Publications by authors named "Roberto Cantello"

125 Publications

Cerebrospinal Tau levels as a predictor of early disability in multiple sclerosis.

Mult Scler Relat Disord 2021 Aug 29;56:103231. Epub 2021 Aug 29.

Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Department of Health Sciences, University of Piemonte Orientale, Novara, Italy; Neurology Unit, S. Andrea Hospital, Department of Translational Medicine, University of Piemonte Orientale, Vercelli, Italy.

Introduction: Axonal loss is an important feature of Multiple Sclerosis (MS), being strongly related to irreversible disability accumulation. Nonetheless, the exact mechanisms underlying axonal loss remain unclear. Cerebrospinal fluid (CSF) levels of Tau and Beta-amyloid (Abeta) currently represent diagnostic biomarkers in other neurodegenerative diseases. In MS, studies on CSF Tau and Abeta provided preliminary informations on disease prognosis, but results have not yet been replicated.

Methods: We investigated whether CSF Tau and Abeta levels could predict early disability accumulation in MS patients. 100 patients underwent CSF analysis during their diagnostic work-up. Demographic, clinical, radiological features and CSF were collected at baseline. MS severity score (MSSS) and age-related MSSS (ARMSS) were calculated at last follow-up. We performed Mann-Whitney test, Spearman's coefficient, and multiple regression analysis for significant predictors of disability based on CSF Abeta and Tau levels, gender, age at diagnosis and MRI characteristics at baseline.

Results: Baseline CSF Tau levels moderately correlated with MSSS (r=0.372 p=0.0001) and weakly with ARMSS (r=0.237 p=0.0176) after a mean two years follow-up. Predictors of early disability evaluated with MSSS and ARMSS were CSF Tau (Beta:0.258 p=0.009 and Beta:0.252 p=0.01) and spinal cord involvement (Beta:0.196 p=0.029 and Beta:0.240 p=0.008); as well as age at MS diagnosis (Beta:0.286 p=0.001) for MSSS, and high brain lesion load (Beta:0.207 p=0.02) for ARMSS.

Conclusion: CSF Tau levels at diagnosis possibly has a predictive value along with MRI features and age at diagnosis. We hypothesize that Tau levels may express chronic axonal damage, possibly contributing to early MS disability.
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http://dx.doi.org/10.1016/j.msard.2021.103231DOI Listing
August 2021

Genomic and functional evaluation of TNFSF14 in multiple sclerosis susceptibility.

J Genet Genomics 2021 Jun 25;48(6):497-507. Epub 2021 May 25.

Department of Health Sciences, Center on Autoimmune and Allergic Diseases (CAAD), UPO, University of Eastern Piedmont, A. Avogadro, Novara 28100, Italy. Electronic address:

Among multiple sclerosis (MS) susceptibility genes, the strongest non-human leukocyte antigen (HLA) signal in the Italian population maps to the TNFSF14 gene encoding LIGHT, a glycoprotein involved in dendritic cell (DC) maturation. Through fine-mapping in a large Italian dataset (4,198 patients with MS and 3,903 controls), we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region. Expression quantitative trait locus (eQTL) analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells, which is consistent with the allelic imbalance in RNA-Seq reads (P < 0.0001). The MS risk allele is associated with reduced levels of TNFSF14 gene expression (P < 0.01) in blood cells from 84 Italian patients with MS and 80 healthy controls (HCs). Interestingly, patients with MS are lower expressors of TNFSF14 compared to HC (P < 0.007). Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs (CD11c, P = 0.035) in 37 HCs, as well as in in vitro monocyte-derived DCs from 22 HCs (P = 0.04). Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells, which may play a role in MS pathogenesis.
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http://dx.doi.org/10.1016/j.jgg.2021.03.017DOI Listing
June 2021

Predictive factors of Status Epilepticus and its recurrence in patients with adult-onset seizures: A multicenter, long follow-up cohort study.

Seizure 2021 Oct 18;91:397-401. Epub 2021 Jul 18.

Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension of Reggio Calabria, National Council of Research, Institute of Clinical Physiology, Reggio Calabria, Italy.

Purpose: Status epilepticus (SE) is associated with high morbidity and mortality. This multicenter retrospective cohort study aims to identify the factors associated with the occurrence of SE and the predictors of its recurrence in patients with adult-onset seizures.

Methods: We retrospectively analyzed data of 1115 patients with seizure onset>18 years, observed from 1983 to 2020 in 7 Italian Centers (median follow-up 2.1 years). Data were collected from the databases of the Centers. Patients with SE were consecutively recruited, and patients without SE history were randomly selected in a 2:1 ratio. To assess determinants of SE, different clinical-demographic variables were evaluated and included in univariate and multivariate logistic regression model.

Results: Three hundred forty-seven patients had a SE history, whereas the remaining 768 patients had either isolated seizures or epilepsy without SE history. The occurrence of SE was independently associated with increasing age at onset of disease (OR 1.02, 95% CI 1.01--1.03, p<0.001), female sex (OR 1.39, 95% CI 1.05--1.83, p=0.02) and known etiology (OR 3.58, 95% CI 2.61--4.93, p<0.001). SE recurred in 21% of patients with adult-onset SE and recurrence was associated with increasing number of anti-seizure medications taken at last follow-up (OR 1.88, 95% CI 1.31--2.71, p<0.001).

Conclusions: In patients with adult-onset seizures, SE occurrence is associated with known etiologies, advanced age and female sex. Patients with recurrent SE are likely to have a refractory epilepsy, deserving careful treatment to prevent potentially fatal events.
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http://dx.doi.org/10.1016/j.seizure.2021.07.009DOI Listing
October 2021

Efficacy of Cannabinoids on Spasticity and Chronic Pain in a Patient with Co-occurrence of Multiple Sclerosis and Neurofibromatosis Type 1.

