The nationwide register-based prevalence of intellectual disability during childhood and adolescence.

BACKGROUND: Many studies have evaluated the prevalence of intellectual disability (ID) by focusing on different ages during childhood and adolescence. Although the prevalence of ID is higher in older age groups, how cumulative prevalence increases, and what level it reaches before adulthood, remains unclear. METHOD: We used Care Register for Health Care to retrieve information on individuals born in 1996-2007 with any of the inclusion diagnoses of ID (F7 group and/or aetiological diagnoses) for the period 1996 to 2013. The cumulative prevalence was calculated as percentages for every age based on Finnish population data. RESULTS: The registration of new diagnoses of ID continued steadily throughout the developmental years. The cumulative prevalence reached 1.19% by age 17.5 among those born in 1996. Later-born age groups appeared to receive their first ID diagnoses earlier in childhood. Those born in 1999 reached a cumulative prevalence of 1.21% already by age 14.5. Of all those with ID, 67% had an F7 diagnosis only, 42% had an aetiological diagnosis only and 9% had both diagnoses. CONCLUSIONS: Cumulative prevalence of ID by year, until the age of 18, will provide a better estimate and understanding of the prevalence of ID than a point prevalence at any one point during the developmental years.

Age-specific prevalence of intellectual disability in Finland at the beginning of new millennium--multiple register method.

BACKGROUND: In the national study of multiple registers in 2000, the average prevalence of intellectual disability (ID) was 0.70%, with marked differences by age group (range 0.38-0.96%) - what are these differences in detail, and can they be understood? METHOD: This study was based on two national health registers and six social benefit registers. Prevalence of ID was calculated by 1-year age cohorts. RESULTS: The multiple register prevalence of ID increased steadily from 0.20% in the first life year to 0.74% (male: 0.90%, female: 0.58%) at 10 years. For boys, the rate fell to 0.71% at 11 years. For both sexes, a steady increase was noted in the distribution up to 40 years (male: 0.84%, female: 0.73%), followed by a sharper increase to the maximum prevalence (male: 1.19% at 48 years, female: 1.05% at 50 years). At the pension age of 66 years, a sudden drop to 0.49% occurred for men and women. Different registers gave very different age distributions. CONCLUSIONS: By examining the data by 1-year age cohorts, and by understanding the role of each register, it could be deduced that a proportion of cases in younger age groups is lacking, and a remarkable proportion of elderly ID persons is missing from the pooled data. The findings were more difficult to interpret, if the data were grouped into bigger age groups.

Increase in non-transferrin bound iron and the oxidative stress status in epilepsy patients treated using valproic acid monotherapy.

OBJECTIVE: This study aims to investigate the alteration of iron homeostasis and oxidative stress status in epilepsy patients treated with valproic acid (VPA) monotherapy. MATERIALS: 24 epilepsy patients receiving VPA monotherapy (12 men, 12 women, age 27.5 ± 7.2 y) and 24 sex- and age-matched healthy volunteers were included in the study. METHODS: The level of iron status parameters; serum iron, ferritin, transferrin saturation, non-transferrin bound iron (NTBI), serum level of trace elements (copper, zinc and selenium), concentration of antioxidant parameters, activities of antioxidant enzymes and level of lipid peroxidation product were determined. RESULTS: NTBI was found in the patients although their other iron status parameters were normal. Levels of antioxidant parameters were decreased while activities of antioxidant enzymes were increased. Levels of serum MDA were significantly increased in patients with epilepsy. The daily dose of valproic acid associated was statistically significant: serum concentration of NTBI (r = 0.579; p = 0.003) and MDA (r = 0.465; p = 0.022). A positive correlation existed between NTBI and zinc (r = 0.522; p = 0.009). CONCLUSION: According to our results, VPA treatment in patients with epilepsy contributes to the metabolism of iron, leading to the formation of NTBI and an increase in oxidative stress.

Prevalence of intellectual disability: a comprehensive study based on national registers.

BACKGROUND: Based on standard social benefit registers, the prevalence of intellectual disability (ID) in Finland is estimated to be 0.6%, while epidemiological surveys yield 1.1%. Combining several registers, our aim was to find a more reliable estimate of the prevalence of ID, especially among children and adolescents. This is important when special or inclusive general services are planned to meet the various needs of people with ID. METHOD: A survey based on eight national health and social benefit registers. RESULTS: Combining different registers yielded a mean ID prevalence of 0.70% (95% CI 0.69-0.70%), with marked differences according to sex and age group (range 0.38-0.96%). Capture-recapture analysis gave higher prevalence estimates (range 0.57-1.08%). CONCLUSIONS: When several health and social benefit registers are surveyed, the estimated prevalence of ID increases, approaching that obtained in epidemiological surveys.

