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.

Posterior circulation collaterals as predictors of outcome in basilar artery occlusion: a sub-analysis of the BASICS randomized trial.

Introduction and purpose: Basilar artery occlusion (BAO) is still one of the most devastating neurological conditions associated with high morbidity and mortality. In the present study, we aimed to assess the role of posterior circulation collaterals as predictors of outcome in the BASICS trial and to compare two grading systems (BATMAN score and PC-CS) in terms of prognostic value. Methods: We performed a sub-analysis of the BASICS trial. Baseline clinical and imaging variables were analyzed. For the imaging analysis, baseline CT and CTA were analyzed by a central core lab. Only those patients with good or moderate quality of baseline CTA and with confirmed BAO were included. Multivariable binary logistic regression analysis was used to test the independent association of clinical and imaging characteristics with a favorable outcome at 3 months (defined as a modified Rankin Score of ≤3). ROC curve analysis was used to assess and compare accuracy between the two collateral grading systems. Results: The mean age was 67.0 (±12.5) years, 196 (65.3%) patients were males and the median NIHSS was 21.5 (IQR 11-35). Median NCCT pc-ASPECTS was 10 (IQR10-10) and median collateral scores for BATMAN and PC-CS were 8 (IQR 7-9) and 7 (IQR 6-8) respectively. Collateral scores were associated with favorable outcome at 3 months for both BATMAN and PC-CS but only with a modest accuracy on ROC curve analysis (AUC 0.62, 95% CI [0.55-0.69] and 0.67, 95% CI [0.60-0.74] respectively). Age (OR 0.97, 95% CI [0.95-1.00]), NIHSS (OR 0.91, 95% CI [0.89-0.94]) and collateral score (PC-CS - OR 1.2495% CI [1.02-1.51]) were independently associated with clinical outcome. Conclusion: The two collateral grading systems presented modest prognostic accuracy. Only the PC-CS was independently associated with a favorable outcome at 3 months.

RapidpulseTM cyclic aspiration system for acute ischemic stroke due to large vessel occlusions.

BACKGROUND: The best strategy to achieve optimal reperfusion outcomes during mechanical thrombectomy remains to be defined. The RapidPulseTM Cyclic Aspiration System is a novel technology, delivering high-frequency pulsed vacuum forces to increase the efficiency of aspiration thrombectomy. METHODS: Prospective, multicenter, open-label, core lab-adjudicated, two-arm study comparing safety and efficacy of a feasibility version of the RapidPulseTM system compared with contemporary controls. Primary endpoint was the rate of mTICI ≥ 2c after first-pass effect (FPE). Additional efficacy endpoints were the rates of mTICI ≥ 2b after first pass (modified FPE (mFPE)), last pass with study device defined as frontline technical success, and after all passes including rescue therapy. The primary safety endpoints included symptomatic ICH (sICH) within 24 h post-procedure. RESULTS: Between February 2022 to December 2022, 80 subjects were consented and enrolled in the study (n = 40 treatment arm, n = 40 control arm). In the intent to treat (ITT) population, mean age was 67.8 ± 11.5 years; 19 (47.5%) were male. Median NIHSS score was 16 (IQR: 13-22). Median ASPECTS score was 9 (IQR: 8-10). The rate of mTICI ≥ 2c after first pass was 53.9% in ITT population (60.0% in per-protocol population) versus 38.5% in the corresponding control population. Functional independence (mRS 0-2) at 90 days was achieved in 61.1% (22/36) in the RapidPulseTM arm and 52.8% (19/36) in the control arm. In the RapidPulseTM arm, no sICH within 24 h and no device-related morbidity or mortality occurred. CONCLUSION: Preliminary data suggests RapidPulseTM Aspiration System is highly effective and safe for recanalization of large vessel occlusions.

Cranial Nerve Thinning Distinguishes RFC1-Related Disorder from Other Late-Onset Ataxias.

