Identifying diagnostic and prognostic factors in cerebral amyloid angiopathy-related inflammation: A systematic analysis of published and seven new cases.

AIMS: Cerebral amyloid angiopathy (CAA)-related inflammation (CAA-RI) is a potentially reversible manifestation of CAA, histopathologically characterised by transmural and/or perivascular inflammatory infiltrates. We aimed to identify clinical, radiological and laboratory variables capable of improving or supporting the diagnosis of or predicting/influencing the prognosis of CAA-RI and to retrospectively evaluate different therapeutic approaches. METHODS: We present clinical and neuroradiological observations in seven unpublished CAA-RI cases, including neuropathological findings in two definite cases. These cases were included in a systematic analysis of probable/definite CAA-RI cases published in the literature up to 31 December 2021. Descriptive and associative analyses were performed, including a set of clinical, radiological and laboratory variables to predict short-term, 6-month and 1-year outcomes and mortality, first on definite and second on an expanded probable/definite CAA-RI cohort. RESULTS: Data on 205 definite and 100 probable cases were analysed. CAA-RI had a younger symptomatic onset than non-inflammatory CAA, without sex preference. Transmural histology was more likely to be associated with the co-localisation of microbleeds with confluent white matter hyperintensities on magnetic resonance imaging (MRI). Incorporating leptomeningeal enhancement and/or sulcal non-nulling on fluid-attenuated inversion recovery (FLAIR) enhanced the sensitivity of the criteria. Cerebrospinal fluid pleocytosis was associated with a decreased probability of clinical improvement and longer term positive outcomes. Future lobar haemorrhage was associated with adverse outcomes, including mortality. Immunosuppression was associated with short-term improvement, with less clear effects on long-term outcomes. The superiority of high-dose over low-dose corticosteroids was not established. CONCLUSIONS: This is the largest retrospective associative analysis of published CAA-RI cases and the first to include an expanded probable/definite cohort to identify diagnostic/prognostic markers. We propose points for further crystallisation of the criteria and directions for future prospective studies.

DWI-FLAIR mismatch guided thrombolysis in patients without large-vessel occlusion: real-world data from a comprehensive stroke centre.

Introduction: A significant proportion of ischaemic stroke patients present with unknown symptom onset time. DWI-FLAIR mismatch on MRI can help to identify those eligible for thrombolysis. We set out to analyse the short-term efficacy and safety of thrombolysis in a real-world setting. Methods: A retrospective single-centre observational study was conducted. We collected data between January 2017 and April 2020. Patients with a large vessel occlusion (LVO) were excluded. Outcomes were compared between thrombolysed patients and those who did not receive alteplase due to lack of DWI-FLAIR mismatch or other contraindications. We analysed baseline and discharge NIHSS scores for efficacy and defined good outcome as any neurological improvement (ANI) on the NIHSS. In terms of safety, the presence and severity of intracerebral haemorrhage on follow-up imaging was analysed, and mortality at 90 days assessed. Results: Seventy-one patients were included in this study, of whom 29 received thrombolysis. Significantly more patients had ANI in the thrombolysed group (OR, 3.16; 95% CI, 1.178-8.479; p = 0.020). In a multivariable logistic regression analysis, only thrombolysis correlated with ANI (OR, 3.051; 95% CI, 1.135-8.206; p = 0.027). Two thrombolysed patients suffered intracerebral haemorrhage (6.90%), of whom one was symptomatic and eventually fatal. We did not find a significant difference in 90-day mortality between the two groups (OR, 0.81, 95% CI, 0.134-4.856; p = 1.000). Conclusions: Our real-world data demonstrate that thrombolysis based on DWI-FLAIR mismatch in patients without LVO has an early beneficial effect. The rate of intracerebral haemorrhage was similar to this complication reported in large thrombolysis trials with known onset times.

Relationships of Ischemic Stroke Occurrence and Outcome with Gene Variants Encoding Enzymes of Tryptophan Metabolism.

