Neurological abnormalities in individuals with Marfan syndrome: results from a genetically confirmed Italian cohort.

BACKGROUND AND AIMS: Neurological abnormalities have been frequently reported in individuals with Marfan Syndrome (MFS). However, available data relies solely on retrospective studies predating current diagnostic criteria. METHODS: Cross-sectional study comprehensively investigating neurological abnormalities within a prospective cohort of adults (≥ 18 years) with genetically confirmed MFS referred to an Italian hub center for heritable connective tissue diseases (Jan. 1st - Nov. 15th, 2021). RESULTS: We included a total of 38 individuals (53% female). The commonest neurological symptom was migraine (58%), usually without aura (73%). Neuropsychological testing was generally unremarkable, whilst anxiety and depression were highly prevalent within our cohort (42% and 34%, respectively). The most frequent brain parenchymal abnormality was the presence of cortico-subcortical hypointense spots on brain MRI T2* Gradient-Echo sequences (39%), which were found only in patients with a prior history of aortic surgery. Migraineurs had a higher frequency of brain vessels tortuosity vs. individuals without migraine (73% vs. 31%; p = 0.027) and showed higher average and maximum tortuosity indexes in both anterior and posterior circulation brain vessels (all p < 0.05). At univariate regression analysis, the presence of brain vessels tortuosity was significantly associated with a higher risk of migraine (OR 5.87, CI 95% 1.42-24.11; p = 0.014). CONCLUSIONS: Our study confirms that neurological abnormalities are frequent in individuals with MFS. While migraine appears to be associated with brain vessels tortuosity, brain parenchymal abnormalities are typical of individuals with a prior history of aortic surgery. Larger prospective studies are needed to understand the relationship between parenchymal abnormalities and long-term cognitive outcomes.

Tacrolimus-associated neurotoxicity isolated to the brainstem: two illustrative cases and a systematic review of the literature.

INTRODUCTION: Tacrolimus-associated neurotoxicity (TAN) manifests with wide clinical spectrum, ranging from mild tremors to severe encephalopathy. The isolated involvement of the brainstem is a rarely documented presentation of TAN, and its clinical and diagnostic characteristics are unclear. METHODS: We report two cases of brainstem-isolated TAN (bi-TAN). Moreover, we performed a systematic review of the literature on bi-TAN and extracted data concerning demographics, clinical characteristics, radiological features, and management. The systematic literature search followed PRISMA guidelines and a pre-defined protocol. RESULTS: Eleven patients, including our two, were identified (mean age: 41.3 years, ± 18.8; five males, 45%). Speech disturbance was the most common clinical presentation (45%). The mean latency from Tacrolimus initiation to bi-TAN onset was 26 days (± 30.8). Tacrolimus serum level tested above the reference range in three patients (mean: 26.83 ± 5.48). Brain MRI showed T2-FLAIR hyperintensities; three showed restricted diffusion on ADC maps. Neurological symptoms resolved completely in seven patients (63%) after Tacrolimus withdrawal or dose reduction. CONCLUSIONS: Our findings suggest that bi-TAN could represent a brainstem variant of posterior reversible encephalopathy syndrome. Recognition of bi-TAN as a potential cause of isolated brainstem lesions is crucial to disentangle the diagnostic work-up and ensure prompt withdrawal or reduction of the offending agent.

Rapid outpatient transient ischemic attack clinic and stroke service activity during the SARS-CoV-2 pandemic: a multicenter time series analysis.

Background and aim: Rapid outpatient evaluation and treatment of TIA in structured clinics have been shown to reduce stroke recurrence. It is unclear whether short-term downtrends in TIA incidence and admissions have had enduring impact on TIA clinic activity. This study aims to measure the impact of the pandemic on hospitals with rapid TIA clinics. Methods: Relevant services were identified by literature search and contacted. Three years of monthly data were requested - a baseline pre-COVID period (April 2018 to March 2020) and an intra-COVID period (April 2020 to March 2021). TIA presentations, ischemic stroke presentations, and reperfusion trends inclusive of IV thrombolysis (IVT) and endovascular thrombectomy (EVT) were recorded. Pandemic impact was measured with interrupted time series analysis, a segmented regression approach to test an effect of an intervention on a time-dependent outcome using a defined impact model. Results: Six centers provided data for a total of 6,231 TIA and 13,191 ischemic stroke presentations from Australia (52.1%), Canada (35.0%), Italy (7.6%), and England (5.4%). TIA clinic volumes remained constant during the pandemic (2.9, 95% CI -1.8 to 7.6, p = 0.24), as did ischemic stroke (2.9, 95% CI -7.8 to 1.9, p = 0.25), IVT (-14.3, 95% CI -36.7, 6.1, p < 0.01), and EVT (0, 95% CI -16.9 to 16.9, p = 0.98) counts. Proportion of ischemic strokes requiring IVT decreased from 13.2 to 11.4% (p < 0.05), but those requiring EVT did not change (16.0 to 16.7%, p = 0.33). Conclusion: This suggests that the pandemic has not had an enduring effect on TIA clinic or stroke service activity for these centers. Furthermore, the disproportionate decrease in IVT suggests that patients may be presenting outside the IVT window during the pandemic - delays in seeking treatment in this group could be the target for public health intervention.

