Kril_Young_US_Neurology5-2_US_Neuro 16/02/2010 10:31 Page 11
The Evolution of White Matter Hyperintensities
significantly more perseverative errors than normotensive controls.
24
increased the risk for death even after adjustment for hypertension,
The latter study found that working memory and general cognitive high cholesterol, diabetes, and coronary artery disease.
37
functions were not affected. In line with these findings, de Carli et al.
25
showed that even in healthy subjects free from vascular risk factors, Progression
severe WMHs were associated with poorer neuropsychological test As there are so few longitudinal studies of WMHs, little is known about
scores. However, this finding is contradicted by both Kozachuk et al.
26
their evolution or how their progression affects clinical outcomes. Several
and Rao et al.,
27
who reported no significant correlation between small studies using semi-quantitative visual rating scales to assess WMHs
cognitive impairment and WMHs in subjects without cerebrovascular over periods of up to five years showed that there was a mildly increased
risk factors. However, the above-mentioned studies have all consisted of lesion load in many, but not all, subjects.
38–40
Interestingly, the increase was
highly selected subjects and relatively small sample sizes. In a large, correlated with diastolic BP at baseline,
39,40
but was not associated with a
population-based study of 3,301 elderly individuals, it was found that change in neuropsychological test scores.
38
Quantitative studies have
WMHs were associated with poorer cognitive function as measured by shown that, in healthy subjects, the average increase in WMH volume
a modified Mini Mental State Examination (MMSE) and the Digit-Symbol was 1.1cm
3
over four years in one study
41
and 0.1cm
3
over six years in
Substitution Test (DSST). After adjustment for age, sex, and the presence another.
42
However, when subjects with only punctate lesions were
of clinically silent infarcts, the correlation co-efficients for the MMSE and excluded from the analysis, those with confluent lesions showed a WMH
DSST were -0.11 and -0.12, respectively.
5
Although these results are volume increase of up to 9.3cm
3
over the six years.
42
From these results
statistically significant, the clinical significance of such low correlations it was concluded that punctate WMHs are not progressive and are
has been questioned.
28
However, in support of the Longstreth et al.
5
therefore clinically inconsequential, whereas early confluent and
study, the Northern Manhattan Study found that WMHs were associated confluent WMHs are progressive and hence a cause for concern.
42
In
with worse performance on timed cognitive tasks. In addition, it was agreement, the recent multicenter, multinational Leukoaraiosis and
demonstrated that there was a threshold effect, with participants having Disability Study (LADIS) showed that WMH progression over three years
WMH volumes >0.75% of total cranial volume performing significantly was significantly associated with baseline WMH severity.
43
However,
slower on tasks of sensorimotor ability and cognitive flexibility.
29
the LADIS group also found that lacunes also progressed and that the
appearance of new lacunes was predicted by the baseline severity of
Longitudinal studies are needed to determine the cause–effect both WMHs and lacunes. The discrepancy between the results from these
relationship between WMHs and cognition, but unfortunately few have two studies is difficult to reconcile because it is not known whether the
been conducted so far. Austrom et al.
30
found a decline on DSST but not punctate WMHs in the study of Schmidt et al.
42
are comparable to
MMSE over an 18-month period in healthy elderly subjects with WMHs the lacunes in the Gouw and colleagues study.
43
It is clear then that a
compared with those without, while no significant effect on cognitive consensus must be reached on a precise radiological definition of WMHs
function was found over three years in the Austrian Stroke Prevention in order to avoid further confusion.
Study despite comprehensive neuropsychological testing.
31
By contrast,
Silbert and colleagues
32
followed 104 cognitively intact individuals for up Pathogenesis
to 13 years and found that greater total and periventricular WMH volume Despite the existence of a number of studies on the neuropathology of
correlated with poorer gait performance, while increased subcortical WMHs, the histological features of these lesions remain unresolved. It has
WMH volume correlated with memory decline. been proposed that WMHs are part of a cerebrovascular disease
continuum, with asymptomatic radiological findings and areas of
Despite the failure to resolve the matter of WMHs and their influence on incomplete subcortical infarction
44
at one end, through to subcortical
cognitive function, there is evidence to suggest that WMHs may have infarcts and dementia at the other extreme.
18,45
While demyelination and
predictive value in terms of patient outcomes. In patients with lacunar sparing of the subcortical U-fibers are the most consistent findings, a
infarction, it was shown that in addition to lowered survival rate and whole range of pathologies has been reported including gliosis, axon loss,
recurrent stroke rate, the prevalence of dementia was significantly arteriosclerosis, dilated perivascular spaces, infarcts, and spongiosis (see
greater in patients with WMHs compared with those without WMHs.
33
Table 1). The lack of consensus is such that some authors even claim that
These results are supported by the prospective MRI study of Yamauchi pathological correlates of WMHs do not exist.
46
This conclusion was drawn
et al.,
34
who showed that severe WMHs at baseline independently because on the one hand, direct topographic correlations could not be
predicted the risk for stroke in a series of neurological outpatients. In made between discrete MRI abnormalities and neuropathological
addition, a longitudinal study of elderly subjects with major depressive changes, and on the other hand, areas of myelin pallor and gliosis were
disorder found that those with severe deep WMHs (DWMHs) had a associated with areas of normal signal intensity.
46
Nevertheless, a number
significantly worse outcome than patients without lesions. Those with of associations have been identified providing indirect evidence that
severe DWMHs were more likely to remain ill or relapse and had a WMHs have an ischemic origin and that blood–brain barrier (BBB)
significantly shorter median survival time than depressed patients dysfunction may be involved. The unique architecture of the blood supply
without WMHs.
35
Similarly, a study assessing the long-term prognosis in to the cerebral white matter is thought to underlie the ischemic nature of
patients with symptomatic carotid artery disease found that those with WMHs. The periventricular area is considered an arterial border zone
47
extensive WMHs had a three-fold higher risk for stroke.
36
However, the because anastomoses between deep penetrating arteries are scarce,
increased risk for death is not limited to those with vascular risk factors. thereby rendering the periventricular area vulnerable to moderate
A recent study on community-dwelling older people without a history of decreases in perfusion.
48
Similarly, the deep white matter is irrigated by
stroke or neurological disease showed that severe WMHs significantly long penetrating arteries that do not arborize, instead giving off short side
US NEUROLOGY 11
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