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.     

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.     

Progression of non-age-related callosal brain atrophy in multiple sclerosis: a 9-year longitudinal MRI study representing four decades of disease development

Background

In multiple sclerosis (MS), multiple periventricular lesions are commonly the first findings on MRI. However, most of these MS lesions are clinically silent. The brain atrophy rate has shown better correlation to physical disability, but it is not clear how atrophy develops over decades. Corpus callosum forms the roof of the third and lateral ventricles. The corpus callosum area (CCA) in a midsagittal image is age independent in a normal adult population up to the seventh decade; therefore it can be used as a marker for non‐age‐related, pathological brain atrophy.

Objectives

To investigate whether and how CCA decreases in size over time in patients with MS.

Methods

In a clinical observational study, 37 patients with MS with a wide range of disease duration at baseline (1–33 years) were followed. Three different MS courses were represented. The mean of individual MRI follow‐up was 9 years. Multiple sclerosis severity score (MSSS) was also applied to evaluate disability at baseline and after 9 years of follow‐up.

Results

A significant decrease in CCA over 9 years (p<0.001) and a persisting association between CCA and the disability status were found. The atrophy rate was similar ever four decades of MS for all MS courses. The mean annual CCA decrease was 9.25 mm² (1.8%). Surprisingly, atrophy rate did not correlate with sex, disease duration, age at MS onset or MS course.

Conclusions

Serial evaluations of CCA might be a robust method in monitoring a non‐age‐related decrease in CCA, reflecting progression of irreversible destructive changes in MS.Multiple sclerosis (MS) is a complex inflammatory disease of the brain and spinal cord,^1,2,3 which leads to a well‐documented early irreversible atrophy.^4,5,6 The main neuroimaging modality used to monitor MS development is MRI, which can visualise both lesions and atrophy. In follow‐up examinations of patients with MS, the correlation between clinical development and extent of MRI findings is generally poor, which is sometimes referred to as “the clinicoradiological paradox”.⁷In contrast with focal MS lesions, atrophy measures of the brain or spinal cord have been regarded as a better predictor of the disability progression in MS.^2,5,8,9,10 However, some reports also show non‐significant correlation between disability and atrophy.^{11,12,13,14,15,16} Focal MS lesions visualised on MRI have a characteristic pattern of oval‐shaped, typically periventricular white matter changes, often located in the corpus callosum. Atrophy of the corpus callosum is common in MS. However, pathological changes in the corpus callosum might develop independently of focal T2‐weighted lesions.¹⁷The corpus callosum, consisting of 2×10⁸ axons in a healthy person, forms the roof of the third and lateral ventricles and has a central role for interhemispheric communication.¹⁸ The corpus callosum area (CCA) is normally resistant to age‐related shrinkage between the third and the seventh decades of life.^19,20 Atrophy of the corpus callosum correlates to other measures of brain atrophy such as widening of third and lateral ventricles.¹ Pelletier et al²¹ reported a persisting association between CCA and disability, as assessed by the Expanded Disability Status Scale (EDSS) in a 5‐year longitudinal study of patients with relapsing–remitting multiple sclerosis (RRMS). Schreiber et al²² reported CCA in patients with MS to be associated with EDSS. In contrast, Barkhof et al²³ reported a lack of correlation between CCA and EDSS. Simon et al¹ found a slight correlation between CCA and EDSS at baseline, but on follow‐up there was no significant correlation between the significant CCA decrease and EDSS change.The corpus callosum atrophy rate has not been reported for different disease durations, sex or types of MS course in longitudinal studies.²¹ The starting point for prospective, longitudinal MRI studies is often close to the time of diagnosis of MS, focusing on the early years of the disease.We followed a patient cohort for 9 years. Disease duration at baseline was widespread (range 1–33 years), giving us the possibility of an overview of disease development over four decades. Our first aim was to study the rate at which the callosal atrophy developed. Second, we wanted to study the correlation between the atrophy rate and disability changes. The third aim was to study the association between CCA and disability at baseline and at the end of the study. The fourth aim was to investigate the association of the atrophy rate to sex, MS course (course at the end of study), disease duration and age at onset.     

