RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an inherited late-onset neurological disease caused by bi-allelic AAGGG pentanucleotide expansions within intron 2 of RFC1. Despite extensive studies, the pathophysiological mechanism of these intronic expansions remains elusive. We screened by clinical exome sequencing two unrelated patients presenting with late-onset ataxia. A repeat-primer polymerase chain reaction was used for RFC1 AAGGG intronic expansion identification. RFC1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction. We identified the first two CANVAS affected patients who are compound heterozygous for RFC1 truncating variants (p.Arg388* and c.575delA, respectively) and a pathological AAGGG expansion. RFC1 expression studies in whole blood showed a significant reduction of RFC1 mRNA for both patients compared to three patients with bi-allelic RFC1 expansions. In conclusion, this observation provides clues that suggest bi-allelic RFC1 conditional loss-of-function as the cause of the disease.

Predictors of Unexplained Early Neurological Deterioration After Endovascular Treatment for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Although the efficacy of endovascular treatment (EVT) in patients with anterior circulation ischemic stroke (AIS) is well documented, early neurological deterioration after EVT remains a serious issue associated with poor outcome. Besides obvious causes, such as lack of reperfusion, procedural complications, or parenchymal hemorrhage, early neurological deterioration may remain unexplained (UnEND). Our aim was to investigate predictors of UnEND after EVT in patients with AIS. METHODS: Patients who underwent EVT for AIS, with an initial National Institutes of Health Stroke Scale score >5, Alberta Stroke Program Early CT Score ≥6, and included in a multicenter prospective observational registry were analyzed. Predictors of UnEND, defined as ≥4-point increase in the National Institutes of Health Stroke Scale score between baseline and day 1 after EVT, were determined via center-adjusted analyses. RESULTS: Among the 1925 included in the analysis, 128 UnEND (6.6%) were recorded. In multivariate analysis, predictors of UnEND were diabetes mellitus (odds ratio [OR], 2.17 [95% CI, 1.32-3.56]), prestroke modified Rankin Scale score ≥2 (OR, 2.22 [95% CI, 1.09-4.55]), general anesthesia (OR, 2.55 [95% CI, 1.51-4.30]), admission systolic blood pressure (OR, 1.10 [95% CI, 1.01-1.20]), age (OR, 1.38 [95% CI, 1.14-1.67]), number of passes (OR, 1.16 [95% CI, 1.04-1.28]), direct admission or not to a comprehensive stroke center (OR, 0.49 [95% CI, 0.30-0.81]), and initial National Institutes of Health Stroke Scale score (OR, 0.65 [95% CI, 0.52-0.81]). CONCLUSIONS: Severely impaired AIS patients with nonmodifiable factors are more likely to develop UnEND. Some modifiable predictors of UnEND such as the number of EVT passes could be the object of improvement in AIS management.

Accelerated MR Evaluation of Patients with Suspected Large Arterial Vessel Occlusion: Diagnostic Performances of the FLAIR Vessel Hyperintensities.

BACKGROUND: Fluid attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) document slowed vascular flow at the level and after the occlusion site patients with acute ischemic stroke (AIS). We aimed to assess the accuracy of FVH for the confirmation and location of a large vessel occlusion (LVO). METHODS: Three radiologists reviewed the FLAIR sequence of the admission MRI exam of patients with suspected AIS at a single academic center. Readers were provided with the main clinical deficit with National Institute of Health Stroke Severity score and were asked to identify and locate an LVO when appropriate. Kappa coefficients were calculated for agreement along with diagnosis performances of FVH to recognize and locate an LVO with digital subtracted angiography (DSA) as gold standard. RESULTS: Among 125 patients screened with MRI for a suspected AIS, 96 (81%) were diagnosed with AIS and 47 (38%) patients had an anterior LVO of whom 25 (20%) had a DSA for mechanical thrombectomy. Kappa coefficients for intra- and inter-readers were good to excellent. Overall, the sensitivity and the specificity of the FVH to predict an anterior LVO was 0.98 (95% confidence interval [CI]: 0.94-1) and 0.86 (95% CI: 0.79-0.96), respectively, while PPV and NPV were 0.87 (95% CI: 0.85-0.95) and 0.98 (0.97-1), respectively. FVH also showed good to excellent accuracy for identifying M1 and M2 versus internal carotid artery occlusion site. CONCLUSION: We found that FVH demonstrated excellent diagnostic performances for the identification of LVO and its level with good to excellent reproducibility. This MRI radio marker of occlusion provides additional arguments and may speed-up the detection of potential candidates for MT.

