Regional hippocampal atrophy reflects memory impairment in patients with early relapsing remitting multiple sclerosis.

BACKGROUND: Research work has shown that hippocampal subfields are atrophic to varying extents in multiple sclerosis (MS) patients. However, studies examining the functional implications of subfield-specific hippocampal damage in early MS are limited. We aim to gain insights into the relationship between hippocampal atrophy and memory function by investigating the correlation between global and regional hippocampal atrophy and memory performance in early MS patients. METHODS: From the Italian Neuroimaging Network Initiative (INNI) dataset, we selected 3D-T1-weighted brain MRIs of 219 early relapsing remitting (RR)MS and 246 healthy controls (HC) to identify hippocampal atrophic areas. At the time of MRI, patients underwent Selective-Reminding-Test (SRT) and Spatial-Recall-Test (SPART) and were classified as mildly (MMI-MS: n.110) or severely (SMI-MS: n:109) memory impaired, according to recently proposed cognitive phenotypes. RESULTS: Early RRMS showed lower hippocampal volumes compared to HC (p < 0.001), while these did not differ between MMI-MS and SMI-MS. In MMI-MS, lower hippocampal volumes correlated with worse memory tests (r = 0.23-0.37, p ≤ 0.01). Atrophic voxels were diffuse in the hippocampus but more prevalent in cornu ammonis (CA, 79%) than in tail (21%). In MMI-MS, decreased subfield volumes correlated with decreases in memory, particularly in the right CA1 (SRT-recall: r = 0.38; SPART: r = 0.34, p < 0.01). No correlations were found in the SMI-MS group. CONCLUSION: Hippocampal atrophy spreads from CA to tail from early disease stages. Subfield hippocampal atrophy is associated with memory impairment in MMI-MS, while this correlation is lost in SMI-MS. This plays in favor of a limited capacity for an adaptive functional reorganization of the hippocampi in MS patients.

Familial Alzheimer's disease associated with heterozygous NPC1 mutation.

INTRODUCTION: NPC1 mutations are responsible for Niemann-Pick disease type C (NPC), a rare autosomal recessive neurodegenerative disease. Patients harbouring heterozygous NPC1 mutations may rarely show parkinsonism or dementia. Here, we describe for the first time a large family with an apparently autosomal dominant late-onset Alzheimer's disease (AD) harbouring a novel heterozygous NPC1 mutation. METHODS: All the five living siblings belonging to the family were evaluated. We performed clinical evaluation, neuropsychological tests, assessment of cerebrospinal fluid markers of amyloid deposition, tau pathology and neurodegeneration (ATN), structural neuroimaging and brain amyloid-positron emission tomography. Oxysterol serum levels were also tested. A wide next-generation sequencing panel of genes associated with neurodegenerative diseases and a whole exome sequencing analysis were performed. RESULTS: We detected the novel heterozygous c.3034G>T (p.Gly1012Cys) mutation in NPC1, shared by all the siblings. No other point mutations or deletions in NPC1 or NPC2 were found. In four siblings, a diagnosis of late-onset AD was defined according to clinical characterisation and ATN biomarkers (A+, T+, N+) and serum oxysterol analysis showed increased 7-ketocholesterol and cholestane-3ß,5α,6ß-triol. DISCUSSION: We describe a novel NPC1 heterozygous mutation harboured by different members of a family with autosomal dominant late-onset amnesic AD without NPC-associated features. A missense mutation in homozygous state in the same aminoacidic position has been previously reported in a patient with NPC with severe phenotype. The alteration of serum oxysterols in our family corroborates the pathogenic role of our NPC1 mutation. Our work, illustrating clinical and biochemical disease hallmarks associated with NPC1 heterozygosity in patients affected by AD, provides relevant insights into the pathogenetic mechanisms underlying this possible novel association.

A Putative Role of Teneurin-2 and Its Related Proteins in Astrocytes.