Bilateral grey-matter increase in the putamen in primary blepharospasm

Background

Primary blepharospasm is a focal dystonia characterised by excessive involuntary closure of the eyelids. The pathophysiology of primary blepharospasm is unresolved.

Aim

To pinpoint grey‐matter changes that are associated with primary blepharospasm.

Methods

16 right‐handed patients with primary blepharospasm (mean age 67.4 (SD 4.3) years; 12 women) were compared with 16 healthy volunteers matched for sex and age. High‐resolution T1‐weighted magnetic resonance imaging of each participant was obtained and analysed by voxel‐based morphometry, a method to detect regionally specific differences in grey matter between patients and control group. To evaluate whether the identified grey‐matter changes were correlated with the duration of primary blepharospasm or botulinum neurotoxin treatment (BoNT), separate regression analyses were carried out.

Results

In patients with primary blepharospasm, grey‐matter increase in the putamina was observed, whereas regression analyses did not indicate a correlation between grey‐matter increases and the duration of primary blepharospasm or BoNT. Grey‐matter decrease was detected in the left inferior parietal lobule; here regression analyses of grey‐matter decrease showed a significant (p = 0.013) correlation of grey‐matter decrease with the duration of BoNT.

Conclusions

The data suggest structural changes in primary blepharospasm and point to a crucial role of the putamen for the pathophysiology of this focal dystonia.Blepharospasm is a common neurological disorder with a prevalence between 12 and 133 per million.¹ This focal dystonia is characterised by excessive involuntary closure of the eyelids, typically caused by spasms of the orbicularis oculi muscles. Primary blepharospasm is a disorder in which dystonia is the only clinical sign, without any identifiable exogenous cause or other inherited or degenerative disease. Accordingly, no lesions can be detected on routine magnetic resonance imaging (MRI). By contrast, secondary blepharospasm is an identifiable disorder and associated lesions have been documented in the basal ganglia, diencephalon, brain stem and cerebellum.^2,3,4,5,6The pathophysiology of primary blepharospasm is unclear. Therefore, we aimed at pinpointing grey‐matter changes that are associated with primary blepharospasm. We compared a group of patients with a control group, matched for sex and age, using voxel‐based morphometry (VBM), a method that allows averaging high‐resolution MRI on people and hence comparisons at the group level.VBM has been cross validated with region‐of‐interest measurements^7,8,9 and several studies have shown that structural changes identified by VBM are directly related to functional changes in brain activity.^10,11 Moreover, VBM has proved to be a powerful method in detecting regional differences in cerebral structure in various disorders such as narcolepsy,¹² restless legs syndrome,¹³ idiopathic cervical dystonia¹⁴ and focal hand dystonia.¹⁵     

Corpus callosum atrophy is associated with mental slowing and executive deficits in subjects with age-related white matter hyperintensities: the LADIS Study

Background

Previous research has indicated that corpus callosum atrophy is associated with global cognitive decline in neurodegenerative diseases, but few studies have investigated specific cognitive functions.

Objective

To investigate the role of regional corpus callosum atrophy in mental speed, attention and executive functions in subjects with age‐related white matter hyperintensities (WMH).

Methods

In the Leukoaraiosis and Disability Study, 567 subjects with age‐related WMH were examined with a detailed neuropsychological assessment and quantitative magnetic resonance imaging. The relationships of the total corpus callosum area and its subregions with cognitive performance were analysed using multiple linear regression, controlling for volume of WMH and other confounding factors.

Results

Atrophy of the total corpus callosum area was associated with poor performance in tests assessing speed of mental processing—namely, trail making A and Stroop test parts I and II. Anterior, but not posterior, corpus callosum atrophy was associated with deficits of attention and executive functions as reflected by the symbol digit modalities and digit cancellation tests, as well as by the subtraction scores in the trail making and Stroop tests. Furthermore, semantic verbal fluency was related to the total corpus callosum area and the isthmus subregion.

