Spontaneous Cervical Artery Dissections
and Implications for Homocysteine

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:   Frankp@chiro.org

FROM:   J Manipulative Physiol Ther 2004 (Feb);   27 (2):   124–132 ~ FULL TEXT

Anthony L. Rosner, PhD

Foundation for Chiropractic Education and Research 1330 Beacon Street, Suite 315 Brookline, MA 02446-3202 USA

Introduction

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 [1-5]; 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. [6-11] 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.

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. [15] The corresponding VAD incidence rate in community settings has been reported to be twice as high. [16, 17] Using an estimated value of 10 from the literature to represent an average number of manipulations per patient per episode,23 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. [15-17] 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.

Genetic factors and elevated homocysteine

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.24 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. [25]

In comparing 3 groups of about 30 patients each, Pezzini et al24 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,24 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/L26; and (2) homocysteine levels exceeding 10.2 µmol/L are associated with a doubling of vascular risk. [27]

What is the clinical significance of elevated homocysteine levels? For years, homocysteine has been implicated as a key component of atherosclerosis and cardiovascular diseases, 27-35] but Pezzini et al [24] 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. [36]

2.   Homocysteine activates metalloproteinases [36] and serine elastases, [37] 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. [36, 37]

3.   Homocysteine has been shown to block aldehydic groups in elastin, inhibiting the cross-linking needed to stabilize elastin. [38]

4.   The cross-linking of collagen may also be impaired by homocysteine. [39]

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.

The Pezzini et al [24] 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. [25] 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 [25]; 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.

Other links between elevated homocysteine and CAD

Links between increased plasma levels of homocysteine and vascular disease were proposed as early as in 1969. [28] 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. [33] In subjects with hyperhomocysteinemia, an impaired reaction of endothelium-dependent and flow-mediated dilation could be observed. [34] Finally, in cell culture experiments, the addition of homocysteine into the cell medium induced the detachment of cells from the endothelial cell monolayer. [40] 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. 28-32]

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