Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis

Background

To assess whether the premorbid dietary intake of fatty acids, cholesterol, glutamate or antioxidants was associated with the risk of developing amyotrophic lateral sclerosis (ALS).

Methods

Patients referred to our clinic during 2001–2002, who had definite, probable or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in a case–control study (132 patients and 220 healthy controls). A food‐frequency questionnaire was used to assess dietary intake for the nutrients of interest. Multivariate logistic regression analysis was performed with adjustment for confounding factors (sex, age, level of education, energy intake, body mass index and smoking).

Results

A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). The intake of flavonols, lycopene, vitamin C, vitamin B₂, glutamate, calcium or phytoestrogens was not associated with the risk of developing ALS.

Conclusion

A high intake of PUFAs and vitamin E is associated with a 50–60% decreased risk of developing ALS, and these nutrients appear to act synergistically.Sporadic amyotrophic lateral sclerosis (ALS) probably develops through the combined effects of several modifying genes and environmental factors.¹ Despite several studies that investigated environmental exposures in relation to ALS, age, gender and smoking are the only established risk factors.² Several, not mutually exclusive, pathological processes may contribute to motor neurone death in ALS in a so‐called convergence model,³ including oxidative stress, mitochondrial dysfunction, protein misfolding, axonal strangulation, apoptosis, inflammation, glutamate excitotoxicity and defects in neurotrophin biology. Nutrients are factors that could influence these processes and thereby the risk of developing ALS or its clinical expression.ALS was previously found to be positively associated with intake of glutamate,⁴ fat,⁴ fish⁵ and milk,^6,7 and inversely associated with intake of lycopene,⁸ dietary fibre,⁴ bread and pasta.⁹ Two other studies, however, failed to establish the relationship with milk.^10,11 Several of these studies included only small samples of patients (<25),^5,6,9 or investigated nutrition as one of many environmental factors, thus increasing the likelihood of chance findings.^{5,6,7,9,10,11} Furthermore, most studies did not account for the possible influence of clinical onset preceding the diagnosis^{5,6,7,8,9,10,11} or adjust for possible confounders including total energy intake, body mass index (BMI), sex, smoking and education.^{5,6,7,9,10,11}One study found an association between intake of total fat and ALS, although this was not hypothesised beforehand.⁴ This finding is of interest considering the observed associations of intake of saturated and unsaturated fatty acids and cholesterol with other neurodegenerative diseases.¹² In this case–control study, therefore, we examined the possible association between premorbid dietary intake of fatty acids, cholesterol, glutamate, phytoestrogens, calcium and anti‐oxidants and the risk of developing ALS, adjusting for confounding factors.     

Hippocampal activation in patients with mild cognitive impairment is necessary for successful memory encoding

Background

Episodic memory enables us to consciously recollect personally experienced past events. Memory performance is reduced in patients with mild cognitive impairment (MCI), an at‐risk condition for Alzheimer''s disease (AD).

Patients and methods

We used functional MRI (fMRI) to compare brain activity during memory encoding in 29 healthy elderly subjects (mean age 67.7 (SD 5.4) years) and 21 patients with MCI (mean age 69.7 (SD 7.0) years). Subjects remembered a list of words while fMRI data were acquired. Later, they had to recognise these words among a list of distractor words. The use of an event related paradigm made it possible to selectively analyse successfully encoded items in each individual. We compared activation for successfully encoded words between healthy elderly subjects and patients with MCI.

Results

The main intergroup difference was found in the left hippocampus and surrounding medial temporal lobe (MTL) regions for the patients with MCI compared with healthy subjects during successful encoding.

Conclusion

These results suggest that in patients with MCI, an increase in MTL activation is necessary for successful memory encoding. Hippocampal activation may help to link newly learned information to items already stored in memory. Increased activation in MTL regions in MCI may reflect a compensatory response to the beginning of AD pathology.Episodic memory, which enables humans to consciously recollect personally experienced past events, is based on at least two fundamental mnemonic operations: memory formation and retrieval. Event related functional MRI (fMRI) provides a unique opportunity to study the neural correlates of these processes and their subcomponents, such as successful and failed encoding.¹Studies in young healthy subjects have shown that successful declarative memory formation, measured as the difference in brain activity during encoding between subsequently remembered and forgotten items, is accompanied by increases in activity in medial temporal and inferior prefrontal areas.^{2,3,4,5,6,7,8,9,10} Structures within the medial temporal lobe (MTL) region, especially hippocampal formation,^7,11 are believed to be essential in establishing new memories.Patients with mild cognitive impairment (MCI)¹² are characterised by significant memory impairment, which is not severe enough to interfere with usual activities of daily living.¹³ The majority of patients with MCI go on to develop Alzheimer''s disease (AD).Patients with AD, in comparison with older controls, show consistently decreased MTL activation during encoding of new materials.^14,15,16,17 Fewer fMRI studies have investigated MTL encoding activation in patients with MCI,^15,16,18 showing inconsistent results. A recent fMRI study showed decreased MTL activation during a memory encoding task.¹⁵ However, another study¹⁶ found that only a subgroup of subjects with “isolated memory decline” demonstrated decreased hippocampal activation during encoding, whereas still another study¹⁹ reported increased MTL activation in cognitively intact individuals genetically at risk for AD. The variability in these fMRI results may be because the groups differed in the degree of impairment and underlying neural pathology.The degree of activation detected by fMRI within MTL regions during encoding strongly correlates with subjects'' subsequent ability to remember the items encoded.^2,8 Decreased MTL activation in patients with MCI and AD has been associated with relatively poor performance on post scan memory testing.^14,15,17 In contrast, subjects who were genetically at risk for AD, but could successfully perform the fMRI encoding task, showed increased MTL activation. It has been hypothesised that increased MTL activation during successful encoding may represent a compensatory response that allows for relatively normal memory function in the face of developing pathological change¹⁹ There is first evidence that elderly subjects with MCI and with a relatively preserved performance in the fMRI memory task show such a compensatory increased hippocampal response in comparison with healthy subjects, while patients with AD who exhibited poorer performance in the task had lower hippocampal activation.²⁰To further examine this question, it is not sufficient to compare general encoding related activation between patients with MCI and healthy subjects as this comparison would be confounded by task performance. Therefore, we used an event related fMRI paradigm, where subjects are instructed to remember visually presented words. According to task performance in subsequent recognition memory tests, all learned items can then be separated into those that are later remembered (subsequent hits) and those that are later forgotten (subsequent misses), individually for each subject. By comparing brain activation between healthy subjects and patients with MCI only for subsequent hits, brain regions can be identified that differ between groups during successful encoding into episodic memory. It has been shown previously that the degree of neural activity increases with the demands of the cognitive task and that the magnitude and spatial extent of brain activation increases with cognitive effort.^21,22,23 We hypothesise that successful memory encoding, which should be more demanding for patients with MCI than for healthy elderly subjects, would result in increased MTL activation in patients with MCI.     

Diffusion anisotropy of the cervical cord is strictly associated with disability in amyotrophic lateral sclerosis

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with severe cervical cord damage due to degeneration of the corticospinal tracts and loss of lower motor neurones. Diffusion tensor magnetic resonance imaging (DT MRI) allows the measurement of quantities reflecting the size (such as mean diffusivity) and orientation (such as fractional anisotropy) of water‐filled spaces in biological tissues.

Methods

Mean diffusivity and fractional anisotropy histograms from the cervical cord of patients with ALS were obtained to: (1) quantify the extent of tissue damage in this critical central nervous system region; and (2) investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts. Cervical cord and brain DT MRI scans were obtained from 28 patients with ALS and 20 age‐matched and sex‐matched controls. Cord mean diffusivity and fractional anisotropy histograms were produced and the cord cross‐sectional area was measured. Average mean diffusivity and fractional anisotropy along the brain portion of the corticospinal tracts were also measured.

Results

Compared with controls, patients with ALS had significantly lower mean fractional anisotropy (p = 0.002) and cord cross‐sectional area (p<0.001). Mean diffusivity histogram‐derived metrics did not differ between the two groups. A strong correlation was found between mean cord fractional anisotropy and the ALS Functional Rating Score (r = 0.74, p<0.001). Mean cord and brain fractional anisotropy values correlated moderately (r = 0.37, p = 0.05).

