A novel de novo truncating variant in a Hungarian patient with CTNNB1 neurodevelopmental disorder.

PURPOSE: We aimed to elucidate the underlying disease in a Hungarian family, with only one affected family member, a 16-year-old male Hungarian patient, who developed global developmental delay, cognitive impairment, behavioral problems, short stature, intermittent headaches, recurrent dizziness, strabismus, hypermetropia, complex movement disorder and partial pituitary dysfunction. After years of detailed clinical investigations and careful pediatric care, the exact diagnosis of the patient and the cause of the disease was still unknown. METHODS: We aimed to perform whole exome sequencing (WES) in order to investigate whether the affected patient is suffering from a rare monogenic disease. RESULTS: Using WES, we identified a novel, de novo frameshift variant (c.1902dupG, p.Ala636SerfsTer12) of the catenin beta-1 (CTNNB1) gene. Assessment of the novel CTNNB1 variant suggested that it is a likely pathogenic one and raised the diagnosis of CTNNB1 neurodevelopmental disorder (OMIM 615,075). CONCLUSIONS: Our manuscript may contribute to the better understanding of the genetic background of the recently discovered CTNNB1 neurodevelopmental disorder and raise awareness among clinicians and geneticists. The affected Hungarian family demonstrates that based on the results of the clinical workup is difficult to establish the diagnosis and high-throughput genetic screening may help to solve these complex cases.

High Prevalence of New Clinically Significant Findings in Patients With Embolic Stroke of Unknown Source Evaluated by Cardiac Magnetic Resonance Imaging.

BACKGROUND: Embolic stroke of unknown source (ESUS) accounts for 1 in 6 ischemic strokes. Current guidelines do not recommend routine cardiac magnetic resonance (CMR) imaging in ESUS, and beyond the identification of cardioembolic sources, there are no data assessing new clinical findings from CMR in ESUS. This study aimed to assess the prevalence of new cardiac and noncardiac findings and to determine their impact on clinical care in patients with ESUS. METHODS AND RESULTS: In this prospective, multicenter, observational study, CMR imaging was performed within 3 months of ESUS. All scans were reported according to standard clinical practice. A new clinical finding was defined as one not previously identified through prior clinical evaluation. A clinically significant finding was defined as one resulting in further investigation, follow-up, or treatment. A change in patient care was defined as initiation of medical, interventional, surgical, or palliative care. From 102 patients recruited, 96 underwent CMR imaging. One or more new clinical findings were observed in 59 patients (61%). New findings were clinically significant in 48 (81%) of these patients. Of 40 patients with a new clinically significant cardiac finding, 21 (53%) experienced a change in care (medical therapy, n=15; interventional/surgical procedure, n=6). In 12 patients with a new clinically significant extracardiac finding, 6 (50%) experienced a change in care (medical therapy, n=4; palliative care, n=2). CONCLUSIONS: CMR imaging identifies new clinically significant cardiac and noncardiac findings in half of patients with recent ESUS. Advanced cardiovascular screening should be considered in patients with ESUS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04555538.

A Recurrent De Novo Variant in EIF2AK2 Causes a Hypomyelinating Leukodystrophy.

De novo pathogenic variants in EIF2AK2 have recently been reported as a novel genetic cause of leukoencephalopathy. Here, we describe a male individual who presented in the first year of life with clinical features resembling Pelizaeus-Merzbacher disease (PMD), including nystagmus, hypotonia, and global developmental delay, and which later progressed to include ataxia and spasticity. Brain MRI at the age of two revealed diffuse hypomyelination. This report adds to the limited number of individuals published and further reinforces de novo variants in EIF2AK2 as a molecular cause of a leukodystrophy that clinically and radiologically resembles PMD.

Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants in POLR3A, POLR3B and POLR1C.