Conclusions

Corpus callosum atrophy seems to contribute to cognitive decline independently of age, education, coexisting WMH and stroke. Anterior corpus callosum atrophy is related to the frontal‐lobe‐mediated executive functions and attention, whereas overall corpus callosum atrophy is associated with the slowing of processing speed.Corpus callosum is the largest commissural structure consisting of white matter tracts that connect the cerebral hemispheres according to an anterior–posterior topographical organisation. Recent research using diffusion tensor magnetic resonance imaging (MRI) has augmented earlier postmortem findings of corpus callosum topography and has shown that the anterior parts of corpus callosum (rostrum and genu) connect the orbitofrontal, lateral and medial frontal cortices, whereas the body and splenium connect parietal, temporal and occipital homotopic regions.¹ In neurodegenerative diseases, the corpus callosum area is markedly reduced, indicating marked axonal loss.^2,3,4,5 In Alzheimer''s disease, the severity and pattern of corpus callosum atrophy have been associated with cortical neuronal loss⁶ independently of white matter hyperintensities (WMH).⁷ In vascular dementia and other ischaemic conditions, however, corpus callosum atrophy is correlated with WMH and hence may result from subcortical ischaemic damage.^8,9Earlier studies have shown that corpus callosum atrophy is associated with global cognitive status,^5,6,10 but, to date, few studies have investigated the role of regional corpus callosum atrophy in specific cognitive processes. Based on the topographical organisation of corpus callosum, the integrity of its subregions may reflect distinct cognitive deficits. In particular, anterior corpus callosum atrophy may be related to the frontal‐lobe‐mediated executive deficits. Previous work of the Leukoaraiosis and Disability (LADIS) Study has shown that age‐related WMH are associated with cognitive impairment in elderly subjects without dementia.¹¹ Moreover, in these subjects, the corpus callosum area has been found to be inversely related to motor deficits and global cognitive decline.¹² This study examined the independent contribution of regional corpus callosum atrophy to deficits in mental speed, attention and executive functions in a large sample of elderly subjects with WMH by using quantitative MRI analysis and targeted neuropsychological test methods. The demographic and medical background variables, and coexisting WMH were controlled by using multivariate analysis.     

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.     

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.     

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.     

Relationship between regional cerebral metabolism and consciousness disturbance in traumatic diffuse brain injury without large focal lesions: an FDG-PET study with statistical parametric mapping analysis

Background

The cerebral metabolism of patients in the chronic stage of traumatic diffuse brain injury (TDBI) has not been fully investigated.

Aim

To study the relationship between regional cerebral metabolism (rCM) and consciousness disturbance in patients with TDBI.

Methods

52 patients with TDBI in the chronic stage without large focal lesions were enrolled, and rCM was evaluated by fluorine‐18‐fluorodeoxyglucose positron emission tomography (FDG‐PET) with statistical parametric mapping (SPM). All the patients were found to have disturbed consciousness or cognitive function and were divided into the following three groups: group A (n = 22), patients in a state with higher brain dysfunction; group B (n = 13), patients in a minimally conscious state; and group C (n = 17), patients in a vegetative state. rCM patterns on FDG‐PET among these groups were evaluated and compared with those of normal control subjects on statistical parametric maps.

Results

Hypometabolism was consistently indicated bilaterally in the medial prefrontal regions, the medial frontobasal regions, the cingulate gyrus and the thalamus. Hypometabolism in these regions was the most widespread and prominent in group C, and that in group B was more widespread and prominent than that in group A.