Conclusions

Cervical cord DT MRI in patients with ALS allows the extent of cord damage to be graded. The conventional and DT MRI changes found are compatible with the presence of neuroaxonal loss and reactive gliosis, with a heterogeneous distribution of the pathological process between the brain and the cord. The correlation found between cord fractional anisotropy and disability suggests that DT MRI may be a useful adjunctive tool to monitor the evolution of ALS.Amyotrophic lateral sclerosis (ALS) is the most common adult‐onset motor neurone disease, characterised by a progressive and simultaneous degeneration of upper and lower motor neurones.^1,2 In its typical form, the disease begins either in one limb or with a combination of bulbar and corticobulbar symptoms, and continues with progressive weakness of the bulbar, limb, thoracic and abdominal musculature.^1,2 By using a variety of conventional magnetic resonance imaging (MRI) sequences, several studies^{3,4,5,6,7,8,9,10,11,12,13,14,15} have shown changes in signal intensity along the brain portion of the corticospinal tracts, particularly in the posterior limb of the internal capsule and cerebral peduncles, varying between 25% and 80%. Reduced magnetisation transfer ratios in the internal capsule^8,11 and N‐acetylaspartate levels in the motor cortex^13,16,17 of patients with ALS have also been observed. However, none of these studies has reported a correlation between such magnetic resonance abnormalities and the degree of disability.^{8,11,13,16,17}Diffusion‐tensor magnetic resonance imaging (DT MRI) enables the random diffusional motion of water molecules to be measured and thus provides quantitative indices of the structural and orientational features of the central nervous system (CNS).¹⁸ DT MRI has been used to assess quantitatively the tissue damage of the brain portion of the corticospinal tracts in ALS,^{12,19,20,21,22,23} and all studies have shown increased mean diffusivity (indicating a loss of structural barriers limiting the motion of water molecules) and decreased fractional anisotropy (indicating a loss of tissue organisation). However, brain DT MRI studies also resulted in heterogeneous clinicopathological correlations, as some authors found a moderate correlation between brain DT MRI metrics and the severity of disability,^12,21,23 but others did not.¹⁹ In the past few years, DT MRI has also been used successfully to grade the extent of cervical cord damage associated with demyelinating conditions.^24,25,26Considering that the cervical cord in ALS is one of the most affected portions of the CNS (owing to the combined presence of neuronal loss in the anterior horns of the grey matter and degeneration of the corticospinal tracts), we obtained mean diffusivity and fractional anisotropy histograms of the cervical cord from patients with ALS with the following aims: (1) to quantify the extent of tissue damage in this critical CNS region; and (2) to investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts.     

Apolipoprotein E epsilon4 and impaired episodic memory in community-dwelling elderly people: a marked sex difference. The Hordaland Health Study

Background

Among elderly people without dementia, the apolipoprotein E ε4 allele (APOE4) has been associated with cognitive deficit, particularly in episodic memory, but few reports are available on whether this association differs by sex.

Methods

In a community‐dwelling Norwegian cohort of 2181 elderly people (55% women), aged 70–74 years, episodic memory was examined in relation to sex and APOE4 zygosity, with the Kendrick Object Learning Test (KOLT).

Results

Possession of at least one APOE4 allele had a modest, detrimental effect on episodic memory in women, whereas in men, heterozygotes were unaffected and homozygotes had markedly lower scores across the distribution of KOLT scores. This sex difference was found consistently in all analyses: on comparing means and medians, examining trends across quintiles, and studying the distribution of scores and the risk of cognitive impairment. Results were broadly similar when adjusted for known determinants of cognition and also when severely impaired participants were excluded. The adjusted odds ratio (OR) of cognitive impairment in women was shown to be 1.8 (95% confidence interval (CI): 1.1 to 2.8) for heterozygotes and 1.1 (0.3 to 3.7) for homozygotes; the adjusted OR in men was observed to be 1.1 (0.6 to 2.1) for heterozygotes and 10.7 (4.7 to 24) for homozygotes.

Conclusions

Although the harmful effect of APOE4 on episodic memory was modest in women, the risk was found to occur in about 30%. APOE4 was observed to have a dramatic effect on episodic memory in men, but only in homozygotes, who comprised about 3% of men: the whole male homozygous group showed a marked shift to lower memory scores.Age and the apolipoprotein E ε4 allele (APOE4) are the most important known risk factors for sporadic Alzheimer''s disease. The disease is thought to have a long presymptomatic phase,¹ which suggests that APOE4 starts exerting its detrimental effects in the preclinical phase. Most studies on elderly people without dementia have found that the APOE4 allele is associated with various cognitive deficits,^{2,3,4,5,6,7,8,9,10,11,12,13,14} particularly in memory.^2,3,4,5,6,7 A recent meta‐analysis of more than 20 000 people concluded that this allele was associated with poorer performance on tests of global cognitive functioning, episodic memory and executive functioning.¹⁵The association of APOE4 with Alzheimer''s disease varies with sex.^{16,17,18,19,20} The meta‐analysis by Farrer et al²⁰ found that APOE4 homozygosity affords a high risk of Alzheimer''s disease for both men and women, but that a single copy of the allele confers a greater risk on women than on men. A similar sex difference related to APOE4 has been found in the degree of hippocampal atrophy in a cohort with mild cognitive impairment.²¹ We may therefore expect to find an effect related to sex of the APOE4 allele in cognitive tests in elderly people without dementia. Two studies^3,22 that have reported an influence of sex on this relationship found a stronger effect of APOE4 in women.^3,22In this study, we investigated whether sex influences the relationship between APOE alleles and episodic memory in community‐dwelling elderly people. We selected episodic memory because memory deficit is a hallmark of Alzheimer''s disease. Tests of episodic memory have been found to be particularly effective in identifying people at risk.^23,24 We compared the influence of sex in our cohort with that found on the risk of Alzheimer''s disease. We studied a relatively large group of 2181 people from western Norway.     

The effect of the apolipoprotein E gene polymorphisms and haplotypes on behavioural and psychological symptoms in probable Alzheimer's disease

Background

Patients with Alzheimer''s disease and dementia commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in Alzheimer''s disease has been demonstrated. Several studies have investigated whether the exon 4 ε2/ε3/ε4 haplotype of the apolipoprotein E (APOE) gene is associated with BPSD, with variable results.

Objective

We investigated the exon 4 polymorphisms and extended this study to include promoter polymorphisms and the resultant haplotypes across the gene.

Methods

Our large independent cohort of 388 patients with longitudinal measures of BPSD assessed by the Neuropsychiatric Inventory was used to analyse whether any of these variants were associated with the presence of BPSD.

Results

We revealed several significant relationships before correction for multiple testing. The exon 4 haplotype was associated with hallucinations and anxiety, A‐491T with irritability, T‐427C with agitation/aggression and appetite disturbances, and T‐219C with depression. Haplotype analyses of all variants did not reveal any statistically significant findings.

Conclusions

Our data and a review of previous studies showed a diversity of relationships, suggesting that these findings might be due to chance and so collectively do not support a role for the APOE gene in BPSD.Many patients with dementia display behavioural and psychological symptoms of dementia (BPSD). Unlike cognitive decline, BPSD do not continuously exist in a patient once they have occurred. Genetic determinants of BPSD in Alzheimer''s disease have been proposed from studies on families.^1,2,3 It has been hypothesised that the genes that increase the risk for Alzheimer''s disease may also determine the presence of BPSD.⁴ The ε4 allele of the apolipoprotein E (APOE) gene is the only risk factor robustly associated with Alzheimer''s disease. However, previous investigations on APOE have produced inconsistent findings on BPSD, with some researchers reporting associations with a variety of different symptoms and alleles^{4,5,6,7,8,9,10,11,12,13,14,15,16} (summarised in the table provided online at http://jnnp.bmjjournals.com/supplemental), whereas others find no relevant relationships.^{17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33} We used a large independent clinical cohort of patients with Alzheimer''s disease, with longitudinal data on BPSD to further extend these studies, and additionally investigated promoter polymorphisms of APOE, which have been shown to independently incur risk of Alzheimer''s disease in some studies.³⁴     

Influence of cognitive impairment on the institutionalisation rate 3 years after a stroke

Background and purpose

Pre‐existing cognitive decline and new‐onset dementia are common in patients with stroke, but their influence on institutionalisation rates is unknown.

Objective

To evaluate the influence of cognitive impairment on the institutionalisation rate 3 years after a stroke.

Design

(1) The previous cognitive state of 192 consecutive patients with stroke living at home before the stroke (with the Informant Questionnaire on COgnitive Decline in the Elderly (IQCODE)), (2) new‐onset dementia occurring within 3 years and (3) institutionalisation rates within 3 years in the 165 patients who were discharged alive after the acute stage were prospectively evaluated.

Results

Independent predictors of institutionalisation over a 3‐year period that were available at admission were age (adjusted odds ratio (adjOR) for 1‐year increase  = 1.08; 95% confidence interval (CI) 1.03 to 1.15), severity of the neurological deficit (adjOR for 1‐point increase in Orgogozo score = 0.97; 95% CI 0.96 to 0.99) and severity of cognitive impairment (adjOR for 1‐point increase in IQCODE score = 1.03; 95% CI 1 to 1.06). Factors associated with institutionalisation at 3 years that were present at admission or occurred during the follow‐up were age (adjOR for 1‐year increase = 1.17; 95% CI 1.07 to 1.27) and any (pre‐existing or new) dementia (adjOR = 5.85; 95% CI 1.59 to 21.59), but not the severity of the deficit of the neurological deficit.

