Search

Background 5–10% of amyotrophic lateral sclerosis (ALS) patients presented a positive family history (fALS). More than 30 genes have been identified in association with ALS/frontotemporal dementia (FTD) spectrum, with four major genes accounting for 60–70% of fALS. In this paper, we aimed to assess the contribution to the pathogenesis of major and rare ALS/FTD genes in ALS patients. Methods We analyzed ALS and ALS/FTD associated genes by direct sequencing or next-generation sequencing multigene panels in ALS patients. Results Genetic abnormalities in ALS major genes included repeated expansions of hexanucleotide in C9orf72 gene (7.3%), mutations in SOD1 (4.9%), FUS (2.1%), and TARDBP (2.4%), whereas variants in rare ALS/FTD genes affected 15.5% of subjects overall, most frequently involving SQSTM1 (3.4%), and CHMP2B (1.9%). We found clustering of variants in ALS major genes in patients with a family history for “pure” ALS, while ALS/FTD related genes mainly occurred in patients with a family history for other neurodegenerative diseases (dementia and/or parkinsonism). Conclusions Our data support the presence of two different genetic components underlying ALS pathogenesis, related to the presence of a family history for ALS or other neurodegenerative diseases. Thus, family history may help in optimizing the genetic screening protocol to be applied.

Amyotrophic lateral sclerosis (ALS) is known to represent a collection of overlapping syndromes. Various classification systems based on empirical observations have been proposed, but it is unclear to what extent they reflect ALS population substructures. We aimed to use machine-learning techniques to identify the number and nature of ALS subtypes to obtain a better understanding of this heterogeneity, enhance our understanding of the disease, and improve clinical care.In this retrospective study, we applied unsupervised Uniform Manifold Approximation and Projection [UMAP]) modelling, semi-supervised (neural network UMAP) modelling, and supervised (ensemble learning based on LightGBM) modelling to a population-based discovery cohort of patients who were diagnosed with ALS while living in the Piedmont and Valle d'Aosta regions of Italy, for whom detailed clinical data, such as age at symptom onset, were available. We excluded patients with missing Revised ALS Functional Rating Scale (ALSFRS-R) feature values from the unsupervised and semi-supervised steps. We replicated our findings in an independent population-based cohort of patients who were diagnosed with ALS while living in the Emilia Romagna region of Italy.Between Jan 1, 1995, and Dec 31, 2015, 2858 patients were entered in the discovery cohort. After excluding 497 (17%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 2361 (83%) patients were available for the unsupervised and semi-supervised analysis. We found that semi-supervised machine learning produced the optimum clustering of the patients with ALS. These clusters roughly corresponded to the six clinical subtypes defined by the Chiò classification system (ie, bulbar, respiratory, flail arm, classical, pyramidal, and flail leg ALS). Between Jan 1, 2009, and March 1, 2018, 1097 patients were entered in the replication cohort. After excluding 108 (10%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 989 patients were available for the unsupervised and semi-supervised analysis. All 1097 patients were included in the supervised analysis. The same clusters were identified in the replication cohort. By contrast, other ALS classification schemes, such as the El Escorial categories, Milano-Torino clinical staging, and King's clinical stages, did not adequately label the clusters. Supervised learning identified 11 clinical parameters that predicted ALS clinical subtypes with high accuracy (area under the curve 0·982 [95% CI 0·980-0·983]).Our data-driven study provides insight into the ALS population substructure and confirms that the Chiò classification system successfully identifies ALS subtypes. Additional validation is required to determine the accuracy and clinical use of these algorithms in assigning clinical subtypes. Nevertheless, our algorithms offer a broad insight into the clinical heterogeneity of ALS and help to determine the actual subtypes of disease that exist within this fatal neurodegenerative syndrome. The systematic identification of ALS subtypes will improve clinical care and clinical trial design.US National Institute on Aging, US National Institutes of Health, Italian Ministry of Health, European Commission, University of Torino Rita Levi Montalcini Department of Neurosciences, Emilia Romagna Regional Health Authority, and Italian Ministry of Education, University, and Research.For the Italian and German translations of the abstract see Supplementary Materials section.

Introduction Isolated complex I deficiency causes several clinical syndromes, including Leigh syndrome (LS), Leber hereditary optic neuropathy (LHON) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Here we reported two new patients carrying the rare m.3890G>A/MT-ND1 (p.Arg195Gln) mitochondrial DNA (mtDNA) pathogenic variant, revisited another two previously reported cases, and reviewed the remaining published cases, to refine the clinical and neuroimaging features. We also quantitatively assessed the mtDNA heteroplasmy in all available tissues. Cases presentation The first patient was a 25-year-old male presenting with axonal polyneuropathy, optic atrophy consistent with LHON, gaze palsy and parkinsonism. MRI correlates included transient centromedullary T2 hyperintensity in the conus medullaris, transient signal intensity and increased lactate in the midbrain periaqueductal gray matter, and late atrophy of the optic nerves and chiasm, dorsal midbrain and conus medullaris. The second patient was a 65-year-old woman with a classical LHON phenotype and a normal MRI. Discussion Including the previously published cases, the clinical spectrum ranged from LHON to Leigh-like syndrome with peculiar CNS lesions and encephalopatic clinical symptoms. The most severe and complex cases were associated with very high heteroplasmy, or nearly homoplasmic m.3890G>A/MT-ND1 pathogenic variant in skeletal muscle, displaying neurological symptoms/signs consistent with Leigh-like lesions on brain MRI. Lower heteroplasmic mutational loads were instead associated with isolated LHON-like optic neuropathy of variable severity. Conclusion The m.3890G>A/MT-ND1 mtDNA pathogenic variant increasingly impairs complex I function dependent on heteroplasmic loads, leading to a spectrum of LHON and Leigh-like encephalopathy with distinguishing MRI features.

