Bariatric surgery and dimethyl fumarate-induced lymphopenia in patients with multiple sclerosis.

INTRODUCTION: Lymphopenia is a known side effect of dimethyl fumarate (DMF), a disease-modifying therapy (DMT) for patients with multiple sclerosis (pwMS). A body mass index ≥ 30 kg/m2 has been identified as a protective factor; however, no data are available on lymphopenia in pwMS undergoing to weight loss due to bariatric surgery. METHODS: We described two pwMS with history of bariatric surgery who started DMF as DMT. RESULTS: The two pwMS experienced persistent lymphopenia during DMF-treatment, which was resolved after its discontinuation. CONCLUSIONS: Several mechanisms might modify DMF pharmacokinetic profiles after bariatric surgery and its bioavailability. Absolute lymphocyte count should be monitored in pwMS treated with DMF and history of bariatric surgery and weight loss.

Phenotypic Variability in Acquired and Idiopathic Dystonia.

Background: To date, a few studies have systematically investigated differences in the clinical spectrum between acquired and idiopathic dystonias. Objectives: To compare demographic data and clinical features in patients with adult-onset acquired and idiopathic dystonias. Methods: Patients were identified from among those included in the Italian Dystonia Registry, a multicenter Italian dataset of patients with adult-onset dystonia. Study population included 116 patients with adult-onset acquired dystonia and 651 patients with isolated adult-onset idiopathic dystonia. Results: Comparison of acquired and idiopathic dystonia revealed differences in the body distribution of dystonia, with oromandibular dystonia, limb and trunk dystonia being more frequent in patients with acquired dystonia. The acquired dystonia group was also characterized by lower age at dystonia onset, greater tendency to spread, lower frequency of head tremor, sensory trick and eye symptoms, and similar frequency of neck pain associated with CD and family history of dystonia/tremor. Conclusions: The clinical phenomenology of dystonia may differ between acquired and idiopathic dystonia, particularly with regard to the body localization of dystonia and the tendency to spread. This dissimilarity raises the possibility of pathophysiological differences between etiologic categories.

Higher Health Service Costs Associated With Delayed Diagnosis of Functional Neurological Disorder.

OBJECTIVE: Functional neurological disorder (FND) is frequently encountered in clinical practice but commonly misdiagnosed, which might lead to higher direct costs for the health care system. The investigators analyzed the direct costs associated with the diagnosis of FND compared with costs associated with other neurological conditions and explored possible cost trends related to the clinical and demographic features of FND. METHODS: Consecutive patients attending a general neurology clinic were recruited and underwent a structured assessment aimed to collect information pertaining to their demographic and clinical characteristics, as well as data regarding their prior diagnostic processes (e.g., the number of consulted specialists, number and type of investigations, emergency department visits, etc.). The costs were hence calculated and compared between the study groups. RESULTS: A total of 155 consecutive patients were recruited; of these, 18.6% had FND, 55.84% had one or more other neurological disorder (OND), and 27.10% presented with comorbid FND and OND. The total prediagnostic costs (in euros [€]) were higher in the FND group compared with the OND group (median=€289, interquartile range [IQR] €385 vs. median=€98, IQR €216; Mann-Whitney U=879.5, p=0.04). There was a higher diagnostic delay in the FND group compared with the OND group (median=48 months, IQR 60 months vs. median=12 months, IQR 6 months; Mann-Whitney U=162.00, p<0.01). Diagnostic delay significantly correlated with the total costs in the entire study sample (Spearman's ρ=0.25, p=0.003) but more strongly in the FND group (Spearman's ρ=0.81, p<0.001). In the FND group, higher numbers of investigations and costs were associated with the presence of a physiological or psychological trigger and multiple symptoms. CONCLUSIONS: Delayed diagnosis of FND significantly affects health care system costs, and raising awareness about FND to improve the diagnostic process and outcomes is necessary.

