendon structure returns to values of asymptomatic individuals after treatment with 2 sub-
stances injected within the tendon, to assess the association between the tendon structure and symptoms, and to assess the
prognostic value of the baseline tendon structure on treatment response.
Study Design: Cohort study; Level of evidence, 2.
Methods: This study was part of a randomized trial on chronic midportion Achilles tendinopathy using eccentric exercises with
either a platelet-rich plasma or saline injection. Symptoms were recorded using the Victorian Institute of Sports Assessment–
Achilles (VISA-A) questionnaire. The tendon structure was quantified with ultrasound tissue characterization (UTC); echo types
I1II (as a percentage of total tendon types I-IV) are structure related. Follow-up was at 6, 12, 24, and 52 weeks. A control
group of asymptomatic subjects (similar age) was selected to compare the tendon structure. Patient symptoms were correlated
with the tendon structure using a linear model.
Results: Fifty-four patients were included in the symptomatic group. The mean (6SD) echo types I 1II in the symptomatic group
increased significantly from 74.6% 610.8% at baseline to 85.6% 66.0% at 24-week follow-up. The result for echo types I 1II at
24 weeks was not significantly different (P= .198) from that of the asymptomatic control group (87.5% 66.0%). In 54 repeated
measurements at 5 time points, the adjusted percentage of echo types I 1II was not associated with the VISA-A score (main
effect: b= .12; 95% CI, –0.12 to 0.35; P= .338). The adjusted baseline echo types I 1II were not associated with a change
in the VISA-A score from baseline to 52 weeks (b= –.15; 95% CI, –0.67 to 0.36; P= .555).
Conclusion: In symptomatic, tendinopathic Achilles tendons, the ultrasonographic tendon structure improved during nonopera-
tive treatment and normalized after 24 weeks to values of matched asymptomatic controls. There was no association between the
tendon structure and symptoms. The percentage of echo types I 1II before treatment was not associated with change in symp-
toms over time. This study demonstrates that restoration of the tendon structure is not required for an improvement of symptoms.
Keywords: Achilles tendon; tendinopathy; ultrasound tissue characterization; injection therapy; eccentric exercise; VISA-A
Active, middle-aged patients frequently suffer from chronic
midportion Achilles tendinopathy, which is a degenerative
disorder with an altered tendon structure.
1,22
Ultrasonog-
raphy is commonly used to image tendon disorders and
can show hypoechoic areas and a disorganized tendon
structure.
5
One previous conventional ultrasonographic,
long-term follow-up study showed an improved tendon
structure and decreased thickness after treatment with
eccentric exercises.
24
However, conventional ultrasonogra-
phy is operator dependent as transducer handling and
machine settings can influence the results. Consequently,
with qualitative measurements, it may be difficult to accu-
rately evaluate changes in the tendon structure over time.
The American Journal of Sports Medicine, Vol. XX, No. X
DOI: 10.1177/0363546515605077
Ó2015 The Author(s)
1
AJSM PreView, published on October 13, 2015 as doi:10.1177/0363546515605077
at Erasmus Univ Rotterdam on October 29, 2015ajs.sagepub.comDownloaded from
Computerized ultrasound tissue characterization (UTC)
has recently been developed.
14,27,29
UTC is a standardized
technique that can quantify the Achilles tendon structure;
it has been successfully used to monitor tendon changes in
patients
8
and elite athletes.
27
Contrary to conventional
qualitative ultrasonography, intraclass correlation coeffi-
cient (ICC) and minimal detectable change (MDC) values
are reported for UTC.
8,10
Patients with symptomatic Achil-
les tendinopathy could be distinguished from asymptom-
atic individuals using mean tendon structure values
measured with UTC.
29
Early UTC was performed manu-
ally,
11,29
and this process was later developed to become
automatic.
8,12,14,27
Midportion Achilles tendinopathy is commonly treated
initially with an exercise protocol consisting of eccentric
exercises. Several systematic reviews have shown benefi-
cial clinical effects of a 12-week eccentric exercise proto-
col.
15,20,23
A small cohort study with manually performed
UTC procedures in 25 symptomatic patients showed no
improvement in the tendon structure 24 weeks after start-
ing a 16-week eccentric exercise program while there were
significant improvements in the functional outcome.
11
A
subsequent larger comparable study of 54 patients showed
that both the functional outcome and tendon structure
measured with a standardized, automatic UTC procedure
improved after eccentric exercises and an intratendinous
injection.
