Fluoroquinolone Antibiotics: A Newly Identified Risk Factor for Cervical Artery Dissection

Original Article

Fluoroquinolone Antibiotics: A Newly Identified Risk Factor for Cervical Artery Dissection

James Demetrious, DC, FIANM(us) 1

1Private Practice, Wilmington, NC

[email protected]

Published: August 2020
Journal of the International Academy of Neuromusculoskeletal Medicine
August 2020, Volume 17, Issue 1

The original article copyright belongs to the original publisher. This review is available from: http://ianmmedicine.org ©2020 Demetrious and the International Academy of Neuromusculoskeletal Medicine. This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

In 2018 Demetrious presented a rationale for the causal relationship of fluoroquinolone antibiotic induced connective tissue degradation and cervical artery dissection. In 2019, Del Zotto and Pezzini published an independent medical case-control study that has initially affirmed the Demetrious hypothesis.. While past studies have associated recent infection and CAD, the presence of FQ antibiotics was neither assessed or considered as a risk factor or trigger.. Fluoroquinolone antibiotics are causative in the pathogenesis of cervical artery dissection.

Background

In a seminal paper written by Demetrious in 2018, the author presented a rationale for the causal relationship of fluoroquinolone (FQ) antibiotic induced connective tissue degradation and cervical artery dissection (CAD). [1] This association was not previously recognized. In 2019, Del Zotto and Pezzini published an independent medical case-control study that has initially affirmed the Demetrious hypothesis. [2]

Reported CAD Risk Factors

Clinical risk factors have been associated with the pathogenesis of CAD including primary disease of the arterial wall (fibrodysplasia), Ehlers Danlos-syndrome IV, Marfan’s syndrome, underlying arteriopathy, vessel tortuosity, recent respiratory tract infection, migraine, hyper-homocysteinemia, major head/neck trauma, and coughing. [3,4,5]

Infection or Fluoroquinolone?

While past studies have associated recent infection and CAD, the presence of FQ antibiotics was neither assessed or considered as a risk factor or trigger. [6,7] Grau et al. reported, “…short-lived trigger mechanisms may play an important role in the pathogenesis of CAD.” Through multivariate analysis, the authors reported, “…mechanical stress does not significantly explain the association between infection and CAD.” [6]

Campos et al. attributed a CAD to recent infection in their case report. [8] Interestingly, their patient suffered CAD, ischemic retinal, and cerebral strokes four days following the utilization of FQ antibiotics. In that paper, the use of the FQ medication was not identified as a CAD trigger.

A reported 32.5 million FQ antibiotics are prescribed annually in the United States. [9] Fluoroquinolone medications include: Cipro, Levaquin, Avelox, Factive and Floxin. The global consumption of FQ antibiotics is approximately 1.5-2.5 Defined Daily Doses per 1000 inhabitants per day in lower and high-income countries. [10] The FDA has reported connective tissue degradation latency from hours to years following FQ use. [11]

Chiropractic Spinal Manipulation Does Not Cause CAD

In their population-based, case-control, and case-crossover study, Cassidy et al. reported that patients seek chiropractic or primary medical care for early vertebrobasilar (VBA) dissection related symptoms before developing strokes. The authors found no evidence of excess risk of VBA stroke associated with chiropractic care compared to primary care. [12]

In 2016, Church et al. reported, “There is no convincing evidence to support a causal link between chiropractic manipulation and CAD.” The authors reported an unfounded belief in causation might have dire consequences. [13]

In 2017, Cassidy et al. published the results of a large population-based, case-crossover study in the Journal of Stroke and Cerebrovascular Diseases. The authors found no excess of carotid artery stroke following chiropractic care and confirmed that patients sought care with early dissection related symptoms before developing strokes. [14]

In a comprehensive review of the literature published in the Annals of Medicine, Chaibi and Russell concluded, “Manual therapy does not result in an increased risk of CAD.” Additionally, the authors state, “…there is no firm scientific basis for direct causality between cervical spinal manipulative therapy and CAD.” [15]

These exhaustive studies did not identify or causally relate FQ pathogenetic dissections and SMT. Additionally, the data indicate that mechanical stress is not a trigger for CAD. [6] The comprehensive studies conducted by Cassidy, Church, and Chaibi did not identify FQs as a contraindication or risk factor to chiropractic manipulative care with or without FQ utilization. [11,12,13,14]

Incorrect, Harmful and Improperly Reported Causality

In their systematic review and meta-analysis of chiropractic care, Church et al. concluded, “We found no evidence for a causal link between chiropractic care and CAD. This is a significant finding because belief in a causal link is not uncommon, and such a belief may have significant adverse effects such as numerous episodes of litigation.” [12] Further, Church et al. reported, “The quality of the published literature on the relationship between chiropractic manipulation and CAD is very low.” [12] The repeated publication of conclusions drawn from studies with methodological limitations and bias represents poor science. Chiropractic spinal manipulation is not a risk factor for CAD or stroke.

