Diagnostics of Fluoroquinolone-associated Tendon Pain
November 3, 2023
Symptoms of fluoroquinolone-induced tendinopathy
Fluoroquinolone-associated tendon symptoms have been documented in a time frame ranging from 2 hours to 6 months after exposure.1,2,3 This means that symptoms do not have to occur immediately. While it is estimated that 50-75% of those affected show symptoms within 48 hours, there is also a significant proportion for whom it takes several weeks or months (or the symptoms steadily increase over the time frame). Where this latency comes from is difficult to say. Possibly, in the area of the tendon under physiological activity, due to the limited regenerative capacity after exposure to Cipro, Levaquin & Co, micro-tears/traumas regularly occur, which then lead to pathology over time.
The decisive symptom is pain upon exertion in the area of the affected tendon. However, this pain can also subside during the load and only occur (more strongly) afterwards. With time and further activity, the pain becomes greater and sports activities are more and more limited. Eventually, even light activities are painful or the pain is present even at rest. Another typical symptom is a “feeling of stiffness” or “decreased elasticity” of the tendon in the morning before getting up or after immobilization.3,4 It is often emphasized in the consultation that the tendons feel completely different, as if they are like a piece of “rotten wood”. There is often isolated pain without classic signs of inflammation such as hyperthermia, redness, and swelling. Compared to the frequency of tendon pain, ruptures occur rather rarely. Out of 100 people in consultation with tendon complaints, more than 50% suffer from moderate to very severe, restrictive tendon pain. In contrast, a rupture that has occurred is anamnestically found only in a small number of affected persons (approx. 5%).
Ultrasound and MRI are the most common imaging performed on patients with tendon pain. MRI or diagnostic ultrasound may be helpful for diagnosis as well as the severity of tendon disease.2
Sonographic studies of tendon disorders caused by fluoroquinolones can reveal typical degenerative changes in the tendon such as thickening and hypoechogenicity.2
However, often the findings from imaging do not match the clinic, i.e., the patient’s symptomatology. This also occurs in other musculoskeletal conditions, such as osteoarthritis or disc herniation. Up to 59% of tendons with pathological changes, such as the presence of blood vessels (neovascularization), thickening of the tendon with increased water content, and disorganization of the collagen fibers are clinically silent, i.e. do not cause any symptoms.5
Overall, this means that not all pathology on imaging is the cause of pain. Likewise, an unremarkable tendon on imaging may be the cause of pain.
One theory for pain in tendon disease is neovascularization which is often associated with the sprouting of nerve fibers. However, there are also studies that have shown that neovascularization can be present in asymptomatic tendons. The conclusion was that the blood vessels formed as well as nerve fibers are not the primary cause of pain.1,2
Thus, the painful tendon should not be defined by local tissue changes alone, but should be considered in the context of the interaction between the local tissue and the peripheral and central nervous systems.5
Imaging has a completely different importance: the diagnosis of pathologies around the tendon, such as tenosynovitis or bursitis, since that has an influence on the optimal therapy. Inflammation around the tendon tissue (paratendinitis) is often seen in fluoroquinolone-associated tendon pain. Why this chronic paratendinitis develops is unclear to date. Has the property of the tendon changed in such a way that it leads to mild, chronic irritation of the surrounding tissue?
Unfortunately, newer radiological methods for diagnosing tendon disorders, such as sonoelastography, which measures the relative elasticity of the tendon, are rarely used in the clinic. An attempt to obtain an elastography of the tendon in Switzerland proved to be impossible, as apparently there is not enough data available so far to be able to determine a deviation of the elasticity from the norm. The examination has so far only been used in the context of studies (as of September 2023). However, studies show that there is a better correlation between findings and clinic in tendon disorders with elastography.5
What imaging should be used for fluoroquinolone-associated tendon pain?
In the case of pain in the region of a tendon, X-ray examination is used only to exclude bony changes in the surrounding structures. The findings are usually unremarkable.6 In the case of fluoroquinolone-associated tendon pain, X-ray examinations are usually not useful.
