Adaptation of hepatic ammonia metabolism after chronic valproate administration in epileptics treated with phenytoin

The effects of phenytoin (PHT) on the modifications of ammonia (NH+4) metabolism caused by sodium valproate (VPA) are here studied in order to identify the drug combinations susceptible of evoking stuporous states in epileptics, a rare condition attributed to a hyperammonemic encephalopathy induced by VPA. During chronic treatment with PHT or VPA-PHT, the acute injection of VPA increases the kidney's output of NH+4. During chronic PHT treatments, the acute injection of VPA modifies the liver's NH+4 metabolism and the arterial hyperammonemia is high (mean = 90 mumol/l). During chronic VPA-PHT treatments, the acute injection of VPA does not affect the hepatic NH+4 metabolism, suggesting that adaptation occurs, and the arterial hyperammonemia is moderate (mean = 60 numol/l). Disturbances of the hepatic adaptive mechanisms may explain certain complications observed during multiple-drug regimens.     

Acute leukoencephalopathy possibly induced by phenytoin intoxication in an adult patient with methylenetetrahydrofolate reductase deficiency

A 19‐year‐old university student with no personal or family history of neurologic disorders developed convulsions and was administered phenytoin. Two months later, he developed lower limb–dominant acute demyelinating polyneuropathy, from which he recovered within 2 months. At age 20, he rapidly developed visual disturbances and paraplegia from phenytoin intoxication. Cranial magnetic resonance imaging (MRI) revealed leukoencephalopathy with no evidence of thrombosis or vasoconstriction. Hyperhomocysteinemia, hypomethioninemia, low serum folate concentration, and an absence of megaloblastic anemia were consistent with the diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency. A genomic DNA sequence analysis demonstrated compound heterozygosity for two missense mutations in the MTHFR gene, namely, [458G>T + 459C>T] (Gly149Val) and 358G>A (Ala116Thr), both of which are known pathogenic mutations. An absence of leukoencephalopathic changes on MRI scans performed 9 months previously strongly suggested that phenytoin intoxication caused acute leukoencephalopathy. Therefore, phenytoin may be an aggravating factor of remethylation defects in patients with MTHFR deficiency.     

Axonal dystrophy in the gracile nucleus of man

Summary The gracile nuclei of 541 consecutive autopsies were examined. Dystrophic axons were found with few exceptions in all patients over 20 years of age. No clear relationship between the severity of the involvement, the age of the patients, chronic alcoholism, or any underlying disease process was detected. The findings were compared with those of other investigators who favor a nutritional deficiency as possible cause of the axonal dystrophy in the gracile nucleus.

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Zusammenfassung Die Nuclei graciles von 541 fortlaufenden Sektionen wurden untersucht. Dystrophische Axone wurden in fast allen Fällen im Alter über 20 Jahre gefunden. Eine eindeutige Beziehung zwischen der Schwere der Befunde, dem Alter der Patienten, chronischem Alkoholismus oder irgendeiner Krankheit konnte nicht festgestellt werden. Die Ergebnisse wurden mit denjenigen anderer Autoren verglichen, deren Beobachtungen einen Wirkstoffmangel als Ursache der dystrophischen Axone im Nucleus gracilis nahelegen.

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This study was supported in part by a grant from the Licensed Beverages Industries, Inc.     

癫[间]患者苯妥英钠的4种药物浓度的关系及意义

目的　探讨苯妥英钠 (PHT)治疗癫时的血清浓度 (Cp)、脑脊液浓度 (Cc)、唾液中浓度 (Cs)、血清游离浓度 (FCp)的关系。方法　用免疫荧光偏振法检测 6 2例单服PHT的癫患者以上 4种PHT浓度。结果　原发性癫和继发性癫病人之间PHT的平均Cp、Cc、Cs、FCp差别无显著性意义 ,6 2例患者Cc、Cs和FCp三者之间平均浓度比较差别无显著性意义 ;FCp、Cc、Cs三者之间及CP与FCp之间有较好的相关性 ,而CP与Cc、Cs之间相关性不明显。结论　测定Cp并不能较好地反映Cc水平 ,而Cs则可反应FCp和Cc的水平 ,因此可通过测定PHT的Cs水平监测PHT实际抗癫药物浓度。     