Ischemic stroke is among the leading causes of mortality and long-term disability worldwide. Among stroke risk factors the importance of genetic background is gaining interest. There is a growing body of evidence of changes of metabolite levels and enzyme activities involved in the conversion of Trp during the course of cerebral ischemia. We compared the frequencies of ten SNPs of five genes related to Trp metabolism between groups of 122 ischemic stroke patients and 120 control individuals. Furthermore, we examined the mRNA levels of TPH1, IDO1 and KYAT1 genes in peripheral venous blood with the aim of assessing (i) whether there are changes in their expression during the course of stroke and (ii) does any of their investigated SNPs have an impact on gene expression. In seven cases out of ten studied polymorphisms we detected significant differences in frequencies in relation to ischemic stroke occurrence, etiology, and clinical parameters. We also detected changes in the expression of TPH1 and IDO1 genes during the course of the disease. We found that those IDO1 variants which show a trend towards elevated mRNA level are more frequent in stroke patients than in controls. Our results are important novel observations which suggest a causal relationship between elevated IDO1 expression and stroke etiology.

Kynurenic acid and kynurenine aminotransferase are potential biomarkers of early neurological improvement after thrombolytic therapy: A pilot study.

BACKGROUND: Biomarkers for predicting treatment response to thrombolysis in acute ischemic stroke are currently lacking. Both, animal models and clinical studies have provided evidence that the kynurenine (KYN) pathway is activated in ischemic stroke. OBJECTIVES: In our pilot study, we aimed to investigate whether KYN pathway enzymes and metabolites could serve as potential biomarkers for treatment response in the hyperacute phase of ischemic stroke. MATERIAL AND METHODS: We included 48 acute ischemic stroke patients who received thrombolysis. Blood samples were taken both before and 12 h after treatment. Concentrations of 11 KYN metabolites were determined using ultra-high-performance liquid chromatography-mass spectrometry. To assess the treatment response, we used early neurological improvement (ENI), calculated as the difference between the admission and discharge National Institutes of Health Stroke Scale (NIHSS) scores. We performed receiver operating characteristic (ROC) analysis for KYN pathway metabolites and enzymes that showed a correlation with ENI. RESULTS: In the samples taken before thrombolysis, significantly lower concentrations of kynurenic acid (KYNA) and kynurenine aminotransferase (KAT) activity were found in patients who had ENI (p = 0.01 and p = 0.002, respectively). According to the ROC analysis, the optimal cut-off value to predict ENI for KYNA was 37.80 nM (sensitivity (SN) 69.2%, specificity (SP) 68.4%) and 0.0127 for KAT activity (SN 92.3%, SP 73.7%). CONCLUSIONS: Our research is the first clinical pilot study to analyze changes in the KYN pathway in ischemic stroke patients who received thrombolytic treatment. Based on our results, baseline KYNA concentration and KAT activity could serve as potential biomarkers to predict early treatment response to thrombolysis.

Comparing Endovascular Treatment Methods in Acute Ischemic Stroke Due to Tandem Occlusion Focusing on Clinical Aspects.

INTRODUCTION: Acute ischemic strokes (AIS) due to tandem occlusion (TO) of intracranial anterior large vessel and concomitant extracranial internal carotid artery (EICA) are represent in 15-20% of all ischemic strokes. The endovascular treatment (EVT) strategy for those patients is still unclear. Although the intracranial mechanical thrombectomy (MT) is considered as a standard treatment approach, the EICA lesion stent necessity remains a matter of debate. We sought to assess the efficacy and safety of EVT in tandem lesions, particularly the EICA stenting management. METHODS: We retrospectively analyzed all patients with anterior circulation stroke associated with EICA lesion and receiving EVT in the three participated stroke centers between November 2017 and December 2020. Patients' data were collected from our prospective stroke registry (STAY ALIVE). Patients enrolled in our study were divided into two groups depending on whether acute carotid stenting (ACS) or balloon angioplasty only (BAO) technique was used. Our primary outcome was the 90-day functional outcome assessed by modified Rankin scale (mRS). Mortality at 90 days and symptomatic intracranial hemorrhage (sICH) were considered as secondary outcomes. RESULTS: A total of 101 patients (age: 67 ± 10 years, 38.6% female) were enrolled in our study, including 29 (28.3%) BAO cases, and 72 (71.3%) patients treated with ACS. Patients in the BAO group were slightly older (70 ± 9 years vs. 66 ± 10 years, p = 0.054), and had higher prevalence of comorbidities such as hypertension (100.0% vs. 59.4%, p < 0.001). There was no significant difference in favorable outcomes (51.7% vs. 54.4%, p = 0.808) between the groups. However, we observed a trend towards higher rates of sICH (8.3% vs. 3.4%, p = 0.382) and 90-day mortality (23.5% vs. 13.8%, p = 0.278) with significantly higher frequency of distal embolization (39.1% vs. 17.9%, p = 0.043) in patients with ACS. In the overall population age (p = 0.013), atrial fibrillation (AF) (p = 0.008), National Institutes of Health Stroke Scale (NIHSS) baseline (p = 0.029), and successful recanalization (p = 0.023) were associated with favorable outcome. CONCLUSION: Endovascular approach of EICA in addition to MT was safe and effective in tandem occlusion of anterior circulation. Furthermore, our results suggest that balloon angioplasty technique without acute stenting shows a comparable favorable outcome rate to ACS with moderately less hemorrhagic events and mortality rates.