BACKGROUND: RFC1-related disorder (RFC1/CANVAS) shares clinical features with other late-onset ataxias, such as spinocerebellar ataxias (SCA) and multiple system atrophy cerebellar type (MSA-C). Thinning of cranial nerves V (CNV) and VIII (CNVIII) has been reported in magnetic resonance imaging (MRI) scans of RFC1/CANVAS, but its specificity remains unclear. OBJECTIVES: To assess the usefulness of CNV and CNVIII thinning to differentiate RFC1/CANVAS from SCA and MSA-C. METHODS: Seventeen individuals with RFC1/CANVAS, 57 with SCA (types 2, 3 and 6), 11 with MSA-C and 15 healthy controls were enrolled. The Balanced Fast Field Echo sequence was used for assessment of cranial nerves. Images were reviewed by a neuroradiologist, who classified these nerves as atrophic or normal, and subsequently the CNV was segmented manually by an experienced neurologist. Both assessments were blinded to patient and clinical data. Non-parametric tests were used to assess between-group comparisons. RESULTS: Atrophy of CNV and CNVIII, both alone and in combination, was significantly more frequent in the RFC1/CANVAS group than in healthy controls and all other ataxia groups. Atrophy of CNV had the highest sensitivity (82%) and combined CNV and CNVIII atrophy had the best specificity (92%) for diagnosing RFC1/CANVAS. In the quantitative analyses, CNV was significantly thinner in the RFC1/CANVAS group relative to all other groups. The cutoff CNV diameter that best identified RFC1/CANVAS was ≤2.2 mm (AUC = 0.91; sensitivity 88.2%, specificity 95.6%). CONCLUSION: MRI evaluation of CNV and CNVIII using a dedicated sequence is an easy-to-use tool that helps to distinguish RFC1/CANVAS from SCA and MSA-C.

The role of intravenous thrombolysis before mechanical Thrombectomy: A subgroup analysis of the RESILIENT trial.

BACKGROUND: Randomized trials have recently evaluated the non-inferiority of direct thrombectomy versus intravenous thrombolysis (IVT) followed by endovascular therapy in anterior circulation large vessel occlusion (LVO) stroke in patients eligible for IVT within 4.5 h from stroke onset with controversial results. We aimed to assess the effect of IVT on the clinical outcome of mechanical thrombectomy (MT) in the RESILIENT trial. METHODS: RESILIENT was a randomized, prospective, multicenter, controlled trial assessing the safety and efficacy of thrombectomy versus medical treatment alone. A total of 221 patients were enrolled. The trial showed a substantial benefit of MT when added to medical management. All eligible patients received intravenous tPA within the 4.5-h-window. Ordinal logistic and binary regression analyses using intravenous tPA as an interaction term were performed with adjustments for potential confounders, including age, baseline NIHSS score, occlusion site, and ASPECTS. A p-value <0.05 was considered statistically significant. RESULTS: Among 221 randomized patients (median NIHSS, 18 IQR [14-21]), 155 (70%) were treated with IVT. There was no difference in the mRS ordinal shift and frequency of functional independence between patients who received or not IV tPA; the odds ratio for the ordinal mRS shift was 2.63 [1.48-4.69] for the IVT group and 1.54 [0.63-3.74] for the no IVT group, with a p-value of 0.42. IVT also did not affect the frequency of good recanalization (TICI 2b or higher) and hemorrhagic transformation. CONCLUSIONS: The large effect size of MT on LVO outcomes was not significantly affected by IVT. TRIAL REGISTRATION: RESILIENT ClinicalTrials.gov number, NCT02216643.

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.

Performance of RAPID noncontrast CT stroke platform in large vessel occlusion and intracranial hemorrhage detection.

