Cognitive and neuroradiological findings in congenital adrenal hyperplasia

Psychoneuroendocrinology. Vol.

19, No. 1, pp. 55-64, 1994

0306-4530/94 $6.00 + .00 © 1993 Pergamon Press Ltd.

Printed in the U.S.A.

COGNITIVE AND NEURORADIOLOGICAL FINDINGS CONGENITAL ADRENAL HYPERPLASIA

IN

E. SINFORIANI, 1 C. LIVIERI, 2 M. MAURI, 1 P. BISIO, 2 L. SIBILLA, 1 L. CHIESA, 2 and A. MARTELLI 1 INeuropsycfiologyUnit and Neuroradiological Service, 1RCCS C. Mondino; and 2Deptartment of Pediatrics, University of Pavia, Italy (Received 12 February 1993; in final form 13 July 1993)

SUMMARY Nineteen patients with congenital adrenal hyperplasia (CAH) aged over 16 years were given a neuropsychologicalevaluation; no significantdifferenceswith individuallymatched normal controls were detected. CAH subjects, however, revealed slightly higher IQs with respect to the expected distribution. No significant learning disabilities could be detected. Fifteen patients underwent nuclear magnetic resonance (NMR); 4 subjects showed small areas of increased signal intensity in the white matter, without prevalence of side; this finding did not correlate with clinical and cognitive characteristics. The results are discussed in the light of possible hormonal influences.

INTRODUCTION CLASSICAL CONGENITAL ADRENAL hyperplasia (CAH) is an inborn autosomal recessive error of cortisol biosynthesis due, in the vast majority of cases, to deficiency of the e n z y m e 21-hydroxylase (21 OH). Impairment of cortisol biosynthesis results in adrenocorticotropic hormone (ACTH) hypersecretion with hyperproduction of cortisol precursors, particularly 17-hydroxyprogesterone. As a consequence, abnormally high amounts of androgens are secreted by the adrenal gland, causing prenatal or postnatal virilization. A salt-wasting condition is also present in more than two thirds of patients as a consequence of defective aldosteron production. As patients of both sexes are exposed to adrenal-derived androgens in the pre and postnatal period (until treatment is instituted) CAH provides a very interesting model with which to study the interactions between hormonal effects and neurobehavioral parameters. Several cognitive studies have been carried out to ascertain whether C A H patients show intellectual changes due to hormonal influences (Nass & Baker, 1991a). High mean full IQ scale has been reported by most authors (Money & Lewis, 1966; Perlman, 1973; McGuire & Omenn, 1975; Wenzel et al., 1978; Resnick et al., 1986; Nass & Baker, 1991b). The IQ of salt-waster (SW) patients, however, has been found to be consistently below that of the simple virilizers (SVs) and this finding has been related to a possible early brain damage secondary to salt-wasting crisis. Despite their high IQ, C A H females Address correspondence and reprint requests to: Dr. E. Sinforiani, IRCCS C. Mondino, via Palestro 3, Pavia, Italy. 55

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show an increased frequency of learning disabilities (measured by extent of Wechsler Verbal/Performance-IQ discrepancy) with respect to same sex unaffected siblings (Nass & Baker, 1991b). On the other hand, females can show a postpubertal spatial advantage (Resnick et al., 1986). As it is well known that testosterone promotes the development of the right hemisfere and delays the maturation of the left hemisphere (Geschwind & Behan, 1984), both these data have been interpreted as a consequence of early androgen exposure. The few neuroradiological data available in small groups of SW patients show the presence of multiple areas of abnormal white matter under nuclear magnetic resonance (NMR) (Haines et al., 1989; Nass et al., 1990). These findings do not have a single interpretation (demyelinating process? gliosis after infarction?) and further correlations with clinical variables are needed. In this study we evaluated cognition and possible correlations between neuropsychological and neuroradiological findings in a selected group of CAH subjects.

