Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease

Damage to specific brain circuits can cause specific neuropsychiatric symptoms. Therapeutic stimulation to these same circuits may modulate these symptoms. To determine whether these circuits converge, we studied depression severity after brain lesions (n = 461, five datasets), transcranial magnetic stimulation (n = 151, four datasets) and deep brain stimulation (n = 101, five datasets). Lesions and stimulation sites most associated with depression severity were connected to a similar brain circuit across all 14 datasets (P < 0.001). Circuits derived from lesions, deep brain stimulation and transcranial magnetic stimulation were similar (P < 0.0005), as were circuits derived from patients with major depression versus other diagnoses (P < 0.001). Connectivity to this circuit predicted out-of-sample antidepressant efficacy of transcranial magnetic stimulation and deep brain stimulation sites (P < 0.0001). In an independent analysis, 29 lesions and 95 stimulation sites converged on a distinct circuit for motor symptoms of Parkinson’s disease (P < 0.05). We conclude that lesions, transcranial magnetic stimulation and DBS converge on common brain circuitry that may represent improved neurostimulation targets for depression and other disorders

Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration: A united approach

Item does not contain fulltextCerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE)

Myoclonus in comatose patients with electrographic status epilepticus after cardiac arrest: corresponding EEG patterns, effects of treatment and outcomes

Objective: To clarify the significance of any form of myoclonus in comatose patients after cardiac arrest with rhythmic and periodic EEG patterns (RPPs) by analyzing associations between myoclonus and EEG pattern, response to anti-seizure medication and neurological outcome.Design: Post hoc analysis of the prospective randomized Treatment of ELectroencephalographic STatus Epilepticus After Cardiopulmonary Resus-citation (TELSTAR) trial.Setting: Eleven ICUs in the Netherlands and Belgium.Patients: One hundred and fifty-seven adult comatose post-cardiac arrest patients with RPPs on continuous EEG monitoring. Interventions: Anti-seizure medication vs no anti-seizure medication in addition to standard care.Measurements and Main Results: Of 157 patients, 98 (63%) had myoclonus at inclusion. Myoclonus was not associated with one specific RPP type. However, myoclonus was associated with a smaller probability of a continuous EEG background pattern (48% in patients with vs 75% without myoclonus, odds ratio (OR) 0.31; 95% confidence interval (CI) 0.16-0.64) and earlier onset of RPPs (24% vs 9% within 24 hours after cardiac arrest, OR 3.86;95% CI 1.64-9.11). Myoclonus was associated with poor outcome at three months, but not invariably so (poor neurological outcome in 96% vs 82%, p = 0.004). Anti-seizure medication did not improve outcome, regardless of myoclonus presence (6% good outcome in the intervention group vs 2% in the control group, OR 0.33; 95% CI 0.03-3.32).Conclusions: Myoclonus in comatose patients after cardiac arrest with RPPs is associated with poor outcome and discontinuous or suppressed EEG. However, presence of myoclonus does not interact with the effects of anti-seizure medication and cannot predict a poor outcome without false positives.Neurological Motor Disorder

Circulating IgM Requires Plasma Membrane Disruption to Bind Apoptotic and Non-Apoptotic Nucleated Cells and Erythrocytes

<div><p>Autoimmunity is associated with defective phagocytic clearance of apoptotic cells. IgM deficient mice exhibit an autoimmune phenotype consistent with a role for circulating IgM antibodies in apoptotic cell clearance. We have extensively characterised IgM binding to non-apoptotic and apoptotic mouse thymocytes and human Jurkat cells using flow cytometry, confocal imaging and electron microscopy. We demonstrate strong specific IgM binding to a subset of Annexin-V (AnnV)⁺PI (Propidium Iodide)⁺ apoptotic cells with disrupted cell membranes. Electron microscopy studies indicated that IgM⁺AnnV⁺PI⁺ apoptotic cells exhibited morphologically advanced apoptosis with marked plasma membrane disruption compared to IgM^-AnnV⁺PI⁺ apoptotic cells, suggesting that access to intracellular epitopes is required for IgM to bind. Strong and comparable binding of IgM to permeabilised non-apoptotic and apoptotic cells suggests that IgM bound epitopes are 'apoptosis independent' such that IgM may bind any cell with profound disruption of cell plasma membrane integrity. In addition, permeabilised erythrocytes exhibited significant IgM binding thus supporting the importance of cell membrane epitopes. These data suggest that IgM may recognize and tag damaged nucleated cells or erythrocytes that exhibit significant cell membrane disruption. The role of IgM <i>in vivo</i> in conditions characterized by severe cell damage such as ischemic injury, sepsis and thrombotic microangiopathies merits further exploration.</p></div

Phenytoin as seizure prophylaxis in hematopoietic stem cell transplantation with busulfan conditioning

