Outpatient follow-up after mild traumatic brain injury: Results of the UPFRONT-study.

OBJECTIVE: To investigate outpatient follow-up after mild traumatic brain injury (mTBI) by various medical specialists, for both hospitalized and non-hospitalized patients, and to study guideline adherence regarding hospital admission. METHODS: Patients (n = 1151) with mTBI recruited from the emergency department received questionnaires 2 weeks (n = 879), 3 months (n = 780) and 6 months (n = 668) after injury comprising outpatient follow-up by various health care providers, and outcome defined by the Glasgow Outcome Scale Extended (GOS-E) after 6 months. RESULTS: Hospitalized patients (60%) were older (46.6 ± 19.9 vs. 40.6 ± 18.5 years), more severely injured (GCS <15, 50% vs. 13%) with more Computed Tomography (CT) abnormalities on admission (21% vs. 2%) compared to non-hospitalized patients (p < 0.01) . Almost half of the patients visited a neurologist at the outpatient clinic within six months (60% of the hospitalized and 25% of the non-hospitalized patients (χ2 = 67.10, p < 0.01)), and approximately ten per cent consulted a psychiatrist/psychologist. Outcome was unfavourable (GOS-E <7) in 34% of hospitalized and 21% of non-hospitalized patients (χ2 = 11.89, p < 0.01). CONCLUSION: Two-thirds of all mTBI patients consult one or more specialists within six months after injury, with 30% having an unfavourable outcome. A quarter of non-hospitalized patients was seen at the outpatient neurology clinic, underling the importance of regular follow-up of mTBI patients irrespective of hospital admittance.

An early prediction of delirium in the acute phase after stroke.

BACKGROUND: We developed and validated a risk score to predict delirium after stroke which was derived from our prospective cohort study where several risk factors were identified. METHODS: Using the ß coefficients from the logistic regression model, we allocated a score to values of the risk factors. In the first model, stroke severity, stroke subtype, infection, stroke localisation, pre-existent cognitive decline and age were included. The second model included age, stroke severity, stroke subtype and infection. A third model only included age and stroke severity. The risk score was validated in an independent dataset. RESULTS: The area under the curve (AUC) of the first model was 0.85 (sensitivity 86%, specificity 74%). In the second model, the AUC was 0.84 (sensitivity 80%, specificity 75%). The third model had an AUC of 0.80 (sensitivity 79%, specificity 73%). In the validation set, model 1 had an AUC of 0.83 (sensitivity 78%, specificity 77%). The second had an AUC of 0.83 (sensitivity 76%, specificity 81%). The third model gave an AUC of 0.82 (sensitivity of 73%, specificity 75%). We conclude that model 2 is easy to use in clinical practice and slightly better than model 3 and, therefore, was used to create risk tables to use as a tool in clinical practice. CONCLUSIONS: A model including age, stroke severity, stroke subtype and infection can be used to identify patients who have a high risk to develop delirium in the early phase of stroke.

Delirium in the acute phase after stroke and the role of the apolipoprotein E gene.

OBJECTIVE: To study the association between the epsilon 4 allele of apolipoprotein E (APOEε4) and delirium in a stroke population. METHODS: 527 consecutive stroke patients were screened for delirium during the first week of admission with the confusion assessment method. In three hundred fifty-three patients genomic DNA isolation was available. RESULTS: The incidence of delirium after stroke in the 353 patients was 11.3%. There was no association between APOEε4 and delirium. Even after adjustment for IQCODE, stroke localization, stroke subtype, stroke severity, infection, and brain atrophy no association was found (odds ratio: 0.9; 95% confidence interval: 0.4-2.1). Delirium did not last longer in patients with an APOEε4 allele compared to patients without an APOEε4 allele (median: 5.6 days [range: 1-21] versus median: 4.6 days [range: 1-15], p = 0.5). CONCLUSION: There was no association between the presence of an APOEε4 allele and the occurrence of delirium in the acute phase after stroke.

The use of EEG in the diagnosis of dementia with Lewy bodies.

