Cerebroretinal microangiopathy with calcifications and cysts.

BACKGROUND: Extensive cerebral calcifications and leukoencephalopathy have been reported in two rare disorders Coats plus and leukoencephalopathy with calcifications and cysts. In the latter, a progressive formation of parenchymal brain cysts is a special feature, whereas Coats plus is characterized by intrauterine growth retardation, bilateral retinal telangiectasias and exudations (Coats disease), sparse hair, and dysplastic nails without cyst formation. METHODS: We identified 13 patients, including two pairs of siblings, with extensive cerebral calcifications and leukoencephalopathy. We reviewed clinical, ophthalmologic, radiologic and neuropathologic data of seven deceased patients and studied five patients prospectively. RESULTS: Eleven patients were small for gestational age; the other symptoms emerged from infancy to adolescence. All patients had neurologic symptoms including seizures, spasticity, dystonia, ataxia, and cognitive decline. Progressive intracerebral calcifications involved deep gray nuclei, brainstem, cerebral and cerebellar white matter, and dentate nuclei and were accompanied by diffuse white matter signal changes and, in five patients, cerebral cysts. Eleven patients had retinal telangiectasias or angiomas. Additional features were skeletal and hematologic abnormalities, intestinal bleeding, and poor growth. Neuropathologic examination showed extensive calcinosis and abnormal small vessels with thickened, hyalinized wall and reduced lumen. CONCLUSIONS: Our data suggest that Coats plus syndrome and leukoencephalopathy with calcifications and cysts belong to the same spectrum. The primary abnormality seems to be an obliterative cerebral angiopathy involving small vessels, leading to dystrophic calcifications via slow necrosis and finally to formation of cysts and secondary white matter abnormalities.

Language development in very low birth weight preterm children: a follow-up study.

The language development of 17 very low birth weight (VLBW) preterm children was compared with that of matched controls at the ages of 2 and 4 years. At the age of 2 years, the VLBW preterm children achieved significantly lower scores in the language comprehension test than their matched controls. In addition, they used shorter and more immature sentences. At the age of 4 years, difficulties in the VLBW preterm children manifested as deficiencies in language comprehension, naming and auditory discrimination. The language test results at the age of 2 years significantly correlated with those at the age of 4 years, but mainly in the preterm group. The highest and most frequent correlations were found between the language test scores at 2 years and the auditory discrimination test scores at 4 years. The only significant correlation to be found in the control group was between the vocabulary test score at 2 years and the consonant discrimination test score at 4 years. Therefore, language development of the VLBW preterm children should be measured and monitored from toddler age onwards. Special attention should be paid to measurements of auditory processing. While the results of the present study, however, represent mainly the outcome in a group of VLBW preterm children with changes in the neonatal MRI, the results should not be generalized to all VLBW preterm children.

Long-term reproductive endocrine health in young women with epilepsy during puberty.

OBJECTIVE: To evaluate the outcome of epilepsy and later reproductive endocrine health in girls who had epilepsy during puberty, using a population-based controlled study. METHODS: Sixty-nine patients (88%) and 51 control subjects (94%) of previously identified cohorts of 78 girls with epilepsy and 54 healthy control girls participated in this study (initial age 8 to 18.5 years, at follow-up 12.5 to 25.8 years). Thirty-five of the patients were initially taking valproate (VPA), 17 carbamazepine, and 17 oxcarbazepine as monotherapy. Most of the patients (61%) were off medication. All the subjects were examined clinically, the medical and menstrual histories were obtained, ovarian ultrasonography was examined, and serum reproductive hormone concentrations were analyzed. RESULTS: There were no significant differences in laboratory or clinical findings between the patients off medication and the control subjects. Postpubertal patients on medication had higher serum testosterone (1.9 nmol/L, SD 0.7 nmol/L) and androstenedione (18.8 nmol/L, SD 15.2 nmol/L) levels than patients off medication (1.4 nmol/L, SD 0.5 nmol/L, and 9.5 nmol/L, SD 2.6 nmol/L) or control subjects (1.4 nmol/L, SD 0.5 nmol/L, and 10.2 nmol/L, SD 3.2 nmol/L) (all comparisons p < 0.02). All patients still on VPA had elevated serum androstenedione levels. Polycystic ovary syndrome was more common in patients on medication (38%; in 63% on VPA, in 25% on other medication) than in patients off medication (6%) or in controls (11%) (p = 0.005). CONCLUSIONS: Epilepsy during pubertal maturation does not affect reproductive endocrine health in female subjects who discontinue the medication before adulthood. However, an increased prevalence of endocrine disorders is detected if the patients remain on antiepileptic drugs, especially VPA, until adulthood.

