No abstract

Summary: Purpose:We reviewed the literature to determine whether an analysis of published data could clarify the relationship between antiepileptic drug (AED) polytherapy and adverse affects (AE). We highlight the problems encountered.Methods: We made a Medline-search for articles published between 1974 and 1994 reporting the number of AE and doses or serum levels of every AED, per patient or treatment group, and used the PDD/DDD ratio to calculate AED load per patient from doses or the OSL/AToxL ratio to do so from serum levels of individual drugs. The PDD/ DDD is the sum of ratios of the actual prescribed daily doses divided by the published average therapeutic dose of each drug. The OSL/AToxL is the sum of each observed serum level divided by its average toxic level.Results: We retrieved 118 trial reports. Most had to be excluded because of incomplete reporting of concomitant medication or AE. The data of the 15 articles selected for further analysis indicate a relationship between drug load and number of AE. We noted no relationship between the number of AEDs administered and AE. In add-on studies, the difference in neurotoxicity between the active and placebo arm may be obscured if the relative increase in drug load is small, as exemplified by the study of McGuire et al. (35).Conclusions: Articles reporting add-on trials of new AEDs generally do not provide detailed information about the basic medication to which the new AED is added, which makes calculation of total drug load impossible. Furthermore, often only frequency of A E is reported, not severity or development of tolerance, making it difficult to judge the impact of AE. However, despite the paucity of available information, we present some evidence that toxicity in AED polytherapy may be related to total drug load, rather than to the number of drugs administered. Therefore, the present trend to reject polytherapy for fear of increased toxicity is not warranted, which removes one of the objections to initiating specific research to prove or disprove the value of AED combinations as long as the drug load is appropriate. Key Words: PolytherapyAntiepileptic drugs-Adverse effects-Drug loadEpilepsy.Antiepileptic drug (AED) pharmacotherapy is aimed at reducing seizure frequency and severity without producing adverse effects (AE). However, the reporting of AE in clinical trials lacks quantitative data because AE are often described in terms of frequency and rarely in terms of severity (1). Although the incidence of AE is important, the degree to which they occur also determines the acceptability of individual AEDs. When quantitative data are presented, a comparison is complicated because of the different rating scales used (2,3).The risk of development of chronic toxicity has been one of the arguments against use of polypharmacy in epilepsy (4). Much of this toxicity is believed Accepted January 13, 1997. Address correspondence and reprint requests to Dr. H. Meinardi, c/o P.O. Box 21,2100 AA Heemstede, The Netherlands.to be directly related to the number ...

We believe that CTX is underdiagnosed worldwide. We recommend that the presence of 2 of the 4 clinical hallmarks of CTX prompt thorough metabolic screening, including determination of urine bile alcohol excretion and serum cholestanol level, because CTX is a treatable disease.

The corticospinal tract develops over a rather long period of time, during which malformations involving this main central motor pathway may occur. In rodents, the spinal outgrowth of the corticospinal tract occurs entirely postnatally, but in primates largely prenatally. In mice, an increasing number of genes have been found to play a role during the development of the pyramidal tract. In experimentally studied mammals, initially a much larger part of the cerebral cortex sends axons to the spinal cord, and the site of termination of corticospinal fibers in the spinal grey matter is much more extensive than in adult animals. Selective elimination of the transient corticospinal projections yields the mature projections functionally appropriate for the pyramidal tract. Direct corticomotoneuronal projections arise as the latest components of the corticospinal system. The subsequent myelination of the pyramidal tract is a slow process, taking place over a considerable period of time. Available data suggest that in man the pyramidal tract develops in a similar way. Several variations in the funicular trajectory of the human pyramidal tract have been described in otherwise normally developed cases, the most obvious being those with uncrossed pyramidal tracts. A survey of the neuropathological and clinical literature, illustrated with autopsy cases, reveals that the pyramidal tract may be involved in a large number of developmental disorders. Most of these malformations form part of a broad spectrum, ranging from disorders of patterning, neurogenesis and neuronal migration of the cerebral cortex to hypoxic-ischemic injury of the white matter. In some cases, pyramidal tract malformations may be due to abnormal axon guidance mechanisms. The molecular nature of such disorders is only beginning to be revealed.

Summary:Purpose: Monotherapy has been the gold standard in epilepsy treatment for the last 20 years, partly because of the reputation for increased toxicity of polytherapy. However, monotherapy and polytherapy have not been compared in a double-blind clinical trial. Open trials that compared the two treatments were not optimally designed and compared the two at unequal drug loads (i.e., at nonequivalent dosages). We report on a double-blind clinical trial in which a combination of carbamazepine (CBZ) and valproate (VPA) was compared with CBZ monotherapy. Patients started with equal drug loads, and neurotoxicity was the primary outcome measure.Methods: The 130 adult patients with untreated generalized tonic-clonic and/or partial seizures were randomized to equal drug loads of either monotherapy (400 mg CBZ per day) or polytherapy (200 mg CBZ plus 300 mg VPA per day). Outcome was measured by seizure counts, clinimetric epilepsy scales, and neuropsychological tests at baseline, at 2 and 12 months, and irregularly between 2 and 12 months.Results: No statistical differences were found between the two treatments in the reduction of seizure frequencies, in overall neurotoxicity, or in overall systemic toxicity. The frequencies and clinimetric scores of certain adverse effects did differ (e.g., more monotherapy patients remained sedated, and more polytherapy patients gained weight). Fewer polytherapy patients withdrew because of adverse effects (14 vs. 22%), although this did not reach statistical significance (p ‫ס‬ 0.15). Neuropsychological assessment did not show significant differences.Conclusions: No differences were found in overall neurotoxicity between monotherapy and polytherapy.