Although reports on EEG in dementia with Lewy bodies (DLB) are conflicting, the recent diagnostic guidelines define EEG abnormalities as being supportive for the diagnosis. We examined EEG abnormalities in 18 patients with DLB, 34 patients with Alzheimer's disease (AD) and 36 patients with subjective memory complaints (SMC) using the Grand Total EEG (GTE) score. There was a difference in median GTE score of DLB (11.0), AD (4.8) and SMC (2.5) (p<0.001). Patients with DLB had higher scores than patients with AD. ROC analyses revealed that patients with DLB could be distinguished from those with AD with a sensitivity of 72% and a specificity of 85% at a GTE cut-off of 9.5. The association between GTE and DLB was independent of age, gender, Mini Mental State Examination and medication use. Frontal intermittent rhythmic delta activity (FIRDA) was found in 2.9% of the patients with AD and in 33.3% of the patients with DLB. The GTE is a simple EEG scoring method that can be helpful in the differential diagnosis between DLB and AD with good sensitivity and specificity.

[Progressive ataxia and cognitive deficits caused by premutation in the fragile-X-mental retardation gene]. / Progressieve ataxie en cognitieve achteruitgang door een premutatie in het fragiele-X-mentale-retardatiegen.

A 75-year-old man had progressive difficulty with walking, intention tremor, ataxia, and mild cognitive deficits. MRI scan ofthe brain showed symmetrical hyperintensities in the middle cerebellar peduncles. DNA analysis ofthe fragile-X gene revealed an expansion of 150-200 repetitions in the FMR1-gene, compatible with a premutation in the fragile-X gene. Two years later, after progression of the symptoms, the patient was admitted to a nursing home. The clinical picture of intention tremor, parkinsonism and ataxia with white matter lesions and atrophy on MRI occurs in carriers of this premutation and has recently been described as the fragile-X-associated tremor/ataxia syndrome. Recognition of this clinical picture is important for the patient but also for the relatives, since female carriers of the premutation have an increased risk of offspring with the fragile-X syndrome.

Clinical and Imaging Follow-Up of Patients with Coiled Basilar Tip Aneurysms Up to 20 Years.

BACKGROUND AND PURPOSE: Long-term follow-up data of coiled basilar tip aneurysms are scarce, and little is known about the risk of late aneurysm-related adverse events. We followed a cohort of 154 patients with basilar tip aneurysms coiled between 1995 and 2006. MATERIALS AND METHODS: Imaging and clinical data were retrospectively reviewed. The incidence and timing of retreatment, rebleeds, and progressive mass effect by continuous aneurysm growth were recorded. Risk factors for retreatment were assessed. RESULTS: Clinical follow-up of 144 of 154 patients who survived the admission period was a mean of 9.8 years (median, 10.2; range, 0.3-20.1 years). During this period, 37 basilar tip aneurysms (26%) were additionally coiled (annual incidence rate, 2.6%; 95% CI, 1.8%-3.6%). Aneurysm size of >15 mm was the most important independent predictor for retreatment (OR, 8.7; 95% CI, 3.4-22.5). The first additional coiling was performed in the first year of follow-up in 17 of 37 patients (46%) and in 20 patients (54%) at a later time up to 17.2 years. Nine rebleeds occurred in 9 of 106 patients who initially presented with SAH after a median follow-up of 8.3 years (range, 0.3-16.6 years). The annual incidence rate was 0.7% (95% CI, 0.4%-1.5%). Eight patients died of aneurysm-related adverse events: 3 of rebleed and 5 of progressive mass effect. CONCLUSIONS: Retreatment of coiled basilar tip aneurysms was frequently needed during follow-up, also at long intervals. Most late mortality was from progressive mass effect, not from rebleeds. Life-long MRA follow-up at yearly intervals is recommended.

The alpha2-macroglobulin gene in AD: a population-based study and meta-analysis.

