1 UMEÅ UNIVERSITY MEDICAL DISSERTATIONS New Series No 860 – ISSN 0346 – 6612 – ISBN 91 – 7305 – 536 - 0 From the Department of Radiation Sciences, Diagnostic Radiology, and the Department of Surgical and Perioperative Sciences, Sports Medicine, Umeå University, Sweden The chronic painful Achilles tendon Sonographic findings and new methods for treatment by Lars Öhberg Umeå 2003
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UMEÅ UNIVERSITY MEDICAL DISSERTATIONS New Series No 860 – ISSN 0346 – 6612 – ISBN 91 – 7305 – 536 - 0
From the Department of Radiation Sciences, Diagnostic Radiology,
and the Department of Surgical and Perioperative Sciences, Sports Medicine,
Umeå University, Sweden
The chronic painful Achilles tendon Sonographic findings and new methods for treatment
by
Lars Öhberg
Umeå 2003
2
Department of Radiation Sciences, Diagnostic Radiology
Umeå University
901 85 Umeå
Sweden
Department of Surgical and Perioperative Science, Sports Medicine,
• US and colour Doppler guided sclerosing therapy of neovessels in chronic
painful mid-portion Achilles tendinosis seems to have a potential to cure the
pain in the short- term perspective.
43
Paper IV:
Sclerosing therapy in chronic Achilles tendon insertional pain-results of a
pilot study
Aim
To use US and colour Doppler guided sclerosing therapy to destroy the neovessels
and most likely also nerves accompanying the vessels, but not addressing any
treatment to the tendon, bursae, or bone, would affect chronic Achilles tendon
insertional pain in order to receive a pain relieve.
Material and Methods
Eleven patients with chronic insertional Achilles tendon pain were treated by US
and colour Doppler guided injections of Polidocanol against the neovessels
entering the Achilles tendon from the anterior aspect. All patients had distal tendon
pathology, 9 patients also had retrocalcaneal bursitis, and 4 patients had tendon
pathology, retrocalcaneal bursitis, and calcaneal bone pathology (spurs, bone
fragments). The effect on pain during Achilles tendon loading activity was
evaluated using VAS.
Main results
Before treatment, all tendons showed thickening, structural abnormalties (hypo-
echoic areas and irregular structure), and neovessels in the distal Achilles tendon.
Nine cases also had neovessels in close relation to the abnormal retrocalcaneal
bursa, and four cases also had bony spurs, calcifications, or loose bone fragments
in the tendon insertion. Before treatment, the mean VAS-score (pain during tendon
loading activity) was 84 (range 64-100). After the treatment the mean VAS-score
of the successfully treated patients (8/11) was decreased to 14 (range 3-40), and in
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the three poor cases to 58 (range 49-74). Among the 3/11 patients that not were
satisfied with the treatment, two had bone pathology.
Conclusion
• US and colour Doppler guided sclerosing therapy of neovessels in chronic
Achilles tendon insertional pain seems to have a potential to cure the pain.
Paper V:
Effects on neovascularisation behind the good results with eccentric training
in chronic mid-portion Achilles tendinosis?
Aim
To use grey-scale US and colour Doppler technique to prospectively investigate if
eccentric calf-muscle training might have an effect on the neovessels demonstrated
in chronic painful mid-portion Achilles tendinosis.
Material and Methods
In this prospective study 30 patients (45 tendons) with chronic painful mid-portion
Achilles tendinosis, were included. All tendons were examined with high-
resolution grey scale US combined with colour Doppler, before and after a 12
weeks eccentric calf-muscle training regimen (Alfredson et al. 1998).
Main results
Before treatment, there was local neovascularisation in the region with tendon
changes (hypo-echoic areas, irregular fibre structure) in all tendons.
45
At follow up after treatment, there was a good clinical result in 40/45 tendons, and
a poor result in 5/45 tendons. In 39/40 tendons with a good clinical result of
treatment there was a normal tendon structure, and in 36/40 tendons there was no
remaining neovascularisation. In 5/5 tendons with a poor result of treatment a
remaining neovascularisation was seen, and in 2/5 tendons there were remaining
structural abnormalities.
Conclusions
• In patients with chronic painful mid-portion Achilles tendinosis, a good
clinical result after treatment with eccentric training seems to be associated
with a “normalised” tendon structure and no remaining neovascularisation.
• Dynamic US and colour Doppler examination demonstrated direct effects
on the neovessels (the flow stopped) during the eccentric load.
Paper VI
Is vasculo-neural ingrowth the cause of pain in chronic Achilles tendinosis?