Teneurins are type II transmembrane proteins comprised of four phylogenetically conserved homologs (Ten-1-4) that are highly expressed during neurogenesis. An additional bioactive peptide named teneurin C-terminal-associated peptide (TCAP-1-4) is present at the carboxyl terminal of teneurins. The possible correlation between the Ten/TCAP system and brain injuries has not been explored yet. Thus, this study examined the expression of these proteins in the cerebral cortex after mechanical brain injury. Adult rats were subjected to cerebral cortex injury by needle-insertion lesion and sacrificed at various time points. This was followed by analysis of the lesion area by immunohistochemistry and conventional RT-PCR techniques. Control animals (no brain injury) showed only discrete Ten-2-like immunoreactive pyramidal neurons in the cerebral cortex. In contrast, Ten-2 immunoreactivity was significantly up-regulated in the reactive astrocytes in all brain-injured groups (p < 0.0001) when compared to the control group. Interestingly, reactive astrocytes also showed intense immunoreactivity to LPHN-1, an endogenous receptor for the Ten-2 splice variant named Lasso. Semi-quantitative analysis of Ten-2 and TCAP-2 expression revealed significant increases of both at 48 h, 3 days and 5 days (p < 0.0001) after brain injury compared to the remaining groups. Immortalized cerebellar astrocytes were also evaluated for Ten/TCAP expression and intracellular calcium signaling by fluorescence microscopy after TCAP-1 treatment. Immortalized astrocytes expressed additional Ten/TCAP homologs and exhibited significant increases in intracellular calcium concentrations after TCAP-1 treatment. This study is the first to demonstrate that Ten-2/TCAP-2 and LPHN-1 are upregulated in reactive astrocytes after a mechanical brain injury. Immortalized cerebellar astrocytes expressed Ten/TCAP homologs and TCAP-1 treatment stimulated intracellular calcium signaling. These findings disclose a new functional role of the Ten/TCAP system in astrocytes during tissue repair of the CNS.

Pre-Procedural Statin Use Is Associated with Improved Long-Term Survival and Reduced Major Cardiovascular Events in Patients Undergoing Carotid Artery Stenting: A Retrospective Study.

Carotid artery stenting (CAS) is a minimal invasive procedure used to resolve carotid occlusion that can be affected by peri-procedural complications. Statin use before CAS has shown to reduce peri-procedural risk and improve survival, though time-dependent cofactors that influence mortality has not been considered. The aim of this study was to evaluate long-term survival of patients who undergo CAS considering new occurred major adverse cardiovascular event (MACE) as time-dependent cofactor. In this study, 171 high cardiovascular risk patients (age 72 ± 8 years, 125 males) were enrolled after CAS procedure and were followed for a median of 8.4 years. Death occurred in 44% of patients with a mean time to death of 69 ± 39 months and MACE in 34% with a mean time of 35 ± 42 months. In patients who used or not statins at baseline, death occurred in 33% and 65%, respectively (p < 0.001). Survival analysis showed that statin use reduced risk of death (hazard ratio HR 0.36, 95% confidence interval CI 0.23⁻0.58, p < 0.0001). Including MACE as time-dependent variable did not change beneficial effects of statins. Additionally, statin use was associated with a protective effect on MACE (HR 0.48, 95% CI 0.27⁻0.85, p = 0.012); particularly, the prevalence of stroke was reduced by 59% (p = 0.018). In multivariate analysis, effects of statins were independent of demographic and anthropometric variables, prevalence of cardiovascular risk factors, renal function, antiplatelet use, and MACE occurrence. In conclusion, use of statins before CAS procedure is associated with increased long-term survival and reduced MACE occurrence. This evidence supports the hypothesis that statin use before CAS might be beneficial in high risk patients.

Radioembolisation in patients with hepatocellular carcinoma that have previously received liver-directed therapies.