SUBJECTS Nineteen CAH patients (12 males and 7 females; mean age -+ SD: 19.2 -+ 2.6 years, range 16-24; mean educational level: 11 -+ 1.9 years, range 8-13) were selected for the study. These subjects have been treated over the years by the staff of the Department of Pediatrics, University of Pavia. Only patients aged over 16 years participated in the study. Nine patients (7 M, 2 F) were simple-virilizers (SV) (mean age: 20.3 -+ 2.9, mean educational level: 11.3 --- 2.2) and 10 (5 M, 5 F) salt-wasters (SW) (mean age: 18.2 - 1.9, mean educational level: 10.7 - 1.7). The mean age at which the diagnosis was made was 39.6 - 23.7 months for the first group, and 2.4 ± 5.8 for the second group. We considered a diagnosis made within the first 4 weeks (neonatal period) as early. Only five out of the seven CAH females underwent plastic surgery, as two simple virilized girls, both with severe clitoral hypertrophy, who referred to our Pediatric Department after puberty, refused to undergo any operation. Mineralcorticoid therapy was begun at birth in all SWs except three, who received substitutive therapy later as CAH was diagnosed between the 2nd and the 6th month of life. During the study all patients were administered substitutive therapy with dexamethasone (0.25-0.5 mg single evening dose), while 15 subjects were also given hydrocortisone (10-25 mg/die) every morning. All SWs also received 0.1-0.15 mg of 9-fiudrocortisone per day. In at least 15 patients, clinical and laboratory overdosage findings could be detected during the follow-up; especially in the first years of life, reduced height velocity with retarded bone age, clinical signs of hypercortisolism, and low levels of sexual and adrenal hormones were found. At the moment of the study none of our patients showed clinical signs of hyperandrogenism or hypercortisolism. As far as hormonal monitoring is concerned, no significant difference was found between ACTH values in all CAH patients and sex and age matched controls (CAH patients: 95 --+ 84; controls: 44 --- 7.9 pg/ml; p -- n.s.), but 4 out of 19 CAH subjects showed ACTH levels higher than +2 SD of controls, together with elevated 17-OHP levels (ACTH: CAH patients: 239 ± 39; controls: 44 --- 7.9 pg/ml; p < 0.05). Nineteen normal subjects, matched one by one for sex, age, IQ, and socio-cultural level, were selected as controls. The subjects were volunteers recruited among inpatients who referred to the neurological department for peripheral nervous disturbances (such

CONGENITAL ADRENAL HYPERPLASIA

57

as sciatalgia), and their relatives. None of them had a history of neurological and/or psychiatric disorders, head trauma, alcohol, or drug abuse. All were right-handed.

METHODS

Neurological Evaluation A standardized neurological examination was performed, which was normal for all subjects; in particular, no signs related to focal lesions were reported.

Neuropsychological Evaluation CAH patients and controls were administered the following neuropsychological tests (Mauri et al., 1993): • Wechsler Adult Intelligence Scale (WAIS) (Wechsler, 1958) for IQ evaluation; • Logical Memory, immediate and delayed recall (after 30 min) (De Renzi, 1977) to assess short- and long-term verbal memory; • Corsi's test (Spinnler & Tognoni, 1987) to assess short- term spatial memory; • Visual Reproduction, immediate and delayed recall (after 30 min), a subtest of the Wechsler Memory Scale (Wechsler, 1945) to assess visuo-spatial memory functions; • Raven's Coloured Progressive Matrices 47 (Raven, 1960; Basso et al., 1987) to evaluate nonverbal intelligence and visuo-spatial abilities; • Cancellation test (Spinnler & Tognoni, 1987) to assess selective attention; • Trail Making test (parts A and B) (Reitan, 1958); this test measures divided attention and psychomotor functioning; • Word Fluency (Spinnler & Tognoni, 1987): this test requires the subject to produce as many words as he or she can belonging to four semantic categories (fruits, colours, animals, and towns); two minutes are allowed for each category; and • Street's Completion test (Spinnler & Tognoni, 1987) to assess visuo-perceptive functions. All the tests were performed at the same hour of the day and in the same order for both patients and controls. The admnistration of the entire neuropsychological assessment took approximately 2 h and 30 min. A pause was allowed after the administration of WAIS and before neuropsychological tests to avoid fatigue and noncooperation. The patients were also administered the Edinburgh Inventory (Oldfield, 1971) for the assessment of handedness. To be defined right-handed, a subject had to obtain a score greater than 70. Neuropsychological evaluation was administered to females in early follicular phase.

