This systematic review asked, ‘What is the risk of awake seizures in pure sleep-related epilepsy?’ 9885 titles were identified; 2312 were excluded (not human or adult); 40 full texts were reviewed; six papers met our inclusion criteria; each of these six studies had a different pure sleep-related epilepsy definition.
Using the largest prospective study, we were able to calculate next year's awake seizure chance (treated with antiepileptic medication). This was maximal in the second year: 5.7% (95% CI 3.0 to 10.4%). European licensing bodies including the UK's Driver and Vehicle Licensing Agency broadly accept a risk of less than 20% for Group 1 licensing. However, this study excluded patients with frontal-lobe epilepsies. Furthermore, follow-up (n=160) varied from 2 to 6 years, yet new awake seizures may occur even after 10–20 years of pure sleep-related epilepsy
A paucity of evidence underpins present licensing law; current rulings would be difficult to defend if legally challenged. The law may be penalising people with pure sleep-related epilepsy without increased risk of awake seizures, while failing to identify subgroups at unacceptable risk of an awake seizure at the wheel.
]]>Conventional structural MRI fails to identify a cerebral lesion in 25% of patients with cryptogenic partial epilepsy (CPE). Diffusion tensor imaging is an MRI technique sensitive to microstructural abnormalities of cerebral white matter (WM) by quantification of fractional anisotropy (FA). The objectives of the present study were to identify focal FA abnormalities in patients with CPE who were deemed MRI negative during routine presurgical evaluation.
Diffusion tensor imaging at 3 T was performed in 12 patients with CPE and normal conventional MRI and in 67 age matched healthy volunteers. WM integrity was compared between groups on the basis of automated voxel-wise statistics of FA maps using an analysis of covariance. Volumetric measurements from high resolution T1-weighted images were also performed.
Significant FA reductions in WM regions encompassing diffuse areas of the brain were observed when all patients as a group were compared with controls. On an individual basis, voxel based analyses revealed widespread symmetrical FA reduction in CPE patients. Furthermore, asymmetrical temporal lobe FA reduction was consistently ipsilateral to the electroclinical focus. No significant correlations were found between FA alterations and clinical data. There were no differences in brain volumes of CPE patients compared with controls.
Despite normal conventional MRI, WM integrity abnormalities in CPE patients extend far beyond the epileptogenic zone. Given that unilateral temporal lobe FA abnormalities were consistently observed ipsilateral to the seizure focus, analysis of temporal FA may provide an informative in vivo investigation into the localisation of the epileptogenic zone in MRI negative patients.
Diminished ability to perceive one's own impairments, whether cognitive or social, is common in dementia, in particular frontotemporal dementia (FTD), where ‘lack of insight’ is listed as a core diagnostic feature. Yet, there is no currently accepted method for measuring insight in dementia. The most commonly used methods, which involve comparing patients' opinions of their level of impairment with the opinions of care givers or close family members, are subjective and require the participation of a knowledgeable informant. Here, the authors introduce a new method that allows objective quantification of an individual's awareness of their cognitive abilities and relies upon objective bedside testing.
The authors administered several tests of everyday, real-world functions to patients with FTD (n=10) and Alzheimer's disease (AD, n=10) and to control subjects (n=10). Prior to the tasks, participants were asked to predict their performance using a percentile-based rating system. They were also asked to estimate their performance after task completion. Differences between their self-rated and actual performances were calculated.
Whereas the control group showed very little discrepancy between pretest predictions, post-task estimates and actual performance (mean difference of 3.9 percentile points for prediction/3.0 percentile points for post-task estimate), both patient groups overpredicted and overestimated their performance, with a significantly greater discrepancy for FTD (49.0/54.3 percentile points) than AD (27.2/28.3 percentile points).
Failures of insight and self-awareness of cognitive dysfunction can be objectively measured in dementia without the assistance of an informant, which will facilitate further study of this key component of higher cognitive functioning.
To evaluate the clinimetric properties of the Rehabilitation Complexity Scale (RCS) in a neurorehabilitation inpatient sample.
Observational cohort analysis in a tertiary specialist setting.
179 consecutive patients (mean age 44.5 years (SD 15 years), males:females 110:69) with complex neurological disabilities, mainly following acquired brain injury.
Repeat RCS ratings of the level of care, nursing, therapy and medical interventions were examined for dimensionality, repeatability, consistency and responsiveness, and compared with the Northwick Park Nursing and Therapy Dependency Scales, the Functional Independence Measure (FIM) and Barthel Index, recorded at the start and end of treatment.
