Intracranial Stenosis Treated with Stenting in Patients with Suspected Cerebral Vasculitis: Two Case Reports.

Central nervous system vasculitis (CNSV) is an uncommon and poorly understood form of vasculitis. Early recognition is important because medical treatment might improve the outcome. However, randomized clinical trials on CNSV treatment do not exist. Endovascular treatment has been reported in few cases, but no data exist for intracranial stenting. We report 2 cases of patients with suspected CNSV and recurrent clinical episodes, treated with intracranial stenting. A 48-year-old man had relapsing episodes of right hemiparesis. Neuroradiological exams showed severe left carotid terminus stenosis. Despite immunosuppressive therapy, neuroradiological follow-up exams showed a worsening of the aforementioned stenosis with many transient episodes of weakness in the right limbs and aphasia. A 64-year-old woman had a sudden onset of dysarthria and transient aphasia. Neuroradiological exams showed a severe arterial stenosis involving the origin of left anterior cerebral artery and middle cerebral artery (MCA). Despite dual antiplatelet therapy, she presented an acute onset of severe aphasia, due to an occlusion of the left carotid terminus and proximal MCA. In both cases, endovascular procedure and intracranial stenting was performed, with marked improvement of cerebral blood flow. No more clinical episodes were reported. Intracranial stenting may be a valid therapeutic option in selected patients with CNSV and involvement of medium or large size vessels with clinical worsening despite best medical treatment.

Proposal of multimodal computed tomography-based scoring system in prediction of hemorrhagic transformation in acute ischemic stroke.

INTRODUCTION: The routinely used computed tomography (CT)-based workup in the setting of acute ischemic stroke (AIS) includes non-contrast brain CT, CT angiography (CTA), and CT perfusion. Several CT, CTA, CTP-based radiological biomarkers of hemorrhagic transformation (HT) were reported. AIM OF THE STUDY: To assess the predictive value of the combined multimodal CT parameters for HT after AIS and proposal of predictive scoring scale. METHODS: The source images of the NCCT, CTA and CTP of 282 AIS patients involving the anterior circulation (HT = 91, non-HT = 191) were retrospectively reviewed and the following biomarkers were recorded and analyzed: Early subtle ischemic signs, hyperdense middle cerebral artery sign (HMCAS) and Alberta Stroke Program Early CT Score (ASPECTS) < 7 in NCCT, large-vessel occlusion (LVO), clot burden score (CBS) < 6, large-vessel occlusion, poor collateral score (CS) and Tmax > 6 s ≥ 56.5 ml. A scoring system to predict HT based on these biomarkers was developed. Each biomarker counts for a single point with the total score ranging from 0 to 7. RESULTS: All the aforementioned multimodal CT biomarkers and the selected cut offs were significantly associated with higher HT risk. The calculated scores were statistically significant different between the HT and the non-HT groups with AUC 0.761 (95% CI 0.703-0.819, P < 0.0000001). Rates of HT were approximately five times higher in patients with score ≥ 3. CONCLUSION: Multimodal CT-based scoring system may provide highly reliable predictive model of hemorrhagic transformation in acute ischemic stroke.

Challenging the Pleiotropic Effects of Repetitive Transcranial Magnetic Stimulation in Geriatric Depression: A Multimodal Case Series Study.

BACKGROUND: Although the antidepressant potential of repetitive transcranial magnetic stimulation (rTMS), the pleiotropic effects in geriatric depression (GD) are poorly investigated. We tested rTMS on depression, cognitive performance, growth/neurotrophic factors, cerebral blood flow (CBF) to transcranial Doppler sonography (TCD), and motor-evoked potentials (MEPs) to TMS in GD. METHODS: In this case series study, six drug-resistant subjects (median age 68.0 years) underwent MEPs at baseline and after 3 weeks of 10 Hz rTMS on the left dorsolateral prefrontal cortex. The percentage change of serum nerve growth factor, vascular endothelial growth factor, brain-derived growth factor, insulin-like growth factor-1, and angiogenin was obtained. Assessments were performed at baseline, and at the end of rTMS; psychocognitive tests were also repeated after 1, 3, and 6 months. RESULTS: Chronic cerebrovascular disease was evident in five patients. No adverse/undesirable effect was reported. An improvement in mood was observed after rTMS but not at follow-up. Electrophysiological data to TMS remained unchanged, except for an increase in the right median MEP amplitude. TCD and neurotrophic/growth factors did not change. CONCLUSIONS: We were unable to detect a relevant impact of high-frequency rTMS on mood, cognition, cortical microcircuits, neurotrophic/growth factors, and CBF. Cerebrovascular disease and exposure to multiple pharmacological treatments might have contributed.

