If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Over the past 5 to 10 years, the issue of cerebrovascular accidents (CVAs) and spinal manipulation has become a debate of ever-increasing intensity. A copious number of studies have investigated spinal manipulation as a putatative causative factor of CVAs
; however, a common theme among these is the failure to consider that the majority of vertebrobasilar accidents (VBAs) may be spontaneous, cumulative, or caused by factors other than spinal manipulation. The problem is not served by the sometimes hysterical reactions apparent in the media over the past 2 years in reaction to the flawed investigations.
In light of these recent reports, the entire phenomenon of spontaneous cervical artery dissections should be revisited to put this matter into a better perspective.
Dissection mechanism
The mechanism of CVAs involves the vertebral and carotid arteries of the upper cervical spine. Following cervical manipulations in particular, the most common site of injury to the vertebral arterial system appears to be in the vicinity of the atlanto-occipital joint, where the vertical artery bends into a horizontal configuration, as shown in Figure 1. By a large majority, most postmanipulative strokes and stroke-like symptoms occur in the segment of the vertebral artery bounded by the transverse foramen of the C2 vertebra and the foramen magnum.
Interestingly, it is precisely in the C1-2 region in which rotational maneuvers have been suggested to produce a slight elevation in the incident rate of CVAs.
arterial traumatic mechanisms may be classified by 1 of 6 categories: (1) subintimal hematoma, (2) intimal tear, (3) intimal tear with embolic formation, (4) vessel wall dissection with subintimal hematoma (dissecting aneurysm), (5) vessel wall dissection with pseudoaneurysm formation, and (6) perivascular bleeding (false saccular aneurysm). Although one might suspect altered vertebral artery hemodynamics and reduced basilar perfusion to be consequences of diagnostic testing and/or spinal manipulation, it is primarily the vertebral arterial dissections (VADs) which have been implicated in the majority of stroke or stroke-like incidents
to be directly attributable to spinal manipulation. VADs, therefore, will form the basis of the ensuing discussion.
Spontaneous VAD rates
As shown in Table 1, the annual incidence of spontaneous VADs in hospital settings has been estimated to occur at the rate of 1 to 1.5 per 100,000 patients.
it becomes apparent that the proposed exposure rate for CVAs attributed to spinal manipulation is equivalent to the spontaneous rates for cervical arterial dissections as reported.
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 on spinal manipulation.
Table 1%Rates of stroke compared with incidence of arterial dissections
Corrected to represent the average incidence per patient assuming the average number of manipulations per patient to equal 10, as reported in the literature.23
Corrected to represent the average incidence per patient assuming the average number of manipulations per patient to equal 10, as reported in the literature.23
Corrected to represent the average incidence per patient assuming the average number of manipulations per patient to equal 10, as reported in the literature.23
∗ Corrected to represent the average incidence per patient assuming the average number of manipulations per patient to equal 10, as reported in the literature.
A consortium of investigators from northern Italy have recently demonstrated that a genetic defect in humans (C677T MTHFR, a thermolabile variant of the enzyme tetrahydrofolate reductase with half the normal activity) is associated with elevated levels of the amino acid homocysteine.
Plasma homocysteine concentration, C677T MTHFR genotype, and 844-ins68bp genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke.
According to Figure 2, A and B, this is shown (1) by the failure of the reductase enzyme to generate sufficient quantities of N5-methyltetrahydrofolate (Fig 2, A), resulting in (2) the inability to convert sufficient quantities of homocysteine to methionine (Fig 2, B). This is due to the fact that there are inadequate amounts of the methyl donor cofactor N5-methyltetrahydrofolate to catalyze the reaction, with the result that the precursor to methionine (homocysteine) accumulates intracellularly.
