INTELLECTUAL FUNCTIONING

In 1936, Gesell and his colleagues described the response to treatment of six cases of CH. The mental devel­ opment of the children was formally assessed at the time of diagnosis and on subsequent follow-up of a period of be­ tween 59 weeks and seven years. Four of the children were started on treatment during their first year of life and the remaining two began treatment close to their second birthday. At diagnosis all the children were reported to have a developmental quotient (DQ) of 50 points or less and all showed DQ gains after periods on treatment. Four of the children remained significantly intellectually impaired (DQ < 75) while the remaining two children were at the lower end of the average range. Gains during treatment ranged from 15 to 65 points. Although the reliability of develop­ mental quotients during the first year may be questioned, the study was important in suggesting that treatment may not only arrest the physical symptomatology of the disorder but could lead to improved cognitive functioning. However,

in this small sample, better outcome was not associated with earlier onset of treatment (Gesell et al 1936).

described by Lewis and his colleagues (Lewis et al 1937). Seventy nine of this sample were assessed for cognitive functioning using either the Binet-Simon, Merrill-Palmer or Gesell tests depending on the severity of their mental impairment. Approximately three quarters of those assessed had an IQ score of less than 70 points. It was noted that these scores could be considered an underestimate of the level of functioning for some of the subjects as their 'mental slowness' lowered their scores on timed tasks. It was also acknowledged that the sample was likely to be biased towards the most severely impaired patients as many of the sample were recruited from large long-stay hospi­ tals. Nevertheless, the cognitive outcome for a substantial proportion of patients with CH was extremely poor.

Lewis, like Gesell, was not convinced that earlier treatment would lead to improved cognitive functioning. A case was described of a patient who began treatment at four months of age and who was assessed to have an IQ of 34. This was contrasted with a patient who did not receive treatment until 31 years of age and who had an IQ of 63. Lewis recognised that the adequacy of treatment could not be assumed and that poor treatment, despite being initiat­ ed early, could account for the poor outcome in some cases. With the benefit of later knowledge it can be seen that the advantages of early treatment were confounded by the tend­ ency for more severe cases of CH to be diagnosed earlier than milder forms of the disorder. In this way, the poorer outcome of some patients treated earlier was probably asso-

elated with a more severe form of the disorder.

This problem was fully addressed in an impressive study on a group of 149 patients with CH treated at the Harriet Lane Endocrine Clinic (John Hopkins University) during the period 1935-55 (Money 1956; Smith et al 1957). In the earlier paper. Money described the results of IQ tests on a randomised group of 70 patients divided into groups according to the age that each child became euthy­ roid following the onset of treatment. The data were pre­ sented by giving the results of each individual assessment without any summary statistics at alii In spite of this apparently limited treatment of the data, Money made a number of perceptive observations which proved to be quite forward looking. He observed that low IQ was not an invar­ iable consequence of CH and also that early treatment did not invariably result in average range IQ scores. He con­ cluded that age at start of treatment was not the only prognostic indicator and that parental IQ, the quality of treatment following diagnosis, the aetiology of the CH and the length of time that the infant was hypothyroid (includ­

ing the fetal period) were also likely to contribute to later mental functioning. In retrospect these considera­ tions have proved remarkably accurate in predicting the questions addressed by many later follow-up studies of early treated children with CH.

Smith et al (1957) described the psychological outcome of 128 patients in relation to three diagnostic groups, namely severe congenital cretinism, mild congenital cretin-

ism, and acquired hypothyroidism. Severe congenital cretin­ ism was defined as those patients who developed definite symptoms and signs of CH within the first six months of life (N=79) . Mild cretins (N=32) did not show 'readily evident' symptoms prior to six months of age but symptoms were 'grossly' manifest by 6 to 18 months of age. Seventeen patients were classified as having acquired hypothyroidism with onset of symptoms between 2 and 12 years of age. The mean duration of therapy was six years (range: 1 to 16 years) prior to the last determination of cognitive func­ tioning. Nearly all of the patients (109) were formally assessed using either the revised Stanford-Binet scale for children under five years or the Wechsler scales for older children and adults. The remaining 19 patients were evalu­ ated on the basis of clinical judgment.

