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Background: For reasons poorly understood, strokes frequently occur in patients with atrial fibrillation (AF) despite oral anticoagulation. Better data are needed to inform randomised trials (RCTs) of new strategies to prevent recurrence in these patients. We investigate the relative contribution of competing stroke mechanisms in patients with AF who have stroke despite anticoagulation (OAC+) compared with those who are anticoagulant naïve (OAC−) at the time of their event. Patients and methods: We performed a cross-sectional study leveraging data from a prospective stroke registry (2015–2022). Eligible patients had ischemic stroke and AF. Stroke classification was performed by a single stroke-specialist blinded to OAC status using TOAST criteria. The presence of atherosclerotic plaque was determined using duplex ultrasonography, computerised tomography (CT) or magnetic resonance (MR) angiography. Imaging was reviewed by a single reader. Logistic regression was used to identify independent predictors of stroke despite anticoagulation. Results: Of 596 patients included, 198 (33.2%) were in the OAC+ group. A competing cause for stroke was more frequent in patients with OAC+ versus OAC− (69/198 (34.8%)) versus 77/398 (19.3%), p Discussion and conclusion: Patients with AF-associated stroke despite OAC are much more likely than patients who are OAC-naïve to have competing stroke mechanisms. Rigorous investigation for alternative stroke causes in stroke despite OAC has a high diagnostic yield. These data should be used to guide patient selection for future RCTs in this population.

BackgroundDhat syndrome, a clinical condition related to semen loss in urine often found among males in India, has rarely been described as a separate clinical condition in females. Women with the syndrome complain of passing vaginal discharge and can be excessively concerned and preoccupied with it, often attributing various physical symptoms to the loss of vaginal fluids.AimsThis study aimed to assess the sociodemographic and clinical profiles of female patients with Dhat syndrome and their perceived stress, disability and sexual functioning.MethodsSociodemographic details of 70 females with non-pathological vaginal discharge were evaluated with a semistructured sociodemographic assessment. The phenomenology of the vaginal discharge was assessed with the Scale for Assessment of Female Dhat Syndrome Questionnaire. Anxiety and depressive symptoms were measured with the Hospital Anxiety and Depression Scale. Perceived stress in the past month and disability caused by the illness were assessed with the Perceived Stress Scale and the World Health Organization Disability Assessment Scale. In addition, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Level 2 Somatic Symptoms Scale was administered to rate the severity of somatic symptoms, and sexual functioning was evaluated using the Female Sexual Function Index (FSFI) scale for women who had had sexual intercourse in the past month.ResultsThe mean age of onset vaginal discharge was 23.0 (6.6) years. Biological factors, such as urinary tract infection, were the commonly attributed cause of the loss of vaginal fluids. Psychiatric comorbidity and perceived moderate stress in the past month were found in 38.6% and 68.6% of female patients with Dhat syndrome, respectively. Disability scores tended to be low. Among the females having had sexual intercourse in the past month, 48.3% had FSFI scores indicative of a female sexual disorder.ConclusionsThe clinical presentation of women with non-pathological vaginal discharge is similar to that of males with Dhat syndrome. It requires comprehensive assessment and management that targets the biological, social and psychological factors and cultural issues.

BACKGROUND AND PURPOSE Predicting the course of behavioural variant frontotemporal dementia (bvFTD) remains a major clinical challenge. This study aimed to identify factors that predict survival and clinical progression in bvFTD. METHODS Consecutive patients with clinically probable bvFTD were prospectively followed up over an 8-year period. Baseline neuropsychological variables, presence of a known pathogenic frontotemporal dementia gene mutation and a systematic visual magnetic resonance imaging assessment at baseline were examined as candidate predictors using multivariate modelling. RESULTS After screening 121 cases, the study cohort consisted of 75 patients with probable bvFTD, with a mean age of 60.8 ± 8.5 years, followed up for a mean duration of 7.2 ± 3.5 years from symptom onset. Median survival time from disease onset was 10.8 years and median survival, prior to transition to nursing home, was 8.9 years. A total of 25 of the 75 patients died during the study follow-up period. Survival without dependence was predicted by shorter disease duration at presentation (hazard ratio, 0.49, P = 0.001), greater atrophy in the anterior cingulate cortex (hazard ratio, 1.75, P = 0.047), older age (hazard ratio, 1.07, P = 0.026) and a higher burden of behavioural symptoms (hazard ratio, 1.04, P = 0.015). In terms of disease progression, presence of a known pathogenic frontotemporal dementia mutation (β = 0.46, P

