Dynamic Chiropractic 2011 (May 20); 29 (11): 29, 43, 45 ~ FULL TEXT
By Anthony Rosner, PhD, LLD [Hon.], LLC
Research director for the International College of Applied Kinesiology
Relative Activity Risks
Several studies have attempted to link chiropractic manipulation to adverse events, the most serious and widely studied being strokes following dissections of the vertebral artery. [1–6] To begin to shed light on this problem, several retrospective studies against large population bases have been conducted. As shown in Table 1, [7–15] a large sampling of such studies indicates that the number of serious complications or cerebrovascular accidents (CVAs), as established by researchers from both the chiropractic and medical professions, ranges from one case per 400,000 manipulations to zero in 5 million.
Data from the Rand Corporation suggests the rate of vertebrobasilar accident or other complications (cord compression, fracture or hematoma) is just 1.46 per million manipulations, with the rates of serious complications and death from cervical spine manipulation estimated to be 0.64 and 0.27 per million manipulations, respectively. 
A more recent review, involving a large number of presumed cervical manipulations performed (134.5 million) over an extended period (10 years), used malpractice claims from the Canadian Chiropractic Protective Association. It revealed a total of 43 cases of neurological symptoms retrieved from patient records, 23 of which involved stroke. The total yield of strokes, therefore, was just 23/134.5 million, a frequency rate of one per 5.85 million (0.17 per million) cervical manipulations. 
The risk estimates attributed to cervical manipulation are significantly less (by orders of magnitude) than those associated with various medical procedures and lifestyle activities, as shown in Table 2. [16, 17–23] In an exhaustive review of risk estimates from multiple phases of life, it can be seen that substantially greater risks attributed to the medical procedures have been deemed "acceptable" by the routine adoption of such terminologies as risk-adjusted mortality rates and net clinical benefits.  The risks inherent in other lifestyle activities, also appearing to be readily accepted by the public at large, are apparent in Table 2 and again outweigh those associated with cervical manipulation by several orders of magnitude, in striking contrast to the dire warnings about the risks of cervical manipulation in the media. [25–30]
Structural considerations: The vertebral and basilar arteries, comprising the vertebrobasilar system, supply blood to the posterior brain. The vertebral artery (VA) itself, emerges from the subclavian artery, passes through the transverse foramina of C6–C1 to become the atlantal segment as it exits through the transverse foramen of C1. It is here that the atlantal segment abruptly bends from a vertical to horizontal orientation. It is at this juncture at which the artery is believed to be most susceptible to injury related to sudden and/or extreme head movement.  Three layers from inside to out (tunica intima, tunica media, tunica adventia) comprise the cervical arteries. 
Mechanisms of dissection: As the layer which makes up the vessel lining, the tunica intima is more susceptible to tearing  and as such is the typical site of the initial defect which initiates a vertebral artery dissection (VAD). A typical developing dissection involves the formation of an intimal flap following an initial tear, with the potential for the separation of layers caused by blood flowing into the breach.
Further damage may be wrought by pulsatile pressure to the muscular layer, causing further splitting of the intima and media during a dissection. Subintimal hemorrhaging may rupture back into the arterial lumen distally, creating a double (false) lumen. As blood accumulates within the separated vessel layers, a thrombus is created with further deformation of the intima and obstruction of blood flow. If emboli detach from the primary thrombus, they may travel distally to block progressively smaller vessels in the brain. 
Putting It in Perspective
Perhaps the most compelling information that needs to be brought forward to bring the debate about cervical manipulations into objective terms has to do with the fact that a significant number (and most likely the majority) of VADs happen to be spontaneous cervical artery dissections (sCADs). Numerous reports (to be discussed below), addressing both the frequency of occurrence of VADs and their association with virtually any activity associated with turning the head, should reduce the utility of attributing strokes to cervical manipulations to virtually an academic exercise.