The test–retest reliability confirmed the RCS to be repeatable ( 0.93 to 0.96) and moderately responsive to changes in levels of intervention over the course of the programme, suggesting the need for serial evaluation. Coefficient- was 0.76 and item-total correlations all >0.50, with moderate to high loadings on the first principal component. Factor analysis revealed two clear factors (‘Nursing/medical care,’ and ‘Therapies’). The RCS demonstrated good convergent and discriminant validity with the Northwick Park Nursing and Therapy Dependency Scales but some ceiling effect. FIM motor and Barthel scores correlated well with basic care and nursing scores (Spearman rho –0.65 to –0.79) but less well with therapy (rho –0.26) and medical (rho –0.28 to –0.33) scores.
In this cohort, the RCS provided a reliable, valid and moderately responsive profile of rehabilitation interventions, separating into two main subscales. It usefully identified medical and therapy inputs not captured by the FIM and Barthel Index, which are commonly used to define case complexity in rehabilitation.
To study the occurrence of utilisation behaviour (UB) in patients with frontotemporal dementia (FTD).
Twenty patients who fulfilled all core Consensus statement criteria for FTD were examined by a neurologist experienced in dementia and by a clinical neuropsychologist. All patients had imaging evidence of predominantly frontal or frontotemporal involvement. Behavioural data were obtained from care givers using a semistructured questionnaire. Questions related to UB were asked in detail. Further assessment for UB was done during the interview with the patient using common objects. Only frank and coherent UB was considered for the study. For comparison, 34 patients with probable Alzheimer's disease diagnosed by the NINCDS-ADRDA criteria were also similarly studied.
80 per cent of our patients with FTD but none with probable Alzheimer's disease exhibited UB. Fourteen out of the 16 patients with FTD who exhibited UB were less than 70 years old. Among patients with UB, 88% exhibited a wide range of ‘incidental’ UB. Objects of daily use tended to trigger UB most commonly. Utilisation behaviour tended to correspond to premorbid habits in at least 75% of our patients.
Utilisation behaviour may be more common in FTD patients than is currently recognised. The presence of UB should be queried in every patient suspected to be suffering from FTD. A comprehensive questionnaire for UB such as that used here could be useful.
To compare the performance of patients with mild–moderate Alzheimer's disease (AD) and vascular dementia (VaD) on tests of information processing and attention.
Patients with AD (n=75) and VaD (n=46) were recruited from a memory clinic along with dementia-free participants (n=28). They underwent specific tests of attention from the Cognitive Drug Research battery, and pen and paper tests including Colour Trails A and B and Stroop. All patients had a CT brain scan that was independently scored for white-matter change/ischaemia.
Attention was impaired in both AD and VaD patients. VaD patients had more impaired choice reaction times and were less accurate on a vigilance test measuring sustained attention. Deficits in selective and divided attention occurred in both patient groups and showed the strongest correlations with Mini Mental State Examination scores.
This study demonstrates problems with the attentional network in mild–moderate AD and VaD. The authors propose that attention should be tested routinely in a memory clinic setting.
Cognitive decline is common in Parkinson's disease (PD). Although some of the aetiological factors are known, it is not yet known whether drugs with anticholinergic activity (AA) contribute to this cognitive decline. Such knowledge would provide opportunities to prevent acceleration of cognitive decline in PD.
To study whether the use of agents with anticholinergic properties is an independent risk factor for cognitive decline in patients with PD.
A community-based cohort of patients with PD (n=235) were included and assessed at baseline. They were reassessed 4 and 8 years later. Cognition was assessed using the Mini-Mental State Examination (MMSE). A detailed assessment of the AA of all drugs prescribed was made, and AA was classified according to a standardised scale. Relationships between cognitive decline and AA load and duration of treatment were assessed using bivariate and multivariate statistical analyses.
More than 40% used drugs with AA at baseline. During the 8-year follow-up, the cognitive decline was higher in those who had been taking AA drugs (median decline on MMSE 6.5 points) compared with those who had not taken such drugs (median decline 1 point; p=0.025). In linear regression analyses adjusting for age, baseline cognition and depression, significant associations with decline on MMSE were found for total AA load (standardised β=0.229, p=0.04) as well as the duration of using AA drugs (standardised β 0.231, p=0.032).
Our findings suggest that there is an association between anticholinergic drug use and cognitive decline in PD. This may provide an important opportunity for clinicians to avoid increasing progression of cognitive decline by avoiding drugs with AA. Increased awareness by clinicians is required about the classes of drugs that have anticholinergic properties.
Among several aetiological factors, PARK2 mutations are the most common cause of Parkinson disease (PD) that result in degeneration of dopaminergic neurons in the substantia nigra.
