Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease.

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson's coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I-V ß = -1.06, P < 0.001; lobules VI-VII ß = -0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion.

Aortic Stiffness Is Independently Associated with Intracranial Carotid Artery Calcification in Patients with Ischemic Stroke.

INTRODUCTION: Intracranial carotid artery calcification (ICAC), as a strong contributor to the occurrence of ischemic stroke, might be present in the medial or intimal arterial layer. Traditional cardiovascular risk factors (CVRFs) are associated with ICAC; however, its association with new markers of vascular function is less understood. The paper aimed to evaluate the relationship between carotid-femoral pulse wave velocity (CF-PWV) and ICAC subtypes. METHODS: We enrolled 65 patients with ischemic stroke. CF-PWV, systolic, diastolic, mean blood pressure, and pulse pressure were measured within 6 ± 2 days after stroke onset, and CT was performed within 24 h. ICAC on the stroke site was classified by two methods: volume and score based. Tertiles of ICAC volume were determined, and low-grade ICAC (T1) was regarded as a reference. According to the score-based method, (dominant) medial and (dominant) intimal ICAC subtypes were determined. Data were analyzed with multivariate logistic regression. RESULTS: Medial and intimal ICAC subtypes were found in 34 (52%) and 24 (37%) patients, respectively. In 11% of patients, no ICAC calcifications were found. CF-PWV was higher in patients with high-grade ICAC (OR = 1.56, 95% CI = 1.03-2.35, p = 0.035). CF-PWV was higher in patients with the medial ICAC subtype (OR = 1.60, 95% CI = 1.00-2.55, p = 0.049) after adjustment for traditional CVRFs. CONCLUSION: Our study demonstrates that among patients with ischemic stroke, aortic stiffness is independently associated with ICAC and that medial ICAC, compared with intimal ICAC, is accompanied by more advanced aortic stiffness.

Off-label use of eculizumab for neurological symptoms and progressive vision loss.

We describe the results of eculizumab treatment of a patient with pachymeningitis, inflammatory infiltration of the left frontal lobe, and cerebral hematoma, who presented with progressive vision loss, epileptic seizures, and abnormal pattern of the complement system parameters. A 30-year-old female patient, initially diagnosed with hypereosinophilia and a tumour of the left orbit, developed a significant visual impairment in the left eye, progressive vision loss in the right eye, and neurological symptoms in the form of epileptic seizures and behavioural changes. Magnetic resonance imaging (MRI) revealed thickening of the dura mater in the left frontal area, slight oedema of the cortex, and subcortical white matter. Orbit biopsy showed non-specific inflammatory infiltrates. Despite the initial good response, symptoms progressed during treatment with glucocorticoids and immunosuppressants. Increased activity of the alternative complement pathway accompanied by a low level of its main inhibitor, factor H (FH), and the presence of anti-FH autoantibodies, was found. Genetic analysis revealed several missense variants of complement proteins, including two disease-linked mutations in FH (p.H402Y) and FI (T300A). An attempt to apply a complement C5 blocker, eculizumab, has been made. Neurological symptoms subsided, vision loss was inhibited, laboratory parameters improved, and discontinuation of steroid therapy was possible. The case underlines the role of complement system dysregulation in neurological distress.

Supine blood pressure normalised by daytime series values is independently associated with ischaemic wake-up stroke.

PURPOSE: Wake-up stroke constitutes up to 1/4 of all ischaemic strokes; however, its pathomechanisms remain largely unknown. Although low nocturnal blood flow may be the underlying cause, little is known about blood pressure (BP) characteristic of wake-up stroke patients. The aim of our study was to look for differences in BP variables between wake-up stroke and known-onset stroke patients and to seek BP indices which could distinguish wake-up stroke patients from other stroke patients. MATERIALS AND METHODS: In the study, we included ischaemic stroke patients in whom office BP measurement and Ambulatory BP monitoring (ABPM) were recorded at day 7, after acute hypertensive response. The daytime period was defined as the interval from 6 a.m. to 10 p.m. From ABPM, we obtained parameters of BP variability. Additionally, we calculated the BP percentage differences defined as (supine office BP-average daytime BP)/average daytime BP for systolic, diastolic, and mean blood pressure. We calculated analogous indices for night-time. The univariate and multivariate relationships between BP variables and wake-up stroke were analysed. RESULTS: Among the recruited 120 patients (aged 61.6 ± 12.3; 88 [73%] males; the baseline National Institutes of Health stroke scale score 4 [3-8]), 36 (30%) had wake-up stroke. In a univariate analysis, the systolic and mean daytime and night-time BP differences were significantly lower in patients with wake-up stroke [(-1.92 (-11.55 to 3.95) vs 4.12 (-2.48 to 11.31), p = 0.006 and -6.20 (-12.32 to 7.42) vs 2.00 (-6.86 to 11.65), p = 0.029 for daytime, respectively; 0.00 (-9.79 to 11.82) vs 9.84 (0.00 to 18.25), p = 0.003 and 0.51 (-8.49 to 12.08) vs 7.82 (-2.47 to 20.39), p = 0.026, for night-time, respectively]. After adjustment for possible confounders, the systolic BP difference remained significantly associated with wake-up stroke (odds ratio = 0.96, 95% confidence interval = 0.92-1.00, p = 0.039). CONCLUSION: The subacute office-ambulatory BP difference including the dynamic (systolic BP), but not static BP component was independently associated with wake-up stroke.