Relationship Between Orthostatic Hypotension and Cognitive Functions in Multiple System Atrophy: A Longitudinal Study.

Introduction: The aim of this study is to investigate the impact of orthostatic hypotension (OH) on cognitive functions in patients with multiple system atrophy (MSA) followed over time. Methods: Thirty-two MSA patients were enrolled and underwent a comprehensive neuropsychological battery; at baseline (T0) 15 out of 32 patients presented OH, assessed by means of orthostatic standing test. All patients underwent a follow-up (T1) evaluation 12 months after baseline. Thirteen out of 32 patients also underwent a second follow-up (T2) evaluation at 24 months. Changes over time on different neuropsychological tasks were compared between patients with and without OH by means of Mann-Whitney's U-test. Moreover, clinical categories of normal cognition, mild cognitive impairment, and dementia were determined, and changes at T1 and T2 in global cognitive status were compared between patients with and without OH. Results: At T0, patients with OH had better performance on words/non-words repetition task (p = 0.02) compared to patients without OH. Compared to patients without OH, patients with OH performed worse on semantic association task (p < 0.01) at T1 and on Stroop test-error effect (p = 0.04) at T2. The percentage of patients with worsened cognitive status at T1 was higher among patients with OH than among patients without OH (93 vs. 59%, p = 0.03). OH (ß = -4.67, p = 0.01), education (ß = 0.45, p = 0.02), age (ß = 0.19, p = 0.03), and Montreal Cognitive Assessment battery (MOCA) score at T0 (ß = -0.26, p = 0.04) were significant predictors of global cognitive status worsening at T1. Discussion: We found that global cognitive status worsened at 1-year follow-up in 93% of patients with OH, and OH, along with age, education, and MOCA score, predicted cognitive worsening over time. To clarify the relationship between OH and cognitive dysfunction in MSA, we suggest the use of clinical categories of normal cognition, mild cognitive impairment, and dementia in further longitudinal studies on MSA patients with and without OH.

Genetic characterization of a cohort with familial parkinsonism and cognitive-behavioral syndrome: A Next Generation Sequencing study.

OBJECTIVE: To perform the genetic characterization of a cohort with familial parkinsonism and cognitive-behavioral syndrome. METHODS: A Next Generation Sequencing - based targeted sequencing of 32 genes associated to various neurodegenerative phenotypes, plus a screening for SNCA Copy Number Variations and C9orf72 repeat expansion, was applied in a cohort of 85 Italian patients presenting with parkinsonism and cognitive and/or behavioral syndrome and a positive familial history for any neurodegenerative disorder (i.e., dementia, movement disorders, amyotrophic lateral sclerosis). RESULTS: Through this combined genetic approach, we detected potentially relevant genetic variants in 25.8% of patients with familial parkinsonism and cognitive and/or behavioral syndrome. Peculiar phenotypes are described (Cortico-basal syndrome with APP, Posterior Cortical Atrophy with GBA, Progressive Supranuclear Palsy-like with GRN, Multiple System Atrophy with TARDBP). The majority of patients presented a rigid-bradykinetic parkinsonian syndrome, while rest tremor was less common. Myoclonic jerks, pyramidal signs, dystonic postures and vertical gaze disturbances were more frequently associated with the presence of a pathogenic variant in one of the tested genes. CONCLUSIONS: Given the syndromic approach adopted in our study, we were able to provide a detailed clinical description of patients beyond the boundaries of specific clinical diagnoses and describe peculiar phenotypes. This observation further supports the knowledge that genetic disorders present phenotypic overlaps across different neurodegenerative syndromes, highlighting the limitations of current clinical diagnostic criteria defining sharp boundaries between distinct conditions.

Posterior Cortical Atrophy phenotype in a GBA N370S mutation carrier: a case report.