Objective To evaluate the prognostic value of needle electromyography (EMG) genioglossus involvement in patients with amyotrophic lateral sclerosis (ALS) at diagnosis. Methods We separately explored the prognostic value of clinical bulbar lower motor neuron (LMN) signs and EMG genioglossus involvement using Cox proportional hazard models adjusted for age, gender, diagnostic delay, presence of bulbar upper motor neuron (UMN) signs, EMG cervical and lumbosacral region involvement, ALSFRS-R score and C9Orf72 gene status. Then, we compared the prognostic value of EMG masseter and genioglossus abnormalities in a subset of patients in whom both muscles were analysed. Results 103 ALS patients were included in the study. Neurophysiological genioglossus involvement was associated with a shorter survival (p = 0.002), a shorter time to moderate dysphagia (p = 0.0001) and to severe dysarthria (p = 0.012). Its prognostic value was still evident in patients without clinical bulbar LMN signs. Bulbar clinical LMN signs were only associated with an earlier onset of moderate dysphagia (p = 0.0001). EMG masseter abnormalities did not reach statistical significance with regard to all the clinical milestones. Conclusions Genioglossus EMG at diagnosis could provide important information about ALS progression rate. The masseter muscle seems to be less involved in ALS. Significance EMG genioglossus involvement is a prognostic factor in ALS.

Introduction: Known risk factors for multiple sclerosis (MS) include smoking, a low vitamin D status, obesity, and EBV, while the inflammatory feature of the disease strongly suggests the presence of additional infectious agents. The association between use of antibiotics and MS risk that could shed light on these factors is still undetermined. We aimed to evaluate the association between antibiotics and MS risk, in the Emilia-Romagna region (RER), Italy. Methods: All adult patients with MS seen at any RER MS center (2015–2017) were eligible. For each of the 877 patients included, clinical information was collected and matched to 5 controls (RER residents) (n = 4,205) based on age, sex, place of residence, and index year. Information on antibiotic prescription was obtained through the linkage with the RER drug prescription database. Results: Exposure to any antibiotic 3 years prior to the index year was associated with an increased MS risk (OR = 1.52; 95% CI = 1.29–1.79). Similar results were found for different classes. No dose-response effect was found. Discussion/Conclusions: Our results suggest an association between the use of antibiotics and MS risk in RER population. However, further epidemiological studies should be done with information on early life and lifestyle factors.

Introduction: Myasthenia gravis (MG) can be aggravated by several classes of drugs, including antibiotics. Penicillins are considered safe drugs for the management of infectious disease in patients with MG. However, a few cases of MG exacerbations after penicillin treatment have been reported in literature. Case reports: We report six patients with MG developing acute worsening of symptoms after amoxicillin or amoxicillin/clavulanate treatment. In most of the cases, symptoms started in a few days after antibiotic administration. In all cases, we observed a worsening of the Myasthenia Gravis Foundation of America (MGFA) clinical classification. Most patients required a therapeutic intervention with dosage increase of the previous therapy or the introduction of new drugs for MG. All patients had a full recovery to baseline neurological conditions within 1–2months. Conclusions: We concluded that patients receiving amoxicillin should be closely monitored for possible acute relapse.

Objective Neuroinflammation is considered a key driver for neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). SOD1 mutations cause about 20% of familial ALS, and related pathology might generate microglial activation triggering neurodegeneration. 11 C-PK11195 is the prototypical and most validated PET radiotracer, targeting the 18-kDa translocator protein which is overexpressed in activated microglia. In this study, we investigated microglia activation in asymptomatic (ASYM) and symptomatic (SYM) SOD1 mutated carriers, by using 11 C-PK11195 and PET imaging. Methods We included 20 subjects: 4 ASYM-carriers, neurologically normal, 6 SYM-carriers with probable ALS, and 10 healthy controls. A receptor parametric mapping procedure estimated 11 C-PK11195 binding potentials and voxel-wise statistical comparisons were performed at group and single-subject levels. Results Both the SYM- and ASYM-carriers showed significant microglia activation in cortical and subcortical structures, with variable patterns at individual level. Clusters of activation were present in occipital and temporal regions, cerebellum, thalamus, and medulla oblongata. Notably, SYM-carriers showed microglia activation also in supplementary and primary motor cortices and in the somatosensory regions. Interpretation In vivo neuroinflammation occurred in all SOD1 mutated cases since the presymptomatic stages, as shown by a significant cortical and subcortical microglia activation. The involvement of sensorimotor cortex became evident at the symptomatic disease stage. Although our data indicate the role of in vivo PET imaging for assessing resident microglia in the investigation of SOD1-ALS pathophysiology, further studies are needed to clarify the temporal and spatial dynamics of microglia activation and its relationship with neurodegeneration.

Objective To verify whether the finding of denervation activity on EMG at the time of diagnosis has a prognostic value in amyotrophic lateral sclerosis (ALS). Methods We retrospectively studied all the patients discharged with a diagnosis of ALS between January 2009 and January 2017. 92 patients met the inclusion criteria. We mainly verified three prognostic targets: (1) Time to non-invasive ventilation (NIV) or tracheostomy. (2) Time to percutaneous endoscopic gastrostomy or parental nutrition. (3) Survival. All EMG examinations were reviewed and a denervation score (DS) was calculated. The association of DS with clinical milestones was analysed, adjusting for disease duration, age , sex, and clinical phenotype. Results We found a significant association between bulbar DS and time to NIV/tracheostomy (HR: 3.34, 95% CI: 1.49 to 7.48, p = 0.002) and with survival (HR 3.633, 95% CI 1.681–7.848, p = 0.001), regardless of the clinical phenotype. Furthermore, we found a significant influence of a general DS on survival (HR: 2.62, 95% CI 1.335–5.160, p = 0.005). Conclusion EMG assessment could be of value not just for ALS diagnosis but also for its intrinsic prognostic value. Significance EMG could provide additional information about the rate of progression of ALS as early as the diagnosis is made.