- An investigation using US and colour doppler, immuno- histochemistry, and
diagnostic injections
Aim
To study the possible importance of neovascularisation in chronic Achilles tendon
pain, by evaluating the combined findings from grey-scale US and colour Doppler
examinations, immunohistochemical analyses of biopsies, and the results of
diagnostic injections.
46
Material and Methods
In this study, 25 Achilles tendons in 24 patients with chronic mid-portion Achilles
tendinosis, and 20 tendons in 14 healthy controls with no history of Achilles tendon
pain, were included.
All tendons were examined with grey-scale US combined with colour Doppler. In
all patients with painful tendinosis, under US and colour Doppler guidance, a local
anaesthetic was injected in the area with neovascularisation outside the anterior
part of the tendon.
In 6 patients, biopsies was taken from the region with tendon changes and
neovascularisation were processed for PGP 0.5 (a general nerve marker)
immunohistochemistry.
Main results
In all tendons with painful tendinosis, but not in any of the pain-free normal
tendons, there was a neovascularisation inside and outside the anterior part of the
region with structural tendon changes.
The pain during tendon loading activity was temporarily cured in all tendons, and
the mean VAS-score for heel-raises decreased significantly from 75 to 6 mm
following injection of local anaesthetic. The immunohistochemistry of the biopsies
showed nerve structures in the vicinity of blood vessels.
Conclusion
• Colour Doppler examination showed a region with neovascularisation in
close relation to the region with structural tendon changes, and findings
from the injection of local anaesthetic support that the neovessels in the
region might be the source of pain in chronic mid-portion Achilles
tendinosis.
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Discussion
Chronic Achilles tendinosis is a most often painful condition with un-known
aetiology and pathogenesis, commonly seen among middle aged recreational
athletes (Kvist 1994, Tuite et al. 1997, Åström 1997, Movin 1998, Alfredson and
Lorentzon 2000). Overuse has been suggested to be the primary causative factor,
but the condition is also seen in physically non-active individuals (Åström 1997,
Fahlström et al. 2003). The background to pain in chronic Achilles tendinosis has
not been clarified (Khan et al. 2000b). For many years, despite the absence of
inflammatory cell infiltrates in tendon tissue samples, an inflammatory component
was considered to be involved. However, recent studies using microdialysis
technique and gene technology have clarified that there is no chemical
inflammation involved in the chronic stage of painful mid-portion Achilles
tendinosis (Alfredson et al.1999 and 2003). Instead, microdialysis studies showed
high levels of the neurotransmitter glutamate and lactate in painful tendinosis
tendons compared with pain-free normal Achilles tendons (Alfredson et al. 1999
and 2002). Glutamate is a well-known and potent modulator of pain in the human
central nervous system, but had never before been identified in tendons. The
possible role of glutamate or lactate in the pain mechanisms in painful tendinosis
has not been clarified, but is focused in present research projects at the Sports
Medicine Unit in Umeå, Sweden.
Chronic painful Achilles tendinosis has been known to be difficult to treat, but
recently a specially designed painful eccentric calf-muscle training regimen has
demonstrated to give very good clinical results (Alfredson et al. 1998, Mafi et al.
2001, Fahlström et al. 2003). The mechanisms behind the good results achieved
with this method are not known, and development of methods suitable for
prospectively studies of the tendons subjected to this treatment have been of high
priority. US is well known to be a good tool for investigations of tendons. Grey-
scale US has been shown to be a good and cost-effective method for examination
of the Achilles tendon (Åström et al. 1996), and a high reliability to locate
structural tendon abnormalities, such as tendinosis (Paavola et al. 1998). Grey scale
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US alone has been used in most scientific studies evaluating Achilles tendon
problems. During the last years, there has been a rapid development of the US
techniques, with successively improved spatial resolution. Furthermore, Colour
Doppler sonography is an established technique to study blood flow in main
arteries and veins, and in tumours, Theodorou et al. (2003), Muller et al. (2001).