To investigate whether primary lateral sclerosis (PLS) represents part of the amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD) spectrum of diseases. Comprehensive assessment was taken on 21 patients with PLS and results were compared to patients diagnosed with pure motor ALS (n = 27) and ALS–FTD (n = 12). Clinical features, Addenbrooke’s Cognitive Examination (ACE) scores, Motor Neuron Disease Behaviour (Mind-B) scores, motor disability on the ALS functional rating scale (ALSFRS) and survival times were documented. Motor cortex excitability was evaluated using transcranial magnetic stimulation (TMS). Global cognition was impaired in PLS (mean total ACE score 82.5 ± 13.6), similar to ALS–FTD (mean total ACE score 76.3 ± 7.7, p > 0.05) while behavioural impairments were not prominent. TMS revealed that resting motor threshold (RMT) was significantly higher in PLS (75.5 ± 6.2) compared ALS–FTD (50.1 ± 7.2, p

Transcranial magnetic stimulation (TMS) is an accessible, non-invasive technique to study cortical function in vivo. TMS studies have provided important pathophysiological insights across a range of neurodegenerative disorders and enhanced our understanding of brain reorganisation after stroke. In neurodegenerative disease, TMS has provided novel insights into the function of cortical output cells and the related intracortical interneuronal networks. Characterisation of cortical hyperexcitability in amyotrophic lateral sclerosis and altered motor cortical function in frontotemporal dementia, demonstration of cholinergic deficits in Alzheimer’s disease and Parkinson’s disease are key examples where TMS has led to advances in understanding of disease pathophysiology and potential mechanisms of propagation, with the potential for diagnostic applications. In stroke, TMS methodology has facilitated the understanding of cortical reorganisation that underlie functional recovery. These insights are critical to the development of effective and targeted rehabilitation strategies in stroke. The present review will provide an overview of cortical function measures obtained using TMS and how such measures may provide insight into brain function. Through an improved understanding of cortical function across a range of neurodegenerative disorders, and identification of changes in neural structure and function associated with stroke that underlie clinical recovery, more targeted therapeutic approaches may now be developed in an evolving era of precision medicine.

There is no consensus approach to safety screening for immune intervention in clinical neuroimmunology. An immunosuppression risk evaluation checklist was used as an audit tool to assess real-world immunosuppression risk management and formulate recommendations for quality improvements in patient safety. Ninety-nine patients from two centres with 27 non-MS diagnoses were included. An average of 1.9 comorbidities with the potential to adversely impact morbidity and mortality associated with immunosuppression were identified. Diabetes and smoking were the most common, however a range of rarer but potentially life-threatening co-morbid disorders in the context of immunosuppression were identified. Inadequate documentation of risk mitigation tasks was common at 40.1% of total tasks across both cohorts. A routine, systematic immunosuppression checklist approach should be considered to improve immunosuppression risk management in clinical neuroimmunology practice.

ObjectiveWhile clinical benefit from thrombolysis decreases with increase in time from stroke onset, the relationship of acute physiologic tissue compartments and collateral response to stroke onset time remains unclear.MethodsWe studied consecutive patients with proximal arterial occlusions (n = 355) with whole-brain perfusion CT with CT angiography within 6 hours of stroke onset. Penumbra and core were defined using voxel-based thresholds. Tissue mismatch was defined as the ratio of penumbra to core. Collateral scores were assessed using a previously validated visual score.ResultsMean (SD) age was 72.1 (12.4) years, median (interquartile range) NIH Stroke Scale score 16 (4), mean (SD) time to imaging 152.5 (69.7) minutes. Penumbra volume (Spearman ρ = 0.119, p = 0.026) and mismatch increased (Spearman ρ = 0.115, p = 0.030) with time from onset. Core volume decreased (Spearman ρ = −0.112, p = 0.035) while collateral scores increased with time (Spearman ρ = 0.117, p = 0.028). On multivariable regression, good collateral scores predicted longer time since onset (β = 0.101, p = 0.039) while mismatch was not a predictor (β = 0.001, p = 0.351). Good collateral score was the strongest independent predictor of final infarct volume and improvement in clinical deficit.ConclusionsIn our large patient cohort study of proximal arterial occlusions, we found an incremental collateral response and preserved penumbral volume with time. Thus, tissue viability can be maintained in this time window (0–6 hours) after stroke if leptomeningeal collaterals are able to sustain the penumbra. Our findings suggest that a longer therapeutic window may exist for intra-arterial intervention and that multimodal imaging may have a role in strokes of unknown onset time.

