Endocrine, metabolic, and cranial computed tomographie findings in anorexia nervosa

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Endocrine, Metabolic, and Cranial Computed Tomographic Findings in Anorexia Nervosa Jargon-Christian

Krieg

,

K~~-~~in

Pirke, Ch~stoph Lauer , and

Herbert Backmund

Computerized tomographic brain scans were completed in 50 inpatients with anorexia nervosa and were compared with an age- and sex-matched control group. Seventy percent of the anorectic patients displayed enlarged lateral ventricles. There was a close link between ventricular size and low weight, but not between ventricular size and duration of the eating disorder. In addition, sulcal widening was observed more frequently in patients with enlarged ventricles than in patients without these structural changes. After weight gain, a statistically significant decrease in ventricular dilatation could be observed even when mean ventricular size stillfar exceeded that of the control subjects. The analysis of the endocrine and metabolic parameters, known to be indicators for the process of starvation, revealed a significant inverse correlation between triiodothyronine and ventricular size. Various possible pathogenetic mechanisms for the morphological brain alterations in patients with eating disorders are discussed.

Introduction Morphological brain alterations in patients with anorexia nervosa have been described in a number of postmortem and neuroradiological studies (Gage1 1953; Heidrich and SchmidtMatthias 1961; Enzmann and Lane 1977; Heinz et al. 1977; Nussbaum et al. 1980; Sein et al. 1981; Kohlmeyer et al. 1983; Artmann et al. 1985; Lankenau et al. 1985; Datlof et al. 1986). We recently reported our finding that more than 80% of 50 anorectic patients examined by cranial computed tomography (CT) revealed enlarged external cerebrospinal fluid (CSF) space; in nearly half of the patients who were reexamined, sulcal widening was at least partially reversible after weight gain (Krieg et al. 1986). To elucidate the pathogenesis of the structural changes, the CT findings were correlated with the plasma levels of cortisol, norepinephrine, triiodothyronine and P-hydroxybutyric acid, as the plasma concentrations of these substances are known to be altered during the anorectic state (Pahl et al. 1985). Apart from a lower body weight, the anorectic patients with enlarged external CSF space displayed significantly higher plasma cortisol levels than those patients without these morphological brain alterations, and we hypothesized that hypercortisolemia may be involved in the pathogenesis of the structural changes (Krieg et al. 1986). From the Max-Planck-Institute

of Psychiatry,

Address reprint requests to Dr. J.-C. Received

0

1988 Society

March

of Biolo8ical

Krieg,

18, 1987; revised May

Psychiatry

Munich,

F.R.G.

Max-Planck-Institute

of Psychiatry,

Kraepelinstr.

10, So00 Mtinchen

40,

F.R.G.

15. 1987.

@!X%3223/88603.50

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_) (‘.Krieg

et XI

We have now analyzed our CT scans to determine whether or not the ventricular enlargement observed by several investigators (Artmann et al. 1985; Lankenau et al. 1985; Datlof et al. 1986) is a common feature in anorectic patients and, if so, to what extent these structural changes are related to body weight, length of illness, or to the metabolic disturbances known to occur in anorexia nervosa. We also posed the question of whether or not possible alterations in ventricular size are reversible after weight gain, as is the case for the external CSF spaces (Kohlmeyer et al. 1983; Artmann et al. 1985; Krieg et al. 1986).

