Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Endovascular Therapy for Stroke Due to Basilar-Artery Occlusion.

BACKGROUND: The effectiveness of endovascular therapy in patients with stroke caused by basilar-artery occlusion has not been well studied. METHODS: We randomly assigned patients within 6 hours after the estimated time of onset of a stroke due to basilar-artery occlusion, in a 1:1 ratio, to receive endovascular therapy or standard medical care. The primary outcome was a favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 to 6, with 0 indicating no disability, 3 indicating moderate disability, and 6 indicating death) at 90 days. The primary safety outcomes were symptomatic intracranial hemorrhage within 3 days after the initiation of treatment and mortality at 90 days. RESULTS: A total of 300 patients were enrolled (154 in the endovascular therapy group and 146 in the medical care group). Intravenous thrombolysis was used in 78.6% of the patients in the endovascular group and in 79.5% of those in the medical group. Endovascular treatment was initiated at a median of 4.4 hours after stroke onset. A favorable functional outcome occurred in 68 of 154 patients (44.2%) in the endovascular group and 55 of 146 patients (37.7%) in the medical care group (risk ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.50). Symptomatic intracranial hemorrhage occurred in 4.5% of the patients after endovascular therapy and in 0.7% of those after medical therapy (risk ratio, 6.9; 95% CI, 0.9 to 53.0); mortality at 90 days was 38.3% and 43.2%, respectively (risk ratio, 0.87; 95% CI, 0.68 to 1.12). CONCLUSIONS: Among patients with stroke from basilar-artery occlusion, endovascular therapy and medical therapy did not differ significantly with respect to a favorable functional outcome, but, as reflected by the wide confidence interval for the primary outcome, the results of this trial may not exclude a substantial benefit of endovascular therapy. Larger trials are needed to determine the efficacy and safety of endovascular therapy for basilar-artery occlusion. (Funded by the Dutch Heart Foundation and others; BASICS ClinicalTrials.gov number, NCT01717755; Netherlands Trial Register number, NL2500.).

Optic Disc and Retinal Architecture Changes in Patients with Spinocerebellar Ataxia Type 2.

BACKGROUND: ATXN2 is the causative gene of spinocerebellar ataxia type 2 (SCA2) and has been implicated in glaucoma pathogenesis. Therefore, studying ocular changes in SCA2 could uncover clinically relevant changes. OBJECTIVE: The aim was to investigate optic disc and retinal architecture in SCA2. METHODS: We evaluated 14 patients with SCA2 and 26 controls who underwent intraocular pressure measurement, fundoscopy, and macular and peripapillary spectral domain optical coherence tomography (SD-OCT). We compared SD-OCT measurements in SCA2 and controls, and the frequency of glaucomatous changes among SCA2, controls, and 76 patients with other SCAs (types 1, 3, 6, and 7). RESULTS: The macula, peripapillary retinal nerve fiber and inner plexiform layers were thinner in SCA2 than in controls. Increased cup-to-disc ratio was more frequent in SCA2 than in controls and other SCAs. CONCLUSIONS: Ocular changes are part of SCA2 phenotype. Future studies should further investigate retinal and optic nerve architecture in this disorder.

Thrombectomy for anterior circulation stroke beyond 6 h from time last known well (AURORA): a systematic review and individual patient data meta-analysis.