The role of automated computed topography perfusion in prediction of hemorrhagic transformation after acute ischemic stroke.

INTRODUCTION: The role of computed tomography perfusion (CTP) in prediction of hemorrhagic transformation (HT) has been evolving. We aimed to study the role of automated perfusion post-processing software in prediction of HT using the commercially available RAPID software. METHODS: Two hundred eighty-two patients with anterior circulation ischemic stroke, who underwent CTP with RAPID automated post-processing, were retrospectively enrolled and divided into HT (n = 91) and non-HT groups (n = 191). The automated RAPID-generated perfusion maps were reviewed. Mismatch volume and ratio, time to maximum (Tmax) > 4-10s volumes, hypoperfusion index, cerebral blood flow (CBF) < 20-38% volumes, cerebral blood volume (CBV) < 34%-42% volumes, and CBV index were recorded and analyzed. RESULTS: The volumes of brain tissues suffering from reduction of cerebral blood flow (CBF < 20%-38%), reduction in cerebral blood volumes (CBV < 34-42%), and delayed contrast arrival times (Tmax > 4-10s) were significantly higher in the HT group. The mismatch volumes were also higher in the HT group (p = .001). Among these parameters, the Tmax > 6s volume was the most reliable and sensitive predictor of HT (p = .001, AUC = 0.667). However, the combination of the perfusion parameters can slightly improve the diagnostic efficiency (AUC = 0.703). There was no statistically significant difference between the non-HT group and either the parenchymal or the symptomatic subtypes. CONCLUSION: The RAPID automated CTP parameters can provide a reliable predictor of HT overall but not the parenchymal or the symptomatic subtypes. The infarct area involving the penumbra and core represented by the Tmax > 6s threshold is the most sensitive predictor; however, the combination of the perfusion parameters can slightly improve the diagnostic efficiency.

Evaluation of stroke prognostication using age and NIH Stroke Scale index (SPAN-100 index) in delayed intravenous thrombolysis patients (beyond 4.5 hours).

OBJECTIVES: the efficacy of delayed intravenous tissue plasminogen activator (tPA), beyond the 4.5 h window, is evolving. Advanced age and high admission National Institutes of Health Stroke Scale (NIHSS) score are proposed to adversely affect the outcome of delayed thrombolysis and limit the inclusion criteria. The summation of patient age and admission NIHSS score was introduced as the SPAN-100 index as a tool of prediction of the clinical outcome after acute ischemic stroke (AIS). We aimed to assess the SPAN-100 index in AIS thrombolysed patients after 4.5 h. MATERIALS AND METHODS: The SPAN-100 index was applied to AIS patients receiving delayed IV thrombolysis (IVT) after 4.5 h. Patients demographics, risk factors, clinical, laboratory and radiological data, mismatch evidence, treatment onset and modality, NIHSS score at baseline and at discharge, and 3 months follow-up modified Rankin Scale (mRS) were reviewed. SPAN-100 score ≥ 100 is classified as SPAN-100 positive while score < 100 is SPAN-100 negative. Clinical outcomes, death and intracerebral hemorrhage (ICH) incidences were compared between SPAN-100 positive and negative groups. RESULTS: SPAN-100-positive delayed IVT-patients (11/136) had a 6-fold increased risk for unfavorable outcome compared to SPAN-negative patients (OR 6.34; 95% CI 1.59-25.24 p=0.004), however there was no relation between the SPAN-100 positivity and mortality or ICH. CONCLUSION: SPAN-100-positive patients are more likely to achieve non-favorable outcome with delayed IVT in comparison to the SPAN-100-negative patients. SPAN-100 index may influence the eligibility criteria of delayed thrombolysis.

