Junichi Oki

Serum melatonin kinetics and long-term melatonin treatment for sleep disorders in Rett syndrome

We studied the circadian rhythm of serum melatonin levels in two patients with classical Rett syndrome having severe sleep disorders; serum melatonin levels were measured before and during melatonin treatment using radioimmunoassay. Patient 1 had a free-running rhythm of sleep-wake cycle from 3 years of age. At the age of 4 years, the peak time of melatonin was delayed 6 h compared to normal control and the peak value was at the lower limit. Patient 2 had a fragmented sleep pattern accompanied by night screaming from 1 year and 6 months of age. At the age of 10 years, the peak time of melatonin secretion was normal but the peak value was at the lower limit. These patients were given 5 mg melatonin orally prior to bedtime. Exogenous melatonin dramatically improved the sleep-wake cycle in patient 1. In patient 2, exogenous melatonin showed a hypnotic effect but early morning awakenings occurred occasionally. When melatonin treatment was stopped, the sleep disorders recurred and re-administration of 3 mg melatonin was effective in both patients. The effect was maintained over 2 years without any adverse effects. These findings suggests that sleep disorders in patients with Rett syndrome may relate with an impaired secretion of melatonin.

The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome

A gene for Methyl-CpG binding protein 2 (MECP2), which locates Xq28, was recently found to be responsible for Rett syndrome. Although mutational analyses of MECP2 in Rett syndrome have been extensively analyzed, the mechanism(s) by which variable clinical phenotype occurred between affected monozygotic twins or sisters have not been clarified. We hypothesized that the difference of X-inactivation pattern might explain this phenomenon. With the method based on methylation-specific PCR, we analyzed polymorphic trinucleotide repeat in the human andorogen receptor gene mapped on Xq11.2-12, using DNA samples derived from previously described monozygotic twins and sisters together with their parents. Their clinical phenotypes were reported to be significantly different between siblings. We found that (1) maternally derived allele is predominantly active than paternally derived one in three out of four patients analyzed, (2) remaining one twin patient, whose ratio of active paternal allele is almost the same level as maternal allele, showed far much severe phenotype when compared with her counterpart. Together with the finding that most of the alleles with de novo mutation are from paternal X chromosome in sporadic cases, the existence of a mechanism that suppresses mutated paternal allele activation, resulting skewed X-inactivation to make clinical phenotype milder, might be speculated. Thus, when this mechanism fails to work sufficiently by an unknown reason, severer clinical phenotype could occur.

Human milk reduces the risk of retinal detachment in extremely low-birthweight infants

Background: Retinopathy of prematurity (ROP) is a major cause of blindness in children. Because the use of oxygen is a known risk factor for development of ROP, supplemental oxygen is used carefully. However, it does not necessarily reduce the morbidity of ROP‐induced blindness. The aim of the present study was to identify the possible risk factors for progression to retinal detachment, a most relevant cause of visual impairment, in extremely low‐birthweight infants (ELBWI).

Computerized version of the Wisconsin card sorting test in children with high-functioning autistic disorder or attention-deficit/hyperactivity disorder

To determine executive dysfunctions in children with autistic disorder or attention-deficit/hyperactivity disorder (ADHD), we investigated high-functioning autistic (full scale IQ score >or==70), ADHD, and control children using the computerized version of the Wisconsin Card Sorting Test. Data were obtained from 17 autistic children (16 boys and 1 girl, mean age+/-SD: 12.5+/-4.3), 22 ADHD children (20 boys and 2 girls, mean age+/-SD 11.3+/-2.6), and 25 control children (13 boys and 12 girls, mean age+/-SD: 12.7+/-3.1). Performances, indicated by mean number of categories achieved (5.4 in autistic, 6.5 in ADHD, and 8.8 in control group), total errors (38.2, 38.4, and 25.6, respectively), perseverative errors (11.4, 13.5, and 5.7), nonperseverative errors (27.1, 25.0, and 19.9), and Nelson type perseverative errors (8.9, 8.4, and 2.3), were significantly poorer in both autistic and ADHD groups than control group (P<0.01). Comparing the autistic group to the ADHD group, there were no significant differences in age, gender, scores of full-scale intelligent quotient (IQ), verbal or performance IQ, number of categories achieved or errors. The ADHD group, however, showed more frequent Milner type perseverative errors than the autistic group (P<0.05). The present study suggests that some kinds of executive function are more impaired in children with ADHD than in those with high-functioning autism, and that Milner type perseverative errors is useful parameter to differentiate the executive dysfunctions between autistic and ADHD children.

Encephalopathy associated with haemophagocytic lymphohistiocytosis following rotavirus infection

Abstract A 2-year-old Japanese boy with a haemophagocytic lymphohistiocytosis (HLH) associated encephalopathy which developed after rotavirus infection is described. The neurological symptoms consisted of coma, seizures and spastic quadriplegia. On therapy with steroids, etoposide and cyclosporin A, the patient recovered without any neurological deficits. The interferon-gamma levels in serum and CSF were elevated at onset of the disease but had returned to normal at the time of clinical remission. Brain MRI revealed diffuse white matter abnormalities and parenchymal volume loss. Proton magnetic resonance spectroscopy revealed elevated lactate in the abnormal lesions observed on MRI, indicating that macrophages not exhibiting aerobic metabolism had infiltrated the CNS. At the time of clinical remission, the white matter abnormalities and brain lactate had disappeared. These findings suggested that the neurological symptoms resulted from the overproduction of cytokines by activated T-cells and macrophages. The pathophysiology of a HLH associated encephalopathy was considered to be a local immune response within the CNS, because interferon-gamma can induce the expression of major histocompatibility complex class I and II antigens on glial cells in the CNS. Conclusion Haemophagocytic lymphohistiocytosis associated encephalopathy should be considered early in the differential diagnosis of cases with acute onset neuropathy.

