Redistribution of monocarboxylate transporter 2 on the surface of astrocytes in the human epileptogenic hippocampus.

Glia. 2012 Apr 25;

Authors: Lauritzen F, Heuser K, de Lanerolle NC, Lee TS, Spencer DD, Kim JH, Gjedde A, Eid T, Bergersen LH

Abstract
Emerging evidence points to monocarboxylates as key players in the pathophysiology of temporal lobe epilepsy (TLE) with hippocampal sclerosis (mesial temporal lobe epilepsy, MTLE). Monocarboxylate transporters (MCTs) 1 and 2, which are abundantly present on brain endothelial cells and perivascular astrocyte endfeet, respectively, facilitate the transport of monocarboxylates and protons across cell membranes. Recently, we reported that the density of MCT1 protein is reduced on endothelial cells and increased on astrocyte plasma membranes in the hippocampal formation in patients with MTLE and in several animal models of the disorder. Because the perivascular astrocyte endfeet comprise an important part of the neurovascular unit, we now assessed the distribution of the MCT2 in hippocampal formations in TLE patients with (MTLE) or without hippocampal sclerosis (non-MTLE). Light microscopic immunohistochemistry revealed significantly less perivascular MCT2 immunoreactivity in the hippocampal formation in MTLE (n = 6) than in non-MTLE (n = 6) patients, and to a lesser degree in non-MTLE than in nonepilepsy patients (n = 4). Immunogold electron microscopy indicated that the loss of MCT2 protein occurred on perivascular astrocyte endfeet. Interestingly, the loss of MCT2 on astrocyte endfeet in MTLE (n = 3) was accompanied by an upregulation of the protein on astrocyte membranes facing synapses in the neuropil, when compared with non-MTLE (n = 3). We propose that the altered distribution of MCT1 and MCT2 in TLE (especially MTLE) limits the flux of monocarboxylates across the blood-brain barrier and enhances the exchange of monocarboxylates within the brain parenchyma. © 2012 Wiley Periodicals, Inc.

PMID: 22535546 [PubMed - as supplied by publisher]

Increased risk of sudden unexpected death in epilepsy in females using lamotrigine: a nested, case-control study.

Epilepsia. 2012 Feb;53(2):258-66

Authors: Aurlien D, Larsen JP, Gjerstad L, Taubøll E

Abstract
PURPOSE: To estimate the incidence of sudden unexpected death in epilepsy (SUDEP) in Rogaland County, Norway, in the period August 1 1995-July 31 2005, and to investigate whether use of lamotrigine (LTG) was associated with increased risk in female patients or other subgroups.
METHODS: SUDEP victims were identified from autopsy reports and data from the Norwegian Cause of Death Registry. In all cases where SUDEP was considered as a possible cause of death, the hospital records were also reviewed. For each deceased, at least three living patients with epilepsy were randomly selected as controls. The market share in defined daily doses was collected for each year to estimate the number of patient-years at risk on each antiepileptic drug.
KEY FINDINGS: We identified 26 cases of SUDEP: 16 definite, 3 probable, and 7 possible; 15 patients were female and 11 were male. Of these, 10 patients (38.5%) were treated with LTG: 9 of these patients were female. The incidence of SUDEP was estimated as 1.0 per 1,000 patient-years when all cases were included, and 0.7 per 1,000 patient-years for definite and probable SUDEP. Seven of 12 (58.3%) of female patients with definite and probable SUDEP and 10 of 41 (24.4%) of controls matched on age and gender were on LTG (p = 0.038). The incidence of definite and probable SUDEP in women on LTG, was estimated as 2.5 per 1,000 patient-years and 0.5 per 1,000 patient-years in female who were not taking LTG (p = 0.007).
SIGNIFICANCE: The incidence of SUDEP was significantly higher among female patients with epilepsy who were being treated with LTG than among female patients with epilepsy who were not taking LTG, and a significantly higher proportion of female SUDEP cases than controls were taking LTG. Our findings may have implications for treatment of epilepsy in female patients.

PMID: 22126371 [PubMed - indexed for MEDLINE]

Pre- and perinatal risk factors in adults with attention-deficit/hyperactivity disorder.

Biol Psychiatry. 2012 Mar 1;71(5):474-81

Authors: Halmøy A, Klungsøyr K, Skjærven R, Haavik J

Abstract
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and disabling lifespan disorder, but little is yet known about risk factors for ADHD persisting beyond adolescence. The present study investigates the association between pregnancy and birth complications and ADHD in adulthood.
METHODS: We used data from the Medical Birth Registry of Norway to compare pre-and perinatal risk factors among 2323 adults approved for medical treatment for ADHD, with the remaining population born during the same years, 1967-1987, and surviving into adulthood (n = 1,170,073). Relative risks (RR) adjusted for potential confounders were calculated.
RESULTS: Preterm (< 37 weeks of gestation) and extremely preterm birth (< 28 weeks of gestation) were associated with 1.3- and 5-fold increased risks of ADHD, respectively. Birth weights <2500 g and <1500 g also increased the risk of ADHD (RR: 1.5, 95% confidence interval [CI]: 1.2-1.8, and RR: 2.1, 95% CI: 1.3-3.6, respectively). Five-minute Apgar scores <4 and <7 were associated with 2.8- and 1.5-fold increased risks of persisting ADHD, respectively. Maternal epilepsy (RR: 1.7, 95% CI: 1.1-2.7) and offspring oral cleft (RR: 2.8, 95% CI: 1.6-4.9) occurred more frequently among adult ADHD patients.
CONCLUSIONS: This is the first population-based study of pre-and perinatal risk factors in adults with ADHD. We show that low birth weight, preterm birth, and low Apgar scores increase the risk of ADHD, persisting up to 40 years after birth. The increased risk of ADHD related to oral cleft and to maternal epilepsy warrants further investigation to explore possible causal mechanisms.

PMID: 22200325 [PubMed - in process]

Molecular biology of epilepsy genes.

Exp Neurol. 2011 Dec 9;

Authors: Williams CA, Battaglia A

Abstract
Multifactorial inheritance is the most important model accounting for the genetic behavior of the common epilepsies. Important to this model is the concept that many cumulative or synergistic risk genes ultimately lead to a threshold effect. Sophisticated molecular testing indicates that the common epilepsies are very polygenic without evidence of any single gene having even a mild-to-modest risk effect. However, enrichment of copy number variants in cohorts of individuals with epilepsy indicates that certain structural changes in the genome can confer significant risk for epilepsy. The mechanisms whereby copy number variants confer this effect are not yet known. The study of epilepsy due to single gene defects however has helped clarify certain seizure mechanisms. For example, discoveries using animal models of SCN1A or ARX mutations implicate a predominant role for interneurons due to disturbed GABAergic function. It is hoped that future genetic and neurobiological studies will provide better insight into how multiple genes contribute to the common epilepsies.

PMID: 22178301 [PubMed - as supplied by publisher]