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(Stroke. 2003;34:1916.)
© 2003 American Heart Association, Inc.

Original Contributions

Editorial Comment—The Progression of Leukoaraiosis

J.V. Bowler, MD, FRCP, Guest Editor

Department of Neurology, Royal Free Hospital, London, England

Leukoaraiosis (LA), the presence of rarefaction of the white matter originally described on CT¹ but now more commonly recognized on MRI, was originally largely ignored as an inconsequential finding seen in association with cerebrovascular disease. More recently, it has become clear that LA impairs cognition.² When LA is sufficiently prominent to be seen on CT, its associated cognitive impairment is readily detected. When seen only on MRI, a more sensitive technique, more sensitive cognitive tools are needed.³ At least as important is the effect of one cognitive disorder to accelerate another, and LA may causally accelerate the progression of Alzheimer disease, for example.⁴ LA is therefore not the unimportant phenomenon it was once considered.

LA encompasses a wide range of histological changes ranging from local edema⁵ to demyelination, loss of axons and oligodendroglia, and mild reactive gliosis without cavitation but does not include frank infarction. The mechanism is not considered to be chronic low perfusion as cerebral blood flow in affected areas lies within normal limits at rest or is modestly decreased in proportion to tissue loss. There is, however, clear evidence of diminished perfusion reserve,^6,7 and it is hypothesized that episodic mild ischemia occurs as a result of intermittent changes in cerebral perfusion pressure. The process has been termed "incomplete infarction."⁸ That extensive areas of LA may be seen without local evidence of completed ischemic events has led to the suggestion that part of the mechanism may be increased blood-brain barrier permeability leading to leakage of serum proteins, which are known to be toxic.⁹

Its new-found importance means that LA has been investigated to only a limited extent. NASCET has already shown that LA is not associated with carotid stenosis but that it is a risk factor for stroke.¹⁰ While NASCET used only CT and did not assess cognition, the data presented in the accompanying article by Streifler et al are invaluable for 2 reasons. The first is the very long follow-up available with a mean of 6.4 years, which is double that of the closest previous data. They have shown that 21% of those without LA at entry developed this during the study and that 31.5% of those with LA at entry deteriorated from this point of view. These data will be of great use in determining sample sizes for future studies of the prevention of progression of LA.

Of at least equal importance are the insights into the etiology of LA that the study provides. These are striking by their relative absence in that the traditional risk factors such as age, hypertension, and diabetes are all identified but are remarkably weak. If traditional vascular risk factors offer only part of the explanation for LA, where might the rest of the explanation be found?

One possible explanation comes simply from the study design. The study was concerned primarily with carotid stenosis and did not look in detail at dysrhythmias or other causes of episodic hypotension, which are one postulated mechanisms by which LA might develop.¹¹ Clearly, if a risk factor was not studied, then its effects cannot be analyzed. Curious in this regard is the previously demonstrated lack of association of carotid stenosis with LA; if episodic hypoperfusion truly was a mechanism by which LA develops, it would be expected that the territory supplied by severely stenosed carotids would be especially vulnerable, and yet this is not the case. This mechanism may therefore be weaker than has been supposed and in any case is certainly not yet proven.

The other insight comes from Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL).¹² This is numerically unimportant when set against the total burden of cerebrovascular disease but is important because it shows that specific diseases of small vessels causing progressive occlusion can and do exist. Furthermore, there may well be at least 2 such conditions since an autosomal recessive condition associated with lumbago and alopecia has been described in Japan.¹³ It is the common experience of practicing neurologists that from time to time they see patients with considerable LA in the absence of much in the way of vascular risk factors. The converse is also true, that patients are seen with extensive risk factors, particularly hypertension, but who have little if any LA. These observations can be tied together by the hypothesis that the ability of patients’ small deep arteries to resist the consequences of hypertension and other risk factors varies; CADASIL is an extreme, but buried within the general non-CADASIL population there may well be other single-gene causes of "fragile" vessels or polygenetic factors producing a continuum of susceptibility. Given that LA predicts lacunar stroke, cognitive decline, and dementia and that it is common, the time is now ripe to look pathologically and genetically at patients with LA (and those with extensive risk factors but no LA) with a view to identifying and ultimately treating 1 or more as yet unrecognized conditions affecting small cerebral arteries.

	References

Top References

 

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