Differences in circadian variation of cerebral infarction, intracerebral haemorrhage and subarachnoid haemorrhage by situation at onset

Background

The precise time of stroke onset during sleep is difficult to specify, but this has a considerable influence on circadian variations of stroke onset.

Aim

To investigate circadian variations in situations at stroke onset—that is, in the waking state or during sleep—and their differences among subtypes.

Methods

12 957 cases of first‐ever stroke onset diagnosed from the Iwate Stroke Registry between 1991 and 1996 by computed tomography or magnetic resonance imaging were analysed. Circadian variations were compared using onset number in 2‐h periods with relative risk for the expected number of the average of 12 2‐h intervals in the waking state or during sleep in cerebral infarction (CIF), intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH).

Results

ICH and SAH showed bimodal circadian variations and CIF had a single peak in all situations at onset, whereas all three subtypes showed bimodal circadian variations of stroke onset in the waking state only. These variations were different in that CIF showed a bimodal pattern with a higher peak in the morning and a lower peak in the afternoon, whereas ICH and SAH had the same bimodal pattern with lower and higher peaks in the morning and afternoon, respectively.

Conclusions

Sleep or status in sleep tends to promote ischaemic stroke and suppress haemorrhagic stroke. Some triggers or factors that promote ischaemic stroke and prevent haemorrhagic stroke in the morning cause different variations in the waking state between ischaemic and haemorrhagic stroke.Stroke occurrence shows chronobiological variations,¹ such as circannual variations, circaseptan variations and circadian variations. Various patterns have been reported but no conclusions have yet been reached on circadian variations. The circadian variations of stroke onset may differ according to subtype or reporter, and are classified as cerebral infarction (CIF) with a single peak^2,3,4,5,6 or double peaks,^7,8 subarachnoid haemorrhage (SAH) with a single peak⁹ or double peaks,^{6,10,11,12,13,14} and intracerebral haemorrhage (ICH) with double peaks.^6,10,12 Most previous studies have not treated the three major subtypes simultaneously. Only three reports^6,7,8 discussed all the three subtypes, but the number of cases of ICH, especially of SAH, was too small for investigation of circadian variation. This may have led to differences in the conceived patterns of circadian variation. Large numbers of cases in population‐based samples are required to investigate and compare the circadian variations of stroke onset among subtypes. For investigation of the triggers and risk factors of stroke onset, it is necessary to determine the circadian variations of stroke onset with precise times. The precise time of stroke onset during sleep is difficult to specify, but this has a considerable influence on circadian variations of stroke onset.We investigated circadian variation in stroke onset by situations at onset in CIF, ICH and SAH in a Japanese population, by using stroke registry data. We also investigated the differences in circadian variations, triggers and risk factors among subtypes.     

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.     

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.     

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     

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.     

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     

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.     

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.     

Perception of longitudinal body axis in patients with stroke: a pilot study

Background and aims

To investigate the hypothesis that patients with a hemisphere stroke may perceive their longitudinal body axis (LBA) rotated in the frontal plane. This error in an egocentric frame of reference could be detrimental to posture, as tilted LBA would imply an unequal distribution of body mass about the true vertical.

Method

26 healthy subjects matched in age with 18 patients living with stroke participated in the study. The 18 patients were tested on average 80 days after a first left (n = 8) or right (n = 10) hemisphere stroke. Participants perceived their LBA by adjustments of the orientation of a luminous rod pivoting around a dorsonavel axis to the subjective direction of LBA. Participants were studied in the supine position to dissociate somaesthetic cues from graviceptive cues.

Results

Patients with stroke perceived their LBA rotated to the contralesional side in comparison with controls (p = 0.004). For all controls and 10 patients with stroke, the perceived LBA was very close to true LBA (mean (SD) 0.24° (1.31°)). For eight patients with stroke (six right stroke, two left stroke), the perceived LBA was rotated from true body orientation in the direction opposite to the lesioned side (range 3–9.5°, mean 5.2°). These eight patients provided similar estimates by tactile manipulation of the rod (without vision). The rotation of perceived LBA was more pronounced for right‐hemisphere strokes. The magnitudes of perceptual rotations correlated with sensory loss, signs of spatial neglect and the degree of postural and gait disability.