In-hospital and out-of-hospital stroke in patients with COVID-19: two different diseases?

BACKGROUND: Ischemic stroke is a known complication of COVID-19. It may have a different pathogenesis and worse outcome compared to stroke in patients without COVID-19. Furthermore, patients with COVID-19 and out-of-hospital stroke onset might have different characteristics compared to patients with COVID-19 and in-hospital stroke onset. The aim of our study was to analyze the characteristics of patients with stroke with and without COVID-19 and of patients with COVID-19 with in-hospital and out-of-hospital stroke. METHODS: We performed a retrospective study of all consecutive patients admitted to our hospital with ischemic stroke between October 2020 and February 2021. We compared functional outcome, lab test, demographic, and clinical characteristics between patients with or without COVID-19. We performed a sub-analysis comparing patients with COVID-19 and in-hospital and out-of-hospital stroke onset. RESULTS: We included in the final analysis 137 patients of whom 26 with COVID-19. Half (13) had out-of-hospital stroke and half in-hospital stroke onset. Overall, patients with COVID-19 had higher mortality compared to the control group (27% vs 9%, p: 0.02), and non-significantly lower rate of good functional outcome (50% vs 63%, p: 0.22). Patients with COVID-19 and out-of-hospital stroke had higher rate of good functional outcome (69% vs 39%, p: 0.05), higher lymphocyte count, and lower D-dimer compared with patients with in-hospital stroke onset. CONCLUSIONS: Patients with stroke and COVID-19 had higher mortality compared to patients without COVID-19. Among patients with COVID-19 those with out-of-hospital stroke had better outcome and fewer blood test abnormalities compared to patients with in-hospital stroke.

Platelet Function Monitoring Performed after Carotid Stenting during Endovascular Stroke Treatment Predicts Outcome.

OBJECTIVES: Many studies showed that platelet reactivity testing can predict ischemic events after carotid stenting or ischemic stroke. The aim of our study was to assess the role of early platelet function monitoring in predicting 90-days functional outcome, stent thrombosis and hemorrhagic transformation in patients with ischemic stroke treated with endovascular procedures requiring emergent extracranial stenting. MATERIALS AND METHODS: We performed a retrospective study on consecutive patients with acute anterior circulation stroke admitted to our hospital between January 2015 and March 2020, in whom platelet reactivity testing was performed within 10 days from stenting. Patients were divided according to validated cutoffs in acetylsalicylic acid and Clopidogrel responders and not responders. Group comparison and regression analyses were performed to identify differences between groups and outcome predictors. RESULTS: We included in the final analysis 54 patients. Acetylsalicylic acid resistance was an independent predictor of poor 90 days outcome (OR for modified Rankin scale (mRS) ≤ 2: 0.10 95% CI: 0.02 - 0.69) whereas Clopidogrel resistance was an independent predictor of good outcome (OR for mRS ≤ 2: 7.09 95%CI: 1.33 - 37.72). Acetylsalicylic acid resistance was also associated with increased 90-days mortality (OR: 18.42; 95% CI: 1.67 - 203.14). CONCLUSION: We found a significant association between resistance to acetylsalicylic acid and poor 90-days functional outcome and between resistance to Clopidogrel and good 90-days functional outcome. If confirmed, our results might improve pharmacological management after acute carotid stenting.

Olfactory function and viral recovery in COVID-19.

BACKGROUND: Olfactory and taste disorders were reported in up to 30%-80% of COVID-19 patients. The purpose of our study was to objectively assess smell impairment in COVID-19 patients and to correlate olfactory function with viral recovery. METHODS: Between 15 and 30 April 2020, hospitalized patients with confirmed SARS-CoV-2 infection underwent an objective assessment of olfactory function with the Smell Identification subtest of the Sniffin' Sticks Test (SI-SST). Association between viral recovery and SI-SST performance was evaluated. RESULTS: 51 patients were enrolled (49% males, mean age 66.2 ± 14.6 years). At the time of test administration, 45% were clinically recovered and 39% were virus-free. Objective hyposmia/anosmia was found in 45% of the patients. Subjective olfactory disorders showed no association with the clinical or viral recovery status of the patients. On the contrary, none of the patients with anosmia and the 5% of hyposmic patients at test had viral recovery. The relative risk for hyposmic patients to be still positive at swab test was 10.323 (95% CI 1.483-71.869, p < .0001). Logistic regression analysis showed an independent and significant correlation between viral clearance and SI-SST scores (OR = 2.242; 95% CI 1.322-3.802, p < .003). ROC curve analysis confirmed that a SI-SST > 10.5 predicts viral clearance with 79% sensitivity and 87% specificity (AUC = 0.883). CONCLUSION: Hyposmia is part of COVID-19 symptoms; however, only objectively assessed olfactory function is associated with viral recovery. SI-SST is an easy and safe instrument, and further large multicentric studies should assess its value to predict infection and recovery.

