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.     

Butyrate infusions in the ovine fetus delay the biologic clock for globin gene switching.

The switch from fetal to adult hemoglobin expression is regulated in many mammalian species by a developmental clock-like mechanism and determined by the gestational age of the fetus. Prolonging fetal globin gene expression is of considerable interest for therapeutic potential in diseases caused by abnormal beta-globin genes. Butyric acid, which is found in increased plasma concentrations in infants of diabetic mothers who have delayed globin gene switching, was infused into catheterized fetal lambs in utero during the time of the normal globin gene switch period. The globin gene switch was significantly delayed in three of four butyrate-treated fetuses compared with controls and was entirely prevented in one fetus in whom the infusion was begun before the globin switch was under way. These data provide a model for investigating and arresting the biologic clock of hemoglobin switching.     

Behavioral dissociation of anterodorsal and posteroventral hippocampus by subseizure stimulation in mice

BALB/c mice were bilaterally implanted with bipolar electrodes either in anterodorsal (ADH) or posteroventral hippocampus (PVH) in order to compare the effects of postsession electrical stimulation on memory processes. For each experiment, 30 s after the end of the first session, the animals were stimulated during 80 s. For both hippocampal regions, the stimulation intensity was half of the afterdischarge threshold value. Control groups were naive, ADH and PVH implanted non-stimulated animals. Different appetitive and aversive tasks were used. Subseizure stimulation never created a deficit. Depending on the region of the hippocampus stimulated and on the learning task, a retention enhancement was eventually observed. These data are in agreement with the involvement of hippocampus in initial stages of memory consolidation. Further, the subseizure stimulation permitted a functional dissociation between the two hippocampal regions. Both regions seemed involved in the integration of information, but the anterodorsal part would be rather related to behavioral inhibition, while the posteroventral part would have the capacity to induce an arousal state allowing behavioral flexibility.     

Source localization of small sharp spikes: low resolution electromagnetic tomography (LORETA) reveals two distinct cortical sources.

OBJECTIVE: We have investigated the cortical sources and electroencephalographic (EEG) characteristics of small sharp spikes (SSS) by using statistical non-parametric mapping (SNPM) of low resolution electromagnetic tomography (LORETA). METHODS: We analyzed 7 SSS patterns (501 individual SSS) in 6 patients who underwent sleep EEG studies with 29 or 23 scalp electrodes. The scalp signals were averaged time-locked to the SSS peak activity and subjected to SNPM of LORETA values. RESULTS: All 7 SSS patterns (mean 72 individual SSS, range 11-200) revealed a very similar and highly characteristic transhemispheric oblique scalp voltage distribution comprising a first negative field maximum over ipsilateral lateral temporal areas, followed by a second negative field maximum over the contralateral subtemporal region approximately 30 ms later. SNPM-LORETA consistently localized the first component into the ipsilateral posterior insular region, and the second component into ipsilateral posterior mesial temporo-occipital structures. CONCLUSIONS: SSS comprise an amalgam of two sequential, distinct cortical components, showing a very uniform and peculiar EEG pattern and cortical source solutions. As such, they must be clearly distinguished from interictal epileptiform discharges in patients with epilepsy. SIGNIFICANCE: The awareness of these peculiar EEG characteristics may increase our ability to differentiate SSS from interictal epileptiform activity. The finding of a posterior insular source might serve as an inspiration for new physiological considerations regarding these enigmatic waveforms.     

Optimization of the quinoline and substituted benzyl moieties of a series of phenyltetrazole leukotriene D4 receptor antagonists.