Ultrasound can detect tendonitis but also changes in the tendon to some extent. Possible findings include alteration of the synovium or tendon.6 Sonography may be useful as a favorable alternative to MRI in fluoroquinolone-associated tendon disease. It is important to note that sonography has very large examiner-dependent specificity and sensitivity compared with other modalities.
MRI is primarily indicated in the case of a chronic course. It can also be used to simultaneously visualize pathologic changes in the musculature or intra-articular changes.6 It is the examination of choice in fluoroquinolone-associated tendon disorders, primarily to exclude pathologies of the surrounding structures, degenerative changes, and (partial) ruptures.
Experience has shown that MRI and ultrasound examinations are usually unremarkable in the context of fluoroquinolone-associated tendon pain. It would be interesting to use elastography of the Achilles tendon to quantify the elasticity of the tendon in FQAD patients. 3 Patients often report thattendons feel less elastic.
As described, there is a reduction of elastin in tendon tissue after exposure to a fluoroquinolone antibiotic. However, whether this is the cause of the reduction in elasticity is unclear. Currently, elastography as described is unfortunately only used for research purposes.
Laboratory diagnostics for fluoroquinolone-associated tendon pain
In the laboratory, changes in inflammatory parameters such as C-reactive protein or evidence of antibodies are found only in cases of a suspected inflammatory etiology (e.g., rheumatism).6 Laboratory diagnostics are useful for diagnosing fluoroquinolone-associated tendon pain, but without findings.
Tendon disorders under the microscope
Histologically, tendinopathies present a picture of impaired regeneration without inflammatory cells, noninflammatory collagen degeneration, disorientation, thinning of collagen fibrils, a hypercellularity, and ingrowing nonfunctional blood vessels.
Histologic studies show changes in fluoroquinolone-associated tendon disease similar to those seen in over-use injuries, i.e., injury caused by constantly repetitive supraphysiologic stress. Among other things, abnormal structure of the fibrils, fibrotic areas, and neovascularization of the tendon occur histologically. This occurs with the significant difference that these degenerative changes occur significantly faster than in non-fluoroquinolone associated tendinopathies.2
The diagnosis of fluoroquinolone-associated tendon pain should be primarily clinical. Imaging may be useful, but interestingly, the majority of those with tendon pain after taking fluoroquinolone antibiotics show little to no change on MRI or ultrasound. Often, all that is seen is mild inflammation around the tendon tissue (paratendinitis). This is a strong contrast to the often extremely limited patient. Unfortunately, this usually results in the patient being taken less seriously by the treating physician or in suboptimal therapy recommendations such as “going through the pain” because the tendon looks “healthy” on MRI or ultrasound. Of course, the difficulty of imaging the often severely limiting tendon pain again brings up the question of whether the pain is caused by pure tendon pathology or by an interaction of the tendon tissue with the peripheral and central nervous systems, similar to the clinical picture of CRPS (Chronic Regional Pain Syndrome) that can occur after injury. A clear distinction must be made between this and the proportion of affected persons in whom a rupture or tendinosis is detectable. As described, a study with elastography of tendons after fluoroquinolone administration would be interesting to get closer to the answer to these questions.
Frage: Degeneration vs. Entzündung hier oder wo anders?
- Fluoroquinolone-Associated Tendinopathy: A Critical Review of the Literature; Yasmin Khaliq,
Geroge G. Zhanel
- Musculoskeletal Complications of Fluoroquinolones: Guidelines and Precautions for usage in the Athletic Population; Mederic M Hall, Jonathan T Finnoff, Jay Smith
- Fluroquinolone-associated Disability FQAD: Pathogenese, Diagnostik, Therapie und Diagnosekriterien; Stefan Pieper
- Pathogenesis of tendinopathies: inflammation or degeneration? Michele Abate et al.
- Tendinopathy: Is Imaging Telling Us the Entire Story? Sean I. Docking, Chin Chin OOI, David Connel