BACKGROUND: Trials examining the benefit of thrombectomy in anterior circulation proximal large vessel occlusion stroke have enrolled patients considered to have salvageable brain tissue, who were randomly assigned beyond 6 h and (depending on study protocol) up to 24 h from time last seen well. We aimed to estimate the benefit of thrombectomy overall and in prespecified subgroups through individual patient data meta-analysis. METHODS: We did a systematic review and individual patient data meta-analysis between Jan 1, 2010, and March 1, 2021, of randomised controlled trials of endovascular stroke therapy. In the Analysis Of Pooled Data From Randomized Studies Of Thrombectomy More Than 6 Hours After Last Known Well (AURORA) collaboration, the primary outcome was disability on the modified Rankin Scale (mRS) at 90 days, analysed by ordinal logistic regression. Key safety outcomes were symptomatic intracerebral haemorrhage and mortality within 90 days. FINDINGS: Patient level data from 505 individuals (n=266 intervention, n=239 control; mean age 68·6 years [SD 13·7], 259 [51·3%] women) were included from six trials that met inclusion criteria of 17 screened published randomised trials. Primary outcome analysis showed a benefit of thrombectomy with an unadjusted common odds ratio (OR) of 2·42 (95% CI 1·76-3·33; p<0·0001) and an adjusted common OR (for age, gender, baseline stroke severity, extent of infarction on baseline head CT, and time from onset to random assignment) of 2·54 (1·83-3·54; p<0·0001). Thrombectomy was associated with higher rates of independence in activities of daily living (mRS 0-2) than best medical therapy alone (122 [45·9%] of 266 vs 46 [19·3%] of 238; p<0·0001). No significant difference between intervention and control groups was found when analysing either 90-day mortality (44 [16·5%] of 266 vs 46 [19·3%] of 238) or symptomatic intracerebral haemorrhage (14 [5·3%] of 266 vs eight [3·3%] of 239). No heterogeneity of treatment effect was noted across subgroups defined by age, gender, baseline stroke severity, vessel occlusion site, baseline Alberta Stroke Program Early CT Score, and mode of presentation; treatment effect was stronger in patients randomly assigned within 12-24 h (common OR 5·86 [95% CI 3·14-10·94]) than those randomly assigned within 6-12 h (1·76 [1·18-2·62]; pinteraction=0·0087). INTERPRETATION: These findings strengthen the evidence for benefit of endovascular thrombectomy in patients with evidence of reversible cerebral ischaemia across the 6-24 h time window and are relevant to clinical practice. Our findings suggest that in these patients, thrombectomy should not be withheld on the basis of mode of presentation or of the point in time of presentation within the 6-24 h time window. FUNDING: Stryker Neurovascular.

Thrombectomy for Stroke in the Public Health Care System of Brazil.

BACKGROUND: Randomized trials involving patients with stroke have established that outcomes are improved with the use of thrombectomy for large-vessel occlusion. These trials were performed in high-resource countries and have had limited effects on medical practice in low- and middle-income countries. METHODS: We studied the safety and efficacy of thrombectomy in the public health system of Brazil. In 12 public hospitals, patients with a proximal intracranial occlusion in the anterior circulation that could be treated within 8 hours after the onset of stroke symptoms were randomly assigned in a 1:1 ratio to receive standard care plus mechanical thrombectomy (thrombectomy group) or standard care alone (control group). The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. RESULTS: A total of 300 patients were enrolled, including 79 who had undergone thrombectomy during an open-label roll-in period. Approximately 70% in the two groups received intravenous alteplase. The trial was stopped early because of efficacy when 221 of a planned 690 patients had undergone randomization (111 to the thrombectomy group and 110 to the control group). The common odds ratio for a better distribution of scores on the modified Rankin scale at 90 days was 2.28 (95% confidence interval [CI], 1.41 to 3.69; P = 0.001), favoring thrombectomy. The percentage of patients with a score on the modified Rankin scale of 0 to 2, signifying an absence of or minor neurologic deficit, was 35.1% in the thrombectomy group and 20.0% in the control group (difference, 15.1 percentage points; 95% CI, 2.6 to 27.6). Asymptomatic intracranial hemorrhage occurred in 51.4% of the patients in the thrombectomy group and 24.5% of those in the control group; symptomatic intracranial hemorrhage occurred in 4.5% of the patients in each group. CONCLUSIONS: In this randomized trial conducted in the public health care system of Brazil, endovascular treatment within 8 hours after the onset of stroke symptoms in conjunction with standard care resulted in better functional outcomes at 90 days than standard care alone. (Funded by the Brazilian Ministry of Health; RESILIENT ClinicalTrials.gov number, NCT02216643.).

Aseptic meningitis in Fabry disease due to a novel GLA variant: an expanded phenotype?