Today it is possible to study blood flow, in vivo, in very small vessels. Altogether,
these technical developments have increased the information about the pathology
in the chronic painful Achilles tendon. In Paper I, grey-scale US was used to
study tendon thickness and structure before and after treatment with eccentric calf-
muscle training. The results showed that in the majority of the successfully treated
patients the tendon thickness had decreased significantly, and the tendon structure
looked “normalised”. Consequently, it seems that the eccentric training regimen
has a potential to “normalise” the structural changes in the tendon, or at least is a
part of a process leading to an US evaluated normalised tendon. In this study, due
to practical reasons, the follow-up was performed 3-5 years after the 12 weeks
eccentric training regimen. However, after 3 months of training the majority of
patients were pain-free during Achilles tendon loading activity, indicating early
effects on the pain mechanisms. In Paper I, we focused on patients with the
combination chronic pain in the mid-portion of the Achilles tendon and
corresponding structural tendon changes demonstrated with US. However,
structural changes have also been demonstrated in the proximal part of pain-free
patellar tendons (Khan et al. 1997, Cook et al. 2000a+b and 2001, Fredberg and
Bolvig 2002). Furthermore, a spindle-shaped thickening in the mid-portion of the
Achilles tendon has been shown not to correlate with tendon pain during activity
(Fredberg and Bolvig 2002). It should be stressed that only thickness, not structural
changes was, evaluated in that study. Fredberg and Bolvig (2002) followed a small
group soccer players during one Danish soccer season, and found that only 5/11 of
the tendons with a local thickening became symptomatic during the season. Also,
in 4/11 of the asymptomatic tendons, the tendon thickness normalized during the
season. Altogether, it seems that the findings of a spindle shaped thickening or
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structural changes alone, not combined with pain during tendon loading activity,
should be evaluated with caution and not render any specific treatment.
All our patients with chronic pain in the Achilles tendon are routinely examined
with grey-scale US. Colour Doppler examination (CDV-technique), was in Paper
II added to the grey-scale US. In consecutive patients referred for examination of
chronic mid-portion Achilles tendon pain, we found a local neovascularisation
inside, and outside the ventral part of the region with structural tendon changes in
28/28 tendons. In 20/20 pain-free tendons, there was a normal tendon structure and
no local neovascularisation. There are only a few studies where CDV or CDE has
been used to study tendons (Weinberg et al.1998, Terslev et al. 2000, Richards et
al. 2001, Khan et al. 2003, Peers et al. 2003, Zanetti et al. 2003). In the studies by
Weinberg et al. (1998) and Terslev et al. (2000), US together with CDVor CDE,
was used to study patellar tendinosis. Both studies showed structural tendon
changes and neovessels in patients with jumper’s knee. Terslev (2000) showed that
there was not always a positive correlation between pain symptoms and US
findings. There were 4/14 asymptomatic patients with both structural changes and
neovessels. Recently, CDV or CDE has been used to study chronic painful
conditions in the Achilles tendon, and in a study by Peers et al. (2003), 22/25 of the
chronic painful tendons with structural changes had a neovascularisation. Six
patients with chronic painful Achilles tendons demonstrated a proliferation of
vessels shown by power Doppler, and structural abnormalities demonstrated by
both standard US and MRI (Richards et al. 2001),. The findings in their studies, a
neovascularisation in the tendons with structural changes and pain, are in line with
the findings in our study. However, Khan et al. (2003) and Zanetti et al. (2003) did
not find any correlation between the occurrence of neovascularisation and pain, in
their studies on patients presenting with Achilles tendinopathy and Achillodynia.
An explanation of the different results might be differences between the patient
groups in the two studies. All patients in our study had structural tendon changes
on US corresponding to a painful swelling localised in the mid-portion of the
Achilles tendon, while only 37/57 tendons in the study by Khan et al. (2003), and
35/55 tendons in the study by Zanetti et al. (2003) had structural changes in the
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tendons. To be included in our studies, it was not enough to have pain in the
Achilles tendon (tendinopathy, Achillodynia), instead, there needed to be structural
tendon changes on US corresponding to the painful region in the mid-portion of the
tendon. It might be that the patients with “tendinopathy” and “Achillodynia” with
normal US structure of the tendon had other diagnoses. Furthermore, in the study
by Khan et al. (2003) MRI showed that in only 19/34 symptomatic tendons were
there structural changes. This, again, raises the question about the diagnosis, since
MRI is a very sensible method to show pathologic changes in tendons. Another
important parameter to have in mind when evaluating studies using US and
CDV/CDE is the influence of imaging technique. As an example, the position of
the probe is very important since a wrong position of the probe might cause
anisotropy, showing low echogenic regions, even when the tendon structure is
normal. Another important factor is the importance of having relaxed calf muscles
when the examination is performed, since a contraction of the muscles will reduce,
or even stop the flow in the neovessels.
The findings in our study raised questions because most commonly
neovascularisation has been considered to be a positive part of the healing response
(Leadbetter et al. 1992, Ferrara 1999). On the other hand, these patients had had a
long duration of pain symptoms, and if this neovascularisation was a part of the
normal healing response it seems that it was not good enough to cure the pain. How
can the neovascularisation be explained? It is likely that something in the region
with structural tendon changes (tendinosis) is triggering vascular ingrowth. In a
recent study by Pufe et al. (2001), hypoxia and growth factors were possible
stimulators of neovascularisation in cultured rat tenocytes. Interestingly, Alfredson
et al. (2002) have recently demonstrated high levels of lactate in Achilles tendons
with chronic painful tendinosis, compared to normal pain-free Achilles tendons.
