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THE CLINICAL CLARITY BLOG
The Antibiotic-Stroke Connection
JULY 31, 2019 by DR MATTHEW D. LONG
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THE CLINICAL CLARITY BLOG
The Antibiotic-Stroke Connection
JULY 31, 2019 by DR MATTHEW D. LONG
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THE CLINICAL CLARITY BLOG
JULY 31, 2019 by DR MATTHEW D. LONG
The practice of cervical manipulation has faced considerable scrutiny over the years. This initially arose out of safety concerns about cervical artery dissection (CAD), although much of the early impetus for investigation was quite frankly political (1,2,3). Thankfully, there has been a significant shift in the narrative over recent years, with a growing acknowledgment that there is no specific association between exposure to chiropractic care and the risk of vertebrobasilar artery stroke (4,5,6,7,8). While there are still those who perpetuate the idea that neck manipulation is singularly dangerous, the consensus now is that CAD typically begins prior to the patient seeking treatment. As I have written in a previous article on the topic (here), the chiropractor often plays the role of "innocent bystander" rather than "causal agent".
According to Dr Donald Murphy (7),
According to Dr Donald Murphy (7),
"Therefore, based upon the best current evidence, it appears that there is no strong foundation for a causal relationship between CMT and VADS. The most plausible explanation for the association between CMT and VADS is that individuals who are experiencing a vertebral artery dissection seek care from a chiropractic physician or other manual practitioner for relief of the neck pain and headache that results from the dissection. Sometime after the visit the dissection proceeds along its natural course to produce arterial blockage, leading to stroke. This natural progression from dissection to stroke appears to occur independent of the application of CMT."
This is an important distinction. The fact that the majority of patients who experience CAD are already in a "state of play" when they arrive in your office should cause us to pause and reflect. Indeed, Murphy further writes (7),
"Thus, the concern for the chiropractic physician and other manual practitioner has shifted. Previously the focus had been on trying to 'screen' for a patient who is 'at risk' of a rare 'complication to CMT'... The issue for practitioners now is one of differential diagnosis. The responsibility of the practitioner is not to attempt to identify the patient who is at risk of 'post-manipulative stroke', but to attempt to identify the patient who is having a dissection in progress so appropriate referral can be made."
Most of us would probably recall the simple mnemonic we were taught at university to identify signs of possible vertebrobasilar ischaemia - the so-called "5 D's And 3 N's". This stands for:
Dizziness
Diplopia
Dysarthria
Drop attacks
Dysphagia
Ataxia
Nystagmus
Nausea
Numbness
Diplopia
Dysarthria
Drop attacks
Dysphagia
Ataxia
Nystagmus
Nausea
Numbness
While this clinical tool is useful, it obviously has significant limitations. Firstly, some of the symptoms listed above can be found in other conditions such as migraine. Secondly, its utility is only realised when the individual is actually having an event of some consequence. It doesn't have any predictive value when the patient is asymptomatic. So what to do?
Of course, we should also realise that there are types of people who are more likely to suffer from vertebral artery dissection. I wrote about this in a recent article entitled "Migraine and Stroke - What's the Connection?" (here). In this piece I looked at the increased prevalence of stroke amongst migraineurs, noting that those with visual aura are more likely to suffer ischaemic stroke (9), whereas those without aura are more susceptible to CAD (10,11). It is this latter group that is particularly relevant to the practising chiropractor, as they are more inclined to harbour connective tissue defects that render their arterial walls more fragile. But there is another group of patients who may also harbour a greater risk for spontaneous vertebral artery dissection - individuals who would otherwise not stand out as particularly vulnerable. I am referring here to those taking antibiotic medication. More specifically, those who are prescribed the broad-spectrum antibiotics known as fluoroquinolones.