BACKGROUND: F abry disease (FD) is an X-linked lysosomal storage disorder with accumulation of globotriosylceramide, causing neurologic involvement mainly as acroparesthesias and cerebrovascular disease. Aseptic meningitis has been reported in 11 patients with FD, but no prior study has correlated alpha-galactosidase (GLA) specific variants with meningitis. We present in this manuscript a family in which a novel GLA pathogenic variant was associated with aseptic meningitis in 2 of 5 family members. METHODS: This study began with identifying the proband, then screening family members for FD symptoms and evaluating symptomatic individuals for genetic and biochemical status. All patients underwent magnetic resonance imaging, and those with headache underwent cerebrospinal fluid (CSF) analysis. RESULTS: Five patients (3 females) from a single family were included in this study. Mean age at diagnosis was 20.6 years. Two patients (40%) had aseptic meningitis; one of them also had cerebrovascular events. C-reactive protein and erythrocyte sedimentation rate were elevated during aseptic meningitis episodes. Both patients responded to intravenous methylprednisolone with resolution of fever, headache, and vomiting. One of them recurred and needed chronic immunosuppression with azathioprine. CONCLUSION: We described aseptic meningitis in a family with a novel GLA variant. Meningitis might be a common phenomenon in FD and not a particularity of this variant. Understanding the mechanisms underlying meningitis and its association with cerebrovascular events may lead to a new paradigm of treatment for stroke in these patients. Further prospective studies with CSF collection in patients with FD and recurrent headache could help to elucidate this question.

RFC1-Related Disorder: In Vivo Evaluation of Spinal Cord Damage.

BACKGROUND: RFC1-related disorder is a novel heredodegenerative condition with a broad phenotypic spectrum. Its neuropathological bases are not yet fully understood, particularly regarding the pattern, extent, and clinical relevance of spinal cord (SC) damage. OBJECTIVES: The objectives were to determine the SC structural signature in RFC1-related disorder in vivo and to identify potential clinical correlates for these imaging abnormalities. METHODS: We enrolled 17 subjects with biallelic RFC1 (AAGGG)n expansions and 11 age- and sex-matched healthy controls that underwent multimodal magnetic resonance imaging SC acquisitions in a 3T Philips Achieva scanner. Both global morphometry and tract-specific analyses were then performed across all cervical levels. Between-group comparisons were assessed using nonparametric tests. RESULTS: In the patient group, mean age and disease duration were 62.9 ± 9.3 and 9.3 ± 4.0, respectively. Compared to controls, patients had remarkable SC cross-sectional area reduction along all cervical levels but anteroposterior flattening only in the lower cervical levels. There was also prominent SC gray matter atrophy. Diffusivity abnormalities were identified in the dorsal columns but not in the lateral corticospinal tracts. Disease severity did not correlate with these imaging parameters. CONCLUSION: SC damage is a hallmark of RFC1-related disorder and characterized by gray as well as white matter involvement. In particular, dorsal columns are severely and diffusely affected. The clinical correlates of these imaging abnormalities still deserve additional investigations. © 2022 International Parkinson and Movement Disorder Society.

Diagnostic Yield of Whole Exome Sequencing for Adults with Ataxia: a Brazilian Perspective.

Previous studies using whole exome sequencing (WES) have shown that a significant proportion of adult patients with undiagnosed ataxia in European and North American cohorts have a known genetic cause. Little is known about the diagnostic yield of WES in non-Caucasian ataxic populations. Herein, we used WES to investigate a Brazilian cohort of 76 adult patients with idiopathic ataxia previously screened for trinucleotide expansions in known ataxia genes. We collected clinical and radiological data from each patient. WES was performed following standard procedures. Only variants labeled as pathogenic or likely pathogenic according to American college of medical genetics and genomics (ACMG) criteria were retrieved. We determined the diagnostic yield of WES for the whole cohort and also for subgroups defined according to presence or not of pyramidal signs, peripheral neuropathy, and cerebellar atrophy. There were 41 women and 35 men. Mean age at testing was 48 years. Pyramidal signs, peripheral neuropathy, tremor, and cerebellar atrophy were found in 38.1%, 13.1%, 10.5%, and 68.3% of all subjects, respectively. Diagnostic yield of WES was 35.5%. Thirty-six distinct mutations were found in 20 different genes, determining the diagnosis of 18 autosomal recessive and 9 autosomal dominant ataxias. SACS and SPG7 were the most frequently found underlying genes. WES performed better in the subgroup with vs the subgroup without spasticity (p = 0.005). WES was diagnostic in 35.5% of cases of the Brazilian cohort of ataxia cases. These results have implications for diagnosis, genetic counseling and eventually treatment.

Optic Nerve Sheath Diameter Detects Intracranial Hypertension in Acute Malignant Middle Cerebral Artery Infarction.