Methods Patients The group studied comprised 48 female and 2 male inpatients treated on a research ward for eating disorders. All patients, aged between 15 and 30 years (mean + SD, 21.5 + 3.4) fulfilled the diagnostic criteria of Feighner et al. (1972) for anorexia nervosa as well as the less stringent DSM-III criteria (American Psychiatric Association 1980). Patients with a physical illness or a history of substance or alcohol dependence were excluded. The patients’ body weights ranged from 55% to 75% (69% + 6%) of the ideal body weight (IBW), according to the tables of the Metropolitan Life Insurance Company (1959). The eating disorder had been present from 4 months to 10 years, with an average of 3.33 c 2.6 years. The specific psychopathology, assessed by standardized instruments, and the therapeutic program have been described previously (Pahl et al. 1985; Bossert et al. 1987). For ethical reasons, a control group of healthy volunteers could not be established. Therefore, 50 age- and sex-matched subjects with a personality or adjustment disorder, on whom a CT scan had been performed to exclude any organic neuropsychiatric disease, served as controls; their body weights ranged between 85% and 115% of the IBW (100% & 9%).

Computed Tomography CT was carried out immediately after hospital admission with a General Electric 9800 scanner using the 256 x 256 matrix and a slice thickness of 10 mm. For evaluation, three scans cut parallel to the glabella-inion line were chosen: (1) a low cut, showing the insular cisterns, the third ventricle, as well as the anterior and posterior horns of the lateral ventricles, (2) a slice through the region of the cella media of the lateral ventricles, and (3) a scan of the superficial cortex. All measurements were performed directly on the monitor.

Measurement of the Ventricular Brain Ratio (VBR) The region of the cella media was framed by a rectangle, and the total number of CSFdense pixels, ranging from - 4 to + 22 Hounsfield units (HU), were reported in square centimeters by the computer (Figure 1). The maximum value of CSF density was calibrated in such a way that no pixels in the white matter and only single pixels in the internal capsule, showing the lowest density values in brain tissue, were recorded (Zeumer et al. 1982). Using this method, inaccuracies resulting from visual tracing of the ventricles or from a possible bias of the examiner could be ruled out. The total brain area was measured

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Figure 1. CT scan of a patient with anorexia nervosa illustrating the method of measuring ventricular size. Within the rectangle, the area of all pixeis with a density ranging from - 4 to i 22 HU (cerebrospinal fluid) is displayed and reported in square centimeters.

by means of a density mask, which repotted all pixels between - 10 and + 100 HU in square centimeters. VBR was calculated by dividing the ventricular cross-sectional area by the brain cross-sectional area and multiplying the result by 100 (Synek and Reuben 1976). ~~~suremen~ of the Ex~ernul CSF Spaces According to our normative data, a width of 3 mm and more of the insular cisterns, the anterior part of the interhemispheric fissure, and the cortical sulci is regarded as abnormal for this age group (Krieg et al. 1987; Schmauss and Krieg 1987). In this study, a width of 3 and 4 mm measured for at least 6 sulci (or for 4 sulci, the interhemisphe~c fissure, and the insular cisterns) was defined as a “slight*’ degree of sulcal widening and a width of more than 4 mm as a “marked’ degree. ~et~boLite and ~~r~~ne Analysis Blood sampling for metabolite and hormone analysis was carried out immediately after hospital admission. At 8:OOAM, after overnight fasting, a butterfly needle was inserted into a forearm vein, and 5 ml blood was taken for the measurement of P-hydroxybutyric acid (BHBA). Blood samples were collected at lo-min intervals from 8:30 to 9:30 AM. During the whole procedure, patients remained in a supine position, except for a IO-min period at 9:lO AM, when patients stood up (orthostatic challenge). Blood (2 ml) was collected in a tube containing 40 p.10.25 M EGTA, 0.20 M glutathione (reduced form;

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.I, -C:

Krieg et al.

