Showing papers in "Journal of Neurology, Neurosurgery, and Psychiatry in 2014"
TL;DR: Feeling lonely rather than being alone is associated with an increased risk of clinical dementia in later life and can be considered a major risk factor that, independently of vascular disease, depression and other confounding factors, deserves clinical attention.
Abstract: Background Known risk factors for Alzheimer9s disease and other dementias include medical conditions, genetic vulnerability, depression, demographic factors and mild cognitive impairment. The role of feelings of loneliness and social isolation in dementia is less well understood, and prospective studies including these risk factors are scarce. Methods We tested the association between social isolation (living alone, unmarried, without social support), feelings of loneliness and incident dementia in a cohort study among 2173 non-demented community-living older persons. Participants were followed for 3 years when a diagnosis of dementia was assessed (Geriatric Mental State (GMS) Automated Geriatric Examination for Computer Assisted Taxonomy (AGECAT)). Logistic regression analysis was used to examine the association between social isolation and feelings of loneliness and the risk of dementia, controlling for sociodemographic factors, medical conditions, depression, cognitive functioning and functional status. Results After adjustment for other risk factors, older persons with feelings of loneliness were more likely to develop dementia (OR 1.64, 95% CI 1.05 to 2.56) than people without such feelings. Social isolation was not associated with a higher dementia risk in multivariate analysis. Conclusions Feeling lonely rather than being alone is associated with an increased risk of clinical dementia in later life and can be considered a major risk factor that, independently of vascular disease, depression and other confounding factors, deserves clinical attention. Feelings of loneliness may signal a prodromal stage of dementia. A better understanding of the background of feeling lonely may help us to identify vulnerable persons and develop interventions to improve outcome in older persons at risk of dementia.
469 citations
TL;DR: In 27 cohort studies, predictors most consistently associated with death were increasing age, decreasing Glasgow Coma Scale score, increasing ICH volume, presence of intraventricular haemorrhage, and deep/infratentorial ICH location.
Abstract: Background and aim There is uncertainty about the long-term prognosis after spontaneous intracerebral haemorrhage (ICH). Therefore, we systematically reviewed the literature for studies reporting long-term survival and ICH recurrence, and their predictors. Methods We searched Ovid Medline 1946–2011 inclusive for cohort studies of ≥50 patients reporting long-term (>30 days) outcome after ICH. Two reviewers independently extracted data from each study. We meta-analysed 1-year and 5-year survival data from population-based studies using a random effects model (and quantified inconsistency using the I 2 statistic). Results We identified 122 eligible studies. The pooled estimate of 1-year survival was 46% (95% CI 43% to 49%; nine population-based studies (n=2408); I 2 =27%) and 5-year survival was 29% (95% CI 26% to 33%; three population-based studies (n=699); I 2 =6%). In 27 cohort studies, predictors most consistently associated with death were increasing age, decreasing Glasgow Coma Scale score, increasing ICH volume, presence of intraventricular haemorrhage, and deep/infratentorial ICH location. The annual risk of recurrent ICH varied from 1.3% to 7.4% in nine studies and this risk was higher after lobar ICH than non-lobar ICH in two of three hospital-based studies. Four studies reporting the risks of recurrent ICH and ischaemic stroke after ICH found no significant differences between these risks. Conclusions Less than a half of patients with ICH survive 1 year and less than a third survive 5 years. Risks of recurrent ICH and ischaemic stroke after ICH appear similar after ICH, provoking uncertainties about the use of antithrombotic drugs.
429 citations
TL;DR: The incidence and prevalence of multiple sclerosis by age and describe secular trends and geographic variations within the UK over the 20-year period between 1990 and 2010 are estimated to provide updated information on the impact of MS throughout the UK.
Abstract: Objectives To estimate the incidence and prevalence of multiple sclerosis (MS) by age and describe secular trends and geographic variations within the UK over the 20-year period between 1990 and 2010 and hence to provide updated information on the impact of MS throughout the UK. Design A descriptive study. Setting The study was carried out in the General Practice Research Database (GPRD), a primary care database representative of the UK population. Main outcome measures Incidence and prevalence of MS per 100 000 population. Secular and geographical trends in incidence and prevalence of MS. Results The prevalence of MS recorded in GPRD increased by about 2.4% per year (95% CI 2.3% to 2.6%) reaching 285.8 per 100 000 in women (95% CI 278.7 to 293.1) and 113.1 per 100 000 in men (95% CI 108.6 to 117.7) by 2010. There was a consistent downward trend in incidence of MS reaching 11.52 per 100 000/year (95% CI 10.96 to 12.11) in women and 4.84 per 100 000/year (95% CI 4.54 to 5.16) in men by 2010. Peak incidence occurred between ages 40 and 50 years and maximum prevalence between ages 55 and 60 years. Women accounted for 72% of prevalent and 71% of incident cases. Scotland had the highest incidence and prevalence rates in the UK. Conclusions We estimate that 126 669 people were living with MS in the UK in 2010 (203.4 per 100 000 population) and that 6003 new cases were diagnosed that year (9.64 per 100 000/year). There is an increasing population living longer with MS, which has important implications for resource allocation for MS in the UK.
278 citations
TL;DR: Both focal lesions as well as diffuse neurodegeneration in the deep grey matter appeared to contribute to the neurological disabilities of MS patients.
