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(Stroke. 1995;26:1593-1597.)
© 1995 American Heart Association, Inc.

Articles

Differences Between Treated and Untreated Hypertensive Subjects in the Extent of Periventricular Hyperintensities Observed on Brain MRI

Hitoshi Fukuda, MD Mitsuhiro Kitani, MD

From the Department of Neurology, Masuda Red Cross Hospital, Shimane, Japan.

Correspondence to Hitoshi Fukuda, MD, I-103-1 Otoyoshi, Masuda, Shimane 698, Japan.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Several reports have stated that the periventricular abnormalities found on T₂-weighted MRI or CT are associated with age and hypertension. However, there have been no reports on the effect of hypertension treatment on white matter abnormalities. We studied the association between cardiovascular risk factors and periventricular hyperintensities (PVHs) on T₂-weighted MRI and the differences between treated and untreated hypertensive subjects in the extent of PVHs.

Methods The extent of PVH observed on 238 MRI scans was assessed retrospectively in 238 patients older than 40 years with the use of a five-point (0 to 4) classification scale. Hypertensive subjects were divided into two groups: patients receiving no or irregular treatment and patients receiving regular treatment for hypertension.

Results Age, hypertension, treatment of hypertension, and multiple cerebral vascular lesions on MRI correlated significantly and independently with the extent of PVH. Sex and diabetes mellitus did not correlate with PVH. The Mann-Whitney U test showed significantly more extensive PVH in subjects with no or irregular treatment of hypertension compared with normotensives (2.5±0.7 versus 1.9±0.6, P<.0001) and compared with subjects receiving regular treatment of hypertension (2.5±0.7 versus 2.1±0.5, P=.0019). The latter patients had more extensive PVH than normotensives, but the difference was not significant. Mean systolic and diastolic blood pressure differed significantly among the three groups.

Conclusions Hypertension and age were major predictors of the extent of PVH. Regular treatment for hypertension appeared to prevent the progression of PVH.

Key Words: drug therapy • hypertension • magnetic resonance imaging • white matter

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Several reports have described PVHs and other hyperintensities of the deep white matter detected on T₂-weighted MRI or PVLs on x-ray CT scans of the head. Since several reports^{1 2 3 4 5 6 7 8 9 10} suggested that such findings are associated with cognitive decline, their prevention would seem important. Age^{1 2 3 11 12 13 14 15 16 17 18 19} and hypertension^{2 3 4 5 6 7 11 12 13 14 15 16 17 20 21} are reportedly major predictors of PVH or PVL. While one can infer that treatment of hypertension can prevent the progression of white matter hyperintensities, there are no such reports. Accordingly, we studied the association between cardiovascular risk factors and PVHs and the differences between treated and untreated hypertensive subjects in the extent of PVHs in a retrospective evaluation.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects
We reviewed the clinical records of 939 patients who visited the Department of Neurology and underwent MRI scans of the head (1083 consecutive brain MRI scans) between 1991 and 1994. From the 939 patients, we selected 238 patients who fulfilled the following conditions: (1) age older than 40 years; (2) complete clinical and laboratory data including urinalysis, complete blood count, fasting plasma glucose, HbA_1c, and blood chemistry tests for liver and kidney function in the fasting state; (3) details on hypertension treatment available; (4) 75-g oral glucose tolerance test performed when DM was suspected; (5) no history of multiple sclerosis, cerebral tumor, or leukodystrophy; and (6) MRI without artifacts and of quality sufficient for evaluating PVH grade. Most patients were excluded from this study because of incomplete laboratory findings. The group consisted of 106 men and 132 women (age range, 41 to 91 years; mean, 66.7 years). Diagnoses were cerebral infarction (108), transient ischemic attack (13), Parkinson's disease (13), epilepsy (9), cerebral bleeding (5), and others (90) such as neurosis, depression, headache, numbness, and dizziness. The number of diabetic patients and hypertensives is shown in Tables 1 and 2.

View this table: [in this window] [in a new window]   Table 1. Relative Frequency of Various Factors in Each PVH Grade (0-4)

View this table: [in this window] [in a new window]   Table 2. Univariate Correlations Between Clinical Parameters and PVH Grade

Methods
Arterial blood pressure was measured with the patient seated. If a patient had received medical treatment, the blood pressure recorded was that measured during treatment. In most cases we used the blood pressure data obtained on the day of MRI examination. When the MRI had been performed only in the acute stage of stroke, we used in our analysis the blood pressure measured at the chronic stage more than 1 month after stroke onset.