Urinary 6-hydroxymelatonin sulfate excretion in intellectually disabled subjects with sleep disorders and multiple medications: validation of measurements in urine extracted from diapers.

The aim of this study was to examine the applicability of urinary 6-hydroxymelatonin sulfate (MT6s) measurements in the evaluation of melatonin secretion in intellectually disabled patients with sleep disorders. All 17 patients received drugs with potential interactions with melatonin metabolism. Serum melatonin 24-h profiles were determined at hourly intervals. The area under the curve (AUC) value, peak amplitude, half-rise time, and half-decline time were calculated individually. Urinary MT6s excretion was determined from samples collected from disposable diapers during three consecutive days at varying intervals. The average excretion rate for each hour of the day was calculated. The excretion profiles were characterized by total amount of MT6s excretion/24 h/kg body mass, amount of excreted MT6s during 6 h of maximum excretion (MAX 6h), and start time of the maximum excretion (start MAX 6h). There were significant positive correlations between serum melatonin AUC value and total excretion of MT6s/body mass, between serum melatonin amplitude and urinary MAX 6h, and between melatonin half-rise time and start MAX 6h; one patient on phenobarbital medication was out of line. The serum melatonin profiles of the patients were classified by comparing them with those of matched healthy volunteers (low-, normal-, or high secretors, normal or delayed rhythm). Similarly, the parameters of MT6s profiles were compared with those obtained from healthy controls, and the patients were reclassified as normal or aberrant. The classifications based on serum melatonin and urinary MT6s measurements were mostly concordant. The daily pattern of urinary MT6s excretion reliably reflected the phase of the serum melatonin rhythm irrespective of the medications, but in some cases, the total amount of excreted MT6s was lower than expected based on serum melatonin measurements.

Why and how to assess the aetiological diagnosis of children with intellectual disability/mental retardation and other neurodevelopmental disorders: description of the Finnish approach.

One of the most important tasks of a physician who has patients with delayed development is to assess the cause of the problem. To help with this work, an aetiological classification based on timing and type of the injury to the central nervous system (CNS), has been created. The main divisions are: genetic causes; CNS malformations and multiple malformation syndromes of unknown origin; external prenatal factors; paranatally acquired disorders (-1 to +4 weeks from delivery); postnatally acquired disorders; and untraceable or unclassified causes. In the classification, the earliest factor injuring the CNS is the primary diagnosis. The first stage, which consists of a quite simple workup, reveals the timing of the injury and allows the possibility for family counselling. The overview of the second stage assessment is also given. The 'aetiological tree' illustrates the classification method and serves as a reference and teaching aid. It can also be used for genetic counselling to demonstrate the situation. This method has been used for almost 20 years and has been proven to enhance diagnostic activity and family counselling.

Neurological impairments and sleep-wake behaviour among the mentally retarded.

The objective of the present study was to evaluate the relationship between the sleep-wake behaviour and neurological impairments among mentally retarded people. The sleep-wake behaviour of 293 mentally retarded subjects living in a rehabilitation center was studied by a standardized observation protocol carried out by trained staff members. The protocol consisted of brief check-ups of the subjects' sleep-wake status at 20-min intervals for five randomly chosen 24-h periods during 4 months. From the raw data five sleep-wake behaviour variables were formed. The data concerning the subject characteristics (age, body mass index (BMI), gender, degree of mental retardation, presence of locomotor disability, that of epilepsy, blindness or deafness and the usage of psychotropic medications) were collected from the medical records. Two main findings emerged: (1) severe locomotor disability, blindness and active epilepsy were found to be independent predictors of increased daytime sleep and increased number of wake-sleep transitions and (2) the subjects with a combination of two or all three of these impairments had a significantly more fragmented and abnormally distributed sleep than those with none or milder forms of these impairments. Age, BMI, degree of mental retardation and the studied medications played a minor role in the sleep disturbances of the study population. Finally, deafness was not found to be associated with any of the measured sleep-wake variables.

A patient with 2 different repeat expansion mutations.