In order to examine the contribution of PARK2 mutations and corresponding Parkin expression in blood of North West Indian PD patients, the authors screened 120 000 patients from 2001 to 2006 for features of PD using UK Parkinson disease society brain bank clinical diagnostic criteria (UKPDBBC), and tested PARK2 mutations in 69 of those that fulfilled this criteria. 43 controls lacking extrapyramidal signs were also analysed.
The PCR analysis revealed the occurrence of homozygous deletions in 28 of 69 samples analysed (40.5%) represented by exon-1 (15.9%), exon-3 (11.5%), and exon-12 (11.5%). Sequencing revealed point mutations in exon 4 and exon 9 in six of these patients (8.7%) including one novel missense Gly1083Trp mutation in one patient. Parkin estimation was done by combination of immunolocalisation and FACS analysis revealing reduced Parkin expression among PD patients. The mutations in exons 1, 3 and 12 among sporadic PD patients were found to be higher among younger onset variants (age<45 years). This report also constitutes the first evidence that PARK 2 mutations contribute to the aberration in Parkin expression in blood leading to PD.
Gait and speech were analysed on 11 Parkinsonian patients (PP) undergoing deep-brain stimulation of the subthalamic nucleus (STN-DBS) and 11 control subjects under three conditions of velocity (natural, slow and speed). The patients were tested with and without
The results confirmed that PP walk and read more slowly than controls. Patient's difficulties in modulating walking and speech velocities seem to be due mainly to an inability to internally control the step length and the interpause-speech duration (ISD).
STN-DBS and levodopa increased patients' walking velocity by increasing the step length. STN-DBS and levodopa had no effect on speech velocity but restored the patients' ability to modulate the ISD. The walking cadence and speech index of rythmicity tended to be lower in patients and were not significantly improved by STN-DBS or levodopa. Speech and walking velocity as well as ISD and step length were correlated in both groups. Negative correlations between speech index of and walking cadence were observed in both groups.
Similar fundamental hypokinetic impairment and probably a similar rhythmic factor similarly affected the patients' speech and gait. These results suggest a similar physiopathological process in both walking and speaking dysfunction.
]]>Magnetic resonance (MR) diffusion and perfusion imaging are used to identify ischaemic penumbra, but there are few comparisons with neuronal loss and ischaemia in vivo. The authors compared N-acetyl aspartate (NAA, found in intact neurons) and lactate (anaerobic metabolism) with diffusion/perfusion parameters.
The authors prospectively recruited patients with acute ischaemic stroke and performed MR diffusion tensor, perfusion (PWI) and proton chemical shift spectroscopic imaging (CSI). We superimposed a 0.5 cm voxel grid on the diffusion-weighted images (DWI) and classified voxels as ‘definitely abnormal,’ ‘possibly abnormal’ or normal on DWI appearance, and ‘mismatch’ for voxels in DWI/PWI mismatch areas. The authors compared metabolite (NAA, lactate), perfusion and apparent diffusion coefficient (ADC) values in each voxel type.
NAA differentiated ‘definitely’ from ‘possibly abnormal,’ and ‘possibly abnormal’ from ‘mismatch’ (both comparisons p<0.01) voxels, but not ‘mismatch’ from ‘normal’ voxels. Lactate was highest in ‘definitely abnormal,’ and progressively lower in ‘possibly abnormal,’ ‘mismatch,’ than ‘normal’ voxels (all differences p<0.01). There was no correlation between NAA and ADC or PWI values, but high lactate correlated with low ADC (Spearman r=–0.41, p=0.02) and prolonged mean transit time (Spearman r=0.42, p=0.02).
ADC and mean transit time indicate the presence of ischaemia (lactate) but not cumulative total neuronal damage (NAA) in acute ischaemic stroke, suggesting that caution is required if using ADC and PWI parameters to differentiate salvageable from non-salvageable tissue. Further refinement of the DWI/PWI concept is required prior to more widespread use.
The pathogenesis of cerebral small-vessel disease (SVD) is incompletely understood. Endothelial dysfunction has been implicated and may result in increased blood–brain barrier (BBB) permeability with leakage of blood constituents into the vessel wall and white matter. We used contrast-enhanced MRI to determine whether there was any evidence for BBB permeability in the white matter of patients with SVD, and whether this was present not only in areas of leucoaraiosis (white-matter lesions) but also in normal-appearing white matter (NAWM).