Cytomegalovirus encephalitis: Undescribed diffusion-weighted imaging characteristics. Original aspects of cases extracted from a retrospective study, and from literature review.

INTRODUCTION: There is paucity of studies analyzing DWI in MRI sequences when imaging cytomegalovirus (CMV) meningoencephalitis. The main objective of this study is to demonstrate that DWI sequence is mandatory when imaging immunocompromised patients presenting with encephalitic symptoms, as this sequence can reveal very peculiar lesions in the setting of CMV encephalitis. PATIENTS AND METHOD: Three CSF PCR CMV positive cases were identified in a 13-year retrospective study with MRI scans including T1, FLAIR, DWI with automated ADC calculation, and T1 with contrast injection, and were reviewed by a senior neuroradiologist. RESULTS: Our three cases presented multiple high-signal intensity punctiform lesions in DWI, which uniformly were in restricted diffusion. Each patient had multiple lesions (mean 19.3, range 12-30): 96.5% were supratentorial and 3.5% were infratentorial. Among supratentorial lesions, 62.5% were subependymal, 28.6% were periventricular and 8.9% were subcortical. Some lesions remained in a long lasting restricted diffusion state. All cases had FLAIR curvilinear periventricular high signal intensities. No contrast uptake was found. DISCUSSION: Punctiform DWI lesions had a clear ventricle wall tropism, consistent with classical autopsy findings. The classical histological knowledge-compatible explanation for long lasting diffusion restriction is non-lethal cytotoxic edema owing to CMV inclusions. CONCLUSION: Subependymal and periventricular punctiform restricted diffusion lesions in the setting of meningoencephalitis in immunocompromised patients seem highly evocative of CMV encephalitis. The diffusion sequence probably reveals focal lesions constitutive of cellular viral inclusions.

A new endovascular technique for small anterior choroidal artery aneurysms. A consecutive series using the 3-catheter-protective technique.

INTRODUCTION: Endovascular treatment of small anterior choroidal artery (AChA) aneurysms can be challenging, especially if the AChA arises from the sac. Preserving its patency during embolization is as important as obliterating the aneurysm. We describe a variant of the "protective microcatheter technique" (PMT) in a series of six patients with AChA aneurysms where the AChA emerged from the sac. METHODS: Three different microcatheters (KT) were used. The first microcatheter was placed in the AChA to protect it. A remodeling balloon-catheter was then positioned in the internal carotid artery to stabilize the coils during embolization and to control a potential rupture. The third microcatheter was finally used to coil the aneurysm. RESULTS: Mean sac size of anterior choroidal artery aneurysms was 2×2×2mm. All aneurysms were successfully occluded. There was neither ischemic complication nor ruptured aneurysm during endovascular treatment. A final angiogram demonstrated AChA patency in all cases. CONCLUSION: The 3KT-PMT for AChA aneurysms appears to be safe and effective to prevent AChA occlusion during aneurysm coiling, especially when the AChA arises from the sac.

Optimization of cerebral oxygenation based on regional cerebral oxygen saturation monitoring during carotid endarterectomy: a Phase III multicenter, double-blind randomized controlled trial.

BACKGROUND: Whether the optimization of cerebral oxygenation based on regional cerebral oxygen saturation (rSO2) monitoring reduces the occurrence of cerebral ischemic lesions is unknown. METHODS: This multicenter, randomized, controlled trial recruited adults admitted for scheduled carotid endarterectomy. Patients were randomized between the standard of care or optimization of cerebral oxygenation based on rSO2 monitoring using near-infrared spectroscopy. In the intervention group, in case of a decrease in rSO2 in the intervention, the following treatments were sequentially recommended: (1) increasing oxygenotherapy, (2) reducing the tidal volume, (3) legs up-raising, (4) performing a fluid challenge and (5) initiating vasopressor support. The primary endpoint was the number of new cerebral ischemic lesions detected using magnetic resonance imaging pre- and postoperatively. Secondary endpoints included new neurological deficits and mortality on day 120 after surgery. RESULTS: Among the 879 patients who were randomized, 665 (75.7%) were men. There was no statistically significant difference between groups for the mean number of new cerebral ischemic lesions per patient up to 3 days after surgery: 0.35 (±1.05) in the standard group vs. 0.58 (±2.83), in the NIRS group; mean difference, 0.23 [95% CI, -0.06 to 0.52]; estimate, 0.22 [95% CI, -0.06 to 0.50]. New neurological deficits up to day 120 after hospital discharge were not different between the groups: 15 (3,39%) in the standard group vs. 42 (5,49%) in the NIRS group; absolute difference, 2,10 [95% CI, -0,62 to 4,82]. There was no significant difference between groups for the median [IQR] hospital length of stay: 4.0 [4.0-6.0] in the standard group vs. 5.0 [4.0-6.0] in the NIRS group; mean difference, -0.11 [95% CI, -0.65 to 0.44]. The mortality rate on day 120 was not different between the standard group (0.68%) vs. the NIRS group (0.92%); absolute difference = 0.24% [95% CI, -0.94 to 1.41]. CONCLUSIONS: Among patients undergoing carotid endarterectomy, optimization of cerebral oxygenation based on rSO2 did not reduce the occurrence of cerebral ischemic lesions postoperatively compared with controlled hypertensive therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01415648.