Hypertension was considered present if the patient's blood pressure was 160/95 mm Hg or higher in any visit or if the patient had received medical treatment for hypertension.

Conditions of treatment for hypertension were defined as follows. If a hypertensive patient had not received medical treatment or had a history of discontinuing medical treatment, that subject was classified as receiving no or irregular treatment. If a hypertensive patient regularly continued taking medical treatment since the hypertension had been diagnosed, he was classified as receiving regular treatment.

MRI studies were performed on a 1.0-T superconductive scanner (Shimadzu SMT100X). Spin-echo pulse sequences were used to generate both T₁-weighted (TR, 400 ms; TE, 15 ms; NEX, 3; or TR, 500 ms; TE, 20 ms; NEX, 3) and T₂-weighted (TR, 3000 ms; TE, 90 ms; NEX, 1) axial brain images. Matrix was 256x256; scanning was done in the orbitomeatal plane with multipolarization radiofrequency head coil; these sections were 8 mm thick and separated by a 2-mm interscan gap; they began at the medullocervical cord junction and extended superiorly to the inner table of the skull.

Definition of Vascular Lesions on MRI
We counted two types of lesions. One type showed hyperintensity on T₂-weighted imaging and obvious low intensity on T₁-weighted imaging; its diameter exceeded 3 mm. We planned to include cerebral infarction on MRI, but a large état criblé can be included in such a lesion.^{22 23} The other type of lesion showed a low or high intensity, circumscribed by low intensity on T₂-weighted imaging. We considered this lesion as intracranial hemorrhage in the chronic stage.²⁴ Vascular lesions were classified as absent, solitary, or multiple according to a total count of these lesions.

Method of Grading PVH on MRI
We excluded from analysis punctate hyperintensities in the deep white matter. Images were read by one of the authors (H.F.) without knowledge of the clinical data. All MRI sections of each subject were used to evaluate PVH grade. We used a newly developed five-point scale to classify PVH (Figure): 0, absent; 1, caps only on anterior horns of the lateral ventricle at the level of the basal ganglia; 2, thin lining, smooth halo, or irregular PVH within an inner half area of the white matter at the level of the body of the lateral ventricle; 3, PVH extending into the outer half area of the white matter at any region around the lateral ventricle; and 4, PVH covering the entire white matter. An MRI study that gave borderline results between two grades was automatically assigned to the lower grade. To dichotomize the PVH score for use in logistic regression analysis, PVH was defined as mild if the score was 2 and as severe if the score was 3.

View larger version (90K): [in this window] [in a new window]   Figure 1. Classification of PVH on T2-weighted MRI. Number indicates grade of PVH.

We studied 238 MRI scans of 238 patients, that is, one MRI scan per patient. Of the 238 patients included in the study, 51 patients underwent more than one MRI scan. When a patient had serial scans, the MRI scan done on the same day as the laboratory examinations or the day closest to the examinations was included in the study.

We determined the interrater reliability of the two raters (H.F. and M.K.) using 35 MRI head scans selected to represent the entire range of PVH grades in the study population. Spearman's rank correlation was 0.921 (P<.0001).

