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Background: Atopic dermatitis (AD) is a chronic inflammatory disease. Recently, dupilumab was approved for moderate-to-severe AD. D-OCT is a noninvasive tool for the characterization of skin diseases., Objective: To describe the changes observed with D-OCT in lesional and clinically healthy skin of patients with refractory severe AD under dupilumab treatment., Methods: We analyzed AD lesions and healthy skin by D-OCT. Clinical scores of AD severity were assessed at baseline (T0) and after 1 and 3 months of treatment (T1, T2). Descriptive statistics, chi-square test, and t test were used to compare the analyzed parameters over time and between AD lesions and clinically healthy skin., Results: At baseline, average EASI was 45.7. During the follow-up, EASI75 and EASI90 were achieved in 57% and 36% of patients at T1 and 100% and 86% of patients at T2, respectively. Lesional skin D-OCT parameters related to epidermal remodeling and inflammation evidenced a significant improvement after 1 month of treatment. In clinically healthy skin, D-OCT parameters improved significantly after 3 months of treatment, especially for collagen remodeling and inflammation., Conclusion: The study demonstrates that the clinical improvement of severe AD patients under dupilumab treatment is correlated with specific D-OCT changes of patients' lesional and clinically healthy skin., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Background: Dupilumab is an anti-IL-4Rα antibody used in the treatment of patients with moderate-to-severe atopic dermatitis (msAD). This study explored the potential benefit of dupilumab in perennial allergic rhinoconjunctivitis (PAR) and perennial allergic asthma (PAA) caused by indoor allergens in adults with msAD., Methods: This multicentric, prospective, observational, real-life study included adult patients with msAD who had been treated with dupilumab in 16 Italian care centres. Efficacy outcomes regarding AD, PAR and PAA were collected at baseline and 16 weeks. Safety was also assessed., Results: We enrolled 123 patients with msAD. Between baseline and 16 weeks of treatment, the following measurements decreased statistically significantly: Eczema Area and Severity Index, SCOring AD, Patient-Oriented Eczema Measure, pruritus score, sleep score, Dermatology Life Quality Index and IgE. Dupilumab treatment in patients with comorbid PAR (n = 41) was associated with significant improvements in PAR disease control (measured using a Rhinitis Control Scoring System) and in PAR Quality of life (QoL) (measured using the Rhinoconjunctivitis QoL Questionnaire scores). In 32 patients with comorbid PAA, dupilumab significantly improved PAA control (measured using the Asthma Control Test and five-item Asthma Control Questionnaire scores) and disease-related QoL (measured using the Asthma QoL Questionnaire scores). Thirty-five patients (28.5%) developed conjunctivitis during the study period., Conclusion: These results support the benefits of dupilumab for adult patients with PAR and/or PAA associated with msAD., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Assessment of nigrostriatal degeneration is a key element to discriminate between dementia with Lewy bodies (DLB) and Alzheimer disease (AD), and it is often evaluated using ioflupane ( 123 I-FP-CIT) single-photon emission computed tomography (SPECT). Given the limited availability of 123 I-FP-CIT SPECT, we evaluated if a mask-based approach to nigroputaminal magnetic resonance imaging (MRI) diffusion-weighted tractography could be able to capture microstructural changes reflecting nigroputaminal degeneration in DLB., Methods: A nigroputaminal bundle mask was delineated on 12 healthy volunteers (HV) and applied to MRI diffusion-weighted data of 18 subjects with DLB, 21 subjects with AD and another group of 12 HV. The correlation between nigroputaminal fractional anisotropy (FA) values and 123 I-FP-CIT SPECT findings was investigated. Shapiro-Wilk, ANOVA, ANCOVA, and parametric correlation statistics as well as receiver operating characteristic (ROC) analysis were used., Results: DLB patients showed a higher nigroputaminal FA values compared with both AD and HV-controls groups (p = 0.001 for both comparisons), while no difference was observed between HV-controls and AD groups (p = 0.450); at ROC analysis, the area under the curve for the discriminating DLB and AD subjects was 0.820; FA values correlated with 123 I-FP-CIT values (on the left, r = -0.670; on the right, r = -720). No significant differences were observed for the FA of the corticospinal tract across the three groups (p = 0.740)., Conclusions: In DLB, nigroputaminal degeneration could be reliably assessed on MRI diffusion scans using a mask of nigroputaminal bundle trajectory. Nigroputaminal FA in DLB patients correlated with 123 I-FP-CIT values data may allow to differentiate these patients from AD patients and HV-controls.

