Journal of Mental Deficiency Research, 1987, 31, 235-240

Neurogenic atherosclerosis in mentally retardedpersons

R. H. CHANEYSchool of Medicine, University of California at Los Angeles, California, USA

ABSTRACT. The question is raised whether arteriosclerosis (AS) may be induced inman by chronic central nervous system injury. In an institutionalized population ofmentally retarded children, more AS than expected was observed. Of 1173 residentswith detailed clinical and autopsy records over 40 years, 78 of them, aged 1—21 years,showed mild to moderate coronary or aorta AS. Thirty control subjects without AS,matched for sex, age and IQ, were studied in comparison. In 65 of the probands, thecondition could not be explained by predisposing diseases or known risk factors. Therewere more lesions in those with convulsive disorder; this was felt to reflect arterialchanges due to neuronal-sympathoadrenal hyperactivity. In addition, more diseaseoccurred in physically restricted patients; this appeared related to the stress of handicapand inability to respond to psychosocial needs. It is concluded that certain areas of braindefect predispose to atherogenesis. Down's syndrome provides a different set ofinfluences on AS, yet the frequency of AS in these patients was similar to that of non-Down's.

I N T R O D U C T I O N

In an institution for mentally retarded persons, more children than expected werefound to have arteriosclerosis (AS). This did not appear to be due to knownpredisposing diseases or traditional risk factors, but it was suggestive that suchvascular changes might relate to certain of the concomitants of brain damage. One ofthese is the frequency of abnormal neuronal discharges, such as manifested byepilepsy, which has been shown to cause arterial changes (Gutstein et al., 1978), aswell as promoting sympathoadrenal overstimulation which may underly earlyatherogenesis (Carruthers, 1979). A second result of brain damage is the physicalrestriction imposed on the patient, in which the helplessness has been described as asource of stress (Chaney et aL, 1985). Therefore, detailed clinical and autopsy data onthese institutionalized individuals were examined to determine whether some types ofbrain pathosis predisposed to atherogenesis.

M E T H O D

One thousand one hundred and seventy-three residents at Lanterman State Hospital,a 1250-bed hospital in Southern California, died and were autopsied between 1944and 1984. There was no basic change in the population at risk or in living conditionsover these 40 years. Most had diffuse brain disease, especially in the white matter, the

Correspondence: Robert H. Chaney MD, Mental Retardation Research Center, LantermanDevelopmental Center, PO Box 100-R, Pomona, CA 91769, USA

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236 R. H. Chaney

cerebrum and the cerebellum. There were rare hypothalamic lesions. Causes ofmental retardation were mainly prenatal factors, trauma and hypoxia, infection,intoxication, and chromosomal and metabolic abnormalities. There were 142 patients(12-1%) with Down's syndrome.

Eight hundred and twelve patients were under age 21 years, 78 (9-6%) of whomwere found by the pathologists to have grade I (White et al., 1950) mild-to-moderategross evidence of AS in the freshly-examined coronary arteries or aorta, with one toten plaques in a segment, each producing less than 10% decrease in the lumen. Theauthor considers the basic arteriosclerotic lesion in infancy and childhood to be thefatty streak, a lipid-containing focus of myo-intimal cells which, in later development,forms the adult plaque (Haust, 1971). Those with coronary involvement, eight ofwhom also had aorta AS, included three with known predisposing factors and 12 withnone. With aorta AS alone, there were 10 with ascribable cause and 53 with none.

All cases with any abnormality known to predispose to AS were rejected from thestudy. Thus excluded were subjects having had such conditions recognized by theAmerican Heart Association (Russek & Russek, 1977), including systemic hyperten-sion, cigarette smoking, obesity, diabetes and, as far as records indicated,hyperlipidemia. Also excluded were all AS cases and controls having abnormalitiespredisposing to childhood AS: (1) hyperlipidemia, including secondary and familialtype II hyperlipidemia; (2) sources of arterial injury such as hypertension, vasculitis,Kawasaki disease, pseudoexanthoma elastica and anomalous coronary artery; (3)diseases causing accumulation of substances which cause atherosclerosis, such asmucopolysaccharidoses, storage diseases and homocystinuria; (4) other heredofamilialdiseases such as Werner's sydrome; and (5) diseases of unknown etilogy includingidiopathic infantile arterial calcifications and progeria.

