Olafur Kjartansson

Depression and suicide attempt as risk factors for incident unprovoked seizures

Major depression has been shown to increase the risk for development of epilepsy, but prior studies have not evaluated whether this is due to specific symptoms of depression. We conducted a population‐based case–control study of all newly diagnosed unprovoked seizures among Icelandic children and adults aged 10 years and older to test the hypothesis that major depression is a risk factor for developing unprovoked seizure and epilepsy, and to address whether specific symptoms of depression account for this increased risk. Cases were matched to the next two same sex births from the population registry. Using standardized interviews, we ascertained symptoms of major depression to make a Diagnostic and Statistical Manual, Fourth Edition (DSM‐IV) diagnosis. A history of major depression was 1.7‐fold more common among cases than among controls (95% confidence interval, 1.1–2.7). A history of attempted suicide was 5.1‐fold more common among cases than among controls (95% confidence interval, 2.2–11.5). Attempted suicide increased seizure risk even after adjusting for age, sex, cumulative alcohol intake, and major depression or number of symptoms of depression. Major depression and attempted suicide independently increase the risk for unprovoked seizure. These data suggest that depression and suicide attempt may be due to different underlying neurochemical pathways, each of which is important in the development of epilepsy. Ann Neurol 2005

Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility – Reykjavik Study

Aortic stiffness increases with age and vascular risk factor exposure and is associated with increased risk for structural and functional abnormalities in the brain. High ambient flow and low impedance are thought to sensitize the cerebral microcirculation to harmful effects of excessive pressure and flow pulsatility. However, haemodynamic mechanisms contributing to structural brain lesions and cognitive impairment in the presence of high aortic stiffness remain unclear. We hypothesized that disproportionate stiffening of the proximal aorta as compared with the carotid arteries reduces wave reflection at this important interface and thereby facilitates transmission of excessive pulsatile energy into the cerebral microcirculation, leading to microvascular damage and impaired function. To assess this hypothesis, we evaluated carotid pressure and flow, carotid-femoral pulse wave velocity, brain magnetic resonance images and cognitive scores in participants in the community-based Age, Gene/Environment Susceptibility--Reykjavik study who had no history of stroke, transient ischaemic attack or dementia (n = 668, 378 females, 69-93 years of age). Aortic characteristic impedance was assessed in a random subset (n = 422) and the reflection coefficient at the aorta-carotid interface was computed. Carotid flow pulsatility index was negatively related to the aorta-carotid reflection coefficient (R = -0.66, P<0.001). Carotid pulse pressure, pulsatility index and carotid-femoral pulse wave velocity were each associated with increased risk for silent subcortical infarcts (hazard ratios of 1.62-1.71 per standard deviation, P<0.002). Carotid-femoral pulse wave velocity was associated with higher white matter hyperintensity volume (0.108 ± 0.045 SD/SD, P = 0.018). Pulsatility index was associated with lower whole brain (-0.127 ± 0.037 SD/SD, P<0.001), grey matter (-0.079 ± 0.038 SD/SD, P = 0.038) and white matter (-0.128 ± 0.039 SD/SD, P<0.001) volumes. Carotid-femoral pulse wave velocity (-0.095 ± 0.043 SD/SD, P = 0.028) and carotid pulse pressure (-0.114 ± 0.045 SD/SD, P = 0.013) were associated with lower memory scores. Pulsatility index was associated with lower memory scores (-0.165 ± 0.039 SD/SD, P<0.001), slower processing speed (-0.118 ± 0.033 SD/SD, P<0.001) and worse performance on tests assessing executive function (-0.155 ± 0.041 SD/SD, P<0.001). When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains.

Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study

BACKGROUND No population-based incidence studies of epilepsy have studied syndrome classification from the outset. We prospectively studied the incidence of a single unprovoked seizure and epilepsy in the population of Iceland, and applied the syndrome classification endorsed by the International League Against Epilepsy to this population. METHODS We used a nationwide surveillance system to prospectively identify all residents of Iceland who presented with a first diagnosis of a single unprovoked seizure or epilepsy between December 1995 and February 1999. All cases were classified by seizure type, cause or risk factors, and epilepsy syndrome. RESULTS The mean annual incidence of first unprovoked seizures was 56.8 per 100,000 person-years, 23.5 per 100,000 person-years for single unprovoked seizures, and 33.3 per 100,000 person-years for epilepsy (recurrent unprovoked seizures). Incidence was similar in males and females. Partial seizures occurred in 40% and a putative cause was identified in 33%. Age-specific incidence was highest in the first year of life (130 per 100,000 person-years) and in those 65 years and older (110.5 per 100,000 person-years). Using strict diagnostic criteria for epilepsy syndromes, 58% of cases fell into non-informative categories. Idiopathic epilepsy syndromes were identified in 14% of all cases. INTERPRETATION Findings are consistent with incidence studies from developed countries. Although the epilepsy syndrome classification might be useful in tertiary epilepsy centers, it has limited practicality in population studies and for use by general neurologists.

Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location

Background and purpose: Incidental foci of signal loss suggestive of cerebral microbleeds (CMBs) are frequent findings on gradient echo T2* weighted MRI (T2* MRI) of patients with haemorrhagic or ischaemic stroke. There are few prevalence data on older populations. This paper reports on the prevalence and location of CMBs in a community based cohort of older men and women (born 1907–1935) who participated in the Age Gene/Environment Susceptibility (AGES)-Reykjavik Study, a population based cohort study that followed the Reykjavik Study Methods: As part of the examination, all eligible and consenting cohort members underwent a full brain MRI, and blood was drawn for genotyping. Results are based on the first 1962 men (n = 820) and women (n = 1142), mean age 76 years, with complete MRI and demographic information available. Results: Evidence of CMBs was found in 218 participants (11.1% (95% CI 9.8% to 12.6%)); men had significantly more CMBs than women (14.4% vs 8.8%; p = 0.0002, age adjusted). The prevalence of CMBs increased with age (p = 0.0001) in both men (p = 0.006) and women (p = 0.007). CMBs were located in the cerebral lobes (70%), the basal ganglia region (10.5%) and infratentorium (18.6%). Having a CMB was significantly associated with a homozygote Apo E 44 genotype (p = 0.01). Conclusion: Cerebral microbleeds are common in older persons. The association with homozygote Apo E 4 genotype and finding a relative predominance in the parietal lobes might indicate an association with amyloid angiopathy.

Operational definitions for the NINDS-AIREN criteria for vascular dementia: an interobserver study.

Background and Purpose— Vascular dementia (VaD) is thought to be the most common cause of dementia after Alzheimer’s disease. The commonly used International Workshop of the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences (AIREN) criteria for VaD necessitate evidence of vascular disease on CT or MRI of the brain. The purposes of our study were to operationalize the radiological part of the NINDS-AIREN criteria and to assess the effect of this operationalization on interobserver agreement. Methods— Six experienced and 4 inexperienced observers rated a set of 40 MRI studies of patients with clinically suspected VaD twice using the NINDS-AIREN set of radiological criteria. After the first reading session, operational definitions were conceived, which were subsequently used in the second reading session. Interobserver reproducibility was measured by Cohen’s &kgr;. Results— Overall agreement at the first reading session was poor (&kgr;=0.29) and improved slightly after application of the additional definitions (&kgr;=0.38). Raters in the experienced group improved their agreement from almost moderate (&kgr;=0.39) to good (0.62). The inexperienced group started out with poor agreement (&kgr;=0.17) and did not improve (&kgr;=0.18). The experienced group improved in both the large- and small-vessel categories, whereas the inexperienced group improved generally in the extensive white matter hyperintensities categories. Conclusions— Considerable interobserver variability exists for the assessment of the radiological part of the NINDS-AIREN criteria. Use of operational definitions improves agreement but only for already experienced observers.

Migraine with aura is a risk factor for unprovoked seizures in children

Migraine is associated with epilepsy, but the time order and nature of the relationship are unclear. We conducted a population based case control study to clarify the time order to determine whether migraine is a risk factor for epilepsy.