PURPOSE: Radioembolisation is part of the multimodal treatment of hepatocellular carcinoma (HCC) at specialist liver centres. This study analysed the impact of prior treatment on tolerability and survival following radioembolisation. METHODS: This was a retrospective analysis of 325 consecutive patients with a confirmed diagnosis of HCC, who received radioembolisation with yttrium-90 resin microspheres at eight European centres between September 2003 and December 2009. The decision to treat was based on the clinical judgement of multidisciplinary teams. Patients were followed from the date of radioembolisation to last contact or death and the nature and severity of all adverse events (AEs) recorded from medical records. RESULTS: Most radioembolisation candidates were Child-Pugh class A (82.5%) with multinodular HCC (75.9%) invading both lobes (53.1%); 56.3% were advanced stage. Radioembolisation was used first-line in 57.5% of patients and second-line in 34.2%. Common prior procedures were transarterial (chemo)embolisation therapies (27.1%), surgical resection/transplantation (17.2%) and ablation (8.6%). There was no difference in AE incidence and severity between prior treatment subgroups. Median (95% confidence interval [CI]) survival following radioembolisation was similar between procedure-naive and prior treatment groups for Barcelona Clinic Liver Cancer (BCLC) stage A: 22.1 months (15.1-45.9) versus 30.9 months (19.6-46.8); p = 0.243); stage B: 18.4 months (11.2-19.4) versus 22.8 months (10.9-34.2); p = 0.815; and stage C: 8.8 months (7.1-10.8) versus 10.8 months (7.7-12.6); p = 0.976. CONCLUSIONS: Radioembolisation is a valuable treatment option for patients who relapse following surgical, ablative or vascular procedures and remain suitable candidates for this treatment.

The PROTAGORAS study to evaluate the performance of the Endurant stent graft for patients with pararenal pathologic processes treated by the chimney/snorkel endovascular technique.

OBJECTIVE: The chimney/snorkel endovascular aortic repair (ch-EVAR) is gaining ever-greater acceptance in the treatment of pararenal pathologic processes. However, the published experience includes mainly short-term clinical results with combinations of several abdominal devices and types of chimney grafts. The aim of this study was the midterm evaluation of the Endurant stent graft (Medtronic, Santa Rosa, Calif) as a standard abdominal device for ch-EVAR. METHODS: Between January 2009 and January 2013, prospectively collected data of high-risk patients with pararenal pathologic processes who underwent ch-EVAR with placement of the Endurant abdominal device were analyzed. The chimney graft intended for use was a balloon-expandable covered stent. Main outcome measures were aneurysm sac regression and chimney graft patency. RESULTS: A total of 187 snorkel/chimney grafts were successfully placed in 128 patients (mean age, 76.6 years). The technical success was 100%. The mean preoperative proximal neck length and aneurysm size were 4.7 mm and 64.8 mm (range, 48-135 mm), respectively. The postoperative new neck length after use of chimney grafts was 18.7 ± 6.3 mm. The mean aneurysm sac decreased significantly (60.8 mm; 95% confidence interval, 2.036-7.084; P = .001) after a mean radiologic follow up of 24.6 ± 17.4 months. Thirty-day mortality and midterm mortality were 0.8% and 17.2%, respectively. Two patients (1.6%) with single chimneys presented with late new onset of type Ia endoleak and underwent additional tube and multiple chimney placement. Primary chimney graft patency was 95.7%. Freedom from chimney graft-related reinterventions was 93.1%. CONCLUSIONS: Standard use of the Endurant abdominal device for ch-EVAR in >120 patients is associated with high technical success, significant aneurysm sac regression, and low incidence of secondary procedures after 2-year radiologic follow-up. These results will give significant impetus to device selection, facilitating the standardization of technique.

Drug-coated balloon dilation before carotid artery stenting of post-carotid endarterectomy restenosis.