BACKGROUND: Whereas several authors recently reported a positive association between the alpha2-macroglobulin gene (A2M) and late-onset AD (LOAD), others were unable to replicate these findings. Early-onset AD (EOAD) is defined as onset age <65 years. Virtually all patients with LOAD are >65 years of age. OBJECTIVE: To evaluate the role of A2M in AD, the authors conducted a population-based study of EOAD and LOAD as well as a meta-analysis of all studies conducted to date. METHODS: Patients with EOAD (n = 100) were derived from a population-based study in four northern provinces of the Netherlands and the area of metropolitan Rotterdam. Patients with LOAD (n = 344) were drawn from the Rotterdam Study, a population-based prospective study on residents aged 55 years and over of a Rotterdam suburb in the Netherlands. Two polymorphisms were studied, A2M-I/D and A2M-Ile1000Val, in relation to the APOE epsilon4 allele (APOE*4). RESULTS: No genotypic or allelic association was found for either polymorphism in the population-based series of patients with LOAD. In patients with EOAD without APOE*4, a significant increase of carriers of A2M-1000Val was found. The meta-analysis of available published case-control data on these polymorphisms in white and mixed ethnic populations yielded no significant differences between cases and controls. Pooling the Asian studies conducted to date showed a significant decrease in the frequency of A2M-D among patients. CONCLUSIONS: These results suggest that A2M is not genetically associated with LOAD in white patients or mixed populations as found in the United States. In these populations A2M does not have clinical relevance. From a scientific perspective, the findings on EOAD and Asian patients require replication and further research in the A2M region.

Effect of the APOE-491A/T promoter polymorphism on apolipoprotein E levels and risk of Alzheimer disease: The Rotterdam Study.

The apolipoprotein E (APOE) gene is involved in lipid transport. A common polymorphism in this gene with the APOE*2, APOE*3, and APOE*4 alleles influences plasma levels of apolipoprotein E and cholesterol. Besides its role in lipid transport, the APOE*4 allele is a genetic risk factor for Alzheimer disease (AD). Recently, a polymorphism in the APOE promoter region was found to be involved in plasma apolipoprotein E levels and was found associated with AD. We studied the effect of this -491A/T promoter polymorphism on plasma apolipoprotein E levels and risk for AD in a population-based case-control study. We found that there was a modest but statistically significant effect of the -491A/T polymorphism on plasma apolipoprotein E levels independent of the APOE genotype. The lowest plasma levels were measured for the AA genotype, highest levels for the TT genotype, and intermediate levels for the heterozygotes. There was a small effect of the -491 AA genotype on AD risk that disappeared after adjusting for APOE genotypes. Our data suggest that the -491A/T polymorphism has an APOE genotype-independent effect on plasma apolipoprotein E levels but no APOE-independent effect on AD risk.

Complex compulsive behaviour in the temporal variant of frontotemporal dementia.

OBJECTIVE: As metabolic and structural changes in frontotemporal-subcortical pathways have been reported in patients with obsessive-compulsive disorders, we investigated the correlation between complex compulsive behaviour (CCB) and the distribution of atrophy in a group of 90 patients with frontotemporal dementia (FTD). METHODS: CCB was defined as complex, intentional, and time consuming repetitive behaviour, which was distinguished from simple compulsive behaviour (SCB), such as verbal and motor repetitions and utilisation behaviour. Cortical atrophy on CT and/or MRI was semi-quantitatively assessed in frontal, temporal, parietal and occipital regions, and the pattern of atrophy was compared between patients with and without CCB or SCB. Linear measures were used to establish the presence of caudate atrophy (bicaudate ratio) and ventricular enlargement (bifrontal ratio). RESULTS: CCB was reported in 18 (21%) and SCB in 53 (61%) FTD patients. Frontotemporal atrophy was present in 64 patients (74%), and predominant temporal atrophy in 23 (26%). The pattern of atrophy was asymmetric in 25 patients (29%). Logistic regression analysis showed that temporal lobe atrophy (p < 0.005), as well as asymmetry of atrophy (p < 0.05) were independently associated with CCB, after adjusting for age at onset, gender, duration of symptoms at the time of imaging, severity of atrophy, and bicaudate and bifrontal ratio. No relationship was found between the presence of SCB and the distribution of atrophy, although patients with SCB tended to have more caudate atrophy (p < 0.1). CONCLUSION: Temporal lobe atrophy appears to mediate CCB in patients with FTD, especially if asymmetry of atrophy is present. Future studies with quantitative and volumetric measurements of the cortical and subcortical structures may further clarify the aetiology of CCB in FTD.

