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.

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.

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.

Brain perfusion after treatment of childhood acute lymphoblastic leukemia.

UNLABELLED: Children with acute lymphoblastic leukemia (ALL) have impairment in their neuropsychological functioning and morphological changes in their brain after cranial irradiation and chemotherapy. The aim of this study was to identify possible brain perfusion defects caused by different types of treatment and their association with abnormalities in cerebral MRI and neuropsychological and clinical neurological findings. METHODS: Twenty-five consecutive children with ALL at the cessation of chemotherapy or after 1 yr were included. All of the children were given intravenous and intrathecal methotrexate for central nervous system therapy, 13 of them received cranial radiation therapy. Brain SPECT, cerebral MRI, clinical neurological and neuropsychological evaluations were performed. RESULTS: Eleven of the 25 patients (44%) had brain perfusion defects in SPECT, eight of whom were treated with chemotherapy alone, and three received cranial irradiation. Two patients had small bilateral white matter changes on MRI; their brain SPECT scans were abnormal, although the findings were not related. Impairment of neuropsychological functioning was found in 86% of the patients tested. No significant difference between the patients with abnormal and normal SPECT were found. Those patients with abnormal SPECT were younger than those with normal SPECT and had received more frequent intravenous methotrexate infusions. CONCLUSION: Brain SPECT detected perfusion defects that had occurred after treatment for childhood ALL. These defects may be related to frequent administration of a combination of intravenous and intrathecal methotrexate and/or young age.

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.

Aminoterminal propeptide of type III procollagen in cerebrospinal fluid. Variation with age and in childhood leukemia.

Analyses of the aminoterminal propeptide of type III procollagen (PIIINP) in the cerebrospinal fluid (CSF) of 55 children and five young adults without any structural central nervous system (CNS) lesion are reported. The concentration was age-dependent, in that infants and small children had quite high values, whereas the concentration remained relatively constant after the age of 1.5 years. The concentrations of PIIINP in the CSF of 44 children with acute lymphoblastic leukemia (ALL) were prospectively determined at the time of diagnosis and during treatment, since deposition of type III collagen is known to occur during fibroproliferative responses triggered by inflammation. Chemical arachnoiditis is known to be associated with intrathecal methotrexate therapy in children with leukemia. The mean concentration in these children at diagnosis (5.8 micrograms/l +/- SD 2.8 micrograms/l) did not differ from that in age-matched controls (6.7 micrograms/l +/- SD 3.2 micrograms/l). Depending on type of the disease, the children were treated according to two different protocols. PIIINP concentrations were significantly higher during the therapy phases which included intrathecally administered methotrexate (P less than 0.001) than at diagnosis of the disease. Corticosteroid treatments were always associated with a significant decrease in PIIINP concentrations (P less than 0.01 and P less than 0.001 in the two groups, respectively), irrespective of the therapy phase. The results suggest that an increase in PIIINP concentration in the CSF of children with ALL is an indicator of a fibroproliferative response in the arachnoid. Corticosteroids may repress this response and possibly also prevent the development of adhesions in the arachnoid.

Vincristine therapy for children with acute lymphoblastic leukemia impairs conduction in the entire peripheral nerve.

Somatosensory evoked potentials were measured prospectively in 38 children with acute lymphoblastic leukemia to evaluate the side effects of vincristine therapy on conduction of the peripheral nerves. Nineteen patients at standard risk received vincristine 12 mg/m2 during induction therapy and 19 patients at intermediate or high risk received 6 mg/m2 during induction therapy and an additional 6 mg/m2 during delayed intensification therapy. These latencies were compared with those of 38 age-, height-, and sex-matched controls. A prolongation in the peripheral conduction time of the posterior tibial nerve was found in the standard risk patients after induction compared with that of the controls, and a delay was found not only from the ankle to the popliteal fossa, but also from the popliteal fossa to the spinal cord (P < .01). The conduction times of the median nerve from the wrist to the plexus (P < .01) and from the wrist to the spinal cord (P < .01) were prolonged after delayed intensification therapy. There was a significant delay in the median and tibial nerve conduction between the intermediate and high risk patients and their controls after a total vincristine dose of 12 mg/m2. These delays were found along the entire length of the nerves, especially in the proximal part of the tibial nerve (P < .001).

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.

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.

Clinical neurological findings of children with acute lymphoblastic leukaemia at diagnosis and during treatment.