Conclusion

Age and cognitive impairment are more important predictors of institutionalisation 3 years after a stroke than the severity of the physical disability.Institutionalisation after a stroke increases with the severity of the neurological deficit, increasing age, female gender, low socioeconomic level, marital status and poor social environment.^1,2,3,4,5,6Dementia is common after a stroke,⁷ leading to autonomy loss.⁸ Pre‐existing dementia is present in up to 16% of patients with stroke,^9,10,11,12 and post‐stroke de mentia (PSD) occurs in up to one third.⁷ Several studies have found a link between cognitive impairment and institutionalisation after a stroke,^1,2,3,4,5 but they had several methodological limitations: (1) cross‐sectional studies were performed in long‐term stroke survivors and did not take into account patients who had been institutionalised but died before the study⁶; (2) there was no systematic cognitive assessment¹³ or only a Mini Mental State Examination,¹⁴ which is not appropriate for patients with stroke; and (3) most studies included only patients recruited in rehabilitation centres, leading to selection bias.^1,2,3,4,5 To our knowledge, no study has prospectively evaluated the influence of pre‐existing cognitive impairment and PSD on the institutionalisation rate after a stroke.The aim of this study was to evaluate the influence of the previous cognitive state and new‐onset dementia on the institutionalisation rate 3 years after a stroke.     

Trunk performance after stroke: an eye catching predictor of functional outcome

Background and aim

Trunk performance is an important predictor of functional outcome after stroke. However, the percentage of explained variance varies considerably between studies. This may be explained by the stroke population examined, the different scales used to assess trunk performance and the time points used to measure outcome. The aim of this multicentre study was to examine the predictive validity of the Trunk Impairment Scale (TIS) and its subscales when predicting the Barthel Index score at 6 months after stroke.

Methods

A total of 102 subjects were recruited in three European rehabilitation centres. Participants were assessed on admission (median time since stroke onset 20 days) and 6 months after stroke. Correlation analysis and forward stepwise multiple regression analysis were used to model outcome.

Results

The best predictors of the Barthel Index scores at 6 months after stroke were total TIS score (partial R² = 0.52, p<.0001) and static sitting balance subscale score (partial R² = 0.50, p<.0001) on admission. The TIS score on admission and its static sitting balance subscale were stronger predictors of the Barthel Index score at 6 months than the Barthel Index score itself on admission.

Conclusions

This study emphasises the importance of trunk performance, especially static sitting balance, when predicting functional outcome after stroke. The TIS is recommended as a prediction instrument in the rehabilitation setting when considering the prognosis of stroke patients. Future studies should address the evolution of trunk performance over time and the evaluation of treatment interventions to improve trunk performance.Although the age specific incidence of major stroke has fallen over the past few years,¹ it is still the main cause of long term disability in adults, with a growing number of survivors being dependent for activities of daily living (ADL).^2,3 Frequently identified variables predicting ADL after stroke are age and initial severity of motor and functional deficits.⁴ Trunk performance has also been identified as an important independent predictor of ADL after stroke.^5,6,7,8,9 However, based on multiple regression analyses, the reported variance of functional outcome after stroke explained by trunk performance ranges from 9% to 71%.^5,6,7,8,9 Differences in reported variance could be explained by the stroke population included, the various scales used to measure trunk performance and the time points used to measure outcome.Previous studies evaluating the predictive validity of trunk performance after stroke were performed in a single rehabilitation setting, warranting caution when generalising results.^5,6,7,8,9,10 Clinical tools used to assess trunk performance are the Trunk Control Test,^5,6,10 trunk control items of the Postural Assessment Scale for Stroke patients^7,8 and trunk assessment of Fujiwara et al.⁹ A limitation of the first two tests is that they both have a ceiling effect, which makes their use less suitable in long term outcome studies.^5,11,12,13 Furthermore, the trunk control items of the Trunk Control Test and Postural Assessment Scale for Stroke patients are largely comparable with the items of the trunk measure of Fujiwara et al.⁹ All previously mentioned clinical tools include items in the supine position which involve rolling as well as only basic balance movements in sitting. Finally, with the exception of the trunk control items of the Postural Assessment Scale for Stroke patients,⁸ no study has evaluated the prognostic value of trunk performance when predicting functional outcome at 6 months after stroke.The Trunk Impairment Scale (TIS) for patients after stroke was designed to measure ADL related selective trunk movements rather than participation of the trunk in gross transfer movements.¹⁴ The TIS assesses static and dynamic sitting balance and trunk coordination. Reliability, validity, measurement error, internal consistency and discriminant ability of the TIS have been reported elsewhere.^14,15 The TIS has no ceiling effect in subacute and chronic stroke patients and already appeared to be strongly related to measures of gait, balance and functional ability in a cross sectional study.¹² To the best of our knowledge, the predictive value of the TIS and its subscales has not been evaluated. Including age and other measures of motor and functional performance could provide a useful combination of variables predicting outcome after stroke. The Barthel Index score is a widely accepted measure in stroke rehabilitation research and assesses functional milestones in stroke recovery. Predicting Barthel Index scores at 6 months after stroke based on measurements taken on admission to a rehabilitation centre would further establish the importance of trunk performance when predicting long term outcome after stroke. Experts in the field of neurological rehabilitation have addressed the trunk as the central key point of the body.¹⁶ Proximal stability of the trunk is a prerequisite for distal head and limb movement and therefore expected to be related to functional ADL.In summary, there is still a lack of clarity regarding the importance of trunk performance in functional outcome after stroke. Scales which have been used in previous studies have important statistical limitations and are likely to be a comprehensive measure of motor performance of the trunk. Therefore, the aim of this multicentre study was to examine the predictive validity of the TIS and its subcomponents, together with other known predictors, in predicting functional outcome measured as a Barthel Index score at 6 months after stroke.     

Profile of cognitive impairment in dementia associated with Parkinson's disease compared with Alzheimer's disease

Objective

To compare the profile of cognitive impairment in Alzheimer''s disease (AD) with dementia associated with Parkinson''s disease (PDD).

Methods

Neuropsychological assessment was performed in 488 patients with PDD and 488 patients with AD using the Mini‐Mental State Examination (MMSE) and the Alzheimer''s Disease Assessment Scale‐cognitive subscale (ADAS‐cog). Logistic regression analysis was used to investigate whether the diagnosis could be accurately predicted from the cognitive profile. Additionally, the cognitive profiles were compared with a normative group using standardised effect sizes (Cohen''s d).

Results

Diagnosis was predicted from the cognitive profile, with an overall accuracy of 74.7%. Poor performance of the AD patients on the orientation test in ADAS‐cog best discriminated between the groups, followed by poor performance of the PDD patients on the attentional task in MMSE. Both groups showed memory impairment, AD patients performing worse than PDD patients.

Conclusion

The cognitive profile in PDD differs significantly from that in AD. Performance on tests of orientation and attention are best in differentiating the groups.Alzheimer''s disease (AD) and Parkinson''s disease (PD) are the most common neurodegenerative diseases in the elderly. AD is primarily a dementing disease whereas PD is mainly characterised by a movement disorder. However, dementia is common among patients with PD (PDD), with an average point prevalence of 31%¹ and a cumulative prevalence close to 80%.² In PD, dementia is associated with rapid motor³ and functional decline,⁴ and increased mortality.⁵Cortical Lewy body pathology correlates best with dementia in PD^6,7,8,9; subcortical pathology¹⁰ and AD‐type pathology¹¹ have also been found to be associated with PDD. In addition to differences in morphological changes, AD and PDD also differ in the regional pattern of the pathology. In AD the first and most pronounced changes are found in the entorhinal cortex and parahippocampal region,¹² subsequently involving neocortical areas, including the posterior association cortices.¹³ In contrast, in patients with PD without dementia, brainstem nuclei and other subcortical structures are initially affected.¹⁴ In PDD, limbic areas, neocortical association cortices, and the motor cortex and primary sensory cortical areas are thought to be successively involved with disease progression.¹⁵Given the difference in the distribution and progression of pathology in AD and PDD, it is expected that their cognitive profiles would also differ.^16,17 AD is characterised by memory loss emerging in the early stages of the disease,¹⁸ primarily involving learning and encoding deficits¹⁹ which are associated with medial temporal lobe pathology.^20,21,22,23 As the disease progresses, deficits in language, praxis, visuospatial and executive functions gradually develop. In contrast, the cognitive deficits in the early stages of PDD are characterised by executive dysfunction, including impairment in attention²⁴ and working memory,^25,26,27 reflecting involvement of brainstem nuclei and frontal–subcortical circuits; deficits in visuoperceptual^28,29,30 and visuoconstructional tasks are also frequent.³¹ Memory impairment is often present^26,32,33,34 but whether it is primarily a consequence of frontally mediated executive deficits resulting in poor learning efficacy and retrieval, or whether involvement of limbic areas directly related to memory encoding (such as hippocampal atrophy) also contribute to memory impairment, is debated. Patients with PDD have difficulties in retrieving newly learned material, but perform better in recognition,³⁵ indicating that executive, rather than encoding, deficits, is the underlying mechanism. Conflicting results, however, have been reported recently^36,37 which could indicate that the type and mechanisms of memory deficits may vary within the PD group.³²Most studies investigating the cognitive profile of PDD patients included small samples which were not community based and thus not necessarily representative of the PD population at large. As there is evidence of interindividual heterogeneity,³³ such studies may not adequately reflect the cognitive profile of patients with PDD. In order to assess the profile of cognitive deficits in PDD compared with AD in larger patient populations, we analysed the baseline cognitive data from large clinical trials conducted with the cholinesterase inhibitor rivastigmine.^38,39     

