Extensive lesions of the cerebral white matter

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1 114 Fontal White Matte Lesions and Dementia in Lacuna Infaction Hitoshi Fukuda, MD, Shotai Kobayashi, MD, Kazunoi Okada, MD, and Tokugoo Tsunematsu, MD We studied the associations of mental deteioation and blood pessue with seveity and location of lesions in the ceebal white matte of 5 patients (27 men and eight women) aged (mean 70.9) yeas with multiple lacuna infacts; 21 had no dementia and 14 wee demented. Using magnetic esonance imaging to evaluate lesion seveity, we detemined that demented patients had moe sevee lesions than nondemented patients; this diffeence was especially pominent fo lesions in the fontal lobe (p). Scoe on the dementia ating scale of Hasegawa et al was negatively coelated with seveity of the lesions in the fontal lobe. Blood pessue was positively coelated with the seveity of white matte lesions. We show that seveity of lesions in the white matte, especially in the fontal lobe, is coelated with mental deteioation of patients with multiple lacuna infacts. Because uncontolled hypetension is elated to the seveity of such lesions, caeful selection of antihypetensive teatment is impotant in peventing both the ceebal lesions and the associated mental deteioation. {Stoke 1990;21: ) Extensive lesions of the ceebal white matte cause the dementia known as Binswange's disease. Seveal investigatos have epoted that hypetension is a majo isk facto fo such ischemic lesions. 1-5 In a clinicopathologic study of the autopsied bains of patients with vascula dementia and a lacuna state, Ishii et al 6 suggested that not only the lacunae but also incomplete softening of the white matte, especially in the fontal lobe, wee impotant causes of the dementia. The pupose of ou study was to investigate the associations of mental deteioation and blood pessue with seveity and location of lesions in the ceebal white matte of patients with multiple lacuna infacts. Subjects and Methods We etospectively evaluated patients who wee seen in the Shimane Medical Univesity Hospital fom 1987 to 1988 and diagnosed as having multiple lacuna infacts fom thei clinical signs and symptoms, laboatoy data, and bain images. All patients had a histoy of stoke. Computed tomogaphy (CT) and magnetic esonance imaging (MRI) using the invesion-ecovey method demonstated multiple ischemic infacts of esticted size in the deepe pats Fom the Thid Division of Intenal Medicine, Shimane Medical Univesity, Izumo, Japan. Addess fo coespondence: Shotai Kobayashi, The Thid Division of Intenal Medicine, Shimane Medical Univesity, 89-1, Enya, Izumo, Shimane, 69, Japan. Received Octobe 0, 1989; accepted Apil 19, of the patients' bains; thei neuologic deficits could be explained by these lacunae. We excluded patients with obvious cotical lesions, those with acute stoke, those who had been obviously demented befoe thei stokes, and those whose MRI scans wee of poo quality (had motion atifacts). Afte exclusion, thee wee 5 patients (27 men and eight women) aged (mean 70.9) yeas; 21 (15 men and six women, aged [mean 69.] yeas) had no dementia, and the othe 14 (12 men and two women, aged [mean 7.2] yeas) wee demented. Dementia was diagnosed based on the DSM-IIIR. 7 Fouteen demented patients had an ischemic scoe of Hachinski et al 8 of >10 points, and thei CT and MRI scans demonstated multiple lacunae without cotical lesions. All 21 demented patients wee diagnosed as having multi-infact dementia. Yoshimua et al 9 epoted that the so-called mixed-type dementia with pathologic featues of both senile and vascula dementia accounted fo only 19 of the 216 autopsied bains fom demented pesons in Japan. Moeove, those patients with mixed-type dementia had signs of cognitive impaiment befoe thei stokes. Theefoe, we excluded patients who had been obviously demented befoe thei stokes. The diastolic, systolic, and mean ateial blood pessues of each patient wee the mean of 10 seial measuements obtained seveal months befoe MRI. We compaed age and blood pessue in the two goups using Student's t test and the incidence of isk