Neuroradiological Evaluation Fifteen out of 19 CAH patients underwent NMR in the same week in which the neuropsychological tests were administered. The remaining four subjects did not receive NMR scans, as two of them had a plaque in the bone and therefore could not perform the examination, and the other two subjects refused to undergo the examination. No patients presented clinical findings, such as delirium or confusion, that have justified a neuroradiological evaluation. All examinations were performed on a 0.5 T (Philips) superconductive scanner. In all cases spin-echo pulse sequences were used to obtain T2-weighted images (TR/TE: 2500/

E. SINFORIANI et al,

58

TABLE I. W A I S SCORES IN C A H PATIENTS AND CONTROLS (M -- SD) (ANOVA 1 WAY)

Full scale range Verbal score range Performance score range

CAH pts.

Controls

F

p

104.2 -+ 9.9 81-120 105.7 + 8.9 86-121 101.4 -+ 10.5 78-117

105.1 -+ 10.5 83-121 106.4 --- 8.5 86-122 102.7 -+ 9.7 79-118

.07

n.s.

.06

"

.16

"

40-100), in axial and coronal projection with 7 mm-thick slices, 0.7 gap, one acquisition. Sagittal Tl-weighted images (TR/TE: 500-600/25) were also performed. MR examinations were evaluated using the following parameters: presence and grading of cortical/ventricular atrophy, site and number of white and grey matter abnormalities. The MR scans were examined double-blind by two neuroradiologists. We compared our examinations with a control group consisting of normal MR scans o f 50 subjects referred with a diagnosis of headache or psychological disturbances and in whom follow-up showed no evidence of a structural CNS lesion.

Psychiatric Assessment The patients were administered psychiatric interview, MMPI, and Zung's rating scales for anxiety and depression, to exclude personality and/or affective disorders that could interfere with the neuropsychological performance. No patients presented a history or current evidence of major depression.

Statistical Analysis. Results were analyzed using A N O V A 1-Way and linear regression. RESULTS

Neuropsychological Findings Both C A H patients and controls were right-handed, i.e., Edinburgh score was greater than 70 in every subject. No significant differences were found between CAH subjects' and controls' WAIS scores, as reported in Table I. Both C A H patients and controls presented slightly higher IQs with respect to the expected distribution. In fact, no patients registered a full IQ under 80, and only one subject scored between 80 and 89 (5.3% instead of the expected 25%), while five (26.3%) scored between 90 and 99, eight (42. I%) between I00 and 109, four (21%) between 110 and 119, and one (5.3%) between 120 and 129 (Fig. 1). N o one o f the controls performed under 80, two subjects scored between 80 and 89 (10.6%), four (21%) between 90 and 99, eight (42.1%) between 100 and 109, four (21%) between 110 and 119, and one (5.3%) between 120 and 129. No significant difference between C A H males and females was registered (males: full IQ = 101.8 -+ 10.5, verbal score = 102.9 --- 9.2, performance score = 99.8 - 11.2; females: full IQ = 108.4 --- 7.5, verbal score = 110.4 --- 6.6, performance score = 104.1 -+ 9.6). N o difference was found in the control group either.

CONGENITALADRENALHYPERPLASIA

59

number of subjects 10 8 6 4 2 0

I

I

I

70-79

80-89

90-99

100-109

110-119

120-129

I.Q. levels I.Q. full aoale

~

l.O. verbal

~

l.O. performance

FIG. 1: IQ distribution in CAH patients.

