The Effect of Antiepileptic Drugs on Cognition: Patient Perceived Cognitive Problems of Topiramate versus Levetiracetam in Clinical Practice

Summary:  Introduction: Neurocognitive complaints may interfere with long-term antiepileptic drug (AED) treatment and are an important issue in clinical practice. Most data about drug-induced cognitive problems are derived from highly controlled short-term clinical trials. We analyzed such cognitive complaints for the two most commonly used AEDs in a clinical setting using patient perceived problems as primary outcome measure.
Method: All patients of the epilepsy center Kempenhaeghe that received topiramate (TPM) or levetiracetam (LEV) from the introduction to mid 2004 were analyzed using a medical information system, an automated medical file. Patients were analyzed after 6, 12, and 18 months of treatment.
Results: Four hundred and two patients used either TPM (n = 260) or LEV (n = 142); 18 months retention showed a statistically significant difference, revealing 15% more patients that continued LEV compared to TPM: 18 months retention 46% for TPM and 61% for LEV [F (1.400) = 3.313, p = 0.043]. Neurocognitive complaints accounted for a significant number of drug discontinuations and especially the high frequency of neurocognitive complaints in the first period of TPM treatment appeared to be significant different from LEV [F(2,547) = 3.192, p = 0.042]. In the remaining patients, the difference in neurocognitive complaints was not statistically significant.
Conclusion: cognitive complaints are common in TPM treatment and frequently lead to drug withdrawal. The impact of LEV on cognitive function is only mild. This leads to a much higher (15%) drug discontinuation rate for TPM compared to LEV.     

Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS

Neurotrophin treatment has so far failed to prolong the survival of individuals affected with amyotrophic lateral sclerosis (ALS), an incurable motoneuron degenerative disorder. Here we show that intracerebroventricular (i.c.v.) delivery of recombinant vascular endothelial growth factor (Vegf) in a SOD1(G93A) rat model of ALS delays onset of paralysis by 17 d, improves motor performance and prolongs survival by 22 d, representing the largest effects in animal models of ALS achieved by protein delivery. By protecting cervical motoneurons, i.c.v. delivery of Vegf is particularly effective in rats with the most severe form of ALS with forelimb onset. Vegf has direct neuroprotective effects on motoneurons in vivo, because neuronal expression of a transgene expressing the Vegf receptor prolongs the survival of SOD1(G93A) mice. On i.c.v. delivery, Vegf is anterogradely transported and preserves neuromuscular junctions in SOD1(G93A) rats. Our findings in preclinical rodent models of ALS may have implications for treatment of neurodegenerative disease in general.     

Vaccination of chickens against a Belgian nephropathogenic strain of infectious bronchitis virus B1648 using attenuated homologous and heterologous strains

White Leghorn chicks without and with maternally derived antibodies (MDA) to infectious bronchitis virus (IBV) and broiler chicks with MDA were vaccinated at 1 day of age either with H120 vaccine, combined H120 and D274 vaccines or with a non-commercial attenuated strain derived from the virulent Belgian nephropathogenic IBV strain, B1648. Protection following challenge with virulent B1648 was assessed 4 weeks later by virus isolation from the trachea, antigen detection in the kidney by immunofluorescence and mortality rates. Vaccination with either homologous or heterologous vaccines reduced the duration of virus replication in the trachea of all groups compared to unvaccinated controls. Homologous vaccination reduced the incidence of virus replication in the kidney. Heterologous vaccination (H120 to D274) did not reduce kidney infection in the MDA + groups; however, partial kidney-protection was found in the MDA - group. There was no correlation between serum antibody titres measured by ELISA and the degree of kidney protection.     

Adhesion/decalcification mechanisms of acid interactions with human hard tissues.