Benign angiopathy of the central nervous system associated with phenytoin intoxication

We report a patient with epilepsy who presented with acute onset of left hemiparesis associated with phenytoin intoxication due to interaction with clobazam. Magnetic resonance angiography of the head revealed stenosis of the M2 segment of the right middle cerebral artery, whereas an erythrocyte sedimentation rate and cerebrospinal fluid analysis were normal, being consistent with a diagnosis of benign angiopathy of the central nervous system. The patient exhibited an elevated plasma level of thrombin-antithrombin III complex along with a marginally increased plasma concentration of soluble E-selectin. The present case suggests that phenytoin intoxication can cause cerebral vasospasm, which may be associated with some inflammatory endothelial injury accompanied by activated intravascular coagulation.     

Axonal pathology of the skin in infantile neuroaxonal dystrophy

Summary Ultrastructural studies on the skin of two patients affected by infantile neuroaxonal dystrophy (INAD) were performed to evaluate its diagnostic value and to discuss the etiology of INAD. While the majority of terminal axons around intradermal glands were dystophic consisting of tubulomembranous and tubulovesicular profiles sometimes accompanied by synaptic vesicles, there were only few dystophic axons inside intradermal nerve bundles. These observations suggest that the primary lesion of INAD is located in terminal and presynaptic axons. Therefore, terminal axons have to be investigated when a diagnostic skin biopsy is performed in INAD.     

Reversible chronic cerebellar ataxia after phenytoin intoxication: possible role of cerebellum in cognitive thought

Reversible chronic cerebellar ataxia followed phenytoin treatment in two epileptic women. Cerebellar ataxia in both patients and axonal polyneuropathy in one patient were improved after administration of thiamine alone or with folate. In one patient, some specific behavioral functions improved. However, recovery could have been spontaneous.     

Patient satisfaction with polypharmacy reduction in chronic epileptics

The effects of polypharmacy reduction on patient satisfaction and subjective seizure severity were assessed prospectively in adult out-patients with chronic epilepsy using Japanese versions of the Side effects and Life Satisfaction (SEALS) and the Seizure Severity Questionnaires (SSQ). Antiepileptic drugs (AED) were withdrawn using a 1-year reduction schedule. The SSQ score was not aggravated and total SEALS score improved significantly. Moreover, temper subscore was also improved in the sedative AED reduction group. Similar to previous studies from the physician's viewpoint, the present study confirms that from the perspective of the patient, polypharmacy reduction, especially withdrawal of sedative AED, has a favorable effect on patient satisfaction.     

Gynecomastia in epileptics treated with phenobarbital, phenytoin and fluoresone: Two case reports

Gynecomastia developed in two epileptic patients some months after the addition of oral fluoresone 750 mg daily to the phenobarbital and phenytoin already being administered. The common systemic diseases that may give rise to gynecomastia were excluded. One of the patients presented hyperprolactinemia and a raised estrogen/androgen ratio but the hormone levels were not raised in the other. The onset of symptoms after fluoresone in both cases is highly suggestive, although the pathogenetic mechanism is not clear.

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Sommario Una ginecomastia insorta in due epilettici viene riportata. Il quadro si è sviluppato alcuni mesi dopo che ad un precedente trattamento con PB e PHT si era aggiunto fluoresone alla dose di 750 mg/die per os. Le comuni malattie sistemiche che possono determinare una ginecomastia sono state escluse. I rilievi ormonali hanno evidenziato soltanto in un caso un'iperprolattinemia ed un aumento del rapporto estrogeni-androgeni circolanti. La relazione temporale fra somministrazione del fluoresone e comparsa del quadro appare cruciate, tuttavia il meccanismo patogenetico resta da chiarire.

