Man Woo

Effect of L-carnitine supplementation on acute valproate intoxication.

Summary: We analyzed urinary valproate (VPA) metabolites and carnitine concentrations in a child who accidentally ingested 400 mg/kg VPA. The concentration of 4‐en VPA, the presumed major factor in VPA‐induced hepato‐toxicity, was markedly increased, without liver dysfunction or hyperammonemia. The other major abnormality was decreased β‐oxidation and markedly increased ω‐oxidation. After L‐carnitine supplementation, VPA metabolism returned to normal. The level of valproylcarnitine was not increased and therefore was not affected by L‐carnitine. L‐Carnitine may be useful in treating patients with coma after VPA overdose.

When do brain abnormalities in cerebral palsy occur? An MRI study

The authors used MRI to analyse retrospectively the brain images of patients with cerebral palsy (CP) to evaluate its the role in the assessment of brain abnormalities and injury, and the relationship of pre‐, peri‐ and postnatal events to CP. 70 patients with CP aged two to 16 years who underwent MRI were divided into four groups: group 1 (26 patients) comprised subjects whose CP was considered to have been caused by neuronal migration disorders in the embryonal stage; group 2 (30 patients) contained subjects whose cause was vascular disorders; in group 3 patients (five) the cause was intra‐uterine infection; and CP clearly attributable to birth asphyxia (group 4) was noted in only nine patients. The results indicate that CP of term infants is often the result of prenatal factors, and their MRI findings indicated migration and cerebral infarction. Brain MRI is an essential examination in identifying the factors causing brain damage in CP.

Hepatotoxicity in Rat Following Administration of Valproic Acid: Effect of L-Carnitine Supplementation

Summary: The effect of prolonged administration (7 days) of valproate (VPA, 500 mg/kg/day), or VPA (500 mglkglday) with L‐carnitine (200 mg/kg/day) on blood carnitine levels and the appearance of liver mitochondria were assessed in the rat. VPA‐treated rats showed hypo‐ carnitinemia and enlarged mitochondria when compared with saline‐injected control rats. In rats treated with bothVPA and L‐carnitine, serum and liver carnitine levels were increased by the L‐carnitine supplement and the liver mitochondria were not enlarged. L‐Carnitine supplement in VPA‐medicated patients seems to prevent hepatotoxicity, especially mitochondrial dysfunction.

Hepatotoxicity in Rat Following Administration of Valproic Acid

Summary: Chronic injections of valproic acid (VPA), VPA with phenobarbital (PB), and PB were studied for their effects on liver mitochondrial morphology and carnitine metabolism in rats. Mitochondrial enlargement was induced by the administration of VPA (500 mg/kg/day) for a period of 7 consecutive days. The administration of VPA (500 mg/kg/day)‐plus‐PB (20 mg/kg/day) for 7 days, however, did not induce megamitochondrial formation, but in these livers an unusual increase was observed in the number of liver mitochondria, microvesicular steatoses, and myeloid bodies. VPA‐treated rats had significantly lower levels of serum‐free and total carnitine and higher levels of acylcarnitine and acyl to free ratio than those of the controls. The free carnitine concentrations in serum and liver of the rats treated with VPA‐plus‐PB were much lower as compared with those treated with either VPA or PB. These morphological and biochemical results, especially of carnitine metabolism, suggest that inhibition of 0‐oxidation in liver mitochondria occurred in rats treated with VPA and PB and that, in particular, polytherapy with VPA‐plus‐PB could be clinically hazardous in causing hepatic injury.

Carnitine Metabolism in Valproate-Treated Rats: The Effect of L-Carnitine Supplementation

ABSTRACT. The effect of the administration for 7 days of valproate (500 mg/kg/day) or valproate (500 mg/kg/day) plus L-carnitine (200 mg/kg/day) on carnitine concentrations in serum, red blood cells, muscle, liver, and urine was evaluated. In the serum and muscle of the valproic acid (VPA) group, free carnitine levels decreased, while acylcarnitine levels and acyl/free ratio increased, when compared to those of the control. When L-carnitine was given to the VPA group, the free carnitine levels increased in the serum, muscle, and liver, and the acyl/free ratio decreased in all tissues when compared to those of the VPA group. The mean of free carnitine level in urine of the VPA group was not different but acylcarnitine increased when compared to values of controls, and after the supplementation with L-carnitine the acylcarnitine (from day 4 to 7) levels were decreased compared to the VPA group. The serum β- OH-butyrate level in the VPA group was decreased when compared to those of controls and VPA plus L-carnitine groups. These results indicate that L-carnitine supplementation protects against the alteration in carnitine metabolism induced by the administration of VPA.