Cognitive impairment and related abnormal brain activity are common in people with multiple sclerosis (PwMS). Adaptive training based on working memory (WM) has been shown to ameliorate cognitive symptoms, although the effects at a neural level are unclear. The aim of this study was to expand the existing research on the effects of an adaptive WM rehabilitative intervention on brain functional activity in PwMS. A sample of eighteen PwMS performed an 8-week home-based cognitive rehabilitation treatment based on adaptive WM training. PwMS were assessed before and after treatment using a validated neuropsychological battery and undergoing an fMRI session while carrying out a cognitive task (i.e., Paced Visual Serial Addition Test - PVSAT). fMRI activations were compared to the activation pattern elicited by eighteen matched healthy subjects performing the same task. At baseline, we found abnormal brain activity during PVSAT in PwMS when compared to healthy subjects, with a pattern including several bilateral activation clusters. Following rehabilitation, PwMS improved cognitive performance, as evaluated by the neuropsychological battery, and showed a different activation map with clusters mainly located in the right cerebellum and in the left hemisphere. The only significant cluster in the right hemisphere was located in the inferior parietal lobule, and the BOLD signal extracted in this area significantly correlated with cognitive performance both before and after the treatment. We suggest that WM training can improve the cognitive performance and reduce the abnormal activation of PwMS by partially maintaining or even restoring brain cognitive function.

Background: People with multiple sclerosis (PwMS) report impaired hand movements and coordination. With an engineered glove we demonstrated altered finger movements in PwMS; increasing age resulted in decreased performance in healthy subjects (normative data). This study aims at investigating aging effects on finger motor performance in PwMS, in relation to disease duration and Expanded Disability Status Scale (EDSS)., Methods: Ninety-six PwMS performed repetitive finger opposition movements with the dominant hand and both hands at maximal velocity or metronome-paced. Performance was compared with the norms, and correlation coefficients between finger motor parameters, age, disease duration and EDSS were calculated., Results: The majority of subjects was outside of the normal range according to age and probability increased with level of disability. Age significantly correlated with the glove parameters (r ranged in absolute value between 0.22-0.31; p-value in the range 0.002-0.049). Older subjects with lower disability showed worse performance than younger (p = 0.044 and 0.02), whilst younger subjects with higher disability performed similarly to older (p = 0.72 and 0.49)., Conclusion: Finger motor performance assessment provides important hints about upper limb disability, which should be evaluated in relation to age, disease duration and EDSS., Competing Interests: Declaration of Competing Interest The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Maria Pia Sormani has received consulting fees from Biogen, TEVA, Merck, Roche, Novartis, Sanofi Genzyme, Medday, GeNeuro Antonio Uccelli has received consulting honoraria and/or speaker fees and basic science study grants from Biogen Idec; consulting honoraria and/or speaker fees from Genzyme, Roche, Sanofi Aventis, and Teva; consulting honoraria and/or speaker fees and a basic science study grant from Novartis; consulting honoraria and/or speaker fees and a basic science study grant from Merck Serono., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The aim of this work was to investigate changes in motor performance and in the brain activation pattern during finger movements, following upper limb motor training in multiple sclerosis. Thirty people with multiple sclerosis with mild upper limb sensorimotor deficits were randomly allocated to one of two groups: the experimental group (n = 15) received an upper limb treatment based on voluntary task-oriented movements; the control group (n = 15) underwent passive mobilization of shoulder, elbow, wrist and fingers. All participants completed three treatment sessions per week for eight weeks. Before and after the intervention, all participants were evaluated for motor performance by means of Action Research Arm Test, Nine Hole Peg Test, and grip strength by a dynamometer, and for brain activations by functional magnetic resonance imaging during right finger opposition movements. Similar effects on motor performance were found in the two groups. A significant improvement with time was found in both groups at NHPT and in GRIP strength; a similar trend was found at ARAT. However, only the experimental group showed increased lateralization towards more normal brain activation following treatment, with activation clusters mainly located in the left brain hemisphere and right cerebellum. In conclusion, both active and passive interventions were effective in improving motor performance. However, only the treatment based on voluntary task-oriented movements could induce changes in brain activity that may have reflected skill acquisition by the right hand, reducing the activation of compensatory areas and decreasing brain resource demand., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate in clinically isolated syndrome (CIS) and migraine with aura (MA) how the number of periventricular lesions (PVLs) detected at MRI influences diagnostic performance when the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) or the 2017 revised criteria are applied., Methods: In this retrospective study, white matter hyperintensities (WMH) of 84 patients with MA and 79 patients with CIS were assessed using manual segmentation technique. Lesion probability maps (LPMs) and voxel-wise analysis of lesion distribution by diagnosis were obtained. Furthermore, we performed a logistic regression analysis based on lesion locations and volumes., Results: Compared to patients with MA, patients with CIS showed a significant overall higher T2 WMH mean number and volume (17.9 ± 16.9 vs 6.2 ± 11.9 and 3.1 ± 4.2 vs 0.3 ± 0.6 mL; p < 0.0001) and a significantly higher T2 WMH mean number in infratentorial, periventricular, and juxtacortical areas ( p < 0.0001). LPMs identified the periventricular regions as the sites with the highest probability of detecting T2 WMH in patients with CIS. Voxel-wise analysis of lesion distribution by diagnosis revealed a statistically significant association exclusively between the diagnosis of CIS and the PVLs. MAGNIMS criteria demonstrated the highest specificity in differentiating patients with CIS from patients with MA (100% vs 87%) against a predictable lower sensitivity (63% vs 72%)., Conclusions: PVLs play a key role in the differential diagnosis between MA and CIS, particularly when there are more than 3. Future studies on multiple sclerosis criteria might reconsider the 3 PVLs to minimize the risk of misdiagnosis., Classification of Evidence: This study provides Class IV evidence that the presence at least 3 PVLs increases the specificity in distinguishing MA from CIS., (© 2019 American Academy of Neurology.)