Longitudinal radiological follow-up of individual level non-ischemic cerebral enhancing lesions following endovascular aneurysm treatment.

BACKGROUND: Non-ischemic cerebral enhancing (NICE) lesions following aneurysm endovascular therapy are exceptionally rare, with unknown longitudinal evolution. OBJECTIVE: To evaluate the radiological behavior of individual NICE lesions over time. METHODS: Patients included in a retrospective national multicentric inception cohort were analyzed. NICE lesions were defined, using MRI, as delayed onset punctate, nodular, or annular foci enhancements with peri-lesion edema, distributed in the vascular territory of the aneurysm treatment, with no other confounding disease. Lesion burden and the longitudinal behavior of individual lesions were assessed. RESULTS: Twenty-two patients were included, with a median initial lesion burden of 36 (IQR 17-54) on the first MRI scan. Of the 22 patients with at least one follow-up MRI scan, 16 (73%) had new lesions occurring mainly within the first 200 weeks after the date of the procedure. The median number of new lesions per MRI was 6 (IQR 2-16). Among the same 22 patients, 7 (32%) had recurrent lesions. The median persistent enhancement of a NICE lesion was 13 weeks (IQR 6-30). No factor was predictive of early regression of enhancement activity with lesion regression kinetics mainly being patient-dependent. CONCLUSIONS: The behavior of individual NICE lesions was found to be highly variable with an overall patient-dependent regression velocity.

Non-ischemic cerebral enhancing lesions after intracranial aneurysm endovascular repair: a retrospective French national registry.

BACKGROUND: Non-ischemic cerebral enhancing (NICE) lesions are exceptionally rare following aneurysm endovascular therapy (EVT). OBJECTIVE: To investigate the presenting features and longitudinal follow-up of patients with NICE lesions following aneurysm EVT. METHODS: Patients included in a retrospective national multicentre inception cohort were analysed. NICE lesions were defined, using MRI, as delayed onset punctate, nodular or annular foci enhancements with peri-lesion edema, distributed in the vascular territory of the aneurysm EVT, with no other confounding disease. RESULTS: From a pool of 58 815 aneurysm endovascular treatment procedures during the study sampling period (2006-2019), 21/37 centres identified 31 patients with 32 aneurysms of the anterior circulation who developed NICE lesions (mean age 45±10 years). Mean delay to diagnosis was 5±9 months, with onset occurring a month or less after the index EVT procedure in 10 out of 31 patients (32%). NICE lesions were symptomatic at time of onset in 23 of 31 patients (74%). After a mean follow-up of 25±26 months, 25 patients (81%) were asymptomatic or minimally symptomatic without disability (modified Rankin Scale (mRS) score 0-1) at last follow-up while 4 (13%) presented with mild disability (mRS score 2). Clinical follow-up data were unavailable for two patients. Follow-up MRI (available in 27 patients; mean time interval after onset of 22±22 months) demonstrated persistent enhancement in 71% of cases. CONCLUSIONS: The clinical spectrum of NICE lesions following aneurysm EVT therapy spans a wide range of neurological symptoms. Clinical course is most commonly benign, although persistent long-term enhancement is frequent.

Is there an inherited anatomical conformation favoring aneurysmal formation of the anterior communicating artery?