     

Axonal transport of taurine along neonatal and young adult rat optic axons

Studies in this laboratory have indicated that taurine is axonally transported along goldfish optic nerves. In the present experiments the axonal transport of taurine was examined in neonatal and young adult rat optic axons. [35S]taurine was injected into the vitreous humor of right eyes of developing (1--15-day-old) or young adult (40-day-old) rats. At various times after injection ranging from 3 h to 7 days, right retinae and left and right geniculates were removed and assayed for radioactivity, left minus right lateral geniculate (L-RLG) radioactivity being used as an index of axonally transported [35S]taurine. Results indicated that taurine was rapidly transported along both neonatal and young optic axons, in contrast to other amino acids (i.e., leucine and proline) which are not axonally transported in this system. Significant developmental variations were seen in both L-RLG and right retinal [35S]taurine activity 24 h after injection. The amounts of L-RLG [35S]taurine corrected for retinal ganglion cell uptake in animals injected at 1,4,7 and 11 days after birth (prior to and during the major period of synaptogenesis in the geniculates) were 4.5, 3.1, 2.3 and 2.6 times higher, respectively, than those in the young adults. In contrast, the amount of corrected L-RLG [35S]taurine in animals injected at 15 days after birth (after synaptogenesis) were not significantly different from that in the young adult.     

An autopsy case of chronic inflammatory demyelinating polyradiculoneuropathy with sever degeneration in the posterior column]

An autopsy case of chronic inflammatory demyelinating polyradiculoneuropathy was reported. It took a progressive course and terminated fatally in eight years. A 41-year-old man noticed motor disturbances when he tried to lift a bath pail and to write on July, 1978. Neurological examination revealed proximal dominant muscle atrophy, weakness of all extremities, and moderately diminished tendon reflex. Sensation was normal. The CSF showed albumin cytologic dissociations. Electromyogram showed neurogenic changes. Histological examination of biopsy specimen obtained from the anterior tibial muscle revealed severe neurogenic changes and showed axonal degeneration on the ventral tibial nerve. The treatment by corticosteroids was not effective, and the disease gradually progressed with repeated improvements and exacerbations. Three years after the onset, he showed vesicorectal dysfunctions. He died of respiratory failure on May, 1986. Neuropathological examination showed severe degeneration of middle root zones in the posterior columns, loss of myelinated fibers in Clarke's columns, demyelination and mild loss of axons accompanied by lymphocytic infiltration in the spinal roots, especially in the anterior roots. The histogram of cervical ventral root, ventral and dorsal roots of thoracic and lumbar regions revealed a decreased number of large myelinated fibers. A characteristic finding of this case was the dissociation of clinical features and neuropathological findings; the clinical features showed a typical motor neuropathy, but neuropathological examination showed severe degeneration on posterior columns of spinal cord like a sensory-ataxic neuropathy. Our observation suggest that the pathway which originates from posterior ganglion cells and runs into Clarke's columns passes through the middle root zones, since severe demyelination in Clarke's columns was observed.     

Serotonin turnover in discrete hypothalamic nuclei and mesencephalic raphe nuclei of young and adult spontaneously hypertensive rats

Serotonin levels and turnover were analyzed in discrete forebrain and mesencephalic nuclei of young (4-week-old) and adult (14-week-old) spontaneously hypertensive rats and age-matched normotensive control Wistar Kyoto rats. Most changes observed were age-dependent, and occurred only in young, early hypertensive rats. Both serotonin levels and the accumulation rate of 5-hydroxy-tryptophan after L-amino acid decarboxylase inhibition were higher in the nuclei periventricularis and paraventricularis of the hypothalamus of young hypertensive rats than in controls. In addition, 4-week-old spontaneously hypertensive rats showed higher 5-hydroxytryptophan accumulation rates in the nuclei supraopticus and dorsomedialis of the hypothalamus than controls. The only difference in serotonin metabolism found in adult hypertensive rats was high serotonin concentration in the median eminence of the hypertensive animals. Our results suggest the presence of anatomically specific, age-dependent alterations in serotonin metabolism, localized to selected hypothalamic nuclei in young hypertensive rats. These data support a role for the hypothalamic serotonin in the development of the spontaneous (genetic) hypertension in the rat.     