Neurophysiological signatures of mild traumatic brain injury in the acute and subacute phase.

BACKGROUND: Mild traumatic brain injury (mTBI) affects 48 million people annually, with up to 30% experiencing long-term complaints such as fatigue, blurred vision, and poor concentration. Assessing neurophysiological features related to visual attention and outcome measures aids in understanding clinical symptoms and prognostication. METHODS: We recorded EEG and eye movements in mTBI patients during a computerized task performed in the acute (< 24 h, TBI-A) and subacute phase (4-6 weeks thereafter). We estimated the posterior dominant rhythm, reaction times (RTs), fixation duration, and event-related potentials (ERPs). Clinical outcome measures were assessed using the Head Injury Symptom Checklist (HISC) and the Extended Glasgow Outcome Scale (GOSE) at 6 months post-injury. Similar analyses were performed in an age-matched control group (measured once). Linear mixed effect modeling was used to examine group differences and temporal changes within the mTBI group. RESULTS: Twenty-nine patients were included in the acute phase, 30 in the subacute phase, and 19 controls. RTs and fixation duration were longer in mTBI patients compared to controls (p < 0.05), but not between TBI-A and TBI-S (p < 0.05). The frequency of the posterior dominant rhythm was significantly slower in TBI-A (0.6 Hz, p < 0.05) than TBI-S. ERP mean amplitude was significantly lower in mTBI patients than in controls. Neurophysiological features did not significantly relate to clinical outcome measures. CONCLUSION: mTBI patients demonstrate impaired processing speed and stimulus evaluation compared to controls, persisting up to 6 weeks after injury. Neurophysiological features in mTBI can assist in determining the extent and temporal progression of recovery.

Neurophysiological signatures reflect differences in visual attention during absence seizures.

OBJECTIVE: Absences affect visual attention and eye movements variably. Here, we explore whether the dissimilarity of these symptoms during absences is reflected in differences in electroencephalographic (EEG) features, functional connectivity, and activation of the frontal eye field. METHODS: Pediatric patients with absences performed a computerized choice reaction time task, with simultaneous recording of EEG and eye-tracking. We quantified visual attention and eye movements with reaction times, response correctness, and EEG features. Finally, we studied brain networks involved in the generation and propagation of seizures. RESULTS: Ten pediatric patients had absences during the measurement. Five patients had preserved eye movements (preserved group) and five patients showed disrupted eye movements (unpreserved group) during seizures. Source reconstruction showed a stronger involvement of the right frontal eye field during absences in the unpreserved group than in the preserved group (dipole fraction 1.02% and 0.34%, respectively, p < 0.05). Graph analysis revealed different connection fractions of specific channels. CONCLUSIONS: The impairment of visual attention varies among patients with absences and is associated with differences in EEG features, network activation, and involvement of the right frontal eye field. SIGNIFICANCE: Assessing the visual attention of patients with absences can be usefully employed in clinical practice for tailored advice to the individual patient.

Capsular Warning Syndrome: Features, Risk Profile, and Prognosis in a Large Prospective TIA Cohort.

INTRODUCTION: Features and prognosis of capsular warning syndrome (CWS) have been poorly investigated prospectively. AIMS: The study aimed to characterize CWS clinical features, risk profile, short- and long-term prognosis, among a large TIA cohort. METHODS: Prospective cohort study of consecutive TIAs was conducted from August 1, 2010, to December 31, 2017. Demographic and clinical characteristics, risk profile, primary (stroke and composite outcome) and secondary (TIA recurrence, cerebral hemorrhage, new onset atrial fibrillation) outcomes were compared between CWS, lacunar (L), and nonlacunar (NL) TIAs. RESULTS: 1,035 patients (33 CWS, 189 L-TIAs, 813 NL-TIAs) were enrolled. Newly diagnosed (ND) hypertension, hypercholesterolemia, cigarette smoking, and leukoaraiosis were independent risk factors of CWS (p < 0.05). CWS showed the highest stroke (30.3% vs. 0.5% and 1.5% for L-TIAs and NL-TIAs, respectively) and composite outcome risk at follow-up (p < 0.001), but better 3-month post-stroke prognosis (mRS 0-2 90.0% vs. 36.8%; p = 0.002). CWS-related stroke mostly occurred <48 h (80.0%) and had a small vessel occlusion etiology (100%), affecting more often the internal capsule (60.0%). Dual antiplatelet therapy (DAPT) versus single antiplatelet therapy was associated with lower 3-month cumulative stroke incidence (12.5% vs. 57.1%; p = 0.010). Intravenous thrombolysis (IVT) showed similar 3-month efficacy and safety in strokes after TIAs groups (median mRS 0, IQR 0-1; p = 0.323). CONCLUSIONS: CWS is associated with higher stroke risk and better functional prognosis than L- and NL-TIAs. CWS risk profile is consistent with severe small vessel disease, and ND hypertension could represent a major risk factor. DAPT and IVT seem effective and safe in preventing and treating stroke following CWS.