OBJECTIVE The pathophysiological mechanisms responsible for the formation of intracranial aneurysms (IAs) remain only partially elucidated. However, current evidence suggests a genetic component. The purpose of this study was to investigate the specific anatomical variations in the arterial complex that are associated with the presence of anterior communicating artery (ACoA) aneurysms in the familial forms of IAs. METHODS This multicenter study investigated bifurcation IAs in patients who had a sporadic ACoA IA without a family history of IA (SACAA group), in patients who had an ACoA IA with a family history of IA (FACAA group), and in their healthy first-degree relatives (HFDRs). Through the use of MR angiography (MRA) reconstructions, the symmetry of the A1 segments and the angle between the A1 and A2 segments were analyzed on 3D models for each group. These measurements were then compared among the 3 groups. RESULTS Twenty-four patients with SACAA, 24 patients with FACAA, and 20 HFDRs were included in the study. Asymmetrical configuration of the A1 segments was more frequent in the FACAA group than in the HFDR group (p = 0.002). The aneurysm-side A1-A2 angle was lower in the FACAA group (p = 0.003) and SACAA group (p = 0.007) than in the HFDR group. On the contralateral side, there was no difference in A1-A2 angles between groups. CONCLUSIONS The anatomical shape of the ACoA complex seems to be similarly associated with the presence of ACoA IAs in both the FACAA and SACAA groups. This highlights the role played by hemodynamic constraints in aneurysm formation and questions the hypothesis of the hereditary character of these anatomical shapes.

Mechanical thrombectomy with the ERIC retrieval device: initial experience.

OBJECTIVE: To report our experience with the Embolus Retriever with Interlinked Cage (ERIC) stentriever for use in mechanical endovascular thrombectomy (MET). METHODS: Thirty-four consecutive patients with acute stroke (21 men and 13 women; median age 66 years) determined appropriate for MET were treated with ERIC and prospectively included over a 6-month period at three different centers. The ERIC device differs from typical stentrievers in that it is designed with a series of interlinked adjustable nitinol cages that allow for fast thrombus capture, integration, and withdrawal. The evaluated endpoints were successful revascularization (Thrombolysis in Cerebral Infarction (TICI) 2b-3) and good clinical outcomes at 3 months (modified Rankin Scale (mRS) 0-2). RESULTS: Locations of the occlusions included the middle cerebral artery (13 patients), terminal carotid artery (11 patients), basilar artery (1 patient), and tandem occlusions (9 patients). IV thrombolysis was performed in 20/34 (58.8%) patients. Median times from symptom onset to recanalization and from puncture to recanalization were 325.5 min (180-557) and 78.5 min (14-183), respectively. Used as the first-line device, ERIC achieved a successful recanalization in 20/24 (83.3%) patients. Successful recanalization was associated with lower National Institutes of Health Stroke Scale scores at 24 h (8±6.5 vs 21.5±2.1; p=0.008) and lower mRS at 3 months (2.7±2.1 vs 5.3±1.1; p=0.04). Three procedural complications and four asymptomatic hemorrhages were recorded. Good clinical outcomes at 3 months were seen in 15/31 (48.4%) patients. CONCLUSIONS: The ERIC device is an innovative stentriever allowing fast, effective, and safe MET.

Understanding the Pathophysiology of Intracranial Aneurysm: The ICAN Project.

BACKGROUND: Understanding the pathophysiologic mechanism of intracranial aneurysm (IA) formation is a prerequisite to assess the potential risk of rupture. Nowadays, there are neither reliable biomarkers nor diagnostic tools to predict the formation or the evolution of IA. Increasing evidence suggests a genetic component of IA but genetics studies have failed to identify genetic variation causally related to IA. OBJECTIVE: To develop diagnostic and predictive tools for the risk of IA formation and rupture. METHODS: The French ICAN project is a noninterventional nationwide and multicentric research program. Each typical IA of bifurcation will be included. For familial forms, further IA screening will be applied among first-degree relatives. By accurate phenotype description with high-throughput genetic screening, we aim to identify new genes involved in IA. These potential genetic markers will be tested in large groups of patients. Any relevant pathway identified will be further explored in a large cohort of sporadic carriers of IA, which will be well documented with clinical, biological, and imaging data. EXPECTED OUTCOMES: Discovering genetic risk factors, better understanding the pathophysiology, and identifying molecular mechanisms responsible for IA formation will be essential bases for the development of biomarkers and identification of therapeutic targets. DISCUSSION: Our protocol has many assets. A nationwide recruitment allows for the inclusion of large pedigrees with familial forms of IA. It will combine accurate phenotyping and comprehensive imaging with high-throughput genetic screening. Last, it will enable exploiting metadata to explore new pathophysiological pathways of interest by crossing clinical, genetic, biological, and imaging information.