Middle cerebral artery ischemic stroke and COVID-19: a case report.

We present a clinical case of a patient with SARS-CoV-2 infection and respiratory symptoms, complicated with a pro-thrombotic state involving multiple vascular territories and concomitant interleukin-6 increase. This case underlines the possibility to develop a COVID-19-related coagulopathy.

The Relation Between Aortic Arch Branching Types and the Laterality of Cardio-Embolic Stroke.

BACKGROUND AND PURPOSE: The trajectory of cardiogenic emboli could be affected by anatomical and flow characteristics of the aortic arch. We aimed to study the relation between the different aortic arch patterns and the laterality of cardiogenic emboli. METHODS: 192 cardioembolic strokes were classified into 3 groups according to the type of the aortic arch; type 1 (n = 69), type 2 (n = 49), type 3 (n = 74). The side and site of the cerebral vessels occlusion were divided into anterior and posterior circulation strokes, and anterior strokes were further subdivided into right or left internal carotid, middle or anterior cerebral arteries occlusion. RESULTS: Overall, the anterior circulation embolic occlusions were more common than the posterior, and middle cerebral artery more commonly affected than internal carotid artery. The left side propensity was higher either in the total patients' pool or after segregation into atrial fibrillation (AF) and non AF cardio-embolic cases in all types of aortic arch except for type 1 aortic arch in the non AF cases. This propensity tended to get higher with advancement of the aortic arch types but failed to show statistically significant difference between the 3 arch types, however combination of type 2 and 3 arches into a single group showed statistically significant rise in the left side propensity in the total cardioembolic cases (P = 0.039) and in the non AF cardioembolic cases (P = 0.029). The bovine arch also showed increased left side propensity. CONCLUSION: Cardioemboli tends to have left anterior cerebrovascular predilection especially with AF. Different geometrical patterns of aortic arch branching seem to affect the laterality of cardioemboli and increase its left side predilection.

Age, Height, and Sex on Motor Evoked Potentials: Translational Data From a Large Italian Cohort in a Clinical Environment.

INTRODUCTION: Motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) are known to be susceptible to several sources of variability. However, conflicting evidences on individual characteristics in relatively small sample sizes have been reported. We investigated the effect of age, height, and sex on MEPs of the motor cortex and spinal roots in a large cohort. METHODS: A total of 587 subjects clinically and neuroradiologically intact were included. MEPs were recorded during mild tonic contraction through a circular coil applied over the "hot spot" of the first dorsal interosseous and tibialis anterior muscles (TAs), bilaterally. Central motor conduction time (CMCT) was estimated as the difference between MEP cortical latency and the peripheral motor conduction time (PMCT) by cervical or lumbar magnetic stimulation. Peak-to-peak MEP amplitude to cortical stimulation and right-to-left difference of each parameter were also measured. RESULTS: After Bonferroni correction, general linear (multiple) regression analysis showed that both MEP cortical latency and PMCT at four limbs positively correlated with age and height. At lower limbs, an independent effect of sex on the same measures was also observed (with females showing smaller values than males). CMCT correlated with both age (negatively) and height (positively) when analyzed by a single regression; however, with a multiple regression analysis this significance disappeared, due to the correction for the multicollinearity within the dataset. CONCLUSION: Physical individual features need to be considered for a more accurate and meaningful MEPs interpretation. Both in clinical practice and in research setting, patients and controls should be matched for age, height, and sex.

