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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are well-recognised as an extended disease spectrum. This study hypothesised that cortical hyperexcitability, an early pathophysiological abnormality in ALS, would distinguish cognitive phenotypes, as a surrogate marker of pathological disease burden. 61 patients with ALS, matched for disease duration (pure motor ALS, n = 39; ALS with coexistent FTD, ALS-FTD, n = 12; ALS with cognitive/behavioural abnormalities not meeting FTD criteria, ALS-Cog, n = 10) and 30 age-matched healthy controls. Cognitive function on the Addenbrooke’s cognitive examination (ACE) scale, behavioural function on the motor neuron disease behavior scale (MiND-B) and cortical excitability using transcranial magnetic stimulation (TMS) were documented. Cortical resting motor threshold (RMT), lower threshold indicating hyperexcitability, was lower in ALS-FTD (50.2 ± 6.9) compared to controls (64.3 ± 12.6, p

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

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 …

A 28 years old primigravida was referred to Department of Obstetrics and Gynaecology, King George's Medical University, as 35 weeks pregnancy with polyhydramnious with suspected fetal omphalocoele. The defect was diagnosed at 24 weeks at some external centre and the patient was counselled regarding continuation of pregnancy with postnatal surgical repair of malformation after delivery. The diagnosis of Beckwith-Wiedemann syndrome (BWS) was missed at that time. Phenotypic presentation of BWS has several variations and low …

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: Stillbirth as an obstetric complication is emotionally devastating for the women as well as the clinician and having a caesarean section for stillbirth is even more catastrophic. The aim of the present research was to study the indications of caesarean section in women with intrauterine fetal demise in a low resource setting.Methods: This was an observational study for assessing the indication of caesarean section among 222/ 550 stillbirths from June 2013 to May 2014 in a tertiary care teaching hospital of North India. 7024 births occurred in the institution over a period of 1 year out of which 550 were stillbirths. Stillbirths which weighed over 500 grams were included in the study. Details of women with intrauterine fetal demise in which caesarian section was done were noted and analyzed.Results: Out of 550 stillbirths, 222 women underwent caesarean section. Rate of caesarean section among women with stillbirth was 40.36%. Placenta previa (23.87%), Rupture uterus (22.1%), obstructed labour (10.8%), transverse lie (9.45%), failed induction (7.20%), massive abruption (5.86%), non-progress of labour (5.40%), eclampsia/pre-eclampsia related causes (4.95%), acute fetal distress (4.95%), were leading indications of caesarean sections. Out of 222 women, 162 (73%) women had anaemia (Hb

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.

ObjectiveA new antibody, active against the common tachykinin (TK) C-terminal, was used to study TK expression in patients with endocrine tumors and a possible association between plasma-TK levels and symptoms of diarrhea and flush in patients with metastasizing ileocecal serotonin-producing carcinoid tumors (MSPCs).MethodTK, serotonin and chromogranin A (CgA) immunoreactivity (IR) was studied by immunohistochemistry in tissue samples from 33 midgut carcinoids and 72 other endocrine tumors. Circulating TK (P-TK) and urinary-5 hydroxyindoleacetic acid (U-5HIAA) concentrations were measured in 42 patients with MSPCs before treatment and related to symptoms in patients with the carcinoid syndrome. Circulating CgA concentrations were also measured in 39 out of the 42 patients.ResultsAll MSPCs displayed serotonin and strong TK expression. TK-IR was also seen in all serotonin-producing lung and appendix carcinoids. None of the other tumors examined contained TK-IR cells. Concentrations of P-TK, P-CgA, and U-5HIAA were elevated in patients experiencing daily episodes of either flush or diarrhea, when compared with patients experiencing occasional or none of these symptoms. In a Spearman partial rank test, the correlation of P-TK with daily diarrhea was independent of both U-5HIAA and CgA levels.ConclusionWe found that TK synthesis occurs in serotonin-IR tumors and that P-TK levels are significantly correlated with symptoms of flush and diarrhea in patients with MSPCs. This is, to our knowledge, the first report demonstrating an independent correlation of P-TKs with carcinoid diarrhea, a symptom that is customarily regarded as serotonin mediated. Further investigations may present opportunities for new therapeutic possibilities.

Background: Whenever pregnancy occurs there is an expectation that every pregnancy will end with the birth of a healthy baby, yet in a developing country like India 22 in every 1000 births are stillborn. The objective of this study was to evaluate the rate and causes of still birth in a tertiary care teaching hospital, Queen Mary, King George Medical college and university, Lucknow, Uttar Pradesh, India.Methods: Present study was an observational study in a tertiary care hospital. 7024 births occurred in the institution over a period of 1 year out of which 550 were stillbirths. Stillbirths which weighed over 500 grams were included in the study. After informed consent, details of history about epidemiological factors, obstetric history and medical history were obtained. Antenatal investigations including imaging, delivery details and stillborn morphological characteristics were analyzed to identify the cause of stillbirthResults: Out of 7024 deliveries, stillbirth rate was 78.30/1000 total births. Cause of intrapartum stillbirth showed statistically significant correlation with patient’s place of residence (rural>urban), distance of health centre from her house, time taken to reach first point of contact and her parity. The major obstetrical causes of stillbirth identified were APH 22.36%, hypertensive disorders of pregnancy 19.27%, IUGR 15.27%, unexplained causes 11.09%, mal-presentations 9.64%, rupture uterus 9.09% and obstructed labour 6.36%. Severe anemia was found in 24.91% as an associated obstetrical cause of stillbirth.Conclusions: The rate of stillbirth is higher as compared to the Indian data (22/1000 total births). Antepartum obstetric complications (APH, hypertensive disorder of pregnancy, IUGR) were the most common. 15.45% cases showed intrapartum causes of stillbirth (obstructed labour and rupture uterus) which was significantly higher than developed countries where such cases are negligible. The higher number of intrapartum deaths indicate that better healthcare services can drastically reduce stillbirth rates in developing countries.

{#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.

Excitotoxicity may contribute to neuronal and synaptic loss in Alzheimer's disease (AD). Aberrant levels of gephyrin, a post-synaptic receptor-stabilizing protein, could affect the inhibitory modulation of excitatory impulses. We assayed gephyrin protein in two brain areas susceptible to neuronal loss in AD, and in a spared area, in autopsy tissue from normal subjects (n=15) and AD patients (n=5). Quantification was by in-gel immunodetection against known concentrations of a recombinant truncated gephyrin standard. Gephyrin abundance was significantly reduced (P

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.