OBJECTIVES: To evaluate optic nerve sheath diameter in the acute phase of patients with malignant ischemic middle cerebral artery stroke submitted or not to decompressive craniectomy surgery. MATERIALS AND METHODS: Forty patients participated in the study and were evaluated bilaterally by ultrasound on admission and at 24h, 48h and 72 h after admission. Optic nerve sheath diameter values were correlated with tomographic and/or clinical criteria compatible with severe intracranial hypertension. RESULTS: A Receiver Operating Characteristic curve was drawn for each eye, determining a cut-off value for severe intracranial hypertension in the right eye of 5.4 mm (sensitivity: 62%; specificity: 100%; AUC: 0.82) and in the left eye 5.4 mm (sensitivity: 76%; specificity: 84%; AUC: 0.77). In patients undergoing craniectomy, there was a decrease in the mean value of 1.04mm in the right eye (pre: 5.84 ± 0.47 mm; post: 4.80 ± 0.84 mm; p = 0.001), while in the left, it decreased around 0.86mm (pre: 5.59 ± 0.69 mm; post: 4.73 ± 0.74 mm; p = 0.003). Patients with fatal outcome showed a persistent high mean ocular nerve sheath diameter. CONCLUSIONS: Monitoring optic nerve sheath by ultrasound can be considered a reliable method for identifying severe intracranial hypertension in patients with large vessel occlusion, as well as for monitoring patients undergoing craniectomy. Additional studies will be necessary to include this parameter in craniectomy indication algorithms in the future.

High-Performance Automated Anterior Circulation CT Angiographic Clot Detection in Acute Stroke: A Multireader Comparison.

Background Identification of large vessel occlusion (LVO) is critical to the management of acute ischemic stroke and prerequisite to endovascular therapy in recent trials. Increasing volumes and data complexity compel the development of fast, reliable, and automated tools for LVO detection to facilitate acute imaging triage. Purpose To investigate the performance of an anterior circulation LVO detection platform in a large mixed sample of individuals with and without LVO at cerebrovascular CT angiography (CTA). Materials and Methods In this retrospective analysis, CTA data from recent cerebrovascular trials (CRISP [ClinicalTrials.gov NCT01622517] and DASH) were enriched with local repositories from 11 worldwide sites to balance demographic and technical variables in LVO-positive and LVO-negative examinations. CTA findings were reviewed independently by two neuroradiologists from different institutions for intracranial internal carotid artery (ICA) or middle cerebral artery (MCA) M1 LVO; these observers were blinded to all clinical variables and outcomes. An automated analysis platform was developed and tested for prediction of LVO presence and location relative to reader consensus. Discordance between readers with respect to LVO presence or location was adjudicated by a blinded tertiary reader at a third institution. Sensitivity, specificity, and receiver operating characteristics were assessed by an independent statistician, and subgroup analyses were conducted. Prespecified performance thresholds were set at a lower bound of the 95% CI of sensitivity and specificity of 0.8 or greater at mean times to notification of less than 3.5 minutes. Results A total of 217 study participants (mean age, 64 years ± 16 [standard deviation]; 116 men; 109 with positive findings of LVO) were evaluated. Prespecified performance thresholds were exceeded (sensitivity, 105 of 109 [96%; 95% CI: 91, 99]; specificity, 106 of 108 [98%; 95% CI: 94, 100]). Sensitivity and specificity estimates across age, sex, location, and vendor subgroups exceeded 90%. The area under the receiver operating characteristic curve was 99% (95% CI: 97, 100). Mean processing and notification time was 3 minutes 18 seconds. Conclusion The results confirm the feasibility of fast automated high-performance detection of intracranial internal carotid artery and middle cerebral artery M1 occlusions. © RSNA, 2021 See also the editorial by Kloska in this issue.

Brain Structural Signature of RFC1-Related Disorder.