Fatigue and activity dependent changes in axonal excitability in amyotrophic lateral sclerosis

Background

While patients with amyotrophic lateral sclerosis (ALS) may complain of fatigue, the underlying mechanisms appear complex, with dysfunction of central and peripheral nervous systems independently reported as contributing factors. The aim of the present study was to further delineate the mechanisms underlying increased fatigability in ALS by measuring activity dependent changes in axonal excitability following a maximum voluntary contraction (MVC).

Methods

Nerve excitability changes were recorded before and after an MVC of the abductor pollicis brevis in 16 patients with ALS and 25 controls.

Results

In patients with ALS, there was a greater increase in threshold (36.5 (5.9)%; controls 19.6 (3.5)%; p<0.05) as a result of MVC, with reduction in the amplitude of the compound muscle action potential generated by a submaximal stimulus (ALS 49 (7.6)%; controls 41.0 (5.4)%). These changes were associated with an increase in superexcitability (ALS 65.1 (25.4)%; controls 42.3 (5.7)%) and reduction in strength–duration time constant (ALS 20 (4.9)%; controls 10 (2.5)%; p<0.01), indicative of axonal hyperpolarisation. The increase in threshold was more pronounced in patients with ALS with predominantly lower motor neuronal involvement.

Conclusions

Higher firing rates of surviving motor axons attempting to compensate for neurogenic weakness are likely to explain the greater activity dependent changes in ALS. As such, the present study suggests a further peripheral factor underlying the development of fatigue in ALS.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects motor neurones in the spinal cord, brainstem and motor cortex.^1,2 The consequences of this neurodegeneration are motor deficits in the limbs, bulbar and respiratory muscles.³ Although the mechanisms of neuronal dysfunction, and ultimately the development of symptoms in ALS, remain unknown, glutamate excitotoxicity,^4,5,6 increased levels of inducible nitric oxide synthase levels⁴ and, in cases of inherited ALS, oxidative stress secondary to mutations in the superoxide dismutase‐1 gene, have been proposed.^7,8,9,10Increased fatigability, defined as an inability to sustain a predictable maximal force during voluntary contraction, is a common symptom of ALS.^11,12,13 The mechanisms underlying fatigue in ALS are complex, and contributions from both the central and peripheral nervous systems have been reported.^11,12 Central fatigue refers to a reduced excitatory drive to motor neurones, secondary to central nervous system dysfunction, resulting in incomplete motor unit recruitment and submaximal motor unit discharge rates. In contrast, peripheral fatigue typically refers to impaired muscle activation, caused by dysfunction at or below the anterior horn cell.^13,14 Perhaps somewhat counterintuitively, fatigue in ALS appears to be independent of muscle strength and disease severity.^15,16 Regardless of the underlying mechanism, fatigue in ALS severely impacts on the patient''s quality of life.^15,16The ability to sustain a motor output may be assessed by measuring changes in axonal membrane threshold following a voluntary contraction. Specifically, in peripheral nerves, voluntary contraction activates the axonal membrane Na⁺/K⁺ pump,¹⁷ which attempts to return the resting membrane potential to baseline after contraction has ceased,^18,19,20,21 resulting in activity dependent hyperpolarisation. The magnitude of activity dependent hyperpolarisation is determined by the impulse load²² and, in neurological diseases where the safety margin for impulse conduction has been reduced as occurs for instance in demyelinating neuropathy, may be sufficient to induce conduction failure.^23,24,25 In an attempt to further delineate the mechanisms underlying fatigability and weakness in ALS, the present study measured activity dependent changes in axonal excitability induced by voluntary contraction.     

Treatment of shoulder pain in spastic hemiplegia by reducing spasticity of the subscapular muscle: a randomised, double blind, placebo controlled study of botulinum toxin A

Objective

This randomised, double blind, placebo controlled, two parallel group study was conducted to assess the beneficial effect of injection of botulinum toxin A (Dysport) into the subscapularis muscle on shoulder pain in stroke patients with spastic hemiplegia.

Methods

A single dose of botulinum toxin A (500 Speywood units) or placebo was injected into the subcapularis muscle. Pain was assessed using a 10 point verbal scale. Subscapularis spasticity was assessed by the change in passive shoulder lateral rotation and abduction. Upper limb spasticity was assessed using the Modified Ashworth Scale for shoulder medial rotators, and elbow, wrist and finger flexors. Assessments were carried out at baseline and at weeks 1, 2 and 4.

Results

Twenty patients (10 patients per group), 11 with ischaemic stroke and 9 with haemorrhagic stroke, completed the study. Pain improvement with botulinum toxin A was observed from week 1; score difference from baseline at week 4 was 4 points versus 1 point with placebo (p = 0.025). Lateral rotation was also improved, with a statistically significant difference compared with placebo at week 2 (p = 0.05) and week 4 (p = 0.018). A general improvement in upper limb spasticity was observed; it was significant for finger flexors at week 4 (p = 0.025).

Conclusions

Subscapularis injection of botulinum toxin A appears to be of value in the management of shoulder pain in spastic hemiplegic patients. The results confirm the role of spasticity in post‐stroke shoulder pain.Pain and spastic shoulder are frequent in hemiplegia following a stroke. Shoulder pain is a major problem for these patients, interfering with physiotherapy, sleep and daily activities. It is usually due to local causes: algoneurodystrophy (shoulder–hand syndrome), capsulitis, gleno‐humeral subluxation and also spasticity because of the prolonged muscular contracture and possible tendinopathies.^1,2,3,4 These causes can be associated, especially spasticity and algoneurodystrophy in severe hemiplegia, and patients exhibit the typical arm posture: adduction and medial rotation of the shoulder, and flexion of the elbow, wrist and finger.Different approaches are used for treatment of pain in such patients, depending on the mechanism involved. Oral medications for pain, as those for spasticity, are usually ineffective or insufficient. Treatment of algoneurodystrophy and capsulitis mainly consists of corticosteroids, systemic treatment being more effective than local administration.^3,5 To treat spasticity or its consequences, transection of the subscapularis tendon^6,7 or subcapularis nerve block^8,9 has been reported, but these treatments are not in common use. Botulinum toxin A has been shown to be effective in reducing spasticity and increasing the passive range of motion of the spastic upper limb in hemiplegic patients^{10,11,12,13,14} with a real functional benefit.¹⁵ The effect of botulinum toxin A on shoulder pain after a stroke has not been systematically studied. However, improvement of pain by the toxin has been reported in a placebo controlled study, although pain was not the main objective of the study.¹⁵ A beneficial effect has also been observed in an open study.¹⁶ Other controlled studies in which upper limb pain was assessed failed to show a significant reduction in pain.^10,11,12No specific treatment of the spastic shoulder muscles has been studied. Suprasupinator and infrasupinator muscles are not involved in painful contracted shoulder,¹⁷ and among the muscles implicated in medial rotation, the subscapularis and pectoralis muscles undoubtedly play a major role,¹⁸ with apparent pre‐eminence of the subscapularis muscle.¹⁹ In a recent study of three cases, injection of botulinum toxin A into the subscapularis muscle was shown to reduce pain and improve the passive range of motion.¹⁸Based on these observations, we formed the hypothesis that shoulder pain occurring in patients with spastic hemiplegia, even with limited range of motion compatible with capsulitis, can be relieved by reducing the spasticity of the main medial rotator muscle (ie, the subscapularis muscle). Therefore, we conducted the present study to further assess the beneficial effect of injection of botulinum toxin A (Dysport) into the subscapularis muscle on shoulder pain. An improvement in the passive range of motion was expected as a parameter of the efficacy of botulinum toxin on spasticity and as a possible secondary benefit.     