As shown in Table 3, the annual incidence of spontaneous VADs in hospital settings has been estimated to occur at the rate of 1–1.5 per 100,000 patients  The corresponding VAD incidence rate in community settings has been reported to be twice as high. [34–35] Using an estimated value of 10 from the literature to represent an average number of manipulations per patient per episode,36 it becomes apparent that the proposed exposure rate for CVAs attributed to spinal manipulation is no more than equivalent to the spontaneous rates for cervical arterial dissections as reported. [33–35]
If the threat of stroke or stroke-like symptoms is to be properly assessed, therefore, at least half our attention needs to be directed toward the spontaneous events instead of primarily or solely upon spinal manipulation. Furthermore, a large number of common lifestyle activities have been shown to be associated with cerebral ischemia (Table 4A)  or VADs themselves (Table 4B).  All are decidedly non-manipulative. By way of illustration, one recent investigation has described beauty parlor stroke syndrome and salon sink radiculopathy, confirmed by both patient symptoms and blood flow velocities in the bilateral vertebral and carotid arteries as measured by a diagnostic ultrasound instrument. 
The Homocysteine Factor
For over 30 years, the amino acid homocysteine has been implicated as key component of atherosclerotic disease. [39–47] More direct observations point toward the disruption of the structures of collagen and elastin in the arterial wall:
In the majority of skin biopsies taken from patients with cervical arterial dissections, irregular collagen fibrils and elastic fiber fragmentations have been found. 
Homocysteine activates metalloproteinases  and serine elastases,  directly or indirectly leading to the decrease in vitro of the elastin content of the arterial wall. The opening and/or enlargement of fenestrae in the medial elastic laminae would be expected to lead to the premature fragmentation of the arterial elastic fibers and degradation of the extracellular matrix. [48–49]
Homocysteine has been shown to block aldehydic groups in elastin, inhibiting the cross-linking needed to stabilize elastin. 
The cross-linking of collagen may also be impaired by homocysteine. 
Experimentally elevated levels of homocysteine produce patchy desquamation of 10 percent of the aortic surface in baboons. 
Endothelium-dependent and flow-mediated vascular dilation is impaired in individuals with elevated levels of homocysteine. 
In cell culture experiments, addition of homocysteine into the medium induces cell detachment from the endothelial cell monolayer. 
Yet even a tighter coupling between sCADs and increased amounts of homocysteine is suggested by the following observations. Patients undergoing sCADs are more than three times as likely as asymptomatic patients to yield plasma homocysteine levels exceeding 12 micromoles/L. They are also more than twice as likely to have elevated homocysteine as patients experiencing ischemic strokes without arterial dissection. 
CAD patients yield average homocysteine levels of 17.9 micromoles/L while asymptomatic patients report an average of 6.0 micromoles/L.  And homocysteine levels exceeding 10.2 micromoles/L are associated with a doubling of vascular risk. 
Finally, genetic defect in humans involving tetrahydrofolate reductase, the enzyme which produces the methyl-donating co-factor required to convert homocysteine to methionine, is associated with elevations of the rates of sCADs.  This metabolic block would be expected to cause homocysteine to accumulate intracellularly. 
The striking association of homocysteine with sCAD raises the possibility that a relatively simple diagnostic test is at hand for determining patients at risk for sCAD and who would accordingly be advised to avoid cervical manipulation. Until recently, the gold-standard methodology for determining plasma homocysteine was high-pressure liquid chromatography, gas chromatography and mass spectrometry. [56–58] Fortunately, this cumbersome technology has recently been correlated with a much simpler enzyme conversion immunoassay (EIA). 
An even more rapid assay method by means of an automated analyzer is also available, requiring only microliter amounts of reagent and sample.  This essentially means that homocysteine levels can be determined in any number of clinical reference laboratories already established to measure blood analytes.
Editor's Note: Part 2 of this article, scheduled for the June 3 issue, discusses symptoms of arterial distress and flaws in the medical literature regarding stroke risk and spinal manipulation.
Dr. Anthony L. Rosner, a 1972 graduate of Harvard University (PhD in biological chemistry/medical sciences), is the former director of research and education for the Foundation for Chiropractic Education and Research and former director of research initiatives at Parker College of Chiropractic. He is the new research director for the International College of Applied Kinesiology. A former DC columnist ("FCER Forum"), Dr. Rosner is again a columnist, writing on the topic of "Research Horizons."