Eur J Case Rep Intern Med 2021 13;8(5):002424. Epub 2021 May 13.

Neurology Unit, Maggiore della Carità Hospital, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease involving the skin and central nervous system (CNS), and also characterized by skeletal and spinal schwannomas that may cause chronic neurogenic pain. Furthermore, pain in NF1 is underestimated, even though it has an impact on quality of life. Multiple sclerosis (MS) is the most common acquired demyelinating disease that may in later stages present with refractory spasticity, particularly in the lower limbs. Oromucosal cannabinoid sprays are currently available for spasticity treatment in MS, with encouraging results on MS pain, but few data have been reported regarding the use of cannabinoids in NF1. We report the successful treatment of chronic neurogenic pain and spasticity in a patient with co-occurrence of NF1 and MS after a poor response to standard approaches.

Learning Points: Chronic pain is a possible complication of several neurological conditions and may show a poor response to standard drugs, thus affecting quality of life.Oromucosal cannabinoid sprays are routinely used in multiple sclerosis spasticity.Cannabinoids may be also effective against neurogenic pain in neurofibromatosis type 1.
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http://dx.doi.org/10.12890/2021_002424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191353PMC
May 2021

Simple Parameters from Complete Blood Count Predict In-Hospital Mortality in COVID-19.

Dis Markers 2021 13;2021:8863053. Epub 2021 May 13.

Università del Piemonte Orientale UPO, Novara, Italy.

Introduction: The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions.

Materials And Methods: In this study, we retrospectively assessed the prognostic value of a simple tool, the complete blood count, on a cohort of 664 patients ( 260; 39%, median age 70 (56-81) years) hospitalized for COVID-19 in Northern Italy. We collected demographic data along with complete blood cell count; moreover, the outcome of the hospital in-stay was recorded.

Results: At data cut-off, 221/664 patients (33.3%) had died and 453/664 (66.7%) had been discharged. Red cell distribution width (RDW) ( 10.4; < 0.001), neutrophil-to-lymphocyte (NL) ratio ( 7.6; = 0.006), and platelet count ( 5.39; = 0.02), along with age ( 87.6; < 0.001) and gender ( 17.3; < 0.001), accurately predicted in-hospital mortality. Hemoglobin levels were not associated with mortality. We also identified the best cut-off for mortality prediction: a NL ratio > 4.68 was characterized by an odds ratio for in-hospital mortality (OR) = 3.40 (2.40-4.82), while the OR for a RDW > 13.7% was 4.09 (2.87-5.83); a platelet count > 166,000/L was, conversely, protective (OR: 0.45 (0.32-0.63)).

Conclusion: Our findings arise the opportunity of stratifying COVID-19 severity according to simple lab parameters, which may drive clinical decisions about monitoring and treatment.
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http://dx.doi.org/10.1155/2021/8863053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123088PMC
June 2021

Flash-evoked high-frequency EEG oscillations in photosensitive epilepsies.

Epilepsy Res 2021 May 2;172:106597. Epub 2021 Mar 2.

Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Azienda Ospedaliero-Universitaria "Maggiore della Carità", Novara, Italy.

Objective: To determine the feasibility of measuring scalp-recorded, flash-evoked, high-frequency EEG oscillations (F-HFOs) using a relatively simple technique. Furthermore, to assess whether F-HFOs are enhanced in photosensitive epileptic patients and if they might be proposed as a putative non-provocative biomarker of photosensitivity.

Methods: We studied 19 photosensitive patients with idiopathic generalized epilepsy, and 22 controls matched for demographic features. We extracted F-HFOs from the broadband scalp flash-visual evoked potential (b F-VEP) through appropriate filtering. We measured F-HFO amplitude, number and latency. Also, we carried out a time-frequency domain spectral F-HFO analysis. Inter-group statistics was performed. Within-groups, F-HFO features were correlated to the b F-VEP.

Results: The N3-N3 wave of the b F-VEP was significantly (p = 0.01) larger in patients compared to controls. The same was true for the inter-group F-HFO amplitude (p = 0.01). F-HFOs showed two main spectral peaks (∼88 and ∼125 Hz), whose power was greater (p = 0.001) in patients than in controls. The ∼88 Hz peak power exceeded the upper normal range in 15/19 patients. Patients showed a significant (p = 0.04) correlation between the ∼88 Hz peak power and the size of the N3-N3 wave.

Significance: A simplified F-HFO measurement proved feasible. In patients, F-HFOs were enhanced in terms of both size and spectral power, suggesting a role in the generation of the photoparoxysmal response. Some spectral features of the F-HFOs may be proposed as a putative non-provocative marker of epileptic photosensitivity.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106597DOI Listing
May 2021

Validation of an Algorithm to Detect Multiple Sclerosis Cases in Administrative Health Databases in Piedmont (Italy): An Application to the Estimate of Prevalence by Age and Urbanization Level.

Neuroepidemiology 2021 10;55(2):119-125. Epub 2021 Mar 10.

Epidemiology Unit, ASL TO3 Regione Piemonte, Grugliasco, Italy.

Introduction: Italy is considered a high-risk country for multiple sclerosis (MS). Exploiting electronic health archives (EHAs) is highly useful to continuously monitoring the prevalence of the disease, as well as the care delivered to patients and its outcomes. The aim of this study was to validate an EHA-based algorithm to identify MS patients, suitable for epidemiological purposes, and to estimate MS prevalence in Piedmont (North Italy).

Methods: MS cases were identified, in the period between January 1, 2012 and December 31, 2017, linking data from 4 different sources: hospital discharges, drug prescriptions, exemptions from co-payment to health care, and long-term care facilities. Sensitivity of the algorithm was tested through record linkage with a cohort of 656 neurologist-confirmed MS cases; specificity was tested with a cohort of 2,966,293 residents presumably not affected by MS. Undercount was estimated by a capture-recapture method. We calculated crude, and age- and gender-specific prevalence. We also calculated age-adjusted prevalence by level of urbanization of the municipality of residence.