TABLE 3. INTELLECTUAL FUNCTIONING IN LATE TREATED CH (Smith et al (1957). TYPE OF CH N %>90 %<50 Severe CH -age at start of treatment 6 mths 22 45 18 7-12 mths 7 29 29 >12 mths 22 0 40 Not adequately treated 28 0 61 Mild CH-treated 6mths-13yrs 32 41 6 Acquired CH 17 7 6

Cognitive outcome has been divided according to the age at which adequate treatment was judged to have been

established. Within the 'severe* group (including the patients not treated adequately) the overall proportion of patients with an IQ less than 50 was 41%. However, of those adequately treated during the first six months, the propor­ tion was only 18%. In contrast, 61% of those patients who were inadequately treated during the first year had an IQ less than 50. Comparisons with the 'mild* group showed a much smaller proportion (6%) of children within this range of IQ scores. The authors concluded that adequate treatment initiated during the first six months of life would reduce the frequency of severe learning impairment in patients with CH.

This finding was supported in studies by Andersen (1961) and Man et al (1963) although these were based on very small samples. Raiti and Newnes (1971) reviewed a consecutive series of 141 cases treated at the Hospital for Sick Children in London. Fifty six of these children were formally assessed for IQ and improved cognitive outcome was evident in those children treated before three months of age. Nearly 75% of children treated before three months of age had an IQ score greater than 90 compared with only 33% of those started on treatment between three and six months of age. This finding was also reported in North America (Klein et al, 1972) in a study of 31 children in which those treated from less than three months of age (mean IQ 89) were functioning over one standard deviation higher compared with later treated patients (four to seven months: mean IQ 70). Despite important methodological deficits in

some of these studies, the overall results of these studies were consistent in indicating the neurological importance of the first six months of life in respect to brain growth. The importance of early treatment was increasingly support­ ed by a number of animal studies (described previously).

Between 1974 and 1981 four studies (Hanefeld et al 1974; MacFaul et al 1978; Wolter et al 1979; Aim et al 1981) presented broadly similar findings in respect to psychological outcome. All four studies suggested that improved IQ scores were related to early treatment, that the overall mean IQ for patients with CH was about one standard deviation below the population mean and that minor neurological impairments appeared unrelated to age at start of treatment. All four studies had relatively small sample sizes (between 30 and 57 cases) which made within group comparisons potentially unreliable.

In the UK two follow-up studies with larger samples (Birrell et al 1983; Hulse 1984b) were carried out in two areas of England. The explicit aim of the study by Hulse was to provide psychological data on a large community sample of children with late treated CH in order to compare thèsedata with the psychological outcome of children with CH detected by screening (early treated). It was intended that this would enable a more accurate evaluation of the value of the screening procedure (Hulse 1984a). The study was carried out in the south east of England and involved the assessment of a sample of 141 children, aged between 1 and 16 years, on a wide range of psycho-neurological meas­

ures including IQ. Retrospective data were collected on the diagnosis and early treatment and 132 cases were confirmed to have CH. Five cases were considered to have acquired hypothyroidism and, for four cases, the diagnosis could not be confirmed. 31.8% of the sample began treatment during the first three months of life and 34.1% after their first birthday. Within this latter group 7.4% began treatment after five years.

With respect to intellectual functioning, there was a remarkably consistent outcome across the age range despite using different assessment procedures. Children younger than four years (N=10) were assessed using the Griffiths scale of Infant Development and had a mean DQ of 83.9. Four to six year olds (N=21) were assessed with the McCarthy scales and had a mean GCI of 81.7. Using the WISC-R, the older children (N=99) had a mean score of 79.5. Overall, children with late treated CH had an intellectual deficit of approximately 1.3 standard deviations compared with the general population.