BACKGROUND: RNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is an autosomal recessive hypomyelinating leukodystrophy characterized by neurological dysfunction, hypodontia and hypogonadotropic hypogonadism. The disease is caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C or POLR3K. Craniofacial abnormalities reminiscent of Treacher Collins syndrome have been originally described in patients with POLR3-HLD caused by biallelic pathogenic variants in POLR1C. To date, no published studies have appraised in detail the craniofacial features of patients with POLR3-HLD. In this work, the specific craniofacial characteristics of patients with POLR3-HLD associated with biallelic pathogenic variants in POLR3A, POLR3B and POLR1C are described. METHODS: The craniofacial features of 31 patients with POLR3-HLD were evaluated, and potential genotype-phenotype associations were evaluated. RESULTS: Various craniofacial abnormalities were recognized in this patient cohort, with each individual presenting at least one craniofacial abnormality. The most frequently identified features included a flat midface (61.3%), a smooth philtrum (58.0%) and a pointed chin (51.6%). In patients with POLR3B biallelic variants, a thin upper lip was frequent. Craniofacial anomalies involving the forehead were most commonly associated with biallelic variants in POLR3A and POLR3B while a higher proportion of patients with POLR1C biallelic variants demonstrated bitemporal narrowing. CONCLUSION: Through this study, we demonstrated that craniofacial abnormalities are common in patients with POLR3-HLD. This report describes in detail the dysmorphic features of POLR3-HLD associated with biallelic variants in POLR3A, POLR3B and POLR1C.

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.

Fatal thrombolysis-related intracerebral haemorrhage associated with amyloid-ß-related angiitis in a middle-aged patient - case report and literature review.

BACKGROUND: Amyloid-ß-related angiitis (ABRA) is a rare complication of cerebral amyloid angiopathy, characterized by amyloid-ß deposition in the leptomeningeal and cortical vessels with associated angiodestructive granulomatous inflammation. The clinical presentation is variable, including subacute cognitive decline, behavioural changes, headaches, seizures and focal neurological deficits, which may mimic other conditions. Here, we present a case with fatal thrombolysis-related haemorrhage associated with ABRA in a middle-aged patient. CASE PRESENTATION: A 55-year-old man was admitted to hospital with sudden onset left-sided cheek, arm and hand sensory loss, blurred vision, and worsening headache, with a National Institutes of Health Stroke Scale (NIHSS) score of 3. An acute CT head scan showed no contraindications, and therefore the decision was made to give intravenous thrombolysis. Post-thrombolysis, he showed rapid deterioration with visual disturbances, headache and confusion, and a repeat CT head scan confirmed several areas of intracerebral haemorrhage. No benefit from surgical intervention was expected, and the patient died four days after the first presentation. Neuropathological examination found acute ischemic infarcts of three to five days duration in the basal ganglia, insular cortex and occipital lobe, correlating with the initial clinical symptoms. There were also extensive recent intracerebral haemorrhages most likely secondary to thrombolysis. Furthermore, the histological examination revealed severe cerebral amyloid angiopathy associated with granulomatous inflammatory reaction, consistent with ABRA. CONCLUSIONS: Presentation of ABRA in a middle-aged patient highlighted the difficulties in recognition and management of this rare condition. There is emerging evidence that patients with CAA may have increased risk of fatal intracerebral haemorrhages following thrombolysis. This may be further increased by a coexisting CAA-related inflammatory vasculopathy which is potentially treatable with steroid therapy if early diagnosis is made.

Thrombus Distribution in Vaccine-induced Immune Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination.