8,12
While there is a clear difference in the tendon structure
between patients with tendinopathy and asymptomatic
persons, there was no association between tendon struc-
ture changes and symptom severity in a small cohort in
which UTC was performed manually.
11
Also, in studies
using conventional ultrasonography as a prognostic tool
for patients with Achilles tendinopathy, there were con-
flicting results on the value of tendon structure abnormal-
ities.
3,4,19
As manually performed procedures might
contain measurement errors, and the only study on the
association between structural outcomes and symptoms
with UTC
11
was performed with a low number of patients,
the association between the tendon structure and symp-
toms remains uncertain. There are also no data on the
quantified tendon structure in nonoperatively treated
patients in relation to healthy persons. It remains
unknown if the tendon structure normalizes after treat-
ment, when measured with an automatic UTC procedure,
and if so, in which time frame this takes place.
This study had 3 aims. The first aim was to compare the
ultrasonographic tendon structure after treatment with
that in asymptomatic individuals to establish whether
the tendon structure can return to values that are compa-
rable with those of asymptomatic persons. The second aim
was to evaluate the association between the tendon struc-
ture and symptoms in a prospective clinical trial. The third
aim was to assess the prognostic value of the baseline ten-
don structure on the change in symptoms.
METHODS
Participants
Symptomatic Group
This prospective study was part of a double-blind, placebo-
controlled randomized clinical trial that was performed at
a sports medicine outpatient department in the Nether-
lands.
8,13
The study protocol was approved by the regional
medical ethics committee and registered with Clinical
Trials.gov (number NCT00761423). Inclusion criteria
were the presence of chronic, midportion Achilles tendin-
opathy (clinically diagnosed) for more than 2 months and
age of 18 to 70 years. Exclusion criteria were clinical suspi-
cion of other musculoskeletal disorders (insertional tendin-
opathy, tendon ruptures, inflammatory internal disorders,
or fluoroquinolone-induced tendinopathy); having previ-
ously undergone a complete, heavy-load eccentric exercise
program or being unable to undergo one; or a previous
injection with platelet-rich plasma (PRP).
13
Control Group
The control group consisted of asymptomatic individuals
previously tested for a reliability study, which was per-
formed in a mixed group of symptomatic and asymptomatic
individuals.
8
UTC images of asymptomatic tendons were
collected once from employees of the sports medicine depart-
ment (n = 4) and patients who visited the sports medicine
department for injuries that were not related to the lower
limb (n = 22). The inclusion criterion for the control tendons
was age between 18 and 70 years. Individuals were asked to
participate in the study for an evaluation of both their Achil-
les tendons if they had no history of Achilles tendon pain.
We also recorded height, weight, body mass index (BMI),
and preinjury Ankle Activity Score (AAS).
16
Procedures
The full details of the randomized study design have been
reported elsewhere.
13
Patients contacted the researcher
for an appointment at the sports medicine outpatient
department of The Hague Medical Centre. Eligibility was
evaluated by 1 experienced sports medicine physician.
Stratification was performed based on the preinjury activ-
ity level of the patients, for which we used the AAS.
16
To
*
Address correspondence to Suzan de Jonge, MD, Department of Orthopaedics, Erasmus Medical Centre, ‘s-Gravendijkwal 230, 3015 CE, Rotterdam,
the Netherlands (email: s.dejonge@erasmusmc.nl).
y
Department of Orthopaedics, Erasmus Medical Centre, Rotterdam, the Netherlands.
z
Department of Sports Medicine, The Hague Medical Center Antoniushove, Leidschendam, the Netherlands.
§
The Sports Physician Group, Department of Sports Medicine, St Lucan Andreas Hospital, Amsterdam, the Netherlands.
||
Department of Sports Medicine, Aspetar Orthopaedic and Sports Medicine Hospital, Doha, Qatar.
{
Academic Center for Evidence Based Sports Medicine, Academic Medical Center, Amsterdam, The Netherlands.
One or more of the authors has declared the following potential conflict of interest or source of funding: This trial was funded by Biomet Biologics LLC.
2de Jonge et al The American Journal of Sports Medicine
at Erasmus Univ Rotterdam on October 29, 2015ajs.sagepub.comDownloaded from
equalize the number of patients in both groups over time,
block randomization was performed.
Evaluations of symptom severity and UTC measurements
were performed directly after inclusion. The injection proce-
dure was performed after UTC scanning, and all patients
received instructions for the rehabilitation program.