2 1144 Stoke Vol 21, No 8, August 1990 FIGURE 1. Top left: Tl-weighted magnetic esonance image; top ight: long spin-echo image; bottom left: invesion-ecovey image; and bottom ight: schema of axial slice, all at level of basal ganglia. Seveity of lesions in white matte was measued on Tl-weighted image in egions 1 and 2 shown in schema. factos fo ceebovascula disease as documented in the patients' ecods using the x 1 test - The MRI studies wee pefomed using an MRT- 15 unit (Toshiba, Tokyo, Japan) with a 0.15-T magnet at Shimane Institute of Health Science. Bain images wee obtained appoximately paallel to the obitomeatal line in the tansvese plane. Absolute Tl-weighted images wee obtained by taking invesion-ecovey (epetition time [TR] 2,000 msec; echo time [TE] 40 msec; invesion time 400 msec) and spin-echo (TR 1,600 msec; TE 40 msec) scans at the same time (Figues 1 and 2). We evaluated seveity of

3 Fukuda et al White Matte Lesions and Dementia 1145 FIGURE 2. Top left: Tl-weighted magnetic esonance image; top ight: long spin-echo image; bottom left: invesion-ecovey image; and bottom ight: schema of axial slice, all at level of body of lateal venticle. Seveity of lesions in white matte was measued on Tl-weighted image in egions -8 shown in schema. the white matte lesions on Tl-weighted images as distance fom the neaest magin of the lateal venticle to the point at which the Tl value exceeded 400 msec on a television monito; distance was measued using commecially available softwae fo the MRI unit. In this study, the Tl value of nomal white matte was <00 msec. The aea in which the Tl value exceeds 400 msec is nealy equal to the aea of hypeintensity shown by the T2- weighted method. This aea shows not only the lacuna but also the so-called peiventicula hypeintensity.

4 1146 Stoke Vol 21, No 8, August 1990 We measued seveity of the white matte lesions in eight egions: the ight and left fontal lobe on an axial slice at the level of the basal ganglia (Figue 1) and the ight and left anteio (fontal), middle (fontopaietal), and posteio (paieto-occipital) potions on an axial slice at the level of the body of the lateal venticle (Figue 2). It was difficult to measue seveity of the white matte lesions in posteio aeas on an axial slice at the level of the basal ganglia because white matte in those aeas was naow, especially when bain atophy was sevee, and contamination of the white matte with the cotex and the subaachnoid space could not be excluded. We compaed seveity between goups fo each egion individually and fo the sum of all eight egions using Student's t test. We investigated the elations of the sum of seveities with diastolic, systolic, and mean ateial blood pessues fo all 5 patients and fo each goup sepaately using linea egession analysis. We studied inteate eliability of the seveity measue using MRI scans fom 10 of the 5 patients analyzed by thee obseves. We evaluated inteate ageement using easons' coelation coefficients. Using the dementia ating scale of Hasegawa et al, 10 we evaluated the mental abilities of 26 of the 5 patients, 12 (nine men and thee women) without dementia and the 14 (12 men and two women) who wee demented. This dementia ating scale is a useful bedside method of scoing cognitive impaiment and consists of five subtests to measue oientation, geneal infomation, calculation, memoy ecall, and memoization. The maximum scoe is 2.5 points, with low scoes eflecting moe cognitive impaiment. We investigated the elations of seveity and location of the white matte lesions with scoe on the dementia ating scale fo the 26 patients using linea egession analysis. Data ae pesented as mean±sd. Statistical significance was tested using Student's t distibution with a pobability value of Results Table 1 shows the clinical chaacteistics of the two goups. Thee wee no significant diffeences in age, blood pessue, o the incidence of isk factos fo ceebovascula disease between goups. In the compaison of lesion seveity as measued by thee obseves, high levels of inteate ageement wee obtained. Coelations anged fom (/J) to (/>) and aveaged Seveity of the white matte lesions in each egion fo the two goups is shown in Figue. White matte lesions in the demented patients wee significantly moe sevee than those in the nondemented patients in all egions, especially in the fontal lobe aound the anteio hons of the lateal venticles. The sum of seveities of the white matte lesions fo all eight egions was also highe in the demented goup than in the nondemented goup (100±25 and 47±25 mm, espectively; p). TABLE 1. Clinical Chaacteistics of Demented and Nondemented atients With Multiple Lacuna Infacts Chaacteistic Age (y) Blood pessue (mm Hg) Diastolic Systolic Mean ateial Risk facto Hypetension Diabetes mellitus Hypecholesteolemia Angina pectois and/o old myocadial infact Atial fibillation None known Nondemented Mean±SD No. 69.