Plasma homocysteine concentration, C677T MTHFR genotype, and 844-ins68bp genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke.
indicated that spontaneous cervical artery dissections (sCADs) are represented in the pool of patients whose homocysteine levels exceed 12 μmol/L—more than 3 times as much as asymptomatic patients and more than twice as much as patients who have undergone ischemic strokes without arterial dissection. Direct correlations of elevated plasma homocysteine levels with the occurrence of sCAD were also demonstrated,
Plasma homocysteine concentration, C677T MTHFR genotype, and 844-ins68bp genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke.
a finding that is echoed elsewhere by the findings that (1) cervical artery dissection (CAD) patients had average homocysteine levels of 17.9 μmol/L, while asymptomatic patients reported 6.0 μmol/L
What is the clinical significance of elevated homocysteine levels? For years, homocysteine has been implicated as a key component of atherosclerosis and cardiovascular diseases,
Plasma homocysteine concentration, C677T MTHFR genotype, and 844-ins68bp genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke.
and other investigations suggest a more direct role. A significant number of clues all point toward the disruption of the structure of collagen and elastin in the arterial wall:
1.
In the majority of skin biopsies taken from patients with cervical arterial dissections, irregular collagen fibrils and elastic fiber fragmentations have been found.
Hyperhomocysteinemia induces elastolysis in minipig arteries structural consequences, arterial site specificity and effect of captopril hydrochlorothiazide.
Hyperhomocysteinemia induces elastolysis in minipig arteries structural consequences, arterial site specificity and effect of captopril hydrochlorothiazide.
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.
Hyperhomocysteinemia induces elastolysis in minipig arteries structural consequences, arterial site specificity and effect of captopril hydrochlorothiazide.
All of these observations would be enhanced by elevated levels of homocysteine and suggest that the resulting potential defects of the extracellular matrix of the vessel wall may play a role in the pathogenesis of arterial dissection.
Plasma homocysteine concentration, C677T MTHFR genotype, and 844-ins68bp genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke.
observations concerning a defective tetrahydrofolate reductase may extend to a second mechanism by which collagen structure is disrupted. As shown in Figure 2, A, the aberrant enzyme leads to an accumulation of the precursor N5,N10-methylenetetrahydrofolate. It is conceivable from the biochemical pathway shown in Figure 3 that this entity may then favor the catabolic conversion of glycine into serine.
By coincidence, glycine, as the smallest existing amino acid, turns out to be an essential component in the repeating tripeptide sequence which constitutes collagen. As shown by Figure 4, virtually all the hairpin turns in the core of the helical structure of collagen are glycine residues
; any lack or substitution thereof would be expected to impart significant kinks and other aberrations to the collagen structure, rendering it more susceptible to spontaneous degradation.
Fig 3Catabolic pathways for glycine and other amino acids. Reproduced with permission.25
Fig 4Structure of collagen. a, Repeating tripeptide sequence Glycine-X-Proline or Glycine-X-Hydroxyproline adopts a left-handed helical structure with 3 residues/turn [Hyp used here]. b, Space-filling model of collagen helix shown in (a). c, Three of these helices wrap around one another with a right-handed twist. d, Three-standed collagen superhelix shown from one end, with glycine residues shown in black. Glycine, because of its small size, is required at the right junction where the 3 chains come into contact. Reproduced with permission.25
After a continuous 3-month infusion of homocysteine in baboons, vascular injury and thrombosis could be induced with patchy endothelial desquamation, observed on up to 10% of the aortic surface.
Finally, in cell culture experiments, the addition of homocysteine into the cell medium induced the detachment of cells from the endothelial cell monolayer.
The common denominator pertaining to risks associated with spinal manipulation is arterial wall fragility, rather than stenosis and the other cardiovascular risks which have been associated with elevated homocysteine.
Practical implications of homocysteine determinations
Until recently, the gold standard methodology for determining plasma homocysteine has been high pressure liquid chromatography, gas chromatography, and mass spectrometry.
Rapid determination of total homocysteine in human plasma by using N(O,S)-ethoxycarbonyl ethyl ester derivatives and gas chromatography-mass spectrometry.
This essentially means that homocysteine levels can be determined in any number of clinical reference laboratories already established to measure blood analytes.
To date, the assessment options for vertebrobasilar artery risk each have significant drawbacks (Table 2) and as a whole have been unable to identify any particular factor that is useful for screening.
Provocation tests, in particular, are problematic in that in several aspects they replicate the risks associated with cervical manipulation by requiring the placement of the head and neck in extreme extension and rotation.