Sigma, St. Louis, MO), pH 6.7, and 20 pJ heparin (10,000 ILJ/ml; Braun Melsungen, Germany). Plasma was separated by centrifugation and kept frozen at - 80°C until analysis. BHBA was analyzed according to Williamson and Mellonby (1974). The intraassay variability was 4.1% at an average concentration of 0.53 pmol/ml. Triiodothyronine (T3) was analyzed by radioimmunoassay using kits supplied by Serono, Freiburg, F.R.G. The intraassay variability was 7.1% at an average concentration of 0.85 ng/ml. T3 was measured in a sample pooled from the seven samples obtained from each subject. According to Pirke et al. (1985), norepinephrine (NE) was measured in the samples taken immediately before and after the subject stood up. The precision was 5% at an average concentration of 340 pg/ml. The detection limit was 51 + 15 pg/ml (mean 4 SD; signalto-noise ratio 2). Cortisol was measured as described earlier (Doerr et al. 1980). In the pooled plasma sample, the intraassay variability was 4.5% at an average concentration of 12.1 pg/dl. Total serum protein was measured using the Biuret method. Intraassay variability was 4.2% at an average concentration of 7.1 g/ 100 ml. In 25 anorectic patients, the CT examination as well as the metabolite and hormone analyses were repeated at discharge, which took place at an average of 78 2 23 days after admission. The subgroup of the 25 reexamined patients did not statistically differ from the group of remaining patients in regard to all assessed variables. Statistical analyses were performed using chi-square tests, Student’s t-tests, and Pearson product-moment correlations (all two-tailed).

Results External CSF Spaces and Ventricular Size in Patients and Control Subjects Enlarged external CSF spaces were found in 43 (86%) of the anorectic patients, whereas this was the case in only 8 (16%) of the control subjects (Table 1). In particular, 25 patients showed a slight and 18 patients a marked degree of sulcal widening. The overall mean VBR value was significantly greater for the patients than for the controls (Table 1). The patients without sulcal widening showed a significantly lower mean VBR value (4.57 ? 3.08) than the patients with slightly and markedly enlarged CSF spaces (VBR = 6.51 rt 2.80 and 9.15 + 3.51, respectively; r-test, p < 0.03). Dichotomizing the group of patients by setting a cut-point at the highest VBR value obtained for the control group resulted in a sample of 35 (70%) patients showing even higher VBR values (Figure 2). This sample also includes significantly more patients with slightly or markedly enlarged external CSF spaces than the group of patients whose VBR values were within the range of the control values (x2 = 1I .27, df = 2, p < 0.004). Ventricular Size, Body Weight, Duration of Illness, Hormone and Metabolic Status In the patients, significant inverse relationships were found between VBR and body weight (r = - 0.27%, n = 50, p < 0.05), VBR and age of the patients (r = - 0.3695, n = 50, p < O.Ol), and between VBR and T3 (r = -0.3870, n = 34,~ < 0.05). No significant association could bc seen between VBR and the variables duration of the eating disorder, cortisol, BHBA, and ANE [ANE: norepinephrine orthostatic increase (Pahl et al. 1985)I. The age of the patients correlated positively with the duration of the eating disorder

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Table 1. Age, Body, Weight, Ventricular Brain Ratio (VBR), and Size of External CSF Spaces Determined for 50 Anorectic Patients and for the Control Subjects

Age (yeW Body weight (% IBW) VBR (9%) Enlargement of external CSF spaces (shown by

Controls (n = 50)

(uv+ed)

21.5 ” 3.4 69 t 5 7.19 rt 3.45

21.6 t 3.6 100 2 9 2.49 + 1.06

p < 0.001 p < 0.001

number of patients) None Slight

Marked Cortisol (&dl) T3 (ng/ml) BHBA (pmoVm1) Norepinephrine, orthostatic increase (pg/ml)

t-Test

Anorectics (n = 50)

17.0 0.7 0.46 134.8

7 25 18 k f 2 2

7.8 0.2 0.77 134.2

42 8 0 (4.0 - 16.2) (0.7-2.3) (CO. 15) (42.3-180.7)

NS

p < 0.001” -

“Chi-squaretest. Plasma levels of cortisol, triiodothymnine(T3). Phydroxybutytic acid (BHBA), aod norepinephrineorthostaticiocrease (ANE) are given for the anorectic patients. Mean 2 SD is shown (values in parentbasesrefer to normal concentrations).