BACKGROUND: The cerebellar ataxia, neuropathy, and vestibular areflexia syndrome was initially described in the early 1990s as a late-onset slowly progressive condition. Its underlying genetic cause was recently mapped to the RFC1 gene, and additional reports have expanded on the phenotypic manifestations related to RFC1, although little is known about the pattern and extent of structural brain abnormalities in this condition. OBJECTIVE: The aim is to characterize the structural signature of brain damage in RFC1-related disorder, correlating the findings with clinical symptoms and normal brain RFC1 expression. METHODS: We recruited 22 individuals with molecular confirmation of RFC1 expansions and submitted them to high-resolution 3T magnetic resonance imaging scans. We performed multimodal analyses to assess separately cerebral and cerebellar abnormalities within gray and white matter (WM). The results were compared with a group of 22 age- and sex-matched controls. RESULTS: The mean age and disease duration of patients were 62.8 and 10.9 years, respectively. Ataxia, sensory neuronopathy, and vestibular areflexia were the most frequent manifestations, but parkinsonism and pyramidal signs were also noticed. We found that RFC1-related disorder is characterized by widespread and relatively symmetric cerebellar and basal ganglia atrophy. There is brainstem volumetric reduction along all its segments. Cerebral WM is also involved-mostly the corpus callosum and deep tracts, but cerebral cortical damage is rather restricted. CONCLUSION: This study adds new relevant insights into the pathophysiological mechanisms of RFC1-related disorder. It should no longer be considered a purely cerebellar and sensory pathway disorder. Basal ganglia and deep cerebral WM are additional targets of damage. © 2021 International Parkinson and Movement Disorder Society.

Brain Damage and Gene Expression Across Hereditary Spastic Paraplegia Subtypes.

BACKGROUND: Spinal cord has been considered the main target of damage in hereditary spastic paraplegias (HSPs), but mounting evidence indicates that the brain is also affected. Despite this, little is known about the brain signature of HSPs, in particular regarding stratification for specific genetic subtypes. OBJECTIVE: We aimed to characterize cerebral and cerebellar damage in five HSP subtypes (9 SPG3A, 27 SPG4, 10 SPG7, 9 SPG8, and 29 SPG11) and to uncover the clinical and gene expression correlates. METHODS: We obtained high-resolution brain T1 and diffusion tensor image (DTI) datasets in this cross-sectional case-control study (n = 84). The MRICloud, FreeSurfer, and CERES-SUIT pipelines were employed to assess cerebral gray (GM) and white matter (WM) as well as the cerebellum. RESULTS: Brain abnormalities were found in all but one HSP group (SPG3A), but the patterns were gene-specific: basal ganglia, thalamic, and posterior WM involvement in SPG4; diffuse WM and cerebellar involvement in SPG7; cortical thinning at the motor cortices and pallidal atrophy in SPG8; and widespread GM, WM, and deep cerebellar nuclei damage in SPG11. Abnormal regions in SPG4 and SPG8 matched those with higher SPAST and WASHC5 expression, whereas in SPG7 and SPG11 this concordance was only noticed in the cerebellum. CONCLUSIONS: Brain damage is a conspicuous feature of HSPs (even for pure subtypes), but the pattern of abnormalities is genotype-specific. Correlation between brain structural damage and gene expression maps is different for autosomal dominant and recessive HSPs, pointing to distinct pathophysiological mechanisms underlying brain damage in these subgroups of the disease. © 2021 International Parkinson and Movement Disorder Society.

Randomized Trial of Botulinum Toxin Type A in Hereditary Spastic Paraplegia - The SPASTOX Trial.

BACKGROUND: Hereditary spastic paraplegia presents spasticity as the main clinical manifestation, reducing gait quality and producing incapacity. Management with botulinum toxin type A (BoNT-A) is not well elucidated. The objective of the current study was to evaluate the efficacy and safety of BoNT-A in patients with hereditary spastic paraplegias. METHODS: This was a double-blind, randomized, placebo-controlled crossover trial. Each participant was randomly assigned to receive 1 injection session of either BoNT-A (100 IU/2 mL of Prosigne in each adductor magnus and each triceps surae) or saline 0.9% (2 mL). The primary outcome measure was change from baseline in maximal gait velocity, and secondary outcome measures included changes in gait at self-selected velocity, spasticity, muscle strength, Spastic Paraplegia Rating Scale, pain, fatigue, and subjective perception of improvement. We also looked at adverse events reported by the patients. RESULTS: We enrolled 55 patients, 36 of whom were men and 41 with the pure phenotype. Mean age was 43 ± 13.4 years (range, 19-72 years), mean age of onset waws 27 ± 13.1 years (range, <1 to 55 yars), and mean disease duration was 17 ± 12.7 years (range, 1-62 years). Compared with baseline, we did not find significant differences between groups in primary and secondary outcomes, except for reduction in adductor tone (P = 0.01). The adverse events were transient and tolerable, and their incidence did not significantly differ between treatments (P = 0.17). CONCLUSIONS: BoNT-A was safe in patients with hereditary spastic paraplegias and reduced the adductor tone, but it was not able to produce functional improvement considering the doses, injection protocol, measures, and instruments used. © 2021 International Parkinson and Movement Disorder Society.