The relationship between intellectual outcome and age at start of treatment was examined without controlling for the severity of the condition. A summary of the results is shown below.

TABLE 4. IQ BY AGE AT START OF TREATMENT IN CH CHILDREN BEFORE SCREENING (Hulse 1984) AGE AT START OF TREATMENT N Mean IQ

Less than six weeks 6 102.5

Six weeks-3 months 14 84.4

3-6 months 22 78.2 6-9 months 4 68.0 9-12 months 6 80.5 12-24 months 15 83.3 24-60 months 11 85.5 >60 months 9 79.4

Intellectual outcome showed a decline when treatment was delayed after six weeks of age. Children treated before six weeks of age obtained a mean IQ close to that of the general population. The decline in IQ scores during the first year further suggested the importance of early treat­ ment but only if the severity of the disease was equivalent

for all groups.

The study by Birrell et al (1983) was very similar in design. 80 children with CH between the age of 5-15 years within the Northern Health region of England were identi­

fied and 56 of these completed full motor and intellectual assessments. Intellectual functioning was assessed using either the WPPSI or the WISC-R as appropriate. The mean IQ for the group was 83.9 points, a result very similar to Hulse's findings. However, in contrast to Hulse, no rela­ tionship between age at start of treatment and cognitive outcome was indicated. However, poorer outcome was associ­ ated with earlier onset of CH (as measured by bone age at diagnosis) and it is probable that this confounded the association with the age at start of treatment.

These estimates of intellectual functioning provided by the two British studies were marginally higher than that calculated by Klein (1980) who carried out a literature review on all studies with IQ data on patients with late treated CH. A sample of 651 cases was obtained with a mean full scale IQ score of 76. It was also noted that some children with IQ scores above 90 were still unable to attend main stream school because of varying problems with speech, perception and attention. This lower estimate of outcome was probably influenced by the inclusion of cases from an earlier time period when the quality of treatment was less certain than that covered by the two UK studies.

The aim of many of the more recent follow-up studies of children and adults with late treated CH was to provide comparative data with the outcome of children following the introduction of screening. However, changes in outcome may also have been influenced by improvements in the clinical management of patients and by more general secular trends (e.g. rising IQ scores) which have occurred over the time between studies of children with late treated CH and subse­ quent studies of screened populations of CH children. This difficulty has been addressed by a more recent study (Sack et al 198 6) who compared early and late treated children who were treated during the same time period. The study consisted of three groups of children with CH, namely those detected by screening (early treated) and two groups of late treated patients. The results are summarised in the table below where age (weeks) refers to age at start of

t r e a t m e n t .

TABLE 5. INTELLECTUAL OUTCOME TREATED CH (Sack et

IN LATE AND EARLY al 1986)

DEFINITION OF GROUP N MEAN AGE AT START TREATMENT (weeks) IQ (Mean) Detected by screening. 14 4.6 104 Late treated, thyroid agenesis 15 19.3 82 Late treated, ectopic thyroid 9 46.4 93

Although the interpretation of the results of this study is limited by the sample size, it provides a useful illustration of the potential benefits of early treatment and that outcome is also likely to be affected by the severity of the condition as well as the age at which treatment is started.

Results from a range of studies between 1930 and 1984 provide strong evidence for substantial intellectual defi­ cits in patients with late treated CH. The size of the IQ deficit can be estimated to be approximately 1.3 standard deviations below the population mean. Patients who began treatment during the first three months of life had a higher IQ than later treated patients and, in some studies, this has approximated to the expected mean for the general population. However, it remained unclear whether the rela­ tionship between age at start of treatment and intellectual

outcome was linear or whether there was a critical period for the initiation of treatment in order for normal intel­ lectual development to be achieved as had been suggested by some of the animal studies described above.