Abstract: In multiple sclerosis (MS), diffuse degenerative processes in the deep grey matter have been associated with clinical disabilities. We performed a systematic study in MS deep grey matter with a focus on the incidence and topographical distribution of lesions in relation to white matter and cortex in a total sample of 75 MS autopsy patients and 12 controls. In addition, detailed analyses of inflammation, acute axonal injury, iron deposition and oxidative stress were performed. MS deep grey matter was affected by two different processes: the formation of focal demyelinating lesions and diffuse neurodegeneration. Deep grey matter demyelination was most prominent in the caudate nucleus and hypothalamus and could already be seen in early MS stages. Lesions developed on the background of inflammation. Deep grey matter inflammation was intermediate between low inflammatory cortical lesions and active white matter lesions. Demyelination and neurodegeneration were associated with oxidative injury. Iron was stored primarily within oligodendrocytes and myelin fibres and released upon demyelination. In addition to focal demyelinated plaques, the MS deep grey matter also showed diffuse and global neurodegeneration. This was reflected by a global reduction of neuronal density, the presence of acutely injured axons, and the accumulation of oxidised phospholipids and DNA in neurons, oligodendrocytes and axons. Neurodegeneration was associated with T cell infiltration, expression of inducible nitric oxide synthase in microglia and profound accumulation of iron. Thus, both focal lesions as well as diffuse neurodegeneration in the deep grey matter appeared to contribute to the neurological disabilities of MS patients.
277 citations
TL;DR: Existing follow-up studies of functional motor symptoms give some insights regarding outcome and prognostic factors but are limited by their largely retrospective and selective nature, and overall prognosis appears unfavourable.
Abstract: Background The prognosis of functional (or psychogenic) motor symptoms (weakness and movement disorder) has not been systematically reviewed. Methods We systematically reviewed PubMed for all studies of eight or more patients with functional motor symptoms reporting follow-up data longer than 6 months (excluding studies reporting specific treatments). We recorded symptom duration, physical and psychiatric comorbidity, disability, occupational functioning at follow-up and prognostic factors. Results 24 studies were included. There was heterogeneity regarding study size (number of patients (n)=10 491), follow-up duration clinical setting and data availability. Most studies (n=15) were retrospective. Reported symptom outcome was highly variable. Mean weighted follow-up duration was 7.4 years (in 13 studies where data was extractable). The mean percentage of patients same or worse at follow-up for all studies was 39%, range 10% to 90%, n=1134. Levels of physical disability and psychological comorbidity at follow-up were high. Short duration of symptoms, early diagnosis and high satisfaction with care predicted positive outcome in two studies. Gender had no effect. Delayed diagnosis and personality disorder were negatively correlated with outcome. Prognostic factors that varied between studies included age, comorbid anxiety and depression, IQ, educational status, marital status and pending litigation. Conclusions Existing follow-up studies of functional motor symptoms give us some insights regarding outcome and prognostic factors but are limited by their largely retrospective and selective nature. Overall, prognosis appears unfavourable. The severity and chronicity of functional motor symptoms argues for larger prospective studies including multiple prognostic factors at baseline in order to better understand their natural history.
256 citations
TL;DR: Baseline clinical features of early relapse frequency and age at onset can be used to select groups at higher risk of developing severe disability based on the probability of their disease becoming progressive within a defined time period.
Abstract: Objectives To assess factors affecting the rate of conversion to secondary progressive (SP) multiple sclerosis (MS) and its subsequent evolution. Methods Among 806 patients with relapsing remitting (RR) onset MS from the London Ontario database, we used Kaplan–Meier, Cox regression and multiple logistic regression analyses to investigate the effect of baseline clinical and demographic features on (1) the probability of, and the time to, SP disease, (2) the time to bedbound status (Disability Status Scale (DSS 8)) from onset of progression. Results The risk of entering the SP phase increased proportionally with disease duration (OR=1.07 for each additional year; p 30 HR=0.52 (p Conclusions The onset of SP MS is the dominant determinant of long-term prognosis, and its prevention is the most important target measure for treatment. Baseline clinical features of early relapse frequency and age at onset can be used to select groups at higher risk of developing severe disability based on the probability of their disease becoming progressive within a defined time period.
229 citations
TL;DR: This study provides pathological validation that the new criteria assist with separating PPA cases with AD pathology into the new lv-PPA syndrome and found that a number of diagnostic clinical features did not assist in discriminating the different FTD syndromes.
Abstract: Objective To assess the impact of new clinical diagnostic criteria for frontotemporal dementia (FTD) syndromes, including primary progressive aphasias (PPA), on prior clinical diagnosis and to explore clinicopathological correlations. Methods 178 consecutive neuropathologically ascertained cases initially diagnosed with a FTD syndrome were collected through specialist programmes: the Cambridge Brain Bank, UK, and Sydney Brain Bank, Australia. 135 cases were reclassified using the revised diagnostic criteria into behavioural variant (bvFTD), semantic variant PPA (sv-PPA), non-fluent/agrammatic variant PPA (nfv-PPA) and logopenic variant PPA (lv-PPA). Pathological diagnoses included FTLD-tau, FTLD-TDP, FTLD-FUS, FTLD-UPS, FLTD-ni and Alzheimer9s disease (AD). Statistical analyses included χ 2 tests, analyses of variance and discriminant statistics. Results Comparison of the original and revised diagnosis revealed no change in 90% of bvFTD and sv-PPA cases. By contrast, 51% of nfv-PPA cases were reclassified as lv-PPA, with apraxia of speech and sentence repetition assisting in differentiation. Previous patterns of pathology were confirmed, although more AD cases occurred in FTD syndromes (10% bvFTD, ∼15% sv-PPA and ∼30% nfv-PPA) than expected. AD was the dominant pathology (77%) of lv-PPA. Discriminant analyses revealed that object agnosia, phonological errors and neuropsychiatric features differentiated AD from FTLD. Conclusions This study provides pathological validation that the new criteria assist with separating PPA cases with AD pathology into the new lv-PPA syndrome and found that a number of diagnostic clinical features (disinhibition, food preferences and naming) did not assist in discriminating the different FTD syndromes.