Spinal cord atrophy is one of the hallmarks of amyotrophic lateral sclerosis (ALS); however, it is not routinely assessed in routine clinical practice. In the present study, we evaluated whether spinal cord cross-sectional area measured at the foramen magnum level using a magnetic resonance imaging head scan represents a clinically meaningful measure to be added to the whole-brain volume assessment. Using an active surface approach, we measured the cord area at the foramen magnum and brain parenchymal fraction on T1-weighted three-dimensional spoiled gradient recalled head scans in two groups of subjects: 23 patients with ALS (males/females, 13/10; mean ± standard deviation [SD] age 61.7 ± 10.3 years; median ALS Functional Rating Scale-Revised score 39, range 27-46) and 18 age- and sex-matched healthy volunteers (mean ± SD age 55.7 ± 10.2 years). Spinal cord area at the foramen magnum was significantly less in patients than in control subjects and was significantly correlated with disability as measured with the ALS Functional Rating Scale-Revised (ρ = 0.593, p  <  0.005). This correlation remained significant after taking into account inter-individual differences in brain parenchymal fraction (ρ = 0.684, p  <  0.001). Our data show that spinal cord area at the foramen magnum correlates with disability in ALS independently of whole-brain atrophy, thus indicating its potential as a disease biomarker., Competing Interests: The local Ethics Committee (IRCCS Azienda Ospedale Università San Martino-IST, Largo Rosanna Benzi 10, 16132, Genova, Italia) approved this study, and written informed consent to participate and to publish results was obtained from all participants.Written informed consent to participate and to publish results was obtained from all participants.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Handwriting is an important activity of daily living, which requires sensorimotor and cognitive skills that could deteriorate in presence of neurological diseases. Handwriting impairments are common in people with multiple sclerosis (PwMS). Aims of the present study were to characterize handwriting movement features of PwMS in comparison with those of healthy adults, and to evaluate the relationship between kinematic parameters of handwriting movements and the results of the assessment of cognitive and motor domains. A new handwriting evaluation methodology was applied to quantify handwriting features of 19 PwMS and 22 age-matched healthy controls who were required to write a sentence on a digitizing tablet. Kinematic parameters of the sentence and of the strokes were used to evaluate handwriting performance. PwMS showed an altered handwriting kinematics with respect to healthy controls: higher movement duration, fragmented velocity profile and higher jerk. Furthermore, motor abilities and cognitive status of PwMS were related to handwriting parameters in accordance with the evidence that MS is a multifactorial disease affecting different domains. These results suggested that the proposed methodology might be a valuable tool to quantitatively assess handwriting impairments and the efficacy of handwriting treatments in PwMS.