Background: Noncontrast CT (NCCT) is used to evaluate for intracerebral hemorrhage (ICH) and ischemia in acute ischemic stroke (AIS). Large vessel occlusions (LVOs) are a major cause of AIS, but challenging to detect on NCCT. Aims: The purpose of this study is to evaluate an AI software called RAPID NCCT Stroke (RAPID, iSchemaView, Menlo Park, CA) for ICH and LVO detection compared to expert readers. Methods: In this IRB approved retrospective, multicenter study, stand-alone performance of the software was assessed based on the consensus of 3 neuroradiologists and sensitivity and specificity were determined. The platform's performance was then compared to interpretation by readers comprised of eight general radiologists (GR) and three neuroradiologists (NR) in detecting ICH and hyperdense vessel sign (HVS) indicating LVO. Results: A total of 244 cases were included. Of the 244, 115 were LVOs and 26 were ICHs. One hundred three cases did not have LVO nor ICH. Stand-alone performance of the software demonstrated sensitivities and specificities of 96.2 and 99.5% for ICH and 63.5 and 95.1% for LVO detection. Compared to all 11 readers and eight GR readers only respectively, the software demonstrated superiority, achieving significantly higher sensitivities (63.5% versus 43.6%, p < 0.0001 and 63.5% versus 40.9%, p = 0.001). Conclusion: The RAPID NCCT Stroke platform demonstrates superior performance to radiologists for detecting LVO from a NCCT. Use of this software platform could lead to earlier LVO detection and expedited transfer of these patients to a thrombectomy capable center.

F-waves persistence in peripheral sensory syndromes.

BACKGROUND: The distinction between sensory neuronopathies (SN), which is by definition purely sensory, and sensory polyneuropathies (SP) and sensory multineuropathies (SM) is important for etiologic investigation and prognosis estimation. However, this task is often challenging in clinical practice. We hypothesize that F-wave assessment might be helpful, since it is able to detect subtle signs of motor involvement, which are found in SP and SM, but not in SN. OBJECTIVE: The aim of the present study was to determine whether F-waves are useful to distinguish SN from SP and SM. METHODS: We selected 21 patients with SP (12 diabetes mellitus, 4 transthyretin familial amyloid polyneuropathy, 4 others), 22 with SM (22 leprosy), and 26 with SN (13 immune-mediated, 10 idiopathic, 3 others) according to clinical-electrophysiological-etiological criteria. For every subject, we collected data on height and performed 20 supramaximal distal stimuli in median, ulnar, peroneal, and tibial nerves, bilaterally, to record F-waves. Latencies (minimum and mean) and persistences were compared across groups using the Kruskal-Wallis and Bonferroni tests. P-values < 0.05 were considered significant. RESULTS: All groups were age, gender, and height-matched. Overall, there were no significant between-group differences regarding F-wave latencies. In contrast, F-wave persistence was able to stratify the groups. Peroneal F-wave persistence was higher, bilaterally, in the SN group compared to SM and SP (p < 0.05). In addition, F-waves persistence of the ulnar and tibial nerves was also helpful to separate SN from SP (p < 0.05). CONCLUSION: F-wave persistence of the peroneal nerves might be an additional and useful diagnostic tool to differentiate peripheral sensory syndromes.

ANTECEDENTES: A distinção entre neuronopatias sensitivas (SN) e polineuropatias sensitivas (SP) e multineuropatias sensitivas (SM) é importante para a investigação etiológica e para o prognóstico. Contudo, esta tarefa é desafiadora na prática clínica. Hipotetizou-se que a avaliação das ondas-F pode ser útil, por ser capaz de detectar envolvimento motor nas SP e SM, mas não nas SN. OBJETIVO: Determinar se as ondas-F podem ajudar a distinguir entre SN, SP e SM. MéTODOS: Selecionou-se 21 pacientes com SP (12 diabetes mellitus, 4 ATTR-FAP e 4 com outras neuropatias), 22 com SM (22 hanseníases) e 26 com SN (13 imunomediadas, 10 idiopáticas e 3 com outras neuronopatias), de acordo com critérios clínicos, etiológicos e eletrofisiológicos. Para cada indivíduo, foi aferida a altura e foram aplicados 20 estímulos distais supramáximos nos nervos mediano, ulnar, fibular e tibial, bilateralmente, para registrar as ondas-F. Uma comparação foi feita, por grupo, das latências (mínimas e médias) e persistências pelos testes Kruskal-Wallis e Bonferroni. Valores de p < 0.05 foram considerados estatisticamente significativos. RESULTADOS: Todos os grupos foram pareados por idade, sexo e altura. Não houve diferença estatística significativa entre os grupos quanto às latências das ondas-F. A persistência da onda-F foi capaz de estratificar os grupos, sendo as dos nervos fibulares bilateralmente maiores no grupo SN que nos grupos SM e SP (p < 0.05). Adicionalmente, a persistência das ondas-F dos nervos ulnares e tibiais também foi útil para distinguir SN de SP (p < 0.05). CONCLUSãO: A persistência das ondas-F dos nervos fibulares pode ser uma ferramenta adicional e útil para diferenciar síndromes sensitivas periféricas.