Conclusions

Bilateral hypometabolism in the medial prefrontal regions, the medial frontobasal regions, the cingulate gyrus and the thalamus may reflect the clinical deterioration of TDBI, which is due to functional and structural disconnections of neural networks rather than due to direct cerebral focal contusion.Diffuse axonal injury (DAI) results in a wide range of neuropsychological and neurological deficits. Patients with DAI show complex combinations of disorders of memory, attention and executive functions, slowed information processing, modifications of behaviour and personality, and disturbed communication and consciousness.¹ These disorders may impose a great burden on the family of the patient with a head injury and compromise psychosocial and vocational reintegration.² Indeed, cognitive, behavioural and personality changes are major causes of the failure of patients with DAI to return to work.In patients with DAI, MRI shows lesions in the corpus callosum, brain stem, internal capsule and the grey matter–white matter junction or the deep matter.^3,4,5 Global MRI indices of patients with DAI, such as ventricular enlargement or atrophy of the white matter tracts (corpus callosum, fornix, internal capsule), correlate well with cognitive outcomes.^6,7 In contrast, neurobehavioural disorders after DAI are reportedly poorly correlated with focal lesions that are detected by morphological neuroimaging techniques, such as CT or MRI.^7,8Cerebral metabolic imaging with positron emission tomography (PET) is useful in assessing the regional cerebral metabolism (rCM). PET studies on cerebral metabolism in patients with traumatic brain injury have been conducted at the acute⁹ or subacute–chronic stages,^2,10,11 and those with region‐of‐interest (ROI) techniques have disclosed a close link between cognitive and behavioural disorders and decreased cortical metabolism in the prefrontal and cingulate cortices in patients with severe DAI.²Patients with DAI have neurological, cognitive and behavioural dysfunctions, which become stable in the chronic stage. The relationship between these dysfunctions and rCM deviations has never been studied in detail. Limitations do exist in the assessment of rCM with ROI techniques. ROI techniques depend either on subjective assessment to establish differences from normal tracer distribution on functional activity maps or on the relatively arbitrary size, shape and placement of the ROIs. As a result, some areas of the brain may not be explored. Statistical parametric mapping (SPM) analysis is an alternative voxel‐by‐voxel analysis method that can avoid subjectivities. To investigate the relationship between cognitive and behavioural disorders, consciousness disturbance and rCM, we conducted a fluorine‐18‐fluorodeoxyglucose‐PET (FDG‐PET) study with SPM analysis in patients with traumatic diffuse brain injury (TDBI) at the chronic stage, which histopathologically is assumed to be mostly DAI.     

A population-based study of depressive symptoms in multiple sclerosis in Stockholm county: association with functioning and sense of coherence

Objectives

To explore and analyse the prevalence of depressive symptoms in people with multiple sclerosis (PwMS), taking into account disease‐related and sociodemographic factors, and also to analyse the association between depressive symptoms and functioning (tested and self‐reported) and sense of coherence (SOC), respectively.

Methods

Home visits were made to a population‐based sample of 166 PwMS. Data were obtained from structured, face‐to‐face interviews using the Beck Depression Inventory (BDI), the Sickness Impact Profile (SIP) and the SOC scale. A range of tests were also carried out for analyses of different aspects of functioning such as cognitive function, walking capacity and manual dexterity, and structured interviews examined activities of daily living and frequency of social/lifestyle activities.

Results

19% (28/149) of the people were depressed (BDI ⩾13). Depressive symptoms were associated with worse self‐reported functioning on the SIP and with poor memory function, but not with any of the other tests of functioning. Depressive symptoms were associated with weak SOC, but not with any of the disease‐related or sociodemographic factors studied.

Conclusion

The prevalence of depressive symptoms in a population‐based sample of PwMS is high. Given the serious nature of depression and its association with worse self‐reported functioning and weak SOC, attention to, and treatment of, mental‐health problems and depression are strongly indicated in the clinical management of multiple sclerosis.Few population‐based studies of depression have been conducted on multiple sclerosis,^1,2,3,4,5 although many reports of depression and its correlation with numerous variables in clinical samples of people with multiple sclerosis (PwMS) have been published. The population‐based studies have all reported a high prevalence of depression^1,2,3,4,5 despite using different methods of data collection.Depressive symptoms are reported to be associated with decreases in functioning.⁶ In multiple sclerosis, it has been reported that depressed PwMS perform worse than the non‐depressed in evaluations of cognitive function,⁷ but there are conflicting reports.⁵ Depressive symptoms in PwMS are also associated with worse self‐reported functioning and health‐related quality of life scores,⁸ and depressed PwMS have been shown to be more likely to perceive their disability as being greater than their doctors'' perception.⁹ It is therefore important to consider different aspects of functioning when evaluating the presence of depression in PwMS.In the salutogenic model, proposed by Antonovsky,¹⁰ health is described as a continuum between ease and disease rather than as the binary opposite of disease; the model is thus appropriate for studying people afflicted with chronic disorders. Sense of coherence (SOC) refers to “general resistance resources”—capacities that facilitate coping with stressors and thereby improve health.¹⁰ The SOC describes the degree to which a person views the world as meaningful, comprehensible and manageable.¹⁰ SOC has been studied in several patient groups^11,12 including those with multiple sclerosis.^13,14 Weak SOC has been found to be associated with a higher prevalence of depression in studies of people with chronic diseases, such as rheumatoid arthritis,¹⁵ but this has not been explored in PwMS.Certain inconsistencies were observed in previously presented results on depression and its association with disease‐related and sociodemographic factors.^1,2,3,4,5 On account of differences in healthcare systems and policies, the results from population‐based studies of depression and functioning in other countries may not easily be extrapolated to Swedish conditions.We have conducted a cross‐sectional, population‐based study of PwMS in Stockholm county, to comprehensively describe and analyse their functioning and health (the Stockholm MS Study). In this report from the Stockholm MS Study, the aim was to explore the prevalence of depressive symptoms, taking into account disease‐related and sociodemographic factors, and also to analyse the association between depressive symptoms and functioning (tested and self‐reported) and SOC, respectively.     