In the midst of this disorder, determining homocysteine levels as a predictor of arterial fragility seems to be a plausible, rapid, and inexpensive procedure that is no more invasive than a routine blood glucose determination.
Little or no actual clinical value; false-negative testing documented; false sense of security.
Doppler ultrasound
Images vertebral arterial flow; may document dissection in evolution.
Manual compression and provocation testing does not appear to obstruct flow in symptomatic individuals or control subjects; normal in unoccluded arteries.
CT, MRI scan
Images brain structure; of value in documenting completed infarct.
Does not image vertebral arteries very well.
MRA
Visualizes vertebral arteries; localizes the dissection and occlusion.
High cost; limited availability; never investigated as a screening tool.
Arteriography
Gold standard for visualizing vertebral arteries; can document congenital abnormalities.
Invasive test with known complication rate; expensive; not demonstrated to show patients at risk.
CT, computed tomography; MRI, magnetic resonance imaging; MRA, magnetic resonance angiography.
Spontaneous rather than traumatic events precipitate CADs
It would appear that arterial dissections due to trauma directly associated with spinal manipulation are unlikely, as experiments with arterial models at the University of Calgary have shown that peak elongations of the vertebral artery during neck manipulations are at most 11% of the elongations that would be seen at the arterial failure limits; in fact, these elongations are consistently lower than those seen during routine diagnostic tests.
All of the preceding arguments have attempted to point out that the occurrence of arterial dissections is more subtle than that suggested by frank trauma. An appreciable body of literature exists to demonstrate that a wide variety of common lifestyle activities have been associated with cerebral ischemia (Table 3)
Terrett AGJ. Malpractice avoidance for chiropractors. Vertebrobasilar stroke following manipulation. Des Moines: National Chiropractic Mutual Insurance Company; 1996. p. 15
but are decidedly nonmanipulative. By way of illustration, one very recent investigation has described beauty parlor stroke syndrome and salon sink radiculopathy, confirmed by both symptoms and blood flow velocities in the bilateral vertebral and carotid arteries as measured by a diagnostic ultrasound instrument.
Prospective study of pain, dizziness, and central nervous system blood flow in cervical extension vascular correlations to beauty parlor stroke syndrome and salon sink radiuculopathy.
Thus, it would appear that the tearing of the arterial wall in a dissection is both cumulative and spontaenous: cumulative in that repeated, low-grade insults to the artery would most likely be required to yield a dissection; and spontaneous in that these more minor impositions appear to be by dint of any number of self-imposed maneuvers as well as any by a practitioner, making it extremely difficult if not impossible to distinguish between them. Finally, spontaneous dissections appear to correlate with the fragility of the arterial wall, which may be attributable to inborn errors of metabolism that might be detectable by means of a homocysteine assay.
Relative risks in perspective
As shown above in Table 1, the bulk of the scientific literature establishes the presumed risk of cerebrovascular accidents (including stroke) associated with spinal manipulation at anywhere from 1 per 400,000 to 1 per 5.85 million cervical manipulations, the latter figure representing the most rigorously derived frequency to date.
On the other hand, the risk of deaths from the use of medicines such as nonsteroidal anti-inflammatory agents (NSAIDs) or from surgery to treat many of the same conditions as those managed by chiropractors is 400 to 700 times greater; yet, warnings pertaining to the use of these particular options are often ignored in both common medical treatment and the media.
Those caused by commonly used NSAIDs (such as ibuprofen) have been reported to approach an annual rate of 16,000, dwarfing any estimates of chiropractic fatalities by several orders of magnitude.
How unsubstantiated or misinterpreted risk estimates regarding CVAs attributed to manipulation find their way into the public forum remains a matter of great concern. A troubling series of citations, which create the misleading impression of having data to support them, needs to be discussed in this regard. Such a problem surfaced in the public domain with the publication of an article on aterial trauma by the respected scientific writer Jane Brody for the New York Times. In April 2001, Brody stated that chiropractic spinal manipulation is “estimated to cause stroke in as many as 1 in 20,000 patients.”