Autonomic function in sporadic and familial ALS type 8.

OBJECTIVE: To characterize and compare autonomic function in patients with sporadic (sALS) and familial ALS type 8 (fALS8). METHODS: We selected 11 patients with sALS (7 men), 14 with fALS8 (8 men) and 26 controls (15 men). All groups were gender and age-matched. For each subject, Scale for Outcomes in Parkinson's Disease for Autonomic Symptoms (SCOPA-AUT) was applied and data from heart rate variability, Quantitative Sudomotor Axon Reflex Test (QSART) and skin sympathetic response (SSR) were collected. These data were compared across groups using nonparametric tests. P-values < 0.05 were considered significant. RESULTS: SCOPA-AUT revealed predominant clinical complaints in thermoregulatory, pupillomotor and sexual domains in fALS8 relative to sALS as well as controls. Neurophysiological tests demonstrated significant differences in Valsalva ratio, Expiratory:Inspiratory index and RR minimum values in both ALS groups relative to controls. Sudomotor dysfunction was also observed in sALS and fALS8 groups, as shown by reduced medial forearm and foot QSART volumes and absence of SSR in lower limbs. CONCLUSIONS: Dysautonomia - cardiac and sudomotor - is part of the phenotype in sALS and fALS8. The profile of autonomic symptoms, however, is different in each group. SIGNIFICANCE: Patients with fALS8 and sALS have autonomic dysfunction involving both sympathetic and parasympathetic divisions.

F-waves persistence in peripheral sensory syndromes / Persistência das ondas-F nas síndromes sensitivas periféricas

Abstract Background The distinction between sensory neuronopathies (SN), which is by definition purely sensory, and sensory polyneuropathies (SP) and sensory multineuropathies (SM) is important for etiologic investigation and prognosis estimation. However, this task is often challenging in clinical practice. We hypothesize that F-wave assessment might be helpful, since it is able to detect subtle signs of motor involvement, which are found in SP and SM, but not in SN. Objective The aim of the present study was to determine whether F-waves are useful to distinguish SN from SP and SM. Methods We selected 21 patients with SP (12 diabetes mellitus, 4 transthyretin familial amyloid polyneuropathy, 4 others), 22 with SM (22 leprosy), and 26 with SN (13 immune-mediated, 10 idiopathic, 3 others) according to clinical-electrophysiological-etiological criteria. For every subject, we collected data on height and performed 20 supramaximal distal stimuli in median, ulnar, peroneal, and tibial nerves, bilaterally, to record F-waves. Latencies (minimum and mean) and persistences were compared across groups using the Kruskal-Wallis and Bonferroni tests. P-values < 0.05 were considered significant. Results All groups were age, gender, and height-matched. Overall, there were no significant between-group differences regarding F-wave latencies. In contrast, F-wave persistence was able to stratify the groups. Peroneal F-wave persistence was higher, bilaterally, in the SN group compared to SM and SP (p < 0.05). In addition, F-waves persistence of the ulnar and tibial nerves was also helpful to separate SN from SP (p < 0.05). Conclusion F-wave persistence of the peroneal nerves might be an additional and useful diagnostic tool to differentiate peripheral sensory syndromes.