This scientific commentary refers to ‘Perfusion computed tomography to assist decision making for stroke thrombolysis’, by Bivard et al. (doi:10.1093/brain/awv071). The ischaemic penumbra, defined as severely hypoperfused, functionally impaired yet salvageable tissue, has been established as the key target for acute stroke therapy for more than three decades (Muir et al. , 2006). However, the penumbra has a limited lifespan and, unless reperfused early, it progresses to become part of the irreversibly damaged tissue referred to as the ‘core’. The core therefore grows over time, incorporating first the most hypoperfused portions of the penumbra, and then progressively less hypoperfused portions, until none remains. How fast this process occurs varies greatly from subject to subject, mainly because of variable pial collaterals and the occurrence of spontaneous reperfusion (Fig. 1). On a mechanistic basis, reperfusion therapy—such as with intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA)—would be expected to be of no benefit, and potentially harmful, in cases with large core or no penumbra (Marchal et al. , 1993). Figure 1 The three main pathophysiological profiles used by Bivard et al. to categorize acute stroke patients, as originally defined using PET with 15oxygen-labelled compounds to generate quantitative maps of cerebral blood flow (CBF, left column ) and the cerebral oxygen metabolic rate (CMRO2, right ). Validated tissue compartments including penumbra (reduced cerebral blood flow but relatively preserved CMRO2) and core (markedly reduced CMRO2) were used to characterize the three profiles of ‘target mismatch', ‘large core' and ‘no mismatch' (Muir et al. , 2006). Consistent with the strikingly distinct spontaneous outcomes associated with these profiles (Marchal et al. , 1993), Bivard et al. provide evidence from their cohort that the target mismatch group, i.e. patients with significant penumbral tissue and a small core, benefit the most from intravenous …

Increasing age is the single largest non-modifiable risk factor for ischaemic stroke. Animal models have substantiated the view that age related neuron vulnerability to ischaemia plays a role in stroke and other age related neurological diseases. Given the key role of the ischaemic penumbra in stroke pathophysiology, we hypothesised that age has an impact on penumbral tissue and its acute determinants.We studied a prospective cohort of patients (n=39) at a mean time of 154.7 min from stroke onset, using state of the art whole brain perfusion CT and CT angiography. Penumbral and core were defined using quantitative voxel based thresholds for mean transit time and cerebral blood volume (CBV). Collateral vessel scores were assessed and haemodynamic variables (ie, cerebral blood flow and CBV) were measured in affected and unaffected tissues.While age correlated negatively with normalised penumbral volume (Kendall's τ b=-0.234, p=0.048) and lesion volume (Kendall's τ b=0.238, p=0.045), core volume remained unchanged, accompanied by an incremental collateral response with age (Kendall's τ b=0.496, p0.0001). Haemodynamic variables remained unaffected by age in our cohort.These findings, described for the first time in a clinical cohort using whole brain CT perfusion and concomitant vascular imaging, suggest that age has a differential effect on acute tissue compartments in the wake of a preserved collateral vascular response and haemodynamic parameters. In agreement with the preclinical literature, the results point to a distinct tissue response to acute ischaemia in the ageing brain and merit validation studies in larger cohorts, particularly in relation to clinical outcomes.

Background Primary lateral sclerosis (PLS), a rare upper motor neuron disorder, remains a debated entity as an upper motor neuron extreme form of amyotrophic lateral sclerosis (ALS) or a distinct disease. It is now well established that ALS and frontotemporal dementia (FTD) lie on two ends of the frontal neurodegenerative spectrum. While early descriptions of PLS excluded cognitive dysfunction, there is accumulating evidence of varying degrees of frontal lobe deficits accompanying structural and functional changes in the brain in PLS. Methodology This study examined the neurophysiological features using transcranial magnetic stimulation (TMS) and neuropsychological profile in a cohort of patients (n = 21) with PLS. Clinical, neuropsychological and TMS findings in PLS patients were compared with two distinct cohorts of patients who had pure ALS (n = 27) and ALSFTD (n = 12). Multivariable regression analysis was used to examine independent predictors of global cognitive function on the Addenbrooke’s cognitive examination (ACE) score and motor disability on the ALS functional rating scale (ALSFRS). Kaplan Meier curves were used to determine survival times for the three groups. Results Mean age in PLS was 60.9 ± 10.4, 47.6% of patients were males and 95% had limb onset disease. The mean survival time was longest in PLS (217.43 ± 22.4 months) and shortest in ALSFTD (38.54 ± 4.5 months). In addition to prominent upper motor neuron (UMN) dysfunction, ACE score was impaired in PLS (mean total ACE score 82.5 ± 13.6), lying intermediately between pure ALS (mean total ACE score 93.4 ± 3.9) and ALSFTD (mean total ACE score 76.3 ± 7.7). Behavioural impairments were not prominent in PLS as indicated by a higher total Motor Neuron Disease Behaviour (MiND-B) score than ALSFTD (PLS 32.1 ± 5.6, ALSFTD 22.4 ± 6.8, p = 0.005). In terms of cortical function, resting motor threshold (RMT) was significantly higher in PLS (93.2 ± 11.7, p RMT predicted higher global cognition score on the ACE ( β = 0.57, p = 0.001), independent of motor progression and clinical upper motor neuron dysfunction. Average SICI predicted motor disability ( β = 0.5, p = 0.008), on the ALS functional rating scale (ALSFRS), independent of disease duration and upper motor neuron score across the three groups. Conclusions There is a distinctive cognitive profile in PLS which resembles ALSFTD, without the behavioural disturbances typical of the FTD spectrum disorders. Cortical motor neuronal hyperexcitability was associated with poorer global cognitive function, independent of motor disease progression, while dysfunction of inhibitory interneuronal circuits predicted motor disability, across ALS, ALSFTD and PLS. Overall, these findings make a strong case for PLS being on the ALS FTD spectrum and suggest that cortical excitability contributes to neuropsychological and motor dysfunction by distinct pathophysiological mechanisms.