Blood Pressure Management in Acute Ischemic Stroke.

PURPOSE OF REVIEW: Abrupt blood pressure (BP) rise is the most common clinical symptom of acute ischemic stroke (AIS). However, BP alterations during AIS reflect many diverse mechanisms, both stroke-related and nonspecific epiphenomena, which change over time and across patients. While extremes of BP as well as high BP variability have been related with worse outcomes in observational studies, optimal BP management after AIS remains challenging. RECENT FINDINGS: This review discusses the complexity of the factors linking BP changes to the clinical outcomes of patients with AIS, depending on the treatment strategy and local vessel status and, in particular, the degree of reperfusion achieved. The evidence for possible additional clinical markers, including the presence of arterial hypertension, and comorbid organ dysfunction in individuals with AIS, as informative and helpful factors in therapeutic decision-making concerning BP will be reviewed, as well as recent data on neurovascular monitoring targeting person-specific local cerebral perfusion and metabolic demand, instead of the global traditional parameters (BP among others) alone. The individualization of BP management protocols based on a complex evaluation of the homeostatic response to focal cerebral ischemia, including but not limited to BP changes, may be a valuable novel goal proposed in AIS, but further trials are warranted.

Changes of augmentation index early after ischaemic stroke predict functional outcome.

Purpose: Outcome after ischaemic stroke (AIS) depends on multiple factors, including values of blood pressure (BP) and arterial stiffness (AS) in the early phase. It is also known that stroke outcome is affected by BP variability; however, the influence of AS oscillations in the early phase of stroke on its prognosis is unknown. The aim of our study was to assess the relationship between changes of AS markers and stroke outcome.Materials and methods: Baseline clinical data, BP parameters, and markers of AS (pulse wave velocity [PWV], augmentation index [AIx]) were assessed 1, 6, and >90 days after AIS. The outcomes were defined using modified Rankin scale (mRS) score: early favourable (EFO) and early poor (EPO), as mRS ≤1 and >2 points at discharge, respectively; late favourable (LFO) and late poor (LPO), as mRS ≤1 and >2 points on day >90, respectively.Results: In the recruited 50 patients (62.2 ± 12.1 years, 68% males), BP and PWV decreased while AIx did not change within 90 days after AIS. Twenty-eight patients (56%) had EFO, 10 (20%) - EPO, 29 (58%) - LFO, and 9 (18%) - LPO. In univariate analysis, rise in AIx in days 1-6 was associated with EFO (odds ratio [OR] = 1.09, 95% confidence interval [CI] = 1.02-1.17, p = 0.01) and LFO (OR = 1.08; 95%CI = 1.01-1.14, p = 0.02), whereas decrease in AIx in days 1-6 was associated with EPO (OR = 1.07, 95%CI = 1.00-1.15, p = 0.05). For EFO and LFO, the relationships remained significant after including confounders (p = 0.03 and p = 0.03, respectively).Conclusions: Rise in AIx within one week after ischaemic stroke may be of additional importance in determining better early and late favourable functional outcome.

A study in a Polish ataxia cohort indicates genetic heterogeneity and points to MTCL1 as a novel candidate gene.