207 citations
TL;DR: In utero exposure to valproate monotherapy exposure in utero carries a significantly higher MCM risk than lamotrigine, and the requirements for seizure control should not be overlooked.
Abstract: Objectives Antiepileptic drug (AED) exposure during pregnancy increases the risk of major congenital malformations (MCMs). The magnitude of this risk varies by AED exposure. Here we provide updated results from the UK Epilepsy and Pregnancy Register of the risk of MCMs after monotherapy exposure to valproate, carbamazepine and lamotrigine. Methods Fifteen-year prospective observational study from 1996 until 2012. The main outcome measure is the MCM rate. Results Informative outcomes were available for 5206 cases. 1290 women were exposed to valproate monotherapy, 1718 to carbamazepine monotherapy and 2198 to lamotrigine monotherapy. The MCM risk with valproate monotherapy exposure in utero was 6.7% (95% CI 5.5% to 8.3%) compared with 2.6% with carbamazepine (95% CI 1.9% to 3.5%) and 2.3% with lamotrigine (95% CI 1.8% to 3.1%). A significant dose effect was seen with valproate (p=0.0006) and carbamazepine (p=0.03) exposed pregnancies. A non-significant trend towards higher MCM rate with increasing dose was found with lamotrigine. MCM rate for high-dose lamotrigine (>400 mg daily) was lower than the MCM rate for pregnancies exposed to Conclusions In utero exposure to valproate carries a significantly higher MCM risk than lamotrigine (p=0.0001) and carbamazepine (p=0.0001) monotherapy. In contrast to prior findings, high-dose lamotrigine was associated with fewer MCMs than all doses of valproate. While lamotrigine has a favourable profile compared with valproate for adverse pregnancy outcomes, the requirements for seizure control should not be overlooked.
206 citations
TL;DR: Depression, irritability/aggression and OCBs are prevalent in all stages of HD, and apathy was the key neuropsychiatric symptom occurring most often in advanced HD stages.
Abstract: Background The majority of Huntington9s disease (HD) mutation carriers experience some psychopathology during their lifetime, varying from irritability to psychosis, but prevalences of particular symptoms vary widely due to diverse study populations in different stages of HD and the use of different assessment methods. Methods The study population consisted of 1993 HD mutation carriers from 15 European countries, all participating in the observational REGISTRY study. The behavioural section of the Unified HD Rating Scale was used to examine the prevalence and correlates of five neuropsychiatric features: depression, irritability/aggression, obsessive/compulsive behaviours, apathy and psychosis. Results Twenty-seven per cent of the participants did not have any neuropsychiatric symptom in the last month. Moderate to severe apathy occurred in 28.1% of the participants, whereas moderate to severe depression was found in 12.7%. Irritable/aggressive symptoms were present in 13.9% of the participants, and 13.2% showed obsessive/compulsive behaviours. Moderate to severe psychotic symptoms were found in only 1.2%. Only 54.9% of all participants with moderate to severe depression used antidepressants, suggesting undertreatment of depression. Obsessive/compulsive behaviours and irritability/aggression were inversely correlated with the Total Functional Capacity score, but with apathy showing the strongest inverse association. Conclusions A variety of neuropsychiatric symptoms are highly prevalent in different stages of HD in this European HD population, with apathy as the most frequent symptom. Depression, irritability/aggression and OCBs are prevalent in all stages of HD. Apathy was the key neuropsychiatric symptom occurring most often in advanced HD stages. Due to possible selection of relatively healthy participants, prevalences reported in this study might be an underestimation of prevalence in the entire HD population.
203 citations
TL;DR: Since pramipexole, ropinirole and rotigotine are non-ergolinic DAs with very similar pharmacodynamic profiles, it is likely that other factors including route of administration (transdermal vs oral) explain the difference in risk of ICD development.
Abstract: Background Impulse control disorders (ICDs) encompass a wide spectrum of abnormal behaviour frequently found in cases of Parkinson's disease (PD) treated with dopamine agonists (DAs). The main aim of this study was to analyse ICD prevalence with different DAs.
Methods We carried out a multicentre transversal study to evaluate the presence of ICDs in patients with PD chronically treated (>6 months) with a single non-ergolinic DA (pramipexole, ropinirole, or rotigotine). Clinical assessment of ICD was performed using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease.
Results Thirty-nine per cent of patients (91/233) fulfilled the clinical criteria for ICD. The group of patients with ICD symptoms (ICD+) differed from those without ICD symptoms (ICD−) in younger age and type of DA intake. Oral DA treatment (pramipexole and ropinirole) was associated with higher risk of ICDs compared with transdermal DA (rotigotine): 84/197 (42%) patients treated with oral DA developed ICD, versus 7/36 (19%) patients treated with transdermal DA (Fisher's exact text <0.01). In univariate analysis, a younger age (p<0.01), treatment with rasagiline (p<0.05), and especially treatment with an oral DA (pramipexole or ropinirole) (p<0.01) were significantly associated with ICD. Multivariate analysis confirmed that oral DA remained significantly associated with ICD (p: 0.014, OR: 3.14; 1.26–7.83).