Results: On December 31, 2017, the algorithm identified 8,850 MS cases. Sensitivity was 95.9%, specificity was 99.97%, and the estimated completeness of ascertainment was 91.9%. The overall prevalence, adjusted for undercount, was 152 per 100,000 among men and 286 among women; it increased with increasing age and reached its peak value in the 45- to 54-year class, followed by a progressive reduction. The age-adjusted prevalence of residents in cities was 15% higher than in those living in the countryside.

Discussion/conclusion: We validated an algorithm based on EHAs to identify cases of MS for epidemiological use. The prevalence of MS, adjusted for undercount, was among the highest in Italy. We also found that the prevalence was higher in highly urbanized areas.
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http://dx.doi.org/10.1159/000513763DOI Listing
March 2021

Telehealth in Neurodegenerative Diseases: Opportunities and Challenges for Patients and Physicians.

Brain Sci 2021 Feb 13;11(2). Epub 2021 Feb 13.

Department of Neurology and ALS Centre, Traslational Medicine, University of Piemonte Orientale, Maggiore della Carità Hospital, 28100 Novara, Italy.

Telehealth, by definition, is distributing health-related services while using electronic technologies. This narrative Review describes the technological health services (telemedicine and telemonitoring) for delivering care in neurodegenerative diseases, Alzheimer's disease, Parkinson's Disease, and amyotrophic lateral Sclerosis, among others. This paper aims to illustrate this approach's primary experience and application, highlighting the strengths and weaknesses, with the goal of understanding which could be the most useful application for each one, in order to facilitate telehealth improvement and use in standard clinical practice. We also described the potential role of the COVID-19 pandemic to speed up this service's use, avoiding a sudden interruption of medical care.
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http://dx.doi.org/10.3390/brainsci11020237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917616PMC
February 2021

Paraneoplastic neuromyelitis optica spectrum disorders: a case series.

Neurol Sci 2021 Jun 28;42(6):2519-2522. Epub 2021 Jan 28.

Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Novara, Italy.

Aquaporin-4 antibody (AQP4-IgG) neuromyelitis optica spectrum disorders (NMOSD) are rare idiopathic autoimmune diseases, presenting with optic neuritis (ON), longitudinally extensive transverse myelitis (LETM), and brainstem syndromes and a prevalence range between 0.5 and 4/100,000. Only 3% to 25% of NMOSD have been described as a paraneoplastic (PN) syndrome (PNNMOSD). Both idiopathic NMOSD (INMOSD) and PNNMOSD cases mostly affect females, but PNNMOSD usually presents with a spinal cord or brainstem involvement in elderly patients. Few cases of both malignancies (for the majority breast or lung cancer) and benign tumors (monoclonal gammopathy) were previously reported. Currently, there is no consensus on treatment approach for PNNMOSD (only surgical removal or surgery combined with chronic immunosuppression). Here, we present a series of three newly diagnosed PNNMOSD cases, who differ from each other for demographic and clinical features, tumor association, long-term treatment, and outcome. We propose that a PN etiology should be considered always whenever a new diagnosis of NMOSD is made, not only in patients over 50 years old or in spinal cord/brainstem lesions presentations. Our findings add to existing evidence and raise awareness on PNNMOSD. We enhance the importance for the clinicians of recognizing tumor symptoms and signs whenever a NMOSD is newly diagnosed.
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http://dx.doi.org/10.1007/s10072-021-05055-yDOI Listing
June 2021

Expanding the genetic spectrum of primary familial brain calcification due to SLC2OA2 mutations: a case series.

Neurogenetics 2021 03 20;22(1):65-70. Epub 2021 Jan 20.

Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.

Primary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition: SLC20A2, PDGFRB, PDGFB, and XPR1 inherited as autosomal-dominant trait, while MYORG and JAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants in SLC20A2, two exonic and one intronic, which we found in patients with PFBC associated to three different clinical phenotypes. One variant is novel and two were already described as variants of uncertain significance. We confirm the pathogenicity of these three variants and suggest a broadening of the phenotypic spectrum associated with mutations in SLC20A2.
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http://dx.doi.org/10.1007/s10048-021-00634-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997821PMC
March 2021

Identification of Key Phospholipids That Bind and Activate Atypical PKCs.

Biomedicines 2021 Jan 6;9(1). Epub 2021 Jan 6.

Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy.

PKCζ and PKCι/λ form the atypical protein kinase C subgroup, characterised by a lack of regulation by calcium and the neutral lipid diacylglycerol. To better understand the regulation of these kinases, we systematically explored their interactions with various purified phospholipids using the lipid overlay assays, followed by kinase activity assays to evaluate the lipid effects on their enzymatic activity. We observed that both PKCζ and PKCι interact with phosphatidic acid and phosphatidylserine. Conversely, PKCι is unique in binding also to phosphatidylinositol-monophosphates (e.g., phosphatidylinositol 3-phosphate, 4-phosphate, and 5-phosphate). Moreover, we observed that phosphatidylinositol 4-phosphate specifically activates PKCι, while both isoforms are responsive to phosphatidic acid and phosphatidylserine. Overall, our results suggest that atypical Protein kinase C (PKC) localisation and activity are regulated by membrane lipids distinct from those involved in conventional PKCs and unveil a specific regulation of PKCι by phosphatidylinositol-monophosphates.
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http://dx.doi.org/10.3390/biomedicines9010045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825596PMC
January 2021

Detection of White Matter Ultrastructural Changes for Amyotrophic Lateral Sclerosis Characterization: A Diagnostic Study from Dti-Derived Data.

Brain Sci 2020 Dec 16;10(12). Epub 2020 Dec 16.

ALS Center & Department of Neurology, "Maggiore della Carità" Hospital, University of Piemonte Orientale (UPO), Via Solaroli 17, 28100 Novara, Italy.