Connection between small vessel disease related stroke and the MTHFR C677T polymorphism in a Hungarian population.

INTRODUCTION: There are conflicting results in the literature regarding the connection between thrombophilias and ischaemic stroke. However, most of the clinical studies have not differentiated between various ischaemic stroke subtypes. Our aim was to investigate whether there is an association between the methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism and ischaemic stroke due to small vessel disease (SVD) in patients ≤50 years of age. PATIENTS AND METHODS: We performed a retrospective search in the database used at our Health Centre. Our study population consisted of 100 ischaemic stroke patients. 65 patients had MTHFR C677T variants: 21 were homozygous (TT allele), 45 were heterozygous (CT). 35 stroke patients did not carry MTHFR C677T polymorphism (wild genotype, CC). Stroke subtypes were determined according to the TOAST classification. Pearson's chi-squared test of independence was used to evaluate differences between subgroups and multivariate logistic regression was also performed. RESULTS: More than half of our study population (52.00%) had lacunar strokes. The ratio of SVD in patients ≤50 years of age with TT homozygous variant was significantly higher compared to heterozygous and wild type subjects (p = 0.032 and p = 0.03 respectively). Multivariate logistic regression also showed, that apart from hypertension, only TT homozygosity was a predictive factor for SVD related stroke (p = 0.014, OR 1.619, 95% CI 1.390-18.338). CONCLUSION: Our results demonstrate that in a Hungarian population of ischaemic stroke patients ≤50 years of age, SVD is the most common stroke subtype. In addition, we found association of SVD stroke with hypertension and MTHFR 677TT homozygous polymorphism.

Detailed severity assessment of Cincinnati Prehospital Stroke Scale to detect large vessel occlusion in acute ischemic stroke.

BACKGROUND: Selecting stroke patients with large vessel occlusion (LVO) based on prehospital stroke scales could provide a faster triage and transportation to a comprehensive stroke centre resulting a favourable outcome. We aimed here to explore the detailed severity assessment of Cincinnati Prehospital Stroke Scale (CPSS) to improve its ability to detect LVO in acute ischemic stroke (AIS) patients. METHODS: A cross-sectional analysis was performed in a prospectively collected registry of consecutive patients with first ever AIS admitted within 6 h after symptom onset. On admission stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and the presence of LVO was confirmed by computed tomography angiography (CTA) as an endpoint. A detailed version of CPSS (d-CPSS) was designed based on the severity assessment of CPSS items derived from NIHSS. The ability of this scale to confirm an LVO was compared to CPSS and NIHSS respectively. RESULTS: Using a ROC analysis, the AUC value of d-CPSS was significantly higher compared to the AUC value of CPSS itself (0.788 vs. 0.633, p < 0.001) and very similar to the AUC of NIHSS (0.795, p = 0.510). An optimal cut-off score was found as d-CPSS≥5 to discriminate the presence of LVO (sensitivity: 69.9%, specificity: 75.2%). CONCLUSION: A detailed severity assessment of CPSS items (upper extremity weakness, facial palsy and speech disturbance) could significantly increase the ability of CPSS to discriminate the presence of LVO in AIS patients.

24-Hour Near-Infrared Spectroscopy Monitoring of Acute Ischaemic Stroke Patients Undergoing Thrombolysis or Thrombectomy: A Pilot Study.