Background: Finger opposition movements are the basis of many daily living activities and are essential in general for manipulating objects; an engineered glove quantitatively assessing motor performance during sequences of finger opposition movements has been shown to be useful to provide reliable measures of finger motor impairment, even subtle, in subjects affected by neurological diseases. However, the obtained behavioral parameters lack published reference values., Objective: To determine mean values for different motor behavioral parameters describing the strategy adopted by healthy people in performing repeated sequences of finger opposition movements, examining associations with gender and age., Methods: Normative values for finger motor performance parameters were obtained on a sample of 255 healthy volunteers executing sequences of finger-to-thumb opposition movements, stratified by gender and over a wide range of ages. Touch duration, inter-tapping interval, movement rate, correct sequences (%), movements in advance compared with a metronome (%) and inter-hand interval were assessed., Results: Increasing age resulted in decreased movement speed, advance movements with respect to a cue, correctness of sequences, and bimanual coordination. No significant performance differences were found between male and female subjects except for the duration of the finger touch, the interval between two successive touches and their ratio., Conclusions: We report age- and gender-specific normal mean values and ranges for different parameters objectively describing the performance of finger opposition movement sequences, which may serve as useful references for clinicians to identify possible deficits in subjects affected by diseases altering fine hand motor skills.

Motor and non-motor basal ganglia (BG) circuits can help healthy subjects cope with task-induced central fatigue and re-establish motor performance after deterioration. This work aimed to assess whether patients with multiple sclerosis (MS) were able to recover motor performance after deterioration due to a demanding task and whether BG activity played a role in performance recovery in this population. Fourteen patients with MS performed a finger-tapping sequence with their right hand during three fMRI sessions: at baseline, after a demanding finger motor task (5-min sequence repetition) and after a short rest period. We observed deterioration of spatial and temporal accuracy with task repetition, as expected; after rest, temporal but not spatial accuracy recovered. Further, higher subjective fatigue was associated with increased motor performance deterioration and reduced temporal accuracy recovery. The amplitude of the BOLD signal change in the left caudate, putamen, globus pallidus, thalamus and amygdala was high at baseline and significantly reduced after the demanding task. Following rest, activity achieved values similar to the baseline in all these regions except for the amygdala. These findings suggest that patients were in a fatigue-like state since task beginning, as they showed enhanced BOLD signal change in the subcortical structures known to be recruited in healthy subjects only when coping with fatigue to recover motor performance. Abnormalities in motor and non-motor BG functions can contribute to fatigue in MS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Cognitive impairment is common in multiple sclerosis (MS), but the definition of the best cognitive rehabilitation tools and features is still an open issue among researchers. The aims of the present study were to evaluate the effectiveness of COGNI-TRAcK (a customized application software delivering personalized working memory-based exercises) on cognitively impaired people with MS and to investigate the effects of an adaptive vs. a non-adaptive cognitive training administered by means of COGNI-TRAcK., Methods: Twenty eight patients (20 women, age 47.5 ± 9.3 years, Expanded Disability Status Scale score 3.8 ± 1.9) were randomized in two homogeneous groups, both performing a 8-week home-based cognitive rehabilitation treatment by means of COGNI-TRAcK. The study group (ADAPT-gr) underwent an adaptive training given by the automatic adjustment of tasks difficulty to the subjects' performance, whilst the control group (CONST-gr) was trained at constant difficulty levels. Before and after the treatment, patients' cognitive status was assessed using a gold standard neuropsychological evaluation. Moreover, the mostly affected cognitive domains in MS (i.e., attention, concentration and information processing speed) were also assessed 6 months after the end of the treatment., Results: The analysis of variance showed a significant Group*Time interaction in six out of ten tests of the cognitive evaluation. Post-hoc analysis revealed a significant improvement between the performances before and after the intervention only in the ADAPT-gr in tests evaluating verbal memory acquisition (p <0.05) and delayed recall (p = 0.001), verbal fluency (p = 0.01), sustained attention, concentration and information processing speed (p < 0.01). This last effect was maintained also after 6 months (p < 0.05)., Conclusions: We concluded that COGNI-TRAcK represents a suitable tool to administer a personalized training to cognitively impaired subjects and that an adaptive working load is a crucial feature determining the effectiveness of cognitive treatment, allowing transfer effects to several cognitive domains and long-term maintenance of results.