Course and outcome of acute limbic encephalitis with negative voltage-gated potassium channel antibodies

Background

Limbic encephalitis is a potentially treatable immunological condition. The presence of voltage‐gated potassium channel antibodies (VGKC‐Ab) in the cerebrospinal fluid (CSF) and serum of patients with the condition is a marker of the disease associated with a non‐paraneoplastic form and good response to treatment. Recent work has highlighted absent serum VGKC‐Ab and distinct immunology in patients with the paraneoplastic form of limbic encephalitis.

Methods

The cases of four patients with the typical clinical presentation, neuropsychological features and brain imaging of acute limbic encephalitis, in the absence of any evidence for associated cancer during a follow‐up of at least 18 months are described here.

Results

All patients had negative testing for VGKC‐Ab measured during their acute presentation. All patients made some recovery, although they were left with marked cognitive deficits and persistent seizures.

Conclusion

These cases demonstrate that the absence of VGKC‐Ab in limbic encephalitis does not necessarily imply a paraneoplastic form. Further work is required to establish the immunological basis for the disorder in these patients, and the optimal treatment regimen.Limbic encephalitis is characterised by three features: a core amnesic syndrome, complex‐partial and secondary‐generalised seizures, and a variable affective prodrome.^1,2 The core memory syndrome includes profound anterograde amnesia with variable recovery.^1,3 The syndrome is associated with an isolated high signal in the mesial temporal lobes on MRI scan⁴ and histological inflammatory change in these areas.^5,6Limbic encephalitis was initially identified as a paraneoplastic phenomenon, occurring more commonly with occult small‐cell bronchial carcinoma (in association with autoantibodies to Hu), testicular carcinoma and thymoma (in association with antibodies to CRMP5/CV2).⁷ In recent years, a non‐paraneoplastic variant has been characterised.^2,8 Patients with this form have been shown to express increased levels of voltage‐gated potassium channel antibodies (VGKC‐Ab) in their serum. This antibody is also expressed in Morvan''s syndrome,⁹ also with affective and memory components. The detection of such antibodies in serum was established by radioimmunoprecipitation asssays using α‐dendrotoxin, which binds to the Kv1.1, Kv1.2 and Kv1.6 ion channel subunits.^10,11More recently, a second antibody has been identified in patients with a paraneoplastic form of the disorder, a subacute course (where the syndrome can evolve over weeks rather than days) and negative VGKC‐Ab.¹² This antibody in the serum and cerebrospinal fluid (CSF) reacts to the neuropil of the hippocampus and cerebellum. This is in contrast with other paraneoplastic syndromes where the antibody reacts either to oligodendrocytes or to the neuronal cytoplasm. The work suggests the existence of immune‐mediated bases for both paraneoplastic and non‐paraneoplastic forms of the disorder, where these bases are distinct. Consistent with an underlying immunological cause, non‐paraneoplastic^2,13 and paraneoplastic^6,14,15 types of the condition have both been shown to respond to immunotherapies including intravenous steroids, immunoglobulins and plasma exchange. Moreover, the antibody titre in non‐paraneoplastic^2,12,13 and paraneoplastic types¹² has been shown to reflect clinical response to treatment.The above studies suggest characteristic antibody “profiles” for neoplastic and non‐paraneoplastic forms of the disorder, where the non‐paraneoplastic form of the disorder is associated with VGKC‐Ab. Here, we provide evidence for a broader immunological spectrum of non‐paraneoplastic limbic encephalitis. We describe four patients with the typical features of acute limbic encephalitis with no evidence of associated cancer in the absence of serum VGKC‐Ab.     