Statistical Analysis
Data are reported as mean±SD. One-way ANOVA was used to compare means of ages and blood pressures among three groups. The Mann-Whitney U test was used to test for significant differences in PVH grade between two groups, and the Kruskal-Wallis rank test was used to test for significant differences in PVH grade among three groups. The ² test was applied to evaluate significant differences between frequency distributions. Spearman's rank correlation was used to make univariate comparisons of PVH grade with age and blood pressures. Multivariate linear regression analysis was used to estimate the independent effects of the predictor variables on the PVH grade. We also performed logistic regression analysis with the PVH score dichotomized and coded as severe (1) or mild (0). A level of P<.05 was accepted as statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 1 shows data on sex, age, hypertension, treatment of hypertension, impaired glucose tolerance, DM, and vascular lesions on MRI in each of the PVH grades. Spearman's rank correlation between age and the PVH grades, systolic blood pressure and the PVH grades, and diastolic blood pressure and the PVH grades was 0.42 (P<.0001), 0.17 (P=.0106), and 0.23 (P=.0004), respectively. All 5 subjects without PVH were normotensive. All 7 subjects with the most severe grade of PVH (grade 4), which covered the entire white matter, were hypertensive. The relative frequency of hypertensive subjects receiving no or irregular treatment for hypertension increased with PVH grade. Of the 7 subjects with PVH grade 4, 6 patients had received no or irregular treatment. Of these 7 patients, 6 patients had multiple lacunar infarcts, 5 patients were demented, and 4 patients had parkinsonism. Five patients receiving no or irregular treatment for hypertension had clinical signs resembling those of subcortical arteriosclerotic encephalopathy (Binswanger's disease).^{2 25} Vascular lesions on MRI were significantly associated with PVH grade (Table 2). The Mann-Whitney U test showed significantly more extensive PVH in the group with multiple MRI lesions versus the group with either no lesion (P<.0001) or a solitary lesion (P<.0001). There was no significant difference in PVH between the group with no lesion versus a solitary lesion (P=.8182). The hypertensives showed more severe PVH scores than the normotensives. Sex or DM was not associated with PVH scores.

Differences in PVH grade and clinical parameters in various conditions of treatment for hypertension are shown in Table 3. The Mann-Whitney U test showed a significantly more extensive PVH in the hypertensives receiving no or irregular treatment than either the normotensives (P<.0001) or the hypertensives receiving regular treatment (P=.0019). The hypertensives receiving regular treatment had a more extensive PVH than the normotensives, but the difference was not significant (P=.0545).

View this table: [in this window] [in a new window]   Table 3. Differences of PVH Grade and Clinical Parameters in Various Conditions of Treatment for Hypertension

The mean systolic or diastolic blood pressure differed significantly among the three groups; it was highest in the hypertensives receiving no or irregular treatment, lower in hypertensives receiving regular treatment, and lowest in the normotensives.

Vascular lesions on MRI were significantly associated with the conditions of treatment for hypertension (P=.0046).

The relative contributions of age (range, 41 to 91 years), sex (female [0], male [1]), hypertension (absent [0], present [1]), treatment of hypertension (no or irregular [0], regular [1]), DM (absent [0], impaired glucose tolerance [1], present [2]), and vascular lesions on MRI (absent [0], solitary [1], multiple [2]) to the PVH score (0 to 4) were assessed by multivariate linear regression analysis. Age, hypertension, treatment of hypertension, and vascular lesions on MRI significantly and independently correlated with PVH. The standardized coefficients were 0.30 (P<.0001), 0.33 (P<.0001), -0.24 (P=.0010), and 0.19 (P=.0036) for these four variables, respectively. Neither sex (P=.3787) nor DM (P=.8556) correlated with PVH scores. The relative contributions of these variables to the PVH score, which was dichotomized and coded as severe (1) or mild (0), were assessed by logistic regression analysis. Age, hypertension, treatment of hypertension, and vascular lesions on MRI significantly and independently correlated with the dichotomized PVH. The r statistics were .23 (P=.0001), .24 (P<.0001), -.17 (P=.0020), and .17 (P=.0018) for these four variables, respectively. Sex (P=.8718) and DM (P=.5721) did not correlate with the dichotomized PVH scores. These results agreed with those of multivariate linear regression analysis.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Previous reports have suggested that PVH or PVL is associated with age,^{1 2 3 11 12 13 14 15 16 17 18 19} hypertension,^{2 3 4 5 6 7 11 12 13 14 15 16 17 20 21} DM,^{16 17 18} a history of stroke,^{12 15 17 19 21} and a history of heart disease.¹³ Although age has consistently been the most powerful predictor of PVH or PVL, the association of other factors such as hypertension, DM, a history of stroke, or a history of heart disease with PVH or PVL remains controversial. Most reports^{2 3 4 5 6 7 11 12 13 14 15 16 17 20 21} have suggested a significant association of hypertension with PVH or PVL, but some^{1 8 18 19} have failed to establish an independent association of hypertension with PVH or PVL. Our study showed that hypertension is significantly associated with PVH, with an association as strong as that of age in multivariate analysis. In previous neuropathological studies,^{2 5 23 26 27 28 29 30} periventricular or focal lesions in white matter were attributed to dilated perivascular spaces, lacunar infarcts, demyelinations, or gliosis. Van Swieten et al²⁷ suggested that arteriolosclerosis is the primary factor in the pathogenesis of diffuse white matter lesions in the elderly. Since arteriolosclerosis has been found with increasing age and hypertension,^{31 32} the lack of any association of hypertension with PVH or PVL is surprising. This inconsistency in results may originate from differences in the conditions of treatment for hypertension among study populations. Our study showed that the difference in PVH grades between hypertensives receiving regular treatment and normotensives was not significant. When most hypertensive subjects in a study receive regular treatment, the association of hypertension with PVH may not be significant.