Writing is a means of communication which requires complex motor, perceptual, and cognitive skills. If one of these abilities gets lost following traumatic events or due to neurological diseases, handwriting could deteriorate. Occupational therapy practitioners provide rehabilitation services for people with impaired handwriting. However, to determine the effectiveness of handwriting interventions no studies assessed whether the proposed treatments improved the kinematics of writing movement or had an effect at the level of the central nervous system. There is need to find new quantitative methodologies able to describe the behavioral and the neural outcomes of the rehabilitative interventions for handwriting. In the present study we proposed a combined approach that allowed evaluating the kinematic parameters of handwriting movements, acquired by means of a magnetic resonance-compatible tablet, and their neural correlates obtained simultaneously from a functional magnetic resonance imaging examination. Results showed that the system was reliable in term of reproducibility of the kinematic data during a test/re-test procedure. Further, despite the modifications with respect to an ecological writing movement condition, the kinematic parameters acquired inside the MR-environment were descriptive of individuals' movement features. At last, the imaging protocol succeeded to show the activation of the cerebral regions associated with the production of writing movement in healthy people. From these findings, this methodology seems to be promising to evaluate the handwriting movement deficits and the potential alterations in the neural activity in those individuals who have handwriting difficulties. Finally, it would provide a mean to quantitatively assess the effect of a rehabilitative treatment.

Actual and imagined movement speed increases from early morning until mid-afternoon. Here, we investigated the neural correlates of these daily changes. Fifteen subjects performed actual and imagined right finger opposition movement sequences at 8 am and 2 pm. Both actual and imagined movements were significantly faster at 2 pm than 8 am. In the morning, actual movements significantly activated the left primary somatosensory and motor areas, and bilaterally the cerebellum; in the afternoon activations were similar but reduced. Contrast analysis revealed greater activity in the cerebellum, the left primary sensorimotor cortex and parietal lobe in the morning than in the afternoon. Imagined movements in the morning significantly activated the parietal association cortices bilaterally, the left supplementary and premotor areas, and the right orbitofrontal cortex and cerebellum. In the afternoon, the frontal lobe was significantly activated with the right cerebellum. Contrast analysis revealed increased activity in the left parietal lobe in the morning than in the afternoon. For both tasks, speed in the morning was significantly related to the BOLD signal in the brain areas resulted more active. These findings suggest that motor performance is continuously updated on a daily basis with a predominant role of the frontoparietal cortex and cerebellum.

Self-administered adrenaline through an auto-injector is the main out-of-hospital treatment for anaphylaxis, and patients should be trained to promptly and correctly use the device. The aim of the study was to verify the proper use of the device and the correct drug administration, and to identify possible misuse by patients. In seven Italian Allergy clinics, patients who were previously provided with self-injectable adrenaline were recruited at the follow-up visit required for the renewal of their prescription. All patients completed a questionnaire covering details of their allergic reactions, and knowledge of the device. The correct use was verified by the physician using a trainer with a four-step examination. 242 patients were included; 46 patients (18 %) did not always carry the auto-injector, and 35 patients (14 %) reported situations in which they were doubtful about whether to use adrenaline. Only 39 % of patients properly managed the device, while some patients (6 %) failed in all four steps. The majority of patients considered it appropriate to use adrenaline at the onset of respiratory symptoms (56 %). The factor most closely related to proper use of the device was the education of the patient (p = 0.03), while age and the time from first prescription did not affect the ability to properly use the auto-injector. Even though accurate training is conducted, many patients are still unable to properly use the adrenaline auto-injector in case of anaphylaxis. Allergists should review the instructions provided to the patients every time a renewal of the auto-injector is prescribed.