A recent article by James S. Demetrious in the journal Chiropractic & Manual Therapies (12) posited an interesting theory about the potential role of fluoroquinolone antibiotics as an initiator of cervical arterial dissection. Fluoroquinolones are broad-spectrum antibiotics that are used to treat respiratory infections, urinary tract infections, kidney infections, and sinus infections, and they generally end in the name '-floxacin'. The trouble is, they have been linked to connective tissue degradation, tendon rupture and even aortic aneurysms (13,14,15,16). Indeed, the FDA felt sufficiently concerned to release a warning that this class of antibiotics should be avoided unless patients have no other treatment options. But how does damage occur, and why might this be relevant to chiropractors?
According to Demetrious' article,
Of course, we should also realise that there are types of people who are more likely to suffer from vertebral artery dissection. I wrote about this in a recent article entitled "Migraine and Stroke - What's the Connection?" (here). In this piece I looked at the increased prevalence of stroke amongst migraineurs, noting that those with visual aura are more likely to suffer ischaemic stroke (9), whereas those without aura are more susceptible to CAD (10,11). It is this latter group that is particularly relevant to the practising chiropractor, as they are more inclined to harbour connective tissue defects that render their arterial walls more fragile. But there is another group of patients who may also harbour a greater risk for spontaneous vertebral artery dissection - individuals who would otherwise not stand out as particularly vulnerable. I am referring here to those taking antibiotic medication. More specifically, those who are prescribed the broad-spectrum antibiotics known as fluoroquinolones.
A recent article by James S. Demetrious in the journal Chiropractic & Manual Therapies (12) posited an interesting theory about the potential role of fluoroquinolone antibiotics as an initiator of cervical arterial dissection. Fluoroquinolones are broad-spectrum antibiotics that are used to treat respiratory infections, urinary tract infections, kidney infections, and sinus infections, and they generally end in the name '-floxacin'. The trouble is, they have been linked to connective tissue degradation, tendon rupture and even aortic aneurysms (13,14,15,16). Indeed, the FDA felt sufficiently concerned to release a warning that this class of antibiotics should be avoided unless patients have no other treatment options. But how does damage occur, and why might this be relevant to chiropractors?
According to Demetrious' article,
"Collagen degradation due to fluoroquinolones reportedly involves the upregulation of matrix metalloproteinases resulting in a reduction in the quantity and quality of collagen fibrils. A considerable latency from the commencement of fluoroquinolones to the onset of symptoms have been attributed to delayed mitochondrial toxicity, depletion, mutation, and cytotoxicity providing a foundation for reported occurrence of associated adverse effects."
He also wrote that,
"The tunica adventitia of the aortic, carotid and vertebral arteries are comprised of dense irregular connective tissue containing loosely organized collagen fibers. As fluoroquinolones may induce degradation of collagen causing aortic dissection and aneurysm, this raises the concern that fluoroquinolones may cause cervical artery dissections by a similar mechanism."
While there are as yet no case studies that have unequivocally linked cervical artery dissections to fluoroquinolones, there are some other circumstantial associations. For example, a recent infection has been shown to increase the likelihood of a cervical dissection (17). Even more interesting, the incidence of such dissection rises during the winter months, with Thomas et al (18) finding a strong trend for the disorder to occur more frequently in autumn-winter compared to spring-summer. While the authors did suggest that winter sports may have exposed the victims to increased mild trauma to the neck vessels, we should also note the increased rate of prescription of antibiotics that occurs during the winter months (19).
So what does all of this mean for chiropractors?
Firstly, I think that we should take comfort from the fact that the scientific literature is beginning to reflect the unbiased reality of cervical artery dissection, and that the historical preoccupation with spinal manipulation as an overtly dangerous pastime should be abandoned. Secondly, it is clear that there are many factors that can increase an individual's risk for spontaneous dissection. Some of these are genetic, some are associated with lifestyle choices, and others may be iatrogenic. While the jury may still be out on fluoroquinolones, there is sufficient concern that I would amend my approach to any patient with acute neck pain (and occipital headache) that has a history of their recent usage.
So what does all of this mean for chiropractors?