Loss-of-function mutations in the gene encoding for the protein progranulin (PGRN), GRN, are one of the major genetic abnormalities involved in frontotemporal lobar degeneration. However, genetic variations, mainly missense, in GRN have also been linked to other neurodegenerative diseases. We found 12 different pathogenic/likely pathogenic variants in 21 patients identified in a cohort of Italian patients affected by various neurodegenerative disorders. We detected the p.Thr272SerfsTer10 as the most frequent, followed by the c.1179+3A>G variant. We characterized the clinical phenotype of 12 patients from 3 pedigrees carrying the c.1179+3A>G variant, demonstrated the pathogenicity of this mutation, and detected other rarer variants causing haploinsufficiency (p.Met1?, c.709-2A>T, p.Gly79AspfsTer39). Finally, by applying bioinformatics, neuropathological, and biochemical studies, we characterized 6 missense/synonymous variants (p.Asp94His, p.Gly117Asp, p.Ala266Pro, p.Val279Val, p.Arg298His, p.Ala505Gly), including 4 previously unreported. The designation of variants is crucial for genetic counseling and the enrollment of patients in clinical studies.

Introduction Sexual dysfunction (SD) is common but still underdiagnosed in women with multiple sclerosis (MS); in fact, the lack of a consistent use of validated diagnostic tools makes the prevalence of SD and related distress difficult to define precisely. Aim To assess the prevalence of SD in Italian women with MS compared with age-matched healthy control subjects (HC) and the association with demographic, psychological, and MS-related characteristics. Methods The Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale were administered to 153 women with MS and 153 HC. Demographic, gynecologic, and neurologic data were obtained. Disability was assessed using the Expanded Disability Status Scale. Psychological symptoms were evaluated in MS patients with Profile of Mood State and the Beck Depression Inventory II. Main Outcomes Measures Prevalence of SD and sexual distress in women with MS compared with HC. Results Among women sexually active in the last month, we found an increased prevalence of SD in MS patients compared with HC subjects (42.0% vs 16.0%, P = .0001). The prevalence of dysfunctional FSFI global scores ( Clinical Implications This study suggests that sexual function investigation should always be a standard part of the consultation with healthcare professionals for MS. Strength & Limitations The strength of this study was the comparison with an age-matched healthy control group and the use of validated questionnaires to assess both sexual function and sexual distress. Larger and multicenter studies may further support our findings. Conclusion In our cohort, the prevalence of SD and sexual distress was higher in women with MS compared to the HC group. Age, disability, and depressive symptoms were associated with increased SD.

© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Leukoencephalopathy with calcifications and cysts (LCC) is an uncommon condition of unknown etiology occurring in children and adults. Pathological findings include obliterative hyalinosis of the small vessels, myelin loss, intense gliosis, Rosenthal fiber formation, microcalcifications, and hemosiderin deposits. Herein we report a 55-year-old man with LCC documented 10 years ago, in whom we examined brain perfusion by pseudocontinuous arterial spin labeling technique. We demonstrated diffused hypoperfusion of the affected white matter (WM) and of the subcortical gray matter (GM) and cortical GM in the patient in comparison to a group of healthy control subjects, using both qualitative evaluation and region of interest analysis. WM and subcortical GM hypoperfusion reflects the known distribution of LCC microangiopathy. We speculate that cortical hypoperfusion may be related to cerebral atrophy or may reflect deafferentation secondary to severe leukoencephalopathy, and may possibly contribute to severe motor and cognitive impairment. Further studies addressing cerebral blood flow in LCC are necessary.

Background Multiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disorder of the central nervous system (CNS). Several observations support interactions between vascular and neurodegenerative mechanisms in multiple sclerosis (MS). To investigate the contribution of the extracranial venous compartment, we analysed expression profiles of internal jugular vein (IJV), which drains blood from CNS, and related plasma protein levels. Methods We studied a group of MS patients (n = 19), screened by echo-color Doppler and magnetic resonance venography, who underwent surgical reconstruction of IJV for chronic cerebrospinal venous insufficiency (CCSVI). Microarray-based transcriptome analysis was conducted on specimens of IJV wall from MS patients and from subjects undergoing carotid endarterectomy, as controls. Protein levels were determined by multiplex assay in: i) jugular and peripheral plasma from 17 MS/CCSVI patients; ii) peripheral plasma from 60 progressive MS patients, after repeated sampling and iii) healthy individuals. Results Of the differentially expressed genes (≥ 2 fold-change, multiple testing correction, P

Amyloid heart disease is one of the most frequent types of cardiomyopathy with restrictive pathophysiology. The familial amyloidoses constitute an extremely heterogeneous group of diseases. The form linked to transthyretin (TTR) mutations is by far the most common variety of familial amyloidosis. The clinical picture is non-specific with progressive chronic heart failure. A definitive diagnosis can readily be made from cardiac histopathology with evidence of amyloid deposits in other tissues. However, amyloid heart disease remains underdiagnosed. Advances in cardiac imaging have resulted in greater recognition of cardiac amyloidosis in everyday clinical practice, but the diagnosis continues to be made in patients with late-stage disease, suggesting that more needs to be done to improve awareness of its clinical manifestations and the potential of therapeutic intervention to improve prognosis. The electrocardiographic and echocardiographic findings are often misleading and indistinguishable from other cardiac conditions including hypertrophic cardiomyopathy and coronary artery disease. In most cases, since the clinical manifestations of systemic amyloidosis are manifold, patients may be referred to any one of a variety of specialists (especially hematologists, nephrologists and neurologists) without necessarily referred to the cardiologist. For patients with transthyretin amyloidosis, there are numerous disease modifying therapies that are currently in late-phase clinical trials.