A population based study of intracranial arachnoid cysts: clinical and neuroimaging outcomes following surgical cyst decompression in adults

Background

We have gradually adopted a liberal attitude towards surgical decompression of arachnoid cysts. This study describes the results from our institution.

Methods

Long term clinical and neuroimaging results of 156 adult patients (aged ⩾16 years) operated on for arachnoid cysts in our department during the period January 1987 to September 2004 were assessed based on their medical and neuroimaging records, and on a questionnaire.

Results

The clinical and/or neuroimaging results indicated that the cyst was successfully decompressed in all patients. 82% of patients were asymptomatic or had insignificant complaints at follow‐up. 12% reported no symptom relief whereas 6% experienced worsening of symptoms. The cyst disappeared after surgery, or was reduced to <50% of the preoperative volume, in 66% of cases. In another 24%, the postoperative volume was also reduced, but was larger than 50% of the original cyst volume. No reduction in fluid volume was observed in 10% of cases. There was no association between volume reduction and clinical improvement. A complication occurred in 26 patients (17%), all with temporal cysts, leading to reoperation in 11 patients (7.1%). In only two patients did the complication cause a permanent slight disability.

Conclusion

Decompression of arachnoid cysts yields a substantial clinical benefit with a low risk of severe complications.Arachnoid cysts are benign congenital malformations of the arachnoid. They can be located along the craniospinal axis, with a predilection for the temporal fossa.¹ They may present with specific symptoms, such as sensorimotor symptoms corresponding to the location of the cyst, but more often they yield unspecific symptoms (eg, headache or dizziness, or symptoms related to suboptimal cerebral function, such as epilepsy or impaired cognition).^{2,3,4,5,6,7,8,9,10}The treatment of such cysts, particularly in the majority of the patients with moderate and unspecific symptoms, has been controversial.^{11,12,13,14,15} Many authors have expressed a reluctance to operate on these patients unless the symptoms are dramatic. This was also the initial attitude of the senior author. However, based on several observations of our own and those of others, we have gradually changed our view. When we encountered patients that were severely impaired, with symptoms such as headache or dizziness, and who also had radiologically expansive cysts, we found it logical to attempt to alleviate the complaints by surgical cyst decompression. It has been our accumulated experience that surgical decompression yields clinical improvement in most patients with arachnoid cysts. Also, a growing literature indicates that cyst decompression improves the function of neighbouring cerebral tissue, thus supporting the view that patients with unspecific symptoms and “clinically silent” cysts may also profit from surgical cyst decompression.^{4,6,7,8,9,10,16}Treating a benign condition that is not life threatening with surgery, with the aim of improving quality of life, can only be justified when a clear clinical benefit, and no severe complications, can be demonstrated. We therefore wished to describe our experience with a relatively liberal indication for surgical decompression of intracranial arachnoid cysts. We have recently published a similar study on our paediatric cyst patients.¹⁷     

Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study

Background

Carotid body (CB) glomus cells are highly dopaminergic and express the glial cell line derived neurotrophic factor. The intrastriatal grafting of CB cell aggregates exerts neurotrophic actions on nigrostriatal neurons in animal models of Parkinson disease (PD).

Objective

We conducted a phase I–II clinical study to assess the feasibility, long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with PD.

Methods

Thirteen patients with advanced PD underwent bilateral stereotactic implantation of CB cell aggregates into the striatum. They were assessed before surgery and up to 1–3 years after surgery according to CAPIT (Core Assessment Programme for Intracerebral Transplantation) and CAPSIT‐PD (Core Assessment Programme for Surgical Interventional Therapies in Parkinson''s Disease) protocols. The primary outcome measure was the change in video blinded Unified Parkinson''s Disease Rating Scale III score in the off‐medication state. Seven patients had ¹⁸F‐dopa positron emission tomography scans before and 1 year after transplantation.

Results

Clinical amelioration in the primary outcome measure was observed in 10 of 12 blindly analysed patients, which was maximal at 6–12 months after transplantation (5–74%). Overall, mean improvement at 6 months was 23%. In the long term (3 years), 3 of 6 patients still maintained improvement (15–48%). None of the patients developed off‐period dyskinesias. The main predictive factors for motor improvement were the histological integrity of the CB and a milder disease severity. We observed a non‐significant 5% increase in mean putaminal ¹⁸F‐dopa uptake but there was an inverse relationship between clinical amelioration and annual decline in putaminal ¹⁸F‐dopa uptake (r = −0.829; p = 0.042).

Conclusions

CB autotransplantation may induce clinical effects in patients with advanced PD which seem partly related to the biological properties of the implanted glomus cells.Parkinson disease (PD) is a progressive neurodegenerative disorder of unknown aetiology. Its main pathological hallmark is the degeneration of midbrain dopaminergic neurons projecting to the striatum, although other neuronal systems are also affected.¹ Current pharmacological and surgical therapies are symptomatically effective but their long term utility is limited because of disease progression.^2,3 Therefore, there is a need for neuroprotective and/or neurorestorative therapies capable of arresting or reversing the neurodegenerative process.Over the past two decades, cell replacement therapies have been tested in PD patients with the objective of restoring the striatal dopaminergic deficit.⁴ Transplantation of fetal mesencephalic neurons, the most frequently used technique, can increase the striatal dopamine storage, but does not always produce the expected clinical benefit and may induce disabling off‐medication dyskinesias.^5,6 Thus it appears that the ectopic placement of dopamine secreting cells in the striatum is not the ideal approach to compensate for progressive nigrostriatal neuronal loss.⁷ Given this scenario, the clinical applicability of other transplantation procedures based on a similar rationale (eg, intrastriatal grafting of porcine mesencephalic neurons, retinal pigment epithelial cells or stem cell derived dopaminergic neurons) is, for the moment, uncertain.More recently, other strategies aiming to protect or restore the nigrostriatal pathway have emerged. Glial cell line derived neurotrophic factor (GDNF) has been shown to exert neuroprotective and neurorestorative actions in animal models of PD.^8,9,10 The clinical efficacy of GDNF has been assayed in clinical trials, but the method of delivery is a critical issue. Whereas intraventricular administration failed to induce clinical benefit,¹¹ intraputaminal infusion showed promising results,^12,13 although a placebo controlled trial using this route has been halted because of lack of efficacy and safety concerns about recombinant human GDNF administration.¹⁴ Other alternative methods being tested experimentally in parkinsonian animals include in vivo gene therapy using GDNF encoding viral vectors^15,16,17 and the intrastriatal grafting of recombinant GDNF producing cell lines.^18,19,20,21 Carotid body (CB) glomus cells are neural crest derived dopaminergic cells that express high levels of GDNF. Glomus cell GDNF production is resistant to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine administration, and maintained in aged rodents or after intrastriatal grafting.^22,23 The survival rate of these cells after transplantation (>70%) is particularly high as hypoxia stimulates their growth and function. Moreover, CB grafts performed in young rats remain active for the entire animal lifespan.^22,23 Transplantation of CB cell aggregates has been shown to induce a neurotrophic mediated recovery in animal models of PD^{22,23,24,25,26,27} and stroke.^28,29We conducted a phase I–II video blinded clinical study to assess the long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with advanced PD. In a pilot report of our first six patients, we showed this procedure to be feasible.³⁰ Here we report the clinical outcomes and prognostic factors in the whole study (n = 13), as well as ¹⁸F‐dopa positron emission tomography (PET) outcomes in a subgroup of patients (n = 7).     

Cognitive outcome in adults after bacterial meningitis

Objective

To evaluate cognitive outcome in adult survivors of bacterial meningitis.

Methods

Data from three prospective multicentre studies were pooled and reanalysed, involving 155 adults surviving bacterial meningitis (79 after pneumococcal and 76 after meningococcal meningitis) and 72 healthy controls.

Results

Cognitive impairment was found in 32% of patients and this proportion was similar for survivors of pneumococcal and meningococcal meningitis. Survivors of pneumococcal meningitis performed worse on memory tasks (p<0.001) and tended to be cognitively slower than survivors of meningococcal meningitis (p = 0.08). We found a diffuse pattern of cognitive impairment in which cognitive speed played the most important role. Cognitive performance was not related to time since meningitis; however, there was a positive association between time since meningitis and self‐reported physical impairment (p<0.01). The frequency of cognitive impairment and the numbers of abnormal test results for patients with and without adjunctive dexamethasone were similar.