Striatal dopaminergic system in dopa-responsive dystonia: a multi-tracer PET study shows increased D2 receptors.

We investigated the integrity of striatal dopaminergic system in seven patients with dopa-responsive dystonia (DRD). Dopamine transporter function ([(11)C]CFT) and D1 ([(11)C]NNC 756) and D2 receptors ([(11)C]raclopride) were studied in same patients using positron emission tomography. Compared to age-adjusted control values the dopamine D2 receptor availability was increased in DRD. The mean age-adjusted [(11)C]raclopride uptake was 116% of the control mean in the putamen (p = 0.004) and 114% in the caudate nucleus (p = 0.007). The mean [(11)C]NNC 756 uptake was not different between DRD patients and controls, the age-adjusted uptake in DRD being 93% of mean control value in the putamen (p = 0.20) and 95% in the caudate nucleus (p = 0.40). The dopamine transporter binding was not altered. The [(11)C]CFT uptake in DRD was 96% of the control value in the putamen (p = 0.64), and 95% in the caudate nucleus (p = 0.44). In conclusion, striatal dopamine D2 receptors availability is increased in DRD whereas dopamine D1 receptors and dopamine transporter ligand binding is unchanged. The pattern of changes in striatal dopaminergic system in DRD is different from that reported in juvenile Parkinson's disease. The increased D2 receptor availability may be due to reduced competition by endogenous dopamine or a compensatory response to dopamine deficiency, or both.

Tooth by tooth survival analysis of dental health in girls with epilepsy.

AIM: The aim of this study was to analyse, tooth by tooth, the timing of caries attacks leading to dental restoration in girls with epilepsy. STUDY DESIGN: The series comprised 60 girls with epilepsy, 8-18 years old, treated in the Departments of Paediatrics or Neurology of the Oulu University Hospital. A group of healthy age matched girls served as control. METHODS: A tooth by tooth survival analysis of the time between tooth eruption and caries attacks to a stage leading to the restorations of the permanent teeth was conducted retrospectively using data from the dental health records with annual examinations. RESULTS: The rate of dental restorations placed due to caries was constantly higher in the girls with epilepsy than in their controls. STATISTICS: The difference was significant between the first molars (p=<0.03), second molars (p=<0.02) and central incisors (p=<0.02) in the maxilla. CONCLUSION: The present observation supports the hypothesis that factors related to epilepsy, the antiepileptic medication in particular, might increase the risk of caries.

Brainstem size and function at term age in relation to later neurosensory disability in high-risk, preterm infants.

UNLABELLED: The aim of this study was to measure brainstem size on magnetic resonance imaging (MRI) scans of high-risk. preterm infants, to assess brainstem function by brainstem auditory-evoked potentials (BAEP) and to determine the predictive value of these measures for the neurosensory outcome. A total of 51 preterm infants (gestational age <34 wk, birthweight <1,500 g) underwent examinations at term age; neuromotor outcome and hearing were followed up until a corrected age of 18 mo. Fourteen (27%) infants had neurosensory disability. Those with a later neurosensory disability had a significantly smaller brain stem than those with a normal outcome. The preterm infants had significantly longer peak latency (L) V and interpeak latency (IPL) III-V than the full-term control infants. Most of the preterm infants with severe cerebral palsy or hearing loss had abnormal BAEP. Sensitivity of morphometric dimensions for predicting neurosensory disability was only 20-31%, but specificity was 97-100%. Abnormal L I and IPL III-V in BAEP predicted disability with a sensitivity of 93% and a specificity of 57-59%. CONCLUSION: We conclude that adverse events during the perinatal period may lead to morphofunctional changes in the brain stem in high-risk, preterm infants, and it seems that functional changes are accurate in predicting neurosensory disability in such patients.