Patients were randomized to the PRP group (PRP injec-
tion with eccentric exercises) or the placebo group (saline
injection with eccentric exercises). The treating sports medi-
cine physician, the researcher who collected the data and
performed the analysis, and the patients were all blinded
to group allocation. The injection was given by a single expe-
rienced sports medicine physician. The skin and subcutane-
ous tissue were anesthetized with a local injection of 2 mL
of 0.5% Marcaine (AstraZeneca BV). With use of a 22-gauge
needle, 4 mL of the fluid was injected under ultrasonographic
guidance (MyLab30; Esaote Pie Medical) via 3 puncture loca-
tions in the area of thickening and hypoechogenicity.
No exercise restrictions were given before inclusion and
the first UTC measurement. During the first 48 hours after
the injection, the patients were allowed to fully bear
weight and advised to walk only short distances. After 1
week, the exercise program was started with 1 week of
stretching exercises and afterward a 12-week, heavy-
load, eccentric calf muscle exercise program for both the
gastrocnemius and soleus muscles.
2
This program con-
sisted of 180 repetitions daily, and patients were advised
to perform the exercises regardless of pain. After 4 weeks,
a gradual return to sports activities was encouraged.
Outcome Measurements
VISA-A Questionnaire
The outcome measurements were recorded by 2 researchers
at baseline and 6, 12, 24, and 52 weeks after the injection.
The severity of symptoms was evaluated by the researcher
using the reliable, validated, and disease-specific Victorian
Institute of Sports Assessment–Achilles (VISA-A) patient-
reported outcome questionnaire,
26
which was the primary
outcome of the study.
13
The VISA-A was performed before
the UTC scan was performed to ensure that this result could
not influence the patients when completing this question-
naire. The questionnaire consists of 3 domains of pain, func-
tion in daily living, and sports activity.
9
The pain domain
(questions 1-3), the function domain (questions 4-6), and
the activity domain (questions 7 and 8) contribute to the
total score. The best possible score for the pain and function
domains is 30 points and 40 points for the activity domain.
Ultrasound Tissue Characterization
The complete mechanisms of UTC have previously been
described in the literature.
14,27,29
In this experiment,
UTC Imaging version 2009 (UTC Imaging BV) was used.
The patients were examined in a prone position with the
affected leg placed in a holding device, thereby ensuring
standardized ankle dorsiflexion of 15°. The UTC measure-
ments were executed with a 5- to 10-MHz linear array
transducer (Terason 2000 with Smartprobe 10L5; Teratech
Corp). To prevent motion of the transducer, it was held in
a frame, which was clamped in the holding device. This
transducer was placed in a transverse position to the Achil-
les tendon and moved automatically from proximal to dis-
tal with a constant speed using an automatic driving
mechanism. The transducer moved automatically along
and perpendicular to the long axis of the Achilles tendon
over a distance of 12 cm. This custom-designed tracking
and data collection device provided digital transverse
images at consistent distances of 0.2 mm. These images
were stored on a computer, and subsequently, a 3-
dimensional data block could be made with use of these
images. The processing of contiguous transverse images
assisted in distinguishing 4 different echo types: types I
and II are generated from a single ultrasound reflection
that typically belongs to 1 interface structure and therefore
represents more (echo type I) or less (echo type II) orga-
nized tendon bundles.
12,28
Echo types III and IV are gener-
ated by multiple reflections that interfere as a consequence
of multiple interfaces that characterize a smaller, disorga-
nized, and fibrillar (echo type III) or amorphous (echo type
IV) tendon matrix, which has been described in the histo-
pathological picture of tendinopathy.
1
The Achilles tendon border was identified in the gray-
scale image at the thickest part in the anterior-posterior
direction. This procedure was also executed at 0.75 and
1.5 cm proximal and distal from the segment of maximum
thickness, resulting in 5 bordered segments within 3 cm.
The contours were automatically interpolated, and subse-
quently, the tendon volume was analyzed within 3 cm of
its length. We quantified the dynamics of gray levels of cor-
responding pixels in contiguous images over a distance of 9
consecutive images (1.6 mm). The proportions of the 4 dif-
ferent echo types within this volume could be calculated.
To ensure that the same part of the tendon was evaluated
at each follow-up moment, the distance from the thickest
part to the calcaneal bone was calculated and used for
follow-up evaluations.
Two trained researchers performed all UTC scans and
could establish the outcomes (combined scanning and anal-
ysis of the images) with excellent reliability.
8
The ICC for
interobserver reliability was 0.89, with a mean difference
of 0.9%.