Effects of target deprivation on the morphology and survival of adult dorsal column nuclei neurons

During development, interaction with target cells plays a critical role in the regulation of survival of afferent neurons. In an attempt to define the role of target cells in the adult central nervous system, the somatodendritic morphology and survival of adult cuneate neurons deprived of their targets by in situ injection of kainic acid in the rat thalamus were studied. In neuron-specific, enolase-immunostained sections, a 20% decrease in the mean longest diameter of the labeled cells was detected at 4 months postlesion. This somatic atrophy was accompanied by a loss of distal dendritic arborizations as observed after labeling by intracellular diffusion of horseradish peroxidase. Cytochrome oxidase staining did not reveal detectable alterations of the metabolic activity of these neurons, and an ultrastructural study also failed to demonstrate major changes in the neuronal somata. Cell counts indicated a much delayed death of 25% of the neurons at 10 months postlesion, whereas no neuronal death was detected at 7 months. The glial cells appeared unaltered both in number and in immunolabeling when using OX-42 antibodies or antiglial fibrillary acidic protein (anti-GFAP) antibodies. Results obtained in this time-course study indicate that neuronal death and alteration of the somatodendritic morphology are much delayed events after excitotoxic loss of targets. Somatodendritic atrophy occurs several months postlesion, and neuronal death occurs close to 1 year after lesion. These results suggest that the hypothesis of a necessary continuous trophic support by target cells does not hold as firmly for the adult central nervous system as during development. © 1995 Wiley-Liss, Inc.     

Axonal regeneration in the adult lamprey spinal cord

Larval sea lampreys recover from complete spinal transection by a process involving directionally specific axonal regeneration. In order to determine whether this is also true of adults, 14 adult lampreys were transected at the level of the 5th gill and allowed to recover for 10 weeks. Müller and Mauthner cells and their giant reticulospinal axons (GRAs) were impaled with microelectrodes and injected with horseradish peroxidase (HRP). The tissue was processed for HRP histochemistry and wholemounts of brain and spinal cord were prepared. All animals recovered coordinated swimming; 61 of 121 (50%) neurites emanating from 30 axons regenerated caudal to the scar into the distal stump. Of the neurites which had grown beyond the scar, 92% were correctly oriented, i.e., caudalward and ipsilateral to the parent axon. Retransection in two additional animals eliminated the recovered swimming. Thus, behavioral recovery in adult sea lampreys is accompanied by directionally specific axonal regeneration.     

Intensive inpatient treatment of young adult chronic patients

Young adults with chronic mental disorders have become a major concern among mental health professionals during the past decade. Many of these patients require frequent hospitalizations, are noncompliant with treatment, experience behavioral crises that threaten themselves or others, abuse drugs and alcohol, and alienate their families and support systems. The authors describe an intensive inpatient program for young adult chronic patients who have repeatedly failed to respond to community-based and standard state hospital care and appear to need extended institutional care. The program, which integrates psychiatric and rehabilitation strategies, has succeeded in increasing the amount of time these patients remain in the community. Although the goal for such patients remains a community-based treatment program, the value of an extended period of active inpatient treatment for some patients may be overlooked in current planning for them.     

The effect of chronic phenytoin treatment on serum lipid profile in adult epileptic patients.

Total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein cholesterol, apolipoproteins A, A1, and B and gamma-glutamyltransferase (ggt) serum concentrations were measured in 100 adult epileptic patients receiving chronic phenytoin (PHT) treatment and in 100 control subjects. In relation to controls, patients showed higher HDL cholesterol, apolipoproteins A and A1, and ggt levels and lower LDL cholesterol and apolipoprotein B values; the significance of the results was greater in women than in men. Among patients, ggt levels were positively correlated with PHT plasma concentrations; likewise, a negative correlation was found between the apolipoprotein A/A1 ratio and the PHT and ggt plasma levels, and a positive correlation between the apolipoprotein A/A1 ratio and the LDL/HDL cholesterol ratio. These data indicate that PHT exerts a beneficial effect on the serum lipids profile.