In amyotrophic lateral sclerosis (ALS), magnetic resonance imaging (MRI) allows investigation at the microstructural level, employing techniques able to reveal white matter changes. In the current study, a diffusion tensor imaging (DTI) analysis, with a collection of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) indexes, was performed in ALS patients to correlate geno- and phenotype features with MRI data, to investigate an in-vivo correlation of different neuropathological patterns. All patients who underwent the MR-DTI analysis were retrospectively recruited. MRI scan was collected within three months from diagnosis. FA and ADC values were collected in corpus callosum (CC), corona radiata (CR), cerebral peduncle (CR), cerebellar peduncle (CbP) and corticospinal tract at posterior limb of internal capsule (CST). DTI analysis performed in the whole ALS cohort revealed significant FA reduction and ADC increase in all selected regions, as widespread changes. Moreover, we observed a higher value of FA in rCR in bulbar patients. A positive correlation between ALS Functional Rating Scale-Revised and FA in rCP was evident. In consideration of the non-invasiveness, the reliability and the easy reproducibility of the method, we believe that brain MRI with DTI analyses may represent a valid tool usable as a diagnostic marker in ALS.
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http://dx.doi.org/10.3390/brainsci10120996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766961PMC
December 2020

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients.

Sci Rep 2020 11 26;10(1):20731. Epub 2020 Nov 26.

Department of Translational Medicine, Università del Piemonte Orientale UPO, Via Solaroli 17, 28100, Novara, NO, Italy.

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO/FiO ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk.
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http://dx.doi.org/10.1038/s41598-020-77698-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692524PMC
November 2020

Telehealth approach for amyotrophic lateral sclerosis patients: the experience during COVID-19 pandemic.

Acta Neurol Scand 2021 May 24;143(5):489-496. Epub 2020 Nov 24.

Department of Neurology and ALS Centre, University of Piemonte Orientale, Maggiore della Carità Hospital, Novara, Italy.

Background And Objective: Specialized multidisciplinary ALS care has been shown to extend survival and improve patient's and caregiver's quality of life. During the COVID-19 pandemic, the management of patients suddenly changed and telemedicine has been proven to be as effective as outpatient care. We elaborate the experience with Telemedicine of a Tertiary ALS Center from an Italian geographical area with high infectious risk during the COVID-19 pandemic.

Methods: 19 patients were evaluated in telemedicine by a multidisciplinary team including a neurologist (clinical evaluation, intercurrent events, and drug prescriptions); a dietician (diet and weight monitoring); a psychologist (psychological assessment and support); and a physiotherapist (physiotherapy treatment and device prescription). Telemedicine was performed using the online platform "IoMT Connected Care Platform (Ticuro Reply)."

Results: All patients reported a positive perception of talking face to face with healthcare professionals and were satisfied with how the team understood their problems. During video televisits, there was a change in the patient's medication regimen in 11/19; 2/19 required pneumological evaluation and started NIV; and 9/16 patients required prescription of devices. The mean monthly decline of ALSFRS-R before televisit was 0.88 (SD 1.17) and during televisit of 0.49 (SD 0.75). Bodyweight and daily caloric content remain stable. Reduction in HADS scores and stability in ALSAQ-40 were observed.

Discussion: Our study positively reproduced the multidisciplinary approach currently used with ALS patients, trying to stabilize the functional and metabolic status and improving the psychological one. Future directions include a personalized telemedicine program according to the patient's needs.
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http://dx.doi.org/10.1111/ane.13373DOI Listing
May 2021

Direct antivirals and cognitive impairment in hepatitis C: a clinical-neurophysiologic study.

J Neurovirol 2020 12 10;26(6):870-879. Epub 2020 Sep 10.

Neurology Unit Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

Cognition was assessed in hepatitis C virus (HCV) patients, who did not meet the criteria for a minimal hepatic encephalopathy. Their liver function was compensated. We then disentangled potential cognitive changes associated with a sustained virologic response at 12 weeks (SVR-12), following treatment with direct antiviral agents (DAAs). We studied 23 selected HCV patients with a battery of standard neuropsychological tests, and with recordings of the P300 wave, a cerebral potential of "cognitive" significance. There was a baseline evaluation (T0) and a second one 6 months later (T1). We had 2 control groups of comparable age and sex, i.e., 15 patients suffering from non-alcoholic fatty liver disease (NAFLD) and 15 healthy subjects. At T0, we detected a significant (p < 0.05) cognitive impairment in the HCV group, which involved episodic and working memory, attention, visuospatial and verbal abilities, executive functions, and logic reasoning. The P300 latency was significantly (p < 0.05) delayed in the group. At T1, we observed some significant (p < 0.05) HCV recovery in given test domains, e.g., memory, executive functions, and reasoning. Accordingly, the P300 latency shortened significantly (p < 0.05). HCV patients exhibited subtle cognitive defects, somehow independent of their liver condition, possibly linked to direct or indirect brain involvement by the virus. These defects partly recovered following the SVR-12, as achieved through DAAs. The P300 wave was a valid neurophysiologic counterpart of these changes. DAAs can have a role in the early preservation of cognition in HCVs.
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http://dx.doi.org/10.1007/s13365-020-00904-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716927PMC
December 2020

Cannabinoids in multiple sclerosis: A neurophysiological analysis.

Acta Neurol Scand 2020 Oct 21;142(4):333-338. Epub 2020 Jul 21.

Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

Objectives: To investigate the action of cannabinoids on spasticity and pain in secondary progressive multiple sclerosis, by means of neurophysiological indexes.

Material And Methods: We assessed 15 patients with progressive MS (11 females) using clinical scales for spasticity and pain, as well as neurophysiological variables (H/M ratio, cutaneous silent period or CSP). Testing occurred before (T0) and during (T1) a standard treatment with an oral spray containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Neurophysiological measures at T0 were compared with those of 14 healthy controls of similar age and sex (HC). We then compared the patient results at the two time points (T1 vs T0).

