Search

Background Longitudinal cohort studies provide important information about the clinical effectiveness of an intervention in the routine clinical setting, and are an opportunity to understand how a population presents for treatment and is managed. Methods INTEREST IN CD2 (NCT01753349) is a prospective, international, 3-year, longitudinal, observational study following the course of adult idiopathic cervical dystonia (CD) treated with botulinum neurotoxin type A (BoNT-A). The primary objective is to document long-term patient satisfaction with BoNT-A treatment. Here we report baseline data. Results This analysis includes 1036 subjects (67.4% of subjects were female; mean age was 54.7 years old; mean TWSTRS Total score was 31.7). BoNT-A injections were usually given in line with BoNT-A prescribing information. The most commonly injected muscles were splenius capitis (87.3%), sternocleidomastoid (82.6%), trapezius (64.3%), levator scapulae (40.9%) and semispinalis capitis (26.9%); 35.5% of subjects were injected using a guidance technique. Most subjects (87.8%) had been previously treated with BoNT-A (median interval between last pre-study injection and study baseline was 4 months); of these 84.8% reported satisfaction with BoNT-A treatment at peak effect during their previous treatment cycle and 51.5% remained satisfied at the end of the treatment. Analyses by geographical region revealed heterogeneity in the clinical characteristics and BoNT-A injection practice of CD subjects presenting for routine treatment. Conclusions These baseline analyses provide sizeable data regarding the epidemiology and clinical presentation of CD, and demonstrate an international heterogeneity of clinical practice. Future longitudinal analyses of the full 3-year study will explore how these factors impact treatment satisfaction. Electronic supplementary material The online version of this article (10.1007/s00415-017-8698-2) contains supplementary material, which is available to authorized users.

To assess the role of percutaneous endoscopic gastrostomy (PEG) insertion, and its timing, on ALS survival, and to study prognostic factors of survival before and after PEG placement in a population-based setting.In this observational population-based, registry study, we enrolled patients with newly- diagnosed ALS, according to the El Escorial revised criteria, who were resident in the Emilia Romagna Region, and who developed severe dysphagia needing enteral nutritional support. The primary outcome measure was tracheostomy-free survival after PEG recommendation.There were 210 patients needing PEG, out of an incident cohort of 545 patients from the Emilia Romagna Registry for ALS, who were diagnosed between 2009 and 2013. One hundred and ninety-three patients were included in the study, and 17 were excluded because they were already tracheostomized at the time of PEG placement. Of the 193 patients included in the study, 152 underwent PEG, whereas 41 did not undergo the procedure. Patients who did not undergo PEG, among the eligible ones, had the same tracheostomy-free survival from onset as patients who did (25 vs. 32 months, p = 0.21). Tracheostomy-free survival from PEG recommendation was greater in patients who underwent PEG placement than in patients who did not (6 vs. 2 months, p = 0.008). Median tracheostomy-free survival from PEG insertion was eight months (95% CI5-12); 30 days after PEG placement, survival was 89.60%. At Cox multivariable analysis, the hazard of death or tracheostomy after PEG insertion was significantly influenced by the difference between BMI at the time of the PEG procedure and BMI at diagnosis (HR 1.05, 95% CI 1.02-1.08; p = 0.002). The hazard of death or tracheostomy was not affected by the timing of PEG insertion.The present study, although it has some limitations, suggests a gain of tracheostomy-free survival from the time of PEG recommendation for patients who undergo PEG placement, and, among patients who undergo PEG, a greater survival if PEG is inserted before a significant weight loss occurs, and if nutritional support avoids further weight loss. Should this association between prevention of weight loss and better clinical outcome be confirmed by further studies, it would have important implications for disease management.

Background Patients with cervical dystonia (CD) typically require regular injections of botulinum toxin to maintain symptomatic control. We aimed to document long-term patient satisfaction with CD symptom control in a large cohort of patients treated in routine practice. Methods This was a prospective, international, observational study (NCT01753349) following the course of adult CD treated with botulinum neurotoxin type A (BoNT-A) over 3 years. A comprehensive clinical assessment status was performed at each injection visit and subjects reported satisfaction in two ways: satisfaction with symptom control at peak effect and at the end of treatment cycle. Results Subject satisfaction remained relatively stable from the first to the last injection visit. At 3 years, 89.9% of subjects reported satisfaction with symptom control at peak effect and 55.6% reported satisfaction with symptom control at end of treatment cycle. By contrast, objective ratings of CD severity showed an overall reduction over 3 years. Mean ± SD Toronto Western Spasmodic Rating Scale (TWSTRS) Total scores (clinician assessed at end of treatment cycle) decreased from 31.59 ± 13.04 at baseline to 24.49 ± 12.43 at 3 years (mean ± SD reduction from baseline of − 6.97 ± 11.56 points). Tsui scale scores also showed gradual improvement; the percent of subjects with a tremor component score of 4 reduced from 12.4% at baseline to 8.1% at 3 years. Conclusions Despite objective clinical improvements over 3 years, subject satisfaction with symptom control remained relatively constant, indicating that factors other than symptom control also play a role in patient satisfaction.