Purpose CT-based perfusion and collateral imaging is increasingly used in the assessment of patients with acute stroke. Time of stroke onset is a critical factor in determining eligibility for and benefit from thrombolysis. Animal studies predict that the volume of ischemic penumbra decreases with time. Here, we evaluate if CT is able to detect a relationship between perfusion or collateral status, as assessed by CT, and time since stroke onset. Materials and methods We studied 53 consecutive patients with proximal vessel occlusions, mean (SD) age of 71.3 (14.9) years, at a mean (SD) of 125.2 (55.3) minutes from onset, using whole-brain CT perfusion (CTp) imaging. Penumbra was defined using voxel-based thresholds for cerebral blood flow (CBF) and mean transit time (MTT); core was defined by cerebral blood volume (CBV). Normalized penumbra fraction was calculated as Penumbra volume/(Penumbra volume + Core volume) for both CBF and MTT (PenCBF and PenMTT, respectively). Collaterals were assessed on CT angiography (CTA). CTp ASPECTS score was applied visually, lower scores indicating larger lesions. ASPECTS ratios were calculated corresponding to penumbra fractions. Results Both PenCBF and PenMTT showed decremental trends with increasing time since onset (Kendall’s tau-b = −0.196, p = 0.055, and −0.187, p = 0.068, respectively). The CBF/CBV ASPECTS ratio, which showed a relationship to PenCBF (Kendall’s tau-b = 0.190, p = 0.070), decreased with increasing time since onset (Kendall’s tau-b = −0.265, p = 0.006). Collateral response did not relate to time (Kendall’s tau-b = −0.039, p = 0.724). Conclusion Even within 4.5 h since stroke onset, a decremental relationship between penumbra and time, but not between collateral status and time, may be detected using perfusion CT imaging. The trends that we demonstrate merit evaluation in larger datasets to confirm our results, which may have potential wider applications, e.g., in the setting of strokes of unknown onset time.

{#article-title-2} To the Editor: We read with interest the article by Larrue et al.1 We recently assessed the impact of newer stroke classification systems on stroke subtypes.2 We also agree with the conclusion regarding the contribution of atrial septal abnormalities to stroke in younger people. Despite the thorough cardiac investigation, Larrue et al. report a relatively low proportion of patients with unexplained stroke with patent foramen ovale (PFO). Of 160 cases investigated, 67 (41.2%) had a PFO (24 isolated, 43 with an atrial septal aneurysm [ASA]). In our institution, of those with …