Results: At T0, neurophysiological variables did not differ significantly between patients and controls. At T1, spasticity and pain scores improved, as detected by the Modified Ashworth Scale or MAS (P = .001), 9-Hole Peg Test or 9HPT (P = .018), numeric rating scale for spasticity or NRS (P = .001), and visual analogue scale for pain or VAS (P = .005). At the same time, the CSP was significantly prolonged (P = .001).

Conclusions: The THC-CBD spray improved spasticity and pain in secondary progressive MS patients. The spray prolonged CSP duration, which appears a promising tool for assessing and monitoring the analgesic effects of THC-CBD in MS.
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http://dx.doi.org/10.1111/ane.13313DOI Listing
October 2020

A prospective longitudinal study on the microbiota composition in amyotrophic lateral sclerosis.

BMC Med 2020 06 17;18(1):153. Epub 2020 Jun 17.

Department of Neurology and ALS Centre, University of Piemonte Orientale, Maggiore della Carità Hospital, Corso Mazzini 18, 28100, Novara, Italy.

Background: A connection between amyotrophic lateral sclerosis (ALS) and altered gut microbiota composition has previously been reported in animal models. This work is the first prospective longitudinal study addressing the microbiota composition in ALS patients and the impact of a probiotic supplementation on the gut microbiota and disease progression.

Methods: Fifty patients and 50 matched controls were enrolled. The microbial profile of stool samples from patients and controls was analyzed via PCR-Denaturing Gradient Gel Electrophoresis, and the main microbial groups quantified via qPCR. The whole microbiota was then analyzed via next generation sequencing after amplification of the V3-V4 region of 16S rDNA. Patients were then randomized to receive probiotic treatment or placebo and followed up for 6 months with ALSFRS-R, BMI, and FVC%.

Results: The results demonstrate that the gut microbiota of ALS patients is characterized by some differences with respect to controls, regardless of the disability degree. Moreover, the gut microbiota composition changes during the course of the disease as demonstrated by the significant decrease in the number of observed operational taxonomic unit during the follow-up. Interestingly, an unbalance between potentially protective microbial groups, such as Bacteroidetes, and other with potential neurotoxic or pro-inflammatory activity, such as Cyanobacteria, has been shown. The 6-month probiotic treatment influenced the gut microbial composition; however, it did not bring the biodiversity of intestinal microbiota of patients closer to that of control subjects and no influence on the progression of the disease measured by ALSFRS-R was demonstrated.

Conclusions: Our study poses the bases for larger clinical studies to characterize the microbiota changes as a novel ALS biomarker and to test new microbial strategy to ameliorate the health status of the gut.

Trial Registration: CE 107/14, approved by the Ethics Committee of the "Maggiore della Carità" University Hospital, Italy.
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http://dx.doi.org/10.1186/s12916-020-01607-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298784PMC
June 2020

Telemedicine and technological devices for amyotrophic lateral sclerosis in the era of COVID-19.

Neurol Sci 2020 06 21;41(6):1365-1367. Epub 2020 May 21.

Department of Neurology and ALS Centre, University of Piemonte Orientale, Maggiore della Carità Hospital, Corso Mazzini 18, 28100, Novara, Italy.

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http://dx.doi.org/10.1007/s10072-020-04457-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240164PMC
June 2020

Cortical visuomotor interactions in Freezing of Gait: A TMS approach.

Neurophysiol Clin 2020 Jul 27;50(3):205-212. Epub 2020 Apr 27.

Department of Translational Medicine, Section of Neurology, University of Piemonte Orientale and "Maggiore della Carità" University Hospital, Novara, Italy.

Objectives: Altered cortical visuomotor integration has been involved in the pathophysiology of freezing of gait (FoG) in parkinsonism. The aim of this study was to assess the connections between the primary visual (V1) and motor (M1) areas with a paired-pulse, twin-coil transcranial magnetic stimulation (TMS) technique in patients with FoG.

Methods: Twelve Parkinson's disease (PD) patients suffering from levodopa-responsive-FoG (off-FoG) were compared with 12 PD patients without FoG and 12 healthy subjects of similar age/sex. In the "off" condition, visuomotor connections (VMCs) were assessed bilaterally. A conditioning stimulus over the V1 phosphene hotspot was followed at interstimulus intervals (ISIs) of 18 and 40ms by a test stimulus over M1, to elicit motor evoked potentials (MEPs) in the contralateral first dorsal interosseous muscle.

Results: Significant (P<0.01), bilateral effects due to VMCs were detected in all three groups, consisting of a MEP suppression at ISI 18 and 40ms. However, in PD patients with FoG, the MEP suppression was significantly (P<0.05) enhanced, both at ISI 18-40ms, in comparison with the other two groups. The phenomenon was limited to the right hemisphere.

Conclusions: PD patients with FoG showed an excessive inhibitory response of the right M1 to inputs travelling from V1 at given ISIs. Right-sided alterations of the cortical visuomotor integration may contribute to the pathophysiology of FoG.
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http://dx.doi.org/10.1016/j.neucli.2020.04.001DOI Listing
July 2020

Location of first attack predicts the site of subsequent relapses in multiple sclerosis.

J Clin Neurosci 2020 Apr 24;74:175-179. Epub 2020 Feb 24.

Neurosciences Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.

