Neuromagnetic studies on cortical somatosensory functions in infants and children : Normal development and effect of early brain lesions

Until recently, objective investigation of the functional development of the human brain in vivo was challenged by the lack of noninvasive research methods. Consequently, fairly little is known about cortical processing of sensory information even in healthy infants and children. Furthermore, mechanisms by which early brain insults affect brain development and function are poorly understood. In this thesis, we used magnetoencephalography (MEG) to investigate development of cortical somatosensory functions in healthy infants, very premature infants at risk for neurological disorders, and adolescents with hemiplegic cerebral palsy (CP). In newborns, stimulation of the hand activated both the contralateral primary (SIc) and secondary somatosensory cortices (SIIc). The activation patterns differed from those of adults, however. Some of the earliest SIc responses, constantly present in adults, were completely lacking in newborns and the effect of sleep stage on SIIc responses differed. These discrepancies between newborns and adults reflect the still developmental stage of the newborns’ somatosensory system. Its further maturation was demonstrated by a systematic transformation of the SIc response pattern with age. The main early adult­like components were present by age two. In very preterm infants, at term age, the SIc and SIIc were activated at similar latencies as in healthy fullterm newborns, but the SIc activity was weaker in the preterm group. The SIIc response was absent in four out of the six infants with brain lesions of the underlying hemisphere. Determining the prognostic value of this finding remains a subject for future studies, however. In the CP adolescents with pure subcortical lesions, contrasting their unilateral symptoms, the SIc responses of both hemispheres differed from those of controls: For example the distance between SIc representation areas for digits II and V was shorter bilaterally. In four of the five CP patients with cortico­subcortical brain lesions, no normal early SIc responses were evoked by stimulation of the palsied hand. The varying differences in neuronal functions, underlying the common clinical symptoms, call for investigation of more precisely designed rehabilitation strategies resting on knowledge about individual functional alterations in the sensorimotor networks.

Juvenile rheumatoid knee : Management of knee growth disturbances in children with juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is associated with growth disturbances, especially leg length discrepancy (LLD) and knee valgus deformity (KVD). Studies have demonstrated growth plate stimulation with chronic arthritis. In the context of surgical treatment of LLD or KVD of a growing knee, the less invasive procedures, which allow immediate mobilisation, are preferred. Establishment of the skeletal age and the correction potential in the knees of rheumatic children is difficult due to rheumatic changes. In this present work, an analysis of the efficacy, safety and long-term results of temporary epiphyseal arrests performed in Rheumatism Foundation Hospital (Heinola, Finland). The distribution of diagnoses among children (n=71) with JIA and LLD (68 knees) was consistent with the normal oligoarthritis-predominated population of children with JIA. A higher male:female ratio (1:1.7 vs. 1:2.4 in population-based studies (PBS)) and earlier mean onset age (4 vs. 7 years in PBSs) were, however, distinct features in the study population. In most cases the correction was reliable and temporary arrest produced a mean correction of 1mm per month. The time of arrest required, however, varied significantly, probably due to the effect of underlying diseases and medication, and the age of the child. All complications encountered (10%) were minor. The correction achieved persisted in long-term follow-up. KVD (n=112, 177 knees) was associated with a high proportion of polyarthritic disease subtype (45% vs. 12-31% in PBSs), and the male:female distribution was grossly female-dominated (1:4.9 vs. 1:2.4 in PBSs). The early mean onset age (3 vs. 7 years in PBSs) was also notable in this cohort. Successful correction was achieved in 2/3 cases and the mean angular correction was 0.7 degrees per month. The required time of arrest, however, varied considerably. In 13% of knees the paucity of follow-up visits resulted in over-correction to varus. The complication rate (3%) in the knees operated for KVD was considerably lower compared to ten per cent in the management of LLD. Most of the complications related to epiphyseal stapling were reversible. However, the risk of premature closure of growth plates does exist. The number of over-corrections was notably high, with 13% knees turning to varus. The correction achieved persisted in long-term follow-up.