PURPOSE: To investigate if drug-coated balloon (DCB) predilation may improve the efficacy of carotid artery stenting (CAS) for restenosis after carotid endarterectomy (CEA). METHODS: Eighteen consecutive patients (11 men; median age 75 years) with significant restenosis within 24 months of CEA were treated with a paclitaxel-coated DCB prior to CAS. Clinical outcomes and stent patency were systematically appraised. RESULTS: All patients were successfully treated according to this clinical protocol. The only complication occurred in a patient who had a transient ischemic attack during prolonged DCB inflation. At a median follow-up of 18 months, no >50% restenosis was observed on duplex ultrasound scans; however, moderate hyperplasia at the proximal stent edge was found in 4 patients. One patient died at 9 months from a myocardial infarction. CONCLUSION: Despite the small sample size and in keeping with the historically high risk of recurrent restenosis after CAS for CEA restenosis, this case series suggests that DCB dilation followed by CAS for postsurgical restenosis is feasible, safe, and may be associated with favorable clinical outcomes at midterm follow-up.

Comparison of the survival and tolerability of radioembolization in elderly vs. younger patients with unresectable hepatocellular carcinoma.

BACKGROUND & AIMS: The European Network on Radioembolization with Yttrium-90 resin microspheres study group (ENRY) conducted a retrospective study to evaluate the outcomes among elderly (≥ 70 years) and younger patients (<70 years) with unresectable hepatocellular carcinoma (HCC) who received radioembolization at 8 European centers. METHODS: Patients with confirmed diagnosis of unresectable HCC who either progressed following resection or locoregional treatment and/or who were considered poor candidates for chemoembolization were evaluated by a multidisciplinary team for radioembolization with (90)Y-resin microspheres (SIR-Spheres; Sirtex Medical). The survival outcome and all adverse events were compared between the two age groups. RESULTS: Between 2003 and 2009, 128 elderly and 197 younger patients received radioembolization. Patients in both groups had similar demographic characteristics. Many elderly and younger patients alike had multinodular, BCLC stage C disease, invading both lobes (p = 0.648). Elderly patients had a lower tumor burden, a smaller median target liver volume (p = 0.016) and appeared more likely to receive segmental treatment (p = 0.054). Radioembolization was equally well tolerated in both cohorts and common procedure-related adverse events were predominantly grade 1-2 and of short duration. No significant differences in survival between the groups were found (p = 0.942) with similar median survival in patients with early, intermediate or advanced BCLC stage disease. CONCLUSIONS: Radioembolization appears to be as well-tolerated and effective for the elderly as it is for younger patients with unresectable HCC. Age alone should not be a discriminating factor for the management of HCC patients.

Infarct-like acute myocarditis: relation between electrocardiographic findings and myocardial damage as assessed by cardiac magnetic resonance imaging.

BACKGROUND: Acute myocarditis (AM) may occasionally have an infarct-like presentation. The aim of the present study was to investigate the relation between electrocardiographic (ECG) findings in this group of patients and myocardial damage assessed by cardiac magnetic resonance imaging (MRI) with the late gadolinium enhancement (LGE) technique. HYPOTHESIS: Myocardial damage may be associated with ECG changes in infarct-like AM. METHODS: Forty-one consecutive patients (36 males; mean age, 36 ± 12 years) with diagnosis of AM according to cardiac MRI Lake Louise criteria and infarct-like presentation were included. The relation between site of ST-segment elevation (STE), sum of STE (sumSTE), time to normalization of STE, and development of negative T wave with the extent of LGE (expressed as % of left ventricular mass [%LV LGE]), was evaluated. RESULTS: Most (80%) patients presented with inferolateral STE; mean sumSTE was 5 ± 3 mm. Normalization of STE occurred within 24 hours in 20 (49%) patients. Development of negative T wave occurred in 28 (68%) patients. Cardiac MRI showed LGE in all patients; mean %LV LGE was 9.6 ± 7.2%. Topographic agreement between site of STE and LGE was 68%. At multivariate analysis, sumSTE (ß = 0.42, P < 0.001), normalization of STE >24 hours (ß = 0.39, P < 0.001), and development of negative T wave (ß = 0.49, P < 0.001) were independently related to %LV LGE. CONCLUSIONS: Analysis of the site of STE underestimates the extent of myocardial injury among patients with infarct-like myocarditis. However, some ECG features (ie, sumSTE, normalization of STE >24 hours, and development of negative T wave) may help to identify patients with larger areas of myocardial damage.