Resumo Antecedentes A distinção entre neuronopatias sensitivas (SN) e polineuropatias sensitivas (SP) e multineuropatias sensitivas (SM) é importante para a investigação etiológica e para o prognóstico. Contudo, esta tarefa é desafiadora na prática clínica. Hipotetizou-se que a avaliação das ondas-F pode ser útil, por ser capaz de detectar envolvimento motor nas SP e SM, mas não nas SN. Objetivo Determinar se as ondas-F podem ajudar a distinguir entre SN, SP e SM. Métodos Selecionou-se 21 pacientes com SP (12 diabetes mellitus, 4 ATTR-FAP e 4 com outras neuropatias), 22 com SM (22 hanseníases) e 26 com SN (13 imunomediadas, 10 idiopáticas e 3 com outras neuronopatias), de acordo com critérios clínicos, etiológicos e eletrofisiológicos. Para cada indivíduo, foi aferida a altura e foram aplicados 20 estímulos distais supramáximos nos nervos mediano, ulnar, fibular e tibial, bilateralmente, para registrar as ondas-F. Uma comparação foi feita, por grupo, das latências (mínimas e médias) e persistências pelos testes Kruskal-Wallis e Bonferroni. Valores de p < 0.05 foram considerados estatisticamente significativos. Resultados Todos os grupos foram pareados por idade, sexo e altura. Não houve diferença estatística significativa entre os grupos quanto às latências das ondas-F. A persistência da onda-F foi capaz de estratificar os grupos, sendo as dos nervos fibulares bilateralmente maiores no grupo SN que nos grupos SM e SP (p < 0.05). Adicionalmente, a persistência das ondas-F dos nervos ulnares e tibiais também foi útil para distinguir SN de SP (p < 0.05). Conclusão A persistência das ondas-F dos nervos fibulares pode ser uma ferramenta adicional e útil para diferenciar síndromes sensitivas periféricas.

Predictors of congruency between clinical and radiographic Oxfordshire Community Stroke Project Classification subtypes.

BACKGROUND: The Oxfordshire Community Stroke Project (OCSP) classification has been widely used to assess ischemic stroke patients based on clinical characteristics alone. However, the correlation between the clinical presentation evaluated using OCSP and imaging findings is yet to be determined. Our study aimed to describe the baseline characteristics of the OCSP subtypes of patients admitted with ischemic stroke and evaluate the predictors of the relationship between clinical and neuroimaging findings. METHODS: Patients with a confirmed diagnosis of ischemic stroke admitted to a comprehensive stroke center in Brazil between February 2015 and October 2017 were eligible for the study. All participants underwent computed tomography (CT) at admission and follow-up neuroimaging within seven days, per the institutional protocol. Trained staff classified patients according to the OCSP at hospital admission. The radiographic OCSP classification was retrospectively assessed based on the last follow-up neuroimaging by investigators unaware of the clinical classification. RESULTS: The overall agreement rates ranged from 65.5% to 88.7%. Lower NIHSS scores, absent hyperdense MCA sign, higher ASPECTS, and absent brainstem symptoms were related to a higher risk of misclassification. Treatment with intravenous tPA was associated with reclassification in patients with total anterior circulation syndrome. For predicting radiographic posterior circulation involvement, vertigo (OR 2.9, 95% CI 1.7-5.1, p < 0.001) and brainstem symptoms (OR 35, 95% CI 20.5-60.2, p < 0.001) were directly associated with correct classification, but motor and higher cerebral function were not correlated. CONCLUSION: The clinical OCSP classification presented good congruency rates with the neuroimaging findings. However, patients with lacunar syndromes are often misclassified when radiological criteria are considered.

In-Hospital Aspirin Dose as a Risk Factor for Hemorrhagic Transformation in Patients Not Treated With Thrombolysis.

