Kirsty Harkness

Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial.

BACKGROUND The clinical benefit of preventive eradication of unruptured brain arteriovenous malformations remains uncertain. A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) aims to compare the risk of death and symptomatic stroke in patients with an unruptured brain arteriovenous malformation who are allocated to either medical management alone or medical management with interventional therapy. METHODS Adult patients (≥18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1:1 ratio, with random permuted block design [block size 2, 4, or 6], stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389181. FINDINGS Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4·10, exceeding the prespecified stopping boundary value of 2·87). At this point, outcome data were available for 223 patients (mean follow-up 33·3 months [SD 19·7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10·1%) patients in the medical management group compared with 35 (30·7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0·27, 95% CI 0·14-0·54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy compared with medical management. INTERPRETATION The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up. FUNDING National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Memory difficulties are not always a sign of incipient dementia: a review of the possible causes of loss of memory efficiency

INTRODUCTION OR BACKGROUND Memory problems are a very common reason for presenting to primary care. There is a need for better treatments for dementia. Increased government and media interest may result in greater number seeking help for memory problems, which may not reduce the dementia gap but rather increase numbers seen who do not have dementia. This review highlights the issues around the diagnostic criteria and terminology used for people with memory complaints. SOURCES OF DATA A comprehensive literature search using PubMed using keywords for articles on subjective memory decline (SMD)/impairment/complaints, subjective cognitive decline (SCD), mild cognitive impairment (MCI) and functional memory disorder (FMD). AREAS OF AGREEMENT There is a need for early accurate detection of dementia syndromes so that trials of new treatments can begin earlier on the disease process. AREAS OF CONTROVERSY Diagnostic criteria and terminology used for disorders of memory including SCD, MCI and FMD. GROWING POINTS This article reviews SCD and whether this can be used to predict Alzheimers disease. The review also discusses the terminology used for non-progressive memory problems and the long-term outcomes for this patient group. AREAS TIMELY FOR DEVELOPING RESEARCH The accurate distinction of premorbid dementia syndromes from benign non-progressive memory problems. Studies of treatment options for people with benign non-progressive memory problems and longer-term follow-up to determine which patients develop chronic problems.

Conversational assessment in memory clinic encounters: interactional profiling for differentiating dementia from functional memory disorders

Objectives: In the UK dementia is under-diagnosed, there is limited access to specialist memory clinics, and many of the patients referred to such clinics are ultimately found to have functional (non-progressive) memory disorders (FMD), rather than a neurodegenerative disorder. Government initiatives on ‘timely diagnosis’ aim to improve the rate and quality of diagnosis for those with dementia. This study seeks to improve the screening and diagnostic process by analysing communication between clinicians and patients during initial specialist clinic visits. Establishing differential conversational profiles could help the timely differential diagnosis of memory complaints. Method: This study is based on video- and audio recordings of 25 initial consultations between neurologists and patients referred to a UK memory clinic. Conversation analysis was used to explore recurrent communicative practices associated with each diagnostic group. Results: Two discrete conversational profiles began to emerge, to help differentiate between patients with dementia and functional memory complaints, based on (1) whether the patient is able to answer questions about personal information; (2) whether they can display working memory in interaction; (3) whether they are able to respond to compound questions; (4) the time taken to respond to questions; and (5) the level of detail they offer when providing an account of their memory failure experiences. Conclusion: The distinctive conversational profiles observed in patients with functional memory complaints on the one hand and neurodegenerative memory conditions on the other suggest that conversational profiling can support the differential diagnosis of functional and neurodegenerative memory disorders.

IL-1β Down-Regulates ADAMTS-13 mRNA Expression in Cells of the Central Nervous System

