Hironori Komori

Abnormal Carbohydrate Metabolism in Cerebrospinal Fluid in Rett Syndrome

We analyzed lactate, pyruvate, and citric acid cycle intermediates in cerebrospinal fluid by high-performance liquid chromatography in Rett syndrome patients (n = 27; mean age, 5.7 ± 3.4 years) and age-matched female controls (n = 12; mean age, 7.0 ± 3.3 years). The lactate, pyruvate, α-ketoglutarate, and malate were significantly elevated in Rett syndrome compared to the controls. The lactate/pyruvate ratio was not different. On the other hand, cerebrospinal fluid citrate, cisaconitate, succinate, fumarate, and oxaloacetate were not significantly different in Rett syndrome patients than in the controls. We also evaluated the correlation between these acids and clinical symptoms and signs, including clinical stage, seizures, medications (anticonvulsants or naltrexone), developmental quotient, self-abuse, and hyperventilation or apnea or both. The concentrations of all these acids did not differ significantly with clinical stage. Lactate elevation significantly correlated with apnea. Lactate and pyruvate elevation significantly correlated with hyperventilation or with both breathing abnormalities. Our observations in this sample of patients with Rett syndrome led us to speculate that patients with the Rett syndrome may have defective carbohydrate metabolism. Elevated mitochondrial reduced nicotinamide-adenine dinucleotide-linked substrates suggest that reduced nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase may be deficient in the brain in Rett syndrome patients. (J Child Neurol 1994;9:26-30).

Sulfamethoxazole-trimethoprim double-blind, placebo-controlled, crossover trial in Machado-Joseph disease : sulfamethoxazole-trimethoprim increases cerebrospinal fluid level of biopterin

We performed a double-blind, placebo-controlled, crossover trial of sulfamethoxazole-trimethoprim (S-T) in 8 patients with Machado-Joseph disease (MJD), and measured the blood and cerebrospinal fluid levels of biopterins, biogenic amines or metabolites, and folate. The clinical results were as follows; mild improvements of hyperreflexia of knee jerks and of rigospasticity of the legs during S-T treatment period. In addition, S-T significantly reduced the times of 8 motor activities on the timed tests. The biochemical results showed that basal levels of all biopterins and homovanillic acid in the cerebrospinal fluid (CSF) were reduced to less than half the levels of those of controls with other neurological diseases. After S-T treatment, total and oxidized form of biopterins in the CSF increased significantly. Therefore, S-T may be effective to neurologic deficits through its mechanism of increasing the level of brain biopterins.

Objective evaluation of pain in various spinal diseases: neuropeptide immunoreactivity in the cerebrospinal fluid.

A quantitative analysis was performed of substance P-like immunoreactivity (SPLI) and of β-endorphin-like immunoreactivity (β-ENDLI), in the cerebrospinal fluid (CSF) in various diseases. The results reported to date have not been consistent. The purpose of this study was to investigate whether or not the concentration of SPLI or that of β-ENDLI in CSF demonstrated any potential for assessing the degree of subjective pain in various spinal diseases. SPLI in CSF was measured by radioimmunoassay in 158 patients with a spinal disease; involving 57 patients with a lumbar disc herniation (LDH), 38 with lumbar canal stenosis (LCS), 46 with cervical myelopathy (CM) and 17 with cervical radiculopathy (CR), and also in 20 healthy controls. β-ENDLI in CSF was measured in 25 of these same patients; involving 12 with LDH, seven with LCS and six with CM, and also five of the same controls. The concentration of serum SPLI was also measured in 50 of these 158. The severity of pain was self-evaluated by each patient using a linear visual analogue scale (VAS). Their Japanese Orthopaedic Association (JOA) score was also calculated objectively using the clinical findings. Correlations were investigated among the concentrations of SPLI and β-ENDLI in the CSF and the VAS and JOA clinical assessments of these patients. The concentration of SPLI in CSF was significantly higher in various spinal diseases than in controls (P<0.05), and was correlated with the severity on the VAS and with the JOA score. However, β-ENDLI was not correlated with either the VAS or the JOA score. We conclude that the measurement of the SPLI concentration in CSF has the potential for assessing objectively the severity of pain associated with various spinal diseases.

The rett syndrome and CSF lactic acid patterns

We investigated both blood and cerebrospinal fluid (CSF) lactate and pyruvate levels in seven girls with the Rett syndrome (RS) and evaluated the relationship between CSF lactate and pyruvate levels and the clinical manifestations, particularly seizures, anticonvulsant medication, and breathing dysfunction including breath holding, apnea and hyperventilation. Elevated lactate and pyruvate levels in CSF with normal serum lactate were found in two RS patients. Elevated CSF lactate correlated significantly with the clinical occurrence of hyperventilation (P0 = 0.048, Fisher exact probability). We measured native and dichloroacetate (DCA)-activated pyruvate dehydrogenase (PDH) complex activities in two patients (#1 and 2) using cultured lymphoblastoid cell lines which were transformed by EB virus and the results were normal. We also analyzed CSF citric acid intermediates from 7 RS patients including citric acid, cis-aconitate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate. These concentrations were not significantly different from those control patients (N = 21). An elevated lactate level may be a clue to clarify the etiology of RS.