Our objective was to verify and expand previous evidence of psychometric inadequacies in the ALSFRS-R, in a different sample of subjects suffering from ALS. Since 2009, a prospective registry records all incident cases of ALS in Emilia Romagna Region, Italy (4.4 million inhabitants) referred to its 17 neurological departments. For each patient, demographic and clinical information is collected by the physician in charge, including compilation of the ALSFRS-R at each clinical follow-up. Results showed that a confirmatory factor analysis on the three-factor model previously found (bulbar, motor, respiratory function) showed a good fit. Rasch analysis on the whole scale showed the need to collapse some rating categories, confirmed the multidimensionality of the ALSFRS-R, and demonstrated the presence of differential item functioning between patients with spinal versus bulbar onset. Moreover, some items included in the three ALSFRS-R subscales showed a problematic fit to the respective construct they were intended to measure. In conclusion, the interpretation of a total raw score of ALSFRS-R is hampered by ambiguities due to the different metric properties of the three domains the scale aggregates, and their content and structure. This study confirms that a refinement of ALSFRS-R is warranted, pointing to the need to revise its whole structure, and providing detailed guidelines for its revision.

This cross-sectional multicentre study aimed at investigating frequency and features of painful diabetic polyneuropathyWe consecutively enrolled 816 patients attending hospital diabetic outpatient clinics. We first definitely diagnosed diabetic polyneuropathy and pure small-fibre polyneuropathy using clinical examination, nerve conduction study, and skin biopsy or quantitative sensory testing. Adhering to widely agreed criteria, we then identified neuropathic pain and diagnosed painful polyneuropathy using a combined approach of clinical examination and diagnostic testsOut of the 816 patients, 36% had a diabetic polyneuropathy associated with male gender, age and diabetes severity; 2.5% of patients had a pure small-fibre polyneuropathy, unrelated to demographic variables and diabetes severity. Of the 816 patients, 115 (13%) suffered from a painful polyneuropathy, with female gender as the only risk factor for suffering from painful polyneuropathyIn this large study, providing a definite diagnosis of diabetic polyneuropathy and pure small-fibre polyneuropathy, we show the frequency of painful polyneuropathy, and demonstrate that this difficult to treat complication is more common in women than in men.

Introduction: The clinical course of late-onset Pompe disease is heterogeneous, and new clinical outcome measures are needed to evaluate enzyme replacement therapy (ERT). Methods: We correlated the 6-Minute Walk Test (6MWT), Walton and Gardner-Medwin (WGM) score, and GSGC (Gait, Stairs, Gower, Chair) scores in 40 patients. Results: At baseline, the GSGC score correlated with both WGM (P < 0.001, n = 33) and 6MWT (P < 0.001, n = 26). After 1 year of ERT, we observed a significant change in gait, stairs and chair performance on the GSGC scale. The 6MWT significantly increased from 319 to 371 meters in 32 patients, and the WGM score was reduced. Conclusions: GSGC is a group of functional tests that requires only a few minutes to perform, therefore, this score might be a good indicator to be used in future studies. Muscle Nerve 45: 831–834, 2012

Muscular fatigue is a biological situation which is very difficult to quantify. The Authors studied through a computer analysis the power spectrum of electromyogram, recorded from abductor digiti minimi muscle during maximal and minimal contraction effort before and after fatigue and after muscle prolonged relaxation in 8 normal subjects. No significant spectrum differences were found between maximal and minimal effort in each trial, and between the spectra obtained before fatigue and after muscle prolonged relaxation. On the contrary significant differences were found between the spectra obtained after fatigue and the other conditions. The power spectrum analysis appears, also, to be a reliable neurophysiological parameter for the study of biological aspects of muscular fatigue.