BACKGROUND: Glucocerebrosidase (GBA) heterozygous variants are the most important genetic risk factor for the development of alpha-synucleinopathies (i.e., Parkinson's disease and Dementia with Lewy Bodies). Herein, we report for the first time on a patient with a clinical diagnosis of Posterior Cortical Atrophy, carrier of the common GBA heterozygous variant N370S (c.1226A > G). CASE PRESENTATION: A 44-year-old woman with positive familial history for Dementia with Lewy Bodies disclosed three related signs characterizing the Balint's syndrome: ocular apraxia, optic ataxia and simultanagnosia. Over 2-year follow up, overt gaze apraxia (psychic paralysis of gaze) appeared leading to functional blindness. Given her young age at onset and positive familial history, she underwent a next-generation-sequencing (NGS) based screening of a panel of 32 genes related to neurodegenerative conditions within the ANAMNESYS (An origiNal Approach to study faMiliarity in NEurodegenerative SYndromeS) study. NGS demonstrated the N370S variant in the GBA gene (rs76763715), confirmed by Sanger sequencing. This is a relatively common variant, with predicted mild impact, already reported to occur in 2.4% of PD Italian patients; however, neither this nor other GBA variants have ever been reported to date in patients with Posterior Cortical Atrophy. Glucocerebrosidase activity was investigated and found to be significantly reduced (4.72 nmol/h/mg) compared to healthy controls as well as patients affected by neurodegenerative diseases, further supporting pathogenicity of the GBA variant. CONCLUSIONS: We report on a patient with a clinical diagnosis of Posterior Cortical Atrophy, carrier of the GBA heterozygous variant N370S (c.1226A > G; p.Asn409Ser) determining reduced GCase activity. This report also confirms the role of NGS-based targeted gene analysis in detecting peculiar clinical phenotypes associated with known pathogenic mutations and reinforces the knowledge that carriers of genetic variants often present phenotypic overlaps across different neurodegenerative syndromes, highlighting the limitations of current clinical diagnostic criteria in defining boundaries between distinct conditions and the difficulties of clinicians in reaching the best clinical diagnosis.

The role of disease duration and severity on novel clinical subtypes of Parkinson disease.

INTRODUCTION: One of the latest subtyping systems of Parkinson disease (PD) identifies motor severity, cognitive dysfunction, dysautonomia, and rapid eye movement behavior disorder as key features for phenotyping patients into three different subtypes (i.e., mild motor-predominant, diffuse-malignant and intermediate). Since PD subtypes are clinically most relevant if they are mutually exclusive and consistent over-time, we explored the impact of disease stage and duration on these novel subtypes. METHODS: One-hundred-twenty-two consecutive patients, with a disease duration ranging from 0 to 20 years, were allocated as suggested into these three subtypes. The relationship between either disease duration or stage, as measured by the Hoehn and Yahr staging, and subtype allocation was explored. RESULTS: Significant differences in subtype distribution were observed across patients stratified according to either disease duration or staging, with the diffuse-malignant subtypes increasing in prevalence as the disease advanced. Both disease duration and staging were independent predictors of subtype allocation. CONCLUSIONS: These novel PD subtypes are significantly influenced by disease duration and staging, which might suggest that they do not represent mutually exclusive disease pathways. This should be taken into account when attempting correlations with putative biomarkers of disease progression.

Subcortical atrophy and perfusion patterns in Parkinson disease and multiple system atrophy.