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.     

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     

Head trauma in primary cranial dystonias: a multicentre case-control study

Background

The relationship between prior trauma and primary adult‐onset dystonia is not well understood. Previous uncontrolled observations and exploratory case–control studies have yielded contradictory results.

Objective

To analyse the association between cranial dystonia and prior head trauma.

Methods

An ad hoc multicentre case–control study was performed using a semistructured interview to collect detailed information on the history of head trauma before disease onset in five Italian tertiary referral centres for movement disorders. The presence of a history of head trauma and of post‐traumatic sequelae (loss of consciousness, bone fractures, scalp/facial wounds) before disease onset was recorded from 177 patients with primary adult‐onset cranial dystonia and from 217 controls with primary hemifacial spasm matched by age strata and sex. Differences between groups were assessed by Mann–Whitney U test and Fisher''s exact test, and the relationship between prior head trauma and case/control status was analysed by multivariate logistic regression models.

Results

No association was found between vault/maxillofacial trauma and cranial dystonia. Most reported traumas occurred several years before disease onset. None of the main post‐traumatic sequelae altered the chance of developing cranial dystonia compared with patients with primary hemifacial spasm, nor did head trauma modify the age at onset of cranial dystonia.

Conclusions

These results do not support prior head trauma as a possible environmental factor modifying the risk of developing late‐onset cranial dystonia. The lack of association may have pathogenetic and medical–forensic implications.Cranial dystonia is an adult‐onset dystonia most commonly affecting the orbicularis oculi and oromandibular muscles.^1,2,3 Like other forms of primary adult‐onset dystonia, cranial dystonias are thought to be multifactorial in origin, with a possible contribution of both genetic and environmental factors.⁴Head trauma leading to structural lesions in the caudate, lentiform nuclei, thalami or midbrain is one of the possible causes of secondary dystonia.^5,6,7,8 A few uncontrolled studies have also suggested an association between cranial dystonia and head trauma in the absence of overt brain lesions.^9,10 Two possible pathogenic mechanisms have been proposed to explain the link between traumatic head injury and cranial dystonia.^9,10,11 The first is discrete brain damage in “sensitive” areas such as the basal ganglia. The second mechanism is that of a peripheral maxillofacial trauma inducing topographically related dystonia^12,13 through maladaptive plastic reorganisation of cortical and subcortical circuits.^{9,10,12,13,14} Two exploratory case–control studies nevertheless found no significant association with cranial dystonia.^15,16 Because these studies assessed a large number of variables owing to multiple testing, they were more liable to a higher risk of false positive results than ad hoc hypothesis‐testing studies. In addition, prior studies^15,16 only partly explored the relationship between dystonia and clinical features of the trauma (loss of consciousness, scalp or facial wounds, cranial or maxillofacial bone fractures), the topographical distribution of the trauma (vault or maxillofacial localisation) and the time elapsed from the trauma to the development of dystonia.To discuss these shortcomings and establish the relationship between previous head trauma and primary late‐onset cranial dystonia, we conducted an ad hoc multicentre case–control study, collecting detailed information on the history of head trauma antecedent to the onset of dystonia.     

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.     

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).     

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     

Visual neglect after right posterior cerebral artery infarction

Objectives

To investigate the characteristics and neuroanatomical correlates of visual neglect after right‐sided posterior cerebral artery (PCA) infarction.

Methods

15 patients with acute PCA strokes were screened for the presence of neglect on a comprehensive battery of cognitive tests. Extra tests of visual perception were also carried out on six patients. To establish which areas were critically associated with neglect, the lesions of patients with and without neglect were compared.