(r = 0.5034, n = 49, p < 0.001). In contrast to the patients, no statistically significant relationship among age, hody weight, and VBR values could he demonstrated in the control subjects. Dichotomizing the group of patients into group 1 (n = IO), with an age under 21 years (median of age distribution) and a body weight under 70% IBW (median of body weight distribution), and into group 2 (n = 9), with an age over 21 years and a body weight over 70%, led to the expected result that the patients of group 1 had a higher mean VBR value (10.78 ? 4.18) than the patients of group 2 (4.62 + 2.43) (t-test, p < 0.002). Furthermore, group 1 also includes a greater number of patients with slight or marked sulcal widening than group 2 (x2 = 11.479, df = 2, p C 0.005). The two groups did not differ in regard to cortisol, BHBA, and ANE. However, there was a tendency toward lower T3 values in group 1 (0.61 + 0.11 ng/ml) than in group 2 (0.78 + 0.23 ng/ml) (t-test, p = 0.08). Except for two cases in which the patients showed slightly decreased serum protein levels of 5.6 and 5.8 g/dl, respectively, the protein levels of the anorectic patients were well within the norm and showed no significant correlation with the VBR values (r = -0.0189, n = 41). Comparison: Admission versus Discharge Table 2 shows the data for the subgroup of 25 patients examined both at admission and discharge. Sulcal widening was reduced in 7 (28%) of the patients studied, but this improvement rate was not statistically significant (x2 = 3.428, df = 2). A significant lower mean VBR value could also be determined at discharge, although it still far exceeded the mean VBR value of the controls. Significant decreases in the elevated cortisol and BHBA mean plasma concentrations, as well as a significant increase of the low T3 mean

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value at admission, could be seen at discharge. ANE showed a tendency mean value at discharge in comparison to admission.

J.-C. Krieg et 4.

toward a lower

Discussion To our knowledge, enlarged CSF spaces in patients with anorexia nervosa have been previously reported in only two controlled studies, which, however, were performed on a relatively small group of patients (Lankenau et al. 1985; Datlof et al. 1986). We have now been able to demonstrate in a larger patient population that the majority of the anorectic patients not only display enlarged external CSF spaces, but also an increase in ventricular size. Both the enlarged external CSF spaces (Krieg et al. 1986) and the ventricular enlargement were most evident in patients who were markedly underweight without relation to the duration of the eating disorder. Moreover, it could also be shown that patients with greater VBR values more frequently displayed sulcal widening. The finding that the VBR values of the anorectic patients correlated inversely with the age of the patients can be explained by the circumstance that the younger patients were usually more emaciated than the older ones. Several authors have stated that sulcal widening in anorectic patients is at least partially reversible after weight gain (Kohlmeyer et al. 1983; Artmann et al. 1985; Krieg et al. 1986). This also seems to be true for the enlarged ventricles, as nearly all VBR values were lower after weight gain than at the time of admission, even though the mean VBR value of the anorectic patients at discharge still far exceeded the mean VBR value of the controls. A higher degree of reversibility of the morphological brain alterations might have been found if the second CT examination, which took place at an average of 3 months after admission, had been performed at a later time. Enlarged cerebrospinal fluid spaces are not exclusively found in anorexia nervosa. Apart from the physiological process of aging, sulcal and ventricular widening, respectively, have also been observed, for example, in patients with schizophrenia (e.g., Andreasen et al. 1982; Owens et al. 1985), in alcoholics (e.g., Carlen et al. 1978; Artmann et al. 198 1; Ron et al. 1982), or in benzodiazepine abusers (Lader et al. 1984; Schmauss and Krieg 1987). Interestingly enough, enlarged CSF spaces have also been seen in patients with Cushing’s disease (Momose et al. 1971; Heinz et al. 1977) and in patients undergoing a corticosteroid therapy (Bentson et al. 1978; Lagenstein et al. 1979; Okuno et al. 1980). In an earlier study, we found that anorectic patients with sulcal widening displayed significantly higher plasma cortisol levels than the patients without these structural changes. We therefore stated that hypercortisolemia may also be involved in the pathogenesis of sulcal widening in patients with anorexia nervosa (Krieg et al. 1986). One explanation for the underlying mechanism was cerebral dehydration caused by the increased plasma cortisol levels. On the other hand, measurements of the longitudinal relaxation time (T,) with magnetic resonance imaging revealed that corticosteroids do not reduce the water content of the brain (Bell et al. 1987). With regard to ventricular size, no statistically significant relationship between VBR values and plasma cortisol concentrations could be demonstrated in this study. Other studies of this aspect of the problem produced divergent results. Kellner et al. (1983) reported that in patients with an affective disorder, ventricular size is related to the degree of cortisol hypersecretion. However, assessing hypothalamic-pituitary-adrenal axis activity by means of the Dexamethasone Suppression Test (DST), patients with an abnormal DST did not differ from patients with normal DST in regard to ventricular size (Targum et al. 1983; Schlegel and

