SUMMARYPurpose: Older enzyme-inducing antiepileptic drugs (AEDs) may induce supraphysiologic plasma concentrations of total (t) homocysteine (Hcy). The aim of the present study was to investigate the effect of new AEDs on plasma tHcy levels. Methods: Patients 18-50 years of age, on AEDs monotherapy, with no other known cause of hyper-tHcy were enrolled. Plasma tHcy, folate, vitamin B 12 , and AEDs levels were determined by standard high-performance liquid chromatography (HPLC) methods. Methylenetetrahydrofolate-reductase (MTHFR) polymorphisms were checked using Puregene genomic DNA purification system (Gentra, Celbio, Italy). A group of healthy volunteers matched for age and sex was taken as control. Results: Two hundred fifty-nine patients (151 on newer and 108 on older AEDs) and 231 controls were enrolled. Plasma tHcy levels were significantly higher [mean values, standard error (SE) 16.8, 0.4 vs. 9.1, 0.2 lM; physiologic range 5-13 lM] and folate lower (6.3, 0.1 vs. 9.3, 0

Hyperhomocysteinemia can result from decreased methylenetetrahydrofolate reductase (MTHFR) enzyme activity, owing to genetic polymorphisms andor inadequate folate intake. This study was aimed at investigating the prevalence of C677T and A1298C MTHFR polymorphisms, and their impact on hyperhomocysteinemia in 95 epileptic patients and 98 controls. Double gradient-denaturing gradient gel electrophoresis screening revealed that the frequency of T677 polymorphic allele was similar between cases and controls (46.3% vs 42.3%), whereas that of C1298 allele was significantly higher in patients (30.5% vs 19.4%, p < 0.05). Significant differences between the two groups were also found for the frequencies of genotypes AA1298 (46.3% in cases vs 67.3% in controls, p < 0.01) and AC1298 (46.3% in cases vs 26.6% in controls, p < 0.01). Other genotype frequencies did not show any statistically significant differences. Haplotype frequencies significantly differed between the two groups. The CT677/AC1298 diplotype was significantly more frequent in epileptic patients than in controls (32.6% vs 18.4%, p < 0.05). Patients treated with enzyme-inducing antiepileptic drugs, having this diplotype and concomitant low folate concentration (i.e., < 3.4 nmol/L), exhibited plasma homocysteine levels significantly higher than normal values (27.1 +/- 2.44 micromol/L, p < 0.001). This increase, however, was lower than that observed in folate-deficient patients with diplotype TT677/AA1298 (41.3 +/- 3.41 micromol/L, p < 0.001). Indeed, these two diplotypes could be regarded as risk factors for hyperhomocysteinemia. Conversely, we found that the CC677/AA1298 diplotype was significantly more frequent in controls (p < 0.01), suggesting a protective role. Our study suggests that both C677T and A1298C MTHFR polymorphisms should be examined when assessing genetic risk factors of hyperhomocysteinemia in epilepsy.

To evaluate in the setting of a stroke unit ward the usefulness of a prolonged (>6 h) video-EEG recording (PVEEG) in identifying non-convulsive status epilepticus (NCSE) in patients with an acute ischemic stroke. Predictors of NCSE were also evaluated. Patients with an acute ischemic stroke, referred to our unit, were included in this prospective observational study. A PVEEG recording was implemented after stroke in all patients during the first week: (a) promptly in those exhibiting a clear or suspected epileptic manifestation; (b) at any time during the routine activity in the remaining patients. After the first week, a standard EEG/PVEEG recording was hooked up only in presence of an evident or suspected epileptic manifestation or as control of a previous epileptic episode. NCSE was identified in 32 of the 889 patients (3.6 %) included in the study. It occurred early (within the first week) in 20/32 (62.5 %) patients and late in the remaining 12. Diagnosis was made on the basis of a specific clinical suspect (n = 19, 59.4 %) or without any suspect (n = 13, 40.6 %). In a multivariate analysis, a significant association of NCSE was observed with NIHSS score, infarct size and large atherothrombotic etiology. NCSE is not a rare event after an acute ischemic stroke and a delayed diagnosis could worsen patient prognosis. Since NCSE can be difficult to be diagnosed only on clinical grounds, implementation of a prompt PVEEG should be kept available in a stroke unit whenever a patient develop signs, although subtle, consistent with NCSE.