The Authors have studied the behaviour of checkerboard pattern visual evoked potential (VEP) latencies by using different spatial frequency stimuli and different stimulating visual fields in order to demonstrate whether spatial frequency might constitute a parameter capable of exciting different retinal regions like different stimulus fields. According to the recent literature low spatial frequency stimuli generate VEP with latencies which are significantly shorter than high spatial frequency stimuli, making this method more reliable for the differentiation of macular and peripheral retinal fields.

Sinus arrhythmia (SA) is a physiological event related to the respiratory activity. The aim of this study was to find a relation between SA and different deep breathings. A transductor monitored the chest respiratory movements and a cardiotachometer calculated and plotted the instantaneous heart rate, synchronously during different breathing efforts. In 10 normal subjects a good linear correlation was found between the breathing depth and SA quantifying the relation between the chest receptor activity and SA also with limited chest expansion.

The Authors studied the checkerboard pattern electroretinogram (PERG) behaviour in normal subjects and in patients suffering from traumatic lesion of optic nerve, demyelinating optic neuritis, axonal optic neuritis, retinal vascular disorders and retinitis pigmentosa in order to verify the PERG origin. According to our data the PERG appears to originate from ganglion cells since the signal diminished or disappeared in axonal lesion of optic nerve, as a result of retrograde ganglion cell degeneration. Furthermore, the demyelinating lesions of optic nerve were not able to modify the PERG wave. In patients suffering from retinal receptor disturbances the flash electroretinogram (FERG), which is probably an expression of receptor activity, was greatly impaired, whereas PERGs were either normal or less impaired than FERGs. These data demonstrate the different origin of PERG and FERG.

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.

20 pags., 5 figs., 3 tabs. This article belongs to the Special Issue Peptides and Proteins as Innovative Biomaterials, The surface-enhanced Raman scattering (SERS) spectra of three amphiphilic oligopeptides derived from EAK16 (AEAEAKAK) were examined to study systematic amino acid substitution effects on the corresponding interaction with Ag colloidal nanoparticles. Such self-assembling molecular systems, known as “molecular Lego”, are of particular interest for their uses in tissue engineering and as biomimetic coatings for medical devices because they can form insoluble macroscopic membranes under physiological conditions. Spectra were collected for both native and gamma-irradiated samples. Quantum mechanical data on two of the examined oligopeptides were also obtained to clarify the assignment of the prominent significative bands observed in the spectra. In general, the peptide–nanoparticles interaction occurs through the COO groups, with the amide bond and the aliphatic chain close to the colloid surface. After gamma irradiation, mimicking a free oxidative radical attack, the SERS spectra of the biomaterials show that COO groups still provide the main peptide–nanoparticle interactions. However, the spatial arrangement of the peptides is different, exhibiting a systematic decrease in the distance between aliphatic chains and colloid nanoparticles.

We describe a novel ATP7A gene mutation associated with distal motor neuropathy, mild connective tissue abnormalities and autonomic disturbances. Next-generation sequencing analysis of a lower-motor neuron diseases gene panel was performed in two sibs presenting with distal motor neuropathy plus an autonomic dysfunction, which main manifestations were retrograde ejaculation, diarrhea and hyperhydrosis. Probands underwent dysmorphological, neurological, electrophysiological as well as biochemical evaluations and somatic and autonomic innervation studies on skin biopsies. A novel missense mutation (p.A991D) was identified in the X-linked ATP7A gene, segregating in both brothers and inherited from their healthy mother. Biochemical studies on patients’ blood samples showed reduced serum copper and ceruloplasmin levels. Clinical and neurophysiological evaluation documented dysautonomic signs. Quantitative evaluation of skin innervation disclosed a small fiber neuropathy with prevalent autonomic involvement. Mutations in the ATP7A gene, encoding for a copper-transporting ATPase, have been associated with the severe infantile neurodegenerative Menkes disease and in its milder variant, the Occipital Horn Syndrome. Only two ATP7A mutations were previously reported as causing, a pure axonal distal motor neuropathy (dHMN-SMAX3). The phenotype we report represents a further example of this rare genotype-phenotype correlation and highlights the possible occurrence in SMAX3 of autonomic disturbances, as described for Menkes disease and Occipital Horn Syndrome.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by thymidine phosphorylase (TP) enzyme defect. As gastrointestinal changes do not revert in patients undergone TP replacement therapy, one can postulate that other unexplored mechanisms contribute to MNGIE pathophysiology. Hence, we focused on the local TP angiogenic potential that has never been considered in MNGIE. In this study, we investigated the enteric submucosal microvasculature and the effect of hypoxia on fibrosis and enteric neurons density in jejunal full-thickness biopsies collected from patients with MNGIE. Orcein staining was used to count blood vessels based on their size. Fibrosis was assessed using the Sirius Red and Fast Green method. Hypoxia and neoangiogenesis were determined via hypoxia-inducible-factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) protein expression, respectively. Neuron-specific enolase was used to label enteric neurons. Compared with controls, patients with MNGIE showed a decreased area of vascular tissue, but a twofold increase of submucosal vessels/mm(2) with increased small size and decreased medium and large size vessels. VEGF positive vessels, fibrosis index, and HIF-1α protein expression were increased, whereas there was a diminished thickness of the longitudinal muscle layer with an increased interganglionic distance and reduced number of myenteric neurons. We demonstrated the occurrence of an angiopathy in the GI tract of patients with MNGIE. Neoangiogenetic changes, as detected by the abundance of small size vessels in the jejunal submucosa, along with hypoxia provide a morphological basis to explain neuromuscular alterations, vasculature breakdown, and ischemic abnormalities in MNGIE. NEW & NOTEWORTHY Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by a genetically driven defect of thymidine phosphorylase, a multitask enzyme playing a role also in angiogenesis. Indeed, major gastrointestinal bleedings are life-threatening complications of MNGIE. Thus, we focused on jejunal submucosal vasculature and showed intestinal microangiopathy as a novel feature occurring in this disease. Notably, vascular changes were associated with neuromuscular abnormalities, which may explain gut dysfunction and help to develop future therapeutic approaches in MNGIE.