Motor nervous pathway function is impaired after treatment of childhood acute lymphoblastic leukemia: a study with motor evoked potentials.

BACKGROUND: The objective was to evaluate whether motor nervous pathways are affected when patients are treated for childhood acute lymphoblastic leukemia (ALL). PROCEDURE: Thirty-two children with ALL were studied at the end of treatment by means of motor evoked potentials (MEPs) elicited by magnetic stimulation (MS) transcranially and peripherally and underwent a detailed neurological examination. Thirty-two healthy children matched with them for age, sex, and height served as a control group. RESULTS: The latencies of the MEPs were significantly prolonged along the entire motor nervous pathway in the patients with ALL compared with the healthy controls, indicating demyelination in the thick motor fibres. The MEP amplitudes of the distal extremities elicited by stimulation at the brachial plexus and LV spinal level were significantly lowered in the patients treated for ALL, also indicating anatomical or functional loss of descending motor fibres and/or muscle fibres. The MEP amplitudes elicited by cortical MS showed wider variation and no clear abnormalities were found. Neurological signs and symptoms were common after treatment: 41% of the patients had depressed deep tendon reflexes, 31% had fine motor difficulties and 63% gross motor difficulties, and 34% had dysdiadochokinesia. The conduction delay within the peripheral nerve was related to the post-therapeutic interval after administration of vincristine and the lesions within the CNS to the number of injections of intrathecal methotrexate. CONCLUSIONS: The present results show adverse effects of the ALL treatment on the entire motor nervous pathways. In our experience, the measurement of MEPs by MS provides an objective, painless, and practical tool for assessing the treatment-related neurotoxicity in both the CNS and the peripheral nerves. These disturbances in the motor nervous pathways at the end of treatment raise the question of the long-term effects of ALL treatment on the motor nerve tracts, and have led us to employ MEPs to study these effects in long-term survivors of ALL.

Brain single photon emission computed tomography at term age for predicting cerebral palsy after preterm birth.

In order to assess the predictive value of neonatal brain perfusion with single photon emission computed tomography (SPET) with regard to neuromotor outcome at a corrected age of 18 months, 34 infants with birth weight <1,500 g and gestation age <34 weeks underwent brain technetium-99m ethylcysteinate dimer (99Tc(m)-ECD) SPET at term age. The perfusion defects were estimated by visual interpretation. Consecutive semiquantitative assessment was made in 26 cases and reference values for the tracer were collected from images of 17 preterm infants with normal outcome after the follow-up period. Relative regional cortical (frontal, sensorimotor, parietal and occipital), cerebellar and thalamic perfusion levels were evaluated in middle sagittal slices and hemispheric asymmetries in transaxial slices. Perfusion defects predicted cerebral palsy (CP) (n = 11) with 82% sensitivity, 70% specificity and 74% accuracy, the corresponding figures for ultrasound (US) being 73, 83 and 79%, respectively. The sensitivity of SPET in predicting moderate or severe CP (n = 7) was 100% and the specificity 67%, the corresponding figures for US being 71% and 74%, respectively. Brain SPET seems to identify the most severe forms of CP in preterm infants very well at term age, but cannot identify all mild ones. In addition to a low specificity, the radiation exposure restricts usefulness of the method for clinical purposes.

Cognitive functions of young adults who survived childhood cancer.

Neuropsychological tests were used to determine the cognitive functioning of adult long-term survivors treatedfor childhood cancer Disease onset before the age of 5 was related to lower test scores in intelligence tests, several memory tests, and motor function tests. The cranial irradiated survivors displayed more difficulties, especially in short-term memory tests and the Wechsler Adult Intelligence Scale Digit Symbol Test as compared to nonradiated survivors. No statistically significant differences in test scores were observed between different forms of cancer The results of this study are consistent with the notion that those memory types that demand special attention and motor speed functions are especially vulnerable to cancer and its treatment.