We did not find any difference as regards different clinical types (SVs: full IQ = 101.6 --- 10.7, verbal score = 103.3 _+ 9.6, p e r f o r m a n c e score = 98.7 -+ 11; SWs: full IQ = 106.6 --- 8.8, verbal score = 103.9 _ 9.9, p e r f o r m a n c e score = 103.7 -+ 9.5). The two groups were age and socioeconomical status matched. No difference was detected w h e n each group was c o m p a r e d to its matched controls. Table II shows the m e a n Verbal-Performance difference and the amount of VerbalP e r f o r m a n c e discrepancy of > 9, > 12, and > 15, respectively, a m o n g C A H patients. N o patient had learning disabilities, which were defined as V e r b a l - P e r f o r m a n c e - I Q difference > 15. We then analyzed the scaled scores of single W A I S subtests; all the C A H patients obtained a significantly lower score with respect to controls only at arithmetic subtest (patients: 8.8 _+ 1.1; controls: 9.5 _ 1; F = 4.21, p < 0.05). M o r e o v e r , arithmetic score was significantly (p < 0.05) lower in comparison to the other verbal subtests both in males and females. N o difference could be detected as regards the clinical forms. The results at the neuropsychological tests are reported in Tables III, IV, and V. N o significant differences between patients and controls (Table III) and b e t w e e n males and

TABLE II. DISTRIBUTION OF MEAN VERBAL-PERFORMANCE DIFFERENCE IN C A H PATIENTS Groups

N

M -+ SD

Total pts. Males Females SVs SWs

19 12 7 9 10

4.3 3.1 6.3 4.7 3.9

___6 - 5.1 -+ 7.2 -+ 5.4 -+ 6.7

>9

1 (5%) 1 (8%) --1 (10%)

>12

>15

i

E. SINFORIANI et al.

60

T A B L E I I I . NEUROPSYCHOLOGICAL EVALUATION ( M -+ S D ) : PATIENTS VERSUS NORMAL CONTROLS ( A N O V A 1 W A Y )

Logical Memory immediate recall delayed " Corsi's test Visual Reproduction immediate recall delayed " Raven's Matrices Cancellation test Trail Making A B Word fluency Street's test

Patients

Controls

F

p

8.8 --- 2.6 10.3 -+ 3.1 6.1 -+ 0.8

10 -+ 2.1 11.3 -+ 3.2 6.2 --- 0.8

2.45 .96 .15

n.s. " "

12.5 -+ !.2 I1 +- 2.4 30.4 -+ 3.2 55.7 -+ 3.3 42.4-+ 13.5 63.5 -+ 24.2 17.9 -+ 4.5 8.8 -+ 1.4

12.4 10.8 30.9 56.3 37.1 56.3 17.2 9.0

.05 .06 .2 .24 1.76 1.05 .06 .12

" " " " " " " "

-+ 1.6 - 2.8 -+ 3.6 -+ 4.2 -+ 11 -+ 18.7 -+ 5.8 -+ 2.1

females (Table IV) were recorded. In particularly, no memory dysfunctions could be detected. On the contrary, as regards different clinical types, we found that SV patients obtained a signicantly (p < 0.05) lower score than SWs only in Trail Making test B (Table V). When SVs were compared with their matched controls no difference at Trail M a k i n g B w a s f o u n d ( S V s : 7 7 . 4 --+ 2 8 . 3 ; c o n t r o l s : 5 5 . 7 --_ 16.5; F = 3 . 9 5 , p < .06). H o w e v e r , S V s p r e s e n t e d a l a t e r d i a g n o s i s i n c o m p a r i s o n t o S W s ( F = 2 3 ; p < .001).

Neuroradiological Findings F o u r ( 2 7 % ) o u t o f 15 s u b j e c t s h a d f o c i o f i n c r e a s e d s i g n a l i n t e n s i t y i n t h e w h i t e m a t t e r on T2-weighted images. The small size of sample did not allow us to carry on statistical analysis, in particular as regards correlations between neuroradiological and neuropsy-

TABLE I V . NEUROPSYCHOLOGICAL EVALUATION ( M -+ S D ) : MALES (10 CASES) VERSUS FEMALES (9 CASES)

Logical Memory i m m e d i a t e recall delayed " Corsi's test Visual R e p r o d u c t i o n i m m e d i a t e recall delayed " Raven's Matrices Cancellation test Trail M a k i n g A B W o r d fluency S t r e e t ' s test