Conclusions ICD was significantly associated with the use of the non-ergolinic oral DA (pramipexole and ropinirole) when compared with transdermal non-ergolinic DA (rotigotine). Since pramipexole, ropinirole and rotigotine are non-ergolinic DAs with very similar pharmacodynamic profiles, it is likely that other factors including route of administration (transdermal vs oral) explain the difference in risk of ICD development.
194 citations
TL;DR: The most important clinical aspects of Leigh syndrome are reviewed, and diagnostic steps as well as treatment options are discussed.
Abstract: Leigh syndrome is a devastating neurodegenerative disease, typically manifesting in infancy or early childhood. However, also late-onset cases have been reported. Since its first description by Denis Archibald Leigh in 1951, it has evolved from a postmortem diagnosis, strictly defined by histopathological observations, to a clinical entity with indicative laboratory and radiological findings. Hallmarks of the disease are symmetrical lesions in the basal ganglia or brain stem on MRI, and a clinical course with rapid deterioration of cognitive and motor functions. Examinations of fresh muscle tissue or cultured fibroblasts are important tools to establish a biochemical and genetic diagnosis. Numerous causative mutations in mitochondrial and nuclear genes, encoding components of the oxidative phosphorylation system have been described in the past years. Moreover, dysfunctions in pyruvate dehydrogenase complex or coenzyme Q10 metabolism may be associated with Leigh syndrome. To date, there is no cure for affected patients, and treatment options are mostly unsatisfactory. Here, we review the most important clinical aspects of Leigh syndrome, and discuss diagnostic steps as well as treatment options.
TL;DR: The current knowledge about the mechanisms underlying the development of DCI is summarized and the known pharmacological treatment options with respect to the presumed mechanism of action and its role in DCI are described and categorised.
Abstract: Cerebral vasospasm has traditionally been regarded as an important cause of delayed cerebral ischaemia (DCI) which occurs after aneurysmal subarachnoid haemorrhage, and often leads to cerebral infarction and poor neurological outcome. However, data from recent studies argue against a pure focus on vasospasm as the cause of delayed ischaemic complications. Findings that marked reduction in the incidence of vasospasm does not translate to a reduction in DCI, or better outcomes has intensified research into other possible mechanisms which may promote ischaemic complications. Early brain injury and cell death, blood-brain barrier disruption and initiation of an inflammatory cascade, microvascular spasm, microthrombosis, cortical spreading depolarisations and failure of cerebral autoregulation, have all been implicated in the pathophysiology of DCI. This review summarises the current knowledge about the mechanisms underlying the development of DCI. Furthermore, it aims to describe and categorise the known pharmacological treatment options with respect to the presumed mechanism of action and its role in DCI.
TL;DR: Multiple factors may account for the increased incidence of ischaemic stroke in people aged <55 years including changes in vascular risk factors, better awareness of the disease and treatment options in the population and among practitioners leading to more frequent referrals for specialised care, and improvements in stroke diagnosis.
Abstract: Background Recent data have suggested that stroke incidence in young people may be rising. In this population-based study, we aimed to determine whether the incidence of stroke in people aged Methods All cases of first-ever stroke (ischaemic stroke, spontaneous intracerebral haemorrhage, and undetermined stroke) occurring in Dijon, France, from 1985 to 2011 were prospectively collected from a population-based registry. Incidence rates were calculated and temporal trends were analysed by age groups and stroke subtypes using a Poisson regression to estimate incidence rate ratios (IRR). Risk factors and premorbid treatments were analysed. Results Over the 27-year study period, 4506 patients were recorded (53% women, mean age 74.6±14.4, 10.1% aged Conclusions Multiple factors may account for the increased incidence of ischaemic stroke in people aged
TL;DR: Preliminary data suggests the CESD, HDRS or the PHQ-9 as the most promising options for detecting poststroke depression, although it should be noted such scales should not be used in isolation but followed up with a more detailed clinical assessment.
Abstract: Background Major depression is common in stroke patients and associated with increased rates of disability and mortality. Identifying depression may improve mental and physical health. The aim of this review was to determine the most accurate tool for detecting poststroke depression. Methods Seven databases were searched up to November 2012. Two authors selected studies using International Classification of Disease or Diagnostic and Statistical Manual diagnosis of depression as the reference standard. Two authors extracted data and assessed methodological quality. Included studies were synthesised using meta-analyses. Results A total of 24 included studies provided data on 2907 participants. The Center of Epidemiological Studies-Depression Scale (CESD) (sensitivity: 0.75; 95% CI 0.60 to 0.85; specificity: 0.88; 95% CI 0.71 to 0.95), the Hamilton Depression Rating Scale (HDRS) (sensitivity: 0.84; 95% CI 0.75 to 0.90; specificity:0.83; 95% CI 0.72 to 0.90) and the Patient Health Questionnaire (PHQ)-9 (sensitivity: 0.86; 95% CI 0.70 to 0.94; specificity: 0.79; 95% CI 0.60 to 0.90) appeared to be the optimal measures for screening measures. However, the clinical utility of all tools was modest for case-finding. Interpretation There are a number of possible instruments that may help in screening for poststroke depression but none are satisfactory for case-finding. Preliminary data suggests the CESD, HDRS or the PHQ-9 as the most promising options. Although it should be noted such scales should not be used in isolation but followed up with a more detailed clinical assessment. While there is promising data for the PHQ-2 in other populations, it performed less well than other measures.