This report describes the development of a series of highly potent quinoline-based leukotriene D4 (LTD4) receptor antagonists containing an N-benzyl-substituted phenyltetrazole moiety. They were designed to provide both the correct positioning of the acidic function and secondary lipophilic domain required for strong receptor binding. Members of this series possess high activity in blocking LTD4-induced contractions of isolated guinea pig ileum. Compound 32, LY287192 (2-[[5-[3-[2-(7-chloroquinolin-2- yl)ethenyl]phenyl]-2H-tetrazol-2-yl]methyl]-5-fluorobenzoic acid sodium salt), blocked contraction with a pKB value of 9.1 +/- 0.3. Qualitative structure-activity studies have demonstrated specific requirements for the best activity. In particular, ortho substitution of the benzyl group with an acidic function was crucial for maximum potency. In cases similar to 32, where the benzyl group possesses an ortho carboxylate, the N-2-substituted tetrazole isomer showed 100-fold greater activity relative to the corresponding N-1 isomer. This pattern was reversed when the acid was substituted at the para position. The quinoline unit may be replaced by other nitrogen-containing heterocycles.     

Changes in the physiologic pattern of mitral prosthesis regurgitation in the presence of a prosthetic dysfunction]

AIM OF STUDY: Evaluation by transesophageal echocardiography of the effect on the characteristics of physiological regurgitant jets (JF) resulting from prosthetic disfunction due to pathologic regurgitation (JF). PATIENTS AND METHODS: We studied 69 consecutive patients with the diagnosis of prosthesis in mitral position using transesophageal echocardiography and color doppler codification. The patients were divided in two groups (N and D groups) according to the presence of prosthesis disfunction by pathologic regurgitation. In each patient we determined planimetric areas and atrial peak depth of each JF and also the sum of JF planimetric areas of each mitral prosthesis. When pathological regurgitation was present we calculated the highest planimetric area, severity degree and atrial peak depth in each JP. RESULTS: The planimetric area in each JF of group N was 330 +/- 167 mm2 and in group D 117 +/- 116 mm2 (p less than 0.001). The sum of the areas of JF in group N was 474 +/- 204 mm2 and in group D 254 +/- 176 mm2 (p less than 0.01). The atrial depth of JF in group was 32 +/- 15 mm and in group D 26 +/- 18 mm (p less than 0.01). In group D 29% of the patients had mild pathological regurgitation, 10% moderate and 61% severe. The maximum planimetric area of JP in group D was 1078 +/- 1007 mm2 with atrial depth of 37 +/- 28 mm. CONCLUSION: The pathological regurgitation in disfunction prosthesis in mitral position has a significant reduction effect in the dimension of prosthesis physiologic regurgitation jets. This transesophageal echocardiographic observation makes it possible to characterize and clarify more precisely the different types of mitral prosthesis jets.     

Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A.

BACKGROUND: Major depressive disorder (MDD) shows increased coronary artery disease (CAD) risk of unknown mechanism(s). MDD is more common in women than men; CAD diagnosis can be difficult in women. Elevations of the inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA) predict increased CAD risk in populations; few data on these markers exist in MDD, particularly in remitted patients. METHODS: We measured fasting am serum CRP (high sensitivity, CRP(hs)) and SAA in 18 unmedicated, remitted women with MDD (mean age 41 +/- (SD)12, body mass index (BMI) 25.2 +/- 4.1 kg/m(2)) and 18 BMI-matched healthy control subjects (age 36 +/- 10, BMI 25.3 +/- 3.8 kg/m(2)) on 2 separate occasions, > or = 6 days apart. RESULTS: Repeat SAA and CRP(hs) measurements strongly correlated across study days (SAA: r = .83, p < .001; CRP(hs): r = .94, p < .001). Both SAA (5.30 +/- 3.39 vs. 2.84 +/- 1.87 mg/L, p < .005) and CRP(hs) (3.23 +/- 3.17 vs. 1.12 +/- 1.45 mg/L; p < .01) were significantly elevated in MDD women versus controls. CONCLUSIONS: Elevated SAA and CRP(hs) in remitted, unmedicated women with MDD indicate a pro-inflammatory state unrelated to current depressive symptoms or pharmacotherapy. These findings suggest that inflammatory mechanisms may in part underlie findings of increased CAD risk in MDD.