BACKGROUND: Aspirin is widely used as secondary prophylaxis for acute ischemic stroke. However, its influence on the risk of spontaneous hemorrhagic transformation (HT) is still unclear. Predictive scores of HT have been proposed. We hypothesized that an increased aspirin dose might be harmful in patients at a high risk of HT. This study aimed to analyze the relationship between in-hospital daily aspirin dose (IAD) and HT in patients with acute ischemic stroke. METHODS: We conducted a retrospective cohort study of patients admitted to our comprehensive stroke center between 2015 and 2017. The attending team defined IAD. All included patients underwent either computed tomography or magnetic resonance imaging within 7 days of admission. The risk of HT was assessed using the predictive score of HT in patients not undergoing reperfusion therapies. Regression models were used to evaluate the correlations between HT and IAD. RESULTS: A total of 986 patients were included in the final analysis. The prevalence of HT was 19.2%, and parenchymatous hematomas type-2 (PH-2) represented 10% (n=19) of these cases. IAD was not associated with HT ( P =0.09) or PH-2 ( P =0.06) among all patients. However, in patients at a higher risk for HT (patients not undergoing reperfusion therapies ≥3), IAD was associated with PH-2 (odds ratio 1.01,95% CI 1.001-1.023, P =0.03) in an adjusted analysis. Taking 200 versus 300 mg aspirin was protective against PH-2 (odds ratio 0.102, 95% CI 0.018-0.563, P =0.009). CONCLUSION: An increased in-hospital aspirin dose is associated with intracerebral hematoma in patients at a high risk of HT. Stratifying the risk of HT may lead to individualized daily aspirin dose choices. However, clinical trials on this topic are required.

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.

Dysautonomia in RFC1-related disorder: Clinical and neurophysiological evaluation.

OBJECTIVE: To characterize and quantify autonomic involvement in patients with RFC1-related disorder of adult-onset cerebellar ataxia and idiopathic sensory neuropathy. METHODS: We enrolled 16 subjects with biallelic RFC1 (AAGGG)n expansions and 16 age and sex-matched healthy controls that underwent comprehensive clinical and neurophysiological evaluation. Scales for Outcomes in Parkinson's Disease Autonomic Dysfunction (SCOPA-AUT) score was used to assess autonomic symptoms. Electrophysiological testing included assessment of heart rate variability and quantitative sudomotor axon reflex test (QSART). Between-group comparisons were assessed using non-parametric tests. RESULTS: In the patient group, there were 9 men/7 women and the median age was 60.5 years. SCOPA-AUT scores were significantly higher in the RFC1 group compared to controls (22 vs 10, p < 0.001). Half of patients had cardiac autonomic neuropathy. In neurophysiology, there was resting tachycardia combined with abnormal responses during Valsalva maneuver and deep breathing among patients. QSART responses were also significantly reduced in the RFC1 group, especially in the lower limbs. CONCLUSIONS: Autonomic dysfunction is frequent, clinically relevant and involves multiple domains in RFC1-related disorder. Patients have both sympathetic and parasympathetic involvement. From a topographical perspective, this condition is characterized by a small fiber autonomic axonopathy. SIGNIFICANCE: Dysautonomia is frequent, severe and related to peripheral damage in RFC1-related disorder.

Controversies and Clinical Applications of Non-Invasive Transspinal Magnetic Stimulation: A Critical Review and Exploratory Trial in Hereditary Spastic Paraplegia.

Magnetic stimulation is a safe, non-invasive diagnostic tool and promising treatment strategy for neurological and psychiatric disorders. Although most studies address transcranial magnetic stimulation, transspinal magnetic stimulation (TsMS) has received recent attention since trials involving invasive spinal cord stimulation showed encouraging results for pain, spasticity, and Parkinson's disease. While the effects of TsMS on spinal roots is well understood, its mechanism of action on the spinal cord is still controversial. Despite unclear mechanisms of action, clinical benefits of TsMS have been reported, including improvements in scales of spasticity, hyperreflexia, and bladder and bowel symptoms, and even supraspinal gait disorders such as freezing and camptocormia. In the present study, a critical review on the application of TsMS in neurology was conducted, along with an exploratory trial involving TsMS in three patients with hereditary spastic paraplegia. The goal was to understand the mechanism of action of TsMS through H-reflex measurement at the unstimulated lumbosacral level. Although limited by studies with a small sample size and a low to moderate effect size, TsMS is safe and tolerable and presents consistent clinical and neurophysiological benefits that support its use in clinical practice.