TL;DR: The natural course of iNPH is symptom progression over time, with worsening in gait, balance and cognitive symptoms, which is only partially reversible, and surgery should be performed soon after diagnosis.
Abstract: Objectives The natural course of idiopathic normal pressure hydrocephalus (iNPH) has not been thoroughly studied. The consequences of postponing shunt treatment are largely unknown. We aimed to describe the effects of waiting for more than 6 months before surgery and to compare the outcome with that seen in patients who waited for less than 3 months. Methods 33 patients (iNPH Delayed ) underwent an initial investigation (Pre-op 1), followed by re-examination, just prior to surgery, after waiting for at least 6 months (Pre-op 2). Outcome was evaluated after 3 months of treatment. 69 patients who were surgically treated within 3 months after Pre-op 1 and who were also evaluated after 3 months of treatment constituted a comparison group (iNPH Early ). Evaluations were done with the iNPH scale and the modified Rankin Scale (mRS). iNPH Delayed patients were prospectively studied with regard to outcome, whereas the comparison group iNPH Early was defined and analysed retrospectively. Results iNPH Delayed patients deteriorated significantly during their wait for surgery, with progression of symptom severity ranging from +7 to −47 on the iNPH scale, and from 0 to +3 on the mRS (both p Delayed patients had worsened while waiting, their final outcome was significantly poorer. Conclusions The natural course of iNPH is symptom progression over time, with worsening in gait, balance and cognitive symptoms. This deterioration is only partially reversible. To maximise the benefits of shunt treatment, surgery should be performed soon after diagnosis.
TL;DR: Interim TOP data confirm natalizumab's overall safety profile and the low relapse rate and stabilised disability levels in natalIZumab-treated patients with RRMS in clinical practice.
Abstract: Background Clinical trials established the efficacy and safety of natalizumab. Data are needed over longer periods of time and in the clinical practice setting. Objective To evaluate long-term safety of natalizumab and its impact on annualised relapse rate and Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting multiple sclerosis (RRMS). Methods The Tysabri (natalizumab) Observational Program (TOP) is an open-label, multinational, 10-year prospective study in clinical practice settings. Results In this 5-year interim analysis, 4821 patients were enrolled. Follow-up for at least 4 years from natalizumab commencement in 468 patients and at least 2 years in 2496 patients revealed no new safety signals. There were 18 cases of progressive multifocal leucoencephalopathy reported, following 11-44 natalizumab infusions. Mean annualised relapse rate decreased from 1.99 in the 12 months prior to baseline to 0.31 on natalizumab therapy (p Conclusions Interim TOP data confirm natalizumab's overall safety profile and the low relapse rate and stabilised disability levels in natalizumab-treated patients with RRMS in clinical practice. Trial registration number NCT00493298.
Katholieke Universiteit Leuven1, Emory University2, UCL Institute of Neurology3, Cleveland Clinic4, Pontifícia Universidade Católica de Goiás5, University of Dundee6, Toronto Western Hospital7, Karolinska Institutet8, Jaslok Hospital9, Aix-Marseille University10, Alfaisal University11, Shanghai Jiao Tong University12, Ninewells Hospital13, North Shore University Hospital14, Cornell University15, Harvard University16, Ohio State University17, Leibniz University of Hanover18, University of Miami19, Yonsei University20, Otto-von-Guericke University Magdeburg21, Brown University22, Capital Medical University23
TL;DR: This consensus document on ethical and scientific conduct of psychiatric surgery worldwide is designed to enhance patient safety and address a broad range of neuropsychiatric disorders, brain targets and neurosurgical techniques.
Abstract: Background For patients with psychiatric illnesses remaining refractory to ‘standard’ therapies, neurosurgical procedures may be considered. Guidelines for safe and ethical conduct of such procedures have previously and independently been proposed by various local and regional expert groups. Methods To expand on these earlier documents, representative members of continental and international psychiatric and neurosurgical societies, joined efforts to further elaborate and adopt a pragmatic worldwide set of guidelines. These are intended to address a broad range of neuropsychiatric disorders, brain targets and neurosurgical techniques, taking into account cultural and social heterogeneities of healthcare environments. Findings The proposed consensus document highlights that, while stereotactic ablative procedures such as cingulotomy and capsulotomy for depression and obsessive-compulsive disorder are considered ‘established’ in some countries, they still lack level I evidence. Further, it is noted that deep brain stimulation in any brain target hitherto tried, and for any psychiatric or behavioural disorder, still remains at an investigational stage. Researchers are encouraged to design randomised controlled trials, based on scientific and data-driven rationales for disease and brain target selection. Experienced multidisciplinary teams are a mandatory requirement for the safe and ethical conduct of any psychiatric neurosurgery, ensuring documented refractoriness of patients, proper consent procedures that respect patient’s capacity and autonomy, multifaceted preoperative as well as postoperative long-term followup evaluation, and reporting of effects and side effects for all patients. Interpretation This consensus document on ethical and scientific conduct of psychiatric surgery worldwide is designed to enhance patient safety.
TL;DR: The SMA shows a wide range of white matter connections with motor, language and lymbic areas, and features of the SMA syndrome can be better understood on the basis of these findings.