In order to study adhesion/decalcification mechanisms of acid interactions with human hard tissues such as bones and teeth, the chemical interaction of five carboxylic acids (acetic, citric, lactic, maleic, and oxalic) and two inorganic acids (hydrochloric and nitric) with enamel and two synthetic hydroxyapatite (HAp) powders with, respectively, a high and a low crystallinity were analyzed using X-ray photoelectron spectroscopy (XPS), atomic absorption spectrophotometry (AAS), and spectrophotometry (S). X-ray diffraction revealed that the crystallinity of the highly crystallized HAp was considerably higher than that of enamel while the crystallinity of the poorly crystallized HAp was similar to that of dentin and bone. XPS of acid-treated enamel demonstrated for all carboxylic acids ionic bonding to calcium of HAp. AAS and S showed for both HAps that all carboxylic and inorganic acids except oxalic acid extracted Ca significantly more than P, leading to a Ca/P ratio close to that of synthetic HAp (2.16 w/w). Oxalic acid extracted hardly any Ca, but substantially more P, leading to a significantly smaller Ca/P ratio than that of HAp. AAS showed that the calcium salt of oxalic acid hardly could be dissolved, whereas the calcium salts of all the other acids were very soluble in their respective acid solution. These results confirm the adhesion/decalcification concept (AD-concept) previously advanced. Depending on the dissolution rate of the respective calcium salts, acids either adhere to or decalcify apatitic substrates. It is concluded that the AD-concept that originally dictated the interaction of carboxylic acids with human hard tissues can be extended to inorganic acids, such as hydrochloric and nitric acid. Furthermore, HAp crystallinity was found not to affect the adhesion/decalcification behavior of acids when interacting with apatitic substrates, so that the AD-concept can be applied to all human hard tissues with varying HAp crystallinity.     

Linking the integrated management of childhood illness (IMCI) and health information system (HIS) classifications: issues and options

Differences in the terms used to classify diseases in the Integrated Management of Childhood Illness (IMCI) guidelines and for health information system (HIS) disease surveillance could easily create confusion among health care workers. If the equivalent terms in the two classifications are not clear to health workers who are following the guidelines, they may have problems in performing the dual activities of case management and disease surveillance. These difficulties could adversely affect an individual's performance as well as the overall effectiveness of the IMCI strategy or HIS surveillance, or both. We interviewed key informants to determine the effect of these differences between the IMCI and HIS classifications on the countries that were implementing the IMCI guidelines. Four general approaches for addressing the problem were identified: translating the IMCI classifications into HIS classifications; changing the HIS list to include the IMCI classifications; using both the IMCI and HIS classification systems at the time of consultations; and doing nothing. No single approach can satisfy the needs of all countries. However, if the short-term or medium-term goal of IMCI planners is to find a solution that will reduce the problem for health workers and is also easy to implement, the approach most likely to succeed is translation of IMCI classifications into HIS classifications. Where feasible, a modification of the health information system to include the IMCI classifications may also be considered.     

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system

We used a modified version of the popliteal lymph node assay in rats to investigate the immunosuppressive potential of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In 10 months we conducted 3 experimental series. Animals were treated with single s.c. injections of TCDD and 7 days later human red blood cells (HRBC) were injected s.c. into the right hind footpad of the rat. Another 7 days later, both popliteal lymph nodes were prepared, weighed, the cell number was counted and the quotients (index) of these variables from the treated and the untreated side were determined. The doses applied in three experimental series were 600, 60, 6, 0.6, and 0.06 ng TCDD/kg body wt. In the first experimental series only the three highest doses were tested, in a second experimental series doses of 60, 6, 0.6, 0.06 ng TCDD/kg body wt were applied. Combining the results of these two experimental series, a statistically significant difference was found in the cell number index between the controls and the two highest doses tested (60 and 600 ng/kg body wt;p <0.01). This result was recently published as an abstract (Korte et al. 1990). However, with slight methodological changes in the third series of experiments (doses applied: 600, 60, 6, 0.6, and 0.06 ng TCDD/kg body wt) and using a greater number of animals we could not confirm these preliminary results. No difference was seen in the immune response to the antigen challenge in controls and in any of the treatment groups. We conclude that TCDD does not clearly influence the immune response as observed in the popliteal lymph node assay under our experimental conditions.     

Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Possible effects on the next generation after long-term exposure (subcutaneous administration) of male rats to very high doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied. Two dose regimes were applied: TCDD-25 (initial dose: 25 g/kg body wt; maintenance dose: 5 g/kg body wt, once weekly) and TCDD-75 (initial dose: 75 g/kg body wt; maintenance dose: 15 g/kg body wt). Male rats were treated for 10 weeks before mating and then throughout the entire 12 week mating period. They were mated to unexposed virgin females. One group of pregnant females was used for teratological evaluations, and another group was allowed to deliver. No significant differences were observed in the number of implantations or fetuses per litter, and resorption rate, and fetal weight between the controls and TCDD-treated groups. No gross-structural anomalies occurred in any of the fetuses sired by TCDD-treated males. In the TCDD-25 group an increased frequency of two types of variations was observed which also occur in controls: incompletely ossified fingers (TCDD-25=5.1%, controls=2.6%), and incompletely ossified ossa zygomatica (TCDD-25=1.8%, controls=0.5%). In the TCDD-25 group a slight but statistically significant increase was observed in the rate of stillbirths (TCDD-25=1.3%, controls=0.1%), apparently due to an unusually low frequency occurring in the controls (overall historical controls=0.6%). There was no difference in postnatal mortality (TCDD-25=1.3%, controls=1.3%). Taken together, despite the very high doses of TCDD used, the data do not provide evidence for biologically significant paternally-mediated developmental toxicity in the fetuses and newborn.     

Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin

The effects of a single dose of TCDD on the testis were studied in rats. The animals were treated (subcutaneously) once with TCDD doses of 0, 0.5, 1.0, 3.0, 5.0 g/kg body weight. Doses of 3.0 or 5.0 g TCDD/kg reduced the number of spermatids/testis significantly (60% of the controls). Electron microscopic inspection revealed that both doses led to a dissolution on the germinal epithelium. Altered germ cells at all developmental stages occurred in all testes evaluated. Doses of 0.5 or 1.0 g TCDD/kg did not induce any effects in the testis; therefore, under these experimental conditions of single exposure to rats the dose of 1.0 g TCDD/kg can be considered as NOAEL.     

Mesenteric pulsatility index analysis predicts response to azathioprine in patients with Crohn's disease

OBJECTIVE: Mesenteric blood flow measurement has been found to predict relapse after steroid-induced remission in patients with Crohn's disease (CD) and ulcerative colitis (UC). Therefore, we assessed prospectively the possible relationship between changes in mesenteric blood flow and prognosis in chronically active patients with need of immunosuppressive therapy with azathioprine (AZA) or 6-mercaptopurine (6-MP). METHODS: Doppler ultrasound (DUS) measurements of the pulsatility index (PI) of the superior mesenteric artery (SMA) and inferior mesenteric artery (IMA) were performed in 52 patients with chronically active inflammatory bowel disease (CD 31 patients; UC 21 patients) before beginning therapy with AZA/6-MP (US1) and during clinical remission (CD activity index <150, Truelove index score I) (US2). Patients were weaned from concomitant therapy with corticosteroids as soon as possible and were followed up for 12 months. RESULTS: After 1 year, 16 patients with CD (51.6%) and 13 patients with UC (61.9%) were in remission, whereas 23 patients had recurrent disease or had undergone surgery. A decreased SMA PI at US2 predicted clinical relapse in all patients with CD [100%; P < 0.001; mean (+/-SD) 77 +/- 67 d after US1], but only 4 of 8 patients (50%; difference not significant; mean 84 +/- 75 d after US1) with UC. Conversely, an increase of SMA PI was associated with sustained remission in the majority of CD patients (12/16 patients; 75%; P < 0.002), but in only 7 of 13 patients (54%) with UC. Flow measurements in the IMA and postprandial values for both arteries were less reliable. CONCLUSION: Repeated DUS measurements of the SMA PI predict response to AZA/6-MP in patients with chronic active CD.