Firstly, I think that we should take comfort from the fact that the scientific literature is beginning to reflect the unbiased reality of cervical artery dissection, and that the historical preoccupation with spinal manipulation as an overtly dangerous pastime should be abandoned. Secondly, it is clear that there are many factors that can increase an individual's risk for spontaneous dissection. Some of these are genetic, some are associated with lifestyle choices, and others may be iatrogenic. While the jury may still be out on fluoroquinolones, there is sufficient concern that I would amend my approach to any patient with acute neck pain (and occipital headache) that has a history of their recent usage.
Something to think about...
Dr Matthew D. Long
BSc (Syd), M.Chiro (Macq)
Dr Matthew D. Long
BSc (Syd), M.Chiro (Macq)
References:
1. Terrett AGJ. Misuse of the literature by medical authors in discussing spinal manipulative therapy. J Manipulative Physiol Ther 1995, 18:203-210.
2. Morley, J., Rosner, A. L., & Redwood, D. (2001). A case study of misrepresentation of the scientific literature: recent reviews of chiropractic. Journal of Alternative and Complementary Medicine (New York, NY), 7(1), 65–78– discussion 79–82. http://doi.org/10.1089/107555301300004547
3. Wenban, A. B. (2006). Inappropriate use of the title 'chiropractor' and term “chiropractic manipulation” in the peer-reviewed biomedical literature. Chiropractic & Osteopathy, 14(1), 16. http://doi.org/10.1186/1746-1340-14-16
4. Kosloff, T. M., Elton, D., Tao, J., & Bannister, W. M. (2015). Chiropractic care and the risk of vertebrobasilar stroke: results of a case-control study in U.S. commercial and Medicare Advantage populations. Chiropractic & Manual Therapies, 23, 19. http://doi.org/10.1186/s12998-015-0063-x
5. Whedon, J. M., Song, Y., Mackenzie, T. A., Phillips, R. B., Lukovits, T. G., & Lurie, J. D. (2015). Risk of stroke after chiropractic spinal manipulation in medicare B beneficiaries aged 66 to 99 years with neck pain. Journal of Manipulative and Physiological Therapeutics, 38(2), 93–101. http://doi.org/10.1016/j.jmpt.2014.12.001
6. Church, E. W., Sieg, E. P., Zalatimo, O., Hussain, N. S., Glantz, M., & Harbaugh, R. E. (2016). Systematic Review and Meta-analysis of Chiropractic Care and Cervical Artery Dissection: No Evidence for Causation. Cureus, 8(2), e498. http://doi.org/10.7759/cureus.498
7. Murphy, D. R. (2010). Current understanding of the relationship between cervical manipulation and stroke: what does it mean for the chiropractic profession? Chiropractic & Osteopathy, 18(1), 22. http://doi.org/10.1186/1746-1340-18-22
8. Moser, N., Mior, S., Noseworthy, M., Côté, P., Wells, G., Behr, M., & Triano, J. (2019). Effect of cervical manipulation on vertebral artery and cerebral haemodynamics in patients with chronic neck pain: a crossover randomised controlled trial. BMJ Open, 9(5), e025219. http://doi.org/10.1136/bmjopen-2018-025219
9. Androulakis, X. M., Kodumuri, N., Giamberardino, L. D., Rosamond, W. D., Gottesman, R. F., Yim, E., & Sen, S. (2016). Ischemic stroke subtypes and migraine with visual aura in the ARIC study. Neurology, 87(24), 2527–2532. http://doi.org/10.1212/WNL.0000000000003428
10. De Giuli, V., Grassi, M., Lodigiani, C., Patella, R., Zedde, M., Gandolfo, C., et al. (2017). Association Between Migraine and Cervical Artery Dissection: The Italian Project on Stroke in Young Adults. JAMA Neurology, 74(5), 512–518. http://doi.org/10.1001/jamaneurol.2016.5704