Abstract: Introduction The supplementary motor area (SMA) is frequently involved by brain tumours (particularly WHO grade II gliomas). Surgery in this area can be followed by the ‘SMA syndrome’, characterised by contralateral akinesia and mutism. Knowledge of the connections of the SMA can provide new insights on the genesis of the SMA syndrome, and a better understanding of the challenges related to operating in this region. Methods White matter connections of the SMA were studied with both postmortem dissection and advance diffusion imaging tractography. Postmortem dissections were performed according to the Klingler technique. 12 specimens were fixed in 10% formalin and frozen at −15°C for 2 weeks. After thawing, dissection was performed with blunt dissectors. For diffusion tractography, high-resolution diffusion imaging datasets from 10 adult healthy controls from the Human Connectome Project database were used. Whole brain tractography was performed using a spherical deconvolution approach. Results Five main connections were identified in both postmortem dissections and tractography reconstructions: (1) U-fibres running in the precentral sulcus, connecting the precentral gyrus and the SMA; (2) U-fibres running in the cingulate sulcus, connecting the SMA with the cingulate gyrus; (3) frontal ‘aslant’ fascicle, directly connecting the SMA with the pars opercularis of the inferior frontal gyrus; (4) medial fibres connecting the SMA with the striatum; and (5) SMA callosal fibres. Good concordance was observed between postmortem dissections and diffusion tractography. Conclusions The SMA shows a wide range of white matter connections with motor, language and lymbic areas. Features of the SMA syndrome (akinesia and mutism) can be better understood on the basis of these findings.
TL;DR: It is confirmed that STN-DBS, using an MRI-guided/MRI-verified technique, remains an effective treatment for motor ‘off’ symptoms of PD in the long term with low morbidity.
Abstract: Background Subthalamic nucleus (STN) deep brain stimulation (DBS) represents a well-established treatment for patients with advanced Parkinson9s disease (PD) insufficiently controlled with medical therapies. This study presents the long-term outcomes of patients with PD treated with STN-DBS using an MRI-guided/MRI-verified approach without microelectrode recording. Methods A cohort of 41 patients who underwent STN-DBS were followed for a minimum period of 5 years, with a subgroup of 12 patients being followed for 8–11 years. Motor status was evaluated using part III of the Unified Parkinson9s Disease Rating Scale (UPDRS-III), in on- and off-medication/on-stimulation conditions. Preoperative and postoperative assessments further included activities of daily living (UPDRS-II), motor complications (UPDRS-IV), neuropsychological and speech assessments, as well as evaluation of quality of life. Active contacts localisation was calculated and compared with clinical outcomes. Results STN-DBS significantly improved the off-medication UPDRS-III scores, compared with baseline. However, UPDRS scores increased over time after DBS. Dyskinesias, motor fluctuations and demands in dopaminergic medication remained significantly reduced in the long term. Conversely, UPDRS-III on-medication scores deteriorated at 5 and 8 years, mostly driven by axial and bradykinesia subscores. Quality of life, as well as depression and anxiety scores, did not significantly change at long-term follow-up compared with baseline. In our series, severe cognitive decline was observed in 17.1% and 16.7% of the patients at 5 and 8 years respectively. Conclusions Our data confirm that STN-DBS, using an MRI-guided/MRI-verified technique, remains an effective treatment for motor ‘off’ symptoms of PD in the long term with low morbidity.
TL;DR: Thalamic DBS is a safe and effective therapy in patients with essential tremor followed for up to 13 years, and a total non-blinded improvement in the tremor rating scale of 39% was observed in the ‘on’ state.
Abstract: Background Deep brain stimulation (DBS) has proven to be a safe and effective therapy for refractory essential tremor, but information regarding long-term outcomes is lacking. Objectives We aimed to assess the long-term safety and efficacy of DBS in patients with essential tremor. Methods Patients treated with DBS for essential tremor for at least 8 years were evaluated in the ‘on’ and ‘off’ state using the Fahn–Tolosa–Marin tremor rating scale, and their medical records were reviewed to assess complications related to this therapy. Results We studied 13 patients (7 men): median age at evaluation 79 years (range 47–88), median age at electrode implantation 68 years (range 37–78) and mean time since electrode implantation 132.54±15.3 months (range 114–164). The difference between the ‘off’ and ‘on’ state on the motor items of the tremor rating scale was 41.9% (58.62 vs 34.08, p Conclusions Thalamic DBS is a safe and effective therapy in patients with essential tremor followed for up to 13 years.
TL;DR: This long-term study shows that whole brain, cortical and putamen atrophy occurs throughout the 10-year follow-up of this MS cohort and is more pronounced in the group that showed disability progression at 5, but not at 10 years of follow- up.
Abstract: Objectives To identify MRI biomarkers associated with long-term disability progression in patients with multiple sclerosis (MS), and to define the rate of evolution of global, tissue-specific and regional atrophy in patients with MS over long-term. Methods MRI of the brain and clinical neurological assessment was performed in 81 patients at time of first visit and after 5 and 10 years of follow-up. MRI was acquired on 1.5 T scanners. T1-lesion and T2-lesion volumes (LVs) were calculated. Global and tissue-specific atrophy changes were longitudinally assessed, using a direct measurement approach, by calculating percentage volume changes between different time points. Regional tissue volumes for the subcortical deep grey matter (SDGM) structures were also obtained. Disability progression was defined as an increase in Expanded Disability Status Scale of ≥1.0 compared to baseline at 5-year and 10-year follow-up. Results Over 5 years, patients with disability progression showed significantly increased loss of whole brain (−3.8% vs −2.0%, p Conclusion This long-term study shows that whole brain, cortical and putamen atrophy occurs throughout the 10-year follow-up of this MS cohort and is more pronounced in the group that showed disability progression at 5, but not at 10 years of follow-up. Overall, GM atrophy showed better association with disease progression than WM atrophy over 5-year and 10-year follow-up.