Conclusion

This is the first study showing that certain patients with a hemisphere stroke perceive their LBA rotated to the contralesional side. The consequences for perceptuomotor coordination have implications for their postural disorders.Patients with cortical stroke may experience forms of spatial disorientation that can affect perception of the spatial organisation of the axes and planes of the body. The resulting distortions of the “egocentric frame of reference” may contribute to the impairment of sensorimotor coordination. A particularly important egocentric reference for the organisation of movement and balance is the longitudinal body axis (LBA)¹ and colinear sagittal plane.² Studies on patients with cortical lesions, particularly affecting the parietal lobe, have shown an ipsilesional shift in their perception of the sagittal plane.^3,4,5,6,7,8 When attempting to point “straight ahead”, their indication deviates to the side of the lesion. This ipsilesional deviation has been interpreted as a result of a rotation of the egocentric frame of reference^9,10 or as a result of a lateral shift of the egocentric frame of reference.^11,12 The phenomena of lateral postural inclination,¹³ lateral pushing¹⁴ and visual vertical tilt^15,16,17,18 in the frontal plane exhibited by some patients with stroke affecting the cerebral hemispheres suggest that cortical lesions may also cause patients to perceive that the LBA tilted from its true orientation. This is the hypothesis of this study. If it were true, this phenomenon would have clear consequences for balance, as tilted LBA and sagittal plane imply an unequal distribution of body mass about the true vertical.Perception of orientation of the sagittal plane is constructed from multisensory components, including visual, auditory, somatosensory and vestibular inputs, and also from information relating eye, head and trunk positions.¹⁹ However, the somatosensory basis of the sagittal plane alone has been shown to be sufficient and robust, as the supine observer is able to indicate his or her LBA and sagittal plane accurately in the absence of vision, even when otolithic and other graviceptive cues are minimised.^{20,21,22,23,24}The main objective of this study to assess the LBA in isolation from gravitoinertial and otolithic cues has not yet been investigated in patients with stroke. Our second aim was to relate any rotation of LBA perception to clinical deficits and the site of the lesion, with the idea that tilted perceived LBA, if present, could be associated with clinical deficits (such as somatosensory loss or spatial neglect) or lesion location (such as the parietal cortex) involved in disorders of body‐sheme construction.²⁵ Our third aim was to analyse the relationship between potential rotation of LBA perception and postural disability.     

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     

Intravenous immunoglobulin treatment in painful sensory neuropathy without sensory ataxia associated with Sjögren's syndrome

Patients having neuropathy associated with Sjögren''s syndrome may present with pain and superficial sensory involvement in the absence of sensory ataxia. Treatment for this form of associated neuropathy has not been established. The case of a patient with painful sensory neuropathy associated with Sjögren''s syndrome, whose symptoms, particularly pain, responded well to intravenous immunoglobulin both at onset and in a relapse, is reported. Other patients with painful sensory neuropathy associated with Sjögren''s syndrome may also be candidates for intravenous Ig treatment.Ataxic sensory neuropathy associated with Sjögren''s syndrome is well recognised.^1,2,3 Pathologically, the underlying lesion is a sensory ganglionopathy affecting predominantly large neurones and their axons.^2,4 Intravenous immunoglobulin (Ig) treatment is reported to be effective in sensory ataxic neuropathy occurring in people with Sjögren''s syndrome.^5,6,7,8 Recently, another type of neuropathy associated with Sjögren''s syndrome was reported to affect small sensory axons in patients presenting with pain and superficial sensory involvement as opposed to sensory ataxia.^1,4,9,10,11 The treatment for this type of neuropathy remains uncertain. We describe a patient with painful sensory neuropathy associated with Sjögren''s syndrome, in whom intravenous Ig treatment dramatically reduced painful symptoms.     

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.     

Dynamic changes in corticospinal tracts after stroke detected by fibretracking

Background and aims

The integrity of motor pathways and functional connectivity patterns are important in assessing plastic changes related to successful recovery, to obtain prognostic information and to monitor future therapeutic strategies of stroke patients. We tested the following hypotheses: (1) that changes in axonal integrity along the corticospinal tract after stroke can be detected as a reduction in fractional anisotropy; and (2) that sustained low fractional anisotropy is indicative of axonal loss and therefore is correlated with poor motor outcome, as measured by specific neurological motor scores.