BACKGROUND: Many inherited progressive encephalopathies have a poor outcome, and some are caused by repeat expansion mutations. How would the presence of 2 different expansion mutations affect the phenotype? OBJECTIVE: To describe a patient who has 2 distinct, rare genetic disorders: myotonic dystrophy (DM, OMIM 160900) and progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1, OMIM 254800). Both conditions are caused by repeat expansion mutations. They affect the central nervous system causing mental retardation, but also produce a wide spectrum of disabilities in daily living. SETTING: Referral center. METHODS: Clinical description with accompanying photographs, electroencephalography and magnetic resonance imaging; DNA analysis of both of the mutations and chromosomal analysis with prometaphase spreads. RESULTS: The patient had clinical characteristics and findings of both myotonic dystrophy and progressive myoclonus epilepsy of the Unverricht-Lundborg type. Electroencephalographic recordings over a 3-year period showed typical findings for myoclonus epilepsy. The patient had no gross anomalies in brain magnetic resonance imaging. She had a normal karyotype, and both of the diagnoses were confirmed at the molecular level with the direct detection of the mutations. CONCLUSIONS: Despite having 2 different progressive inherited disorders affecting the central nervous system, the patient, at age 28 years, showed only mild mental retardation with very slow progression. However, clear deterioration in activities of daily living has taken place during last 3 years. Arch Neurol. 2000;57:1199-1203

Smith-Lemli-Opitz syndrome and other sterol disorders among Finns with developmental disabilities.

Smith-Lemli-Opitz syndrome (SLOS) is an inherited disorder of cholesterol metabolism in which 7- and 8-dehydrocholesterols are accumulated in blood and tissues. Diagnosis of SLOS and other disorders in cholesterol metabolism (eg, cerebrotendinous xanthomatosis, phytosterolemia, desmosterolosis, and X-linked dominant Conradi-Hünermann-Happle syndrome) can be performed by gas-liquid chromatographic analysis of serum sterols. To elucidate their involvement in developmental disability, we evaluated serum sterols in two study groups: developmentally disabled subjects in long-term care (N = 322) and newborns and young children (N = 49) with features of SLOS in the Finnish population of 5 million. Only 1 SLOS case (type II) was found from among the 49 children. Seven additional adult cases (type I) with a wide range of clinical features and the serum sterol abnormalities characteristic of SLOS were detected from among the developmentally disabled subjects. The frequency of SLOS in the latter group was relatively high (7 in 322). No other hereditary sterol disorders were found, but two subgroups with low serum cholesterol precursor sterols and high serum plant sterols were identified. Several subjects, including the 7 SLOS patients, used ample medication and had abnormalities in serum sterol concentrations. Thus, among the subjects taking melperone, a high serum delta8-cholestenol level suggests an interference by the drug with cholesterol synthesis. Our results emphasize the importance of analyzing the serum sterols of developmentally disabled subjects to diagnose SLOS and of finding putative undiagnosed disorders in sterol metabolism associated with these clinical conditions.

Aetiology of intellectual disability--the Finnish classification: development of a method to incorporate WHO ICD-10 coding.

The present authors made an attempt to ease the diagnostic work of physicians who have patients with intellectual disability by creating an aetiological classification system based on the time and mechanism of injury to the central nervous system (CNS). The current paper presents the work-up needed for understanding at least the timing of the causative factor/factors. The timing principle opens a direct course to family counselling. This method has been very well accepted during its 18 years of use in Finland, and therefore, it was felt that it would be helpful to organize the relevant ICD-10 diagnoses according to the timing principle. This method has been published as a manual. An image of a tree became the obvious metaphor for this system. The genetic category forms the main root and stem, from which multiple branched roots and limbs emerge. The individual diagnoses appear as root nodules and leaves. The system is flexible, making it possible to add new branches for groups of diagnoses when improved diagnostic methods create these options (e.g. microdeletions). The aetiological diagnoses change accordingly. Over the course of further development, new incidents damaging the CNS may affect the functional level of an individual and require additional diagnoses. It is a constant challenge for physicians to keep the diagnoses of their patients up to date. The image of the tree helps professionals to think in terms of timing, and thus, makes family counselling easier. It is also helpful in the education of medical professionals.

Detection and quantification of protein-losing enteropathy with indium-111 transferrin.