Results

Neglect of varying severity was documented in 8 patients. In addition, higher‐order visual perception was impaired in 5 of the 6 patients. Neglect was critically associated with damage to an area of white matter in the occipital lobe corresponding to a white matter tract connecting the parahippocampal gyrus with the angular gyrus of the parietal lobe. Lesions of the thalamus or splenium of the corpus callosum did not appear necessary or sufficient to cause neglect, but may mediate its severity in these patients.

Conclusions

PCA stroke can result in visual neglect. Interruption of the white matter fibres connecting the parahippocampal gyrus to the angular gyrus may be important in determining whether a patient will manifest neglect.Visual neglect is a frequently observed syndrome after unilateral brain damage, characterised by a failure to respond to contralesional stimuli.^1,2 Neglect is particularly prevalent acutely after right‐hemisphere stroke. Most patients with the syndrome have damage in the territory of the middle cerebral artery, although the critical lesion areas responsible for causing neglect are controversial.^2,3,4,5 Neglect has also been reported after lesions of the thalamus,^2,6,7 but it is less well documented that the syndrome can follow strokes in the wider territory of the superficial posterior cerebral artery (PCA).The anatomy of neglect after PCA infarction was first directly addressed only recently by Mort et al.⁵ Visual neglect was associated with lesions that extended from the occipital lobe anteriorally to the parahippocampal region and centred on an area of white matter in the ventromedial temporal lobe. The authors raised the possibility that disruption of the parietotemporal white matter tracts may explain the presence of neglect in these patients. Interestingly, in this context, a recent study⁸ using diffusion‐weighted imaging and probabilistic tractography in healthy humans has documented robust projections between the parahippocampal gyrus and the angular gyrus of the parietal lobe, homologous to the tract that connects the same regions in non‐human primates.⁹ A second study by Park et al¹⁰ reported several areas as being associated with visual neglect, including the parahippocampal gyrus and the thalamus. However, multiple regression analyses showed that the only combination of lesions to contribute considerably to the frequency and severity of neglect was damage to both the occipital lobe and the splenium of the corpus callosum. The authors proposed that this pattern of damage results in deafferentation and disconnection of visual information to one hemisphere, which may be sufficient to cause neglect.In addition to neglect, PCA infarction may also lead to other visual perceptual deficits, as might be expected with damage to areas characterised as being in the ventral visual pathway.¹¹ However, visual perceptual deficits from damage to areas in the ventral visual stream in the right hemisphere are usually documented only in the context of category‐specific agnosias, such as prosopagnosia or landmark agnosia (or topographagnosia).^{12,13,14,15,16} It therefore remains an open question whether damage to the ventral medial temporal and occipital cortices results in more general perceptual impairments. We aimed (1) to examine the characteristics of neglect and perceptual deficits from PCA infarction, by assessing patients with right‐sided PCA infarction on a battery of neglect tests and a subgroup on tests of visual perception; (2) to investigate which anatomical areas are most commonly damaged in PCA neglect, paying particular attention to those areas implicated in previous studies (the thalamus, parahippocampal gyrus and splenium); and (3) to explore whether disconnection of cortical areas is a likely cause of neglect after PCA infarction.     

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.     

Cognitive outcome 5 years after bilateral chronic stimulation of subthalamic nucleus in patients with Parkinson's disease

Aim

To assess the long‐term cognitive and behavioural outcome after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients affected by Parkinson''s disease, with a 5‐year follow‐up after surgery.

Methods

11 patients with Parkinson''s disease treated by bilateral DBS of STN underwent cognitive and behavioural assessments before implantation, and 1 and 5 years after surgery. Postoperative cognitive assessments were carried out with stimulators turned on.

Results

A year after surgery, there was a marginally significant decline on a letter verbal fluency task (p = 0.045) and a significant improvement on Mini‐Mental State Examination (p = 0.009). 5 years after surgery, a significant decline was observed on a letter verbal fluency task (p = 0.007) and an abstract reasoning task (p = 0.009), namely Raven''s Progressive Matrices 1947. No significant postoperative change was observed on other cognitive variables. No patient developed dementia 5 years after surgery. A few days after the implantation, two patients developed transient manic symptoms with hypersexuality and one patient developed persistent apathy.