Laryngeal electromyography in amyotrophic lateral sclerosis.

BACKGROUND: Bulbar involvement is a hallmark of amyotrophic lateral sclerosis (ALS), but surprisingly very few studies have addressed the frequency, pattern and clinical relevance of laryngeal involvement in the disease. METHODS: Twenty-six patients with spinal-onset ALS underwent nasofibroscopy (NF), followed by laryngeal electromyography (LEMG). We also studied resting activity and motor unit potentials of the genioglossus and masseter muscles. RESULTS: Twenty-four patients presented neurogenic changes in at least one laryngeal muscle. There were fibrillation and/or fasciculation potentials associated with chronic neurogenic changes in the same muscle in 16 patients; of these, 9 had no alteration in the genioglossus. We found no patient with tongue neurogenic changes and normal LEMG. NF was abnormal in 14 patients; in the remaining 12, LEMG identified neurogenic changes in 11 of them. CONCLUSION: LEMG is able to identify laryngeal denervation in patients with ALS, sometimes before clinical manifestations are noticed. This technique may be a useful diagnostic tool for selected patients with suspicion of ALS.

The Role of Hemorrhagic Transformation in Acute Ischemic Stroke Upon Clinical Complications and Outcomes.

BACKGROUND AND PURPOSE: Hemorrhagic transformation (HT) is a common neurological complication after ischemic stroke. The influence of symptomatic HT upon clinical outcomes post-stroke is well established, however, the role of asymptomatic HT upon prognosis is still unclear. We aimed to analyze the relationship between HT, clinical complications and outcomes in patients not submitted to reperfusion therapies (RT). METHODS: We included 448 randomly selected patients admitted with acute ischemic stroke to a tertiary hospital stroke unit from 2015 to 2017. Patients submitted to RT were excluded. All patients were evaluated with computed tomography (CT) at admission and within 7 days from the initial CT. Patients with HT were divided into two groups: symptomatic and asymptomatic cases based on the ECASS II definition. A good clinical outcome was defined as a modified Rankin Scale (mRS) 0-2 at discharge. RESULTS: A total of 95 patients (21.2%) had HT (51 asymptomatic and 44 symptomatic). Age, NIHSS at admission and symptomatic HT were associated with a higher risk of developing pneumonia and seizures during hospitalization. Symptomatic HT was also associated with a prolonged length of hospitalization and death and inversely associated with good clinical outcomes at discharge (OR 0.96, 95% CI 0.94-0.98, p<0.001). In an adjusted analysis, even asymptomatic HT was independently associated with worse clinical outcomes at discharge (mRS 4-6) (OR 5.99, 95% CI 1.83-19.58, p = 0.003). CONCLUSIONS: Symptomatic HT is associated with a higher risk of clinical complications, prolonged hospitalization, death and worse clinical outcome at discharge. Furthermore, even patients with asymptomatic HT had a higher chance of worse clinical outcomes at discharge.

Predicting hemorrhagic transformation in patients not submitted to reperfusion therapies.