8
The MDC of the automatic procedure was 7%
for echo types I 1II and III 1IV; 8% for echo type I;
and 4% for each of the echo types II, III, and IV.
10
An expe-
rienced researcher, blinded to the clinical outcome, deter-
mined whether the UTC scans could be included in the
final analysis. UTC scans with artifacts that potentially
could influence the measurements were excluded.
Statistical Analysis
The normality of distribution of the data was tested with
the Kolmogorov-Smirnov test. To evaluate between-group
differences in the mean echo types I 1II in the symptom-
atic and asymptomatic groups, an independent-samples t
test was used in case of normal distribution of the data.
Associations between the measurements of the VISA-A
scores (including the 3 different domains) and echo type I
1II at the different time points were evaluated using a linear
mixed model with repeated measurements. Adjustments
Vol. XX, No. X, XXXX Ultrasonographic Tendon Structure in Tendinopathy 3
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were made for the variables that influenced the outcome with
P\.10 and for multiple comparisons (Bonferroni) when
applicable. bcoefficients and 95% CIs were displayed for
important associations to estimate the strength of the associ-
ation. In linear regression models, bcoefficients were used in
the equation Y=a1(b1*X1) 1(b2*X2) 1(b3*X3). The
VISA-A scores were set as a dependent factor, and echo types
I1II was included as a covariate. To determine the associa-
tion between changes in the VISA-A score and early changes
in echo types I 1IIorthebaselinepercentageofechotypes
I1II, a univariate linear general model was used. To ana-
lyze the association between changes in the VISA-A score
and the baseline percentage of echo types I to IV as indepen-
dent predictors, a multivariate linear general model was
used. Statistics was performed using SPSS version 21.0.1
(SPSS Science), and significance was assumed when Pvalues
were \.05.
RESULTS
Participants
Patients were included from August 2008 to January 2009,
and the last follow-up was in January 2010. A flow dia-
gram of the progress of the study participants has been
published previously.
8
The baseline patient characteristics
are presented in Table 1.
No patients were lost to follow-up during the study. All
patients received the injection at baseline. No significant
differences were found in the VISA-A score between the
PRP and placebo groups at any time during follow-up.
The mean (6SD) compliance with the exercise program
was 72.8% 622.6%. Between baseline and 24 weeks, no
additional treatments were used. After 24 weeks, 5
patients decided to undergo another treatment because of
failure to improve. One patient received 2 additional treat-
ments. The additional treatments included extracorporeal
shockwave therapy (n = 3), glyceryl trinitrate patches
(n = 2), and orthotics (n = 1).
Twelve UTC scans (4%) could not be used for final anal-
ysis for several reasons: skin problem resulting in artifacts
(n = 5; from 1 patient), bad scanning technique (n = 4), data
lost with transmission (n = 1), reverberation artifact (n =
1), and failure to attend the scanning appointment (n = 1).
The group of asymptomatic individuals was included
from June to August 2009. There were no significant differ-
ences in age, sex, and AAS between the asymptomatic
group and symptomatic group at baseline, but the asymp-
tomatic group had a significantly lower BMI (Table 1). All
data were normally distributed, and therefore, between-
group differences were evaluated with a simple ttest.
UTC Echo Types
Changes Over Time in the Symptomatic Group
Combined Echo Types I 1II. The mean echo types I 1II
increased significantly over time (P\.001). From baseline,
there was a significant increase at each time point. The
mean increment in echo types I 1II from baseline to
6 weeks was 7.4% (95% CI, 5.0%-9.9%; P\.001), to 12
weeks was 7.5% (95% CI, 4.3%-10.7%; P\.001), to 24
weeks was 10.9% (95% CI, 8.5%-13.2%; P\.001), and to
52 weeks was 7.8% (95% CI, 4.7%-10.8%; P\.001). From
6 to 12 weeks, there was no change (P= .100); from 12 to
24 weeks, the increase was significant (P= .012); and
from 24 weeks to 52 weeks, there was again no change (P
= .131). Figure 1 shows the increase in echo types I 1II.
Single Echo Types. Mean echo types I and II increased
significantly over time (P= .005 and P\.001, respectively).