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r988;23:377-387

VBR (O/o)

0

16

0 l

:

12

;

3 8

_-_----.

4I-

aI-

anorectics

controls

Figure 2. Ventricular brain ratio (VBR) in 50 anorectic patients and in 50 age- and sex-matched control subjects. Kretzschmar 1987). Further studies are needed to clarify the question of whether or not hypercortisolism is involved in the pathogenesis of the described morphological brain alterations and, if so, whether or not hypercortisolemia only provokes enlargement of the external CSF spaces or both sulcal and ventricular widening. Apart from hypercortisolism with its alleged influence on brain water content, other

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Table 2. CT, Endocrine, and Metabolic Parameters, as Listed in Table 1, Determined for 25 of the Anorectic Patients at Admission and at Discharge (For Comparison, the Data of the Control Subjects Are Also Presented) Anorectics Controls r-Test A Admission

Age (years) Body weight (% IBW) VBR (%) Enlargement of external CSF spaces

B

c

linpaired

(n = 25)

Discharge (n = 25)

20.7 t 2.9 71 r 4

20.7 -+ 2.9 87 -+ 4

21.6 f 3.6 100 5 9

p < 0.001

NS p < 0.001

NS p < 0.001

7.96 + 3.82

5.71 t

2.49 T 1.06 p i 0.001

p < 0.001

p < 0.001

(shown by number of patients) None Siight Marked Coctisol (kg/dl) 17.4 T3 &/ml) 0.7 BHBA (~mo~rnl) 0.39 Norepinephrine, 139.6 orthostatic increase @g/ml)

2.48

(n = 50)

5 6 42 9 14 8 II 5 0I 2 7.9 13.46 k.5.15 (4.0-16.2) p rt 0.2 0.9 + 0.2 (0.7-2.3) p z!z0.61 0.06 c 0.05 (C0.15) p + 158.1 68.2 + 101.4 (42.3-180.7) p