Therefore, theoretically, hypoxia might potentially stimulate neovascularisation in
chronic Achilles tendinosis. Also, the high concentrations of glutamate
demonstrated in chronic painful Achilles tendinosis tendons (Alfredson et al.
1999), might possibly be a trigger for vascular ingrowth.
51
To evaluate the importance a local neovascularisation had for chronic pain in the
Achilles tendon, in Paper VI, we combined the findings from US and CDV
examinations, immunohistochemical analyses of biopsies, and the results of
injections of a local anaesthetic. We found that if local anaesthetic was injected
locally against the neovessels entering the structurally changed Achilles tendon, the
patients were temporarily pain-free during heel raises. Furthermore, using the pan-
neuronal marker PGP 9.5 immunohistochemistry on biopsies taken from the region
with structural tendon changes, nerve structures were demonstrated in the vicinity
of blood vessels. This was not an unexpected finding, as it is well known that
nerves usually “travels with” blood vessels. From this study it was concluded that
there is a vasculo-neural ingrowths in the structurally changed part of the tendon
that possibly can explain the pain suffered from chronic painful mid-portion
Achilles tendinosis tendons.
In Paper III the hypothesis that the region with neovessels (vessels +
accompanying nerves) is responsible for the pain was evaluated by, US and CDV
guided injection of the sclerosing substance Polidocanol to destroy the neovessels.
The injections were given in very close relation to the neovessels in the region
anterior of the ventral part of the tendon where the vessels entered the region with
structural tendon changes. The immediate effect was a closure of the vessels
entering the tendon. After the injection the patients were temporarily pain-free
because of the anaesthetic effect of Polidocanol. The results at the 6-months
follow-up showed that after a mean of 2 injections (treatments), the majority of the
patients were satisfied and had no Achilles tendon pain during tendon loading
activity. US and CDV examination showed that these patients had no remaining
neovessels inside the region with structural tendon changes. In patients with
remaining tendon pain during activity, remaining neovessels were seen. These
results indicating that the neovessels and accompanying nerves have a crucial role
in the pain mechanism. However, the follow-up was short, the group of patients
was small, and there was no control group. Recently, a 2-year follow-up of these
patients showed that the same 8 patients were still pain-free and satisfied, and had
no neovessels. Furthermore, the tendon structure was normalised (non-published
52
material). We have now treated more than 70 patients (1-5 injections/treatments
with the sclerosing agent Polidocanol) with chronic painful mid-portion tendinosis,
and about 80 % of the patients are satisfied and pain free. Also, we have a present
ongoing randomised blinded study evaluating the results of injections of a
sclerosing or a non-sclerosing substance.
So far only 1/70 patients have suffered from any complication possibly related to
the sclerosing injections. It was a patient who sustained a total Achilles tendon
rupture at the end of an 800 meter race, six weeks after his second injection. The
rupture was localised in the proximal part of the tendon, not in the distal part were
he had received the injections. Theoretically, if the treatment causes an impaired
local vascularity in the tendon there might be an increased risk for tendon injury.
However, the neovessels might not be a part of the normal circulation, but instead
be considered as “pathological”. Furthermore, the injections are given outside the
tendon, under US and CDV, and only a small region is injected. The trauma using
sclerosing injections is minimal compared to surgical treatment, where excision of
tendinosis tissue or multiple longitudinal incisions is performed. Follow ups are
continuously performed on all treated patients. Furthermore, we routinely take
biopsies from the tendinosis tissue and the tissue surrounding the tendon in patients
who have had a poor result of injections and are treated surgically. Preliminary
results of two cases (the only cases that have needed surgical treatment during the
last two years) that each had received 5 injections of Polidocanol, showed minor
atrophy in the fat tissue on the ventral side of the tendon.
By using grey-scale US and CDV, we found neovessels entering the tendon from
the ventral side, also in patients with chronic pain in the Achilles tendon insertion.