Central and peripheral nervous system dysfunction in the clinical variation of Salla disease.

OBJECTIVE: To evaluate the degree of possible peripheral nervous system (PNS) involvement in addition to CNS manifestations in Salla disease, a free sialic acid storage disorder leading to severe mental retardation with a wide clinical variation. BACKGROUND: Salla disease is a lysosomal storage disorder that affects the white matter of the CNS. MRI findings and recent 1H MRS study results provide evidence for delayed central myelination, but there is no previous evidence for PNS involvement in this disease. The gene coding for a presumptive sialic acid transport protein has recently been identified, and the first disease-causing mutations have been characterized. METHODS: Nerve conduction studies; evoked potentials to visual (VEP), brainstem auditory (BAEP), and somatosensory stimuli (SEP); and EEG were carried out on 22 patients (age range 2 months to 57 years) with biochemically and genetically confirmed Salla disease. Brain MRI were available on 14 patients. RESULTS: Nerve conduction studies revealed abnormalities in nearly half of the patients (10/21). The four severely disabled patients and the oldest patient had greatly reduced nerve conduction velocities and prolonged distal latencies compatible with demyelinating polyneuropathy. In addition, SEP was abnormal in the majority of the patients, but VEP and BAEP in only a few cases. PNS involvement was clearly associated with both the phenotypic severity and MRI findings. CONCLUSIONS: The results indicate that dysmyelination in Salla disease occurs not only in the CNS but also in the peripheral nervous system, contributing to the phenotypic variation, which can now be correlated with the molecular basis of the disease.

Prediction of permanent hearing loss in high-risk preterm infants at term age.

UNLABELLED: The aim of this series was to assess hearing screenings; auditory brainstem responses (ABR), transient evoked otoacoustic emissions (TEOAE) and free field auditory responses (FF) for the prediction of permanent bilateral hearing loss in high-risk preterm infants at term post-conceptional age. A total of 51 preterm infants (gestational age < 34 weeks, birth weight < 1500 g) underwent examinations at term and hearing, speech and neurological development were followed up until a corrected age of 18 months. Significant hearing defects were verified by broader ABR examinations under sedation and by clinical ward observation including responsiveness to sounds and enhancement of hearing using an amplification device. Seven bilateral fails in ABR were found, together with nine bilateral fails in TEOAE and four fails in FF screening at term age. Six preterm infants were later confirmed to have a significant permanent bilateral hearing loss, four of whom had also cerebral palsy. Bilateral failure in ABR screening predicted hearing loss with a sensitivity of 100% and a specificity of 98%, TEOAE with a sensitivity of 50% and a specificity of 84% and in the FF examination at the levels of 50% and 98%, respectively. CONCLUSION: Transient evoked otoacoustic emissions alone seem not to be so applicable to the neonatal screening of hearing in high-risk preterm infants as shown earlier in full-term infants, possibly because a hearing defect may be due to retrocochlear damage. Consequently, auditory brainstem response screening seems to be more suitable for very low birth weight preterm infants.

Magnetic resonance imaging at term and neuromotor outcome in preterm infants.

In order to evaluate the value of neonatal brain magnetic resonance imaging (MRI) for predicting neuromotor outcome in very low birthweight (VLBW) preterm infants, 51 such infants with gestational age <34 wk underwent brain MRI at term age. Myelination, parenchymal lesions (haemorrhage, leukomalacia, infarction, reduction of white matter), parenchymal lesions without subependymal haemorrhage, ventricular/brain ratios and widths of the extracerebral spaces were assessed. The MRI findings were compared with cranial ultrasound (US) performed at term. Infants' neuromotor development was followed up until 18 mo corrected age. Parenchymal lesions seen in MRI at term predicted cerebral palsy (CP) with 100% sensitivity and 79% specificity, the corresponding figures for US being 67% and 85%, respectively. Parenchymal lesions in MRI, excluding subependymal haemorrhages, predicted CP with a sensitivity of 82% and a specificity of 97%, the corresponding figures for US being 58% and 100%, respectively. Delayed myelination, ventricular/brain ratios and widths of the extracerebral spaces failed to predict CP. Term age is a good time for neuroradiological examinations in prematurely born high-risk infants. Parenchymal lesions seen in MRI are reliable predictors for CP.