BACKGROUND: Phenytoin is widely used as primary seizure prophylaxis in hematopoietic stem cell transplantation in patients undergoing myeloablative conditioning with busulfan. Because of the negative side effects of phenytoin, we abandoned phenytoin use in these patients. To assess the effect of this change, we performed a retrospective cohort study on all patients receiving busulfan. METHODS: We included 139 patients who underwent conditioning with busulfan for hematopoietic stem cell therapy. We registered the use of phenytoin, as well as the occurrence of seizures, until 7 days after busulfan administration. We compared seizure incidence between patients who received phenytoin and those who did not. RESULTS: Of the 43 patients who received phenytoin prophylaxis, four patients (9.3%) had a seizure during the conditioning regimen, of which two patients had cerebral non-Hodgkin lymphoma. Furthermore, all these 4 patients had very high levels of phenytoin (intoxication). Of the 96 patients that did not receive phenytoin prophylaxis, three patients (3.1%) had a seizure, and one of these patients had an undefined cerebral lesion. Phenytoin did not relate to seizure prevention in a logistic regression analysis. CONCLUSION: We conclude that phenytoin prophylaxis in patients treated with busulfan is obsolete and possibly harmful, as phenytoin intoxication can occur. We recommend discontinuing the use of phenytoin as primary seizure prophylaxis in these patients

Family History of Stroke Is an Independent Risk Factor for Lacunar Stroke Subtype With Asymptomatic Lacunar Infarcts at Younger Ages

Background and Purpose-Results from case-control and case-case studies indicate that a positive family history of stroke (FHstroke) is an independent risk factor for lacunar stroke. Different lacunar stroke phenotypes can be distinguished on the basis of the presence of asymptomatic lacunar infarcts (aLACs), ischemic white-matter lesions, or brain microbleeds. The aim of the present study was to determine whether familial aggregation of stroke was different for lacunar stroke phenotypes. Methods-In 157 patients with a first-ever lacunar stroke, a complete first-degree FHstroke was obtained by a standardized questionnaire and additional interview. Lacunar stroke patients were categorized successively into groups, depending on the presence of aLACs, ischemic white-matter lesions, and brain microbleeds on magnetic resonance imaging. Results-Fifty-two percent of patients reported a positive FHstroke in at least one of their first-degree relatives. In younger (<65 years) probands, a high frequency of parental FHstroke (59% versus 20%, P<0.01) in those with aLACs compared with probands without aLACs was found. In multivariate analysis, the strongest associations were found for parental FHstroke (odds ratio=6.46; 95% CI=1.96 to 21.33), maternal FHstroke (odds ratio=4.00; 95% CI=1.18 to 13.56), and paternal FHstroke (odds ratio=5.40; 95% CI=1.14 to 25.61). Conclusions-A family history of stroke might be an independent risk factor for the lacunar stroke phenotype with aLACs at younger ages, suggesting a role for genetic factors in this phenotype caused by diffuse vasculopathy. (Stroke. 2011; 42: 1196-1200.

Cognition and quality of life in patients with poststroke epilepsy:A case-control study

Introduction: Though seizures are a common complication after stroke, only little scientific evidence is available about the impact of epilepsy on cognitive functioning and quality of life in patients who have had a stroke. Therefore, we assessed these items in a case–control study. Methods: We studied 36 patients with poststroke epilepsy (PSE) and 36 matched patients who have had a stroke without epilepsy using parts of the FePsy (the computerized visual searching task (CVST) for central information processing speed and a reaction time test), the mini-mental-state examination (MMSE), the EuroQol, the stroke-adapted Sickness Impact Profile questionnaire (SA-SIP-30), the Barthel index, the modified Rankin scale, and the National Institutes of Health stroke scale (NIHSS). Results: Patients with PSE had significantly lower scores on the CVST and MMSE. Generic quality of life was the same in patients with poststroke epilepsy and patients with stroke only, however, the SA-SIP-30 showed a lower disease-specific quality of life in patients with poststroke epilepsy. The Barthel index showed no difference between both groups, but both the modified Rankin scale and the NIHSS were significantly higher in patients with poststroke epilepsy, indicating more disability and neurological impairment in patients with PSE. Conclusions: We found that PSE relates to impaired cognitive functioning, a lower disease-specific quality of life and more disability and neurological impairment. This underlines the importance of further clinical research in this field. This article is part of the Special Issue “Seizures & Stroke

Medication use in poststroke epilepsy:A descriptive study on switching of antiepileptic drug treatment

Objective: Currently, as evidence-based guidelines are lacking, in patients with poststroke epilepsy (PSE), the choice of the first antiepileptic drug (AED) is left over to shared decision by the treating physician and patient. Although, it is not uncommon that patients with PSE subsequently switch their first prescribed AED to another AED, reasons for those switches are not reported yet. In the present study, we therefore assessed the reasons for switching the first prescribed AED in patients with PSE. Method: We gathered a hospital-based case series of 53 adult patients with poststroke epilepsy and assessed the use of AEDs, comedication, and the reasons for switches between AEDs during treatment. We also determined the daily drug dose (DDD) at the switching moment. Results: During a median follow-up of 62 months (Interquartile range [IQR] 69 months), 21 patients (40%) switched their first prescribed AED. Seven patients switched AED at least once because of ineffectivity only or a combination of ineffectivity and side effects, whereas 14 patients switched AED at least once because of side effects only. The DDD was significantly (p < 0.001) higher in case of medication switches due to ineffectivity (median 1.20, IQR 0.33) compared to switching due to side effects (median 0.67, IQR 0.07). There was no difference in the use of comedication between the group that switched because of ineffectivity compared to the group that switched because of side effects. Conclusion: In our case series, up to 40% of patients with epilepsy after stroke needed to switch their first prescribed AED, mostly because of side effects in lower dosage ranges