Children and adolescents in full-time special education : an epidemiological and magnetic resonance imaging study

The need for special education (SE) is increasing. The majority of those whose problems are due to neurodevelopmental disorders have no specific aetiology. The aim of this study was to evaluate the contribution of prenatal and perinatal factors and factors associated with growth and development to later need for full-time SE and to assess joint structural and volumetric brain alterations among subjects with unexplained, familial need for SE. A random sample of 900 subjects in full-time SE allocated into three levels of neurodevelopmental problems and 301 controls in mainstream education (ME) provided data on socioeconomic factors, pregnancy, delivery, growth, and development. Of those, 119 subjects belonging to a sibling-pair in full-time SE with unexplained aetiology and 43 controls in ME underwent brain magnetic resonance imaging (MRI). Analyses of structural brain alterations and midsagittal area and diameter measurements were made. Voxel-based morphometry (VBM) analysis provided detailed information on regional grey matter, white matter, and cerebrospinal fluid (CSF) volume differences. Father’s age ≥ 40 years, low birth weight, male sex, and lower socio-economic status all increased the probability of SE placement. At age 1 year, one standard deviation score decrease in height raised the probability of SE placement by 40% and in head circumference by 28%. At infancy, the gross motor milestones differentiated the children. From age 18 months, the fine motor milestones and those related to speech and social skills became more important. Brain MRI revealed no specific aetiology for subjects in SE. However, they had more often ≥ 3 abnormal findings in MRIs (thin corpus callosum and enlarged cerebral and cerebellar CSF spaces). In VBM, subjects in full-time SE had smaller global white matter, CSF, and total brain volumes than controls. Compared with controls, subjects with intellectual disabilities had regional volume alterations (greater grey matter volumes in the anterior cingulate cortex bilaterally, smaller grey matter volume in left thalamus and left cerebellar hemisphere, greater white matter volume in the left fronto-parietal region, and smaller white matter volumes bilaterally in the posterior limbs of the internal capsules). In conclusion, the epidemiological studies emphasized several factors that increased the probability of SE placement, useful as a framework for interventional studies. The global and regional brain MRI findings provide an interesting basis for future investigations of learning-related brain structures in young subjects with cognitive impairments or intellectual disabilities of unexplained, familial aetiology.

Hospital-related fears and coping strategies in 4-6-year-old children

There is only little information available on the 4-6-year-old child s hospital-related fears, and on the coping with such fears, as expressed by the children themselves. However, previous data collected from parents and hospital personnel indicate that hospitalization is an anxiety-producing experience for young children. The purpose of this study was to describe the experience of hospital-related fears and the experience of coping with hospital-related fears of 4-6-year-old children. The aim of this study was to form a descriptive model of the subjective experience of hospital-related fears and coping strategies of 4-6-year old children. The data were collected by interviewing 4-6-year-old children from a hospital and kindergarten settings in Finland from 2004 to 2006. Ninety children were interviewed in order to describe the hospital-related fear and the experience of fear, and 89 to describe their coping with the fear and the experience of coping. The children were chosen through purposive sampling. The data were gathered by semi-structured interview, supported by pictures. The data about hospital-related fears and on strategies for coping with hospital-related fears were reviewed by qualitative and quantitative methods. The experience of hospital-related fears and coping with these fears were analyzed using Colaizzi s Method of Phenomenological Analysis. The results revealed that more than 90 % of the children said they were afraid of at least one thing in hospital. Most of the fears could be categorized as nursing interventions, fears of being a patient, and fears caused by the developmental stage of the child. Children interviewed in the hospital expressed substantially more fears than children interviewed in kindergarten. Children s meanings of hospital-related fears were placed into four main clusters: 1) insecurity, 2) injury, 3) helplessness, 4) and rejection. The results also showed that children have plenty of coping strategies, to deal with their fears, especially such strategies in which the children themselves play an active role. Most often mentioned coping strategies were 1) the presence of parents and other family members, 2) the help of the personnel, 3) positive images and humour, 4) play, and 5) the child s own safety toy. The children interviewed in the hospital mentioned statistically significantly more often play, positive imagination and humour as their coping strategy than children interviewed in kindergarten. The meaning of coping with hospital fears consisted of six clusters: pleasure, security, care, understanding the meaning of the situation participating, and protecting oneself. Being admitted to a hospital is an event which may increase the fears of a 4-6-year-old child. Children who have personal experience of being admitted to a hospital describe more fears than healthy children in kindergarten. For young children, hospital-related fear can be such a distressing experience that it reflects on their feelings of security and their behaviour. Children can sometimes find it difficult to admit their fear. Children need the help of adults to express their hospital-related fears, the objects of the fears, and to cope with the fears. Personnel should be aware of children s fears and support them in the use of coping strategies. In addition to the experiences of security and care, pre-school-aged children need active coping strategies that they can use themselves, regardless of the presence of the parents or nurses. Most of all, children need the possibility to play and experience pleasure. Children can also be taught coping strategies which give them an active, positive role.