There is evidence that increased homocysteine (Hcy) levels might accelerate dopaminergic cell death in Parkinson's disease (PD) through neurotoxic effects. Homocysteine neurotoxicity mainly relies on redox state alterations. The present work was aimed at investigating the relationships between plasma Hcy concentrations and percent content of oxidized versus total Coenzyme Q10 (%CoQ10) in 60 PD patients and 82 healthy subjects. Both groups were screened for plasma levels of Hcy, vitamin B12, folate, %CoQ10 and C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism. The MTHFR TT677 mutated genotype was found more frequently in patients than in controls (p = 0.01). In a multivariate analysis, Hcy levels and %CoQ10 were associated with the case/control category (p < 0.0001), MTHFR genotype (p < 0.0001) and their interaction term (p = 0.0015), even after adjusting for age, sex, folate and vitamin B12. Patients carrying the TT677 genotype exhibited the highest values of Hcy and %CoQ10 (p < 0.0001). Structural equation modelling evidenced that the TT677 genotype and levodopa daily dose were independently and directly correlated with Hcy (p < 0.0001, and p = 0.003, respectively), which, in turn, showed a significant correlation (p < 0.0001) with the %CoQ10 in PD patients. Our results suggest that increased Hcy levels act as mediator of the systemic oxidative stress occurring in PD, and %CoQ10 determination might be regarded as a predictor of toxic Hcy effects.

Summary:The influence of antiepileptic drugs (AEDs) and/or common polymorphisms (677C → T, 1298A → C) of the methylene-tetrahydrofolate-reductase (MTHFR) gene on the recurrence time of hyper-total-homocysteinemia (tHcy > 13 µmol/L) was investigated in 59 hyper-homocysteinemic patients (34M/25F, 20-49 years). Plasma tHcy and folate were assayed before and after 1-month folate supplementation (5mg/day), and after 2, 4, and 6 months. Four MTHFR polymorphism groups were identified with the following tHcy (µmol/L) and folate (nmol/L) levels (mean ± SD): (a) MTHFR677TT/1298AA, 24 patients, 36.0 ± 4.8, 4.1 ± 0.7; (b) MTHFR677CT/1298AC 27.1 ± 2.7, 5.3 ± 1.0 (n = 15); (c) MTHFR677CT/1298AA 16.6 ± 3.6, 6.8 ± 1.0 (n = 11), all taking enzyme-inducing AEDs; and (d) MTHFR677TT/1298AA 24.5 ± 3.2, 5.6 ± 1.1 (n = 9), treated with new AEDs. After folate therapy, plasma t-Hcy and folate were normal in all patients. At 6 months, 43 patients (72.9%) exhibited hyper-tHcy, the greater proportion belonging to the EI-AED-MTHFR677TT/1298AA (39%). Knowledge of the hyper-tHcy recurrence time after folate therapy discontinuation may help in optimizing folate supplementation pulses. Key Words: Hyper-homocysteinemia-MTHFR polymorphisms-Antiepileptic drugs.A 10-40% proportion of epileptic patients develop hyper-total-homocysteinemia (tHcy) (Apeland et al., 2002;Huemer et al., 2005) as a consequence of: (a) intake of enzyme-inducing (EI) AEDs, which deplete organism of B vitamins serving as cofactors/substrates in Hcy metabolism (Herrmann et al., 2007) and/or (b) the presence of C677T and A1298C polymorphisms implying reduced activity of the methylenetetrahydrofolate reductase (MTHFR), which converts Hcy to methionine (Carmel et al., 2003). Hyper-tHcy, observed in ∼5% of the general population, is associated with increased risk of vascular and neurodegenerative diseases (Herrmann et al., 2007 (Herrmann et al., 2007). The present study was aimed at investigating the influence of AEDs and MTHFR polymorphisms on hyper-tHcy recurrence once folate has been discontinued. Information on this parameter may help optimize folate therapy pulses over time. PATIENTS AND METHODS Study designThis prospective, observational investigation, conducted at the Epilepsy Centers in Messina and Napoli University, Italy, from April 2005 to March 2006, consisted of two parts: (a) a cross-sectional phase, in which out-patients were screened for hyper-tHcy; and (b) an interventional phase, in which folate was given for 30 days to hyper-tHcy patients.The study was approved by the local ethic committees and informed consent was signed by participants. PatientsPatients exhibiting hyper-tHcy at least on two separate occasions in the last 6 months were recruited according to the following criteria: (a) 18-50 years of age; this range was chosen to minimize the age influence on tHcy 1990

I M factors, SUA levels are associated with carotid IMT even in subjects without the metabolic syndrome. This confirms and expands the role of uric acid in the determinism of CVD. Prospective trials would be useful to evaluate interventions aimed at lowering the uric acid level.

No abstract

This result could suggest that the development of cardiovascular disease after menopause is due not only to estrogen decline but also to androgen decline. More studies are needed to evaluate the role of androgen replacement therapy on postmenopausal women with low level of this hormone.