Objective To assess the long-term effects of combined oral contraceptives (COCs) on the clinical course of relapsing–remitting multiple sclerosis (RRMS), focusing on disability progression and evolution to secondary-progressive multiple sclerosis (SPMS). Design Retrospective and exploratory study. Setting Academic medical center. Patient(s) A total of 174 women with clinically confirmed MS; of these, 33 had evolved to SPMS at the time of enrollment in the study, whereas 141 still had a relapsing–remitting form of disease. Intervention(s) Women were interviewed to obtain gynecologic and obstetric history. Main Outcome Measure(s) Expanded Disability Status Scale (EDSS); Multiple Sclerosis Severity Score (MSSS); annualized relapse rate; evolution to SPMS. Result(s) Mean ± SD duration of disease was 14.3 ± 9.8 years. Compared with non-users of COCs, COC users had lower EDSS scores and MSSS only in the subset of the population with prior or current immunomodulatory treatment. Nonuse of COCs was a predictor of disease evolution in SPMS, whether treated or not with immunomodulatory drugs. The annualized relapse rate was not influenced by COC use. No differences in EDSS scores and evolution to SPMS depending on COC formulation were detected. Conclusion(s) Our results suggest that COC use is associated with a less severe disease and less severe evolution. Whether different doses or types of progestin may have different effects remains to be defined.

In multiple sclerosis (MS) plaques are known to be venocentric; in addition, MS lesions and peripheral venous disorders share a number of key features. To date, however, despite the anatomical relationship between MS lesions and the venous system, no informa- tion on the intracranial venous haemodynamics of MS is available. Eighty-nine consecutive MS patients (58 relapsing-remitting, 31 sec- ondary progressive) matched with 60 controls underwent transcranial color-coded duplex sonography (TCCS). We assessed, in supine as well as in sitting positions, the direction of flow at the activation of the thoracic pump in the deep middle cerebral veins (dMCVs), and in the transverse sinus (TS). In the dMCVs, we also measured peak systolic velocity (PSV), peak diastolic velocity (PDV), as well as the re- sistance index (RI). Reflux/bidirectional flow rate was significantly higher in the MS population determining also significant differences in PDV, characterized by negative values (16.2±1 cm/sec in controls vs. -1.3 ±2.6 cm/sec in MS, respectively, p

Background: Thalidomide is effective as a first-line therapy for the treatment of multiple myeloma (MM), but its use is limited by peripheral neurotoxicity. Objective: To study the occurrence of both myeloma-related neuropathy and thalidomide-induced neuropathy in 31 patients with newly diagnosed MM. Methods: Clinical and electrophysiologic examinations were performed in 31 patients with newly diagnosed MM before and after 4 months of therapy with thalidomide (200 mg/day, total dose: 21 g) aimed at debulking MM, before autologous transplantation. After transplantation, the patients took thalidomide, 200 mg/day for another 3 months (total dose over three months: 18 g) and then underwent a final clinical and electrophysiologic checkup. Results: At baseline, four patients presented a mild sensorimotor peripheral neuropathy related to MM, which tended to worsen slightly during treatment with thalidomide. At the end of treatment, 83% of the patients had clinical and electrophysiologic evidence of a mild sensory rather than motor, axonal, length-dependent polyneuropathy, whereas 100% of the patients showed improvement to the basic pathology (≥partial response). Conclusions: Peripheral neuropathy, sometimes subclinical, and mild in our patients, is a common, early side effect of thalidomide therapy. The high doses (21 g) used in all patients for a relatively short time (4 months) rule out any correlations between neuropathy, total dose, and duration of treatment.

Mutations in the superoxide dismutase-1 (SOD1) gene occur in some forms of familial amyotrophic lateral sclerosis (ALS). To date about 150 mutations are known to involve this gene. Here we describe a novel missense mutation in exon 5 of the SOD1 gene in an Italian family with two members affected by ALS. Sequencing of the SOD1 gene was performed on 11 members of the family and 75 healthy controls. Electron microscopy was also performed on one ALS patient. We identified a heterozygous mutation in codon 137 leading to substitution of threonine by alanine. Further studies are needed to clarify the role of this alteration in ALS aetiopathogensis; nevertheless, T137A seems to represent a new missense mutation of the SOD1 gene in ALS patients.

Importance Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by restricted venous outflow from the brain and spinal cord. Whether this condition is associated with multiple sclerosis (MS) and whether venous percutaneous transluminal angioplasty (PTA) is beneficial in persons with MS and CCSVI is controversial. Objective To determine the efficacy and safety of venous PTA in patients with MS and CCSVI. Design, Setting, and Participants We analyzed 177 patients with relapsing-remitting MS; 62 were ineligible, including 47 (26.6%) who did not have CCSVI on color Doppler ultrasonography screening. A total of 115 patients were recruited in the study timeframe. All patients underwent a randomized, double-blind, sham-controlled, parallel-group trial in 6 MS centers in Italy. The trial began in August 2012 and concluded in March 2016; data were analyzed from April 2016 to September 2016. The analysis was intention to treat. Interventions Patients were randomly allocated (2:1) to either venous PTA or catheter venography without venous angioplasty (sham). Main Outcomes and Measures Two primary end points were assessed at 12 months: (1) a composite functional measure (ie, walking control, balance, manual dexterity, postvoid residual urine volume, and visual acuity) and (2) a measure of new combined brain lesions on magnetic resonance imaging, including the proportion of lesion-free patients. Combined lesions included T1 gadolinium-enhancing lesions plus new or enlarged T2 lesions. Results Of the included 115 patients with relapsing-remitting MS, 76 were allocated to the PTA group (45 female [59%]; mean [SD] age, 40.0 [10.3] years) and 39 to the sham group (29 female [74%]; mean [SD] age, 37.5 [10.6] years); 112 (97.4%) completed follow-up. No serious adverse events occurred. Flow restoration was achieved in 38 of 71 patients (54%) in the PTA group. The functional composite measure did not differ between the PTA and sham groups (41.7% vs 48.7%; odds ratio, 0.75; 95% CI, 0.34-1.68;P = .49). The mean (SD) number of combined lesions on magnetic resonance imaging at 6 to 12 months were 0.47 (1.19) in the PTA group vs 1.27 (2.65) in the sham group (mean ratio, 0.37; 95% CI, 0.15-0.91;P = .03: adjustedP = .09) and were 1.40 (4.21) in the PTA group vs 1.95 (3.73) in the sham group at 0 to 12 months (mean ratio, 0.72; 95% CI, 0.32-1.63;P = .45; adjustedP = .45). At follow-up after 6 to 12 months, 58 of 70 patients (83%) in the PTA group and 22 of 33 (67%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 2.64; 95% CI, 1.11-6.28;P = .03; adjustedP = .09). At 0 to 12 months, 46 of 73 patients (63.0%) in the PTA group and 18 of 37 (49%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 1.80; 95% CI, 0.81-4.01;P = .15; adjustedP = .30). Conclusion and Relevance Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS. Trial Registration clinicaltrials.gov Identifier:NCT01371760