Valproate Metabolites in High‐Dose Valproate Plus Phenytoin Therapy

Summary: Purpose: We wished to determine the relation between liver function, β‐, and ω‐, and ω‐1‐oxidation metabolites and 4‐en‐valproate (VPA).

Computed tomography in young children with herpes simplex virus encephalitis

Computed tomographic (CT) scans were obtained from eight infants and young children with herpes simplex virus encephalitis. In two cases the initial scan showed diffuse edematous changes as a mass effect without laterality. Unilateral localized low attenuation in the initial scan was evident 4 days after the onset in one patient, and high attenuation in the initial scan appeared on the 6th day in another patient, but in general, it was not possible to establish an early diagnosis of herpes simplex virus encephalitis from CT scan. In the longitudinal study the calcification with ventriculomegaly appeared in 3 of 5 survivors, and gyriform calcification in 2 of 3 patients, respectively. The appearance of multicystic encephalomalacia was evident in one patient 6 months after the onset of neonatal herpes simplex encephalitis. It is shown that the CT findings of neonates and young children with herpes simplex encephalitis are different from those of older children and adults, and the importance of longitudinal CT studies was stressed in clarifying the pathophysiology of the central nervous system involvement in survivors.

Vascular involvement in benign infantile mitochondrial myopathy caused by reversible cytochrome c oxidase deficiency

A 1-month-old Japanese girl had profound generalized weakness, hypotonia, and severe lactic acidosis. The infant improved gradually: she held her head at 9 months, learned to walk by 15 months. At the first muscle biopsy at 11 weeks of age, the specimen was characterized by numerous ragged-red fibers and decreased enzyme activity on cytochrome c oxidase (COX) staining. Electron microscopic findings were characterized by the presence of excessive abnormal mitochondria not only in skeletal muscle fibers but also in blood vessels. Vascular abnormalities consisted of an increased number of enlarged mitochondria in endothelial and smooth muscle cells of small arteries. Biochemical analysis showed an isolated defect of COX activity, which was only 16% of the mean control level. At the second biopsy at 44 months of age, the COX activity had increased to normal in the entire specimen. On electron microscopy, the abnormal mitochondria present on the first biopsy specimen had disappeared both in muscle fibers and blood vessels; nearly all mitochondria were morphologically normal at the second biopsy. Now at 5 years of age she can run and does not show muscle weakness. We report reversibility of abnormal mitochondria with age not only in skeletal muscle fibers but also in blood vessels in a patient, who had reversible COX deficiency with a benign clinical course.

Serum and urinary carnitine and organic acids in reye syndrome and Reye-like syndrome

Free and acyl-carnitine in serum and urine, and urinary organic acids were measured in 6 patients with Reye syndrome and Reye-like syndrome. The free and total carnitine concentrations were significantly reduced in serum during the acute phases of the diseases. Thus, the ratio of acylcarnitine to free carnitine was significantly increased. Urinary excretion of acylcarnitine was greatly increased, and the acylcarnitine to total carnitine ratio was therefore greater than in controls. The urinary organic acids comprised large amounts of lactic acid, dicarboxylic acids and ketone bodies. It is suggested that carnitine deficiency is induced as more carnitine is consumed to buffer the increased amount of toxic acyl-CoA compounds metabolized from free fatty acids and the many organic acids. These results indicate that administration of L-carnitine should generally be considered in patients with Reye syndrome and Reye-like syndrome.

Metabolite profiles in patients on high-dose valproate monotherapy

To investigate the mechanism of valproate (VPA)-induced hepatotoxicity, we measured the serum and urine metabolites of VPA in high-dose VPA monotherapy by GC/MS/SIM and discussed the relationship between liver function and beta-oxidation, omega-, (omega-1)-oxidation metabolites and 4-en-VPA. In high-dose VPA monotherapy, the concentrations of beta-oxidation metabolites were not increased except for 2-en-VPA, but the concentrations of {omega + (omega-1)}-oxidation metabolites and of 4-en-VPA were increased about 4-5 times compared to those of standard dose VPA monotherapy. Serum GOT was not significantly correlated to 4-en-VPA and the ratio of beta-oxidation/{omega + (omega-1)} oxidation metabolites of VPA in serum. In high-dose VPA monotherapy, it is speculated that the beta-oxidation of VPA in the mitochondria reached the saturation point. However, instead of the beta-oxidation, the {omega + (omega-1)}-oxidation in microsomes was increased. We could not find significant relationship between the formation of toxic metabolites of VPA and liver dysfunction. Our data in VPA monotherapy suggest that the mechanisms of VPA-induced fatal hepatotoxicity cannot be explained by decreased beta-oxidation, increased omega-oxidation and increased 4-en-VPA level.