Bone Health in Children and Adolescents with Juvenile Idiopathic Arthritis and Solid Organ Transplant

Osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes to increased fracture risk. Childhood and adolescence are critical periods for bone mass gain. Peak bone mass is mostly acquired by the age of 18 years and is an important determinant of adult bone health and lifetime risk for fractures. Medications, especially glucocorticoids (GCs), chronic inflammation, decreased physical activity, hormonal deficiencies, delayed puberty, and poor nutrition may predispose children and adolescents with a chronic disease to impaired bone health. In this work, we studied overall bone health, the incidence and prevalence of fractures in children and adolescents who were treated for juvenile idiopathic arthritis (JIA) or had undergone solid organ transplantation. The first study cohort included 62 patients diagnosed with JIA and treated with GCs. The epidemiology of fractures after transplantation was investigated in 196 patients and a more detailed analysis of bone health determinants was performed on 40 liver (LTx) and 106 renal (RTx) transplantation patients. Bone mineral density (BMD) and vertebral morphology were assessed by dual-energy x-ray absorptiometry. Standard radiographs were obtained to detect vertebral fractures and to determine bone age; BMD values were adjusted for skeletal maturity. Our study showed that median BMD values were subnormal in all patient cohorts. The values were highest in patients with JIA and lowest in patients with LTx. Age at transplantation influenced BMD values in LTx but not RTx patients; BMD values were higher in patients who had LTx before the age of two years. BMD was lowest during the immediate posttransplantation years and increased subnormally during puberty. Delayed skeletal maturation was common in all patient groups. The prevalence of vertebral fractures ranged from 10% to 19% in the cohorts. Most of the fractures were asymptomatic and diagnosed only at screening. Vertebral fractures were most common in LTx patients. Vitamin D deficiency was common in all patient groups, and only 3% of patients with JIA and 25% of transplantation patients were considered to have adequate serum vitamin D levels. The total cumulative weight-adjusted dose of GC was not associated with BMD values in JIA or LTx patients. The combination of female gender and age over 15 years, parathyroid hormone concentration over 100 ng/L, and cumulative weight-adjusted methylprednisolone dose over 150 mg/kg during the three preceding years were found to be important predictors for low lumbar spine BMD in RTx patients. Based on the high prevalence of osteoporosis in the study cohorts more efforts should be put to prevention and early diagnosis of osteoporosis in these pediatric patients.

Assessment of Risk for Type 1 Diabetes in Children of Affected Families and in the General Population : Role of Immunological and Metabolic Markers