11. Mawet, J., Debette, S., Bousser, M.-G., & Ducros, A. (2016). The Link Between Migraine, Reversible Cerebral Vasoconstriction Syndrome and Cervical Artery Dissection. Headache, 56(4), 645–656. http://doi.org/10.1111/head.12798
12. Demetrious, J. S. (2018). Spontaneous cervical artery dissection: a fluoroquinolone induced connective tissue disorder? Chiropractic & Manual Therapies, 26(1), 1050–3. http://doi.org/10.1186/s12998-018-0193-z
13. Daneman, N., Lu, H., & Redelmeier, D. A. (2015). Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open, 5(11), e010077–e010077. http://doi.org/10.1136/bmjopen-2015-010077
14. Arabyat, R. M., Raisch, D. W., McKoy, J. M., & Bennett, C. L. (2015). Fluoroquinolone-associated tendon-rupture: a summary of reports in the Food and Drug Administration's adverse event reporting system. Expert Opinion on Drug Safety, 14(11), 1653–1660. http://doi.org/10.1517/14740338.2015.1085968
15. Morales, D. R., Slattery, J., Pacurariu, A., Pinheiro, L., McGettigan, P., & Kurz, X. (2018). Relative and Absolute Risk of Tendon Rupture with Fluoroquinolone and Concomitant Fluoroquinolone/Corticosteroid Therapy: Population-Based Nested Case-Control Study. Clinical Drug Investigation. http://doi.org/10.1007/s40261-018-0729-y
16. Binz, J., Adler, C. K., & So, T.-Y. (2016). The Risk of Musculoskeletal Adverse Events With Fluoroquinolones in Children: What Is the Verdict Now? Clinical Pediatrics, 55(2), 107–110. http://doi.org/10.1177/0009922815599959
17. Guillon B, Berthet K, Benslamia L, Bertrand M, Bousser MG, Tzourio C. Infection and the risk of spontaneous cervical artery dissection: a case- control study. Stroke. 2003;34:e79–81
18. Thomas, L. C., Makaroff, A. P., Oldmeadow, C., Attia, J. R., & Levi, C. R. (2017). Seasonal variation in cervical artery dissection in the Hunter New England region, New South Wales, Australia: A retrospective cohort study. Musculoskeletal Science & Practice, 27, 106–111. http://doi.org/10.1016/j.math.2016.10.007
19. Suda KJ, Hicks LA, Roberts RM, Hunkler RJ, Taylor TH. Trends and seasonal variation in the outpatient antibiotic prescription rates in the United States, 2006 to 2010. Antimicrob Agents Chemother. 2014;58(5):2763–6.
1. Terrett AGJ. Misuse of the literature by medical authors in discussing spinal manipulative therapy. J Manipulative Physiol Ther 1995, 18:203-210.
2. Morley, J., Rosner, A. L., & Redwood, D. (2001). A case study of misrepresentation of the scientific literature: recent reviews of chiropractic. Journal of Alternative and Complementary Medicine (New York, NY), 7(1), 65–78– discussion 79–82. http://doi.org/10.1089/107555301300004547
3. Wenban, A. B. (2006). Inappropriate use of the title 'chiropractor' and term “chiropractic manipulation” in the peer-reviewed biomedical literature. Chiropractic & Osteopathy, 14(1), 16. http://doi.org/10.1186/1746-1340-14-16
4. Kosloff, T. M., Elton, D., Tao, J., & Bannister, W. M. (2015). Chiropractic care and the risk of vertebrobasilar stroke: results of a case-control study in U.S. commercial and Medicare Advantage populations. Chiropractic & Manual Therapies, 23, 19. http://doi.org/10.1186/s12998-015-0063-x
5. Whedon, J. M., Song, Y., Mackenzie, T. A., Phillips, R. B., Lukovits, T. G., & Lurie, J. D. (2015). Risk of stroke after chiropractic spinal manipulation in medicare B beneficiaries aged 66 to 99 years with neck pain. Journal of Manipulative and Physiological Therapeutics, 38(2), 93–101. http://doi.org/10.1016/j.jmpt.2014.12.001