ThemeanechotypeIincreasedsignificantlyby5.8%(95%
CI, 3.0%-8.6%) from baseline to 52 weeks, and the mean
echo type II increased significantly by 2.0% (95% CI, 0.7%-
3.3%)frombaselineto52weeks.EchotypesIIIandIVboth
decreased significantly (both P\.001). Echo type III
TABLE 1
Characteristics and Outcome Variables at Baseline in the Symptomatic and Asymptomatic Groups
a
Symptomatic Group (n = 54) Asymptomatic Group (n = 26) PValue
Age, mean 6SD, y 49.7 68.7 51.4 613.6 .514
Sex, n (%) .076
Male 26 (48) 18 (69)
Female 28 (52) 8 (31)
Body mass index, mean 6SD, kg/m
2
26.5 63.7 24.9 62.3 .042
Duration of symptoms, median (IQR), wk 32 (16-78) — —
Active in sports, n (%) 46 (85) 24 (92) .367
Preinjury Ankle Activity Score (0-10), mean 6SD 5.7 61.8 5.8 62.0 .066
Echo types, mean 6SD, %
I 48.6 68.0 62.7 65.6 \.001
II 26.0 65.1 24.8 63.5 \.268
III 14.3 65.6 6.7 62.8 \.001
IV 11.1 65.6 5.6 63.4 \.001
I1II 74.6 610.8 87.5 66.0 \.001
Maximum tendon thickness, mean 6SD, mm 9.8 62.5 6.5 61.0 \.001
a
There were no significant between-group differences in the matching criteria (age, sex, and activity level), but there was a significantly
lower body mass index in the asymptomatic group compared with the symptomatic group. IQR, interquartile range.
4de Jonge et al The American Journal of Sports Medicine
at Erasmus Univ Rotterdam on October 29, 2015ajs.sagepub.comDownloaded from
decreased by 3.8% (95% CI, 2.2%-5.8%) from baseline to 52
weeks and type IV by 3.9% (95% CI, 2.4%-5.3%). The change
in the different echo types is displayed in Figure 2.
Comparison Between the Symptomatic
and Asymptomatic Groups
At baseline, there was a significant difference in the mean
echo types I 1II between the symptomatic and asymptom-
atic groups, with a mean difference of 12.9% (95% CI, 8.3%-
17.4%; P\.001) in favor of the asymptomatic group. At 6-
and 12-week follow-up, the mean echo types I 1II was still
significantly different from the asymptomatic group, with
a mean difference of 5.3% (95% CI, 2.0%-8.7%; P= .002)
and 5.5% (95% CI, 1.6%-9.5%; P= .007), respectively. At
24-week follow-up, there was no significant difference
between the symptomatic and asymptomatic groups, with
a mean difference of 1.9% (95% CI, –4.8% to 1.0%; P=
.198). At the last follow-up time point of 52 weeks, there
was a significant difference between the symptomatic and
asymptomatic groups, with a mean difference of 4.9%
(95% CI, 0.7%-9.1%; P= .023) in favor of the asymptomatic
group. Figure 3 shows the comparison in structure-related
echoes (echo types I 1II) between the symptomatic and
asymptomatic groups.
VISA-A Score
Changes Over Time in the Symptomatic Group
The mean VISA-A score increased significantly and linearly
over time (P\.001). From baseline, there was a significant
increase at each time point. The increase in the mean
VISA-A score from baseline to 6 weeks was 6.3 points (95%
CI, 1.5-11.0; P= .010), to 12 weeks was 9.8 points (95% CI,
4.4-15.2; P= .001), to 24 weeks was 21.1 points (95% CI,
15.1-27.1; P\.001), and to 52 weeks was 28.2 points (95%
CI, 22.5-33.9; P\.001). Figure 1 shows the increase in the
VISA-A score.
Association Between the VISA-A Score and
Echo Types I 1II in the Symptomatic Group
Overall VISA-A Score
The 270 repeated measurements from baseline and differ-
ent follow-up moments were used to establish the associa-
tion between the VISA-A score and the percentage of echo
types I 1II (Figure 4). Variables that influenced these
VISA-A scores with P\.10 were sex (women had lower
VISA-A scores; P\.001) and preinjury AAS (a higher
AAS was associated with a higher VISA-A score; P=
.080), and these were included in the model. In this linear
mixed model, the percentage of echo types I 1II was not
associated with VISA-A scores (main effect: b= .12; 95%
CI, –0.12 to 0.35; P= .338). There were also no significant
associations between the VISA-A score and echo type I
(main effect: b= .09; 95% CI, –0.18 to 0.35; P= .523),
echo type II (main effect: b= .24; 95% CI, –0.35 to 0.83;
P= .420), echo type III (main effect: b= –.09; 95% CI,
–0.51 to 0.33; P= .672), and echo type IV (main effect:
b= –.35; 95% CI, –0.87 to 0.16; P= .179).