INTRODUCTION: Monitoring of acute ischaemic stroke patients during thrombolysis or thrombectomy is based mostly on frequent physical examinations, since no objective measurement of cerebrovascular haemodynamics is available in routine clinical practice. Near-infrared spectroscopy (NIRS) is a bed-side, noninvasive assessment tool that could help monitor these patients and potentially guide therapeutic interventions. Our goal in this pilot study was to investigate whether NIRS is a suitable method to monitor leptomeningeal collateral circulation via changes in cortical oxygen saturation in the first 24 hours of acute ischaemic stroke. PATIENTS AND METHODS: Our study included 5 patients with acute anterior circulation infarcts. All patients received thrombolytic therapy and 1 had thrombectomy. 24-hour continuous NIRS monitoring was performed on all participants. RESULTS: We aimed to give a detailed description of each NIRS recording and explain how the observed findings could correlate with changes in anterior watershed territory collateral circulation and clinical outcome. CONCLUSION: Our pilot study supports the use of NIRS monitoring in acute ischaemic stroke. We believe that this technique could provide real-time information on the dynamic changes of leptomeningeal collateral circulation and help monitor the effects of thrombolysis and thrombectomy.

Paraneoplastic neuromyelitis optica spectrum disorder: A case report and review of the literature.

Neuromyelitis optica spectrum disorders (NMOSD) are demyelinating, autoimmune diseases affecting the central nervous system. Typically, recurrent optic neuritis and longitudinal extensive transverse myelitis dominates the clinical picture. In most cases NMOSD are associated with autoantibodies targeting the water channel aquaporin-4 (AQP-4). NMOSD usually present in young adults. Clinical findings suggestive of NMOSD in elderly patients should raise the suspicion of a paraneoplastic etiology. To our knowledge, we report the first case of a 66 year-old female patient with paraneoplastic NMOSD that is associated with squamous cell lung carcinoma. Anti-AQP-4 was present in both the serum and cerebrospinal fluid of the patient. However, immunhistological staining of the malignant tissue did not show presence of AQP-4 on the surface of tumour cells.

Kynurenine System and Multiple Sclerosis, Pathomechanism and Drug Targets with An Emphasis on Laquinimod.

Multiple sclerosis is a common chronic, disabling autoimmune neurological disease affecting mainly young adults. In its pathomechanism, neurodegenerative and acute inflammatory characteristics are both involved. Disease-modifying therapies aim to reduce relapse-rate and slow down the deterioration in neurological functions. The currently available therapies fail to exert neuroprotective effects and most of them are associated with potentially toxic side-effects, therefore, ongoing research aims to develop novel drug candidates to cover these therapeutic gaps. The kynurenine pathway has been implicated in both the physiological processes of the central nervous system and in the pathomechanism of several neurological disorders as well. Alterations of the kynurenine pathway metabolites have been detected in multiple sclerosis and a number of potential therapeutic targets related to this metabolic route have been already identified. Laquinimod is a quinoline carboxamide showing structural similarities with kynurenic acid, which proved to have beneficial effects on reduction of brain atrophy and disability progression. The kynurenine pathway is therefore a promising target for the development of future drugs for the treatment of autoimmune diseases such as multiple sclerosis.

Levodopa/carbidopa intestinal gel can improve both motor and non-motor experiences of daily living in Parkinson's disease: An open-label study.

BACKGROUND: Levodopa/carbidopa intestinal gel therapy (LCIG) can efficiently improve several motor and non-motor symptoms of advanced Parkinson's disease (PD). The recently developed Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) improved the original UPDRS making it a more robust tool to evaluate therapeutic changes. However, previous studies have not used the MDS-UPDRS and the Unified Dyskinesia Rating Scale (UDysRS) to assess the efficacy of LCIG. OBJECTIVES: Our aim was to determine if the MDS-UPDRS and UDysRS could detect improvement in the experiences of daily living following 1-year LCIG treatment. METHODS: In this prospective, multicenter, open-label study, 34 consecutive patients undergoing LCIG treatment were enrolled. Patients were examined twice: prior to LCIG initiation and 12 months later. Impact of PD-related symptoms and dyskinesia was assessed by the MDS-UPDRS and UDysRS. RESULTS: Non-motor Experiences of Daily Living part of MDS-UPDRS improved from 20 (median, interquartile-range, IQR:14-23) to 16 points (median, IQR:12-20, p = 0.044) and the Motor Experiences of Daily Living ameliorated from 24 (median, IQR:20-29) to 18 points (median, IQR:13-25, p = 0.025). Health-related quality of life, measured by PDQ-39, also improved from 35.4 (median, IQR:26.9-50.3) to 27.0 (median, IQR:21.3-31.4) points (p = 0.003). The total score of UDysRS decreased from 47 (median, IQR:36-54) to 34 (median, IQR:21-45) points (p = 0.003). CONCLUSIONS: As far as the authors are aware of, our paper is the first to evaluate the impact of LCIG on dyskinesia by the means of UDysRS. Changes in MDS-UPDRS and UDysRS confirm that LCIG treatment can efficiently improve experiences of daily living in advanced PD.