Childhood encephalopathies and myopathies: a prospective study in a defined population to assess the frequency of mitochondrial disorders.

OBJECTIVES: To assess the frequency of mitochondrial abnormalities in muscle histology, defects in respiratory chain enzyme activities, and mutations in mitochondrial DNA (mtDNA) in children with unexplained psychomotor retardation in the population of Northern Finland. BACKGROUND: The frequency of mitochondrial diseases among patients with childhood encephalopathies and myopathies is not known. Frequencies are difficult to estimate because the clinical presentation of these disorders is variable. METHODS: A total of 116 consecutive patients with undefined encephalopathies and myopathies were enrolled during a 7-year period in a hospital serving as the only neurologic unit for a pediatric population of 97 609 and as the only tertiary level neurologic unit for a pediatric population of 48 873. Biochemical and morphologic investigations were performed on muscle biopsy material, including oximetric and spectrophotometric analyses of oxidative phosphorylation, histochemistry, electron microscopy, and molecular analysis of mtDNA. RESULTS: Ultrastructural changes in the mitochondria were the most common finding in the muscle biopsies (71%). Ragged-red fibers were found in 4 cases. An oxidative phosphorylation defect was found in 26 children (28%), complex I (n = 15) and complex IV (n = 13) defects being the most common. Fifteen percent of patients (n = 17/116) with unexplained encephalomyopathy or myopathy had a probable mitochondrial disease. Common pathogenic mutations were found in the mtDNA of only 1 patient (.9%). CONCLUSIONS: The common known mutations in mtDNA are rarely causes of childhood encephalomyopathies, which is in contrast to the considerable frequency of the common MELAS mutation observed among adults in the same geographical area. Biochemically and morphologically verified mitochondrial disorders were nevertheless common among the children, making the analysis of a muscle biopsy very important for clinical diagnostic purposes.

Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy.

Valproate is effective for treatment of a variety of seizure types both in adults and in children with epilepsy, but it induces obesity and polycystic ovaries in a considerable proportion of adult women, particularly when the medication is started before the age of 20. In the present study we evaluated reproductive endocrine function in 41 girls, 8 to 18 years old, taking valproate for epilepsy and in 54 healthy control girls. Among the girls taking valproate, 16 were prepubertal, 11 were pubertal, and 14 were postpubertal, and the corresponding numbers were 20, 13, and 21 in the control group. The mean serum testosterone concentrations of prepubertal, pubertal, and postpubertal girls taking valproate were significantly higher than those of the control girls at the same pubertal stage. Hyperandrogenism, defined as serum testosterone levels higher than the mean + 2SD in the control girls at the same pubertal stage, was seen in 38% of prepubertal, 36% of pubertal, and 57% of postpubertal girls taking valproate. In addition, postpubertal girls taking valproate were more obese than the controls and the mean serum insulin-like growth factor binding protein-1 concentration of pubertal and postpubertal hyperandrogenic girls taking valproate was lower than in valproate-treated girls without hyperandrogenism. Valproate may induce hyperandrogenism in girls with epilepsy during the sensitive period of pubertal maturation, and the frequency of hyperandrogenism increases with pubertal development. This emphasizes the importance of careful endocrine observation of girls taking valproate for epilepsy.

The effects of valproate, carbamazepine, and oxcarbazepine on growth and sexual maturation in girls with epilepsy.