Pain, Function, and Activity Domains of the VISA-A Score
Potential associations were also evaluated between the 3
different domains of the VISA-A score and the percentage
of echo types I 1II. Sex (negative influence of female
sex) influenced the pain domain (P\.001), function
domain (P= .009), and activity domain (P= .002) of the
Figure 1. Change in the mean Victorian Institute of Sports
Assessment–Achilles (VISA-A) score (severity of symptoms)
and mean echo type I 1II (percentage of structure-related
echoes) over time in the symptomatic group. Both the
VISA-A score and echo type I 1II increased significantly
over time. Error bars denote SDs.
Figure 2. Change in mean echo types I to IV over time in the
symptomatic group. Echo types I and II increased signifi-
cantly over time, and echo types III and IV decreased signif-
icantly. Error bars denote SDs.
Vol. XX, No. X, XXXX Ultrasonographic Tendon Structure in Tendinopathy 5
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VISA-A score. The preinjury AAS positively influenced the
activity domain of the VISA-A score (P= .011). These var-
iables were therefore included in the model.
The adjusted echo types I 1II were not significantly
associated with the pain domain (main effect: b= .04;
95% CI, –0.02 to 0.11; P= .211), function domain (main
effect: b= .07; 95% CI, –0.02 to 0.16; P= .109), or activity
domain (main effect: b= .06; 95% CI, –0.08 to 0.21; P=
.373) of the VISA-A score. There were no significant asso-
ciations between the separate echo types and the subdo-
mains of the VISA-A score (data not shown).
Association Between Baseline Echo Types I 1II
and Change in the VISA-A Score
The adjusted baseline echo types I 1II was not signifi-
cantly associated with a change in the VISA-A score from
baseline to 52 weeks (b= –.15; 95% CI, –0.67 to 0.36; P=
.555). Adjustments were made for duration of symptoms
and the baseline VISA-A score (both negatively influenced
a change in the VISA-A score; P\.001). The change in
echo types I 1II from baseline to 6 weeks (P= .878),
12 weeks (P= .793), and 24 weeks (P= .978) was also
not related to a change in the VISA-A score from baseline
to 52 weeks after adjustment.
Baseline echo types I (P= .125), II (P= .270), III
(P= .485), and IV (P= .720) were also not significantly
associated with a change in the adjusted VISA-A score
from baseline to 52 weeks in a univariate model. In the
multivariate model with echo types I to IV included, there
was no significant association with a change in the VISA-A
score (P= .201).
DISCUSSION
This largest prospective study examining Achilles tendin-
opathy with automated UTC to date shows that the tendon
structure returns to values of matched asymptomatic con-
trols within 24 weeks. However, no association between
symptoms and the quantified, ultrasonographic tendon
structure was found. The quantified tendon structure at
baseline did not predict a change in symptoms over time.
These findings are important because ultrasonographic
measurements are frequently used clinically, and the
results are thought to provide information about disease
severity or prognosis.
3,4
A previous smaller study using conventional ultraso-
nography also found no association between the tendon
structure and symptoms; however, these findings were
limited because of a potential influence of transducer han-
dling.
19
However, 2 other studies that used conventional
ultrasonography showed that worse tendon structure
abnormalities are associated with a worse clinical out-
come.
3,4
In our previous prospective, observational study
on the effects of eccentric exercises on the tendon structure
in 25 patients with chronic Achilles tendinopathy, there
was also no correlation between symptoms and the tendon
structure that was measured with UTC.
11
Furthermore,
the baseline percentage of echo types I 1II did not corre-
late with a change in symptoms. The limitations of that
study were the small number of patients, with some lost to
Figure 3. Change in the mean echo types I 1II (percentage
of structure-related echoes) over time in the symptomatic
group compared with the asymptomatic group. The data of
the asymptomatic group were collected with a cross-
sectional design, with the aim to compare asymptomatic val-
ues to symptomatic values. At baseline and 6 and 12 weeks,
there was a significant difference in the mean echo type I 1II
between the symptomatic and asymptomatic groups (*);
however, at 24-week follow-up, there was no longer a signif-
icant difference. At 52 weeks, there was again a significant
difference in the mean echo type I 1II between the symp-
tomatic and asymptomatic groups (*). Error bars denote
SDs; dashed lines are representative of the upper and lower
limits of the SD in the asymptomatic group.