Improving the Identification of a Developing CAD and Stroke

Patients seek chiropractic care with CAD and stroke symptoms. Developing symptoms need to be scrutinized for the utilization of FQ antibiotics in patients’ past histories. Chaibi et al. report that history taking is the single most important factor for detecting subtle symptoms of CAD. [13] Caregivers and the public need to be aware of the degradative effect of FQ medications and their role in the genesis of CAD.

Conclusion

Fluoroquinolone antibiotics are causative in the pathogenesis of cervical artery dissection. Symptoms associated with developing cervical artery dissections cause patients to seek chiropractic care. Cases of suspected and confirmed cervical artery dissection need to be carefully vetted for a history of fluoroquinolone usage. The current evidence indicates that spinal manipulation is not a causative risk factor for CAD with or without FQ utilization.

References

1. Demetrious J. Spontaneous cervical artery dissection: a fluoroquinolone induced connective tissue disorder? Chiropractic & Manual Therapies. 2018;26:22.

2. Del Zotto E, Pezzini A. Use of fluoroquinolones and the risk of spontaneous cervical artery dissection. European Journal of Neurology. 2019;26:1028–1031.

3. Micheli S, Paciaroni M, Corea F, Agnelli G, Zampolini M, Caso V. Cervical artery dissection: emerging risk factors. Open Neurol J. 2010;4:50–55.

4. Debette S, Leys D. Cervical-artery dissections: predisposing factors, diagnosis, and outcome. Lancet Neurol. 2009;8(7):668-78.

5. Rubinstein SM, Peerdeman SM, van Tulder MW, Riphagen I, Haldeman S. A systematic review of the risk factors for cervical artery dissection. Stroke. 2005;36(7):1575-80.

6. Grau AJ, Brandt T, Buggle F, Orbeck E, Mytilineos J, Werle E, Conradt C, Krause M, Winter R, Hacke W. Association of cervical artery dissection with recent infection. Arch Neurol. 1999;56:851-856.

7. Guillon B, Berthet K, Benslamia L, Betrand M, Bousser MG, Tzourio C. Infection and the risk of spontaneous cervical artery dissection: a case-control study. Stroke. 2003;34:e79-e81.

8. Campos CR, Bassi TG, Pinto F, Abrahão DKP. Internal carotid artery dissection in a patient with recent respiratory infection. Arq Neuropsiquiatr. 2005;63(2-B):523-526.

9. Centers for Disease Control and Prevention. Outpatient antibiotic prescriptions—United States, 2015. https://www.cdc.gov/antibiotic-use/community/pdfs/Annual-Report-2015.pdf. Accessed: 2 Sept. 2019.

10. Klein EY, Van Boeckel TP, Martinez EM, Pant S, Gandra S, Levin SA, Goossens H, Laxminarayan R. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. PNAS. 2018;115(15):E3463-E3470.

11. FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. 2016. https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm. Accessed 2 Feb 2018.

12. Cassidy JD, Boyle E, Côté P, He Y, Hogg-Johnson S, Silver FL, Bondy SJ. Risk of vertebrobasilar stroke and chiropractic care: results of a population-based case-control and case-crossover study. Spine. 2008;33(4 Suppl):S176-83.

13. Church EW, Sieg EP, Zalatimo O, Hussain NS, Glantz M, Harbaugh RE. Systematic review and meta-analysis of chiropractic care and cervical artery dissection: no evidence for causation. Cureus. 2016;8(2):e498.

14. Cassidy JD, Boyle E, Côté P, Hogg-Johnson S, Bondy SJ, Haldeman S. Risk of carotid stroke after chiropractic care: a population-based case-crossover study. J Stroke Cerebrovasc Dis. 2017;26(4):842-850.

15. Chaibi A, Russell BR. A risk-benefit assessment strategy to exclude cervical artery dissection in spinal-therapy: a comprehensive review. Annals of Medicine. 2019; 51 (2)118-127.