Background and aims. Type 1 diabetes (T1D), an autoimmune disease in which the insulin producing beta cells are gradually destroyed, is preceded by a prodromal phase characterized by appearance of diabetes-associated autoantibodies in circulation. Both the timing of the appearance of autoantibodies and their quality have been used in the prediction of T1D among first-degree relatives of diabetic patients (FDRs). So far, no general strategies for identifying individuals at increased disease risk in the general population have been established, although the majority of new cases originate in this population. The current work aimed at assessing the predictive role of diabetes-associated immunologic and metabolic risk factors in the general population, and comparing these factors with data obtained from studies on FDRs. Subjects and methods. Study subjects in the current work were subcohorts of participants of the Childhood Diabetes in Finland Study (DiMe; n=755), the Cardiovascular Risk in Young Finns Study (LASERI; n=3475), and the Finnish Type 1 Diabetes Prediction and Prevention Study (DIPP) Study subjects (n=7410). These children were observed for signs of beta-cell autoimmunity and progression to T1D, and the results obtained were compared between the FDRs and the general population cohorts. --- Results and conclusions. By combining HLA and autoantibody screening, T1D risks similar to those reported for autoantibody-positive FDRs are observed in the pediatric general population. Progression rate to T1D is high in genetically susceptible children with persistent multipositivity. Measurement of IAA affinity failed in stratifying the risk assessment in young IAA-positive children with HLA-conferred disease susceptibility, among whom affinity of IAA did not increase during the prediabetic period. Young age at seroconversion, increased weight-for-height, decreased early insulin response, and increased IAA and IA-2A levels predict T1D in young children with genetic disease susceptibility and signs of advanced beta-cell autoimmunity. Since the incidence of T1D continues to increase, efforts aimed at preventing T1D are important, and reliable disease prediction is needed both for intervention trials and for effective and safe preventive therapies in the future. Our observations confirmed that combined HLA-based screening and regular autoantibody measurements reveal similar disease risks in pediatric general population as those seen in prediabetic FDRs, and that risk assessment can be stratified further by studying glucose metabolism of prediabetic subjects. As these screening efforts are feasible in practice, the knowledge now obtained can be exploited while designing intervention trials aimed at secondary prevention of T1D.

Psychiatric disturbances in children with intellectual disability : Prevalence, risk factors and assessment

Children with intellectual disability are at increased risk for emotional and behavioural problems, but many of these disturbances fail to be diagnosed. Structured checklists have been used to supplement the psychiatric assessment of children without intellectual disability, but for children with intellectual disability, only a few checklists are available. The aim of the study was to investigate psychiatric disturbances among children with intellectual disability: the prevalence, types and risk factors of psychiatric disturbances as well as the applicability of the Finnish translations of the Developmental Behaviour Checklist (DBC-P) and the Child Behavior Checklist (CBCL) in the assessment of psychopathology. The subjects comprised 155 children with intellectual disability, and data were obtained from case records and five questionnaires completed by the parents or other carers of the child. According to case records, a psychiatric disorder had previously been diagnosed in 11% of the children. Upon careful re-examination of case records, the total proportion of children with a psychiatric disorder increased to 33%. According to checklists, the frequency of probable psychiatric disorder was 34% by the DBC-P, and 43% by the CBCL. The most common diagnoses were pervasive developmental disorders and hyperkinetic disorders. The results support previous findings that compared with children without intellectual disability, the risk of psychiatric disturbances is 2-3-fold in children with intellectual disability. The risk of psychopathology was most significantly increased by moderate intellectual disability and low socio-economic status, and decreased by adaptive behaviour, language development, and socialisation as well as living with both biological parents. The results of the study suggest that both the DBC-P and the CBCL can be used to discriminate between children with intellectual disability with and without emotional or psychiatric disturbance. The DBC-P is suitable for children with any degree of intellectual disability, and the CBCL is suitable at least for children with mild intellectual disability. Because the problems of children with intellectual disability differ somewhat from those of children without intellectual disability, checklists designed specifically for children with intellectual disability are needed.