ADAMTS-13 is the Von Willebrand factor (vWF) cleaving protease, responsible for the cleavage and down-regulation of the pro-thrombotic properties of ultra large VWF multimers. It is expressed predominantly by the hepatic stellate cells of the liver, but is also found to be expressed in other tissues, including brain. Reduced ADAMTS-13 is associated with a variety of thrombotic microangiopathies. Since the cellular origin and regulation of ADAMTS-13 expression in the brain is unknown, we aimed to investigate this in four different central nervous system (CNS)-derived cell lines, SHSY–5Y (human neuroblastoma), U373 (human astroglioma), CHME-3 (human foetal microglia) and hCMEC/D3 (adult human brain endothelial cells). All cell lines expressed ADAMTS-13 mRNA constitutively with neuroblastoma cells showing the highest expression. Interleukin (IL)-1β down-regulated ADAMTS-13 mRNA expression in astroglioma cells and microglial cells whereas TNF and IL-6 treatment showed no significant differences in ADAMTS-13 mRNA expression in any cell line tested. ADAMTS-13 protein expression was reduced in a dose-dependent manner only in astroglioma cells following stimulation by IL-1β. The ability of IL-1β to significantly reduce ADAMTS-13 mRNA expression in human microglia and astroglioma cells suggests a role in the haemostasis of the local microenvironment under inflammatory conditions. This is the first report of ADAMTS-13 expression in cells of the CNS; however, its function remains to be determined.

Letter by Blackburn et al Regarding Article, “Is the Montreal Cognitive Assessment Superior to the Mini-Mental State Examination to Detect Poststroke Cognitive Impairment? A Study With Neuropsychological Evaluation”

To the Editor: We read with interest the recent publication by Godeoroy and colleagues.1 The authors show that the Montreal Cognitive assessment (MoCA) with a cut-off of 27 (which is the cut-off used in memory clinics to detect mild cognitive impairment) detects more poststroke patients with cognitive impairment (82%) than does the Mini-Mental State Examination (MMSE; 45%). Godefroy et al1 show that the MoCA with a cut-off of 27 has a sensitivity of 1.00, but low specificity of 0.13. However, using a cut-off of 23 gives a sensitivity of 0.84, specificity of 0.81, positive predictive value of 0.91, and negative predictive value of 0.71. It is surprising that the final message from the authors is that the MMSE using a cut-off <29 is …

Toward the Automation of Diagnostic Conversation Analysis in Patients with Memory Complaints

BACKGROUND The early diagnosis of dementia is of great clinical and social importance. A recent study using the qualitative methodology of conversation analysis (CA) demonstrated that language and communication problems are evident during interactions between patients and neurologists, and that interactional observations can be used to differentiate between cognitive difficulties due to neurodegenerative disorders (ND) or functional memory disorders (FMD). OBJECTIVE This study explores whether the differential diagnostic analysis of doctor-patient interactions in a memory clinic can be automated. METHODS Verbatim transcripts of conversations between neurologists and patients initially presenting with memory problems to a specialist clinic were produced manually (15 with FMD, and 15 with ND). A range of automatically detectable features focusing on acoustic, lexical, semantic, and visual information contained in the transcripts were defined aiming to replicate the diagnostic qualitative observations. The features were used to train a set of five machine learning classifiers to distinguish between ND and FMD. RESULTS The mean rate of correct classification between ND and FMD was 93% ranging from 97% by the Perceptron classifier to 90% by the Random Forest classifier.Using only the ten best features, the mean correct classification score increased to 95%. CONCLUSION This pilot study provides proof-of-principle that a machine learning approach to analyzing transcripts of interactions between neurologists and patients describing memory problems can distinguish people with neurodegenerative dementia from people with FMD.

Stretch syncope: Reflex vasodepressor faints easily mistaken for epilepsy

The pathophysiology of stretch syncope is demonstrated through the clinical, electrophysiological, and hemodynamic findings in three patients. Fifty-seven attacks were captured by video/EEG monitoring. Simultaneous EEG, transcranial (middle cerebral artery) doppler, and continuous arterial pressure measurements were obtained for at least one typical attack of each patient. They all experienced a compulsion to precipitate their attacks. Episodes started with a stereotyped phase of stretching associated with neck torsion and breath holding, followed by a variable degree of loss of consciousness and asymmetric, recurrent facial and upper limb jerks in the more prolonged episodes. Significant sinus tachycardia coincided with the phase of stretching and was followed within 9-16 seconds by rhythmic generalized slow wave abnormalities on the EEG in attacks with impairment of consciousness. Transcranial doppler studies showed a dramatic drop in cerebral perfusion in the middle cerebral arteries during the episodes. The combination of the stereotyped semiology of the attacks, the pseudofocal myoclonic jerking, and the rhythmic generalized slow wave EEG abnormalities with the tachycardia make differential diagnosis from epilepsy challenging.