Cardiac amyloidosis (CA) is often misdiagnosed because of both physician-related and disease-related reasons including: fragmented knowledge among different specialties and subspecialties, shortage of centres and specialists dedicated to disease management, erroneous belief it is an incurable disease, rarity of the condition, intrinsic phenotypic heterogeneity, genotypic heterogeneity in transthyretin-related forms and the necessity of target organ tissue histological diagnosis in the vast majority of cases. Pitfalls, incorrect beliefs and deceits challenge not only the path to the diagnosis of CA but also the precise identification of aetiological subtype. The awareness of this condition is the most important prerequisite for the management of the risk of underdiagnoses and misdiagnosis. Almost all clinical, imaging and laboratory tests can be misinterpreted, but fortunately each of these diagnostic steps can also offer diagnostic “red flags” (i.e. highly suggestive findings that can foster the correct diagnostic suspicion and facilitate early, timely diagnosis). This is especially important because outcomes in CA are largely driven by the severity of cardiac dysfunction and emerging therapies are aimed at preventing further amyloid deposition.

Isolated bilateral optic neuropathy is an exceedingly rare presentation of perinuclear-antineutrophil cytoplasmic autoantibody (p-ANCA) vasculitis. We report one such case with MRI documentation of a compressive mechanism mediated by pachymeningitis. A 69-year-old woman had a 6-month history of progressive visual failure caused by bilateral optic neuropathy. Cranial MRI showed diffuse contrast enhancement of the dura mater extending to the perioptic sheaths bilaterally with encasement of the optic nerves. Extensive laboratory study showed increased levels of p-ANCA titres and autoimmune markers. Corticosteroid treatment improved both visual acuity and the neuroradiological signs of active pachymeningitis. In conclusion, our case demonstrates that bilateral optic neuropathy may be the presenting symptom of p-ANCA-associated pachymeningitis, whose causative role may be demonstrated by MRI.

BACKGROUND AND PURPOSE: CCSVI was recently described in patients with MS. CCSVI is diagnosed noninvasively by Doppler sonography and invasively by catheter venography. We assessed the role of conventional MRV for the detection of IJV anomalies in patients with MS diagnosed with CCSVI and in healthy controls who underwent MRV and Doppler sonography examinations during 6 months. MATERIALS AND METHODS: Ten patients with MS underwent TOF, TRICKS, Doppler sonography, and catheter venography at baseline. They were treated at baseline with percutaneous angioplasty and re-evaluated 6 months9 posttreatment with MRV and Doppler sonography. In addition, 6 healthy controls underwent a baseline and a 6-month follow-up evaluation by Doppler sonography and MRV. RESULTS: At baseline, the sensitivity, specificity, PPV, and NPV of Doppler sonography for detecting IJV abnormalities relative to catheter venography in patients with MS were calculated, respectively, at 82%, 100%, 99%, and 95%. The figures were 99%, 33%, 33%, 99% for TOF and 99%, 39%, 35%, and 99% for TRICKS. Venous anomalies included the annulus, septum, membrane, and malformed valve. No agreement was found between TOF and catheter venography in 70% of patients with MS and between TRICKS and catheter venography in 60% of patients with MS. At follow-up, 50% of the patients with MS presented with abnormalities on Doppler sonography but only 30% were diagnosed with restenosis. CONCLUSIONS: Conventional MRV has limited value for assessing IJV anomalies for both diagnostic and posttreatment purposes.

Mutations in the FUS gene have recently been described as a cause of familial amyotrophic lateral sclerosis (ALS), but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of all coding exons of FUS in 228 sporadic ALS cases, and, as previous reports suggest that exon 15 represents a mutational hotspot, we sequenced this exon in an additional 1295 sporadic cases. Six variants in six different cases were found, indicating that FUS mutations can underlie apparently sporadic ALS, but account for less than 1% of this form of disease. © 2010 .