TL;DR: PRBD is common and under-recognised in early Parkinson's disease, associated with increased severity and frequency of non-motor features, poorer subjective motor performance and a greater impact on health-related quality of life.
Abstract: Background Concomitant REM sleep behaviour disorder (RBD) is commonly observed in patients with Parkinson’s disease (PD). Although the brainstem structures responsible for the symptoms of RBD correspond to the premotor stages of PD, the association of RBD with motor and non-motor features in early PD remains unclear. Methods The study evaluated 475 patients with PD within 3.5 years of diagnosis for the presence of probable RBD (pRBD) using the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ). A neurologist and a trained research nurse carried out evaluation of each participant blinded to the results of the RBDSQ. Standardised rating scales for motor and non-motor features of PD, as well as health-related quality of life measures, were assessed. Multiple linear and logistic regression analyses were used to determine the relationship between pRBD and a variety of outcomes, controlling for confounding factors. Results The overall frequency of pRBD was 47.2% (95% CI 42.7% to 51.9%). None of the patients had a previous diagnosis of RBD. Patients with PD and concomitant pRBD did not differ on motor phenotype and scored comparably on the objective motor scales, but reported problems with motor aspects of daily living more frequently. Adjusted for age, sex, disease duration and smoking history, pRBD was associated with greater sleepiness (p=0.001), depression (p=0.001) and cognitive impairment (p=0.006). Conclusions pRBD is common and under-recognised in early PD. It is associated with increased severity and frequency of non-motor features, poorer subjective motor performance and a greater impact on health-related quality of life.
TL;DR: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres, and presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome.
Abstract: Background Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS. Methods Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months. Results At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%). Conclusions HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.
TL;DR: Localisation of interictal spikes provides an excellent estimate of the SOZ in the majority of patients, indicating that ESI should be taken into account for the management of patients undergoing intracranial recordings.
Abstract: Objective It remains controversial whether interictal spikes are a surrogate of the seizure onset zone (SOZ). Electric source imaging (ESI) is an increasingly validated non-invasive approach for localising the epileptogenic focus in patients with drug-resistant epilepsy undergoing evaluation for surgery, using high-density scalp EEG and advanced source localisation algorithms that include the patient9s own MRI. Here we investigate whether localisation of interictal spikes by ESI provides valuable information on the SOZ. Methods In 38 patients with focal epilepsy who later underwent intracranial EEG monitoring, we performed ESI of interictal spikes recorded with 128–256-channel EEG. We measured the distance between the ESI maximum and the nearest intracranial electrodes in the SOZ and irritative zone (IZ, the source of interictal spikes). The resection of the region harbouring the ESI maximum was correlated to surgical outcome. Results The median distance from the ESI maximum to the nearest electrode involved in the SOZ was 17 mm (IQR 8–27). The IZ and SOZ colocalised in most patients (median distance 0 mm, IQR 0–14), supporting the notion that localising interictal spikes is a valid surrogate for the SOZ. There was no difference in accuracy among patients with temporal or extratemporal epilepsy. In the 32 patients who underwent resective surgery, including the ESI maximum in the resection correlated with favourable outcome (p=0.03). Conclusions Localisation of interictal spikes provides an excellent estimate of the SOZ in the majority of patients. ESI should be taken into account for the management of patients undergoing intracranial recordings.
TL;DR: Clinical signs for functional neurological symptoms are numerous but only 14 have been validated; overall they have low sensitivity but high specificity and their use should thus be recommended, especially with the introduction of the new DSM-V criteria.
Abstract: Experts in the field of conversion disorder have suggested for the upcoming DSM-V edition to put less weight on the associated psychological factors and to emphasise the role of clinical findings. Indeed, a critical step in reaching a diagnosis of conversion disorder is careful bedside neurological examination, aimed at excluding organic signs and identifying 'positive' signs suggestive of a functional disorder. These positive signs are well known to all trained neurologists but their validity is still not established. The aim of this study is to provide current evidence regarding their sensitivity and specificity. We conducted a systematic search on motor, sensory and gait functional signs in Embase, Medline, PsycINfo from 1965 to June 2012. Studies in English, German or French reporting objective data on more than 10 participants in a controlled design were included in a systematic review. Other relevant signs are discussed in a narrative review. Eleven controlled studies (out of 147 eligible articles) describing 14 signs (7 motor, 5 sensory, 2 gait) reported low sensitivity of 8-100% but high specificity of 92-100%. Studies were evidence class III, only two had a blinded design and none reported on inter-rater reliability of the signs. Clinical signs for functional neurological symptoms are numerous but only 14 have been validated; overall they have low sensitivity but high specificity and their use should thus be recommended, especially with the introduction of the new DSM-V criteria.
TL;DR: It can be concluded that fMRI is reliable when there is strong left-lateralised language and the Wada test is warranted when fMRI fails to show clear left- lateralisation.