Lee KP, Carlini WG, McCormick GF, Walters GW. Neurologic complications following chiropractic manipulation: a survey of California neurologists.
Bin Saeed A, Shuaib A, Al Sulaiti G, Emery D.
Vertebral Artery Dissection: Warning Symptoms, Clinical Features and Prognosis in 26 Patients
Canadian Journal of Neurological Sciences 2000 (Nov); 27 (4): 292–296
Hufnagel A, Hammers A, Schonle P-W, Bohm K-D, Leonhardt G. Stroke following chiropractic manipulation of the cervical spine.
Journal of Neurology, 1999;246(8):683-688.
Norris JW, Beletsky V, Nadareishvilli ZG, Canadian Stroke Consortium.
Canadian Medical Association Journal, 2000;163(1):38-40.
Rothwell DM, Bondy SJ, Williams JI. Chiropractic manipulation and stroke: a population-based case-control study.
Smith WS, Johnston SC, Skalabrin EJ, Weaver M, Azari P, Albers GW, Gress DR. Spinal manipulative therapy is an independent risk factor for vertebral artery dissection.
Dvorak J, Orelli F. How dangerous is manipulation of the cervical spine?
Manual Medicine, 1985;2:1-4.
Patijn J. Complications in manual medicine: a review of the literature.
Manual Medicine, 1991;6:89-92.
Haldeman S, Chapman-Smith D, Petersen DM. Guidelines for Chiropractic Quality Assurance and Practice Parameters. Gaithersburg, MD: Aspen Publishers, 1993:170-172.
Jaskoviak PA. Complications arising from manipulation of the cervical spine.
Journal of Manipulative and Physiological Therapeutics, 1980;3:213-219.
Henderson DJ, Cassidy JD. Vertebral Artery Syndrome. In: Vernon H, ed. Upper Cervical Syndrome: Chiropractic Diagnosis and Treatment. Baltimore: Williams & Wilkins, 1988:195-222.
Carey PF. A report on the occurrence of cerebral vascular accidents in chiropractic practice.
Journal of the Canadian Chiropractic Association, 1993;57(2):104-106.
National Chiropractic Mutual Insurance Company, unpublished case records, 1991-1993.
Haldeman S, Carey P, Townsend M, Papadopoulos C.
Arterial Dissections Following Cervical Manipulation: The Chiropractic Experience
Canadian Medical Association Journal (CMAJ) 2001 2001 (Oct 2); 165: 905–906
Thiel HW, Bolton JE, Docherty S, Portlock JC:
Safety of Chiropractic Manipulation of the Cervical Spine: A Prospective National Survey
Spine (Phila Pa 1976). 2007 (Oct 1); 32 (21): 2375–2378
Hurwitz EL, Aker PO, Adams AH, Meeker WC, Shekelle PG.
Manipulation and Mobilization of the Cervical Spine: A Systematic Review of the Literature
Spine (Phila Pa 1976) 1996 (Aug 1); 21 (15): 1746–1760
Deyo RA, Cherkin DC, Loesser JD, Bigos SJ, Ciol MA. Morbidity and mortality in association with operations on the lumbar spine: the influence of age, diagnosis, and procedure.
Journal of Bone and Joint Surgery Am, 1992;74(4):536-543.
Seagroat V, Tan HS, Goldacre M. Bulstrode C, Nugent I, Gill L. Effective total hip replacement: incidence, emergency, readmission rate, and post-operative mortality.
British Medical Journal, 1991;330:1431-1435.
Stremple JS, Boss DS, Davis CH, McDonald GO. Comparison of post-operative mortality and morbidity in Veterans Affairs and nonfederal hospitals.
Journal of Surgical Research, 1994;S6:405-416.
Roebuck DJ. Diagnostic imaging: reversing the focus.
[Letter] Medical Journal of Australia, 1995:162:175.