Vaccination strategies have been at the forefront of controlling the COVID-19 pandemic. An association between vaccine-induced immune thrombotic thrombocytopenia (VITT) and one of these vaccines, the ChAdOx1 nCov-19 vaccine, is now recognized. The purpose of this study was to investigate the frequency and location of thrombosis in each vascular system using CT, MRI, and US to identify additional sites of thrombus in a United Kingdom-wide sample of patients with confirmed VITT. Thirty-two radiology centers identified through the national collaborative Radiology Academic Network for Trainees were invited from the United Kingdom; seven of these contributed to this study. All patients with confirmed VITT ¬between February 3 and May 12, 2021, who met the inclusion criteria were included. The location and extent of thrombi were evaluated using CT, MRI, and US. A total of 40 patients (median age, 41 years [IQR, 32-52]; 22 [55%] men) with confirmed vaccine-induced immune thrombotic thrombocytopenia after administration of their first ChAdOx1 nCov-19 vaccine were included. Thirty-two patients (80%) developed symptoms within the first 14 days, and eight (20%) developed symptoms within 14-28 days. Twenty-nine patients (72%) experienced neurologic symptoms and were confirmed to have cerebral venous sinus thrombosis, 12 (30%) had clinical deterioration and repeat imaging demonstrated extension of their primary thrombus, and eight (20%) died. Twenty-five of 30 patients (83%) who underwent additional imaging had occult thrombosis. In conclusion, patients with VITT are likely to have multiple sites of thrombosis, with the most frequent being cerebral venous sinus thrombosis in combination with pulmonary embolism and portomesenteric venous thrombosis. Whole-body imaging with contrast-enhanced CT can be used to identify occult thrombosis.

Atrial CARdiac Magnetic resonance imaging in patients with embolic stroke of unknown source without documented Atrial Fibrillation (CARM-AF): Study design and clinical protocol.

Background: Initiation of anticoagulation therapy in ischemic stroke patients is contingent on a clinical diagnosis of atrial fibrillation (AF). Results from previous studies suggest thromboembolic risk may predate clinical manifestations of AF. Early identification of this cohort of patients may allow early initiation of anticoagulation and reduce the risk of secondary stroke. Objective: This study aims to produce a substrate-based predictive model using cardiac magnetic resonance imaging (CMR) and baseline noninvasive electrocardiographic investigations to improve the identification of patients at risk of future thromboembolism. Methods: CARM-AF is a prospective, multicenter, observational cohort study. Ninety-two patients will be recruited following an embolic stroke of unknown source (ESUS) and undergo atrial CMR followed by insertion of an implantable loop recorder (ILR) as per routine clinical care within 3 months of index stroke. Remote ILR follow-up will be used to allocate patients to a study or control group determined by the presence or absence of AF as defined by ILR monitoring. Results: Baseline data collection, noninvasive electrocardiographic data analysis, and imaging postprocessing will be performed at the time of enrollment. Primary analysis will be performed following 12 months of continuous ILR monitoring, with interim and delayed analyses performed at 6 months and 2 and 3 years, respectively. Conclusion: The CARM-AF Study will use atrial structural and electrocardiographic metrics to identify patients with AF, or at high risk of developing AF, who may benefit from early initiation of anticoagulation.

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.

A Novel Homozygous Frameshift WDR81 Mutation associated with Microlissencephaly, Corpus Callosum Agenesis, and Pontocerebellar Hypoplasia.

Microlissencephaly is a brain malformation characterized by microcephaly and extremely simplified gyral pattern. It may be associated with corpus callosum agenesis and pontocerebellar hypoplasia. In this case report, we described two siblings, a boy and a girl, with this complex brain malformation and lack of any development. In the girl, exome sequencing of a gene set representing 4,813 genes revealed a homozygous AG deletion in exon 7 of the WDR81 gene, leading to a frameshift (c.4668_4669delAG, p.Gly1557AspfsTer16). The parents were heterozygous for this mutation. The boy died without proper genetic testing. Our findings expand the phenotypic and genotypic spectrum of WDR81 gene mutations.

Cerebral venous sinus thrombosis and thrombocytopenia after COVID-19 vaccination - A report of two UK cases.

Recent reports have highlighted rare, and sometimes fatal, cases of cerebral venous sinus thrombosis (CVST) and thrombocytopenia following the Vaxzevria vaccine. An underlying immunological mechanism similar to that of spontaneous heparin-induced thrombocytopenia (HIT) is suspected, with the identification of antibodies to platelet factor-4 (PF4), but without previous heparin exposure. This unusual mechanism has significant implications for the management approach used, which differs from usual treatment of CVST. We describe the cases of two young males, who developed severe thrombocytopenia and fatal CVST following the first dose of Vaxzevria. Both presented with a headache, with subsequent rapid neurological deterioration. One patient underwent PF4 antibody testing, which was positive. A rapid vaccination programme is essential in helping to control the COVID-19 pandemic. Hence, it is vital that such COVID-19 vaccine-associated events, which at this stage appear to be very rare, are viewed through this lens. However, some cases have proved fatal. It is critical that clinicians are alerted to the emergence of such events to facilitate appropriate management. Patients presenting with CVST features and thrombocytopenia post-vaccination should undergo PF4 antibody testing and be managed in a similar fashion to HIT, in particular avoiding heparin and platelet transfusions.

