Absence of Selective Deep White Matter Ischemia in Chronic Carotid Disease

In a recent article in the AJNR, Derdeyn et al (1) concluded that “normal deep white matter among patients with carotid occlusion is not subject to a greater degree of ischemia than is the overlying cortex.” This conclusion may be appropriate for the population studied and the measurements made; however, it should be qualified because of patient selection bias. The conclusion is not applicable to the larger clinical population, and it does not settle the question at hand.

The study is subject to selection bias because 19 of 55 patients who had raised superficial (cortical) oxygen extraction fraction ratios (compared to the contralateral hemisphere) were excluded because “all three deep white matter regions were abnormal, as revealed by CT or MR imaging.” These patients may have been the ones that should have been examined to show the changes that were sought. Furthermore, CT and MR imaging “changes” do not necessarily indicate infarction and, by eliminating these patients and studying only patients with “normal” white matter, the authors biased their study.

The authors further biased the study by selecting only patients with unilateral occlusion (for a ratio-based approach for calculating the oxygen extraction fraction). Seventeen of the 36 patients had never had a neurologic event or were 5 months past their last event. Because patients with bilateral occlusion were excluded, the patients studied were less likely to have severe or prolonged hemodynamic compromise. Widder et al (2) showed that cerebrovascular hemodynamics improves by 5 months after the onset of symptoms in unilateral carotid disease, but remains impaired in bilateral carotid disease. Thus, nearly half of the patients may have overcome the disorder by the time of this study.

Further selection bias is evident because few individuals in the study presented with ischemic claudication (Dr. William Powers, personal communication). These coarse, rhythmic, shaking movements, often induced in a patient with carotid occlusion who assumes an erect posture, are associated with the appearance of unilateral deep white matter changes. Firlik et al observed a patient with this syndrome and white matter changes who had near-zero perfusion selectively within the deep white matter with a vasodilator challenge by acetazolamide (3). A similar response was observed within the deep white matter of 13 patients who had recurrent hemispheric symptoms despite maximal medical therapy, and who subsequently developed deep white matter infarctions in the lowest flow regions. A hemodynamic mechanism for this disorder was indicated by the fact that all of these patients stabilized clinically and had positive cerebrovascular reserve after superficial temporal artery-middle cerebral artery bypass surgery (4).

Patients with ischemic claudication and ipsilateral deep white matter ischemic changes presumably suffered infarctions because of modest alterations in cerebral perfusion pressure, as may occur when assuming an erect posture. Perhaps a simple way to answer the question raised by Derdeyn et al would be to measure the cerebral blood flow (CBF) response to a transient, moderate lowering of arterial blood pressure. In a recently treated patient who had carotid occlusion, we observed that blood pressure elevation resulted in cessation of recurrent neurologic events. A blood pressure–lowering, xenon/CT, CBF study was performed 5 days later to determine whether hypertensive therapy was still needed (Fig 1, page 225). A dramatic decrease of CBF values to near zero was recorded selectively within the deep white matter, in and near the site of white matter infarction.

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fig 1.

Cerebral blood flow decreased throughout the right middle cerebral artery territory and selectively within the deep white matter during systolic blood pressure reduction from 168 to 145 mm Hg. The lavender color indicates increase of area with flow levels at or below 8 mL/100 g/min (arrows)

In conclusion, we believe that a significant number of individuals who come to clinical attention because of recurrent ischemic events ipsilateral to a carotid occlusion, despite anticoagulation, suffer from a hemodynamic disorder. The predilection of these individuals for deep white matter infarctions within regions of maximal hemodynamic challenge (evidenced by the development of ischemia in response to a hemodynamic challenge) is a real phenomenon that warrants further study.