After excluding all cases with any predisposing factors, there remained 65 subjects,or 8-0%, of the 812 residents under age 21 years. Twelve of these had coronary (plusaorta) involvement and 53 had aorta AS alone. Of these, 39 were male and 26 female.Their ages were 1-20 years (X:10"l years) and IQs 1-75 (X:16-6). Blood pressuresranged from 80/60 to 124/82 mmHg (X: 108/73). Body weights were low: 81-6% wereat or less than the fifth percentile, 18-4% were in the tenth to ninetieth and none wasover the ninetieth percentile (Behrman & Vaughan, 1983). Six (9-1%) had congenitalheart disease. None smoked and none had diabetes. All of our patients, however, led asedentary life, and family history was inadequate and could not be applied. The dietfed to the ambulatory patients was comparable to that provided the non-ambulatoryresidents with total nursing care. Nine of the 65 subjects (13-8%) were Down'ssyndrome.

A control group of 30 patients without AS and without any of the above-describedpredisposing conditions was selected via a table of random numbers (RandCorporation, cl955). They matched the A§ group in sex, 17 males and 13 females; age1-20 years (X:10-5 years); and IQ, 1-73 (X:19). They had no gross or microscopicbrain lesions that were basically different from those of the experimental group.

Finally, a subset of Down's syndrome was examined. Of the 812 patients under age21 years, there were 101 Down's (12 4%). They included 56 males and 45 females, ofage 1-20 years (X:6-l years), and IQ 1-90 (X:31-9). Their nutrition was good to fair

Neurogenic atherosclerosis 237

in 66"3%, poor to emaciated in 31-7% and unknown in 2-0%. There were 58-4%non-ambulatory, and 5% were epileptic. Their blood pressures were 68/40 to118/90 mmHg (X:93/60), with the exception of one individual with a cerebralabscess and extreme intracranial edema, and BP 160/110. Down's heart diseasesincluded ventricular septal defect in 23-8%, atrial septal defect in 18'8%, patentductus arteriosus in 9-9%, and tetralogy of Fallot and Eisenmenger's syndromein 5-0%.

R E S U L T S

Of the 12 cases of coronary AS of unknown origin, there were eight males and fourfemales of ages 3-20 years (X:12-8). Ofthe 53 with aorta AS, there were 31 males and22 females of ages 1-20 years (X:9-5). Aorta lesions were both thoracic andabdominal. All patients had a few to numerous fatty streaks grossly and they had avariation from localized intimal thickening with lipid deposition of fibroelastic plaqueformation microscopically.

The 65 cases of AS of unknown cause had the same ratio of sex, age and IQ as the30 matched controls. There was no male preponderance: 60% of AS patients weremales, and 57% of controls. Up to age 20 years, there was no more AS in olderpatients than those under 5 years; there were 14-16 cases in each 5-year subset to 20years in the AS subjects. AS patients included many more who were severely andprofoundly retarded (i.e. IQ<35) (89%) but so did the controls (90%). Mentalretardation diagnoses in AS subjects versus controls were similar. Nutrition wasdescribed as good to fair in 38 (58%) ofthe AS patients and 18 (60%) of controls, poorto emaciated in the remainder.

For the demographic, medical and behavioral variables considered, an X^df=i testwas utilized to determine differences between the AS and control groups. There was ahigher prevalance of epilepsy in the AS group, 39 patients (60%), than in the controls,10 patients (33%), (X^=4-825; df=l; P=0-027). There was also more physicalrestriction among AS patients in that 47 (72%) were non-ambulatory, in contrast to 16(53%) of controls (X^=4-810; df=l; P=0-027).

The majority of AS patients had poor nutrition, retarded physical growth anddevelopment, cranial anomalies and requirement for complete nursing care, althoughnot significantly different from control patients. There was no difference in the ASand control groups in racial origin, sensory or verbal ability, behavioral characteristicsas measured by the Behavior Development Survey (BDS) or the Client DevelopmentEvaluation Report (CDSER) (Harris, 1982), or use of antiepileptic or othermedications.

Of the 101 people with Down's syndrome, nine (8-9%) had AS, including twocoronary and seven aortic. These included six males and three females of ages 2-11years (X:5-0 years) and with IQs of 12-46 (X:30-5). Nutrition was good to fair in five,poor to emaciated in four. Blood pressure ranged from 80-110/60 mmHg (X:94/60).There was one each of ventricular septal defect, patent ductus arteriosus andEisenmenger's complex.