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.

Predicting hemorrhagic transformation in posterior circulation stroke patients not treated with reperfusion therapies.

INTRODUCTION: Posterior Circulation (PC) stroke represents one-fifth of all ischemic strokes, with peculiar physiological characteristics. Hemorrhagic Transformation (HT) is a dreaded complication among stroke patients. Many predictive scores of this complication have been proposed, but none is designed specifically for PC stroke patients - therefore, patients who are not eligible for reperfusion therapies (RT) represent about 80% of hospitalized cases. We propose a scoring system to assess the HT risk in PC stroke patients not submitted to RT. METHODS: We retrospectively evaluated data of patients diagnosed with PC stroke not treated with RT from 5 Comprehensive Stroke Centers (four in Brazil, 1 in the US) from 2015 to 2018. All patients underwent CT scan or MRI at admission and a follow-up neuroimaging within seven days. Independent variables identified in a logistic regression analysis were used to produce a predictive grading score. RESULTS: We included 952 patients in the final analysis. The overall incidence of HT was 8.7%. Male gender (1 point), NIH Stroke Scale at admission ≥ 5 points (1), blood glucose at admission ≥ 160 mg/dL (1), and cardioembolism (2) were independently associated with HT. The AUC of the grading score (0 to 5 points) was 0.713 (95% CI 0.65-0.78). Subjects with a score ≥ 3 points had an OR of 4.8 (95% CI 2.9-7.9, p < 0.001) for HT. CONCLUSIONS: Our score has good accuracy in identifying patients at higher risk of HT. This score may be useful for evaluating secondary prevention and stratifying patients in the context of even clinical trials.

Predictors of hemorrhagic transformation differences between patients treated or not with reperfusion therapy.

BACKGROUND: Hemorrhagic transformation (HT) is a dreaded complication in stroke patients who were treated or not with recombinant tissue plasminogen activator (tPA). There are many predictive scores of HT, but all of them included patients treated with tPA. Molecular effects of tPA and clinical aspects of eligible patients for tPA therapy may imply specific HT's risk factors. We aimed to describe HT's characteristics and risk factors in patients treated or not with tPA. METHODS: We included 1565 consecutive stroke patients admitted to a Comprehensive Stroke Center, from 2015 to 2017. All included patients underwent a follow-up neuroimaging within seven days after admission. From a logistic regression model, we derived a score based on the beta-coefficients. The accuracy of the models was attested by Receiver Operating Characteristic analysis. RESULTS: Low ASPECTS, blood glucose ≥ 180 mg/dL, tPA treatment, and cardio-aortic embolism were predictors of HT. Male sex, leukoaraiosis, and hyperdense MCA sign were associated with HT in non-treated patients. Diastolic blood pressure ≥ 105 mmHg was a risk factor only in non-treated patients. The cutoff of our predictive score of HT was higher in patients not treated with tPA (5 vs 2 points). CONCLUSIONS: High arterial blood pressure was associated with HT only in patients treated with tPA. Different cutoffs and accuracy measurements suggest that scoring systems derived from patients treated with tPA may not be efficient to predict HT in non-treated patients. Further directions indicate considering the use of reperfusion therapies to select the most accurate predictive variables of HT.

Accuracy of predictive scores of hemorrhagic transformation in patients with acute ischemic stroke / Acurácia de escores preditivos de transformação hemorrágica em pacientes com isquemia cerebral aguda