Methods

We developed a segmentation tool based on magnetic resonance diffusion tensor imaging in conjunction with three dimensional fibretracking for longitudinal studies of the corticospinal tract, and used specific neurological motor scores to test the hypotheses in five stroke patients within the first week and 30 and 90 days after the stroke.

Results

Reduction in fractional anisotropy within the first weeks after stroke reflected a decline in axonal integrity, leading to Wallerian degeneration, and demonstrated a correlation between the temporal evolution of fractional anisotropy and motor function in patients with poor motor outcome.

Conclusion

The study demonstrated the feasibility of fibretracking as a segmentation tool for mapping distal parts of the corticospinal motor pathways and showed that fractional anisotropy in the segmented corticospinal tract is a sensitive measure of structural changes after stroke.Studies on the recovery of cerebral grey matter after stroke with positron emission tomography,^1,2,3 functional MRI^4,5,6 or transcranial magnetic stimulation^7,8 demonstrate that the adult brain is capable of regeneration and compensation for motor deficits after ischaemia. However, the integrity of the underlying motor pathways is crucial in understanding the dynamics of cortical activation patterns and qualitatively the substrate of successful recovery in individual patients. The recent introduction of magnetic resonance diffusion tensor imaging (DTI) allows the characterisation of the integrity of the white matter tract by recording the diffusion characteristics of water molecules in the highly organised environment of hydrophobic myelin sheets. White matter fibre orientation can be inferred by measuring the preferred direction of water movements and the course of fibre tracts subsequently visualised by so called “fibretracking”. The extent to which myelin sheets directs water diffusion along a specific direction is parameterised by the fractional anisotropy (FA) index. FA values have been measured in studies of both healthy subjects and chronic stroke patients.^9,10,11 In the latter, reduced FA values measured distally to the infarct were low, interpreted as evidence of axonal loss and Wallerian degeneration (WD). In stroke patients,^12,13,14 DTI tracks the pyramidal fibres in their craniocaudal course and delineates lesions to motor fibres in relation to existing neurological deficits. A recent study demonstrated a clear prognostic value of the procedure by showing that the degree of corticospinal involvement in the infarcts is related directly to stroke severity, and inversely to functional recovery.¹⁵ Furthermore, DTI revealed changes consistent with WD within the first 2 weeks of the insult, thus proving that this technique detects structural changes earlier than conventional T2 and proton density magnetic resonance images.^16,17In the present study, we developed a fibretracking based technique to segment the corticospinal tract on initial DTI images and, using this volume as a template and in a longitudinal setting, to monitor FA from the early phase in stroke patients. Using specific neurological scores, we then studied patients, testing the hypothesis that sustained low FA values associate with poor motor outcome.     

Type of stroke after transient monocular blindness or retinal infarction of presumed arterial origin

Background

Retinal infarction and transient monocular blindness (TMB) are associated with an increased risk of future ischaemic stroke. Little information is available on the type of subsequent ischaemic strokes that may occur (anterior or posterior circulation and small vessel or large vessel).

Aim

To analyse the type of stroke after TMB.

Methods

Patients with transient or permanent retinal ischaemia were selected from three prospective studies: the Dutch TIA Trial, the Dutch Amaurosis Fugax Study and the European/Australian Stroke Prevention in Reversible Ischaemia Trial. On follow‐up the type of stroke was classified according to the supply territory and the type of vessel involved.

Results

654 patients were included. During a mean follow‐up of 5.2 years, 42 patients were found to have had a cerebral or retinal infarct, of which 27 occurred in the carotid territory ipsilateral to the symptomatic eye, 9 in the territory of the contralateral carotid artery and 6 were infratentorial strokes. Thirty patients had a large‐vessel infarct, four had a small‐vessel infarct and eight had a retinal infarct. Characteristics associated with a notable increased risk for subsequent stroke or retinal infarction were age ⩾65 years, a history of stroke, a history of intermittent claudication, diabetes mellitus, Rankin score ⩾3, more than three attacks of retinal ischaemia and any degree of ipsilateral carotid stenosis on duplex ultrasonography observation.