Serial neuroimages of acute necrotizing encephalopathy associated with human herpesvirus 6 infection

A previously healthy 8-month-old girl developed exanthem subitum and acute encephalopathy with status epilepticus, quadriplegia and bilateral abducens nerve palsies. Human herpesvirus-6 DNA was found in the cerebrospinal fluid by the polymerase chain reaction at the acute stage. Cranial computed tomography showed low density areas in the thalami and in the cerebellar and abducens nuclei. The distribution of the lesions was consistent with acute necrotizing encephalopathy. As for the thalamic lesions, a T2 weighted magnetic resonance image on the 24th day of the illness demonstrated low signal intensity surrounded by high intensity; 99mTc-ECD SPECT showed hypoperfusion, which suggested irreversible tissue damage. The patient is now 1 year 6 months old and has spastic quadriparesis with mental retardation and abducens nerve palsies.

Proton magnetic resonance spectroscopy to study the metabolic changes in the brain of a patient with Leigh syndrome.

Localized proton magnetic resonance spectroscopy (MRS) was performed to study the metabolic changes in the brain of a patient with Leigh syndrome, who had a T-->G point mutation at nt 8993 of mitochondrial DNA. In this patient, sodium dichloroacetate therapy normalized the lactate and pyruvate levels in both blood and cerebrospinal fluid (CSF). However, his psychomotor retardation did not improve and magnetic resonance imaging showed progressive cerebral atrophy. In the patients spectra, elevation of brain lactate was observed throughout the brain with regional variations, predominantly in the basal ganglia and brainstem with an abnormal MRI appearance. Although the lactate/creatine ratio observed on proton-MRS was related to the CSF lactate level, the ratio did not completely parallel the CSF lactate level, i.e. brain lactate was detected even when the CSF lactate level had become normalized. Furthermore, proton-MRS revealed a decrease in the N-acetylaspartate/creatine ratio and an increase in the choline/creatine ratio, representing neuronal loss and breakdown of membrane phospholipids. The clinical and MRI findings were well related to the changes in spectroscopically determined brain metabolites. These results indicate that the brain metabolites observed on proton-MRS are useful indicators of a response to therapy and prognosis in Leigh syndrome.

Acute transverse myelitis caused by ECHO virus type 18 infection

Abstracta 14-year-old boy developed acute quadriplegia, associated with sensory impairment and bowel and urinary dysfunction. MRI of the cervical cord showed diffuse increased signal intensity on T2-weighted images with gadolinium-diethylenetriamine penta-acetic acid enhancement. Based on the clinical presentation and MRI findings, the diagnosis of acute transverse myelitis was made. Enterovirus RNA was amplified from CSF by the reverse transcriptase-polymerase chain reaction. Serum neutralizing antibody to ECHO virus type 18 rose from 1/4 on admission to 1/16 2 months later.ConclusionThis is the first reported case of acute transverse myelitis caused by ECHO virus type 18 infection.

Beta-2-microglobulin and ferritin in cerebrospinal fluid for evaluation of patients with meningitis of different etiologies.

To determine whether or not the beta-2-microglobulin (beta2-m) and/or ferritin levels in cerebrospinal fluid (CSF) can be used as markers for the differential diagnosis of meningitis and determination of the response to treatment, 122 subjects with etiologically well-characterized diagnoses were classified into three groups: bacterial meningitis (n = 5; mean age +/- SD. 1.0+/-1.0 year), viral meningitis (n = 39; 5.9+/-3.8 years), and a non-meningitis group (n = 78; 5.2+/-4.9 years). The levels of beta2-m and ferritin in CSF were determined by means of a latex photometric immunoassay. The statistical significance of the data was analyzed with the Mann Whitney U-test. A receiver operating characteristic curve was used to evaluate the diagnostic accuracy of each prediction marker. This study indicated that (1) the levels of beta2-m and ferritin in CSF were related with age in the non-meningitis group: subjects of up to 5 months of age exhibited higher concentrations of these proteins than ones of above 6 months of age (beta2-m, 1.89+/-1.13 vs. 0.84+/-0.65 mg/l. P < 0.01; ferritin, 2.97+/-2.04 vs. 1.81+/-1.34 microg/l, P = 0.09); (2) the beta2-m level was significantly higher in the CSF of patients with viral meningitis than in ones without meningitis (2.41+/-1.23 vs. 0.84+/-0.65 mg/l, P < 0.01): the best cut-off value was 1.2 mg/l (3) the ferritin level was significantly higher in the CSF of patients with bacterial meningitis than in ones with viral meningitis (43.24+/-39.49 vs. 6.81+/-7.41 microg/l, P < (.01): the best cut-off value was 7.5 microg/l; and (4) sequential measurement of the CSF ferritin level was of value for determination of the response to antibiotic treatment for bacterial meningitis. These results only apply to patients of greater than 6 months of age. beta2-m and ferritin in the CSF can be used as an ancillary tool for diagnostic guidance in the acute phase of meningitis and determination of the response to treatment for bacterial meningitis.

Serial imaging in MELAS

Abstract We report two patients with fatal mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Single-photon emission computed tomography (SPECT) with 123I-N-isopropyl-p-iodoamphetamine was more sensitive to the lesions than CT or MRI. SPECT showed focal hyperperfusion before or during the stroke and diffuse hypoperfusion of the brain, sparing the basal ganglia in the terminal stages. These findings support the theory that metabolic disturbance in the brain causes the “stroke” in MELAS.