Paired A-B

A-C

B-C

NS” < 0.02 < 0.02 < 0.05 = 0.08

p < 0.001” p < 0.001” --

-

pathogenetic mechanisms have been thought to be responsible for the enlarged CSF spaces in anorexia nervosa: for example, changes in the permeability of the blood vessels, protein loss with a movement of intracellular fluid into extracellular spaces, or inhibition of brain protein biosynthesis (Heidrich and Schmidt-Matthias 1961; Heinz et al. 1977; Artmann et al. 1985). As, at admission, the serum protein levels of our patients were (except for two cases) well within normal range, the possibility of an altered colloid osmotic pressure resulting in disturbances in water distribution seems unlikely. Loss in lean body mass, as suggested by Datlof et al. (1986), cannot adequately explain the pathogenesis of the described mo~hological brain alterations, as quite a few normal weight bulimic patients display the same stmctural changes as the anorectic patients (Krieg et al. 1987). A large number of bulimic patients also undergo intermittent periods of starvation, which result in metabolic and humoral disturbances similar to those in anorexia nervosa [e.g., elevated BHBA and cortisol plasma levels, low T3 plasma concentrations, reduced norepinephrine increase after orthostatic challenge (Pahl et al. 1985; Pirke et al. 1985)]. One may therefore hypothesize that the process of starvationregardless of whether or not it leads to excessive weight loss4s responsible for the mo~hologic~ brain alterations observed in anorectic patients, as well as in normal weight bulimic patients. Regarding the indices for starvation, VBR values did not significantly correlate with the plasma levels of BHBA or with ANE. However, the group of patients with higher VBR values displayed significantly lower T3 values. The most likely explanation for this finding is the ~sumption that starvation causes changes in both T3 values

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and VBR. We have no evidence that low T3 levels directly cause changes in brain morphology. The pattern of the metabolic and endocrine findings, determined at admission and discharge, can be best explained as follows. Elevated plasma levels of BHBA usually normalize when caloric intake becomes sufficient again. T3 concentrations, however, remain low for several weeks after patients start gaining weight. ANE values, which are also a good indicator of starvation, are often elevated at the beginning of inpatient treatment. This is because the starvation-induced decrease in ANE is observed in many patients only when the stress of hospital admission is no longer operative (Pahl et al. 1985). In this study, we did not differentiate between “vomiters” and “restrictors.” Vomiting or the abuse of laxatives and diuretics, with their influence on electrolyte and water distribution, may also represent intervening factors influencing the size of the CSF spaces. Neuronal damage during starvation, as described by Martin (1958) in his postmortem studies, and subsequent gliosis or regrowth of axonal and dendritic arborization after remission may be another explanation for the CT findings in patients with eating disorders. It has been suggested that a similar pathogenetic mechanism may be responsible for the reversible cerebral atrophy observed in recently abstinent chronic alcoholics (Carlen et al. 1978; Ron et al. 1982). Another possible explanation for the CT findings in anorexia nervosa is offered by Artmann et al. (1985). In their CT study, these authors described signs of a minimal early acquired brain lesion in 60% of their anorectic patients, and they wondered whether an early acquired brain lesion might be a predisposing factor for anorexia nervosa. This implies, however, that a number of the described morphological brain alterations existed prior to the onset of the anorexia nervosa. If so, the observations that the structural changes are at least partially reversible after overcoming the eating disorder would pose the question of which structural changes-and to what degreecould be ascribed to an early acquired brain lesion, and which to the eating disorder itself. As patients with various organic and psychiatric disorders may display enlarged CSF spaces, various pathogenetic mechanisms have been assumed to be responsible for the respective morphological brain alterations. However, it may also turn out that in quite different disorders, identical pathogenetic factors cause the widening of the cerebrospinal fluid spaces. As far as patients with eating disorders are concerned, up to now, the etiology of the morphological brain alterations cannot be satisfactorily explained. We hope that follow-up studies will lead to some clarification.

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to

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ab-

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benzo-

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ACTH

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Synek V, Reuben JR (1976): The ventricular-brain ratio using planimetric measurement of EMI scans. Br J Radio1 49:233-237. Targum SD, Rosen LN, DeLisi LE, Weinberger DR, Citrin CM (1983): Cerebral ventricular size in major depressive disorder: Association with delusional symptoms. Biol Psychiatry 18:329336. Williamson DH, Mellonby J (1974): Betahydroxybutyrat. In Bergmeyer HU (ed), Methoden der Enzymatischen Analyse. Weilheim: Verlag Chemie GmbH, pp 1883-1886. Zeumer H, Hacke W, Hartwich P (1982): A quantitative approach to measuring the cerebrospinal fluid space with CT. Neuroradiology 221193-197.