Gastrointestinal (GI) symptoms can originate from severe dysmotility due to enteric neuropathies. Current methods used to demonstrate enteric neuropathies are based mainly on classic qualitative histopathological/immunohistochemical evaluation. This study was designed to identify an objective morphometric method for paraffin-embedded tissue samples to quantify the interganglionic distance between neighboring myenteric ganglia immunoreactive for neuron-specific enolase, as well as the number of myenteric and submucosal neuronal cell bodies/ganglion in jejunal specimens of patients with severe GI dysmotility. Jejunal full-thickness biopsies were collected from 32 patients (22 females; 16–77 yr) with well-characterized severe dysmotility and 8 controls (4 females; 47–73 yr). A symptom questionnaire was filled before surgery. Mann-Whitney U test, Kruskal-Wallis coupled with Dunn’s posttest and nonparametric linear regression tests were used for analyzing morphometric data and clinical correlations, respectively. Compared with controls, patients with severe dysmotility exhibited a significant increase in myenteric interganglionic distance ( P = 0.0005) along with a decrease in the number of myenteric ( P < 0.00001) and submucosal ( P < 0.0004) neurons. A 50% reduction in the number of submucosal and myenteric neurons correlated with an increased interganglionic distance and severity of dysmotility. Our study proposes a relatively simple tool that can be applied for quantitative evaluation of paraffin sections from patients with severe dysmotility. The finding of an increased interganglionic distance may aid diagnosis and limit the direct quantitative analysis of neurons per ganglion in patients with an interganglionic distance within the control range. NEW & NOTEWORTHY Enteric neuropathies are challenging conditions characterized by a severe impairment of gut physiology, including motility. An accurate, unambiguous assessment of enteric neurons provided by quantitative analysis of routine paraffin sections may help to define neuropathy-related gut dysmotility. We showed that patients with severe gut dysmotility exhibited an increased interganglionic distance associated with a decreased number of myenteric and submucosal neurons, which correlated with symptoms and clinical manifestations of deranged intestinal motility.

BACKGROUND: Chronic-intestinal-pseudo-obstruction (CIPO) is a rare condition due to severe impairment of gut motility responsible for recurrent sub-occlusive episodes. Although neuro-muscular-glial-ICC abnormalities represent the main pathogenetic mechanism, the pathophysiology of CIPO remains poorly understood. Intestinal epithelial and vascular-endothelial barrier (IEVB) abnormalities can contribute to neuro-epithelial changes by allowing passage of harmful substances. METHODS: To test retrospectively whether IEVB defects occur in patients with CIPO we measured the jejunal protein expression of the major tight junction (TJ) components. CIPO patients were subdivided according to gut neuromuscular histopathology: apparently normal (AN); with inflammation (INF); or with degenerative alterations (DEG). The presence of occludin/claudin oligomers (index of TJ assembly), the amount of occludin, claudin-4 and zonula occludens-1 (ZO-1), as well as the expression of vasoactive intestinal polypeptide (VIP) and glial fibrillary acidic protein (GFAP) immunoreactivities were evaluated on jejunal full thickness biopsies using Western Blot. KEY RESULTS: Oligomers were absent in the 73% of CIPO. Total occludin decreased in CIPO with AN and INF changes. Claudin-4 was upregulated in CIPO with INF and DEG features. ZO-1 and VIP expression decreased selectively in DEG group. GFAP increased in CIPO regardless the histopathological phenotype. CONCLUSIONS & INFERENCES: The absence of oligomers demonstrated in our study suggests that IEBV is altered in CIPO. The mechanism leading to oligomerization is occludin-dependent in AN and INF, whereas is ZO-1-dependent in DEG. Our study provides support to IEVB abnormalities contributing to CIPO clinical and histopathological features.