Spotlight on opicapone as an adjunct to levodopa in Parkinson's disease: design, development and potential place in therapy.

Parkinson's disease (PD) is a progressive, chronic, neurodegenerative disease characterized by rigidity, tremor, bradykinesia and postural instability secondary to dopaminergic deficit in the nigrostriatal system. Currently, disease-modifying therapies are not available, and levodopa (LD) treatment remains the gold standard for controlling motor and nonmotor symptoms of the disease. LD is extensively and rapidly metabolized by peripheral enzymes, namely, aromatic amino acid decarboxylase and catechol-O-methyltransferase (COMT). To increase the bioavailability of LD, COMT inhibitors are frequently used in clinical settings. Opicapone is a novel COMT inhibitor that has been recently approved by the European Medicines Agency as an adjunctive therapy to combinations of LD and aromatic amino acid decarboxylase inhibitor in adult PD patients with end-of-dose motor fluctuations. We aimed to review the biochemical properties of opicapone, summarize its preclinical and clinical trials and discuss its future potential role in the treatment of PD.

Prion diseases: New considerations.

The transmissible spongiform encephalopathies, which include Creutzfeldt-Jakob disease, are fatal neurodegenerative disorders caused by the pathological accumulation of abnormal prion protein. The diagnosis of Creutzfeldt-Jakob disease is complex. The electroencephalogram, magnetic resonance imaging, lumbar puncture and genetic testing findings can help in the differential diagnosis of rapidly progressive dementia. There has recently been considerable debate as to whether proteins involved in the development of neurodegenerative diseases should be regarded as prions or only share prion-like mechanisms. Two recent reports described the detection of abnormal prion protein in the nasal mucosa and urine of patients with Creutzfeldt-Jakob disease. These findings raise major health concerns regarding the transmissibility of human prion diseases. We set out to address this neurological hot topic and to draw conclusions on the basis of what is known in the literature thus far.

Unilateral thalamic infarction causing downward gaze palsy in a patient with uncorrected tetralogy of fallot: a case report.

Introduction - Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease (CHD). Adults with surgically uncorrected forms of this condition are extremely rare, since operation is recommended in childhood to prevent cyanosis. Cyanotic CHD increases the risk of thromboembolic events. An endothelial dysfunction caused by chronic hypoxia and shear stress due to rheological alterations with a platelet dysfunction appear to be the explanation behind this finding. Paramedian thalamic infarction causing vertical gaze palsy without midbrain involvement is an infrequent finding. We report here a rare case of a patient with untreated TOF, who suffered a left-sided unilateral thalamic infarction presenting as downward gaze palsy and diplopia. Case presentation - A 44-year-old women complained of sudden onset diplopia and vertigo. Neurological examination revealed a downward gaze palsy with other symptoms related to a vertebrobasilar territory circulatory disturbance. The MRI scan revealed an acute infarction, 8 mm in diameter in the left medial thalamic region without midbrain involvement. Discussion - Adults with uncorrected forms of TOF are extremely uncommon, and descriptions of stroke in these patients are therefore rarities. We set out to give a concise survey of the literature regarding TOF patients with stroke. Conclusion - We present a rare case of unilateral thalamic infarction causing downward gaze palsy in an adult patient with uncorrected TOF. Cyanotic CHD is regarded as one of the risk factors of stroke. Besides other pathologic conditions, ischaemic stroke at an early age should raise the suspicion of a cardioembolic origin and, in rare cases, might result from cyanotic CHD.