Coronary Artery Calcium, Brain Function and Structure The AGES-Reykjavik Study

Background and Purpose— Several cardiovascular risk factors are associated with cognitive disorders in older persons. Little is known about the association of the burden of coronary atherosclerosis with brain structure and function. Methods— This is a cross-sectional analysis of data from the Age, Gene, Environment Susceptibility (AGES)-Reykjavik Study cohort of men and women born 1907 to 1935. Coronary artery calcification (CAC), a marker of atherosclerotic burden, was measured with CT. Memory, speed of processing, and executive function composites were calculated from a cognitive test battery. Dementia was assessed in a multistep procedure and diagnosed according to international guidelines. Quantitative data on total intracranial and tissue volumes (total, gray matter volume, white matter volume, and white matter lesion volume), cerebral infarcts, and cerebral microbleeds were obtained with brain MRI. The association of CAC with dementia (n=165 cases) and cognitive function in nondemented subjects (n=4085), and separately with MRI outcomes, was examined in multivariate models adjusting for demographic and vascular risk factors. Analyses tested whether brain structure mediated the associations of CAC to cognitive function. Results— Subjects with higher CAC were more likely to have dementia and lower cognitive scores, more likely to have lower white matter volume, gray matter volume, and total brain tissue, and to have more cerebral infarcts, cerebral microbleeds, and white matter lesions. The relations of cognitive performance and dementia to CAC were significantly attenuated when the models were adjusted for brain lesions and volumes. Conclusions— In a population-based sample, increasing atherosclerotic load assessed by CAC is associated with poorer cognitive performance and dementia, and these relations are mediated by evidence of brain pathology.

Cerebral Infarcts and Cognitive Performance: Importance of Location and Number of Infarcts

Background and Purpose— Cerebral infarcts increase the risk for cognitive impairment. The relevance of location and number of infarcts with respect to cognitive function is less clear. Methods— We studied the cross-sectional association between number and location of infarcts and cognitive performance in 4030 nondemented participants of the Age Gene/Environment Susceptibility-Reykjavik Study. Composite scores for memory, processing speed, and executive function were created from a neuropsychological battery. Subcortical, cortical, and cerebellar infarcts were identified on brain MRI. We performed linear regression analyses adjusted for demographic and vascular risk factors, depression, white matter lesions, and atrophy. Results— Compared to participants with no infarcts, those with infarcts in multiple locations (n=287, 7%) had slower processing speed (β=−0.19; P<0.001) and poorer memory (β=−0.16; P<0.001) and executive function (β=−0.12; P=0.003). Compared to no infarcts, the presence of either subcortical infarcts only (n=275; β=−0.12; P=0.016) or cortical infarcts only (n=215; β=−0.17; P=0.001) was associated with poorer memory performance. Compared to no infarcts, a combination of cortical and subcortical infarcts (n=45) was associated with slower processing speed (β=−0.38; P<0.001) and poorer executive function (β=−0.22; P=0.02), whereas a combination of cerebellar and subcortical infarcts (n=89) was associated with slower processing speed (β=−0.15; P=0.04). Infarcts in all 3 locations was associated with slower processing speed (β=−0.33; P=0.002). Conclusions— Having infarcts in >1 location is associated with poor performance in memory, processing speed, and executive function, independent of cardiovascular comorbidities, white matter lesions, and brain atrophy, suggesting that both the number and the distribution of infarcts jointly contribute to cognitive impairment.

Socioeconomic status is a risk factor for epilepsy in Icelandic adults but not in children.

Summary:  Purpose: Two earlier population‐based studies provide conflicting information on the association between low socioeconomic status (SES) and risk for epilepsy. Seizure etiologies (e.g., head injury, stroke) associated with low SES were not addressed in prior analyses. We assess the relation between SES indices and incident epilepsy separately for children and adults and in subgroups defined by seizure etiology.

Diabetes, markers of brain pathology and cognitive function: the Age, Gene/Environment Susceptibility-Reykjavik Study.

We investigated whether, and the extent to which, vascular and degenerative lesions in the brain mediate the association of diabetes with poor cognitive performance.