Objective: Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by combined stenoses of the principal pathways of extracranial venous drainage, including the internal jugular veins (IJVs) and the azygous (AZY) vein, with development of collateral circles and insufficient drainage shown by increased mean transit time in cerebral magnetic resonance (MR) perfusion studies. CCSVI is strongly associated with multiple sclerosis (MS). This study evaluated the safety of CCSVI endovascular treatment and its influence on the clinical outcome of the associated MS. Methods. Sixty-five consecutive patients with CCSVI, subdivided by MS clinical course into 35 with relapsing remitting (RR), 20 with secondary progressive (SP), and 10 with primary progressive (PP) MS, underwent percutaneous transluminal angioplasty (PTA). Mean follow-up was 18 months. Vascular outcome measures were postoperative complications, venous pressure, and patency rate. Neurologic outcome measures were cognitive and motor function assessment, rate of MS relapse, rate of MR active positive-enhanced gadolinium MS lesions (Gad), and quality of life (QOL) MS questionnaire. Results: Outpatient endovascular treatment of CCSVI was feasible, with a minor and negligible complication rate. Postoperative venous pressure was significantly lower in the IJVs and AZY (P < .001). The risk of restenosis was higher in the IJVs compared with the AZY (patency rate: IJV, 53%; AZY, 96%; odds ratio, 16; 95% confidence interval, 3.5-72.5; P < .0001). CCSVI endovascular treatment significantly improved MS clinical outcome measures, especially in the RR group: the rate of relapse-free patients changed from 27% to 50% postoperatively (P < .001) and of MR Gad lesions from 50% to 12% (P < .0001). The Multiple Sclerosis Functional Composite at 1 year improved significantly in RR patients (P < .008) but not in PP or SP. Physical QOL improved significantly in RR (P < .01) and in PP patients (P < .03), with a positive trend in SP (P < .08). Mental QOL showed significant improvement in RR (P < .003) and in PP (P < .01), but not in SP. Conclusions: PTA of venous strictures in patients with CCSVI is safe, and especially in patients with RR, the clinical course positively influenced clinical and QOL parameters of the associated MS compared with the preoperative assessment. Restenosis rates are elevated in the IJVs but very promising in the AZY, suggesting the need to improve endovascular techniques in the former. The results of this pilot study warrant a subsequent randomized control study. (J Vasc Surg 2009;50:1348-58.) The blood leaves the brain by using the back propul

Our objective was to investigate grey matter (GM) contraction in patients with amyotrophic lateral sclerosis (ALS) using tensor based morphometry (TBM). Using a 1.5 Tesla scanner, T1-weighted MRI scans were obtained at baseline and at follow-up (mean interval, 9 months) from 16 ALS and 10 controls. Standard TBM procedures in Statistical Parametric Mapping (SPM2) were used for image processing and statistical analyses. The frontotemporal cortex and basal ganglia were considered areas of interest, based on pathological studies. Eight patients showed rapid clinical progression of ALS during the follow-up period. Compared to controls, all ALS patients showed progression of GM atrophy in left premotor cortex and right basal ganglia. Patients with rapidly progressing ALS showed GM atrophy changes in a larger motor cortical-subcortical area and in extramotor frontal regions compared to both controls and to non-rapidly progressing cases. Thus, TBM detected longitudinal atrophy changes in the motor network in ALS occurring over less than one year. The faster the clinical progression, the greater was the GM loss in motor and prefrontal areas. Further advances in tracking longitudinal changes in cortical and subcortical regions in ALS may provide an objective marker for monitoring disease progression, and the disease-modifying effect of potential treatments.

article i nfo Iron stores in the white and deep grey matter in course of multiple sclerosis (MS) have never been explained and could be related to abnormalities in venous drainage, but this possibility has never before been investigated. From an initial cohort of 320 subjects, after application of exclusion criteria, we selected 109 patients affected by MS, and 177 controls respectively composed by age- and sex-matched, healthy aged, and patients affected by other neurological diseases. They blindly underwent transcranial and extracranial Color-Doppler sonographic examination (TCCS-ECD), aimed at investigating five parameters related to normal cerebral venous outflow haemodynamics. Overall we analyzed 1430 TCSS-ECD parameters. In controls we found 861 normal parameters of cerebral venous return vs. 24 anomalous, whereas in MS 288 parameters were normal and 257 anomalous, respectively. Consequently, each of the considered Doppler haemodynamic parameters, when compared to revised McDonald criteria as a gold standard of MS diagnosis, showed separately a highly significant sensitivity and a noteworthy specificity. However, the detection ≥2 parameters in the same subject, never observed in controls, perfectly overlapped the diagnosis of MS (value, 95%CI: sensitivity 100%, 97-100; specificity 100%, 98-100; positive predictive value 100%, 97-100, negative predictive value 100%, 98-100; pb0.0001). Moreover, this study demonstrates a significant impairment of cerebral venous drainage in patients affected by MS, a mechanism potentially related to increased iron stores.

We used quantitative proton magnetic resonance spectroscopy (1H-MRS) to evaluate mean relative concentrations ratios for NAA, Cr, Cho and mI during the study of cervical spinal cord plaques in a relapsing-remitting multiple sclerosis (RRMS). A cervical spine MR exam was repeated five times on the following days for two months starting from the onset of a relapse phase, using a 3T whole-body system, with the voxel placed along the demyelinazation lesion. The quantification results were compared with the healthy metabolites content. Quantitative cervical spectroscopy is a reliable tool and can offer important metabolic information as already used on the brain to evaluate the severity, progression and pathogenesis of multiple sclerosis.