Localisation and quantification of protein loss in protein-losing enteropathy (PLE) is useful in the clinical management of hypoalbuminaemia. Indium-111 transferrin offers the opportunity of combining localisation and quantification using a single agent. Twenty-five studies were performed in 23 patients with suspected PLE: 111In-transferrin was prepared by incubating autologous cell-free plasma with 111In chloride in vitro for 15 min. Protein loss was quantified by comparing whole-body counts recorded with an uncollimated gamma camera at 3 h and 5 or 6 days after injection of 111In-transferrin. Gamma camera imaging performed at 3 and 24 h after injection demonstrated a site of protein loss in 15 studies. Whole-body 111In excretion was abnormally elevated in 13 of these, ranging from 16% to 34% (normal <10%), was not assessed in one and was less than 10% in a patient with carcinoid syndrome. In the ten studies that were negative on imaging, whole-body 111In excretion was normal in nine and elevated at 22% in a further patient with carcinoid syndrome. Overall, the mean whole-body 111In excretion in studies with positive imaging was 21.4% (SD 6.1%) (n=14), significantly higher (P<0.01) than in studies with negative imaging, in which it was 7.5% (SD 6.7%) (n=10). This technique should be useful for the combined approach of localising and quantifying protein loss in PLE.

Corticosteroids reduce regenerative repair of epithelium in experimental gastric ulcers.

The association between corticosteroid treatment and gastric ulcer healing is controversial. The effects of corticosteroids on experimental ulcer healing in the rat were studied and the effect of coadministration of a prostaglandin E1 analogue was determined. Forty male adult rats were divided into five groups and pretreated for 10 days as follows: (a) control, (b) prednisolone (10 mg/kg), (c) prednisolone and misoprostol (300 micrograms/kg), (d) misoprostol, and (e) indomethacin (2 mg/kg) Gastric ulcer was induced by applying a cryoprobe to the serosal surface of the stomach. Healing was assessed by determining the ulcer size at three and six days. Mucosal regenerative activity at the ulcer edge was assessed by quantitating DNA synthesis in cells by immunohistochemical techniques using monoclonal antibodies to detect expression of proliferating cell nuclear antigen (PCNA) and incorporated 5-bromo-5-iododeoxyuridine (BrdU). Compared with control rats, the rate of healing and the mucosal regenerative activity were significantly reduced in rats treated with prednisolone and indomethacin (p < 0.05). Coadministration of misoprostol and corticosteroids reversed the delay in healing and the reduction in mucosal regeneration induced by corticosteroids alone. With misoprostol alone, the ulcer size and the number of epithelial cells that actively synthesised DNA did not differ from control animals. A comparison between the two immunohistochemical markers of cell proliferation showed a highly significant correlation between the two techniques (r = 0.64, p < 0.005), indicating that the simpler PCNA technique should prove valuable in assessing regeneration in experimental ulcer disease.

Age-related cognitive decline and electroencephalogram slowing in Down's syndrome as a model of Alzheimer's disease.

We studied quantitative electroencephalogram and neuropsychological performance in an aging series of 31 patients with Down's syndrome and compared the findings with those of 36 patients with probable Alzheimer's disease and age-matched controls. We found an age-related decline of cortical functions and slowing of the electroencephalogram in Down's syndrome patients aged from 20 to 60 years. Slowing of the electroencephalogram, i.e. the decrease of the peak frequency, was significantly related to Mini-Mental status scores, and visual, praxic and speech functions, as well as memory in the Down patients, similar to the Alzheimer patients. Similar correlations were not demonstrated for young or elderly controls. This study provides neuropsychological and electrophysiological data to suggest that studying Down's syndrome patients of different ages can serve as a model for progression of Alzheimer's disease.

Circulating immune complexes in sera from patients with Alzheimer's disease, multi-infarct dementia and Down's syndrome.

Recent data suggest that immunological mechanisms may be implicated in the pathogenesis of Alzheimer's disease (AD). We tested the presence of circulating immune complexes (CIC) in the sera from dementia and Down's syndrome (DS) patients and age-matched controls using two methods: Clq-binding Elisa (ClqB-Elisa) and conglutinin-binding Elisa (KgB-Elisa). The probable AD and multi-infarct dementia (MID) patients had more frequently CIC in their sera as compared to elderly non-demented subjects (Chi-square; P < 0.05). The highest frequency of positive findings was detected for 10 DS patients (8 KgB-Elisa and 7 ClqB-Elisa positive) whereas only 1 of 10 young controls showed ClqB-positivity. In the AD patients the cognitive decline as assessed by the Mini-Mental Status test correlated significantly with CIC values. The study supports the view that systemic autoimmune mechanisms may be involved, at least partly, in dementing processes.

Pulmonary granulocyte margination is increased in patients with inflammatory bowel disease.