Phillips DP, Christenfeld N, Glynn LM. Increase in US medication-error deaths between 1983 and 1993.
Dabbs V Lauretti WJ
A Risk Assessment of Cervical Manipulation vs. NSAIDs for the Treatment of Neck Pain
J Manipulative Physiol Ther 1995 (Oct); 18 (8): 530–536
Dinman BD. The reality and acceptance of risk.
Journal of the American Medical Association, 1980; 244(11):1226-1228.
Rome PL. Perspectives: an overview of comparative considerations of cerebrovascular accidents.
Chiropractic Journal of Australia, 1999;29(3):87-102.
Brody J. "When Simple Actions Ravage Arteries."
New York Times, April 30, 2001.
Bill Carroll Show, CFRB 1010 radio, Feb. 6, 2002; posted on the Internet.
Evenson B. National Post, Feb. 7, 2002.
Hamburg J, Medical Minute, WOR AM 710 radio, Feb. 22, 2002.
Jaroff L. "Back Off, Chiropractors!" TIME.com, Feb. 27, 2002.
"A Different Way to Heal." Episode of Scientific American Frontiers Public Broadcasting System telecast, June 4, 2002.
Reddy M, Redy B, Schoggle A, Saringer W, Matula C. The complexity of trauma to the cranio-cervical junction: correlation of clinical presentation with Doppler flow velocities in the V3-segment of the vertebral arteries.
Acta Neurochiropractic (Wien), 2002;144(6):575-580.
Haneline M.T., Rosner A.L.
The Etiology of Cervical Artery Dissection
Journal of Chiropractic Medicine 2007; 6 (3): 110–120
Shievink WT, Mokri, B, O'Fallon WM. Recurrent spontaneous cervical-artery dissection.
New England Journal of Medicine, 1994;330(6):393-397.
Shievink WT, Mokri B, Whisnant JP. Internal carotid artery dissection in a community: Rochester, Minnesota, 1987-1992.
Giroud M, Fayolle H, Andre N, Dumas R, Becker F, Martin D, Baudoin N, Krause D. Incidence of internal carotid artery dissection in the community of Dijon.
[Letter] Journal of Neurology and Neurosurgical Psychiatry, 1994;57(11):1443.
Carey TS, Garrett J, Jackman A, et al.
The Outcomes and Costs of Care for Acute Low Back Pain Among Patients
Seen by Primary Care Practitioners, Chiropractors, and Orthopedic Surgeons
New England J Medicine 1995 (Oct 5); 333 (14): 913–917
Terrett, AGJ. "Malpractice Avoidance for Chiropractors. 1. Vertebrobasilar Stroke Following Manipulation." Des Moines, IA. National Chiropractic Mutual Insurance Company, 1996.
Foye PM, Najar MP, Camme A Jr, Stitik TP, DePrince ML, Nadler SF, Chen B. Prospective study of pain, dizziness, and central nervous system blood blow in cervical extension: vascular correlations to beauty parlor stroke syndrome and salon sink radiculopathy.
American Journal of Physical Medicine and Rehabilitation, 2002;81(6):395-399.
Graham IM, Daley LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, Palma-Reis RJ, Boers GH, Sheahan RG, Israelsson B, Uiterwaal CS, Meleady R, McMaster D, Verhoef P, Witterman J, Rubba P, Bellet H, Wautrecht JC, de Valk HW, Sales Luis AC, Parrot-Rouland RM, Tan KS, Higgins I, Garcon D, Medrano MJ, Candito M, Evans AE, Andria G. Plasma homocysteine as a risk factor for vascular disease: the European Concerted Action Project.
Journal of the American Medical Association, 1997;277: 1775-1781.
McCully KS. Vascular pathology of homocysteinemia: implications for pathogenesis of arteriosclerosis.
American Journal of Pathology, 1969;56(1):111-128.
Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PW, Belanger AJ, O'Leary DH, Wolf PA, Schaefer EJ, Rosenberg IH. Association between plasma homocysteine concentrations and extracranial carotid artery stenosis.
New England Journal of Medicine, 1995;332(5):286-291.
Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM. Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention.
Archives of Internal Medicine, 1998;158(8):862-867.
Nygard O, Nordehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE, Plasma homocysteine levels and mortality in patients with coronary artery disease.
New England Journal of Medicine, 1997;337(4):230-236.
Stampfer MJ, Malinow R, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homoycyst(e)ine and risk of myocardial infarction in US physicians.
Journal of the American Medical Association, 1992;268(7):877-881.
Harker LA, Slichter J, Scott CR, Russell R. Homocysteinemia: vascular injury and arterial thrombosis.
New England Journal of Medicine, 1974;291:537-543.
Lenz SR, Sobey CG, Piegors DJ, Bohoptakar MY, Faraci FM, Malinow MR, Heistad DD. Vascular dysfunction in monkey with diet-induced hyperhomocysteinemia.
Journal of Clinical Investigation, 1996;98:24-29.
Woo KS, Chook P, Lolin YI, Cheung AS, Chan LT, Sun YY, Sanderson JE, Metreweli C, Celermajar DS. Hyperhomocysteinemia is a risk factor for endothelial dysfunction in humans.
Charplot P, Bescond A, Augler T, Chereyre C, Fratermo M, Rolland PH, Garcon D. Hyperhomocysteinemia induces elastolysis in minipig arteries: Structural consequences, arterial site specificity and effect of captoprilhydrochlorothiazide.
Matrix Biology, 1998;17:559-574.
Rahmani DJ, Rolland PH, Rosset E, Branchereau A, Garcon D. Homocysteine induces synthesis of a serine elastase in arterial smooth muscle cells from multi-organ donors.
Cardiovascular Research, 1997;34(3):597-602.
Jackson SH. The reaction of homocysteine with aldehyde: an explanation of the collagen defects in homocystinuria.
Clinica Chimica Acta, 1973;45(3):215-217.
Kang AH, Trelstad RL. A collagen defect in homocystinuria.
Journal of Clinical Investigation, 1973;52(10):2571-2578.
Wall RT, Harlan JM, Harker LA, Striker GF. Homocysteine-induced endothelial cell injury in vitro: a modelfor the study of vascular injury.
Thrombolytic Research, 1980;18:113-121.
Pezzini A, Del Zotto E, Archetti S, Negrini R, Bani P, Albertini A, Grassi M, Assanelli D, Gasparotti R, Vignolo LA, Magoni M, Padovani A. Plasma homocysteine concentration, C677T MTHFR genotype, and 844-ins68bp genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke.
Gallai V, Caso V, Paciaroni M, Cardaioli G, Arning E, Bottiglieri T, Pernetti L. Mild hyperhomocyst(e)inemia: a possible risk factor for cervical artery dissection.
Lehninger AL, Nelson DL, Cox MM. Principles of Biochemistry, 2nd Edition. New York, NY: Worth, 1993:524-526.
Ueland PM, Refsum H, Stabler SP, Mainow MR, Anderson A, Allen RH. Total homocysteine in plasma and serum: methods and clinical applications.
Clinical Chemistry, 1993;39(9):1764-1779.
Stabler SP, Marcell PD, Podell ER, Allen RH. Quantitation of total homocysteine, total cysteine, and methionine in normal serum and urine using capillary gas chromatography-mass spectrometry.
Analytical Biochemistry, 1987;162(1):185-196.
Pietzsch J, Julius U, Hanefeld M. Rapid determination of total homocysteine in human plasma by using N(O,S)-ethoxycarbonyl ethyl ester derivatives and gas chromatography-mass spectrometry.
Clinical Chemistry, 1997;43(10):2001-2004.
Frantzen F, Faaren AL, Alfheim I, Nordhei AK. Enzyme conversion immunoassay for determining total homocysteine in plasma or serum.
Clinical Chemistry, 1998;44(2):311-316.
Shipchandler MT, Moore EG. Rapid, fully automated measurement of plasma homocyst(e)ine with the Abbott IMx analyzer.
Clinical Chemistry, 1995;41(7): 991-994.
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