±7.8 84± ± Goup Demented Mean±SD No. 7.2±9.4 84±16 140±27 10 ±20 Hypecholesteolemia, total cholesteol concentation of >200 mg/dl. The coelations between seveity of the white matte lesions in all eight egions and scoe on the dementia ating scale fo 26 patients appea in Table 2. Seveity was significantly coelated with scoe in the anteio half of the bain, namely, the fontal lobe. The coelation was stongest in the fontal lobe aound the anteio hons (Figue 4). Diastolic, systolic, and mean ateial blood pessues in all 5 patients and in each goup individually wee significantly coelated with the sum of seveities of the white matte lesions (Table ). Diastolic 25 " 20-15" 10" n n n n 1 - O -L O X t n n -L JL U U 0 J t REGION NUMBER FIGURE. Mean±SD seveity of white matte lesions (SWML) in nondemented (o, n=21) and demented (*, n=14) patients in eight egions. 1, 2: ight (R), left (L) fontal lobe;,4: R, L anteio potion; 5, 6: R, L middle potion; 7, 8: R, L posteio potion. *ft p<0.007, 0.07, and 0.025, espectively, diffeent between goups by Student's t test.

5 Fukuda et al White Matte Lesions and Dementia 1147 TABLE 2. Coelation Coefficients and obabilities fo Seveity of White Matte Lesions and Scoe on Dementia Rating Scale fo 26 atients Region Anteio hons 1 2 Location R fontal lobe anteio L fontal lobe < < Body of lateal venticle R anteio L anteio R middle L middle R posteio L posteio <0.005 NS NS NS Total R, ight; L, left; NS, not significant. blood pessue was most stongly coelated with seveity of the white matte lesions (Figue 5). Discussion Seveal investigatos have suggested an association between dementia and extensive lesions in the white matte of patients with multiple lacuna infacts. 6 ' 11-1 ositive elations of white matte lesions to a histoy of stoke 2-14 and to atheoscleogenic isk factos such as hypetension 1 " 5 and diabetes mellitus 1 have been epoted. The aea suounding the anteio hons is a common site fo the lacunae. 615 We studied the association of mental deteioation and blood pessue with seveity and location of white matte lesions in patients with multiple lacuna infacts. Demented patients had moe sevee white matte lesions than nondemented patients, with the diffeence between goups especially maked in the fontal lobe. Scoe on the dementia ating scale of Hasegawa et al 10 was negatively coelated with the seveity of white matte lesions in the fontal lobe, especially in the aea suounding the anteio hons. Ishii et al 6 descibed a clinicopathologic study of 0 autopsied bains of patients with vascula dementia and a lacuna state and suggested that not only the lacunae but also incomplete softening of the white matte, especially in the fontal lobe, wee impotant causes of the dementia. Kameyama 11 studied 700 autopsied bains and epoted that pesons with fontal ceebovascula lesions, especially multiple infacts in the bilateal white matte of the fontal lobe, cingulate gyus, and anteio pat of the copus callosum, had a highe incidence of dementia. Ou findings agee with these pevious epots. In a study of multi-infact dementia using oxygen- 15 positon emission tomogaphy, Ujike et al 16 epoted that deceases in ceebal blood flow and metabolism wee most pominent in the fontal lobe. We suggest that thei esults coespond with a pedominant lesion in the white matte of the fontal lobe in pesons with multi-infact dementia _ H D R S (points) FIGURE 4. Scatte plot of coelation between seveity of white matte lesions aound left anteio hon of lateal venticle (SWML) and scoe on dementia ating scale of Hasegawa et al' (HDRS) fo 12 nondemented (o) and 14 demented ( ) patients. Maximum scoe on HDRS is 2.5 points. = , p diastolic blood pessue (nhg) FIGURE 5. Scatte plot of coelation between sum of seveities of white matte lesions (SWML) and diastolic blood pessue in 21 nondemented patients. =0.711, p.