Variable expression of presenilin 1 is not a major determinant of risk for late-onset Alzheimer's disease.

We have previously reported a significant association between early-onset Alzheimer's disease (EOAD) and an allele in the promoter of presenilin 1 (PSEN1) significantly decreasing PSEN1 expression in vitro. For late-onset Alzheimer's disease (LOAD), numerous studies have reported inconsistent associations with a PSEN1 intronic polymorphism. We therefore hypothesized that linkage disequilibrium between the intronic PSEN1 polymorphism and the functional promoter polymorphism might explain the conflicting reports in LOAD. We analysed both variations in 356 LOAD patients and 230 controls in a population-based case-control study. In addition, we re-analysed all published literature on the PSEN1 intronic polymorphism in a meta-analysis. No significant association was found with the PSEN1 intronic or promoter polymorphism in our case-control sample. In the meta-analysis no major differences between patients and controls were found for the PSEN1 intronic variation. Together, our results do not support a major role for variable expression of PSEN1 in LOAD.

The -491 A/T polymorphism in the regulatory region of the apolipoprotein E gene and early-onset Alzheimer's disease.

The -491 polymorphism in the promoter region of the apolipoprotein E gene (APOE) has been suggested to be associated with increased risk for Alzheimer's disease (AD) independent of APOE status. We studied the association between the -491 polymorphism and risk for early-onset Alzheimer's disease in 99 Dutch and 78 Spanish patients. In patients with early-onset AD, we found no consistent relationship with a single allele of the -491 polymorphism. Linkage disequilibrium between the polymorphism and the APOE gene was found which most likely might explain the inconsistent findings.

Amyloid beta secretase gene (BACE) is neither mutated in nor associated with early-onset Alzheimer's disease.

The beta-site of beta-amyloid precursor protein cleaving enzyme (BACE) cleaves the beta-amyloid (Abeta) precursor protein at the N-terminal end of Abeta, allowing for the production of Abeta by C-terminal gamma-secretase cleavage. We hypothesized that over-activity of BACE might lead to the overproduction of Abeta, hence causing Alzheimer's disease (AD). Molecular genetic analyses of BACE in 9 autosomal dominant AD families and a population-based sample of 101 presenile AD cases did not identify genetic linkage, pathogenic mutations or genetic association with BACE, suggesting that BACE is not genetically involved in the etiology of AD.

The microtubule associated protein Tau gene and Alzheimer's disease--an association study and meta-analysis.

Several studies have suggested an association between polymorphisms and an extended haplotype of the microtubule associated protein tau gene and Alzheimer's disease (AD) in synergy with apolipoprotein E (APOE) epsilon 4 status. However these findings have not been consistently replicated. We investigated the role of the tau haplotype in AD by conducting an association study as well as a meta-analysis of all the studies conducted to date. We examined six polymorphisms known to be in the extended tau haplotypes, one in exon 7 and five in and around exon 9 in 200 late onset AD and 189 control samples. All the polymorphisms examined fell into the recognised tau haplotypes. There was no statistical significant association with any of the polymorphisms and late onset AD. Stratification of data by APOE epsilon 4 status also produced no strongly significant association. The meta-analysis showed no significant differences between AD cases and controls, however stratification of data by APOE epsilon 4 status showed a small significant decrease in the H1 haplotype in AD before correction for multiple testing.

Mutation screening of the tau gene in patients with early-onset Alzheimer's disease.

Hyperphosphorylated microtubule associated protein tau, present in neurofibrillary tangles, is a prominent pathological feature of Alzheimer's disease (AD). The gene encoding tau (MAPT) was recently found mutated in frontotemporal dementia (FTD) and other tauopathies. We studied MAPT as a candidate gene in the etiology of AD. The study population consisted of 101 early-onset AD patients and 117 controls. Mutation analysis did not detect causal mutations in exons 9 to 13 encoding the microtubule-binding domains involved in FTD, however, two novel polymorphisms were detected in exon 9. Using the Ala169 polymorphism in exon 9 and a previously reported (CA)n-repeat polymorphism in intron 9, an association study was performed. No association with early-onset AD was detected. Together, our data indicate that MAPT does not play a role in early-onset AD.