ABSTRACT Background: Hemorrhagic transformation (HT) is a complication in ischemic strokes, regardless of use of reperfusion therapy (RT). There are many predictive scores for estimating the risk of HT. However, most of them include patients also treated with RT. Therefore, this may lead to a misinterpretation of the risk of HT in patients who did not undergo RT. Objective: We aimed to review published predictive scores and analyze their accuracy in our dataset. Methods: We analyzed the accuracy of seven scales. Our dataset was derived from a cohort of 1,565 consecutive patients from 2015 to 2017 who were admitted to a comprehensive stroke center. All patients were evaluated with follow-up neuroimaging within seven days. Comparison of area under the curve (AUC) was performed on each scale, to analyze differences between patients treated with recombinant tissue plasminogen activator (tPA) and those without this treatment. Results: Our dataset provided enough data to assess seven scales, among which six were used among patients with and without tPA treatment. HAT (AUC 0.76), HTI (0.73) and SEDAN (0.70) were the most accurate scores for patients not treated with tPA. SPAN-100 (0.55) had the worst accuracy in both groups. Three of these scores had different cutoffs between study groups. Conclusions: The predictive scores had moderate to fair accuracy for predicting HT in patients treated with tPA. Three scales were more accurate for predicting HT in patients not treated with tPA. Through standardizing these characteristics and including more patients not treated with RT in a large multicenter series, accurate predictive scores may be created.

RESUMO Background: Transformação hemorrágica (TH) é uma complicação frequente no acidente vascular cerebral (AVC) isquêmico independente do uso de terapia de reperfusão (TR). Diversos escores preditivos de TH foram elaborados. Entretanto, a maioria desses escores incluíram pacientes submetidos a TR — o que pode levar à má interpretação do risco de TH nos pacientes não submetidos a TR. Objetivo: Nosso objetivo é revisar escores preditivos já publicados e analisar a sua acurácia em nossa amostra. Métodos: Analisamos a acurácia de sete escores. Nosso banco foi criado de uma coorte de 1.565 pacientes consecutivos, admitidos entre 2015 e 2017 em um centro avançado de AVC. Os pacientes realizaram neuroimagem de controle em até sete dias. Uma comparação entre áreas abaixo da curva/característica de operação do receptor (AUC) foi realizada, analisando-se as diferenças entre grupos de pacientes tratados ou não com ativador de plasminogênio tecidual recombinante (tPA). Resultados: Nosso banco de dados proporcionou informação suficiente para avaliar sete escores, dos quais seis foram aplicados em pacientes tratados ou não com tPA. HAT (AUC 0,76), HTI (0,73) e SEDAN (0,70) foram os escores mais acurados em pacientes não tratados com tPA. SPAN-100 (0,55) teve a pior acurácia nos grupos. Três desses escores apresentaram diferentes valores de corte entre os grupos. Conclusões: Os escores apresentaram de boa a moderada acurácia na predição de TH em pacientes tratados com tPA. Três escores foram mais acurados em pacientes não tratados com tPA. A parametrização dessas características e a inclusão de mais pacientes não tratados com TR em um estudo multicêntrico poderia levar a escores mais acurados.

Accuracy of predictive scores of hemorrhagic transformation in patients with acute ischemic stroke.

BACKGROUND: Hemorrhagic transformation (HT) is a complication in ischemic strokes, regardless of use of reperfusion therapy (RT). There are many predictive scores for estimating the risk of HT. However, most of them include patients also treated with RT. Therefore, this may lead to a misinterpretation of the risk of HT in patients who did not undergo RT. OBJECTIVE: We aimed to review published predictive scores and analyze their accuracy in our dataset. METHODS: We analyzed the accuracy of seven scales. Our dataset was derived from a cohort of 1,565 consecutive patients from 2015 to 2017 who were admitted to a comprehensive stroke center. All patients were evaluated with follow-up neuroimaging within seven days. Comparison of area under the curve (AUC) was performed on each scale, to analyze differences between patients treated with recombinant tissue plasminogen activator (tPA) and those without this treatment. RESULTS: Our dataset provided enough data to assess seven scales, among which six were used among patients with and without tPA treatment. HAT (AUC 0.76), HTI (0.73) and SEDAN (0.70) were the most accurate scores for patients not treated with tPA. SPAN-100 (0.55) had the worst accuracy in both groups. Three of these scores had different cutoffs between study groups. CONCLUSIONS: The predictive scores had moderate to fair accuracy for predicting HT in patients treated with tPA. Three scales were more accurate for predicting HT in patients not treated with tPA. Through standardizing these characteristics and including more patients not treated with RT in a large multicenter series, accurate predictive scores may be created.