Tremor as an early sign of hereditary spastic paraplegia due to mutations in ALDH18A1.

BACKGROUND: The ALDH18A1 gene is located at 10q24.1 and encodes delta-1-pyrroline-5-carboxylate synthetase (P5CS), a mitochondrial bifunctional enzyme that catalyzes the first two steps in de novo biosynthesis of proline, ornithine, citrulline, and arginine. ALDH18A1-related disorders have been classified into four groups, such as autosomal dominant and recessive hereditary spastic paraplegia (SPG9A and SPG9B, respectively), as well as autosomal dominant and recessive cutis laxa (ADCL3 and ARCL3A, respectively). Neurodegeneration is a characteristic feature of all groups. CASE REPORT: Here, we report a girl with compound heterozygous disease-causing variants (c.-28-2A>G and c.383G>A, p.Arg128His) in the ALDH18A1 gene, revealed by whole exome sequencing. The c.-28-2A>G variant in intron 1, inherited from the mother, is a novel mutation, while the c.383G>A variant in exon 4, inherited from the father, has already been reported. The patient presented with vigorous infantile tremor preceding progressive spastic paraplegia. Dysmorphic features included elongated face, deep-set ears, upturned nose, long philtrum and pointed chin. Intrauterine and postnatal growth retardation, microcephaly, global developmental delay and profound intellectual disability were also noticed. Blood fasting ammonia level, plasma proline, ornithine and arginine levels were normal, while citrulline level was slightly decreased. Brain MRI revealed moderate hypoplasia of the corpus callosum and reduction of white matter volume. CONCLUSIONS: The patient represents SPG9B, a rare form of autosomal recessive hereditary spastic paraplegias. The early onset tremor, preceding lower limb spasticity appears to be a unique early manifestation of neurodegeneration in this case.

Cortical foot.

An 83-year-old woman presented with an acute onset of foot drop. Whilst the pattern of weakness initially appeared to be most likely due to a peripheral cause, an MR scan of the brain showed a small cortical stroke. This rare phenomenon appears similar to the more widely described 'cortical hand'.

Subacute Changes in N-Acetylaspartate (NAA) Following Ischemic Stroke: A Serial MR Spectroscopy Pilot Study.

Preservation of neuronal tissue is crucial for recovery after stroke, but studies suggest that prolonged neuronal loss occurs following acute ischaemia. This study assessed the temporal pattern of neuronal loss in subacute ischemic stroke patients using 1H magnetic resonance spectroscopy, in parallel with functional recovery at 2, 6 and 12 weeks after stroke. Specifically, we measured N-acetylaspartate (NAA), choline, myoinositol, creatine and lactate concentrations in the ipsilesional and contralesional thalamus of 15 first-ever acute ischaemic stroke patients and 15 control participants and correlated MRS concentrations with motor recovery, measured at 12 weeks using the Fugl-Meyer scale. NAA in the ipsilesional thalamus fell significantly between 2 and 12 weeks (10.0 to 7.97 mmol/L, p = 0.003), while choline, myoinositol and lactate concentrations increased (p = 0.025, p = 0.031, p = 0.001, respectively). Higher NAA concentrations in the ipsilesional thalamus at 2 and 12 weeks correlated with higher Fugl Meyer scores at 12 weeks (p = 0.004 and p = 0.006, respectively). While these results should be considered preliminary given the modest sample size, the progressive fall in NAA and late increases in choline, myoinositol and lactate may indicate progressive non-ischaemic neuronal loss, metabolically depressed neurons and/or diaschisis effects, which have a detrimental effect on motor recovery. Interventions that can potentially limit this ongoing subacute tissue damage may improve stroke recovery.

