Elias Olafsson

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.

Cause-Specific Mortality in Adults with Unprovoked Seizures

Purpose: To determine the cause-specific mortality relative to that expected in a population-based incidence cohort of people with unprovoked seizures. Methods: The cohort comprises 224 inhabitants of Iceland first diagnosed as suffering from unprovoked seizures during a 5-year period from 1960 to 1964. The expected number of deaths was calculated by multiplying person-years of observation within 5-year age categories for each year from diagnosis through 1995 by cause-specific and sex-specific national death rates for those aged 20 years and above. The standardized mortality ratio (SMR) and 95% confidence intervals (95% CI) were calculated. Results: All-cause mortality was increased among men (SMR 2.25, 95% CI 1.56–3.14) but not women (SMR 0.79, 95% CI 0.38–1.46). Among men, there were 8 deaths from accidents, poisoning and violence observed versus 2.82 expected (SMR 2.84, 95% CI 1.22–5.59) and 4 deaths from suicide versus 0.69 expected (SMR 5.80, 95% CI 1.56–14.84). All-cause mortality for men was still elevated after restriction of analysis to those with seizures of unknown etiology (SMR 1.73, 95% CI 1.05–2.67) with the excess deaths attributable to suicide (SMR 5.26, 95% CI 1.06–15.38). Both males and females with remote symptomatic unprovoked seizures had an increase in all-cause mortality due to excess mortality from all cancers, cerebrovascular disease and accidents. Conclusion: When compared with the age-, time-period- and gender-specific mortality in the general population, there is excess mortality in men but not women. The increased mortality for men is partly attributable to excess mortality from accidents and suicides.

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.

A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries

Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease.

Incidence and prevalence of multiple system atrophy: a nationwide study in Iceland

Background Multiple system atrophy (MSA) is a neurodegenerative disorder characterised by autonomic dysfunction with parkinsonism (MSAp) or cerebellar (MSAc) symptoms. At autopsy, α-synuclein inclusions in glial cells of the brain are needed to confirm a definite diagnosis. We determined the 10 year incidence of MSA, point prevalence and survival in a well defined population with a high number of neurologists. Methods Cases were identified from the only neurology department and all practising neurologists in Iceland, over a 10 year period. The diagnosis of MSA was in accordance with the Second Consensus Criteria of MSA. Findings 19 incidence cases were diagnosed with MSA (11 women, eight men) during the study period, giving an average annual incidence of 0.7:100 000 (95% CI 0.4 to 1.1). Ten cases were alive on the prevalence day, giving a point prevalence of 3.4:100 000 (95% CI 1.6 to 6.3). 16 of the cases had probable and three possible MSA; 16 had MSAp and three had MSAc. Mean age at symptom onset was 65 years and mean age at diagnosis was 68 years. Patients were followed for an average of 31 months, and 15 died during the follow-up period. Survival from symptom onset was mean 5.7 years. The 1 and 5 year survival rates from diagnosis were 74% and 28%, respectively. Interpretation We reported on the incidence of MSA (both MSAp and MSAc) in a nationwide study where a definite diagnosis of MSA was confirmed in four out of five patients autopsied. We found survival to be shorter than reported in other studies.

Prevalence of symptomatic Charcot-Marie-Tooth disease in Iceland: a study of a well-defined population.

Background/Aim: To determine the prevalence and clinical spectrum of Charcot-Marie-Tooth disease (CMT) in Iceland. Methods: We identified all individuals with symptomatic CMT, based on information from all practicing neurologists, both neurophysiology laboratories and the only neurology department in the country. The diagnosis was based on clinical features and neurophysiological testing. DNA testing was regarded as confirmatory. Results: We identified 37 individuals in 18 families, which were not linked by identifying 5 generations of ancestors. The point prevalence (January 1, 2007) for all CMT subtypes in Iceland was 12.0/105, 10.1/105 for CMT1 and 2.0/105 for CMT2. The clinical features include lower limb weakness (95%), impaired gait (68%), decreased or absent deep tendon reflexes (86%), pes cavus (70%) and hammer toes (46%). Clinical symptoms were similar for the 2 main CMT subtypes. Conclusion: We report the prevalence and clinical spectrum of CMT, which is comparable to the results of other prevalence studies, in a well-defined, total population sample.