Males

Females

8.9 -+ 2.7 10.2 -+ 3.4 6.1 -+ 0.8

8.6 --+ 2.4 10.4 --- 2.9 6.0 - 0.8

12.3 11 30.4 54.7 41.7 65.1 17.0 8.5

12.9 11 31.1 57.4 43.7 60.9 19.4 9.3

--- 1.2 -+ 2.5 - 3.6 --+ 3.7 - 14.9 - 22.3 -+ 3.8 -+ 1.4

---+ -+ -------

1.3 2.5 2.6 1.3 11.8 28.7 5.5 1.4

F

.1 .1 .07 .8 .1 .5 3.6 .1 .1 1.4 1.4

p

n.s. " " " " " " " " " "

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TABLE V. NEUROPSYCHOLOGICALEVALUATION (M - SD): SV PATIENTS (9 CASES) VERSUS SW PATIENTS (10 CASES) ( A N O V A I WAY)

Logical Memory immediate recall delayed " Corsi's test Visual Reproduction immediate recall delayed " Raven's Matrices Cancellation test Trail Making A B Word fluency Street's test

SV patients

SW patients

F

8 - 2 9.4 --- 2.8 6 - 0.8

8.9 - 2.6 10.3 + 2.8 6.2 - 0.8

.7 .47 .3

n.s. " "

2.75 1.05 .9 .06 .56 5.1 3.52 .1

" " " " " <.04 " "

12.1 10.4 29.7 55.4 45.9 77.4 15.7 8.8

-+ 1.5 + 2.9 +- 4.1 +-- 4.3 --- 15.4 - 28.3 - 2.8 -+ 1.44

13 11.6 30.8 55.8 41.2 53.9 19.3 8.6

-+ 0.8 -+ 2.2 -+ 2.1 +- 2.7 +- 11.9 - 15.8 --- 5.1 - 1.3

p

chological parameters; therefore, we analyzed the subjects individually. The first of these patients had a small area of increased signal on T2-weighted images in the left peritrigonal white matter, with diffuse cortical atrophy (Fig. 2). The second subject presented two small lesions, one in the left external capsule and the other in the left peritrigonal white matter; a mild ventricular dilatation and cortical atrophy was also present. The third patient had two very small hyperintense foci, one in the right frontal white matter and the other in the right corona radiata. The fourth patient had a medium size lesion of increased signal in the retrolenticular portion of the left internal capsula, and many hyperintense foci in the corona radiata and the frontal white matter of both hemispheres (Fig. 3). Mild enlargement of cortical sulci and moderate ventricular dilatation were also evident. N o n e of these patients presented abnormal cognitive and/or affective character-

P**N

FIG. 2: Axial and coronal SE images (TR 2500, TE 40/100). Single punctate focus of hyperintensity in the left periventricular frontal white matter (Patient 1).

62

E. SINFORIAN| et al.

FIG. 3: Axial SE images (TR 2500, TE 40/100). Diffuse bilateral foci of increased signal in the corona radiata with a small hyperintense area in the retrolenticular portion of the left internal capsula (upper images) (Patient 4).

istics. Two cases were salt-wasters, the other two were SVs. One of the SWs had presented severe salt-wasting crisis a few weeks after birth and again when the parents decided to interrupt substitutive therapy; the other three patients had presented periods of therapeutic overdosage during follow-up. At the moment of the study only one patient showed high ACTH levels (case no. l). In another two patients (1 SW and 1 SV), a mild ventricular enlargement was the only abnormal finding; these patients did not present cognitive abnormalities or pathologic hormonal levels. Out of those nine patients who did not show NMR abnormalities, four were SWs and five were SVs. Almost all cases had presented signs of overdosage in the past, especially during the first year of life. At the moment of the study only two patients showed elevated ACTH levels. The fourth subject with high hormonal values did not undergo NMR as he had a plaque in the bone. No patient presented abnormal cognitive findings. NMR scans were normal in all controls. No subjects, both patients and controls, presented medical illness such as hypertension or cardiovascular diseases, which have been highly correlated with white matter abnormalities. CONCLUSIONS The results of this study indicate that our CAH patients do not present significant cognitive abnormalities with respect to normal matched controls. As regards the IQ levels, the subjects showed a slightly higher IQs in comparison to the expected distribution; in particular, patients with IQs less than 89 were underrepresented. However, they did not evidence higher IQs than match controls. Even though we did not compare CAH patients with their parents and relatives, we consider that this finding, which is in agreement with previous studies (Nass & Baker, 1991a), may be due to a sample selection bias, as suggested by McGuire & Omenn (1975); our subjects, in fact, represented a very homogeneous group as regards age, schooling, and socioeconomical conditions are concerned. No significant incidence of learning disabilities, expressed as verbal-performance discrepancy, could be found; furthermore, our patients did not present difficulties with