Figure 4. Scatter plot of Victorian Institute of Sports
Assessment–Achilles (VISA-A) scores (severity of symptoms)
and echo type I 1II (percentage of structure-related echoes)
at baseline and different follow-up time points (P= .338 after
adjustment).
6de Jonge et al The American Journal of Sports Medicine
at Erasmus Univ Rotterdam on October 29, 2015ajs.sagepub.comDownloaded from
follow-up, and manually performed UTC. This manual pro-
cedure might have caused larger variations in the distribu-
tions of the echo types, which is also reflected in the SDs of
the change from baseline to 24 weeks (SD of 13% in the
previous study vs 8% in the present study). We previously
showed that this manually performed procedure can be
evaluated with high interobserver reliability,
29
but we
only studied the reliability of image analysis after collec-
tion, and the manual procedure was not evaluated for reli-
ability. With an automatic UTC machine and evaluation
with different statistical tests to adjust for possible varia-
bles of influence, we still found no association between
the quantified tendon structure and symptoms in patients
with Achilles tendinopathy. No association between the
subdomains of the VISA-A score (measuring pain, function,
and activity) and structure could be found either.
The lack of association between the degree of structural
abnormalities and patients’ symptoms is not unique to ten-
dinopathy; radiographic changes in patients with knee
osteoarthritis also exhibit a discordance between pain lev-
els and joint space narrowing.
17
It is possible that there is
a missing link between pain and the degree of tendon
structural disorganization on imaging. The role of bio-
chemical agents that could contribute by irritating nocicep-
tors in close proximity to the tendon is interesting in this
field. A systematic review already showed that the periph-
eral neuronal phenotype is altered in tendinopathy.
7
Also,
central sensitization might play a role in the long-standing
experience of pain.
25
Future research in this area might
provide more information on the source of pain.
The fact that the baseline quantified tendon structure
did not predict a change in symptoms is clinically relevant.
This means that a symptomatic Achilles tendon with
severe structural abnormalities on ultrasound may have
the same clinical outcome as a tendon with only mild ultra-
structural changes. We also found an initial improvement
in the quantified tendon structure not to be associated
with an improvement in symptoms. Thus, an improvement
in the tendon structure in the initial phases during and
after nonoperative treatment is also not of prognostic
value. It is therefore questionable if ultrasonography is of
additional value in the evaluation of midportion Achilles
tendinopathy because the diagnosis can be accurately
established clinically.
21
In this study, we found a significant improvement in the
tendon structure over time, which is in contrast with a pre-
vious study using a manually performed UTC procedure.
11
There are a few possible explanations for this discrepancy.
It could be possible that the injection procedure, regardless
of the substance given within the tendon, improved the
structure. Another possibility is that the participants
between both studies differed, as the previous study was
conducted in an academic setting. It may also be because
of the small number of patients and large variations in
the manually performed UTC measurements in our previ-
ous study.
11
Automatic UTC was performed in 2 other
studies in which a better tendon structure was found.
14,27
This may be because of the younger age of the participants,
different regions scanned, or better resolution of the ultra-
sound transducer.
The eccentric exercises in the present study may also
have resulted in positive effects on the tendon structure
in symptomatic patients. Ohberg et al
24
previously
reported that eccentric training improved the tendon
structure on conventional ultrasonography at long-term
follow-up in patients with Achilles tendinopathy. Using
qualitative analysis, they demonstrated an improved
structure at 3.8-year follow-up. We showed that quantified
ultrastructural improvements were measurable earlier
and with a linear progression. The study design makes it
impossible to assess if the injections, eccentric exercises,
or a normal progression over time caused this improve-
ment. While a meta-analysis showed alterations in tendon
stiffness and cross-sectional area in asymptomatic partici-
pants performing eccentric exercises,
6
no data are avail-
able on tendon structure changes.
Between 24 and 52 weeks, echo types I 1II decreased
nonsignificantly (3.1% 68.7%). A possibility is that this
was caused by the lack of treatment in most of the patients
between 24 and 52 weeks. Only 5 patients decided to
undergo any other treatment for their injury.
8
It could
also be a change in the measurement error, as the MDC
for echo types I 1II was 7%.
10
Our study found that the tendon structure normalized
within 24 weeks after treatment to become comparable
with asymptomatic controls with a similar age, sex, and
sports activity. It is important to mention that the mean
VISA-A score of the patient group at this time point was
86.2 66.0, and patient satisfaction was only 60%.
13
This
again emphasizes the absence of an association between
the tendon structure and symptoms. It is therefore ques-
tionable whether future therapies should focus primarily
on achieving an improved tendon structure in patients
with tendinopathy.