Background: Despite use in clinical practice and major positive trials of thrombolysis, non-contrast computed tomography (NCCT) is not sensitive for identifying penumbral tissue in acute stroke. This study evaluated how physiological imaging using CT perfusion (CTP) could add to the diagnostic utility of an NCCT and inform clinical decisions regarding thrombolysis. Methods: Forty imaging datasets containing NCCT and CTP were retrospectively identified from a cohort of consecutive acute stroke patients. Two sets of observers (n = 6) and a neuroradiologist evaluated the images without knowledge of clinical symptoms. Inter-observer agreement was calculated using the ĸ statistic for identifying acute ischaemic change on NCCT: perfusion abnormalities (namely cerebral blood volume, cerebral blood flow and time to peak), and penumbral tissue on perfusion maps obtained by two image processing algorithms. Results: Inter-rater agreement was moderate (ĸ = 0.54) for early ischaemic change on NCCT. Perfusion maps improved this to substantial for cerebral blood volume (ĸ = 0.67) and to almost perfect for time to peak (ĸ = 0.87) and cerebral blood flow (ĸ = 0.87). The agreement for qualitative assessment of penumbral tissue was substantial to perfect for images obtained using the two different perfusion algorithms. Overall, there was a high rate of decision to thrombolyse based on NCCT (81.25%). CTP strengthened the decision to thrombolyse based on NCCT in 38.3% of cases. It negatively influenced the decision in 14.6% of cases, this being significantly more common in experienced observers (p = 0.02). Conclusions: We demonstrate that the qualitative evaluation of CTP produces near perfect inter-observer agreement, regardless of the post-processing method used. CTP is a reliable, accessible and practical imaging modality that improves confidence in reaching the appropriate diagnosis. It is particularly useful for less experienced clinicians, to arrive at a physiologically informed treatment decision.

Telemedicine refers to the transfer of medical information from one site to another using distance communications technology. This approach has benefitted many medical specialties, with telestroke being a prelude to its applications in neurology. Our review will focus on the use of telemedicine in neurological practice (teleneurology) following a brief discussion of telestroke. Given the emerging nature of trial evidence in teleneurology, our aim is to provide a narrative review and highlight areas that merit further investigation.

Objective: We report an unusual case of a dominant hemisphere, medial occipital and medial temporal cortical infarction precipitating Korsakoff9s psychosis and a disinhibition syndrome, reminiscent of a frontal lobe phenotype. A 66 year-old, right handed man, while driving to watch the Monaco Grand Prix, developed acute headache and amnesia accompanied by emotional lability, disinhibited behavior, inappropriate laughter and a right homonymous hemianopia. He had deficits in both episodic and working memory, a mild degree of executive dysfunction and a tendency to confabulate. There were no other focal neurological signs. He had been well previously, except for moderately high alcohol consumption. The cognitive deficits persisted 6 months after presentation, despite thiamine replacement. Acute imaging demonstrated restricted diffusion in the medial occipital and temporal lobes involving the fusiform and parahippocampal gyri with sparing of thalamus and other deeper structures. The rest of the parenchymal structures were normal and there was no evidence of small vessel ischaemia. An occlusion of P2 segment of the left posterior cerebral artery and its cortical branches was seen on vascular imaging. Cognitive deficits associated with posterior cerebral artery infarctions include a constellation of behavioural symptoms including transcortical aphasia, alexia without agraphia, Gerstmann syndrome, episodic memory deficit, visual agnosia, prosopagnosia and rarely acute delirium with/without aggressive behavior. Disinhibition syndromes of frontal phenotype have rarely been reported and may be associated with cortical deafferentation following a non-dominant thalamic lesion. This case demonstrates that behavioural deficits after cortical PCA territory infarction are not restricted to memory, language and vision and may occur without thalamic involvement. We hypothesise that the Korsakoff9s syndrome may have been the result of a functional disruption of mamillothalamic connections, as previously described, whereas the frontal behavioural features may be caused by a disruption of occipito temporal and occipito frontal connectivity. Disclosure: Dr. Agarwal has nothing to disclose. Dr. Manford has received personal compensation for activities with UCB Pharma and Eisai.

Background Despite use in clinical practice and trials of thrombolysis, a non-contrast CT is not sensitive for identifying penumbral tissue in acute stroke. This study evaluated how it compares with physiological imaging using CT perfusion. Methods 40 imaging datasets with non-contrast CT (NCCT) and perfusion CT (CTP) were retrospectively identified. 2 sets of observers (n=6) and a neuroradiologist made a blind evaluation of the images. Inter-observer agreement was calculated for identifying ischaemic change on NCCT, and abnormalities on cerebral blood flow, time to peak and cerebral blood volume maps. A prospective cohort of 73 patients with anterior circulation cortical strokes were thrombolysed based on qualitative assessment of penumbral tissue on CTP within 3 h of stroke onset. Functional outcome was assessed at 3 months. Results Inter-rater agreement was moderate (k=0.54) for early ischaemic change on NCCT. Perfusion maps improved this to substantial for deficit in cerebral blood volume (k=0.67) and almost perfect for time to peak and cerebral blood flow (both k=0.87). In the prospective arm, 58.9% of patients with cortical strokes were thrombolysed. There was no significant difference in attainment of complete recovery (p=0.184) between the thrombolysed and non-thrombolysed group. Conclusions We demonstrate how perfusion CT aids clinical decision-making in acute stroke. Good functional outcomes from thrombolysis can be safely achieved using this physiologically informed approach.