Her documentation for this statement was a paper by Wouter Schievink who, in the New England Journal of Medicine, indicated: “As many as 1 in 20,000 spinal manipulations causes a stroke.”
As in Jane Brody's article, there were no data in Schievink's paper to support such a statement. Instead, the author quoted yet another study published by Andrew Vickers 2 years earlier in the British Medical Journal. Unfortunately, Vickers likewise failed to provide any data to support this contention but rather provided only the declaration: “Adverse events range from 1 in 20,000 patients undergoing cervical manipulation to 1 million procedures.”
Through this entire trail of some of the most trusted medical journals, therefore, there is nothing more than the authors' opinions to support this rather drastic contention regarding stroke estimates attributable to spinal manipulation. Worse, the lowest frequency stated by the original author has been completely suppressed in citations in the subsequent scientific and popular literature. Only the suggested figure, which is 50-fold greater than the lower boundary, ever appears to have been carried forward and mentioned.
Dietary folate consumption: a possible solution
As suggested by the biochemical pathways in Figure 2, B, it is conceivable that ensuring adequate levels of folate by dietary intake could depress elevated levels of homocysteine and alleviate the risk of stroke. Indeed, previous studies have shown there to be an inverse relationship between folate and homocysteine concentrations in the blood.
Advancing this suggestion a step further is the dramatic finding from a follow-up study of the National Health and Nutrition Examination Survey (NHANES I) that in a population of 9764 noninstitutionalized US men and women aged 25 to 75 years, dietary intake of folate from food sources is independently and inversely related to the risk of stroke and cardiovascular disease. The relative risk for incident stroke and incident CVD events was 0.79 and 0.86 for patients with the highest daily folate intake (median value 405 μg/d) as compared with the lowest (median value 99 μg/d). In this particular investigation, folic acid supplements were not measured or taken into account in the analysis.
food fortifications with an additional 95 μg/d in the diet of middle-aged and older adults have been proposed to be consistent with approximately a 12% reduction in stroke risk over 20 years. Dietary interventions of this magnitude have thus been proposed63 and would seem to be appropriate advice for the general population, in addition to prospective chiropractic patients.
Conclusion
All signs from the foregoing discussion point to aberrations of arterial structure brought on by elevated levels of homocysteine. When applied to cervical manipulations, this body of evidence suggests that the inherent fragility of the arterial wall of the cerebrovascular system rather than any trauma associated with maneuvers by the attending physician is the major culprit regarding arterial dissections. The actual risk of CVAs that can be directly attributable to spinal manipulation may be reduced to far less conspicuous levels when compared with everyday lifestyle risks and those brought on by medications. Certainly, the propagation of risk estimates attributable to visits to the chiropractor's office without adequate justification from data does not perform a useful service to the public; indeed, it does just the opposite. Homocysteine measurement as a clinical tool would appear to afford the chiropractic physician a means to bring the actual risks of CVAs to even lower levels than those previously reported. In addition, nutritional counseling regarding the intake of increased folate might be expected to reduce elevated homocysteine levels and therefore reduce the risk of spontaneous VADs. At present, homocysteine determinations appear to be the most plausible means of assessing patients who are most at risk for CVAs from routine activities, let alone from cervical spinal manipulations.
References
Lee K.P.
Carlini W.G.
McCormick G.F.
Walters G.W.
Neurologic complications following chiropractic manipulation.
Plasma homocysteine concentration, C677T MTHFR genotype, and 844-ins68bp genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke.
Rapid determination of total homocysteine in human plasma by using N(O,S)-ethoxycarbonyl ethyl ester derivatives and gas chromatography-mass spectrometry.
Terrett AGJ. Malpractice avoidance for chiropractors. Vertebrobasilar stroke following manipulation. Des Moines: National Chiropractic Mutual Insurance Company; 1996. p. 15
00231-8&id=gr1.gif){kind=link}
00231-8&id=gr2a.gif){kind=link}
00231-8&id=gr2b.gif){kind=link}
00231-8&id=gr3.gif){kind=link}
00231-8&id=gr4.gif){kind=link}