Background and purpose: Neuropathological examination in Friedreich ataxia (FRDA) reveals neuronal loss in the gray matter (GM) nuclei and degeneration of the white matter (WM) tracts in the spinal cord, brainstem and cerebellum, while the cerebral hemispheres are substantially spared. Tract-based spatial statistics (TBSS) enables an unbiased whole-brain quantitative analysis of the fractional anisotropy (FA) and mean diffusivity (MD) of the brain WM tracts in vivo. Patients and methods: We assessed with TBSS 14 patients with genetically confirmed FRDA and 14 age- and sex-matched healthy controls who were also examined with voxel-based morphometry (VBM) to assess regional atrophy of the GM and WM. Results: TBSS revealed decreased FA in the inferior and superior cerebellar peduncles and the corticospinal tracts in the medullary pyramis, in WM tracts of the right cerebellar hemisphere and in the right occipito-frontal and inferior longitudinal fasciculi. Increased MD was observed in the superior cerebellar peduncles, deep cerebellar WM, posterior limbs of the internal capsule and retrolenticular area, bilaterally, and in the WM underlying the left central sulcus. Decreased FA in the left superior cerebellar peduncle correlated with clinical severity. VBM showed small symmetric areas of loss of bulk of the peridentate WM which also correlated with clinical severity. Conclusions: TBSS enables in vivo demonstration of degeneration of the brainstem and cerebellar WM tracts which neuropathological examination indicates to be specifically affected in FRDA. TBSS complements VBM and might be a more sensitive tool to detect WM structural changes in degenerative diseases of the CNS.

Charles Bonnet syndrome (CBS) is a disorder characterized by the occurrence of complex visual hallucinations in patients with acquired impairment of vision and without psychiatric disorders. In spite of the high incidence of visual field defects following antero-mesial temporal lobectomy for refractory temporal lobe epilepsy, reports of CBS in patients who underwent this surgical procedure are surprisingly rare. We describe a patient operated on for drug-resistant epilepsy. As a result of left antero-mesial temporal resection, she presented right homonymous hemianopia. A few days after surgery, she started complaining of visual hallucinations, such as static or moving "Lilliputian" human figures, or countryside scenes, restricted to the hemianopic field. The patient was fully aware of their fictitious nature. These disturbances disappeared progressively over a few weeks. The incidence of CBS associated with visual field defects following epilepsy surgery might be underestimated. Patients with post-surgical CBS should be reassured that it is not an epileptic phenomenon, and that it has a benign, self-limiting, course which does not usually require treatment.

Familial amyotrophic lateral sclerosis can be related to mutations in the Cu/Zn superoxide dismutase gene (SOD1) located on chromosome 21q22.1. This is the first report of a SOD1 mutation in a patient with Down syndrome. A 34-year-old woman with Down syndrome developed a lower motor neuron disease that led to death in two years. Autopsy findings confirmed the diagnosis. DNA examination identified a missense mutation at nucleotide 134 of exon 5 of the SOD1 gene resulting in the aminoacid substitution serine-134-asparagine (S134N). A real time PCR detected the mutation in two out of three alleles. The 70-yearold mother of the patient carries the same mutation but has not yet developed the disease. The missense mutation of SOD1 gene in two of the three alleles could have increased its toxic effects in the Down syndrome patient leading to an earlier onset and rapid progression of the disease. 2007 Elsevier B.V. All rights reserved.

Transthyretin-related hereditary amyloidosis (ATTR) is genotypically/phenotypically heterogeneous. We investigated myocardial involvement in ATTR in a cohort of patients with a wide range of mutations. Clinical/echocardiographic follow-up of 41 consecutive symptomatic ATTR patients from a single referral center was analyzed according to TTR mutation. Diagnosis was based on histology, immunohistochemistry and genotyping. Median follow up was 40 months (range 8-120). Among the 12 different mutations identified, Val30Met was found in 10 patients and Glu89Gln in seven. Compared with Val30Met, Glu89Gln was associated with higher LV mass index, lower left ventricular ejection fraction and shorter E-wave deceleration time. All Glu89Gln carriers had cardiomyopathy, which was more severe (for left ventricular thickness, left ventricular mass and restrictive pathophysiology) than in the six affected Val30Met patients. Glu89Gln was independently associated with higher risk of major cardiovascular events among cardiomyopathy patients. This follow-up study of ATTR patients carrying a wide range of mutations indicates that (1) cardiac involvement is a very important component of phenotypic expression; and (2) genotype is an important source of heterogeneity in myocardial involvement, with Glu89Gln being associated with a severe, heart-driven prognosis. We think that combined heart-liver transplantation could be considered for Glu89Gln carriers with established, morphologically severe cardiomyopathy.

Leucoencephalopathy with intracranial calcifications and cysts (LCC) is a rare disorder of unknown origin characterised radiologically by white matter abnormalities, calcifications and cysts with contrast enhancing nodules.1–4 Neuropathology reveals “angiomatous-like” rearrangements of microvessels and Rosenthal fibres (RF).1–3 The onset is almost invariably in early infancy to adolescence. Occurrence of disease in siblings suggests autosomal recessive inheritance.2 3 Neurological manifestations include cognitive decline, seizures, obstructive hydrocephalus, and progressive cerebellar, extrapyramidal and pyramidal signs. As some patients have visual disturbances and retinal vascular abnormalities resembling Coats’ disease,2 LCC has been linked to Coats plus syndrome, a rare disease characterised by retinal vascular abnormalities, leucoencephalopathy and calcifications without brain cysts.2 5 Systemic involvement is common with haematological, enteric, dermatological or skeletal abnormalities.2 5 We describe two sporadic patients with late onset LCC. ### Patient No 1 A 27-year-old woman, born to healthy non-consanguineous parents, presented with 5 month progression of symptoms of intracranial hypertension. Brain MRI showed the following: a large left thalamic cyst compressing the aqueduct and the third ventricle with triventricular hydrocephalus; another cerebellar cyst with a rim of post contrast enhancement; supratentorial and left cerebellar white matter hyperintensities on T2 weighted images; and post contrast enhancing nodules in the basal ganglia, thalami and centra semiovalia, densely calcified at CT (fig 1). Spinal …