Cerebrospinal fluid biopterin and biogenic amine metabolites during oral R-THBP therapy for infantile autism

Treatment with 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP) has been suggested to improve autistic behavior. Cerebrospinal fluid (CSF) levels of total biopterin, oxidized and reduced forms of biopterin, homovanillic acid, and 5-hydroxyindoleacetic acid were measured in 14 autistic children and 18 controls to clarify the mechanism of action of R-THBP. The 14 autistic children received R- THBP orally at 1 mg/kg per day; 7 children showed clinical improvement (responders) and the other 7 patients did not (nonresponders). There were no significant differences between responders, nonresponders, and controls in the CSF levels of the metabolites before R- THBP administration. When lumbar puncture was repeated in 6 autistic children in the 24th week of R-THBP therapy, there was no significant change in the CSF levels of any metabolites.

Effect of age on cerebrospinal fluid levels of metabolites of biopterin and biogenic amines

We identified an age effect on biopterin and biogenic amine metabolites in the cerebrospinal fluid from 56 neurologically normal patients, aged 1 mo to 80 y. The levels of total and reduced forms of biopterin, homovanillic acid, and 5‐hydroxyindoleacetic acid were found to peak during the first year of life. The levels of these metabolites then gradually decreased, plateauing at the age of 20 y. We found significant correlations between biopterin, homovanillic acid, and 5‐hydroxyindoleacetic acid.

Age-related changes in the cerebrospinal fluid level of β-endorphin and substance P

Summary. To evaluate the early age-related changes in neuropeptides, we have measured the cerebrospinal fluid (CSF) levels of β-endorphin and substance P in young patients over a range of ages. Specimens of CSF were obtained from 39 neurologically normal children, aged 1 month to 10 years of age, and in 9 adult controls. CSF levels of both neuropeptides were observed to peak during the first year of life, and showed a negative correlation with increasing age. A significant positive correlation was observed between the CSF level of β-endorphin and that of substance P.

The efficacy of MR imaging in subdural empyema.

MRI findings of a 14-year-old boy with subdural empyema (SE) are reported and compared with those of serial CT-scan. He was admitted with fever, headache, right hemiplegia and facial palsy. Initial enhanced CT-scan revealed a slit left lateral ventricle and a shift in the mid-line structures, but failed to detect any SE. MRI at 10 days after admission clearly demonstrated SE as an area of low intensity on T1-weight (T1WI) and very high intensity on T2-weight (T2WI). Post-contrast enhanced MRI (CE-MRI), using Gd-DTPA, showed a contrast enhancement in the wall of SE. However, no definite parenchymal abnormal intensity areas were detected, suggesting that the diagnosis was made sufficiently early for timely treatment and good neurological outcome. CE-MRI proved to be a more powerful and better diagnostic procedure than enhanced CT-scan, and was very useful in determining the state and development of the disease.

Elevated biopterin and homovanillic acid levels in cerebrospinal fluid from children with aseptic meningitis.

To examine biopterin fractions and biogenic amine metabolites in cerebrospinal fluid in aseptic meningitis, the concentrations of homovanillic acid, 5-hydroxyindoleacetic acid, and the total, the oxidized form, and the reduced form of biopterin were determined in cerebrospinal fluid specimens from 15 children with aseptic meningitis in the acute phase, 15 children with aseptic meningitis in the recovery phase, and six other children as controls. The concentration of each substance was significantly higher in the acute phase than in the recovery phase. Homovanillic acid in the acute phase was significantly increased compared to that in the control group. The concentrations of the total, the oxidized form, and the reduced form of biopterin, and 5-hydroxyindoleacetic acid were higher in the acute phase than those in the controls; however, the differences were not significant. The concentration of each substance in the recovery phase was not significantly different from that in the controls. There was no difference in the 5-hydroxyindoleacetic acid/homovanillic acid ratio or in the reduced form/total biopterin ratio among the patients in acute and recovery phases and the controls. These results suggested that levels of biopterin and biogenic amine metabolites in cerebrospinal fluid are increased in the acute phase of aseptic meningitis and return to normal during the recovery phase. This is the first report of increased concentrations of biopterin fractions and biogenic amine metabolites in aseptic meningitis. (J Child Neurol 1994;9:22-25).