Conclusion

Ischaemic strokes after TMB or retinal infarction were found to be mainly large‐vessel infarcts in the territory of the ipsilateral carotid artery. TMB and retinal infarction are probably manifestations of large‐vessel disease.Transient monocular blindness (TMB) is caused by temporary ischaemia of the retina in one eye, secondary to transient occlusion of a retinal artery, hypoperfusion or vasospasm.¹ TMB is a risk factor for subsequent ischaemic stroke,² but this risk is lower than after transient ischaemic attacks of the brain.^3,4,5,6 The annual incidence of ischaemic stroke after TMB or retinal infarcts in unselected patients ranges between 2.0% and 2.8%,^2,3,4,7,8,9 and increases up to 8.4% in the presence of high‐grade stenosis of the ipsilateral carotid artery.⁵ That TMB often occurs in patients with atherosclerotic lesions of the carotid artery^3,6,10,11,12 suggests that it should be regarded as a manifestation of large‐vessel atherosclerosis. But, even among patients with stenosis of the internal carotid artery, the risk for subsequent stroke is lower in patients with TMB than in those who have had a cerebral transient ischaemic attack,^5,6 which may indicate a difference in pathophysiological background between hemispheric and retinal ischaemia. Patients who have had a transient ischaemic attack or non‐disabling ischaemic stroke caused by large‐vessel disease are more likely to have subsequent large‐vessel stroke during follow‐up.¹³ If TMB is considered to be a manifestation of large‐vessel disease, the subsequent ischaemic stroke may be large‐vessel ischaemic stroke. To date, no information is available on whether brain infarcts after TMB are caused by small‐vessel or by large‐vessel disease, and whether subsequent ischaemic strokes occur mainly in the ipsilateral or also in the contralateral hemisphere, or in the vertebrobasilar territory. Given the low incidence of recurrent stroke after TMB, many patients have to be followed up for a long time for a meaningful analysis. We aimed to analyse the type of subsequent ischaemic stroke in patients with TMB or retinal infarction, to obtain more insight into the pathophysiology of retinal ischaemia, especially with respect to the type of vascular disease.     

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.     

Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage

Background

Rodent models of acute ischaemic stroke and head injury suggest that apolipoprotein E (APOE) genotype influences neuronal repair, regeneration and survival after brain injury. Possession of an APOE ε4 allele is associated with poor outcome after head injury in clinical studies. APOE might therefore influence outcome after acute stroke in humans.

Objective and methods

To comprehensively search, identify, assess and carry out meta‐analyses of studies reporting on the association between APOE and the combined outcome of death or dependency, or death alone, several months after ischaemic stroke, intracerebral haemorrhage (ICH) or subarachnoid haemorrhage (SAH).

Results

Main analyses included data from nine studies on 2262 patients (1453 with ischaemic stroke, 199 with ICH and 610 with SAH). Overall, ε4+ genotypes were not significantly associated with risk of death or dependency several months after stroke. However, there was significant heterogeneity between studies, and between the three pathological types of stroke. ε4+ genotypes were associated with increased death or dependency after SAH (relative risk (RR) 1.40, 95% confidence interval (CI) 1.06 to 1.84), with a trend towards a similar association with ICH (RR 1.38, 95% CI 0.99 to 1.92), but not with ischaemic stroke (RR 0.98, 95% CI 0.85 to 1.12). Results were similar for death alone.

Conclusions

APOE may differentially affect outcome after the three main pathological types of stroke. Further, large studies are needed to confirm or refute these findings, and to assess the possibility of an interaction between the effects of APOE and age.In contrast with the many studies assessing the role of various candidate genes in the causation of stroke and its subtypes,^1,2,3 the role of genetic factors influencing outcome after acute stroke has been relatively little studied in humans.^4,5 However, studies on animal models of stroke comparing outcomes among genetically manipulated animals with those among wild‐type animals suggest that this should be a promising subject, which may ultimately improve our understanding of the pathways of neuronal protection and recovery, and even lead to new therapeutic insights.^4,6The apolipoprotein E gene (APOE) is one of the most widely studied genes in vascular and neurodegenerative diseases. Its protein product is a 34‐kDa glycoprotein with three common isoforms, E2, E3 and E4, encoded by the alleles ε2, ε3 and ε4, respectively, giving rise to six genotypes, the ε3/ε3 genotype occurring in about 50–66% of people in most populations.⁷ APOE has a major role in lipid redistribution, which is important for membrane maintenance and repair in the brain, and in the regulation of synaptic remodelling during or after brain injury.^6,8,9,10,11 Rodent models of head injury and ischaemic stroke suggest that APOE influences neuronal repair, regeneration and survival after brain injury.^6,11 In clinical studies, possession of an APOE ε4 allele is associated with poor outcome after head injury.⁵ These observations suggest that APOE might influence outcome after acute stroke in humans, but clinical studies have produced conflicting results.⁵Here, we use systematic review and meta‐analysis methods to assess the effect of APOE on outcome after the three main pathological types of acute stroke: ischaemic stroke, intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH).     