Incidence of First Stroke A Population Study in Iceland

Background and Purpose— Iceland is an island in the North Atlantic with ≈319 000 inhabitants. The study determines the incidence of first stroke in the adult population of Iceland during 12 months, which has not been previously reported in the entire Icelandic population. Methods— The study population consisted of all residents of Iceland, aged ≥18 years, during the 12-month study period. Cases were identified by multiple overlapping approaches. Medical records were reviewed to verify diagnosis, to determine stroke subtype and to determine selected risk factors. Results— A total of 343 individuals, aged ≥18 years, had a first stroke during the study period. Incidence was 144 per 100 000 person years; 81% ischemic infarction; 9% intracerebral hemorrhage; 7% subarachnoid hemorrhage; and 3% unknown. Fifty percent of the individuals were men. Mean age for ischemic infarction and intracerebral hemorrhage was 71 years for men and 73 years for women. Atrial fibrillation was previously known in 18% with first ischemic stroke or intracerebral hemorrhage and another 6% were diagnosed on routine admission ECG. Long-term ECG study (24 hours) found that 12% (18/154) of the remaining individuals had paroxysmal atrial fibrillation. Conclusions— Incidence of first stroke in Iceland is similar to other Western countries. The high number of paroxysmal atrial fibrillation found during the 24-hour ECG suggests that atrial fibrillation may be underdiagnosed in patients with stroke.

Incidence of multiple sclerosis in Iceland, 2002–2007: a population-based study:

Background: We conducted a study to determine the incidence of multiple sclerosis (MS) among the whole Icelandic population during a 6-year period (2002–2007). Methods: We included all Icelandic residents diagnosed with MS during the study period. Cases were identified from records of the only neurology department in Iceland, plus the records of all practicing neurologists and all radiology departments. All patients had experienced at least two confirmed MS relapses (i.e. clinically definite MS) or had primary progressive MS as defined by the Poser criteria. Results:We identified 136 individuals who met the inclusion criteria, including 102 (75%) women. The mean age at diagnosis was 36.3 years (women 35.7 years, men 38.3 years). Average annual incidence was 7.6 per 100,000 population. All but one patient (99%) had an MRI study done at diagnosis and 61% of these (83/135) fulfilled the Barkhof criteria for diagnosis of MS; one had a normal MRI. A visual evoked potential test was done in 68% (93/136) at the time of diagnosis and 44% (41/93) were abnormal. Spinal fluid was obtained from 78% (106/136), and 75% (80/106) had oligoclonal bands. Conclusion:A total population study is the most reliable method of determining the spectrum of clinical symptoms and the results of investigations in MS patients at diagnosis.

Deposition of collagen IV and aggrecan in leptomeningeal arteries of hereditary brain haemorrhage with amyloidosis.

Hereditary Cystatin C Amyloid Angiopathy (HCCAA) is a rare genetic disease in Icelandic families caused by a mutation in the cystatin C gene, CST3. HCCAA is classified as a cerebral amyloid angiopathy and mutant cystatin C forms amyloid deposits in cerebral arteries resulting in fatal haemorrhagic strokes in young adults. The aetiology of HCCAA pathology is not clear and there is, at present, no animal model of the disease. The aim of this study was to increase understanding of the cerebral vascular pathology of HCCAA patients with an emphasis on structural changes within the arterial wall of affected leptomeningeal arteries. Examination of post-mortem samples revealed extensive changes in the walls of affected arteries characterised by deposition of extracellular matrix constituents, notably collagen IV and the proteoglycan aggrecan. Other structural abnormalities were thickening of the laminin distribution, intimal thickening concomitant with a frayed elastic layer, and variable reduction in the integrity of endothelia. Our results show that excess deposition of extracellular matrix proteins in cerebral arteries of HCCAA is a prominent feature of the disease and may play an important role in its pathogenesis.

Pathological changes in basement membranes and dermal connective tissue of skin from patients with hereditary cystatin C amyloid angiopathy

Hereditary cystatin C amyloid angiopathy (HCCAA) is a genetic disease caused by a mutation in the cystatin C gene. Cystatin C is abundant in cerebrospinal fluid and the most prominent pathology in HCCAA is cerebral amyloid angiopathy due to mutant cystatin C amyloid deposition with associated cerebral hemorrhages, typically in young adult carriers. Analyses of post-mortem brain samples shows that pathological changes are limited to arteries and regions adjacent to arteries. The severity of pathological changes at post-mortem has precluded the elucidation of the evolution of histological changes. Mutant cystatin C deposition in carriers is systemic and has, for example, been described in the skin, suggesting similar pathological mechanisms both in the brain and outside of the central nervous system. The aim of this study was to use skin biopsies from asymptomatic and symptomatic carriers to study intermediate events in HCCAA pathogenesis. We found that cystatin C deposition in minimally affected samples was limited to the basement membrane (BM) between the dermis and epidermis. When the deposits were more advanced, they extended to other BM regions in the skin. Our results showed that the immunoreactivity of the BM protein COLIV was increased to a similar extent in all carrier biopsies and cystatin C deposits were in close association with COLIV. The density of fibroblasts in the upper dermis of carrier skin was increased, whereas the distribution of other cell types examined did not differ compared with control biopsies. COLIV and cystatin C immunoreactivity in carrier biopsies was closely associated with the fibroblasts. The results of this study, in conjunction with our previous results regarding pathological BM changes in leptomeningeal arteries of patients, suggest that BM changes are early and important events in HCCAA pathogenesis that could facilitate cystatin C deposition and aggregation.