6 1148 Stoke Vol 21, No 8, August 1990 TABLE. Coelation Coefficients and obabilities fo Sum of Seveities of White Matte Lesions and Blood essue Blood pessue (mm Hg) Diastolic Systolic Mean ateial Nondemented (n = 21) <0.025 <0.005 Goup Demented (n-14) <0.025 < < Total (JV=5) < <0.01 <0.025 What does elongation of the Tl values eflect? MRI-pathologic studies using the T2-weighted method show that white matte lesions on MRI coespond to such conditions as etat cible, 17 demyelination, and lacunae o gliosis Although we used Tl values, the aea in which the Tl value exceeds 400 msec is nealy equal to the high-intensity aea shown by the T2- weighted method. Theefoe, we conside the white matte lesions in ou study to be ischemic lesions, especially lacunae and aeas of incomplete softening. The positive coelation between blood pessue and seveity of white matte lesions suggests that uncontolled hypetension acceleates the pogession of white matte lesions. An association between hypetension and white matte lesions has been epoted. 1-5 Hypetension is a majo isk facto fo lacunae. 15 The cases of subcotical ateioscleotic encephalopathy epoted by Olszewski 4 wee attibuted to hypetensive vasculopathy of small ateies and ateioles in the white matte. Ishizaki epoted that multiple small infacts aound the basal ganglia (etat lacunaie) may be associated with subcotical ateioscleotic encephalopathy in the bains of eldely patients with a histoy of hypetension. Multiple lacunae and incomplete softening may enlage moe easily in those patients with multiple lacuna infacts and uncontolled hypetension. Ischemic lesions elongate both the Tl and T2 values on MRI. Extensive fontal white matte lesions ae closely elated to mental deteioation. Although a diffeence between demented and nondemented patients in the seveity of white matte lesions was pominent in ou study, mean ateial blood pessue did not diffe significantly between goups. We speculate that thee ae diffeences in the histoy of hypetension such as seveity, duation, theapy, and episodes of tansient hypotension. Howeve, these factos cannot be accuately detemined in a etospective study. Moe detailed pospective studies ae necessay to investigate this possibility. Ou study shows that seveity of white matte lesions, especially in the fontal lobe, is coelated with mental deteioation in patients with multiple lacuna infacts. Because uncontolled hypetension is elated to the seveity of white matte lesions, selection of appopiate antihypetensive theapy is impotant in peventing both white matte lesions and mental deteioation. To what level must we educe blood pessue in a hypetensive patient to pevent white matte lesions? This question is vey difficult to answe, especially duing the late stages of uncontolled hypetension when vasculopathy may aleady be sevee. Duing this stage, oveeduction of blood pessue may lead to ischemic bain lesions. Autoegulation of the ceebal ciculation also changes in hypetensive patients. The lowe limit of ceebovascula autoegulation is highe among pesons with hypetension than among those who ae nomotensive, and the extent of the change vaies among patients Theefoe, optimal blood pessue, which not only maintains sufficient ceebal blood flow but also pevents the fomation of hypetensive vasculopathy, may also diffe in each case. Acknowledgments We acknowledge the technical contibutions of Akia Besho, Shimane Institute of Health Science. Thanks ae also due to D. Shuhei Yamaguchi, D. Hiomi Koide, D. Nobuo Suyama, and D. Hiokazu Bokua fo much help. Refeences 1. Ketesz A, Black SE, Toka G, Benke T, Ca T, Nicholson L: eiventicula and subcotical hypeintensities on magnetic esonance imaging: 'Rims, caps, and unidentified bight objects.'