6. Church, E. W., Sieg, E. P., Zalatimo, O., Hussain, N. S., Glantz, M., & Harbaugh, R. E. (2016). Systematic Review and Meta-analysis of Chiropractic Care and Cervical Artery Dissection: No Evidence for Causation. Cureus, 8(2), e498. http://doi.org/10.7759/cureus.498
7. Murphy, D. R. (2010). Current understanding of the relationship between cervical manipulation and stroke: what does it mean for the chiropractic profession? Chiropractic & Osteopathy, 18(1), 22. http://doi.org/10.1186/1746-1340-18-22
8. Moser, N., Mior, S., Noseworthy, M., Côté, P., Wells, G., Behr, M., & Triano, J. (2019). Effect of cervical manipulation on vertebral artery and cerebral haemodynamics in patients with chronic neck pain: a crossover randomised controlled trial. BMJ Open, 9(5), e025219. http://doi.org/10.1136/bmjopen-2018-025219
9. Androulakis, X. M., Kodumuri, N., Giamberardino, L. D., Rosamond, W. D., Gottesman, R. F., Yim, E., & Sen, S. (2016). Ischemic stroke subtypes and migraine with visual aura in the ARIC study. Neurology, 87(24), 2527–2532. http://doi.org/10.1212/WNL.0000000000003428
10. De Giuli, V., Grassi, M., Lodigiani, C., Patella, R., Zedde, M., Gandolfo, C., et al. (2017). Association Between Migraine and Cervical Artery Dissection: The Italian Project on Stroke in Young Adults. JAMA Neurology, 74(5), 512–518. http://doi.org/10.1001/jamaneurol.2016.5704
11. Mawet, J., Debette, S., Bousser, M.-G., & Ducros, A. (2016). The Link Between Migraine, Reversible Cerebral Vasoconstriction Syndrome and Cervical Artery Dissection. Headache, 56(4), 645–656. http://doi.org/10.1111/head.12798
12. Demetrious, J. S. (2018). Spontaneous cervical artery dissection: a fluoroquinolone induced connective tissue disorder? Chiropractic & Manual Therapies, 26(1), 1050–3. http://doi.org/10.1186/s12998-018-0193-z
13. Daneman, N., Lu, H., & Redelmeier, D. A. (2015). Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open, 5(11), e010077–e010077. http://doi.org/10.1136/bmjopen-2015-010077
14. Arabyat, R. M., Raisch, D. W., McKoy, J. M., & Bennett, C. L. (2015). Fluoroquinolone-associated tendon-rupture: a summary of reports in the Food and Drug Administration's adverse event reporting system. Expert Opinion on Drug Safety, 14(11), 1653–1660. http://doi.org/10.1517/14740338.2015.1085968
15. Morales, D. R., Slattery, J., Pacurariu, A., Pinheiro, L., McGettigan, P., & Kurz, X. (2018). Relative and Absolute Risk of Tendon Rupture with Fluoroquinolone and Concomitant Fluoroquinolone/Corticosteroid Therapy: Population-Based Nested Case-Control Study. Clinical Drug Investigation. http://doi.org/10.1007/s40261-018-0729-y
16. Binz, J., Adler, C. K., & So, T.-Y. (2016). The Risk of Musculoskeletal Adverse Events With Fluoroquinolones in Children: What Is the Verdict Now? Clinical Pediatrics, 55(2), 107–110. http://doi.org/10.1177/0009922815599959
17. Guillon B, Berthet K, Benslamia L, Bertrand M, Bousser MG, Tzourio C. Infection and the risk of spontaneous cervical artery dissection: a case- control study. Stroke. 2003;34:e79–81
18. Thomas, L. C., Makaroff, A. P., Oldmeadow, C., Attia, J. R., & Levi, C. R. (2017). Seasonal variation in cervical artery dissection in the Hunter New England region, New South Wales, Australia: A retrospective cohort study. Musculoskeletal Science & Practice, 27, 106–111. http://doi.org/10.1016/j.math.2016.10.007
19. Suda KJ, Hicks LA, Roberts RM, Hunkler RJ, Taylor TH. Trends and seasonal variation in the outpatient antibiotic prescription rates in the United States, 2006 to 2010. Antimicrob Agents Chemother. 2014;58(5):2763–6.