Predictors of attack location in relapsing-remitting multiple sclerosis (RRMS) are poorly known. It has been suggested that the site of the first relapse may influence the location of the subsequents. We aimed to ascertain this hypothesis in a sample of patients consecutively recruited in two Italian MS Centres, with at least two MS attacks. The following data were collected from medical records: demographic data, locations involved in the first two (or three) MS attacks (optic nerve, spinal cord, brain stem/cerebellum, cerebral hemispheres, according to symptoms presented), time elapsed between relapses and onset of disease-modifying treatment (DMT). We enrolled 199 patients (67% females; MS onset age 30.0 ± 8.69 years), in 148 of whom we could define the precise attack location. In 70/148 patients (47%) the second attack involved exactly the same location as the first. There was an increased risk of relapsing in the same location of the first attack when this involved the optic nerve (OR 4.5, 95% CI 2.2-9.2, p < 0.0001), the brainstem/cerebellum (OR 3.5, 95% CI 1.7-6.9, p < 0.0001), or the spinal cord (OR 3.0, 95% CI 1.5-5.9, p = 0.001). The location of third relapse (N = 90) was equally influenced by the site of first attack. In 24 patients with optic neuritis in both the two first attacks, the side coincided in 50% of cases. The location of first attack has a major role in influencing the site of subsequent ones in RRMS.
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http://dx.doi.org/10.1016/j.jocn.2020.02.017DOI Listing
April 2020

Nerve conduction, circulating osteopontin and taxane-induced neuropathy in breast cancer patients.

Neurophysiol Clin 2020 Feb 9;50(1):47-54. Epub 2020 Jan 9.

Department of Translational Medicine, Section of Neurology, University of Piemonte-Orientale, Via Solaroli 17, 28100 Novara, Italy; Department of Neurology, "Maggiore della Carità" University Hospital, Corso-Mazzini 18, 28100 Novara, Italy.

Objective: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling complication related to taxanes. Underlying mechanisms are not completely understood and no specific treatment exists. We investigated the role of nerve conduction studies (NCS) and of serum osteopontin (OPN) measurement as a means to stratify the risk of developing taxane-induced neuropathy (TIN).

Methods: We enrolled 50 women with breast cancer treated with taxanes (docetaxel or paclitaxel) in a 3-month prospective study. They were evaluated before chemotherapy (time-point T0) and followed up at 1 (T1) and 3 (T2) months with clinical examinations/scales, quality of life (QoL) questionnaires, NCS, and serum OPN dosages.

Results: A reduction of sural and superficial peroneal sensory action potentials was seen at T1, with a progression at T2 (P<0.001). In contrast, a significant impact of neuropathic symptoms on QoL only occurred at T2 (P<0.01). OPN levels at T0 inversely correlated to axonal loss in the sural nerve (T0-T2, P<0.01). OPN levels at T0 were lower in the intermediate and poor outcome patient subgroups, compared to the good outcome subgroup, as specifically defined (P<0.05).

Conclusion: Lower limb NCS changes occurred earlier than the detrimental effects of TIN on patients' QoL. Low serum OPN levels before chemotherapy may represent a novel biomarker of TIN risk.
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http://dx.doi.org/10.1016/j.neucli.2019.12.001DOI Listing
February 2020

Optic nerve sheath diameter asymmetry in healthy subjects and patients with intracranial hypertension.

Neurol Sci 2020 Feb 5;41(2):329-333. Epub 2019 Oct 5.

Department of Neurology, Saarland University Medical Center, Homburg, Germany.

Background: Ultrasonography of the optic nerve sheath diameter (ONSD) is used for the non-invasive assessment of increased intracranial pressure (ICP). ONSD values are usually obtained by averaging the measurements of the two eyes, but asymmetric ONSD dilation is possible, leading to potentially inaccurate ICP estimation when using binocular averaging. In addition, few data are available about the asymmetry of the ONSD and the use of the maximum ONSD value between eyes for raised ICP detection. The aim of the study was to evaluate the interocular ONSD asymmetry in healthy subjects and patients with intracranial hypertension (IH) by ultrasonography and to investigate whether the maximum ONSD could be as useful as the binocular assessment.

Methods: Forty healthy subjects and 40 patients with IH (20 with idiopathic intracranial hypertension and 20 with intracerebral hemorrhage) who underwent transorbital sonography were retrospectively enrolled. The prevalence and degree of ONSD asymmetry were compared among groups; ONSD median binocular and maximum values were compared.

Results: Forty-two out of 80 subjects (52.5%) showed significant ONSD asymmetry, without significant differences in prevalence among groups (p = 0.28). The median asymmetry was higher in patients than in healthy subjects (0.45 mm vs 0.23 mm; p = 0.007), without significant differences between the two pathologies (p = 0.58). Both binocular and maximum ONSD measurements were significantly higher in patients with IH than in controls (p < 0.001).

Conclusions: Interocular ONSD asymmetry occurs both in healthy subjects and, more consistently, in patients with IH. Both binocular and maximum ONSD may be useful markers for increased ICP detection.
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http://dx.doi.org/10.1007/s10072-019-04076-yDOI Listing
February 2020

Probiotics May Have Beneficial Effects in Parkinson's Disease: Evidence.

Front Immunol 2019 7;10:969. Epub 2019 May 7.

Neurology Unit, Department of Translational Medicine, Interdisciplinary Research Centre of Autoimmune Diseases, Movement Disorders Centre, University of Piemonte Orientale, Novara, Italy.