Conclusions

Adult survivors of bacterial meningitis are at risk of cognitive impairment, which consists mainly of cognitive slowness. The loss of cognitive speed is stable over time after bacterial meningitis; however, there is a significant improvement in subjective physical impairment in the years after bacterial meningitis. The use of dexamethasone was not associated with cognitive impairment.The estimated annual incidence of bacterial meningitis is 4–6 per 100 000 adults and Streptococcus pneumoniae (pneumococcus) and Neisseria meningitidis (meningococcus) are the causative bacteria in 80% of cases.^1,2 Fatality rates in patients with pneumococcal meningitis (26%) and meningococcal meningitis (7%) are significant.^1,2,3 Even in patients with apparent good recovery, cognitive impairment occurs frequently,⁴ especially after pneumococcal meningitis.^4,5,6 The cognitive functions affected by bacterial meningitis differ between studies, most likely because of the limited numbers of patients examined, and the lack of uniformity across studies in assessment methods and in the definition of cognitive impairment.^{4,5,6,7,8,9,10} We therefore pooled data on cognitive outcome after bacterial meningitis from three of our previous studies to more clearly determine which cognitive functions are affected by bacterial meningitis and to identify which patients are at risk of developing cognitive impairment.     

Generalised sensory system abnormalities in amyotrophic lateral sclerosis: a European multicentre study

Background

Amyotrophic lateral sclerosis (ALS) is defined as a disease of the motor neurones, although several studies indicate involvement of the sensory nervous system.

Aim

To evaluate the sensory nerve conduction studies (NCS) in 88 patients with ALS as part of a European multicentre study.

Methods

Seven European clinical neurophysiologists examined consecutive series of ALS patients. The examinations were peer reviewed, and the diagnosis of ALS was confirmed clinically.

Results

20 (22.7%) patients with ALS had sensory NCS abnormalities in at least one nerve. Of those, 11 (12.5% of all patients) obtained an additional peer review diagnosis of electrophysiological polyneuropathy. There was no difference between the subgroups of patients with normal versus abnormal sensory NCS findings with respect to age, duration and region of onset.

Conclusion

The findings support previous reports of sensory involvement in ALS, and raise the question of whether patients with ALS with sensory nerve abnormalities represent a variant of ALS. ALS associated with generalised sensory system abnormalities may be consistent with degeneration of motor neurones and dorsal root ganglion cells.Sporadic amyotrophic lateral sclerosis (ALS) is defined as a progressive degeneration of upper motor neurones (UMNs) and lower motor neurones (LMNs). Normal electrophysiological studies on sensory nerves are generally required for the diagnosis of ALS.¹ Nevertheless, several neurological, clinical neurophysiological and neuropathological studies have suggested that ALS is a more generalised neurodegenerative disorder.^{2,3,4,5,6,7,8,9,10,11,12,13,14,15,16}The aim of this study was to determine the incidence of patients with ALS with electrophysiological sensory nerve abnormalities and to examine the possible differences between patients with ALS with normal versus abnormal sensory nerve conduction studies (NCS). The study was carried out on the basis of electrodiagnostic examinations of 88 patients with ALS included in the European multicentre project ESTEEM (European Standardised Telematic tool to Evaluate Electrodiagnostic Methods).¹⁷     

Psychiatric disorders in preclinical Huntington's disease

Background

Psychiatric symptoms are a common feature of Huntington''s disease (HD) and often precede the onset of motor and cognitive impairments. However, it remains unclear whether psychiatric changes in the preclinical period result from structural change, are a reaction to being at risk or simply a coincidental occurrence. Few studies have investigated the temporal course of psychiatric disorder across the preclinical period.

Objectives

To compare lifetime and current prevalence of psychiatric disorder in presymptomatic gene carriers and non‐carriers and to examine the relationship of psychiatric prevalence in gene carriers to temporal proximity of clinical onset.

Methods

Lifetime and current psychiatric histories of 204 at risk individuals (89 gene carriers and 115 non‐carriers) were obtained using a structured clinical interview, the Composite International Diagnostic Interview. Psychiatric disorders were classified using both standardised diagnostic criteria and a more subtle symptom based approach. Follow‐up of gene carriers (n = 51) enabled analysis of the role of temporal proximity to clinical onset.

Results

Gene carriers and non‐carriers did not differ in terms of the lifetime frequency of clinical psychiatric disorders or subclinical symptoms. However, gene carriers reported a significantly higher rate of current depressive symptoms. Moreover, the rate of depression increased as a function of proximity to clinical onset.

Conclusions

Affective disorder is an important feature of the prodromal stages of HD. The findings indicate that depression cannot be accounted for by natural concerns of being at risk. There is evidence of a window of several years in which preclinical symptoms are apparent.Huntington''s disease (HD) is an inherited neurodegenerative disorder, characterised by motor dysfunction, cognitive impairment and psychiatric disturbance. HD is associated with a wide range of psychiatric disturbances, including affective disorders,^1,2,3 irritability,^4,5,6 apathy^1,3,6 and psychosis.^4,7,8 Both major depression^1,2,4,9 and more subtle mood disturbances¹⁰ have been reported to predate clinical onset, conventionally defined by onset of motor symptoms. However, the basis for psychiatric symptoms remains unclear. Depression has been observed to occur up to 20 years before the onset of motor symptoms,^9,11 raising the possibility that psychiatric symptoms are an early indicator of HD and result from incipient neurodegenerative changes. However, the finding that psychiatric symptoms tend to cluster in certain HD families might indicate that psychiatric changes have a genetic basis and reflect a “switching on” of the HD gene early in life.^2,8 High rates of psychiatric disturbance have also been observed in HD family members who do not carry the genetic mutation,^9,10 raising the alternative possibility that affective changes arise in response to emotional stressors, such as being at risk, or the burden of growing up in a family with affected members. A more thorough understanding of the underlying basis of psychiatric changes in preclinical gene carriers is crucial, as future therapeutic strategies are most likely to target such individuals.Previous psychiatric studies of at risk individuals have yielded inconsistent results. Earlier studies reported high lifetime rates of psychiatric disorder in preclinical gene carriers (eg, 18% major affective disorder),² whereas more recent studies indicate little difference between rates for gene carrier and non‐carrier groups.^10,12,13,14 A number of factors may account for these discrepancies. The majority of earlier reports were limited to retrospective observation of affected individuals and therefore lacked appropriate controls.^4,5 The advent of predictive testing has enabled direct comparison of at risk individuals who have the HD mutation and those who do not, thereby controlling for social and environmental factors.^10,12,13,14 Whereas the majority of earlier studies lacked standardised assessment criteria,^4,7 more recent studies have utilised operational diagnostic criteria, although these have in turn been criticised for failing to detect the more subtle psychiatric disturbances that can occur in HD.^3,15Few studies have taken account of the temporal distance to onset of motor symptoms. It is now well established that the clinical onset of HD is typically preceded by a prodromal period of several months or years during which non‐specific mild neurological signs arise intermittently.¹⁶ The difficulty in establishing exact dates of onset for retrospective cases may have led to the inclusion in earlier studies of individuals who were already in the early stages of HD. Studies of presymptomatic individuals have typically recruited participants without motor signs, who may have been further from clinical onset.The present study is a double blind comparison of lifetime and current prevalence of psychiatric disorders in preclinical gene carriers and non‐carriers, using a combination of standardised psychiatric diagnostic criteria and a more subtle symptom based approach. Follow‐up of gene carriers has enabled analysis of the role of temporal proximity to clinical onset.     

Cerebral venous thrombosis and plasma concentrations of factor VIII and von Willebrand factor: a case control study

Background

High plasma concentrations of factor VIII (FVIII) and von Willebrand factor (VWF) have been recently associated with a moderately increased risk of venous thrombosis, but their roles in cerebral sinus and venous thrombosis (CSVT) have not been addressed. To determine whether elevation of FVIII and VWF is more frequent in CSVT, we analysed plasma levels of FVIII and VWF in a case control study.

Methods

The study population consisted of 25 consecutive patients (of whom nine were excluded) admitted for CSVT to the Department of Neurology, Amiens University Hospital, France, from January 1997 to December 2002, for a general screening for thrombophilia. Sixty‐four healthy subjects matched for age and sex formed the group control.

Results

Mean FVIII (CSVT: 167.3 (SD 48.8) IU/dl; control group: 117.9 (39.8) IU/dl; p = 0.001) and VWF levels (CSVT: 165.4 (76.5)%; control group: 108.5 (27.8)%; p = 0.01) were significantly higher in the CSVT group. Using the 95th percentile of the control group as the cut off value, elevated FVIII (>190 IU/dl) occurred in 25% (4/16) (p = 0.005) and elevated VWF (>168%) in 37.5% (6/16) of patients with CSVT (p<0.001). Using previously reported cut off values (>150 IU/dl or >150%) showed the same results (FVIII: p = 0.005; VWF: p = 0.009).