Blood pressure characteristics in patients with acute basilar artery occlusion undergoing endovascular thrombectomy.

Acute basilar artery occlusion (BAO) is a rare but potentially life-threatening neurological condition. While endovascular therapy (EVT) has been shown to improve outcome, there is limited knowledge about prognostic factors beyond early recanalization. We studied whether blood pressure (BP) exceeds or falls below suggested thresholds during intervention and whether these changes are associated with complications and outcome. BP measurements mostly with one-minute intervals were available in 39 patients. An individual systolic blood pressure (SBP) reference value was defined as the median of the first five intra-procedural measurements. Half of the patients (51.3%) received drugs for BP augmentation and two a BP lowering drug (5.1%). Thrombolysis in cerebral infarction grade 2b and 3 (TICI) was achieved in 29 (74.4%) and 23 patients (58.9%) had good outcome at three months. We observed a continuous intra-procedural increase of median SBP (+11%) and mean arterial pressure (MAP, +10%, both p < 0.001), and a unique temporal pattern of intermittent peaks and troughs. Successful recanalization was more common in patients whose intra-procedural duration with SBP under 140 mmHg was shorter (p = 0.009). Patients with isolated tip of basilar artery (TBA) occlusion had significantly more BP excursion of 20% below the reference SBP and required more frequent use of sympathomimetic drugs compared to vertebrobasilar occlusion (p = 0.008 and p = 0.041, respectively). Brain hemorrhage was more prevalent in patients who experienced SBP excursions at least 20% above the individual reference value (p = 0.038) and a longer duration of time spent with SBP above 180 mmHg (p = 0.029). Patients with higher pre-procedural mean SBP had a greater chance of a good outcome (p = 0.03). This study using high resolution BP monitoring suggests a relationship between intra-procedural BP characteristics and recanalization, hemorrhagic complications and outcome in patients receiving EVT for acute posterior circulation cerebrovascular syndromes. Differences with regard to BP regulation during recanalization therapy for vertebrobasilar and TBA occlusion deserves further attention.

Early prolonged ambulatory cardiac monitoring in stroke (EPACS): an open-label randomised controlled trial.

BACKGROUND: Cardioembolism in paroxysmal atrial fibrillation (PAF) is a preventable cause of transient ischaemic attack (TIA) or ischaemic stroke; however, due to its transient nature, a short-duration Holter monitor may miss a significant proportion of events. METHODS: We conducted an open-label randomised controlled trial of cardiac monitoring after a TIA or ischaemic stroke comparing a 14-day ECG monitoring patch (Zio® Patch, iRhythm Technologies) with short-duration Holter monitoring for the detection of PAF. The primary outcome was the detection of one or more episodes of ECG-documented PAF lasting at least 30 s within 90 days in each of the study arms. A budget impact analysis from the healthcare perspective was performed. RESULTS: From February 2016 through February 2017, 43 (76.8%) of the 56 patients assigned to the patch-based monitoring group and 47 (78.3%) of the 60 patients assigned to short-duration Holter monitoring group had successful monitor placement with 90 days of follow-up. Of the 26 protocol failures between the two groups, 23 (88.5%) were due to patient refusal for outpatient short-duration ECG monitor placement, whilst only 1 (3.8%) was due unsuccessful ZioPatch placement. The rate of detection of PAF at 90 days was 16.3% in the patch-based monitoring group (seven patients) compared to 2.1% in the short-duration Holter monitoring group (1 patient), with an odds ratio of 8.9 (95% CI 1.1-76.0; P = 0.026). An economic model demonstrated that implementation of the Zio Patch service would result in 10.8 more strokes avoided per year compared to current practice with Holter monitoring with an associated yearly saving in direct medical costs of £113,630, increasing to £162,491 over 5 years. CONCLUSIONS: Early, prolonged, patch-based monitoring after an index stroke or TIA is superior to short-duration Holter monitoring in the detection of PAF and likely cost-effective for preventing recurrent strokes. Trial registration http://www.isrctn.com. Unique identifier: ISRCTN 50253271. Registered 21 January 2016.