Post-surgical changes in brain metabolism detected by magnetic resonance spectroscopy in normal pressure hydrocephalus: results of a pilot study

Background

Adult normal pressure hydrocephalus (NPH) is one of the few potentially treatable causes of dementia. Some morphological and functional abnormalities attributed to hydrocephalus improve following treatment.

Objectives

We focused on analysis of changes in cerebral metabolites using proton magnetic resonance spectroscopy (¹H‐MRS) after NPH treatment, and its clinical and cognitive correlation.

Methods

¹H‐MRS, neuropsychological and clinical status examinations were performed before and 6 months after shunting in 12 adults with idiopathic NPH. We obtained N‐acetyl‐aspartate (NAA), choline (Cho), myoinositol (MI) and creatine (Cr) values.

Results

After surgery, NAA/Cr was significantly increased. Moreover, NAA/Cr values were related to cognitive deterioration.

Conclusion

MRS could be a marker of neuronal dysfunction in NPH.Normal pressure hydrocephalus (NPH) is a potentially treatable cause of dementia,^1,2 characterised by progressive cognitive dysfunction, gait disturbance and urinary incontinence associated with ventricular enlargement and abnormalities in CSF dynamics. In these patients, some morphological and functional abnormalities attributed to hydrocephalus improve after treatment.^3,4,5 Proton magnetic resonance spectroscopy (¹H‐MRS) allows non‐invasive in vivo measurement of brain metabolites. Findings from MRS studies reveal that ¹H‐MRS is a potentially non‐invasive technique with sufficient sensitivity to detect subtle changes in neuronal function in neurodegenerative diseases, allowing investigation of neuronal injury or dysfunction^6,7 and the assessment of treatment efficacy.^8,9,101H‐MRS studies in patients with hydrocephalus are scarce.^{6,7,11,12,13,14,15} Changes in cerebral metabolites after treatment with hydrocephalus using this technique have been analysed in only two studies, which concentrated exclusively on the results of lactate metabolites.^11,12The aim of our study was to describe changes in other major metabolites, using ¹H‐MRS, before and after treatment in idiopathic NPH patients, and to obtain preliminary data on their clinical and cognitive correlation, which could serve as the basis for larger studies with control subjects.     

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.     

Functional and magnetic resonance imaging correlates of corpus callosum in normal pressure hydrocephalus before and after shunting

Background

Normal pressure hydrocephalus (NPH) is associated with corpus callosum abnormalities.

Objectives

To study the clinical and neuropsychological effect of callosal thinning in 18 patients with idiopathic NPH and to investigate the postsurgical callosal changes in 14 patients.

Methods

Global corpus callosum size and seven callosal subdivisions were measured. Neuropsychological assessment included an extensive battery assessing memory, psychomotor speed, visuospatial and frontal lobe functioning.

Results

After surgery, patients showed improvements in memory, visuospatial and frontal lobe functions, and psychomotor speed. Two frontal corpus callosum areas, the genu and the rostral body, were the regions most related to the clinical and neuropsychological dysfunction. After surgery, total corpus callosum and four of the seven subdivisions presented a significant increase in size, which was related to poorer neuropsychological and clinical outcome.