Conclusion

Our study suggests that elevation of plasma factor VIII levels is the most common prothrombotic risk factor for CSVT. Elevation of VWF is also associated with an increased risk of CSVT but its effect seems to be partly mediated through FVIII.Cerebral sinus and vein thrombosis (CSVT) is a rare localisation of venous thromboembolic disease. It generally occurs in young or middle‐aged adults and accounts for approximately 1% of strokes.¹ Many coagulation disorders have been associated with CSVT.^2,3,4Several prospective studies showed that high concentrations of factor VIII (FVIII) are associated with a moderately increased risk of venous thromboembolism (VTE).^5,6 The role of increased levels of von Willebrand Factor (VWF) in VTE remains unclear.^5,7 Recent studies suggest that the effect of VWF is fully explained by FVIII concentrations.⁵ Indeed, the ABO blood group, which regulates plasma concentrations of both FVIII and VWF, may also play a role in susceptibility to thrombosis.^8,9,10The increased risk of VTE with elevated levels of FVIII or VWF has been observed in previous studies.^5,6,7,11 However, they did not specifically include patients with CSVT^7,9 or they were incomplete.¹²The aim of our study was to assess plasma levels of FVIII, VWF and other thrombophilic factors in patients with CSVT in a case control study.     

A randomised pilot study to assess the efficacy of an interactive, multimedia tool of cognitive stimulation in Alzheimer's disease

Objective

To determine the usefulness of an interactive multimedia internet‐based system (IMIS) for the cognitive stimulation of Alzheimer''s disease.

Methods

This is a 24‐week, single‐blind, randomised pilot study conducted on 46 mildly impaired patients suspected of having Alzheimer''s disease receiving stable treatment with cholinesterase inhibitors (ChEIs). The patients were divided into three groups: (1) those who received 3 weekly, 20‐min sessions of IMIS in addition to 8 h/day of an integrated psychostimulation program (IPP); (2) those who received only IPP sessions; and (3) those who received only ChEI treatment. The primary outcome measure was the Alzheimer''s Disease Assessment Scale‐Cognitive (ADAS‐Cog). Secondary outcome measures were: Mini‐Mental State Examination (MMSE), Syndrom Kurztest, Boston Naming Test, Verbal Fluency, and the Rivermead Behavioral Memory Test story recall subtest.

Results

After 12 weeks, the patients treated with both IMIS and IPP had improved outcome scores on the ADAS‐Cog and MMSE, which was maintained through 24 weeks of follow‐up. The patients treated with IPP alone had better outcome than those treated with ChEIs alone, but the effects were attenuated after 24 weeks. All patients had improved scores in all of the IMIS individual tasks, attaining higher levels of difficulty in all cases.

Conclusion

Although both the IPP and IMIS improved cognition in patients with Alzheimer''s disease, the IMIS program provided an improvement above and beyond that seen with IPP alone, which lasted for 24 weeks.Alzheimer''s disease is the most frequent form of dementia in elderly people,^1,2 and its current treatment includes cholinesterase inhibitors (ChEIs),^3,4,5 and n‐methyl‐d‐aspartate receptor blockers (eg, memantine).⁶ However, symptomatic treatment often entails non‐pharmacological treatments as well, and adequate dementia management requires a wide range of intervention to help maximise the patient''s independence, increase their self‐confidence and relieve burden to the care giver.Current symptomatic treatment of Alzheimer''s disease can improve cognition and functionality.^3,4,5,6 However, before the emergence of these drugs, non‐pharmacological treatments had already been evaluated and cognitive stimulation had been found to be potentially beneficial for patients with dementia.^7,8,9 Although these non‐pharmacological treatments do not always seem efficacious, methodological problems may limit the validity of some studies.¹⁰ A recent Cochrane review¹¹ emphasised caution when interpreting the results of non‐pharmacological treatments, but suggested that certain cognitive domains could, in fact, benefit from these types of interventions.Clinical and laboratory studies have shown that mental and physical activity can positively influence cognition in normal elderly people and people with dementia. Education¹² and lifestyle choices (eg, occupation and leisure activities)^13,14,15 can modulate the risk of developing dementia, and psychomotor stimulation improves cognition in patients with Alzheimer''s disease.^16,17 Environmental enrichment can improve cognition in transgenic mice.^18,19 Despite the continued deposition of β‐amyloid, exercise can increase the levels of brain‐derived neurotrophic factor²⁰ and may reduce amyloid burden.²¹Despite the progressive nature of the degenerative process, patients with Alzheimer''s disease also seem to retain the physiological capacity to alter brain structure and function. Recent studies have shown cognitive plasticity and learning potential not only in patients with Alzheimer''s disease but also in healthy elders.^22,23 Positron emission tomography studies that used activation paradigms^24,25 have found that people with Alzheimer''s disease have a greater activation than those without dementia in the brain regions usually associated with memory tasks, as well as in the frontal lobes that were activated only with increasing difficulty of tasks. Pathological studies conducted on biopsy specimens of patients with Alzheimer''s disease with mild or moderate dementia have shown increased synaptic contact size.²⁶ Thus, the brain may be able to compensate during the early stages of Alzheimer''s disease, suggesting that there may be some utility to non‐pharmacological adjunctive interventions.Although studies on cognitive stimulation show that it is possible to stimulate the memory of patients with Alzheimer''s disease, the results are often modest. Because of methodological limitations, there is a need to conduct more randomised‐controlled trials with larger samples to validate this therapeutic approach. Computerised systems²⁷ and internet‐based distance programs offer one potential mechanism by which non‐pharmacological cognitive stimulation can be conducted in patients with dementia. In this study, we evaluated an interactive multimedia internet‐based system (IMIS) as an adjunct to ChEI treatment and classic psychostimulation treatment.     

Secondary motor disturbances in 101 patients with musician's dystonia

Objective

Musician''s focal dystonia is usually considered to be task specific but secondary motor disturbances have been reported also. We carried out a detailed evaluation of the incidence of these secondary motor problems in 101 patients.

Method

Symptoms were assessed using clinical histories, neurological examinations and observation of instrumental manoeuvres.

Results

53.5% of patients reported secondary motor disturbances in activities other than playing their main instrument, with the onset delayed in some cases by up to 12 years from the awareness of dystonic symptoms. 46.5% suffered from simple, 19.8% from complex and 33.7% from progressive cramps. Plucked string players (guitarists) mainly suffered from simple cramps while keyboardists more frequently displayed the progressive form. In all patients, symptoms were focal, and the type of cramp was unrelated to the severity of the perceived symptoms. Those patients playing a second instrument similar to their main instrument showed symptoms which worsened to a higher degree than those playing either only one instrument or whose second instrument was different.

Conclusions

Longer follow‐up assessments may reveal secondary motor symptoms that are not visible over shorter examination periods. Therefore, a thorough evaluation of everyday life motor activities should be considered in any clinical and treatment protocol. We speculate that the avoidance of movements that are similar to the main affected task may be of help in limiting symptoms. Consequently, focal dystonia may be considered more movement than task specific.The term occupational cramps is used to describe “a group of maladies in which certain symptoms are excited by the attempt to perform some often repeated muscular action, commonly one that is involved in the occupation of the sufferer”.¹ The term task specific dystonia is used to address the fact that one specific task and not other manual activities are affected. The best known focal dystonia is probably writer''s cramp, which inhibits the ability to write.² Dystonia has been diagnosed in, for example, surgeons, milkers, money counters, golfers, tennis and dart players and bowlers,^3,4,5 as well as in musicians.^6,7,8,9 Focal dystonia can manifest with a high degree of specificity, for example during longhand and not shorthand writing,³ or while playing classical but not electric guitar.¹⁰ Nevertheless, approximately 50% of writer''s cramp sufferers also report movement difficulties during other manual activities.^2,3,11 Such secondary motor problems have not been evaluated in detail in musicians, and reports focusing on the issue were based on small samples.Musicians achieve an exquisite level of motor performance, which is specific to the manual task they usually exercise, in agreement with reports on the neurophysiological basis of motor control of the hand.^{12,13,14,15,16,17,18} The reported percentages of secondary motor problems in affected musicians are usually low,^{7,8,9,19,20,21} but the heterogeneity of existing results does not allow one to draw satisfactory conclusions. Thus the question arises as to whether the per cent estimates reported previously are reliable, and what other factors may cause a bias towards the often used task specific characterisation of the disorder.We assessed the secondary motor problems reported by 101 musicians suffering from focal dystonia. The degree of specificity of the symptoms they reported, the type of secondary tasks being affected, as well as the characteristics they shared with the main affected tasks were inspected. Based on this, we discuss a possible explanation for the spreading of symptoms, and some aspects of relevance to prevent secondary motor effects.     

Botulinum toxin for writer's cramp: a randomised, placebo-controlled trial and 1-year follow-up

Background

Botulinum toxin type A (BoNT‐A) has become the treatment of choice for most types of focal dystonia.