/4c/i Neuol 1988;45: Awad IA, Spetzle RF, Hodak JA, Awad CA, Caey R: Incidental subcotical lesions identified on magnetic esonance imaging in the eldely: I. Coelation with age and ceebovascula isk factos. Stoke 1986;17: Ishizaki T: Coexistence of etat lacunaie and subcotical ateioscleotic encephalopathy in old age. Rinsho Shinkeigaku 1975;15: Olszewski J: Subcotical ateioscleotic encephalopathy: Review of the liteatue on the so-called Binswange's disease and pesentation of two cases. Wold Neuol 1962;: McQuinn BA, O'Leay DH: White matte lucencies on computed tomogaphy, subacute ateioscleotic encephalopathy (Binswange's disease), and blood pessue. Stoke 1987; 18: Ishii N, Nishihaa Y, Imamua T: Why do fontal lobe symptoms pedominate in vascula dementia with lacunes? Neuology 1986;6: Ameican sychiatic Association: Diagnostic and Statistical Manual of Mental Disodes, ed. Washington, DC, Ameican sychiatic Association, 1987, pp Hachinski VC, Iliff LD, Zilhka E, Du Boulay GH, McAlliste VL, Mashall J, Russell RWR, Symon L: Ceebal blood flow in dementia. Ach Neuol 1975;2: Yoshimua M, Tomonaga M: Mixed type of dementia: Its clinico-pathological aspects. Shinkei Kenkyu Shinpo (Tokyo) 1985;29:

7 Fukuda et al White Matte Lesions and Dementia Hasegawa K, Inoue K, Moiya K: An investigation of dementia ating scale fo the eldely. Seishin Igaku (Tokyo) 1974; 16: Kameyama M: Vascula lesions in the fontal association field and dementia. Seishin Igaku (Tokyo) 197;15: Goto K, Ishii N, Fukasawa H: Diffuse white-matte disease in the geiatic population: A clinical, neuopathological, and CT study. Radiology 1981;141: Ekinjuntti T, Ketonen L, Sulkava R, Sipponen J, Vuoialho M, Iivanainen M: Do white matte changes on MRI and CT diffeentiate vascula dementia fom Alzheime's disease? / Neuol Neuvsug sychiaty 1987;50: Inzitai D, Diaz F, Fox A, Hachinski VC, Steingat A, Lau C, Donald A, Wade J, Mulic H, Meskey H: Vascula isk factos and leuko-aaiosis. Ach Neuol 1987;44; Fishe CM: Lacunes: Small, deep ceebal infacts. Neuology 1965;15: Ujike T, Teashi A, Soeda T, Kitamua S, Kato T, Iio M: Ceebal bloodflowand metabolism in multi-infact dementia. No To Shinkei 1985;7: Awad IA, Johnson C, Spetzle RF, Hodak JA: Incidental subcotical lesions identified on magnetic esonance imaging in the eldely: II. ostmotem pathological coelations. Stoke 1986;17: Kikpatick JB, Hayman LA: White-matte lesions in MR imaging of clinically healthy bains of eldely subjects: ossible pathologic basis. Radiology 1987;162: Baffman BH, Zimmeman RA, Tojanowski JQ, Gonatas NK, Hickey WF, Schlaepfe WW: Bain MR: athologic coelation with goss and histopathology. 2. Hypeintense white-matte foci in the eldely. AW? 1988;151: Mashall VG, Badley WG J, Mashall CE, Bhoopat T, Rhodes RH: Deep white matte infaction: Coelation of MR imaging and histopathologic findings. Radiology 1988; 167: Standgaad S, Olesen J, Skinhoj E, Lassen NA: Autoegulation of bain ciculation in sevee ateial hypetension. B Med J 197;l: Standgaad S: Autoegulation of ceebal ciculation in hypetension. Ada Neuol Scand 1978;57(suppl 66):l-82 KEY WORDS dementia hypetension lacuna infaction