To improve patient care and help clinical research, the Neuropathic Pain Special Interest Group of the Italian Neurological Society appointed a task force to elaborate a consensus statement on pharmacoresistant neuropathic pain. The task force included 19 experts in neuropathic pain. These experts participated in a Delphi survey consisting of three consecutive rounds of questions and a face-to-face meeting, designed to achieve a consensus definition of pharmacoresistant neuropathic pain. In the three rounds of questions, the participants identified and described the main distinguishing features of pharmacoresistance. In the face-to-face meeting the participants discussed the clinical features determining pharmacoresistance. They finally agreed that neuropathic pain is pharmacoresistant when "the patient does not reach the 50% reduction of pain or an improvement of at least 2 points in the Patient Global Impression of Change, having used all drug classes indicated as first, second, or third line in the most recent and widely agreed international guidelines, for at least 1 month after titration to the highest tolerable dose." Our consensus statement might be useful for identifying eligible patients for invasive treatments, and selecting patients in pharmacological trials, thus improving patient care and helping clinical research.

A 69-year-old white man was admitted because of a clinical history of persistent cough and fever. Chest x-rays showed bilateral lung infiltrates with air bronchograms, whereas the urine antigen test resulted positive for Legionella pneumophila. The next day, he was transferred to the intensive care unit and intubated because of severe renal and respiratory distress. Neurological examination revealed distal weakness and loss of deep tendon reflexes in lower extremities. Nerve conduction studies displayed severe demyelinating sensorimotor polyneuropathy, and plasmapheresis was therefore applied with mild improvement. Few weeks after, dysphagia occurred and electrophysiologic tests showed progressive axonal involvement with spread of demyelination to the cranial nerves. The patient underwent a new plasmapheresis course and slowly reached stable clinical improvement of neurological status, which allowed him to be safely discharged. This case showed a critical onset with respiratory failure and kidney functional impairment due to L. pneumophila, subsequently disclosing Guillain-Barré syndrome.

The present case report was aimed at identifying the molecular profile characteristic of a primitive neuro-ectodermal tumor (PNET) in a 3-year-old child affected by a lesion localized in the cerebellar region. The histological diagnosis was medulloblastoma. In vivo single voxel 1H magnetic resonance spectroscopy (MRS) shows high specificity in detecting the main metabolic alterations in the primitive cerebellar lesion; a very high amount of the choline-containing compounds and very low level of creatine derivatives and N-acetylaspartate. Ex vivo high resolution magic angle spinning (HR-MAS) 1H magnetic resonance spectroscopy, performed at 9.4 Tesla on the neoplastic specimen collected during surgery, allows for the unambiguous identification of several metabolites giving a more in-depth evaluation of the metabolic pattern of the lesion. The ex vivo HR-MAS MR spectra show that the spectral detail is much higher than that obtained in vivo and that, for example, myo-inositol, taurine and phosphorylethanolamine contribute to the in vivo signal at 3.2 ppm, usually attributed to choline-containing compounds. In addition, the spectroscopic data appear to correlate with some morphological features of the medulloblastoma. Consequently, the present study shows that ex vivo HR-MAS 1H MRS is able to strongly improve the clinical possibility of in vivo MRS and can be used in conjunction with in vivo spectroscopy for clinical purposes.

This study presents a multinuclear ( 1 H, 13 C and 31 P) magnetic resonance spectroscopy characterization of the total lipid fraction extracted from different regions of a human kidney affected by a clear cell renal carcinoma. It was thus possible to demonstrate that cholesteryl esters and phosphatidylcholine are markers of the tumor infiltration, histologically confirmed, in the kidney medulla. The tumor tissue contains twice the amount. of phospatidylcholine compared to normal cortex. The results appear relevant in light of new clinical applications based on the biochemical composition of human tissues.