Inherited ataxias are a group of highly heterogeneous, complex neurological disorders representing a significant diagnostic challenge in clinical practice. We performed a next-generation sequencing (NGS) analysis in 10 index cases with unexplained progressive cerebellar ataxia of suspected autosomal recessive inheritance. A definite molecular diagnosis was obtained in 5/10 families and included the following diseases: autosomal recessive spastic ataxia of Charlevoix-Saguenay, POLR3B-related hypomyelinating leukodystrophy, primary coenzyme Q10 deficiency type 4, Niemann-Pick disease type C1 and SYNE1-related ataxia. In addition, we found a novel homozygous MTCL1 loss of function variant p.(Lys407fs) in a 23-year-old patient with slowly progressive cerebellar ataxia, mild intellectual disability, seizures in childhood and episodic pain in the lower limbs. The identified variant is predicted to truncate the protein after first 444 of 1586 amino acids. MTCL1 encodes a microtubule-associated protein highly expressed in cerebellar Purkinje cells; its knockout in a mouse model causes ataxia. We propose MTCL1 as a candidate gene for autosomal recessive cerebellar ataxia in humans. In addition, our study confirms the high diagnostic yield of NGS in early-onset cerebellar ataxias, with at least 50% detection rate in our ataxia cohort.

CD271+, CXCR7+, CXCR4+, and CD133+ Stem/Progenitor Cells and Clinical Characteristics of Acute Ischemic Stroke Patients.

Ischemic stroke causes mobilization of various groups of progenitor cells from bone marrow to bloodstream and this correlates with the neurological status of stroke patients. The goal of our study was to identify the activity of chosen progenitor/stem cells in the peripheral blood of acute ischemic stroke patients in the first 7 days after the incident, through associations between the levels of the cells and clinical features of the patients. Thirty-three acute ischemic stroke patients and 15 non-stroke control subjects had their venous blood collected repeatedly in order to assess the levels of the CD45-CD34 + CD271+, the CD45-CD34 + CXCR4+, the CD45-CD34 + CXCR7+, and the CD45-CD34 + CD133+ stem/progenitor cells by means of flow cytometry. The patients underwent repeated neurological and clinical assessments, pulse wave velocity (PWV) assessment on day 5, and MRI on day 1 and 5 ± 2. The levels of the CD45-CD34 + CXCR7+ and the CD45-CD34 + CD271+ cells were lower in the stroke patients compared with the control subjects. Only the CD45-CD34 + CD271+ cells correlated positively with lesion volume in the second MRI. The levels of the CD45-CD34 + CD133+ cells on day 2 correlated negatively with PWV and NIHSS score on day 9. The patients whose PWV was above 10 m/s had significantly higher levels of the CD45-CD34 + CXCR4+ and the CD45-CD34 + CXCR7+ cells on day 1 than those with PWV below 10 m/s. This study discovers possible activity of the CD45-CD34 + CD271+ progenitor/stem cells during the first 7 days after ischemic stroke, suggests associations of the CD45-CD34 + CD133+ cells with the neurological status of stroke patients, and some activity of the CD45-CD34 + CD133+, the CD45-CD34 + CXCR4+, and the CD45-CD34 + CXCR7+ progenitor/stem cells in the process of arterial remodeling.

Blood pressure in acute ischemic stroke: challenges in trial interpretation and clinical management: position of the ESH Working Group on Hypertension and the Brain.

: Altered blood pressure (BP) is a common phenomenon in acute ischemic stroke (AIS), with high BP being the most frequent scenario. The pathophysiology of BP changes in AIS is complex and only partially understood. The available evidence indicates that extremely high BP during AIS is associated with a poor outcome. Importantly, the observed relationship between BP and stroke outcome may or may not be causally related. Higher baseline BPs in focal cerebral ischemia may indicate preexisting hypertension, but may also be an effect of both nonspecific and stroke-related factors. Although antihypertensive therapy effectively reduces BP in AIS, studies on early BP lowering in AIS produce conflicting results in terms of functional outcome and mortality. Systematic reviews on BP management in AIS did not result in clinically applicable conclusions in general. However, the investigation on the effect of BP and its alterations in AIS are hampered by various important methodological issues. This position statement was prepared by a group of experts from the European Society of Hypertension and invited neurologists to discuss the main reasons for the discrepancies in the current evidence on the prognosis and treatment of altered BP in AIS which should be taken into account in future studies.

Left ventricular ejection fraction and aortic stiffness are independent predictors of neurological outcome in acute ischemic stroke.