Conclusion

The decline of verbal fluency observed 5 years after implantation for DBS in STN did not have a clinically meaningful effect on daily living activities in our patients with Parkinson''s disease. As no patient developed global cognitive deterioration in our sample, these findings suggest that DBS of STN is associated with a low cognitive and behavioural morbidity over a 5‐year follow‐up, when selection criteria for neurosurgery are strict.Chronic bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective neurosurgical procedure for treatment of motor symptoms in patients with advanced Parkinson''s disease, who cannot be satisfactorily treated with pharmacological treatments. The safety of this procedure has been investigated by several studies, which have assessed the effects of STN DBS on cognition and behaviour.^1,2,3 Some investigations have also attempted to distinguish between the cognitive effects of surgical intervention and those of DBS of STN in itself.^4,5,6,7All neuropsychological investigations in patients treated by STN DBS showed a postoperative decline of verbal fluency, whereas less consistent effects have been reported on other cognitive tasks in different studies. A postoperative decline of episodic verbal memory, which was detectable 3 months after surgery, has been reported in some investigations.^6,8Different effects of STN DBS on various frontal cognitive functions have been described. STN stimulation may impair response‐inhibition performance on the interference task of the Stroop test, as compared with the off‐stimulation condition.^5,7,9 A positron emission tomography study showed that such impaired performance on the Stroop test in the on‐stimulation condition is associated with decreased activation in both the right anterior cingulate cortex and the right ventral striatum.⁹ Conversely, short‐term STN stimulation may improve performance on cognitive flexibility tasks, including random number generation⁷ and the Modified Wisconsin Card Sorting Test (MWCST).⁵Various behavioural effects have been described in patients with Parkinson''s disease treated by STN DBS. Some studies reported cases of depression¹⁰ or increased apathy,¹¹ whereas cases of mania were described in other studies^12,13,14 and an improvement of depression¹ or apathy¹⁵ was also found.The long‐term cognitive and behavioural effects of bilateral STN DBS were investigated in 70 patients with Parkinson''s disease followed up for 3 years.¹¹ In this study, a decline of verbal fluency, an improvement of depression and an increased apathy were observed 3 years after surgery. Some patients showed behavioural changes (aggressive behaviour, hypomania, depression and psychosis), which were mostly transient. Recently, the long‐term outcome of bilateral DBS of STN was investigated in a multicentre study conducted in 49 patients with Parkinson''s disease followed up for 3 or 4 years.¹⁶ This study showed that stimulation of the STN induced a significant improvement in Parkinsonian motor symptoms and activities of daily living 3–4 years after surgery. Among the adverse events, the authors reported memory decline or psychiatric disturbances (including hallucinations, delirium, depression, apathy and anxiety), which occurred in about 30% of the patients.In two recent investigations, the long‐term outcome of bilateral DBS of STN was investigated in patients with a 5‐year follow‐up.^17,18 In one study conducted on 49 patients with Parkinson''s disease,¹⁷ cognitive performance was assessed by means of the Mattis Dementia Rating Scale (MDRS)¹⁹ and a frontal‐lobe score.⁴ Five years after surgery, there was a marked improvement of both motor function, while off drugs, and activities of daily living, a statistical trend towards a decline on the MDRS (reflecting the appearance of progressive dementia in three patients between the third and the fifth postoperative years) and a significant decline in the average frontal‐lobe score. Another study carried out on 37 patients with Parkinson''s disease¹⁸ also assessed cognitive performance by means of MDRS¹⁹ and a frontal score.²⁰ Five years after the implantation, there was an improvement in Parkinsonian motor symptoms and activities of daily living and a reduction of levodopa‐related motor complications and levodopa daily doses. However, a significant decline in cognitive performance was detected on the MDRS and the frontal score.To our knowledge, no extensive neuropsychological data have been reported so far in patients with a follow‐up >3 years. The aim of the present study was to assess the long‐term cognitive and behavioural outcome after bilateral DBS of the STN in a series of patients followed up for 5 years after surgery.