Biventricular non-compaction demonstrated on multi-slice computed tomography with echocardiographic correlation.

Left ventricular non-compaction (LVNC) is a myocardial disorder characterized by prominent trabeculations and deep intertrabecular recesses within the left ventricular wall. Multi-slice computed tomography (CT) might represent a valid non-invasive imaging technique for the diagnostic work-up of these patients, being able to visualize the compacted and non-compacted layers and to simultaneously rule out the presence of associated coronary artery disease and congenital heart disease. In the present report, the CT features of LVNC are described.

Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis.

BACKGROUND: There is no established management algorithm for portal vein thrombosis (PVT) in cirrhotic patients. The aim of our study was to prospectively evaluate anticoagulation and transjugular intrahepatic portosystemic shunt (TIPS) to treat PVT. METHODS: Cirrhotics with non-malignant PVT were included. Low weight molecular heparin anticoagulation was considered in all; TIPS was indicated if thrombosis progressed or anticoagulation was contraindicated. Patients who were not anticoagulated nor received TIPS served as controls. RESULTS: Fifty-six patients (of whom 21 controls) were included. PVT was occlusive in 11/35, with extension to the superior mesenteric or splenic vein in 13/35. In the study group 33 patients were anticoagulated, with a recanalization rate of 36% (12/33) compared with 1/21 among controls. A time interval between appearance of thrombosis and anticoagulation < 6 months predicted chance of repermeation. Thrombus progression occurred in 15/21 non anticoagulated patients and in 5/33 anticoagulated patients (P < 0.001). TIPS was placed in six patients. There were five variceal bleedings and two intestinal venous ischaemia episodes in the control group, compared with one variceal bleeding episode in the study group. CONCLUSIONS: In cirrhotics with PVT, a treatment algorithm using anticoagulation and TIPS achieves a good chance of complete repermeation, reduces portal hypertensive complications, and decreases the rate of thrombosis progression.

Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation.

UNLABELLED: A multicenter analysis was conducted to evaluate the main prognostic factors driving survival after radioembolization using yttrium-90-labeled resin microspheres in patients with hepatocellular carcinoma at eight European centers. In total, 325 patients received a median activity of 1.6 GBq between September 2003 and December 2009, predominantly as whole-liver (45.2%) or right-lobe (38.5%) infusions. Typically, patients were Child-Pugh class A (82.5%), had underlying cirrhosis (78.5%), and had good Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 0-1; 87.7%), but many had multinodular disease (75.9%) invading both lobes (53.1%) and/or portal vein occlusion (13.5% branch; 9.8% main). Over half had advanced Barcelona Clinic Liver Cancer (BCLC) staging (BCLC C, 56.3%) and one-quarter had intermediate staging (BCLC B, 26.8%). The median overall survival was 12.8 months (95% confidence interval, 10.9-15.7), which varied significantly by disease stage (BCLC A, 24.4 months [95% CI, 18.6-38.1 months]; BCLC B, 16.9 months [95% CI, 12.8-22.8 months]; BCLC C, 10.0 months [95% CI, 7.7-10.9 months]). Consistent with this finding , survival varied significantly by ECOG status, hepatic function (Child-Pugh class, ascites, and baseline total bilirubin), tumor burden (number of nodules, alpha-fetoprotein), and presence of extrahepatic disease. When considered within the framework of BCLC staging, variables reflecting tumor burden and liver function provided additional prognostic information. The most significant independent prognostic factors for survival upon multivariate analysis were ECOG status, tumor burden (nodules >5), international normalized ratio >1.2, and extrahepatic disease. Common adverse events were: fatigue, nausea/vomiting, and abdominal pain. Grade 3 or higher increases in bilirubin were reported in 5.8% of patients. All-cause mortality was 0.6% and 6.8% at 30 and 90 days, respectively. CONCLUSION: This analysis provides robust evidence of the survival achieved with radioembolization, including those with advanced disease and few treatment options.