OBJECTIVE: Antiepileptic drugs (AEDs) have endocrine effects that may interfere with growth and sexual maturation in children. The aim of this study was to evaluate the effects of AEDs on growth and pubertal development in girls with epilepsy. STUDY DESIGN: Forty girls taking valproate (VPA), 19 girls taking carbamazepine (CBZ), and 18 girls taking oxcarbazepine (OXC) for epilepsy and 49 healthy control girls participated in the study, which included a cross-sectional clinical examination when the girls were 8 to 18 years old and a longitudinal growth analysis from the age of 1 year. RESULTS: VPA, CBZ, or OXC did not affect linear growth or pubertal development in girls with epilepsy. However, the patients taking VPA gained weight, and an increase in relative weight was seen in girls who started their medication before as well as during puberty. The body mass index of the VPA-treated girls (19.8 +/- 4.8 kg/m2) was higher than that of the control girls (18.0 +/- 2.5 kg/m2) at clinical examination. The weight of the girls taking CBZ or OXC for epilepsy was similar to that of the control girls. Plasma insulin-like growth factor-I (IGF-I) levels were higher in girls treated with CBZ and OXC than in the control girls, but AEDs did not affect fasting serum insulin, IGF-binding protein-1, or IGF-binding protein-3 concentrations in girls on VPA, CBZ, or OXC medication during the period of exposure (average 2.8, 4.1, and 1.9 years, respectively) in this study. CONCLUSIONS: AEDs do not seem to have any adverse effects on linear growth or sexual maturation in girls with epilepsy. VPA-related weight gain can be seen already in prepuberty and it is not associated with hyperinsulinemia in these young patients. The clinical significance of high circulating concentrations of IGF-I in patients taking CBZ or OXC remains to be defined.

Increased brain glucose utilization in Salla disease (free sialic acid storage disorder).

UNLABELLED: Salla disease is an autosomal recessive lysosomal free sialic acid storage disorder characterized by psychomotor retardation and ataxia. MRI studies have revealed evidence of dysmyelination, but the biological mechanism of the brain dysfunction is unknown. METHODS: Nine patients with Salla disease (age 2.5 mo-42 y) presenting the disease in varying degrees of severity were studied by PET using 2-fluoro-2-deoxy-D-glucose (FDG) as a tracer. Local cerebral metabolic rates for glucose (LCMRGlc) in individual brain regions were compared with controls. RESULTS: The FDG PET results showed significantly increased LCMRGlc values in the frontal and sensorimotor cortex and especially in the basal ganglia of the patients. Cerebellar hypometabolism was present in all seven patients with marked ataxia, whereas the less severely affected patients without obvious ataxia had normal or even high glucose uptake in the cerebellum. CONCLUSION: The increased cerebral glucose utilization is a constant finding in Salla disease and may reflect the basic defect of the sialic acid metabolism in this disorder. The FDG PET findings in the cerebellum suggest a correlation between glucose uptake and the severity of the clinical symptoms.

Psychological findings in preterm children related to neurologic status and magnetic resonance imaging.

OBJECTIVE: Preterm children experience learning disabilities more often than full-term children, but detailed information on their neuropsychological and neurologic determinants is lacking. We therefore examined these problems more closely and also studied if clinical neurologic examination and/or magnetic resonance imaging (MRI) can be used as tools to screen the preterm children at risk for these problems. METHODS: In a population-based study, the psychological performance of 42 preterm children with a birth weight <1750 g and of their matched controls was assessed at 8 years of age and the findings were then related to clinical neurologic examination and MRI. Learning disabilities of these children, reported by the teachers, were also studied. RESULTS: The cognitive ability of the preterm children, although in the normal range, was significantly lower than that of the control children. They performed particularly poorly in tasks requiring spatial and visuoperceptual abilities, which were associated with the finding of periventricular leukomalacia in MRI, especially with posterior ventricular enlargement. The preterm children with minor neurodevelopmental dysfunction (MND) had the most problems in neuropsychological tests, whereas the clinically healthy preterm children and those with cerebral palsy had fewer problems. The problems of MND children emerged in the domain of attention. They also experienced the most problems at school. CONCLUSIONS: Visuospatial problems were associated with periventricular leukomalacia in MRI, but learning disabilities were most frequent among the preterm children with minor neurologic abnormalities. We recommend closer follow-up of preterm children with MND.