Conclusion

The postsurgical corpus callosum increase might be the result of decompression, re‐expansion and increase of interstitial fluid, although it may also be caused by differences in shape due to cerebral reorganisation.Ventricular dilatation and corpus callosum abnormalities are the anatomical changes most often reported in association with normal pressure hydrocephalus (NPH). Callosal abnormalities include changes in the morphology and the magnetic resonance imaging (MRI) signal. The most consistent findings are stretching, uniform and focal thinning, and upward elevation.^1,2,3,4 Callosal damage has been primarily attributed to lateral ventricle dilatation¹ and to the impingement of the corpus callosum against the falx.²Two studies indicated a partial or complete recovery of different callosal parameters after shunt surgery.^4,5 However, in these studies, only five and eight patients with different types of hydrocephalus were analysed postsurgically. Other studies have reported corpus callosum abnormalities after surgery in 3–17% of cases, including signal changes,^6,7,8,9,10 a transient scalloping deformity⁶ and increased thickness.^7,8 Although the nature of the postsurgical changes in the corpus callosum remains unclear, several causes have been suggested, including callosal compression against the falx, decompression and overdrainage.^6,7,8,9To our knowledge, no morphological MRI quantitative studies of corpus callosum in NPH have been performed to date, nor has the possible involvement of the corpus callosum in the neuropsychological deterioration in NPH been investigated in depth. As damage to the corpus callosum can affect cognition,¹¹ the aim of this study was to investigate the contribution of corpus callosum thinning to the neuropsychological deficits in NPH and to determine the postsurgical callosal changes and their relationship with cognitive outcome.     

Movement disorders in patients taking anticonvulsants

Background

A wide variety of movement disorders may occur as a consequence of the administration of antiepileptic drugs (AEDs). Although it has been suggested that the risk of parkinsonism is 10‐fold higher in those taking valproate as compared with other AEDs, there have been no large, systematic trials assessing this.

Aim

To establish more precisely the prevalence of and risk factors for developing parkinsonism associated with valproate use,and to assess the occurrence of movement disorders with the newer AEDs.

Methods

Patients with epilepsy were recruited from the Toronto Western Hospital Epilepsy Clinic (University of Toronto, Toronto, Ontario, Canada). Each patient was examined by a movement disorder specialist who was blinded to the treatment status of the patient.

Results

201 patients were included. Postural tremor was the most common movement disorder (45%), followed by parkinsonism (4.5%). The odds of having parkinsonism were 5 times higher with valproate than with other AEDs. No single factor predicted the presence of parkinsonism; however, many (5/9) of the patients concurrently used other drugs or had comorbidities that could have caused or exacerbated parkinsonism. None of the newer AEDs were clearly associated with the presence of movement disorders; however, the numbers were too small to make a formal analysis.

Conclusion

Although the risk of parkinsonism with valproate is higher than with other AEDs, it is lower than originally reported. The cases available were not enough to accurately comment on the prevalence of movement disorders with the newer AEDs.A wide variety of movement disorders may occur as a consequence of the administration of antiepileptic drugs (AEDs). Among the common movement disorders associated with AEDs, cerebellar ataxia is the most commonly reported, followed by asterixis and myoclonus, although a variety of others, including chorea, orofacial dyskinesias, tremor, tics and dystonia, can occur.^1,2,3,4,5 Most of the AEDs have been implicated at one time or another, with the most common offenders being phenytoin and carbamazepine, followed by valproate and phenobarbital.⁶ Despite its utility, valproate commonly exerts side effects on the central nervous system (CNS). The most common is dose‐related tremor, occurring in as many as one quarter of chronically treated patients.^7,8,9,10,11 Less often asterixis, chorea, sensorineural hearing loss and encephalopathy have been reported.^3,12,13 Although there have been case reports of parkinsonism induced by AEDs such as phenytoin^14,15 and carbazamepine,¹⁶ the most common drug associated with parkinsonism by far is valproate.⁶ Several case reports of valproate‐induced parkinsonism, often accompanied by cognitive disturbances have been published.^{11,17,18,19,20,21} A report of a multiple system atrophy‐like syndrome is also available.²² Both syndromes are said to resolve when the drug is withdrawn.^11,17,22 However, most studies have reported isolated cases and the few series looking at the prevalence of valproate‐induced parkinsonism have been based on small sample sizes.^18,21 Moreover, there have been no recent systematic studies dealing with the prevalence of movement disorders related to new AEDs such as topiramate, vigabatrin, lamotrigine and gabapentin among others.The primary purpose of this study was to establish more precisely the prevalence of and risk factors for developing valproate‐induced parkinsonism. The secondary aim was to attempt to delineate the profile of new AEDs with regard to involuntary movement abnormalities. To avoid biases that may have influenced previous reports, we evaluated patients with epilepsy for the presence of movement disorders, blinded to the knowledge of which AEDs they were taking.