In some patients there were also vessels in relation to an enlarged and
pathologically changed retrocalcanel bursa. Treatment of this condition is known to
be difficult, and often there are difficulties to decide if the treatment should be
addressed to the tendon, bursae, bone, or all these tissues in combination. In a
small non-controlled pilot-study (Paper IV), we tested the hypothesis that it was
the region with neovascularisation in the insertional part of the Achilles tendon that
was source of the pain. As described in Paper III, US and CDV guided injections
53
of the sclerosing agent Polidocanol were given towards the region with neovessels
entering the ventral surface of the tendon. The results showed that sclerosing the
region with neovessels outside the pathologically changed Achilles tendons, close
to the bursal walls and bone (spurs, calcifications, fragment), allowed the majority
of these patients to return to pain-free tendon loading activity. Absence of
neovessels after treatment correlated well with reduced pain from the Achilles
tendon insertion. In a few patients with tendon, bone, and bursal pathology in
combination, there was remaining pain in the tendon insertion after treatment.
These patients had remaining neovessels. In one patient with remaining pain after
treatment, there were no remaining neovessels, but a loose bone fragment.
Naturally, it is unlikely that this therapy would help patients with considerable
bone pathology causing mechanical problems, such as large spurs or loose bone
fragments. The results are interesting, but studies on larger groups of patients are
needed to be able to draw any conclusions on what type of distal pathology this
therapy might be best suited. Anyhow, the results again indicate that the region
with neovessels is involved in the pain mechanism, and submits additional
information of importance for decisions about treatment of this chronic condition.
In Paper V, the primary aim was to use grey-scale US and CDV technique to study
the occurrence of a neovascularisation before and after treatment with eccentric
training, and to relate the findings to the clinical results of the treatment, in patients
with chronic painful mid-portion Achilles tendinosis. For that study, observations
in Paper II was of significant importance. During the US and colour Doppler
examination, passive dorsiflexion in the ankle stopped the flow in the neovessels.
This finding raised questions whether the good clinical effects demonstrated with
painful eccentric training might be due to effects on the region with
neovascularisation? In Paper V, the results showed that before treatment there was
a local neovascularisation in the region with tendon changes in all tendons. At
follow-up after treatment, there was a good clinical result (no tendon pain during
activity) in 90 % of the tendons, and a poor result in 10 % of the tendons. In the
majority of the tendons with a good result, there was no remaining
neovascularisation, but in a few tendons a minor neovascularisation remained. In
54
all tendons with a poor result there was a remaining neovascularisation in the
tendon. Altogether, these findings again indicate that the region with
neovascularisation might be the source of pain in this condition. It is difficult to
explain exactly how the eccentric exercises may influence on the region with
neovessels, but a possible explanation might be the repeated occlusion of the
vessels during the heel-drop. The vessels travel from the soft fatty tissue anterior to
the Achilles tendon, into the hard tendinosis tissue, and there might possibly be a
“breaking point” between the soft and hard tissues. Theoretically, during the
“eccentric heel drop”, when the tendon is stretched, there might possibly be a
mechanical trauma to the neovessels and accompanying nerves. It is tempting to
believe that the severe local pain these patients experience in the region with
tendinosis during the period with eccentric training, especially during the first 2
weeks of treatment, might be due to interference with nerves accompanying the
neovessels.
55
Conclusion
Sonographic methods (grey-scale US and CDV) have provided important
information about the chronic painful Achilles tendon, leading to a better
understanding of the pain mechanism, as well as to a new treatment method.
However, since the methods are sensible to investigator technique, it is
fundamental to stress the importance of an experienced radiologist. The
neovascularisation demonstrated by colour Doppler, found in close relation to the
region with structural tendon changes that was demonstrated by grey-scale US, has
been demonstrated to be a very likely source of pain in the chronic painful Achilles
tendon. Treatment with US and CDV guided sclerosing injections of the region
with neovascularisation has shown promising short-term clinical results.
56
Acknowledgements
I would like to thank all who have contributed to this thesis and specially:
Håkan Alfredson, my friend and my tutor who really have encouraged me in my
work with my thesis. He also stimulates me to look forwards towards new exciting
research projects. We also have had much laughter together when we have worked
together with the project.
Katrine Riklund-Åhlström, my friend and colleague, who has supported me in my
writing, and encouraged me to work more with research.
Ronny Lorentzon, my friend, for his help and advices.
Christer Holmgren and Esa Åkerman, my friends and colleagues at the ultrasound
section, who have had a heavy burden in their work with the never ending
ultrasound queue, and therefore have made it possible for me to work with my
thesis.
Birgitta Lundström, who has given me technical support when we have performed
our examinations. Doris Fagerlund och Zara Nilsson-Nordensvärd, who have made
the work possible at the ultrasound section. There is no day without a laugh!
Everyone at the department of diagnostic radiology for help and support.
Finally I thank my wife Elna and my sons, Fredrik, Claes, Henrik and Anders, and
also, of course, my grandchild Oscar and his mother Helena, for all support during
all the years.
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