Abstract: Recent studies have shown that fMRI (functional magnetic resonance imaging) may be of value for pre-surgical assessment of language lateralisation. The aim of this study was to systematically review and analyse the available literature. A systematic electronic search for studies comparing fMRI with Wada testing was conducted in the PubMed database between March 2009 and November 2011. Studies involving unilateral Wada testing, study population consisting exclusively of children younger than 12 years of age or involving five patients or fewer were excluded. 22 studies (504 patients) were included. A random effects meta-analysis was conducted to obtain pooled estimates of the positive and negative predictive values of the fMRI using the Wada test as the reference standard. The impact of several study features on the performance of fMRI was assessed. The results showed that 81% of patients were correctly classified as having left or right language dominance or mixed language representation. Techniques were discordant in 19% of patients. fMRI and Wada test agreed in 94% for typical language lateralisation and in 51% for atypical language lateralisation. Language production or language comprehension tasks and different regions of interest did not yield statistically significant different results. It can be concluded that fMRI is reliable when there is strong left-lateralised language. The Wada test is warranted when fMRI fails to show clear left-lateralisation.
TL;DR: The Armstrong criteria usefully broadens the recognised clinical phenotype of CBD but does not sufficiently improve the specificity of diagnosis to increase the power of clinical trials or targeted applications of tau-based disease-modifying therapies.
Abstract: Background Corticobasal degeneration (CBD) is a complex neurodegenerative disorder. Accurate diagnosis is increasingly important, with the advent of clinical trials of drugs aimed at modifying the underlying tau pathology. CBD often presents with a ‘corticobasal syndrome’ including impairments of movement and cognition. However, patients with similar corticobasal syndromes can have neurodegenerative pathologies that are not CBD. In addition, patients with CBD may present with aphasia or behavioural change. The clinical diversity of CBD and mimicry by non-CBD pathologies hinders accurate diagnosis. Methods We applied the new consensus criteria of
TL;DR: The currently available biomarkers for the three most common forms of neurodegenerative dementia are reviewed, and an overview of research techniques that may in due course make their way into the clinic are given.
Abstract: Imaging, cerebrospinal fluid (CSF) and blood-based biomarkers have the potential to improve the accuracy by which specific causes of dementia can be diagnosed in vivo, provide insights into the underlying pathophysiology, and may be used as inclusion criteria and outcome measures for clinical trials. While a number of imaging and CSF biomarkers are currently used for each of these purposes, this is an evolving field, with numerous potential biomarkers in varying stages of research and development. We review the currently available biomarkers for the three most common forms of neurodegenerative dementia, and give an overview of research techniques that may in due course make their way into the clinic.
TL;DR: Investigation of the associations between depression and mortality, stroke recurrence, disability, cognitive impairment, anxiety and quality of life (QoL), up to 5 years post-stroke found depression is independently associated with poor health outcomes.
Abstract: Background Post-stroke depression is a frequent chronic and recurrent problem that starts shortly after stroke and affects patients in the long term. The health outcomes of depression after stroke are unclear. Aims (1) To investigate the associations between depression at 3 months and mortality, stroke recurrence, disability, cognitive impairment, anxiety and quality of life (QoL), up to 5 years post-stroke. (2) To investigate these associations in patients recovering from depression by year 1. (3) To investigate associations between depression at 5 years and these outcomes up to 10 years. Methods Data from the South London Stroke Register (1997–2010) were used. Patients (n at registration=3240) were assessed at stroke onset, 3 months after stroke and annually thereafter. Baseline data included sociodemographics and stroke severity measures. Follow-up assessments included anxiety and depression (Hospital Anxiety and Depression scale), disability, QoL and stroke recurrence. Multivariable regression models adjusted for age, gender, ethnicity, stroke severity and disability were used to investigate the association between depression and outcomes at follow-up. Results Depression at 3 months was associated with: increased mortality (HR: 1.27 (1.04 to 1.55)), disability (RRs up to 4.71 (2.96 to 7.48)), anxiety (ORs up to 3.49 (1.71 to 7.12)) and lower QoL (coefficients up to �8.16 (�10.23�6.15)) up to year 5. Recovery from depression by 1 year did not alter these risks to 5 years. Depression in year 5 was associated with anxiety (ORs up to 4.06 (1.92 to 8.58)) and QoL (coefficients up to �11.36 (�14.86 to �7.85)) up to year 10. Conclusions Depression is independently associated with poor health outcomes.
TL;DR: It is suggested, by analogy with other neurodegenerations and from SOD1 ALS mouse studies, that vulnerability might be induced in the perinatal period.
Abstract: The onset of amyotrophic lateral sclerosis (ALS) is conventionally considered as commencing with the recognition of clinical symptoms. We propose that, in common with other neurodegenerations, the pathogenic mechanisms culminating in ALS phenotypes begin much earlier in life. Animal models of genetically determined ALS exhibit pathological abnormalities long predating clinical deficits. The overt clinical ALS phenotype may develop when safety margins are exceeded subsequent to years of mitochondrial dysfunction, neuroinflammation or an imbalanced environment of excitation and inhibition in the neuropil. Somatic mutations, the epigenome and external environmental influences may interact to trigger a metabolic cascade that in the adult eventually exceeds functional threshold. A long preclinical and subsequent presymptomatic period pose a challenge for recognition, since it offers an opportunity for protective and perhaps even preventive therapeutic intervention to rescue dysfunctional neurons. We suggest, by analogy with other neurodegenerations and from SOD1 ALS mouse studies, that vulnerability might be induced in the perinatal period.