Pharmacokinetics, efficacy, and safety of pravastatin in children : Studies in children with heterozygous familial hypercholesterolemia and in pediatric cardiac transplant recipients

Background. Hyperlipidemia is a common concern in patients with heterozygous familial hypercholesterolemia (HeFH) and in cardiac transplant recipients. In both groups, an elevated serum LDL cholesterol level accelerates the development of atherosclerotic vascular disease and increases the rates of cardiovascular morbidity and mortality. The purpose of this study is to assess the pharmacokinetics, efficacy, and safety of cholesterol-lowering pravastatin in children with HeFH and in pediatric cardiac transplant recipients receiving immunosuppressive medication. Patients and Methods. The pharmacokinetics of pravastatin was studied in 20 HeFH children and in 19 pediatric cardiac transplant recipients receiving triple immunosuppression. The patients ingested a single 10-mg dose of pravastatin, and plasma pravastatin concentrations were measured up to 10/24 hours. The efficacy and safety of pravastatin (maximum dose 10 to 60 mg/day and 10 mg/day) up to one to two years were studied in 30 patients with HeFH and in 19 cardiac transplant recipients, respectively. In a subgroup of 16 HeFH children, serum non-cholesterol sterol ratios (102 x mmol/mol of cholesterol), surrogate estimates of cholesterol absorption (cholestanol, campesterol, sitosterol), and synthesis (desmosterol and lathosterol) were studied at study baseline (on plant stanol esters) and during combination with pravastatin and plant stanol esters. In the transplant recipients, the lipoprotein levels and their mass compositions were analyzed before and after one year of pravastatin use, and then compared to values measured from 21 healthy pediatric controls. The transplant recipients were grouped into patients with transplant coronary artery disease (TxCAD) and patients without TxCAD, based on annual angiography evaluations before pravastatin. Results. In the cardiac transplant recipients, the mean area under the plasma concentration-time curve of pravastatin [AUC(0-10)], 264.1 * 192.4 ng.h/mL, was nearly ten-fold higher than in the HeFH children (26.6 * 17.0 ng.h/mL). By 2, 4, 6, 12 and 24 months of treatment, the LDL cholesterol levels in the HeFH children had respectively decreased by 25%, 26%, 29%, 33%, and 32%. In the HeFH group, pravastatin treatment increased the markers of cholesterol absorption and decreased those of synthesis. High ratios of cholestanol to cholesterol were associated with the poor cholesterol-lowering efficacy of pravastatin. In cardiac transplant recipients, pravastatin 10 mg/day lowered the LDL cholesterol by approximately 19%. Compared with the patients without TxCAD, patients with TxCAD had significantly lower HDL cholesterol concentrations and higher apoB-100/apoA-I ratios at baseline (1.0 ± 0.3 mmol/L vs. 1.4 ± 0.3 mmol/L, P = 0.031; and 0.7 ± 0.2 vs. 0.5 ± 0.1, P = 0.034) and after one year of pravastatin use (1.0 ± 0.3 mmol/L vs. 1.4 ± 0.3 mmol/L, P = 0.013; and 0.6 ± 0.2 vs. 0.4 ± 0.1, P = 0.005). Compared with healthy controls, the transplant recipients exhibited elevated serum triglycerides at baseline (median 1.3 [range 0.6-3.2] mmol/L vs. 0.7 [0.3-2.4] mmol/L, P=0.0002), which negatively correlated with their HDL cholesterol concentration (r = -0.523, P = 0.022). Recipients also exhibited higher apoB-100/apoA1 ratios (0.6 ± 0.2 vs. 0.4 ± 0.1, P = 0.005). In addition, elevated triglyceride levels were still observed after one year of pravastatin use (1.3 [0.5-3.5] mmol/L vs. 0.7 [0.3-2.4] mmol/L, P = 0.0004). Clinically significant elevations in alanine aminotransferase, creatine kinase, or creatinine ocurred in neither group. Conclusions. Immunosuppressive medication considerably increased the plasma pravastatin concentrations. In both patient groups, pravastatin treatment was moderately effective, safe, and well tolerated. In the HeFH group, high baseline cholesterol absorption seemed to predispose patients to insufficient cholesterol-lowering efficacy of pravastatin. In the cardiac transplant recipients, low HDL cholesterol and a high apoB-100/apoA-I ratio were associated with development of TxCAD. Even though pravastatin in the transplant recipients effectively lowered serum total and LDL cholesterol concentrations, it failed to normalize their elevated triglyceride levels and, in some patients, to prevent the progression of TxCAD.