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons and intraneuronal accumulation of alpha-synuclein, both in the basal ganglia and in peripheral sites, such as the gut. Peripheral immune activation and reactive oxygen species (ROS) production are important pathogenetic features of PD. In this context, the present study focused on the assessment of effects of probiotic bacterial strains in PBMCs isolated from PD patients vs. healthy controls. 40 PD patients and 40 matched controls have been enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with a selection of probiotics microorganisms belonging to the and genus. release of the major pro- (Tumor Necrosis Factor-alpha and Interleukin-17A and 6) and anti-inflammatory (Interleukin 4 and 10) cytokines by PBMCs, as well as the production of ROS was investigated. Furthermore, we assessed the ability of probiotics to influence membrane integrity, antagonize the growth of potential pathogen bacteria, such as and and encode tyrosine decarboxylase genes (). All probiotic strains were able to inhibit inflammatory cytokines and ROS production in both patients and controls. The most striking results were obtained in PD subjects with LS01 and which significantly reduced pro-inflammatory and increased the anti-inflammatory cytokines ( < 0.05). Furthermore, most strains determined restoration of membrane integrity and inhibition of and . Finally, we also showed that all the strains do not carry gene, which is known to decrease levodopa bioavailability in PD patients under treatment. Probiotics exert promising results in decreasing pro-inflammatory cytokines, oxidative stress and potentially pathogenic bacterial overgrowth. longitudinal data are mandatory to support the use of bacteriotherapy in PD.
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http://dx.doi.org/10.3389/fimmu.2019.00969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513970PMC
September 2020

Results from Phase I Clinical Trial with Intraspinal Injection of Neural Stem Cells in Amyotrophic Lateral Sclerosis: A Long-Term Outcome.

Stem Cells Transl Med 2019 09 18;8(9):887-897. Epub 2019 May 18.

Eastern Piedmont University, "Maggiore della Carità" Hospital, Dipartimento di Neurologia, Novara.

The main objective of this phase I trial was to assess the feasibility and safety of microtransplanting human neural stem cell (hNSC) lines into the spinal cord of patients with amyotrophic lateral sclerosis (ALS). Eighteen patients with a definite diagnosis of ALS received microinjections of hNSCs into the gray matter tracts of the lumbar or cervical spinal cord. Patients were monitored before and after transplantation by clinical, psychological, neuroradiological, and neurophysiological assessment. For up to 60 months after surgery, none of the patients manifested severe adverse effects or increased disease progression because of the treatment. Eleven patients died, and two underwent tracheotomy as a result of the natural history of the disease. We detected a transitory decrease in progression of ALS Functional Rating Scale Revised, starting within the first month after surgery and up to 4 months after transplantation. Our results show that transplantation of hNSC is a safe procedure that causes no major deleterious effects over the short or long term. This study is the first example of medical transplantation of a highly standardized cell drug product, which can be reproducibly and stably expanded ex vivo, comprising hNSC that are not immortalized, and are derived from the forebrain of the same two donors throughout this entire study as well as across future trials. Our experimental design provides benefits in terms of enhancing both intra- and interstudy reproducibility and homogeneity. Given the potential therapeutic effects of the hNSCs, our observations support undertaking future phase II clinical studies in which increased cell dosages are studied in larger cohorts of patients. Stem Cells Translational Medicine 2019;8:887&897.
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http://dx.doi.org/10.1002/sctm.18-0154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708070PMC
September 2019

Hypertension, seizures, and epilepsy: a review on pathophysiology and management.

Neurol Sci 2019 Sep 4;40(9):1775-1783. Epub 2019 May 4.

Medical and Surgical Sciences Department, School of Medicine, Magna Græcia University of Catanzaro, Viale Europa, Catanzaro, Italy.

Background: Epilepsy and hypertension are common chronic conditions, both showing high prevalence in older age groups. This review outlines current experimental and clinical evidence on both direct and indirect role of hypertension in epileptogenesis and discusses the principles of drug treatment in patients with hypertension and epilepsy.

Methods: We selected English-written articles on epilepsy, hypertension, stroke, and cerebrovascular disease until December, 2018.

Results: Renin-angiotensin system might play a central role in the direct interaction between hypertension and epilepsy, but other mechanisms may be contemplated. Large-artery stroke, small vessel disease and posterior reversible leukoencephalopathy syndrome are hypertension-related brain lesions able to determine epilepsy by indirect mechanisms. The role of hypertension as an independent risk factor for post-stroke epilepsy has not been demonstrated. The role of hypertension-related small vessel disease in adult-onset epilepsy has been demonstrated. Posterior reversible encephalopathy syndrome is an acute condition, often caused by a hypertensive crisis, associated with the occurrence of acute symptomatic seizures. Chronic antiepileptic treatment should consider the risk of drug-drug interactions with antihypertensives.

Conclusions: Current evidence from preclinical and clinical studies supports the vision that hypertension may be a cause of seizures and epilepsy through direct or indirect mechanisms. In both post-stroke epilepsy and small vessel disease-associated epilepsy, chronic antiepileptic treatment is recommended. In posterior reversible encephalopathy syndrome blood pressure must be rapidly lowered and prompt antiepileptic treatment should be initiated.
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http://dx.doi.org/10.1007/s10072-019-03913-4DOI Listing
September 2019

K Index is a Reliable Marker of Intrathecal Synthesis, and an Alternative to IgG Index in Multiple Sclerosis Diagnostic Work-Up.

J Clin Med 2019 Apr 2;8(4). Epub 2019 Apr 2.

Institute of Neurology, Department of Transational Medicine, AOU Maggiore della Carità, University of PiemonteOrientale, corso Mazzini 18, 28100 Novara, Italy.

The K free light chain (K) index has been suggested as a reliable marker of intrathecal synthesis,despite the 2017 McDonald criteria for multiple sclerosis (MS) suggesting to "interpret with caution positiveimmunoglobulin G (IgG) index when testing for oligoclonal bands (OB) is negative or not performed". Theaim of this study was to compare the performance of K and IgG indexes for MS diagnosis and OB detectionin a cohort of Italian patients. We enrolled 385 patients (127 MS, 258 non-MS) who had cerebrospinal fluid(CSF) analysis, including isoelectric focusing (IEF), to detect OB in the diagnostic work-up. Albumin, IgGand free light chains were measured by nephelometry and used to calculate IgG and K indexes. Althoughthe two markers were highly related (r = 0.75, r2 = 0.55, p < 0.0001), the K index showed greater sensitivity andnegative predictive value (versus the IgG index) for OB detection (97% versus 48% and 97% versus 71%) andMS diagnosis (96% versus 50% and 98% versus 78%). These results support K index (and not IgG index) as afirst-line marker for MS, followed by IEF, according to a sequential testing approach in CSF analysis.
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http://dx.doi.org/10.3390/jcm8040446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518364PMC
April 2019

Holmes tremor caused by a natalizumab-related progressive multifocal leukoencephalopathy: a case report and brief review of the literature.