Vascular lesions on MRI were significantly associated with PVH in our study. Multiple MRI lesions probably show the progressive state of arteriosclerosis. PVH is, therefore, closely connected with cerebrovascular risk factors. Since DM is an important cerebrovascular risk factor, it is probably associated with PVH or PVL. However, our study failed to establish a significant association between PVH and DM. Some studies^{16 17 18} have suggested an association between DM and PVH or PVL, while others^{1 3 7 8 12 15 19 21 33} have not. Several possibilities could explain these conflicting results. First, DM is probably a weaker predictor of PVH than hypertension. Several studies on the association of DM with silent infarction have also given conflicting results.^{34 35 36 37} Reed et al³⁸ reported that serum glucose is marginally associated with atherosclerosis in the large arteries of the circle of Willis, but it is not associated with that in the small arteries; diastolic blood pressure is the only variable that is consistently associated with both atherosclerosis in the large and small arteries and clinical stroke. Second, there may be differences in DM severity and duration among study populations. Third, the number of patients having abnormal glucose metabolism may have been too small in some studies to assess the association of DM with PVH or PVL, since DM is apparently a weak predictor of PVH or PVL. The number was 156 in the study by Manolio et al¹⁵ and 142 in the study by Jorgensen et al³³ but was less than 38 in other studies.^{1 3 7 8 12 16 17 18 19 21}

Our main purpose was to study differences in the extent of PVH among hypertensives receiving no or irregular treatment or regular treatment for hypertension. Our study showed significantly more extensive PVH in hypertensives receiving no or irregular treatment than in those receiving regular treatment. Of 7 patients with extensive PVH covering the entire white matter, 6 had received no or irregular treatment. Five of the 6 had clinical signs resembling those of subcortical arteriosclerotic encephalopathy (Binswanger's disease).^{2 25} Although the association of white matter hyperintensities with cognitive decline and other neurological deficits remains controversial,^{1 2 3 4 5 6 7 8 9 10 11 20 39 40 41 42} when the lesions cover the entire white matter, cognitive decline and other neurological deficits become obvious.^{2 6 9 43} The fact that normotensives did not show PVH covering the entire white matter suggested that PVH does not extend to cover the entire white matter in the absence of hypertension. If regular treatment of hypertension prevents the progression of white matter hyperintensity and decreases the possibility of obvious cognitive decline, the regular treatment of hypertension is extremely important. Our study has shown that the difference in the extent of PVH between the hypertensives receiving regular treatment and normotensives is not significant. Although this study is retrospective, these findings suggest that regular treatment of hypertension may prevent the progression of white matter hyperintensity.

Regular treatment of hypertension was defined as regular, continuous medical treatment since the diagnosis of hypertension. Blood pressure need not have been maintained within the normal range. Diastolic and systolic blood pressure differed significantly between patients receiving regular treatment of hypertension and normotensives. The differences in the extent of PVH between the two groups, although not significant, may originate from this difference in blood pressures. This suggests that maintaining the blood pressure of hypertensive patients within the normal range from the time of diagnosis may lessen the difference in the extent of PVH between the two groups.

	Selected Abbreviations and Acronyms

 

DM = diabetes mellitus NEX = number of excitations PVH = periventricular hyperintensity PVL = periventricular lucency TE = echo time TR = repetition time

	Acknowledgments

 
We are grateful to Makiko Nishiyama of the Department of Neurology for her assistance in laboratory examinations.

Received January 18, 1995; revision received June 1, 1995; accepted June 1, 1995.

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