BACKGROUND: Stroke is a leading cause of disability and one of the major causes of death worldwide. The short-term prognosis in individual patients is highly variable and cannot be explained solely by stroke severity. We investigated the association of left ventricular ejection fraction with early neurological outcome in acute ischemic stroke. METHODS: In total, 216 patients enrolled in a prospective study, underwent echocardiography and applanation tonometry performed within 1 week after stroke onset. At day 10, favorable outcome was defined as a 4 or more point improvement from baseline National Institutes of Health Stroke Scale or final National Institutes of Health Stroke Scale of 0-1. RESULTS: In patients with favorable outcome, the ejection fraction was significantly higher comparing with patients with poorer prognosis (54.3 ±â€Š7.9 vs. 49.9 ±â€Š9.8%, P = 0.005). Favorable neurological outcome at day 10 was also associated with lower heart rate and lower pulse wave velocity at baseline. Univariate analyses showed that left ventricle ejection fraction and arterial stiffness were the strongest predictors of the poststroke improvement. In multivariate analysis, ejection fraction at least 50% remained significantly associated with favorable outcome after full adjustment for potential confounders (odds ratio 3.81, [95% confidence interval, 1.18-12.35]; P = 0.02). CONCLUSION: These findings provide evidence that in ischemic stroke, preserved ejection fraction and lower pulse wave velocity are associated with early favorable outcome, independently of other known prognostic factors, including blood pressure.

Acute hypertensive response in ischemic stroke is associated with increased aortic stiffness.

BACKGROUND AND AIMS: Acute hypertensive response (AHR) affects more than 60% of patients with ischemic stroke and is associated with poor outcomes. We hypothesized that its development is related to arterial stiffening. "The gold standard" estimate of arterial stiffness is carotid-femoral pulse wave velocity (CF-PWV). We compared CF-PWV and indirect indices of arterial stiffness (central augmentation index (cAIxHR), central systolic (cSBP) and pulse (cPP) pressures) between acute ischemic stroke patients who developed AHR and those who were normotensive in the early phase of stroke. METHODS: AHR was assessed through hourly BP measurements within 24 h from admission using an oscillometric device. The stiffness was assessed using applanation tonometry with a SphygmoCor(®) device (Atcor, Sydney, Australia) 7 ± 2 days after stroke. RESULTS: Among 102 patients with acute ischemic stroke, 73(71.5%) met AHR criteria. In an univariate analysis, CF-PWV, cAIxHR, cSBP and cPP were higher in those who developed AHR (10.9 vs. 8.3 m/s, p < 0.001; 30.8 vs. 23.9%, p = 0.004; 138.2 vs. 117.2 mmHg, p < 0.001; 54.6 vs. 44 mmHg, p = 0.005, respectively). In a multivariate logistic regression analysis, CF-PWV was independently associated with AHR after adjustment for age and peripheral mean blood pressure (pMBP) (p = 0.04), for age, pMBP and diabetes mellitus (DM) (p = 0.045), and age, pMBP, DM and hypertension (p = 0.047). CONCLUSION: This study revealed for the first time that AHR in ischemic stroke is associated with elevated aortic stiffness independently of other clinical factors including age and hypertension preceding stroke. A potential pathophysiological mechanism responsible for this relationship includes impaired baroreceptor function in stiff arteries resulting in impaired BP autoregulation.

Hypertension is associated with dysfunction of both peripheral and central auditory system.

OBJECTIVES: Arterial hypertension negatively influences the peripheral auditory system, causing sensorineural hearing loss. Much less is known about the detrimental effects of hypertension on the central auditory functions. METHODS: We tested 32 arterial hypertension patients and 32 age and sex-matched healthy volunteers with the expanded tonal audiometry (0.125-12.5 kHz), distortion product otoacoustic emissions (0.75-8 kHz), horizontal minimum audible angle test for eight azimuths with binaural stimulation and the random gap detection test. RESULTS: Peripheral hearing of the hypertensive patients was impaired in comparison with the controls within all audiometric frequencies (0.125-12.5 kHz) and within specific groups of frequencies. Distortion product otoacoustic emission results were significantly lower for frequencies 4 (P = 0.04) and 6 kHz (P < 0.001). The sound localization ability in the horizontal minimum audible angle test was significantly worse in the hypertensive patients in the 0°, 45°, 90°, 135°, and 270° azimuth when the interaural pure tone average (0.5-1-2 kHz) was set less than 20 dB hearing level (P < 0.05), and in the 0°, 90°, 225°, and 270°azimuth when the binaural pure tone average (0.5-1-2 kHz) was set 20 dB or less hearing level (P < 0.05). Gap detection thresholds in the random gap detection test did not differ between the two groups. CONCLUSION: Arterial hypertension is independently related to the damage of the peripheral part of the auditory system resulting in high-frequency hearing loss. Hypertensive disturbances of central auditory processing are more discrete and concern the spatial hearing resolution.

Hypertension and cochlear hearing loss.