238 R. H. Chaney

DISCUSSIONWhile, for most of this century, fatty streaks have been known to develop in thearteries of children (Klotz & Manning, 1911), recent studies emphasize that theselesions occur commonly in young children (Strong & McGill, 1969) and are probablyprecursors of adult AS (Haust, 1971; Pesonen et al., 1975). The question is not thefrequency of AS in children but for what reason some of them are predisposed to it.The author has observed no relation of the atherosclerotic lesions in his 65 youngpatients to the risk factors recognized by the American Heart Association (Russek &Russek, 1977) or to the several known predisposing diseases. If these factors simplyaccelerate the lipid deposit-intimal lesion progression, what initiates the basic change?

Ofthe many patient characteristics evaluated in our series, convulsive disorder hadthe highest correlation with AS. Evidence for nervous system overstimulationinitiating atherogenesis is an increasing body of literature relating neural stimulationand increased catecholamine production to atherogenesis (Friedman et al., 1972;Kalbak, 1976; Troxler et al., 1977). Thus, the disease can be experimentally causedby stimulation of the hypothalamus, producing elevated plasma triglyceride (Gutsteinet al., 1967), serum cholesterol and free fatty acid, and lipid intimal infiltration inrabbits and monkeys (Correll, 1963), and causing aortic and coronary atheroscleroticlesions (Gutstein et al., 1978). Related to this is the experimental promotion offibrocalcific arteriosclerosis in the rat aorta by stimulation of autonomic nerves to thatartery (Gutstein et aL, 1962). Clinically, it becomes more prominent in persons withhigh plasma cortisol (Troxler et aL, 1977) as well as in persons treated withcorticosteroids (Kalbak, 1976).

Also significantly related to atherogenesis in our series is physical restriction, suchas inability for ambulation and the necessity for complete nursing. This inability torespond to environmental changes is felt to promote undue stress. This is shown ineven severely retarded subjects whose hmitations of vision, communication, andmotor and sphincter control predisposed them to development of peptic ulcers (Kimet aL, 1981; Chaney etal., 1985). Psychosocial stress has been well documented as acause of ischemic arterial lesions in man (Jenkins, 1978) and in animals (Kaplan et al,1983).

It is noteworthy that the Down's syndrome individuals had slightly moreatherosclerosis than the other mentally retarded residents under age 21 years, i.e.8-9% ofthe 101 Down's versus 7-9% ofthe 711 non-Down's syndrome residents. Thisis in contrast to the findings of Murdoch et al. (1977), who reported no atheroma infive older Down's, but it is consistent with the conclusions of Moss & Austin (1980),who described the same frequency of pre-atherosclerotic lesions in seven Down'ssyndrome patients as in the general population, and Fleisher's (1978) report of ayoung Down's syndrome girl with diffuse primary intimal fibroplasia. The author'sdiscovery of 9% of Down's patients having AS is also surprising in view of the Down'shaving much less epilepsy: 0-05% versus 61% of the 65 cases in the experimental ASgroup. That factors influencing AS in the group of Down's are not the same as those

"affecting the 65 subjects with unexplained atherosclerosis is also suggested by severalother differences. For example, they had higher IQs (31 9 versus 16-6), betterambulation (41-6% versus 28-0%), more congenital heart disease (57-5% versus 9-1%)

Neurogenic atherosclerosis 239

and better nutrition (good to fair in two-thirds versus 94-7% under the ninetiethpercentile in the larger group). Their blood pressures were minimally lower(80-110/60 mmHg; X:94/60 mmHg versus 80-124/60-82; X: 108/73 mmHg). Lowerblood pressures were also found by Murdoch et al. (1977), by Richards & Enver(1979) and by Salo et al. (1979) in older institutionalized Down's syndrome patients.Therefore, it appears likely that the disparate reports in the literature are due toDown's syndrome not only providing different sets of variables which predispose toand protect from AS, but also consisting of subgroups as proposed by Moss & Austin(1980). Further investigation will be necessary to dehneate these groups, such as anextension ofthe work of Salo et al. (1979) who found certain lipid levels to be higher inDown's syndrome than in non-Down's institutionalized mentally retarded persons.

It is reasonable to suggest, then, that there is a relationship between some kinds ofbrain damage and arterial pathology. To determine whether these are cause andeffect, further studies with localization of the brain lesions are recommended. Thestudy of mentally retarded individuals has much to contribute to our knowledge of notonly their own conditions and treatment, but also the physiological and pathologicalchanges in non-retarded persons.

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Received 8 August 1986; revised 28 October 1986