Cortical involvement in celiac disease before and after long-term gluten-free diet: A Transcranial Magnetic Stimulation study.

OBJECTIVE: Transcranial Magnetic Stimulation in de novo patients with Celiac Disease previously revealed an imbalance in the excitability of cortical facilitatory and inhibitory circuits. After a median period of 16 months of gluten-free diet, a global increase of cortical excitability was reported, suggesting a glutamate-mediated compensation for disease progression. We have now evaluated cross-sectionally the changes of cortical excitability to TMS after a much longer gluten-free diet. METHODS: Twenty patients on adequate gluten-free diet for a mean period of 8.35 years were enrolled and compared with 20 de novo patients and 20 healthy controls. Transcranial Magnetic Stimulation measures, recorded from the first dorsal interosseous muscle of the dominant hand, consisted of: resting motor threshold, cortical silent period, motor evoked potentials, central motor conduction time, mean short-latency intracortical inhibition and intracortical facilitation. RESULTS: The cortical silent period was shorter in de novo patients, whereas in gluten-free diet participants it was similar to controls. The amplitude of motor responses was significantly smaller in all patients than in controls, regardless of the dietary regimen. Notwithstanding the diet, all patients exhibited a statistically significant decrease of mean short-latency intracortical inhibition and enhancement of intracortical facilitation with respect to controls; more intracortical facilitation in gluten-restricted compared to non-restricted patients was also observed. Neurological examination and celiac disease-related antibodies were negative. CONCLUSIONS: In this new investigation, the length of dietary regimen was able to modulate the electrocortical changes in celiac disease. Nevertheless, an intracortical synaptic dysfunction, mostly involving excitatory and inhibitory interneurons within the motor cortex, may persist. The clinical significance of subtle neurophysiological changes in celiac disease needs to be further investigated.

Correlation between Motor Cortex Excitability Changes and Cognitive Impairment in Vascular Depression: Pathophysiological Insights from a Longitudinal TMS Study.

Background. Transcranial magnetic stimulation (TMS) highlighted functional changes in dementia, whereas there are few data in patients with vascular cognitive impairment-no dementia (VCI-ND). Similarly, little is known about the neurophysiological impact of vascular depression (VD) on deterioration of cognitive functions. We test whether depression might affect not only cognition but also specific cortical circuits in subcortical vascular disease. Methods. Sixteen VCI-ND and 11 VD patients, age-matched with 15 controls, underwent a clinical-cognitive, neuroimaging, and TMS assessment. After approximately two years, all participants were prospectively reevaluated. Results. At baseline, a significant more pronounced intracortical facilitation (ICF) was found in VCI-ND patients. Reevaluation revealed an increase of the global excitability in both VCI-ND and VD subjects. At follow-up, the ICF of VCI-ND becomes similar to the other groups. Only VD patients showed cognitive deterioration. Conclusions. Unlike VD, the hyperfacilitation found at baseline in VCI-ND patients suggests enhanced glutamatergic neurotransmission that might contribute to the preservation of cognitive functioning. The hyperexcitability observed at follow-up in both groups of patients also indicates functional changes in glutamatergic neurotransmission. The mechanisms enhancing the risk of dementia in VD might be related either to subcortical vascular lesions or to the lack of compensatory functional cortical changes.

Cholinergic circuitry functioning in patients with vascular cognitive impairment--no dementia.

BACKGROUND: An impairment of central cholinergic activity, as evaluated non-invasively by the short-latency afferent inhibition (SAI) of motor responses evoked by transcranial magnetic stimulation (TMS), was observed in patients with Alzheimer's disease (AD) and amnestic Mild Cognitive Impairment. Conversely, the involvement of central cholinergic neurotransmission in vascular dementia (VaD) is still under debate and data on Vascular Cognitive Impairment--No Dementia (VCI-ND) at risk for future VaD are lacking. OBJECTIVE: To test for the first time SAI in patients with VCI-ND. METHODS: Single-pulse TMS measures of cortical excitability and SAI were evaluated in 25 VCI-ND patients with subcortical ischemic lesions and 20 age-matched healthy controls. Functional status, neuropsychological tests evaluating frontal lobe abilities, and white matter lesions (WMLs) load were assessed. RESULTS: A significant difference was found between patients and controls for the mean SAI, although this result did not resist after the Bonferroni correction. In the whole group of patients and controls, SAI showed a correlation with worse scores at the Montreal Cognitive Assessment (r = 0.376, p < 0.01). SAI also positively correlated with the total vascular burden (r = 0.345, p < 0.05) but not with the WML severity. CONCLUSIONS: Central cholinergic pathway does not seem to be involved in VCI-ND, and the current results differ from those reported in primary cholinergic forms of dementia, such as AD. SAI might represent a valuable additional tool in the differential diagnosis of the dementing processes and in identifying potential responders to cholinergic agents.