Subjects underwent T1 volumetric MRI before and after bolus injection of contrast. Scanning was continued for 30 min postinjection to determine the contrast-enhancement time course. The mean signal intensity change was plotted against time to calculate the area under the curve values, a parameter related to BBB permeability. Automated brain segmentation and regions of interest analysis were performed to determine ‘permeability’ in different brain compartments.
Compared with controls (n=15), the SVD patient group (n=24) had signal changes consistent with increased BBB permeability in NAWM (p=0.033). Multivariate regression analyses identified leucoaraiosis grade as an independent predictor of these permeability related signal changes in NAWM after adjustment for age, gender, weight, brain volume, area under the curve in the internal carotid arteries and cardiovascular risk factors.
This study provides evidence for increased BBB permeability in SVD, and this is particularly seen in SVD with leucoaraiosis. Its presence in NAWM would be consistent with it playing a causal role in disease pathophysiology.
Infections in patients with stroke are common and significantly affect outcome. Various predictors of poststroke infections were determined, such as degree of neurological impairment and implementation of therapeutic interventions. The authors investigated whether stroke location and stroke size are independent risk factors for poststroke infections.
591 patients with acute stroke who were treated on our stroke unit were included in a prospective observational study. Predefined endpoints were pneumonia, urinary-tract infection (UTI) and other infections. The OR of infections was calculated for various stroke locations, stroke lateralisation and three categories of stroke size. Logistic regression models were used to adjust for factors significantly associated with poststroke infections in a single-factor analysis.
In the single-factor analysis, the left anterior cerebral artery territory was associated with pneumonia. After adjustment for relevant covariates, this association was no longer statistically significant. Stroke lateralisation showed no association with infection frequency. The largest stroke size was positively associated with pneumonia (OR 3.5, p<0.001). The smallest lesion size was significantly less associated with the occurrence of UTI (OR 0.4, p<0.01).
In this study, lesion size is an independent risk factor for the development of poststroke infection. Particular brain regions associated with infections could not be determined.
Conventional MRI lesion measures modestly predict long term disability in some clinically isolated syndrome (CIS) studies. Brain atrophy suggests neuroaxonal loss in multiple sclerosis (MS) with the potential to reflect disease progression to a greater extent than lesion measures.
To investigate whether brain atrophy and lesion load, during the first year in patients presenting with CIS, independently predict clinical outcome (development of MS and disability at 6 years).
99 patients presenting with CIS were included in the study. T1 gadolinium enhanced and T2 weighted brain MRI was acquired at baseline and approximately 1 year later. Percentage brain atrophy rate between baseline and follow-up scans was analysed using SIENA.
Mean annual brain atrophy rates were –0.38% for all patients, –0.50% in patients who had developed MS at 6 years and –0.26% in those who had not. Brain atrophy rate (p = 0.005) and baseline T2 lesion load (p<0.001) were independent predictors of clinically definite MS. While brain atrophy rate was a predictor of Expanded Disability Status Scale (EDSS) score in a univariate analysis, only 1 year T2 lesion load change (p = 0.007) and baseline gadolinium enhancing lesion number (p = 0.03) were independent predictors of EDSS score at the 6 year follow-up. T1 lesion load was the only MRI parameter which predicted Multiple Sclerosis Functional Composite score at the 6 year follow-up.
The findings confirm that brain atrophy occurs during the earliest phases of MS and suggest that 1 year longitudinal measures of MRI change, if considered together with baseline MRI variables, might help to predict clinical status 6 years after the first demyelinating event in CIS patients, better than measurements such as lesion or brain volumes on baseline MRI alone.
To characterise West Australian cases of longitudinally extensive myelopathy (LEM).
Twenty six patients with LEM were identified from a cohort of 983 patients with demyelinating disease. Clinical and MRI data and AQP4-IgG results were reviewed.
LEM cases were classified as conventional MS (CMS) 13, neuromyelitis optica (NMO) 7, and isolated LEM 6. LEM was the initial presentation in 13/26 cases. In CMS cases lesions were mainly in the lower cervical cord (C4–C7) whereas in NMO and isolated LEM they were more often thoracic and were longer. The severity of disability was highly variable but was greater in the NMO than the CMS group. Only one of 20 patients tested was seropositive for AQP4-IgG.
LEM occurred as part of CMS or NMO or in isolation. Patients with LEM had highly heterogeneous clinical characteristics and a low rate of AQP4-IgG seropositivity.
To determine the risk of cancer before and after the diagnosis of motor neuron disease (MND), multiple sclerosis (MS) and Parkinson's disease (PD).
Analysis of statistical database of linked statistical abstracts of hospital and mortality data in an area in southern England.