Serial neurological evaluation was performed on 40 consecutive children with acute lymphoblastic leukaemia (ALL) at the time of diagnosis and during treatment. Abnormal neurological signs were found in 23% of the patients, including some without neurological symptoms on admission. Six patients (15%) had abnormal funduscopy findings, papilloedema or preretinal haemorrhages, and 3 of them had increased intracranial pressure measured in connection with a diagnostic lumbar puncture but without blasts in their CSF. The reason for the increased intracranial pressure remained unclear. The development of neurological symptoms caused by peripheral neuropathy during induction therapy was related to the total dose and duration of vincristine therapy. The most severe walking difficulties, patients moving about on all fours for as long as 6 weeks-5 months, occurred in a group who were significantly younger than the other children (P < 0.03). Fine and gross motor disturbances occurred in 18% and 30% of the whole patient group, respectively, after 2-3 years of therapy. Impaired short-term memory was observed in 21% of the patients after 2-3 years of therapy, indicating impaired CNS function. The results indicate that chemotherapy also seems to influence CNS abilities, since there was no significant difference between the patients treated with or without cranial irradiation. Neurological evaluation of children with ALL at diagnosis and during treatment is of value with respect to abnormal findings which persist and are not caused by leukaemia, in order to determine the types of difficulties involved and to consider intervention.

Cranial computed tomographic findings in children with newly diagnosed acute lymphoblastic leukemia: a prospective follow-up study during treatment.

Cranial computed tomography (CT) was performed on 40 consecutive children with newly diagnosed acute lymphoblastic leukemia (ALL) on admission before any chemotherapy, 5 months after CNS therapy (n = 39) and after 2 to 3 years of therapy (n = 31). Changes related to leukemia were found in only 10% of the patients at the time of diagnosis (4/40). These initial changes, two intracranial hemorrhages, one dural thickening and one contrast enhancement, all disappeared during therapy. The findings which persisted unchanged in the next two CT scans were thought to be normal variations or caused by earlier disorders. CNS therapy consisted of intrathecally and intravenously administered methotrexate in 20 standard risk (SR) patients and cranial irradiation in addition to chemotherapy in 19 intermediate risk (IR) or high risk (HR) patients. Four SR patients developed changes during therapy. Three had enlarged cerebrospinal fluid (CSF) spaces and one developed a focal low density area suggesting disturbances in brain blood circulation and also experienced disturbances in level of consciousness. Of the 19 IR or HR patients, eight developed changes related to the therapy, including four with white matter hypodensity areas, of whom three also had enlarged CSF spaces, and four others who developed enlarged CSF spaces. The medians of the widths of the cortical sulci (P less than .001), insular cisterns (P less than .01), third ventricles (P less than .01), and frontal horns (P less than .05), and also of Evans' ratios (P less than .05) increased significantly after CNS therapy as compared with the findings at diagnosis in the patients who had received cranial irradiation. Most of these changes persisted during the follow-up. We conclude that the clinical value of CT scanning during therapy for ALL is restricted to patients with neurological symptoms or those who have undergone CNS irradiation.

Effect of acetaminophen and of low intermittent doses of diazepam on prevention of recurrences of febrile seizures.

Acetaminophen and low doses of diazepam were evaluated for the prevention of recurrences of febrile seizures in a placebo-controlled, double-blind trial. Children after their first febrile seizure were assigned to receive either one dose of rectally administered diazepam, and then, after 6 hours, oral doses of 0.2 mg/kg three times a day for the first 2 days if the fever stayed greater than 38.5 degrees C, or a placebo similarly during forthcoming febrile episodes. In addition, each febrile episode was randomly assigned to be treated with acetaminophen or the placebo. Thus four groups were examined for 2 years: patients receiving two kinds of placebo, patients receiving diazepam and a placebo, patients receiving acetaminophen and a placebo, and patients receiving both diazepam and acetaminophen. Of a total of 180 patients (102 boys), 161 were followed for the 2-year period and 157 were seen at the last outpatient examination: 80 in the diazepam group and 77 in the placebo group. The final analysis of the efficacy of the drugs was made on the basis of the data from 153 patients who had had at least one febrile episode during follow-up. There were 641 fever events during this period, and 38 children (21.1%) had 55 recurrences of febrile seizures. Acetaminophen had no effect on the recurrence rate. Seizures recurred at least once in 21 patients (28.4%) receiving diazepam and 17 (21.5%) receiving a placebo (p = 0.4138, log-rank test). The combination of antipyretic agents with anticonvulsant medication did not reduce the recurrence of febrile seizures. Our results show that low doses of acetaminophen or diazepam or both are ineffective for preventing febrile seizures.

Initial electroencephalographic findings in children with acute lymphoblastic leukaemia.

Electroencephalography (EEG) was performed on 66 children with acute lymphoblastic leukaemia, 45 before treatment and 21 during the first 5 days of chemotherapy. The patients, aged 7 months to 16 years, 33 boys and 33 girls, had been admitted to the Department of Paediatrics, University of Oulu, between March 1976 and January 1987. The EEG findings were compared with those in 66 age and sex-matched control children chosen at random from the local population. The patients had significantly more frequent and more severe disturbances in background activity (p less than 0.001) than the controls and increased slow waves in the occipital (p less than 0.001) and temporal regions (p less than 0.01). The patients who had received chemotherapy before the EEG recording had EEG disturbances significantly more frequently than the other patients (p less than 0.01), but the latter still had EEG abnormalities significantly more frequently than their matched controls, although they did not have severe changes (grade 3). The results suggest that chemotherapy increases EEG changes during the early days of induction therapy and possibly induces long-term disturbances in brain function. The associations between EEG changes and clinical findings were also analysed and the results show that a long duration of leukaemic symptoms or an aggressive disease may lead to EEG abnormalities.