Effect of a Gluten-Free Diet on Cortical Excitability in Adults with Celiac Disease.

INTRODUCTION: An imbalance between excitatory and inhibitory synaptic excitability was observed in de novo patients with celiac disease (CD) in a previous study with Transcranial Magnetic Stimulation (TMS), suggesting a subclinical involvement of GABAergic and glutamatergic neurotransmission in asymptomatic patients. The aim of this investigation was to monitor the eventual changes in the same cohort of patients, evaluated after a period of gluten-free diet. METHODS: Patients were re-evaluated after a median period of 16 months during which an adequate gluten-free diet was maintained. Clinical, cognitive and neuropsychiatric assessment was repeated, as well as cortical excitability by means of single- and paired-pulse TMS from the first dorsal interosseous muscle of the dominant hand. RESULTS: Compared to baseline, patients showed a significant decrease of the median resting motor threshold (from 35% to 33%, p<0.01). The other single-pulse (cortical silent period, motor evoked potentials latency and amplitude, central motor conduction time) and paired-pulse TMS measures (intracortical inhibition and intracortical facilitation) did not change significantly after the follow-up period. Antibodies were still present in 7 subjects. DISCUSSION: In patients under a gluten-free diet, a global increase of cortical excitability was observed, suggesting a glutamate-mediated functional reorganization compensating for disease progression. We hypothesize that glutamate receptor activation, probably triggered by CD-related immune system dysregulation, might result in a long-lasting motor cortex hyperexcitability with increased excitatory post-synaptic potentials, probably related to phenomena of long-term plasticity. The impact of the gluten-free diet on subclinical neurological abnormalities needs to be further explored.

Different patterns of cortical excitability in major depression and vascular depression: a transcranial magnetic stimulation study.

BACKGROUND: Clinical and functional studies consider major depression (MD) and vascular depression (VD) as different neurobiological processes. Hypoexcitability of the left frontal cortex to transcranial magnetic stimulation (TMS) is frequently reported in MD, whereas little is known about the effects of TMS in VD. Thus, we aimed to assess and compare motor cortex excitability in patients with VD and MD. METHODS: Eleven VD patients, 11 recurrent drug-resistant MD patients, and 11 healthy controls underwent clinical, neuropsychological and neuroimaging evaluations in addition to bilateral resting motor threshold, cortical silent period, and paired-pulse TMS curves of intracortical excitability. All patients continued on psychotropic drugs, which were unchanged throughout the study. RESULTS: Scores on one of the tests evaluating frontal lobe abilities (Stroop Color-Word interference test) were worse in patients compared with controls. The resting motor threshold in patients with MD was significantly higher in the left hemisphere compared with the right (p < 0.05), and compared with the VD patients and controls. The cortical silent period was bilaterally prolonged in MD patients compared with VD patients and controls, with a statistically significant difference in the left hemisphere (p < 0.01). No differences were observed in the paired-pulse curves between patients and controls. CONCLUSIONS: This study showed distinctive patterns of motor cortex excitability between late-onset depression with subcortical vascular disease and early-onset recurrent drug resistant MD. The data provide a TMS model of the different processes underlying VD and MD. Additionally, our results support the "Vascular depression hypothesis" at the neurophysiological level, and confirm the inter-hemispheric asymmetry to TMS in patients with MD. We were unable to support previous findings of impaired intracortical inhibitory mechanisms to TMS in patients with MD, although a drug-induced effect on our results cannot be excluded. This study may aid the understanding of the pathogenetic differences underlying the clinical spectrum of depressive disorders.