There are a few potential limitations of our study. The
first is related to imaging as we could not obtain 4% (n =
12) of the UTC data. In half of the cases, this was caused
by patient-related issues and the other half because of
technical errors. Another disadvantage for this study is
the development of the UTC machine. Since completion
of this study, the machine’s properties have been further
developed, and more recent studies have been conducted
with a newer machine with a higher resolution and 2
more standardized procedures.
14,27
In these recent studies,
MDC values ranging from 0.3% to 0.9% for the different
echo types were reported.
27
This could be the result of
improved machine settings but also because the majority
of the included participants were healthy athletes (causing
less variability of data) or because these researchers
decided to correlate the gray values over 25 consecutive
transverse images
14,27
versus 9 consecutive images in
the first publications.
11,12,29
Standardization of this pro-
cedure is needed to compare the different studies
adequately.
The second limitation is that the power analysis of this
study was based on the difference in the primary outcome
measure (VISA-A score) between 2 treatment groups.
13
As
post hoc power analyses are discouraged,
18
we decided to
display the associations with bcoefficients. To demon-
strate the value of these associations, we provide an
Vol. XX, No. X, XXXX Ultrasonographic Tendon Structure in Tendinopathy 7
at Erasmus Univ Rotterdam on October 29, 2015ajs.sagepub.comDownloaded from
example for the association between baseline echo types
I1II and change in the VISA-A score from baseline to
52 weeks. For this association, the equation of the linear
regression model was as follows: change in VISA-A score
= 62.2 1(–0.08 *duration of symptoms)1(–0.36 *baseline
VISA-A score)1(–0.15 *baseline echo types I 1II). For
example, if an athlete with 20 weeks’ duration of symptoms
and a baseline VISA-A score of 40 points has baseline echo
types of 60% and 70%, the mean predicted change in the
VISA-A score would be 37.2 and 35.7, respectively. This
equation emphasizes that large differences in baseline
echo types result in merely small changes in the clinical
outcome over time. While this study might be underpow-
ered to draw definite conclusions on the individual predic-
tion of change in symptoms based on the baseline echo
types, this model demonstrates that differences in baseline
echo types are not sufficient for symptom prediction. There
are probably other unknown variables that influence the
change in symptoms. Future studies could include
strength measurements to correlate with UTC echo types.
A third potential limitation is that these findings may
not be generalizable to other tendinopathy locations. The
Achilles midportion is a suitable location to establish a clin-
ical diagnosis without concomitant bursal injuries. Future
well-designed studies should be conducted to investigate
whether these results could be extrapolated to other ten-
dinopathy locations. Furthermore, the use of UTC as
a screening tool could still be valuable. A recent study
showed a transient change in UTC echo types in asymp-
tomatic Achilles tendons as a result of an Australian foot-
ball game.
27
Whether this has a prognostic value could be
an interesting topic for future research in a large group of
athletes.
The strengths of this study were the relatively large
number of patients included, for which we performed
repeated measurements with a low number of those lost
to follow-up; the fact that UTC was performed with stan-
dardized procedures and high reliability; an independent
evaluation of the UTC procedure and VISA-A score; and
ability to compare the results obtained in patients to
asymptomatic individuals.
This prospective study using reliable, quantitative
ultrasound measurements and a validated, patient-related
outcome score in symptomatic, chronic Achilles tendinop-
athy and matched asymptomatic controls had 3 important
findings. The mean percentage of the ultrasonographic
tendon structure improved during nonoperative treatment
and attained values that are comparable with those of
asymptomatic tendons at 24 weeks. Second, the degree of
alteration in the ultrasonographic tendon structure was
not associated with symptoms at any point in time. Third,
there was no prognostic value of the baseline ultrasono-
graphic tendon structure. These results should be con-
firmed in larger studies with newer UTC machines that
provide better test characteristics. Given the absence of
a clinical association or prognostic ability, the interpreta-
tion of ultrasonographic alterations for individual patients
with midportion Achilles tendinopathy in daily clinical
practice is challenging.
ACKNOWLEDGMENT
The authors thank Biomet Biologics LLC for its support of
this study, the patients for their participation, and the
health professionals for referrals. They also thank some
coworkers of this study, who were not compensated for
their efforts. The authors are grateful for the logistical
help of Cora van der Heijden, Ank de Vries, and Pauline
Verschoor (Department of Sports Medicine, The Hague
Medical Centre, The Hague, the Netherlands).
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