The pulmonary granulocyte content of the lung was quantified in patients with inflammatory bowel disease (IBD) after injection of 111In-labelled granulocytes and compared with patient controls, who, on the basis of their negative white cell scans, were not considered to have active inflammation. The mean ratios of lung:liver count rates per pixel on the posterior gamma camera image in patient controls was 0.34 (S.D. 0.16, n = 8) at 1-1.5 h after injection of the cells, and 0.29 (S.D. 0.14, n = 18) at 2-4 h. This ratio was higher in patients with active IBD at both imaging times: 0.45 (0.13, n = 13, P > 0.05) and 0.44 (0.1, n = 19, P < 0.001). Patients with inactive IBD also had increased ratios at both imaging times: 0.6 (0.14, n = 7, P < 0.01) and 0.54 (0.15, n = 12, P < 0.001), respectively. In a further group of 12 patients with active IBD, there was no correlation between the lung:liver ratio and the severity of the IBD as assessed by whole-body 111In retention at 4-6 days after labelled cell injection. These patients were treated for 3 weeks with an oral, non-absorbable corticosteroid, after which there was a significant decrease in disease activity but no significant change in the lung:liver ratio. Inflammatory bowel disease appears to be associated with abnormal pulmonary granulocyte accumulation. It is not apparently related to disease activity but may be the result of an associated pulmonary abnormality.

Platelet imaging of thromboembolism. Natural history of postoperative deep venous thrombosis and pulmonary embolism illustrated using the 111In-labelled platelet-specific monoclonal antibody, P256.

BACKGROUND: Deep venous thrombosis (DVT) and pulmonary thromboembolic disease are difficult to diagnose, particularly following surgery. This report demonstrates the use of 111In-labelled platelet-specific monoclonal antibody, P256 Fab', for the diagnosis and study of the time course of thromboembolic disease in a patient following total hip replacement. METHOD: One hundred micrograms of pentetic acid (DTPA)-P256 Fab' was labelled with 8 to 10 MBq of 111In chloride by incubation at room temperature for 15 min. After dilution in physiologic saline, the tracer was injected intravenously on the third and sixth days postoperatively. Imaging of the chest, pelvis, and legs was carried out at 24, 48 and 72 h following each injection. RESULTS: The first image four days after surgery demonstrated activity in the right heart which moved to the right pulmonary artery on the following day. Activity was seen in both femoral veins; on the left, this increased over two days, followed by a reduction on the seventh day after surgery, at which time new activity was seen in the right heart. After a further two days, this activity moved to the left pulmonary artery. The DVT was confirmed by venography and the pulmonary embolism (PE) by ventilation perfusion scan. CONCLUSIONS: 111Indium-labelled platelet-specific monoclonal antibody, P256 Fab', provides a technique for studying the natural history of thromboembolic disease and its treatment.

Indium-111 whole-body retention: a method for quantification of disease activity in inflammatory bowel disease.

Quantification of disease activity in inflammatory bowel disease (IBD) has been by measurement of fecal excretion of 111In-granulocytes. The difficulties of this method prompted us to evaluate quantification of whole-body 111In retention, expressed as a percentage of whole-body activity at 3 hr following injection, as an alternative method. The patient stood in front of the uncollimated gamma camera at a distance of 4 m and counts were collected over 2 min. The geometric mean was taken of posterior and anterior counts and compared with a 111In standard. The lower limit of the 95% confidence interval for whole-body retention in normals was 90%. Forty-five studies were performed on 33 patients with IBD. They were assessed in two groups, one to whom routine instructions for the collection of feces were given (Group A) but who did not always comply. The other group received oral and written instructions and were also monitored during the collection period (Group B) and reported full fecal collection. Although in Group A the correlation between fecal excretion and whole-body retention was good (r = 0.7, n = 32; p less than 0.001), in Group B the relationship between fecal excretion and whole-body retention was significantly better (r = 0.95, n = 18; p less than 0.001). On average, 111In whole-body retention was consistent with findings obtained during imaging: 111In excretion (100-whole-body retention) was 7.8% +/- 4.9% in 5 normal scans, 10% +/- 5.9% in 17 (+) scans, 22.3% +/- 8% in 20 (++) scans and 57% +/- 16% in 8 ( ) scans. We conclude that imaging is more sensitive than whole-body retention and fecal excretion in the detection of disease, but for quantification, whole-body retention is an accurate reliable alternative to fecal excretion.