This paper presents a review of experimental and clinical research on the contribution of hypertension to cochlear hearing loss. Hypertension is one of the crucial risk factors underlying pathophysiological processes taking place in the cochlea. Several mechanisms explaining these processes have been described, mainly in animal models, such as the disturbance of the inner ear potassium recycling process due to the detrimental action of natriuretic hormone, and the decrease in the cochlear oxygen partial pressure. Current evidence linking hypertension to sensorineural high-frequency cochlear hearing loss in humans may be confounded by other concomitant diseases or risk factors such as age, coronary artery disease, diabetes, obesity, hyperlipidemia, smoking and noise exposure. Therefore, further research in this field is clearly needed.

Hypertension, brain damage and cognitive decline.

Loss of cognitive function is one the most devastating manifestations of ageing and vascular disease. Cognitive decline is rapidly becoming an important cause of disability worldwide and contributes significantly to increased mortality. There is growing evidence that hypertension is the most important modifiable vascular risk factor for development and progression of both cognitive decline and dementia. High blood pressure contributes to cerebral small and large vessel disease resulting in brain damage and dementia. A decline in cerebrovascular reserve capacity and emerging degenerative vascular wall changes underlie complete and incomplete brain infarcts, haemorrhages and white matter hyperintensities. This review discusses the complexity of factors linking hypertension to brain functional and structural changes, and to cognitive decline and dementia. The evidence for possible clinical markers useful for prevention of decreased cognitive ability, as well as recent data on vascular mechanism in the pathogenesis of cognitive decline, and the role of antihypertensive therapies in long-term prevention of late-life cognitive decline will be reviewed.

Pulse wave velocity is associated with early clinical outcome after ischemic stroke.

BACKGROUND AND PURPOSES: Pulse wave analysis (PWV), a marker of aortic stiffness, has independent predictive value for cardiovascular morbidity and mortality in both healthy and high-risk populations, especially fatal stroke, and for long-term functional stroke prognosis. Whether arterial stiffness and wave reflection are related to stroke in-hospital short-term outcome has never been demonstrated. METHODS: In a prospective study, we enrolled 134 patients with acute ischemic stroke, aged 63.4 ± 12.5 years, mean ± SD, National Institutes of Health stroke scale (NIHSS) scored 7.1 ± 6.5 at admission. Carotid-femoral (CF) PWV and central augmentation index (cAIx) were measured (SphygmoCor) one week after stroke onset. At hospital discharge, favorable outcome was defined as a 4 or more point improvement from baseline NIHSS or NIHSS of 0-1. Data were analyzed with logistic regression. RESULTS: In univariate analysis, low CF-PWV (P = 0.000,001), but not cAIx, was significantly associated with early favorable outcome. In multivariate analysis, CF-PWV > 9.0 m/s remained significantly associated with favorable early outcome after adjustment for age, NIHSS and blood glucose level on admission, as well as heart rate, systolic and mean blood pressure, measured at day 7 (OR = 0.17 [95% CI, 0.05-0.60];P = 0.006). CONCLUSIONS: In ischemic stroke, low aortic stiffness (CF-PWV) is associated with early favorable outcome, independently of other known prognostic factors.

Aortic stiffness predicts functional outcome in patients after ischemic stroke.

BACKGROUND AND PURPOSE: Increased aortic stiffness (measured by carotid-femoral pulse wave velocity) and central augmentation index have been shown to independently predict cardiovascular events, including stroke. We studied whether pulse wave velocity and central augmentation index predict functional outcome after ischemic stroke. METHODS: In a prospective study, we enrolled 99 patients with acute ischemic stroke (age 63.7 ± 12.4 years, admission National Institutes of Health Stroke Scale score 6.6 ± 6.6, mean ± SD). Carotid-femoral pulse wave velocity and central augmentation index (SphygmoCor) were measured 1 week after stroke onset. Functional outcome was evaluated 90 days after stroke using the modified Rankin Scale with modified Rankin Scale score of 0 to 1 considered an excellent outcome. RESULTS: In univariate analysis, low carotid-femoral pulse wave velocity (P=0.000001) and low central augmentation index (P=0.028) were significantly associated with excellent stroke outcome. Age, severity of stroke, presence of previous stroke, diabetes, heart rate, and peripheral pressures also predicted stroke functional outcome. In multivariate analysis, the predictive value of carotid-femoral pulse wave velocity (<9.4 m/s) remained significant (OR, 0.21; 95% CI, 0.06-0.79; P=0.02) after adjustment for age, National Institutes of Health Stroke Scale score on admission, and presence of previous stroke. By contrast, central augmentation index had no significant predictive value after adjustment. CONCLUSIONS: This study indicates that aortic stiffness is an independent predictor of functional outcome in patients with acute ischemic stroke.