CONGENITAL ADRENAL HYPERPLASIA

63

everyday life, and the academic performance of those subjects still at school was good, in the opinion of their teachers. However, both males and females showed a mild impairment of arithmetic subtest at their WAIS scores. This finding has been reported by some previous researchers (Nass & Baker, 1991) and related to early androgen exposure, which can cause a delayed maturation of the left hemisphere. In addition, a developmental Gerstmann syndrome has been suggested (Nass & Baker, 1991b). Further studies are needed to test these hypotheses. In our opinion, at least in our patients, this finding may be related to relatively poor concentration rather than to arithmetic disabilities in themselves, even if digit span and the other mnesic and attentive tests were within the normal range. Furthermore, we did not find any cognitive difference between males and females, nor between clinical types, as reported in some previous studies. The poorer performance of SVs at Trail Making B, which explores visuo-conceptual and visuo-motor tracking, is probably related to the later diagnosis in this group; it is also well known that Trail Making is highly sensitive to brain damage, independently of type. NMR abnormalities could be detected in about 25% of the cases; the white matter lesions were very small, nonspecific, without side prevalence, and present only in the supratentorial regions. Nass et al. (1990) have reported pathologic findings in about i of their CAH patients; ischemic injury has been suggested by the authors. In our opinion, the meaning of these lesions remains difficult to interpret. Hyperintensities, in fact, correspond to an increase of extracellular water content that may result from different processes (such as et~tt cribl6, myelin pallor, gliosis, perivascular atrophic demyelinization, and lacunae), and MR cannot distinguish among them (Drayer, 1988; BrandtZawadzky et al., 1985; Braffman et al., 1988b). White matter abnormalities have been described, although rarely, in young healthy people; however, they were not present in our control group. Therefore, these abnormalities could be related to CAH, but the aspecificity of these findings and the absence of peculiar clinical characteristics (not only in patients with white matter lesions, but also in those without pathologic findings) prevent us from formulating a pathologic hypothesis with any certainty. However, at least for our patients, given the type of NMR lesions, we do not think that white matter abnormalities can represent infarction; neverthless, microangiopathy cannot be excluded. Both overdosage and discontinous therapy (detectable in particular in one subject with white matter lesions) could be possible causes, at least for a subgroup of patients. On the other hand, no subject showed signs of disorders of myelination, which could be related to excessive glucocorticoids. As far as the presence of atrophy is concerned, data in the literature suggest some correlation between dosage of steroids and degree of cerebral atrophy, which can be reversible (Bentson et al., 1978; Okuno et al., 1980). On the other hand, during the study none of our patients presented signs of steroids overdosage; moreover, only one of the patients with high ACTH levels showed white matter abnormalities and mild atrophy. We did not find any correlation between neuroradiological findings and neuropsychological parameters, in particular as regards attentive functions. In addition, the data in the literature concerning the clinical significance of white matter lesions are controversial. It has been recently suggested that a "threshold" area of white matter lesions must be present before neuropsychological deficits are observed (Boone et al., 1992). Undoubtedely, the lesions in our patients were very small. Moreover, we think it important to distinguish among those patients with white matter lesions associated with stroke or other neurological conditions, such as multiple sclerosis, and those nonsymptomatic

64

E. SINFORIANI et al.

subjects with white matter lesions, like our C A H patients. In our opinion a follow-up study o f patients with NMR abnormalities is needed to verify the evolution of the lesions and the possible onset of neurological and/or personality disturbances, which can be related to cerebral lesions.

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