Only people with PD showed a significant difference in the overall incidence of cancer compared with controls (rate ratio (RR) 0.76, 95% CIs 0.70 to 0.82 before PD; RR 0.61, 0.53 to 0.70, after PD). RRs were close to 1 for cancer in patients after MND (0.98, 0.75 to 1.26) and after MS (0.96, 0.83 to 1.09). There were high rate ratios for malignant brain cancer (7.4, 2.4 to 17.5) and Hodgkin's lymphoma (5.3, 1.1 to 15.6) in patients diagnosed with MND after cancer. In people with MS, malignant brain cancer also showed an increased RR both before hospital admission with a diagnosis of MS (3.2, 1.1 to 7.6) and after (2.4, 1.2 to 4.5). In people with PD, several specific cancers showed significantly and substantially reduced RRs for cancer, notably smoking related cancers, including lung cancer (0.5, 0.4 to 0.7, before PD; 0.5, 0.4 to 0.8, after PD) but also cancers that are not strongly smoking related, including colon cancer (0.7, 0.6 to 0.9, before PD; 0.5, 0.4 to 0.8, after PD).
People with MND, or MS, do not have an altered risk of cancer overall. There may sometimes be misdiagnosis between MND or MS and brain tumours. PD carries a reduced risk of cancer overall, of some smoking related cancers and of some cancers that are not smoking related.
Upregulation of persistent Na+ conductances has been linked to axonal degeneration in sporadic amyotrophic lateral sclerosis (ALS) and has also been reported in the transgenic superoxide dismutase-1 (SOD-1) mouse model. The mechanisms of ectopic activity (fasciculations and cramp) and axonal degeneration still require clarification in familial ALS (FALS) in humans, and specifically whether there are any differences to the processes identified in sporadic patients. Consequently, novel threshold tracking techniques were used to assess whether upregulation of persistent Na+ conductances was a feature linked to axonal degeneration in FALS.
Axonal excitability studies were undertaken in six FALS patients, 13 asymptomatic SOD-1 mutation carriers and 45 sporadic ALS (SALS) patients.
Compound muscle action potential amplitude was significantly reduced in FALS (6.3±1.3 mV) and SALS (6.0±0.4 mV) compared with controls (10.0±0.4 mV, p<0.05). The mean strength duration time constant (SD) was significantly increased in FALS (0.55±0.10 ms, p<0.05) and SALS (0.52±0.02 ms, p<0.01) compared with controls (0.41±0.02). There were no differences in SD between asymptomatic SOD-1 mutation carriers and controls. The increase in SD correlated with the CMAP amplitude (r=–0.4) and neurophysiological index (r=–0.4). In separate studies that assessed cortical processes, short interval intracortical inhibition (SICI) was significantly reduced (FALS, –2.7±1.3%; controls 13.7±1.3%, p<0.0001) and intracortical facilitation increased (FALS, –5.0±2.2%; controls –0.4±1.1%, p<0.05) in FALS. The reduction in SICI correlated with SD (r=–0.8).
Taken together, these studies suggest that persistent Na+ conductances are upregulated in FALS and that this upregulation is intrinsically associated with axonal degeneration.
Lipid-storage myopathy (LSM), defined by triglyceride accumulation in muscle fibres, is a heterogeneous group of lipid metabolic disorders predominantly affecting skeletal muscle. In the past 15 years, more than 200 cases of LSM have been reported in the Chinese literature, but the accurate pathogenic mechanisms are still unknown.
In order to gain more insight into the metabolic and genetic dysfunctions of LSM, the authors described a group of Chinese patients with LSM who were very responsive to isolated riboflavin treatment (riboflavin responsive LSM, RR-LSM).
Nineteen consecutive LSM patients collected during 1995–2007 in our Neuromuscular Laboratory who were dramatically responsive to riboflavin and presented with proximal muscle weakness, exercise intolerance and elevated serum CK but without episodic encephalopathy were subjected to pathological, biochemical and molecular analysis.
On the basis of muscle pathology, all 19 patients were diagnosed as LSM. Seventeen patients were suspected of having multiple acyl-coenzyme A dehydrogenase deficiency (MADD) according to blood acylcarnitine profiles and urine organic acid analysis. Genetic analysis identified 19 novel mutations in ETFDH gene in 18 patients, among which one was homozygote, 16 were compound heterozygotes, and one was a single heterozygote. No pathogenic mutation was detected in ETFA or ETFB genes. Western blot analysis showed there was no significant decrease in ETF:QO expression except for one patient.
The research findings suggest that the majority of Chinese patients with RR-LSM are caused by a mild type of MADD with unique myopathy which is due to ETFDH gene mutation.