Radiological treatment of renal artery occlusion after blunt abdominal trauma in a pediatric patient: is it never too late?

A 15-year-old boy was severely injured in a motor vehicle accident. A blunt abdominal trauma resulted in multiple lesions requiring urgent surgical treatment. Seven days after the trauma, renal Doppler sonography showed absence of arterial signal in the left kidney hilum. Selective renal angiography was performed, showing localized aneurysmatic dilatation in the principal branch of the left renal artery with interruption of renal parenchyma blood flow. Stent graft placement resulted in the resumption of a normal perfusion. After long-term follow-up, symmetric renal function has been demonstrated. Our results confirmed the efficacy of endovascular treatment in the management of pediatric patients with renal artery occlusion after blunt abdominal trauma. The outcome appeared excellent even after a prolonged period of renal ischemia.

Transluminal stenting in type A acute aortic dissection: does the Djumbodis system have any impact on false lumen evolution?

BACKGROUND: We reviewed our experience with the transluminal placement of the Djumbodis system in the aortic arch and isthmus in patients with type A acute aortic dissection to assess its impact on true and false aortic lumen evolution. METHODS: Between January 2005 and September 2009, 50 patients underwent surgery for type A acute aortic dissection. Twenty-eight patients (group A) were operated on by implanting the Djumbodis prosthesis, and 22 patients (group B) without the prosthesis. Contrast-enhanced computed tomography and magnetic resonance imaging controls were performed on survivors at or soon after discharge and at follow-up. RESULTS: Preoperative and operative data and complication rates were not significantly different between the two groups. Three in-hospital deaths occurred within 30 days, 1 in each group due to aortic rupture. At 1- and 4-year follow-up, actuarial survival was 82% ± 7% versus 90% ± 6% and 73% ± 9% versus 84% ± 9%, in group A and B, respectively (p = 0.35). Three reoperations were performed, 2 in group A and 1 in group B (p = 0.66). At follow-up, there was no significant difference between groups regarding the ratio between true lumen and aortic diameters and false lumen patency rates at the aortic arch, isthmus, and descending aorta level. CONCLUSIONS: Placement of the Djumbodis prosthesis does not confer any additional surgical benefit and does not seem to contribute to reducing the incidence of postoperative false lumen patency in patients operated on for type A acute aortic dissection in comparison with conventional surgery.

Endovascular snare kit in the combined antegrade and retrograde management of ureteral avulsion: report of two cases.

We report the feasible and safe use of the Amplatz Goose Neck Snare kit for avulsed ureter retrieval during ureteroscopy. A 49-year-old lady and a 61-year-old man complaining of urolithiasis underwent ureteroscopy; following stone fragmentation, and basketing avulsion of the ureter occurred. Using the Amplatz Goose Neck Snare kit it was possible to place an indwelling ureteral catheter in both cases aiming at restoring the urinary upper tract continuity. The snare-assisted endovascular technique may be an interesting tool even in endourology for the management of ureteral avulsion. This endoscopic mini-invasive procedure makes it possible to avoid an immediate invasive surgical approach often resulting in nephrectomy, having time for planning a possible durable conservative treatment.

Embolisation of arteriovenous intrahepatic fistulas associated with diffuse haemangiomatosis of the liver. Report of a case in an adult and review of the literature.

Diffuse hepatic haemangiomatosis is rare in adults. Association with high output intrahepatic arteriovenous fistulas has been described. To avoid heart failure complications, treatment is essential. The second case in the literature, treated with repeated transcatheter arterial embolizations (TAE) but complicated by infection of multiple haemangiomas and by Kasabach-Merritt syndrome, is presented. Complications were due to the persistent presence of haemangiomas within the liver, where an impressive collection of platelets and a superinfection were observed. Therefore, to treat arteriovenous fistula-related problems and to prevent possible complications due to persistence of the haemangiomas, surgical removal should be preferred over embolisation.