BACKGROUND: The clinical differentiation between Parkinson disease (PD) and multiple system atrophy (MSA) is difficult. OBJECTIVES: Arterial spin labeling (ASL) is an advanced MRI technique that obviates the use of an exogenous contrast agent for the estimation of cerebral perfusion. We explored the value of ASL in combination with structural MRI for the differentiation between PD and MSA. METHODS: Ninety-four subjects (30 PD, 30 MSA and 34 healthy controls) performed a morphometric and ASL-MRI to measure volume and perfusion values within basal ganglia and cerebellum. A region-of-interest analysis was performed to test for structural atrophy and regional blood flow differences between groups. RESULTS: MSA patients showed higher subcortical atrophy than both PD patients and HC, while no differences were observed between the latter. MSA and PD showed lower volume-corrected perfusion values than HC in several cerebellar areas (Crus I, Crus II, right VIIb, right VIIIa, right VIIIb), right caudate and both thalami. MSA and PD patients displayed similar perfusion values in all aforementioned areas, but the right cerebellar area VIIIb (lower in MSA) and right caudate and both thalami (lower in PD). Similar results were obtained when comparing PD and MSA patients with the parkinsonian variant. CONCLUSIONS: A perfusion reduction was equally observed in both MSA and PD patients in cerebellar areas that are putatively linked to cognitive (i.e., executive) rather than motor functions. The observed hypo-perfusion could not be explained by atrophy, suggesting the involvement of the cerebellum in the pathophysiology of both MSA and PD.

Impairment of acquired color vision in multiple sclerosis: an early diagnostic sign linked to the greatness of disease.

OBJECTIVE: To assess the type and degree of both red-green and blue-yellow color vision deficiencies of Calabrian males affected by multiple sclerosis. MATERIAL: Eighty Calabrian male patients were enrolled (age range 18-70 years; mean age 40.6 ± 12.4 years) showing a disease duration mean of 10.6 ± 8.2 years (range = 0.5-46 years) coming from the Institute of Neurology, Magna Graecia University, Catanzaro. Optic neuritis present in the medical histories of the 21 patients does not influence color vision. Excluding seven colorblind subjects and one affected by a bilateral maculopathy, the analyzed sample group was 72. Seventy controls were matched for age and sex. METHOD: An ophthalmologist examined all patients and controls in order to rule out diabetic retinopathy, cataracts, senile maculopathy, or ocular fundus' anomalies. The Ishihara test identified the colorblind patients. The City University Test screened for people with abnormal color vision by grading the severity of color vision deficiency. The second part of the City University Test as well as the Farnsworth Test confirmed both the color vision deficiency type and degree. RESULTS: Fifty-one percentage (37/72) of the patients showing a color vision deficiency were subdivided into two subgroups: subgroup one showed red-green deficiency (57%, 21/37); subgroup two showed a coupled red-green and blue-yellow deficiency (43%, 16/37). Furthermore, we found two distinct curves showing a groove within the first 10 years of the disease. Both monocular and binocular analyses allowed us to identify the patients showing the monocular color vision deficiency, but they were well compensated by binocular vision. CONCLUSION: We think that the majority of the patients with the red-green deficiency will develop the coupled red-green and blue-yellow deficiency in the latter years of multiple sclerosis.

Exosome-associated miRNA profile as a prognostic tool for therapy response monitoring in multiple sclerosis patients.

Multiple sclerosis (MS) is an autoimmune pathology leading to neurodegeneration. Because of the complexity and heterogenic etiology of this disease, diagnosis and treatment for individual patients are challenging. Exosome-associated microRNAs (miRNAs) have recently emerged as a new class of diagnostic biomarkers involved in both autoimmune and neurologic disorders. Interesting new evidence has emerged showing that circulating miRNAs are dysregulated in MS body fluids, including serum, plasma, and cerebrospinal fluid. We hypothesized that exosome-associated miRNAs could present a readily accessible blood-based assay for MS disease. We detected expression of miRNAs by quantitative PCR on a small cohort of MS patients. We analyzed circulating exosome-associated miRNAs of MS patients before and after therapy and found that 14 exosome-associated miRNAs were significantly down-regulated, while 2 exosome-associated miRNAs were significantly up-regulated in IFN-ß-treated relapsing-remitting MS patients with response to therapy compared to those without response. We identified a serum miRNA panel that could be used to monitor the response to IFN-ß therapy. Overall, these data suggest that circulating exosome-associated miRNA profiling could represent an easily detectable biomarker of disease and treatment response.-Manna, I., Iaccino, E., Dattilo, V., Barone, S., Vecchio, E., Mimmi, S., Filippelli, E., Demonte, G., Polidoro, S., Granata, A., Scannapieco, S., Quinto, I., Valentino, P., Quattrone, A. Exosome-associated miRNA profile as a prognostic tool for therapy response monitoring in multiple sclerosis patients.