Neurol Sci 2019 Sep 1;40(9):1943-1945. Epub 2019 Mar 1.

Department of Translational Medicine, Section of Neurology, University of Eastern Piedmont, Novara, Italy.

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http://dx.doi.org/10.1007/s10072-019-03779-6DOI Listing
September 2019

Ultrasonography Monitoring of Optic Nerve Sheath Diameter and Retinal Vessels in Patients with Cerebral Hemorrhage.

J Neuroimaging 2019 05 3;29(3):394-399. Epub 2019 Feb 3.

Department of Neurology, Saarland University Medical Center, Homburg, Germany.

Background And Purpose: Evaluation of the diagnostic accuracy of optic nerve sheath diameter (ONSD) and Doppler indices of central retinal arteries and veins for the detection of increased intracranial pressure (ICP) in intracerebral hemorrhage (ICH) and of the usefulness of a second assessment of these variables in the monitoring of ICH.

Methods: A total of 46 acute ICH patients with (group 1, n = 25) and without (group 2, n = 21) clinical and radiological computed tomography signs of raised ICP and 40 healthy controls were recruited. The median binocular ONSD and Doppler indices of retinal vessels including resistive index (RI) and retinal venous pulsation (RVP) were compared among groups, both at admission and later during ICH monitoring.

Results: Median binocular ONSD showed higher accuracy for the detection of increased ICP (sensitivity and specificity 100%), while Doppler indices were less accurate (sensitivity 48% and specificity 95% for RI; 80% and 62% for RVP). In ICH patients, ONSD was significantly elevated in group 1 both at admission (6.40 mm [interquartile range [IQR] = .70] vs. 4.70 [.40]) and at control time (6.00 [.55] vs. 4.55 [.40]; P < .01), as well as RI (.79 [.11] vs. .77 [.03] and .80 [.06] vs. .75 [.35]; P = .01). RVP was significantly increased in group 1 only at admission (3.20 cm/s [1.05] vs. 2.00 [1.55], P = .02).

Conclusions: Median binocular ONSD evaluation showed higher accuracy for the estimation of elevated ICP compared with Doppler indices of retinal vessels. The ONSD enlargement detected in the early phase of ICH persists at control time.
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http://dx.doi.org/10.1111/jon.12604DOI Listing
May 2019

Depression and risk of cognitive dysfunctions in amyotrophic lateral sclerosis.

Acta Neurol Scand 2019 May 28;139(5):438-445. Epub 2019 Feb 28.

Department of Neurology, Maggiore della Carità Hospital, University of Piemonte Orientale, Novara, Italy.

Objectives: Amyotrophic lateral sclerosis (ALS) is not only a motor disorder: More than 50% of patients have cognitive dysfunctions over the course of the disease. At the same time, mood disorders may also occur in ALS patients following diagnosis due to the fatal prognosis; however, little data are available on any depression beforehand. Starting from these considerations, the aim of our study was to investigate the occurrence of depression in Italian ALS patients prior to diagnosis, evaluating its prevalence in the subjects who have developed cognitive dysfunctions and in those who did not.

Materials And Methods: We included 318 patients, establishing the presence of depression in the 5 years before ALS diagnosis. Patients underwent a complete battery of neuropsychological tests with the aim to evaluate the executive functions, behavior, language, and memory.

Results: Before diagnosis, 40 patients with ALS had been diagnosed with depression: Among them, 29 patients had cognitive impairment over the course of the disease and only 11 did not develop any cognitive alteration (OR 1.46; 95% CI: 1.26-1.66, adjusted for sex, age, and disease phenotype, P: 0.038). Moreover, there is a significant difference in survival time between ALS patients with depression before ALS, compared to ALS patients without previous depression (P: 0.006).

Conclusions: We reported a high prevalence of depression in the past in patients with ALS and cognitive impairment, as compared to patients without cognitive deficits, showing also that patients with both had a shorter survival time. These aspects require multidisciplinary approach at disease onset.
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http://dx.doi.org/10.1111/ane.13073DOI Listing
May 2019

Post-lumbar puncture headache: an adverse effect in multiple sclerosis work-up.

Neurol Sci 2019 Apr 21;40(4):759-762. Epub 2019 Jan 21.

Neurology Unit, Department of Translational Medicine, AOU Maggiore della Carità and University of Piemonte Orientale, Novara, Italy.

Background: Lumbar puncture (LP) is a safe procedure commonly performed in the diagnostic work-up of multiple sclerosis (MS), and its main adverse event is post-LP headache (PLPH). Predictors for PLPH in MS are not established.

Aims: To describe the occurrence of, and, factors related to PLPH in patients with suspected MS, studied on a daily-basis admission.

Patients And Methods: One hundred patients (70 females) were admitted for a diagnostic LP (standardized with a traumatic 19-G needle), observed for 6 h, and evaluated for adverse events 2 and 7 days later. Descriptive statistics and a multivariate analysis (for PLPH) were performed.

Results: Fifty-seven (57%) patients had PLPH at 48 h, which persisted 1 week in 31, and only two presented beyond the first 2 days. Other adverse events were tinnitus and neck stiffness. None required investigations or was hospitalized. Age was the only predictor for PLPH at day 2, whereas the onset of headache within 48 h and female gender were predictors for PLPH at day 7.

Conclusion: PLPH is a frequent complication of LP performed on daily-basis admission in MS work-up. The maximum onset is within the first 48 h. Age and gender seem the only predictors for the appearance and persistence of PLPH.
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http://dx.doi.org/10.1007/s10072-019-3724-zDOI Listing
April 2019
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