BACKGROUND: Well studied in patients with ischemic stroke after reperfusion therapies (RT), hemorrhagic transformation (HT) is also common in patients not treated with RT and can lead to disability even in initially asymptomatic cases. The best predictors of HT in patients not treated with RT are not well established. Therefore, we aimed to identify predictors of HT in patients not submitted to RT and create a user-friendly predictive score (PROpHET). MATERIAL AND METHODS: Patients admitted to a Comprehensive Stroke Center from 2015 to 2017 were prospectively evaluated and randomly selected to the derivation cohort. A multivariable logistic regression modeling was built to produce a predictive grading score for HT. The external validation was assessed using datasets from 7 Comprehensive Stroke Centers using the area under the receiver operating characteristic curve (AUROC). RESULTS: In the derivation group, 448 patients were included in the final analysis. The validation group included 2,683 patients. The score derived from significant predictors of HT in the multivariate logistic regression analysis was male sex (1 point), ASPECTS ≤ 7 (2 points), presence of leukoaraiosis (1 point), hyperdense cerebral middle artery sign (1 point), glycemia at admission ≥180 mg/dL (1 point), cardioembolism (1 point) and lacunar syndrome (-3 points) as a protective factor. The grading score ranges from -3 to 7. A Score ≥3 had 78.2% sensitivity and 75% specificity, and AUROC of 0.82 for all cases of HT. In the validation cohort, our score had an AUROC of 0.83. CONCLUSIONS: The PROpHET is a simple, quick, cost-free, and easy-to-perform tool that allows risk stratification of HT in patients not submitted to RT. A cost-free computerized version of our score is available online with a user-friendly interface.

Mechanical Thrombectomy in Patients With Milder Strokes and Large Vessel Occlusions.

Background and Purpose- We aimed to describe the safety and efficacy of immediate mechanical thrombectomy (MT) in patients with large vessel occlusions and low National Institutes of Health Stroke Scale (NIHSS) versus best medical management. Methods- Patients from prospectively collected databases of 6 international comprehensive stroke centers with large vessel occlusions (distal intracranial internal carotid, middle cerebral artery-M1 and M2 segments, or basilar artery with or without tandem occlusions) and NIHSS 0 to 5 were identified and divided into 2 groups for analysis: immediate MT or initial best medical management which included rescue MT after neurological deterioration (best medical management-MT). Uni- and multivariate analyses and patient-level matching for age, baseline NIHSS, and occlusion site were performed to compare baseline and outcome variables across the 2 groups. The primary outcome was defined as good outcome (modified Rankin Scale score, 0-2) at day 90. Safety outcome was symptomatic intracranial hemorrhage as defined by the ECASS (European Cooperative Acute Stroke Study) II and mortality at day 90. Results- Compared with best medical management-MT (n=220), patients with immediate MT (n=80) were younger (65.3±13.5 versus 69.5±14.1; P=0.021), had more often atrial fibrillation (44.8% versus 28.2%; P=0.012), higher baseline NIHSS (4, 0-5 versus 3, 0-5; P=0.005), higher Alberta Stroke Program Early CT Score (10, 7-10 versus 10, 5-10; P=0.023), more middle cerebral artery-M1, and less middle cerebral artery-M2 (41.3% versus 21.9% and 28.8% versus 49.3%; P=0.016) occlusions. The adjusted odds ratio for good outcome was 3.1 (95% CI, 1.4-6.9) favoring immediate MT. In the matched analysis, there was a 14.4% absolute difference in good outcome (84.4% versus 70.1%; P=0.03) at day 90 favoring immediate MT. There were no safety concerns. Conclusions- Our retrospective, pilot analysis suggests that immediate thrombectomy in large vessel occlusions patients with low NIHSS on presentation may be safe and has the potential to result in improved outcomes. Randomized clinical trials are warranted to establish the optimal management for this patient population.

Oxidative Stress Biomarkers of Brain Damage: Hyperacute Plasma F2-Isoprostane Predicts Infarct Growth in Stroke.

BACKGROUND AND PURPOSE: Oxidative stress is an early response to cerebral ischemia and is likely to play an important role in the pathogenesis of cerebral ischemic injury. We sought to evaluate whether hyperacute plasma concentrations of biomarkers of oxidative stress, inflammation, and tissue damage predict infarct growth (IG). METHODS: We prospectively measured plasma F2-isoprostane (F2-isoP), urinary 8-oxo-7,8-dihydro-2'-deoxyguoanosine, plasma oxygen radical absorbance capacity assay, high sensitivity C reactive protein, and matrix metalloproteinase 2 and 9 in consecutive patients with acute ischemic stroke presenting within 9 hours of symptom onset. Patients with baseline diffusion-weighted magnetic resonance imaging and follow-up diffusion-weighted imaging or computed tomographic scan were included to evaluate the final infarct volume. Baseline diffusion-weighted imaging volume and final infarct volume were analyzed using semiautomated volumetric method. IG volume was defined as the difference between final infarct volume and baseline diffusion-weighted imaging volume. RESULTS: A total of 220 acute ischemic stroke subjects were included in the final analysis. One hundred seventy of these had IG. Baseline F2-isoP significantly correlated with IG volume (Spearman ρ=0.20; P=0.005) and final infarct volume (Spearman ρ=0.19; P=0.009). In a multivariate binary logistic regression model, baseline F2-isoP emerged as an independent predictor of the occurrence of IG (odds ratio, 2.57; 95% confidence interval, 1.37-4.83; P=0.007). In a multivariate linear regression model, baseline F2-isoP was independently associated with IG volume (B, 0.38; 95% confidence interval, 0.04-0.72; P=0.03). CONCLUSIONS: Elevated hyperacute plasma F2-isoP concentrations independently predict the occurrence of IG and IG volume in patients with acute ischemic stroke. If validated in future studies, measuring plasma F2-isoP might be helpful in the acute setting to stratify patients with acute ischemic stroke for relative severity of ischemic injury and expected progression.