A Potential Multimodal Test for Clinical Assessment of Visual Attention in Neurological Disorders.

Attention is an important aspect of human brain function and often affected in neurological disorders. Objective assessment of attention may assist in patient care, both for diagnostics and prognostication. We present a compact test using a combination of a choice reaction time task, eye-tracking and EEG for assessment of visual attention in the clinic. The system quantifies reaction time, parameters of eye movements (i.e. saccade metrics and fixations) and event related potentials (ERPs) in a single and fast (15 min) experimental design. We present pilot data from controls, patients with mild traumatic brain injury and epilepsy, to illustrate its potential use in assessing attention in neurological patients. Reaction times and eye metrics such as fixation duration, saccade duration and latency show significant differences (p < .05) between neurological patients and controls. Late ERP components (200-800 ms) can be detected in the central line channels for all subjects, but no significant group differences could be found in the peak latencies and mean amplitudes. Our system has potential to assess key features of visual attention in the clinic. Pilot data show significant differences in reaction times and eye metrics between controls and patients, illustrating its promising use for diagnostics and prognostication.

Case Report: Optic Atrophy and Nephropathy With m.13513G>A/MT-ND5 mtDNA Pathogenic Variant.

Isolated complex I deficiency represents the most common mitochondrial respiratory chain defect involved in mitochondrial disorders. Among these, the mitochondrial DNA (mtDNA) m.13513G>A pathogenic variant in the NADH dehydrogenase 5 subunit gene (MT-ND5) has been associated with heterogenous manifestations, including phenotypic overlaps of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, Leigh syndrome, and Leber's hereditary optic neuropathy (LHON). Interestingly, this specific mutation has been recently described in patients with adult-onset nephropathy. We, here, report the unique combination of LHON, nephropathy, sensorineural deafness, and subcortical and cerebellar atrophy in association with the m.13513G>A variant.

Clinicoradiological Profile and Functional Outcome of Acute Cerebral Venous Thrombosis: A Hospital-Based Cohort Study.

Introduction Acute cerebral venous thrombosis (CVT) may result in a variety of clinical presentations, with headache being the most common. The relationship between clinical and neuroradiological characteristics in acute CVT patients is still not univocally characterized. Materials and methods We enrolled 32 consecutive acute CVT patients admitted to our emergency department from January 1, 2012, to June 30, 2019. Clinicoradiological associations and their relationship with the functional outcome at the discharge were tested. Results Headache was the presenting symptom in 85% of patients, more frequently subacute (82%), new-onset (67%), with unusual features in respect to prior headache episodes (100%), and associated with concomitant neurological symptoms/signs (74%). Patients with holocranial headache showed more frequent venous ischemia (VI) compared to those with bilateral and unilateral headache (50% vs. 20% vs. 0%, respectively; p=0.027). Patients with concomitant neurological defects had a higher prevalence of VI (50.0% vs. 15.0%; p=0.049) and superior sagittal sinus thrombosis (67% vs. 30%; p=0.043) than those without. Vomit was more frequently observed in patients with straight sinus thrombosis (67% vs. 8%; p=0.005). Increasing age and VI were independently associated with poor (modified Rankin scale (mRS) 2-5) functional outcome (odds ratio (OR) = 1.081, 95% confidence interval (CI) 1.004-1.165; p=0.038 and OR = 12.089, 95% CI 1.141-128.104; p=0.039, respectively). Conclusions Our study confirms and enriches available data on the clinicoradiological profile of patients with acute CVT and suggests that increasing age and venous ischemia are independently associated with poor outcomes.

Absence epilepsy: Characteristics, pathophysiology, attention impairments, and the related risk of accidents. A narrative review.

OBJECTIVE: Absence epilepsy (AE) is related to both cognitive and physical impairments. In this narrative review, we critically discuss the pathophysiology of AE and the impairment of attention in children and adolescents with AE. In particular, we contextualize the attentive dysfunctions of AE with the associated risks, such as accidental injuries. DATA SOURCE: An extensive literature search on attention deficits and the rate of accidental injuries in AE was run. The search was conducted on Scopus, Pubmed, and the online libraries of the University of Twente and Maastricht University. Relevant references of the included articles were added. Retrospective and prospective studies, case reports, meta-analysis, and narrative reviews were included. Only studies written in English were considered. Date of last search is February 2020. The keywords used were "absence epilepsy" AND "attention"/"awareness", "absence epilepsy" AND "accidental injuries"/"accident*"/"injuries". RESULTS: Ten retrospective and two prospective studies on cognition and AE were fully screened. Seventeen papers explicitly referring to attention in AE were reviewed. Just one paper was found to specifically focus on accidental injuries and AE, while twelve studies generally referring to epilepsy syndromes - among which AE - and related accidents were included. CONCLUSION: Absence epilepsy and attention deficits show some patterns of pathophysiological association. This relation may account for dysfunctions in everyday activities in the pediatric population. Particular metrics, such as the risk related to biking in children with AE, should be used in future studies to address the problem in a novel way and to impact clinical indications.