Functional impairments for outcomes in a randomized trial of unruptured brain AVMs

Objective: To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA). Methods: We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults ≥18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score ≥2. ARUBA closed recruitment on April 15, 2013. Results: After a median of 33.3 months of follow-up (interquartile range 16.3–49.8 months), of the 223 enrolled in the trial, those in the MM arm were less likely to experience primary outcomes with an mRS score ≥2 than those who underwent IT. The results applied for both those as randomized (MM n = 109 vs IT n = 114) (hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.11–0.57, p = 0.001) and as treated (MM n = 125 vs IT n = 98) (HR 0.10, 95% CI 0.04–0.28, p < 0.001). Functional impairment for the outcomes showed no significant difference by Spetzler-Martin grade for MM but was more frequent with increasing grades for IT (p < 0.001). Conclusion: Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades. ClinicalTrials.gov identifier: NCT00389181. Classification of evidence: This study provides Class II evidence that for adults with unruptured brain AVMs, interventional management compared to MM increases the risk of disability and death over ≈3 years.

Patients who are not driving 6 weeks after transient ischaemic attack have higher levels of anxiety

Dear Editor, Transient ischaemic attack (TIA) is by definition a condition with no long-term consequences. Evidence is emerging that what we have considered to be a TIA in the past does have effects that can last for many weeks. We recently audited our highand low-risk TIA clinics, in particular investigating whether patients were being informed of the driving restrictions advised by the UK Driver and Vehicle Licensing Agency. We found that most people were informed of the driving regulations post TIA, but some patients had decided not to return to driving after 4 weeks. In total, 90 patients were interviewed during a 2month audit process. Of these, 57 patients (43 patients did not have a TIA) were asked questions about their driving status; 33 responded that they had driven before the TIA and 24 said they had not. After the TIA, 13 patients (39.4%; mean age: 66.3 years) did not return to driving. The level of anxiety in the TIA patients who did not return to driving was high at 6 weeks (Generalized Anxiety Disorder 7 mean: 5.42; 95% confidence interval: 1.86–8.98) compared to those who had returned to driving (mean age 73.4 years; Generalized Anxiety Disorder 7 mean: 1.45; 95% confidence interval: 0.6–2.3). The average Montreal Cognitive Assessment score was 2 points higher in the group that had not returned to driving (26 vs 24). These results suggest that although physical recovery post TIA may happen quickly, functional cognitive recovery can take longer than 24 h. The fact that nearly 40% of our patients did not return to driving is quite striking. Moreover, not driving can potentially lead to social isolation. The majority of patients that did not return to driving were anxious. Driving may be only one example of multiple aspects of a patient’s functional life that are affected after TIA. Anxiety is a psychological condition that is amenable to different treatments. Prior research has also shown lasting effects on cognition and mood after TIA. Mood disturbance can last for 12 months or longer, and cognitive disorders can last for many years. Although the rapid nature of TIA clinical assessment enables patients to be treated quickly, the diagnosis, management, and acceptance of psychological consequences of a TIA may not be fully realized by the patient or physician in this setting. Screening to detect anxiety and depression are likely to be required very early in TIA management, something that is currently not done routinely. As more evidence emerges that TIA may have long-term consequences, this may mean that followup should extend beyond 6 weeks. This will be a significant challenge to available resources and may require joint ventures between both stroke and primary health services, involving multidisciplinary teams.

CONVERSATION ANALYSIS IN THE MEMORY CLINIC

Introduction Conversation Analysis (CA) can help with the differential diagnosis of seizure disorders. We investigated if CA could be used in the memory clinic to distinguish neurodegenerative (NDD) from functional memory disorders (FMD). Methods We recruited consecutive, patients newly referred to the Neurology-led memory Clinic. Consultations were video & audio recorded. All participants underwent detailed Neuropsychology testing and MRI. Results 111 patients of 178 approached were recruited (20 ND, 24 FMD, 87 other). We identified profiles of 14 interactional features that can distinguish NDD from FMD consultations based on encounters with 15 patients with NDD and 15 with FMD. Features of NDD included an inability to answer compound questions fully, inability to give detailed examples of memory failures, shorter length of turn and reduced complexity of replies. Prospective analysis of an additional 10 encounters proved that Conversation Analysts could use these features to predict the diagnoses of FMD and ND with high sensitivity and specificity. Conclusions Simple differences in the communication behaviour of patients can help to distinguish between ND and FMD, suggesting that a targeted observation of interactional features could improve screening for ND in primary or secondary or care settings.