The FAST-ED App: A Smartphone Platform for the Field Triage of Patients With Stroke.

BACKGROUND AND PURPOSE: The Emergency Medical Services field triage to stroke centers has gained considerable complexity with the recent demonstration of clinical benefit of endovascular treatment for acute ischemic stroke. We sought to describe a new smartphone freeware application designed to assist Emergency Medical Services professionals with the field assessment and destination triage of patients with acute ischemic stroke. METHODS: Review of the application's platform and its development as well as the different variables, assessments, algorithms, and assumptions involved. RESULTS: The FAST-ED (Field Assessment Stroke Triage for Emergency Destination) application is based on a built-in automated decision-making algorithm that relies on (1) a brief series of questions assessing patient's age, anticoagulant usage, time last known normal, motor weakness, gaze deviation, aphasia, and hemineglect; (2) a database of all regional stroke centers according to their capability to provide endovascular treatment; and (3) Global Positioning System technology with real-time traffic information to compute the patient's eligibility for intravenous tissue-type plasminogen activator or endovascular treatment as well as the distances/transportation times to the different neighboring stroke centers in order to assist Emergency Medical Services professionals with the decision about the most suitable destination for any given patient with acute ischemic stroke. CONCLUSIONS: The FAST-ED smartphone application has great potential to improve the triage of patients with acute ischemic stroke, as it seems capable to optimize resources, reduce hospital arrivals times, and maximize the use of both intravenous tissue-type plasminogen activator and endovascular treatment ultimately leading to better clinical outcomes. Future field studies are needed to properly evaluate the impact of this tool in stroke outcomes and resource utilization.

Electroencephalography Patterns and Prognosis in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: The prognostic significance of interictal epileptiform discharges (IED) and periodic patterns (PP) after ischemic stroke has not been assessed. We sought to test whether IED and PP, detected on standard Electroencephalography (EEG) performed during the acute phase of ischemic stroke are associated with a worse functional outcome. METHODS: One-hundred-fifty-seven patients 18 years or older with a diagnosis of acute ischemic stroke presenting within 72 h from stroke onset were prospectively enrolled and followed. Patients with a pre-stroke history of seizures or epilepsy, previous debilitating neurological disease or conditions that precluded the performance of EEG were excluded. Interpretation was performed by a blinded board certified neurophysiologist. IED and PP (grouped as epileptiform activity [EA]) were defined according to proposed guidelines. Univariable and multivariable analyses were used to identify predictors of outcome (modified Rankin Scale dichotomized ≤2 vs. ≥3) at 3 months. RESULTS: In the univariable analysis, admission NIHSS (OR 1.20, 95% CI 1.12-1.28, p = 0.001), age (OR 1.03, 95% CI 1.01-1.05, p = 0.02), and presence of EA (OR 2.94, 95% CI 1.51-5.88, p = 0.001) were significantly associated with the outcome at 3 months. In the multivariable analysis, only admission NIHSS (OR 1.19, 95% CI 1.11-1.28, p < 0.001) and the presence of EA (OR 2.27, 95% CI 1.04-5.00, p = 0.04) were independently associated with the prognosis. SIGNIFICANCE: The importance of EEG in the prognosis of acute ischemic stroke warrants additional research, examining the role of medication therapy on the outcome and the occurrence of seizures for those patients with specific EEG patterns.