Genetic and environmental factors in Alzheimer's disease.

In recent years, considerable progress has been made in unraveling the etiology of Alzheimer's disease (AD). Dominant mutations have been identified, in the beta-amyloid precursor protein gene (APP), and in two homologous genes presenilin 1 (PSEN-1) and presenilin 2 (PSEN-2). The contribution of these mutations to the occurrence of AD in the general population is estimated to be lower than 1p. 100. A genetic risk factor of more importance on the population level is the Apolipoprotein E (APOE) gene that may explain up to 17p. 100 of the prevalence of AD in the general population. It is clear that other yet unknown genes must be involved in the etiology of AD. Two loci on chromosome 12 have been suggested, but no consistent effect could be found. Important progress with regard to non-genetic risk factors concerns the role of vascular and endocrine factors in the pathogenesis. Of major interest for the prevention of AD will be the interaction of genetic and non-genetic risk factors. Large scale, long term follow-up studies, ongoing at present, may clarify this issue.

Delirium in the acute phase after stroke: incidence, risk factors, and outcome.

OBJECTIVES: This prospective cohort study assesses incidence of delirium after stroke. In addition, risk factors during the first week were assessed. Finally, outcome in relation to development of delirium was studied. METHODS: A total of 527 consecutive patients with stroke (median age, 72 years; range, 29-96 years) were screened for delirium during the first week after admission. We diagnosed delirium with the Confusion Assessment Method. Cognitive functioning prior to the stroke was assessed with the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Neurologic deficits were assessed with the NIH Stroke Scale. RESULTS: A total of 62 patients with stroke (11.8%) developed delirium during the first week of admission. Independent risk factors were preexisting cognitive decline (odds ratio [OR] for IQCODE above 50: 2.6, 95% confidence interval [CI] 1.2-5.7) and infection (OR 3.4, 95% CI 1.7-6.8). Furthermore, right-sided hemispheric stroke (OR 2.0, 95% CI 1.0-3.0), anterior circulation large-vessel stroke (OR 3.4, 95% CI 1.1-10.2), the highest tertile of the NIH Stroke Scale (OR for highest vs lowest tertile 15.1, 95% CI 3.3-69.0), and brain atrophy (OR for highest versus lowest tertile 2.7, 95% CI 1.1-6.8) increased the risk for delirium. Delirium was associated with a worse outcome in terms of duration of hospitalization, mortality, and functional outcome. CONCLUSIONS: Delirium occurs in almost 1 out of every 8 patients with stroke on a stroke unit and is associated with cognitive decline, infection, right-sided hemispheric stroke, anterior circulation large-vessel stroke, stroke severity, and brain atrophy. Delirium after stroke is associated with a worse outcome.

Delirium in acute stroke: a review.

BACKGROUND: Delirium is a complex neuropsychiatric syndrome characterized by disturbances of consciousness, attention, cognition, and perception. It may be the presenting feature of acute stroke, but more often it complicates the clinical course in the early stage of rehabilitation. SUMMARY OF REVIEW: Risk factors for delirium are older age, pre-existing cognitive decline, metabolic disturbances, infections, and polypharmacy. Recognition of delirium in patients with stroke is important because of its association with a longer stay in the hospital, a poor functional outcome, and an increased risk of developing dementia. The diagnosis may be difficult because of the fluctuating course and the neurological deficits that are caused by the stroke. Nonpharmacological preventive measures, early identification, and additional medical intervention are the key measures in the management of delirium after stroke. CONCLUSION: This review describes incidence, risk factors, pathophysiology, diagnostic tools, and management of delirium in patients with a recent stroke.

Creutzfeldt-Jakob disease 38 years after diagnostic use of human growth hormone.

A 47 year old man is described who developed pathology proven Creutzfeldt-Jakob disease (CJD) 38 years after receiving a low dose of human derived growth hormone (hGH) as part of a diagnostic procedure. The patient presented with a cerebellar syndrome, which is compatible with iatrogenic CJD. This is the longest incubation period described so far for iatrogenic CJD. Furthermore, this is the first report of CJD after diagnostic use of hGH. Since the patient was one of the first in the world to receive hGH, other cases of iatrogenic CJD can be expected in the coming years.