Carboxyterminal propeptide of type I procollagen in cerebrospinal fluid in childhood and in children with leukemia undergoing intrathecal treatment.

We determined the reference interval for the carboxyterminal propeptide of type I procollagen (PICP), an indicator of the synthesis of type I collagen, in cerebrospinal fluid (CSF) by studying 32 infants and children, ages less than or equal to 15 years. The concentration of PICP is age dependent, with particularly high concentrations occurring in children younger than 1.5 years. In older children the concentration is stable (reference interval 20-92 micrograms/L). We also investigated the possibility that PICP in CSF could reflect local fibroproliferative changes in the arachnoid in a cohort of 42 children with acute lymphoblastic leukemia who were monitored by repeated sampling in connection with intrathecal therapy. Initially, there was no difference in PICP between the children with newly diagnosed leukemia and the controls. PICP concentrations were significantly higher (P less than 0.01) during intrathecal methotrexate therapy, with median values above the reference interval. Continuous corticosteroid treatment was associated with a significant decrease in PICP (P less than 0.02 and P less than 0.01, respectively, in two groups treated according to different protocols), close to the lower limit of the reference interval. Intrathecally administered methotrexate and systemic corticosteroid treatment are known to be associated with the development of arachnoiditis and with general repression of collagen synthesis, respectively. We conclude that PICP in CSF is a sensitive indicator of local fibroproliferation and ongoing collagen synthesis.

Physical and psychosocial outcome for young adults with treated malignancy.

We reexamined the physical, neurological, neuropsychological, social, and psychiatric circumstances of a group of 27 (10 females, 17 males) patients at the ages of 16-26 years who had survived a malignant disease during childhood. Twenty survivors had had leukemia and the rest different solid tumors. Only a third (31%) of the subjects were considered to be without any clinically significant physical health problems or functional symptoms, musculoskeletal and endocrinological disorders being the most common. In the neuropsychological test panel including verbal and performance IQ the survivors had significantly lower scores. Early onset of the disease and receiving radiotherapy correlated with impaired test results most significantly, especially on memory functions. One in five of the survivors reported having suffered from reading and writing problems that interfered with success in school and the subjects of the study group had progressed to high school less often than control subjects. The social indices indicated delayed development of sexuality and separation from parents. Overt mental problems appearing at a one-off interview were the same as in the control group. In conclusion, up to two thirds of the childhood cancer survivors as young adults still have physical or neuropsychological health problems and half showed delayed psychosexual maturation. This magnitude of various disorders indicates a long-term but individually oriented follow-up of this small group with the opportunity of physical, social, or psychological management of their main problem.

Chemotherapy for acute lymphoblastic leukemia may cause subtle changes of the spinal cord detectable by somatosensory evoked potentials.

Intrathecal chemotherapy has been determined to cause transient or permanent paraparesis due to myelopathy in patients with leukemia or other malignancies. To systematically evaluate the effect of methotrexate on spinal cord function, somatosensory evoked potentials (SEP) were measured in children with acute lymphoblastic leukemia (ALL). A prospective evaluation was performed in 38 consecutive children aged 1.4-15.3 years with newly diagnosed ALL during treatment. Intrathecal methotrexate therapy was included in the therapy schedule of all patients as central nervous system (CNS) therapy in addition to intravenous chemotherapy in 19 standard risk patients and intravenous chemotherapy with cranial irradiation in 19 intermediate or high-risk patients. The measured conduction times were compared with those of 38 control children matched for age, height, and sex. A significant increase in the conduction time of the tibial nerve SEP was found between the Th12 level and the cortex in children with ALL after receiving intrathecal methotrexate therapy during the induction and CNS therapy phases when compared with their controls. The difference of the mean latencies was 1.45 ms (95% CI 0.39-2.51; P < 0.01). There was no significant delay in the median nerve SEP from the brain stem to the cortex, indicating that the conduction delay was in the area of the spinal cord exposed to intrathecal methotrexate. Moreover, the cortical amplitudes of the median nerve SEPs were significantly reduced when measured immediately after intravenous and intrathecal methotrexate and compared to the amplitudes measured after induction therapy in standard risk patients (P = 0.001). Intrathecal methotrexate with systemic chemotherapy causes a deterioration in the somatosensory pathways within the CNS, suggesting also spinal cord dysfunction in children with ALL in addition to the cerebral dysfunction described earlier.