Department of Neurological and Psychiatric Sciences,
University of Florence, Florence, Italy
To the Editor:
Changes in the cerebral white matter are detected with high frequency
by CT and MRI in aged individuals.1 The
descriptive term leukoaraiosis, meaning rarefaction of the white
matter, was proposed some 10 years ago to describe these radiological
changes.2 Although the mechanism of leukoaraiosis
in different clinical conditions such as Alzheimer's disease
or stroke remains undefined, vascular mechanisms probably underlie a
reasonably large part of these alterations.3
Leukoaraiosis has been inconsistently associated with cognitive
impairment, assorted motor dysfunctions, and gait disturbances,
but its contribution to Alzheimer's disease and vascular
dementia is controversial.1 Part of these
discrepancies stem from different sensitivities of rating scales for
white matter changes, small sample sizes of patients, and use of
disparate neuropsychological tests.1
Recently, new evidence has suggested that leukoaraiosis may be
clinically important. First, patients with leukoaraiosis have a poor
prognosis in terms of death, stroke, and myocardial infarction. This
has been documented both in patients with motor impairment and
extensive leukoaraiosis on CT4 and in clinically
heterogeneous patients with any degree of
leukoaraiosis.5 Second, the results of
prospective studies indicate that leukoaraiosis may be an independent
and strong predictor of dementia in stroke
patients.6 7 Among 300 patients with TIA,
cerebral infarction, or intracerebral
hemorrhage, those with poststroke dementia showed leukoaraiosis
on their entry CT scan three times more frequently than nondemented
patients.7 Third, and most recent, the presence
of leukoaraiosis increases the risk of intracranial bleeding in
patients with cerebrovascular diseases treated with
anticoagulants.8 The SPIRIT (Stroke Prevention In
Reversible Ischemia Trial) was a multicenter randomized study
designed to examine the role of oral anticoagulants and
antiplatelet drugs as secondary prevention treatments in sinus
rhythm patients with minor cerebral ischemic events of supposed
atherothrombotic origin. Anticoagulation was set at a rather high
international normalized ratio (INR) level (3 to 4.5), in
accordance with Dutch national guidelines. The trial had to be stopped
prematurely after the first interim analysis because of the
excess of bleeding in the group of anticoagulated patients. Major
bleedings were reported in 53 of the 651 patients randomized to
warfarin treatment. About one half of all the bleedings were
intracranial hemorrhage, which were fatal in 17 cases. Age
Thus, although much about the pathogenesis and clinical significance of
leukoaraiosis remains to be elucidated, white matter changes relate to
the prognosis of patients and can no longer be considered a secondary
issue. Moreover, the above-mentioned results will require clinicians to
examine in greater detail the status of the brain before deciding
optimal preventive measures. It is therefore essential that
investigators collaborate in the task of harmonizing the classification
of white matter changes to better understand the clinical and
pathological correlates. An European multinational research group (The
European Task Force on Age-Related White Matter Changes) has been
recently founded with these aims.
Footnotes
1 The European Task Force on
Age-Related White Matter Changes (country coordinators): F.
Fazekas (Austria), J. De Reuck (Belgium), E. Garde (Denmark), T.
Erkinjuntti (Finland), D. Leys (France), M. Hennerici (Germany), Z.
Nagy (Hungary), N. Bornstein (Israel), D. Inzitari (Italy), P.
Scheltens (Netherlands), J. Ferro (Portugal), T. del Ser (Spain), L.-O.
Wahlund (Sweden), J. Bogousslavsky (Switzerland), and M. Brown (United
Kingdom).
References
1.
Pantoni L, Garcia JH. The significance of cerebral
white matter abnormalities 100 years after Binswanger's report: a
review. Stroke. 1995;26:1293–1301.
2.
Hachinski VC, Potter P, Merskey H. Leuko-araiosis.
Arch Neurol.. 1987;44:21–23.
3.
Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a
review. Stroke. 1997;28:652–659.
4.
Inzitari D, Di Carlo AS, Mascalchi M, Pracucci G,
Amaducci L. The cardiovascular outcome of patient with
motor impairment and extensive leukoaraiosis. Arch Neurol. 1995;52:687–691.
5.
Inzitari D, Cadelo M, Marranci ML, Pracucci G, Pantoni
L. Vascular deaths in elderly neurological patients with leukoaraiosis.
J Neurol Neurosurg Psychiatry. 1997;62:177–181.
6.
Miyao S, Takano A, Teramoto J, Takahashi A.
Leukoaraiosis in relation to prognosis for patients with lacunar
infarction. Stroke. 1992;23:1434–1438.
7.
van Kooten F, Maasland L, Dippel DWJ, Kluft C, Grobbee
DE, Koudstaal PJ. CT-scan abnormalities in relation to dementia in
patients with stroke. Cerebrovasc Dis. 1997;7(suppl 4):42.
Abstract.
8.
Gorter JW, Algra A, van Gijn J, Kappelle LJ, Koudstaal
PJ, Tjeerdsma HC, on behalf of the SPIRIT Study Group. SPIRIT:
predictors of anticoagulant-related bleeding complications in patients
after cerebral ischemia. Cerebrovasc Dis.
1997;7(suppl 4):3. Abstract.
9.
Inzitari D, Giordano GP, Ancona AL, Pracucci G,
Mascalchi M, Amaducci L. Leukoaraiosis, intracerebral
hemorrhage, and arterial hypertension.
Stroke. 1990;21:1419–1423.
© 1998 American Heart Association, Inc.
Letters to the Editor
New Clinical Relevance of Leukoaraiosis
65
years, elevated INR levels, and presence of leukoaraiosis on CT scan
were predictors of hemorrhage.8 The
association between white matter abnormalities and cerebral
hemorrhage is not new, but it had previously been explained
primarily by the common association with arterial
hypertension.9 Since the strongest predictor of
leukoaraiosis is advanced age, the SPIRIT results need to be viewed
with some caution in the light of the possible confounding effects of
age and hypertension. Nevertheless, these data have already had an
impact on the scientific community: a second forthcoming randomized
trial, the European Stroke Prevention in Reversible Ischemia
Trial (ESPRIT), which will evaluate the preventive efficacy of warfarin
in patients with noncardioembolic stroke, lists the presence of
leukoaraiosis among its exclusion criteria. This will certainly raise
the problems of definition and grading of these changes on CT and
MRI. 
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