Background Iron involvement/imbalance is strongly suspected in multiple sclerosis (MS) etiopathogenesis, but its role is quite debated. Iron deposits encircle the veins in brain MS lesions, increasing local metal concentrations in brain parenchyma as documented by magnetic resonance imaging and histochemical studies. Conversely, systemic iron overload is not always observed. We explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes in MS patients. Methods By the pyrosequencing technique, we investigated 414 MS cases [Relapsing-remitting (RR), n=273; Progressive, n=141, of which: Secondary (SP), n=103 and Primary (PP), n=38], and 414 matched healthy controls. Five SNPs in 4 genes were assessed: hemochromatosis (HFE: C282Y, H63D), ferroportin (FPN1: -8CG), hepcidin (HEPC: -582AG), and transferrin (TF: P570S). Results The FPN1-8GG genotype was overrepresented in the whole MS population (OR=4.38; 95%CI, 1.89-10.1; PHEPC -582GG genotype was overrepresented only in progressive forms (OR=2.53; 95%CI, 1.34-4.78; P=0.006) so that SP and PP versus RR yielded significant outputs (P=0.009). For almost all SNPs, MS disability score (EDSS), severity score (MSSS), as well as progression index (PI) showed a significant increase when comparing homozygotes versus individuals carrying other genotypes: HEPC -582GG (EDSS, 4.24±2.87 vs 2.78±2.1; P=0.003; MSSS, 5.6±3.06 vs 3.79±2.6; P=0.001); FPN1-8GG (PI, 1.11±2.01 vs 0.6±1.31; P=0.01; MSSS, 5.08±2.98 vs 3.85±2.8; P=0.01); HFE 63DD (PI, 1.63±2.6 vs 0.6±0.86; P=0.009). Finally, HEPC -582G-carriers had a significantly higher chance to switch into the progressive form (HR=3.55; 1.83-6.84; log-rank P=0.00006). Conclusions Polymorphisms in the genes coding for iron binding and transporting proteins, in the presence of local iron overload, might be responsible for suboptimal iron handling. This might account for the significant variability peculiar to MS phenotypes, particularly affecting MS risk and progression paving the way for personalized pharmacogenetic applications in the clinical practice.

Background Temporal, i.e., 24-hour, weekly, and seasonal patterns in the occurrence of acute cardiovascular and cerebrovascular events are well documented; however, little is known about temporal, especially seasonal, variation in multiple sclerosis (MS) and its relapses. This study investigated, by means of a validated chronobiological method, whether severe relapses of MS, ones requiring medical specialty consultation, display seasonal differences, and whether they are linked with seasonal differences in local meteorological variables. Results We considered 96 consecutive patients with severe MS relapse (29 men, 67 women, mean age 38.5 ± 8.8 years), referred to the Multiple Sclerosis Center, Bellaria Hospital, Bologna, Italy, between January 1, 2007 and December 31, 2008. Overall, we analyzed 164 relapses (56 in men, 108 in women; 115 in patients aged < 40 years, 49 in patients ≥40 years). Relapses were more frequent in May and June (12.2% each) and the least frequent in September (3.7%). Chronobiological analysis showed a biphasic pattern (major peak in May-June, secondary peak in November-December, p = 0.030). Analysis of monthly mean meteorological data showed a significant seasonal pattern in ambient temperature (peak in July, p < 0.001), relative humidity (peak in January, p < 0.001), and wind speed (peak in June, p = 0.011). Conclusions In this Italian setting, we found a biphasic pattern (peaks in spring and autumn) in severe MS relapses requiring medical consultation by doctors of the MS specialty center, apparently unrelated to meteorological variables. Confirmations of the findings on larger multi-center populations residing in different climatic conditions are needed to further explore the potential seasonality of MS relapses and associated environmental triggers.

Background Several studies have reported hypoperfusion of the brain parenchyma in multiple sclerosis (MS) patients. We hypothesized a possible relationship between abnormal perfusion in MS and hampered venous outflow at the extracranial level, a condition possibly associated with MS and known as chronic cerebrospinal venous insufficiency (CCSVI). Methods We investigated the relationship between CCSVI and cerebral perfusion in 16 CCSVI MS patients and 8 age- and sex-matched healthy controls. Subjects were scanned in a 3-T scanner using dynamic susceptibility, contrast-enhanced, perfusion-weighted imaging. Cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were measured in the gray matter (GM), white matter (WM) and the subcortical GM (SGM). The severity of CCSVI was assessed according to the venous hemodynamic insufficiency severity score (VHISS) on the basis of the number of venous segments exhibiting flow abnormalities. Results There was a significant association between increased VHISS and decreased CBF in the majority of examined regions of the brain parenchyma in MS patients. The most robust correlations were observed for GM and WM (r = -0.70 to -0.71, P < 0.002 and P corrected = 0.022), and for the putamen, thalamus, pulvinar nucleus of thalamus, globus pallidus and hippocampus (r = -0.59 to -0.71, P < 0.01 and P corrected < 0.05). No results for correlation between VHISS and CBV or MTT survived multiple comparison correction. Conclusions This pilot study is the first to report a significant relationship between the severity of CCSVI and hypoperfusion in the brain parenchyma. These preliminary findings should be confirmed in a larger cohort of MS patients to ensure that they generalize to the MS population as a whole. Reduced perfusion could contribute to the known mechanisms of virtual hypoxia in degenerated axons.

It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (familial ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1,757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1,523 from mainland Italy. Sixty (3.7%) of 1,624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat expansion. None of the 619 regionally-matched control samples (1,238 chromosomes) carried the expansion. Twenty-five cases (36.2%) had behavioral FTD in addition to ALS. FTD or unspecified dementia was also detected in 19 pedigrees (27.5%) in first-degree relatives of ALS patients. Cases carrying the C9ORF72 hexanucleotide expansion survived one year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucloetide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the commonest mutation in Italy and the second more common in Sardinia.

We have previously documented that 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has a high affinity for transthyretin (TTR)-infiltrated myocardium, allowing a differential diagnosis with light-chain cardiac amyloidosis [(1)][1] and other non-amyloidotic cardiomyopathies with a