Hepatic microabscesses during CMV reactivation in a multiple sclerosis patient after alemtuzumab treatment.

The anti-CD52 monoclonal antibody alemtuzumab is a highly active treatment for multiple sclerosis (MS) causing rapid depletion of B and T lymphocytes with nadir one month after last infusion. Opportunistic Cytomegalovirus (CMV) infections have been reported in MS patients treated with this drug. We report one patient who developed a CMV reactivation with hepatic involvement three weeks after the first cycle of alemtuzumab. This patient, promptly diagnosed and treated, achieved a complete recovery with valganciclovir. The possibility of this treatable opportunistic infection should be considered by neurologists in febrile patients with hepatic markers alteration after treatment with alemtuzumab.

Serum IGF-1 is associated with cognitive functions in early, drug-naïve Parkinson's disease.

OBJECTIVE: Cognitive deficits are common in Parkinson's disease (PD) since the early stages and many patients eventually develop dementia. Yet, occurrence of dementia in PD is unpredictable. Evidence supports the hypothesis that insulin-like growth factor-1 (IGF-1) is involved in cognitive deficits. Our aim was to evaluate the relationship between serum IGF-1 levels and neuropsychological scores in a large cohort of drug-naïve PD patients during the earliest stages of the disease. METHODS: Serum IGF-1 levels were determined in 405 early, drug-naïve PD patients and 191 healthy controls (HC) enrolled in the Parkinson's Progression Markers Initiative (PPMI). The association between serum IGF-1 levels and neuropsychological scores was evaluated with linear regression analysis. RESULTS: IGF-1 levels were similar in PD and HC. In PD patients the lowest IGF-1 quartile was a predictor of lower performances at the Semantic Fluency task (ß = -3.46, 95%CI: -5.87 to -1.01, p = 0.005), the Symbol Digit Modalities Score (ß = -2.09, 95%CI: -4.02 to -0.15, p = 0.034), and Hopkins Verbal Learning Test Retention (ß = -0.05, 95%CI: -0.09 to -0.009, p = 0.019). CONCLUSIONS: Lower serum IGF-1 levels are associated to poor performances in cognitive tasks assessing executive function, attention and verbal memory in a large cohort of early PD patients. Follow-up studies are warranted to assess if IGF-1 is related to the development of dementia in PD.

Gender differences in non-motor symptoms in early Parkinson's disease: a 2-years follow-up study on previously untreated patients.

BACKGROUND: We recently showed specific sex-related patterns of non motor symptoms (NMS) in early, drug-naïve PD patients. However, to date studies investigating gender-related effects of dopaminergic treatment on NMS in early PD are lacking. METHODS: In the present study, we first report a prospective assessment of gender-related differences in the spectrum of NMS before (baseline) and after starting dopaminergic therapy (2-year follow-up) in a large cohort of newly diagnosed PD patients. Differences in NMS frequency between baseline and follow-up were evaluated by McNemar test. Spearman's rank test was employed to explore interactions between NMS and drug treatment. RESULTS: One-hundred and thirty four PD patients (86M and 48W) were included in the present study. At 2-year follow-up, Sadness/blues presented a significant percentage reduction as compared to baseline in both sexes, while Urgency, Daytime sleepiness, Weight change and Sex drive presented a significant percentage increase only in men. At follow up men complained of a greater number of NMS as compared to women. Occurrence of Weight change was related to therapy in both sexes. Male gender was found to be a risk factor for developing Dribbling and Nocturia, irrespective of therapy and clinical features. CONCLUSIONS: In conclusion, our study showed that mood symptoms improved after the introduction of therapy in both sexes, while men appeared to be more prone to develop some NMS possibly linked to dopaminergic treatment.