Objective

To investigate the efficacy of BoNT‐A injections in patients with writer''s cramp in a double‐blind, randomised, placebo‐controlled trial and to evaluate the follow‐up results.

Methods

Forty participants were randomised to treatment with either BoNT‐A or placebo injections in two sessions. Trial duration was 12 weeks. The primary outcome measure was the patients'' choice to continue with the treatment, despite its possible disadvantages. Secondary outcome measures included several clinical rating scales on the levels of impairment and disability. Assessments were made at baseline and 2 months (secondary outcomes) and 3 months (primary outcome). Duration of follow‐up was 1 year.

Results

39 patients completed the trial. Fourteen of 20 patients (70%) receiving BoNT‐A reported a beneficial effect and chose to continue treatment, versus 6 of 19 patients (31.6%) in the placebo group (p = 0.03). The changes on most of the clinical rating scales were significantly in favour of BoNT‐A. Side effects reported were hand weakness, which was mostly mild and always transient, and pain at the injection site. After 1 year, 20 of 39 patients were still under treatment with a positive effect.

Conclusion

Treatment with BoNT‐A injections led to a significantly greater improvement compared with placebo, according to patients'' opinion and clinical assessment scales. Weakness in the hand is an important side effect of BoNT‐A injections, but despite this disadvantage, most patients preferred to continue treatment. About 50% of our patients were still under treatment after 1 year.Writer''s cramp is a task‐specific, focal hand dystonia. It is characterised by involuntary, repetitive or sustained contractions of finger, hand or arm muscles that occur during writing and produce abnormal postures or movements that interfere with normal handwriting.^1,2,3,4 Two categories are recognised: simple writer''s cramp, in which dystonic posturing of the hand and arm occurs only during writing, and complex or dystonic writer''s cramp, in which the condition manifests also during other manual tasks and sometimes with spontaneous abnormal posturing.^1,2,5 In most patients, no specific cause can be identified. Although the prevalence is relatively low, varying from 3 to 7/100 000,^6,7,8 writer''s cramp may be responsible for considerable morbidity in terms of working impairment, pain, embarrassment, low self‐esteem and poor social interaction.Therapeutic recommendations have included physical treatment, postural and writing re‐education exercises, relaxation techniques, hypnosis, biofeedback, use of special writing devices, acupuncture and transcranial magnetic stimulation, but most of the patients do not obtain satisfactory and sustained benefit.^9,10,11,12 Some patients learn to write with their non‐dominant hand, but there is a 25% chance that this hand will become afflicted with the same problem.¹³ Drug treatment has been disappointing so far.^3,9,14 The use of splints or braces and constraint‐induced movement treatment may occasionally be helpful, but it is not clear if they produce sustained relief.^15,16,17 There is presently only limited experience with stereotactic neurosurgical procedures for focal hand dystonia.^18,19 The treatment of dystonic syndromes such as blepharospasm and cervical dystonia has been much improved by the introduction of botulinum toxin as a therapeutic agent.^20,21 When botulinum toxin is injected into muscles, the toxin produces local chemodenervation by interfering with the release of acetylcholine from the presynaptic nerve terminal.⁴ However, there are also several drawbacks. Firstly, the effects of botulinum toxin type A (BoNT‐A) are not permanent, lasting for only approximately 3 months; thus, regular injections are required. Secondly, inconvenient muscle weakness interfering with other non‐writing activities may occur.²² Regarding the treatment of writer''s cramp, three randomised, double‐blind, placebo‐controlled studies have been undertaken, however, with small numbers of patients, different methods and inconclusive results.^23,24,25We performed a randomised, double blind, placebo‐controlled trial in 40 patients with writer''s cramp, to assess whether the benefits of BoNT‐A treatment outweigh its disadvantages. The trial duration was 12 weeks and thereafter patients were followed for 1 year.     

Prospective comparison of acute confusion severity with duration of post-traumatic amnesia in predicting employment outcome after traumatic brain injury

Background

Measurement of the duration of post‐traumatic amnesia (PTA) is common practice, serving as an important index of the severity of traumatic brain injury (TBI) and a predictor of functional outcome. However, controversy exists regarding the nature of PTA; some studies indicate that it is a confusional state with symptoms that extend beyond disorientation and amnesia.

Objective

To evaluate the contribution of the severity of acute confusion 1 month after TBI to prediction of employment at 1 year after injury, comparing it with PTA duration.

Methods

Prospective study involving 171 participants with complete data, who met the study criteria, from 228 consecutive TBI Model System admissions. Outcome measures included weekly administration of the Delirium Rating Scale‐Revised‐98 (DelRS‐R98) to measure the severity of acute confusion. Evaluations closest to 1 month after injury were used for study purposes. Duration of PTA was defined as the interval from injury until two consecutive Galveston Orientation and Amnesia Test scores of ⩾76 were obtained within a period of 24–72 h. Univariable and multivariable logistic regression were used to predict employment status at 1 year after injury.

Results

Age, education and DelRS‐R98 were significant predictors accounting for 34% of outcome variance. Individuals with greater confusion severity at 1 month after injury, older age and lower levels of education were less likely to be employed at 1 year after injury. Severity of confusion was more strongly associated with employment outcome (r_s = −0.39) than was PTA duration (r_s = −0.34).

Conclusions

In addition to demographic indices, severity of acute confusion makes a unique contribution to predicting late outcome after TBI.Impaired consciousness represents the clinical hallmark of non‐penetrating traumatic brain injury (TBI).^1,2 Individuals with mild TBI may experience a brief period of confusion, while others with greater injury severity may become comatose followed by prolonged confusion with amnesia.² This transitory state of impaired consciousness is commonly referred to as post‐traumatic amnesia (PTA). Determination of the duration of PTA is important as it yields an index of injury severity and is one of the best predictors of recovery and functional outcome.^3,4,5,6,7 Prospective evaluation of PTA is common practice in rehabilitation settings, largely because it provides an ongoing index of the patient''s progress³ and suitability for neuropsychological testing.^7,8Historically, investigations of PTA primarily focus on the disorientation and amnestic aspects of impaired consciousness after TBI, yet other neurobehavioral manifestations commonly occur. Stuss et al found that attentional disturbance is a key aspect of impaired consciousness among confused patients with TBI.⁹ They noted similarities between post‐traumatic impaired consciousness and delirium, a confusional state in which attentional deficits are commonly observed. They further proposed that the term “post‐traumatic confusional state” replace the more commonly used “post‐traumatic amnesia” as PTA less accurately represents cognitive impairments after TBI.⁹ Similarly, Nakase‐Thompson et al and later Sherer et al studied confusion among neurorehabilitation admissions with TBI and found that traditional measures of PTA did not adequately reflect the range of observed neurobehavioral impairments.^10,11 In addition to attentional, orientation and memory impairments, prevalent manifestations found among confused patients after TBI included sleep–wake cycle disturbance, decreased daytime arousal, fluctuation in cognitive and behavioural symptom severity, motor agitation, affective lability, and perceptual and thought process abnormalities.^10,11Studies addressing PTA as a predictor of outcome typically examine duration; that is, the time elapsed from injury until meeting a criterion for return of orientation and/or memory.^12,13,14,15 Important methodological limitations exist, however, in the determination of PTA duration.^3,16,17 While the early stages of PTA are easily recognised, identifying the end point is more challenging.^16,17,18 In some cases, patients are no longer available for determination of PTA emergence, having been transferred to home or another setting. Conversely, PTA resolution may occur prior to the initial evaluation, requiring retrospective estimation. Furthermore, different PTA measures may yield discrepant PTA duration recordings in the same patient, raising questions of test validity.^3,17,19,20 As duration of PTA is influenced by injury severity, evaluating the severity of confusion at a set time after injury potentially reduces the confounding influence of evaluation results with those of duration of TBI recovery.In an effort to clarify the relevance of severity, rather than duration of confusion symptoms, after TBI on functional outcome, we examined the predictive utility of a measure that encompasses many aspects of neurobehavioral impairment associated with acute confusion. We hypothesised that a rating scale that evaluates the range and severity of behavioural, cognitive and physiological changes associated with early confusion will provide unique utility in predicting late functional outcome. Moreover, clinicians caring for persons with TBI whose contacts with patients are too limited in time to permit determination of PTA duration could still have useful prognostic information. This study primarily aimed to examine the nature and severity of acute confusion utilising a common measure in the delirium literature, the Delirium Rating Scale‐Revised‐98 (DelRS‐R98),²¹ at 1 month after TBI, and its relationship to employment outcome at 1 year after injury. The second aim was to compare the functional prognostic value of the 1 month DelRS‐R98 with that of PTA duration, as assessed by the Galveston Orientation and Amnesia Test (GOAT),²² a common measure of PTA.^16,19