Objective measurement of concomitant finger motor performance is recommended for functional magnetic resonance imaging (fMRI) studies investigating brain activity during finger tapping tasks, because performance modality and ability can influence the selection of different neural networks. In this study, we present a novel glove system for quantitative evaluation of finger opposition movements during fMRI (called Glove Analyzer for fMRI, GAF). Several tests for magnetic resonance (MR) compatibility were performed concerning magnet forces, image artifacts and right functioning of the system. Then, pilot fMRI of finger opposition tasks were conducted at 1.5T and 3T to investigate the neural correlates of sequences of finger opposition movements with the right hand, with simultaneous behavioral recording by means of GAF. All the MR compatibility tests succeeded, and the fMRI analysis revealed mainly the activation of the left sensorimotor areas and right cerebellum, regions that are known to be involved in finger movements. No artifactual clusters were detected in the activation maps. At the same time, through the parameters calculated by GAF it was possible to describe the sensorimotor strategy adopted by the subjects during the required task. Thus, the proposed device resulted to be MR compatible and can be useful for future fMRI studies investigating the neural correlates of finger opposition movements, allowing follow-up studies and comparisons among different groups of patients.

Background: Cognitive impairment is common in people with neurological diseases and severely affects their social and professional life. It has been shown that intensive and personalized cognitive rehabilitation (CR), based on working memory exercises, leads to improved cognitive status of healthy and cognitive-impaired subjects. New technologies would help to promote accessible, at-home, and self-managed CR interventions., Objective: The aim of this paper is to describe the design of Cognitive Training Kit (COGNI-TRAcK), an app for mobile devices, to self-administer an at-home, intensive, and personalized CR intervention based on working memory exercises, and test its disposability-to-use (usability, motivation to use, compliance to treatment) on cognitive-impaired patients with multiple sclerosis (MS)., Methods: COGNI-TRAcK includes user-friendly interfaces for personal data input and management and for CR intervention configurations. Inner routines automatically implement adaptive working load algorithms and allow data processing and analysis. A dedicated team developed COGNI-TRAcK with C# programming language, by using the platform Xamarin Studio 4.0.10 for Android (API level 15 and following). Three exercises based on working memory are now available. To assess the disposability-to-use of the system, patients with MS were selected as likely users due to the young age of disease onset. Cognitive-impaired patients with MS (N=16) with a mean age of 49.06 years (SD 9.10) and a mean score of 3.75 (SD 1.92) on the Expanded Disability Status Scale (EDSS) were submitted to an 8-week at-home intervention administered by the app. The intervention consisted of 5 daily scheduled 30-minute sessions per week. Disposability-to-use of COGNI-TRAcK was investigated by means of a questionnaire administered to patients at the end of the training., Results: The adherence to the treatment was 84% (33.4/40). Of the patients with MS, 94% (15/16) understood the instructions given, 100% (16/16) felt independent to use COGNI-TRAcK at home, 75% (12/16) found the exercises interesting, and 81% (13/16) found the exercises useful and were motivated to use the app again. Moreover, during the exercises, patients with MS were highly motivated to perform well (mean score 3.19/4, SE 0.16), experienced rather low levels of stress (mean score 2.19/4, SE 0.26), were not bored (mean score 1.81/4, SE 0.30), and felt amusement (mean score 2.25/4, SE 0.23)., Conclusions: As COGNI-TRAcK is highly usable, motivating, and well-accepted by patients with MS, its effectiveness can now be investigated. To improve COGNI-TRAcK, new releases should contain more working memory exercises, have enhanced perceived amusement, and promote Internet communication procedures for data transfer and fostering remote control of the intervention.

Bilastine is a new second generation H1-antihistamine recently approved for the symptomatic treatment of allergic rhinitis (AR) and chronic urticaria (CU). Bilastine epitomizes the evolution of research on antihistamines concerning both efficacy and safety. In AR treatment, a number of large controlled clinical trials documented its efficacy, as assessed by improvement of all nasal and ocular symptoms and quality of life. These outcomes show that bilastine meets current EAACI/ARIA criteria for medications used in the treatment of AR. Also in CU, the review of the literature indicates that once-daily treatment with bilastine 20 mg was effective in managing symptoms and improving patient's quality of life. Concerning safety and tolerability, the profile of bilastine is very similar to placebo and in particular the adverse effects on central nervous system are insignificant. The balance of efficacy and safety of bilastine is particularly helpful when dosages higher than standard are needed to control the symptoms, as frequently occurs in patients with urticaria, in whom antihistamines doses up to four times the standard dose may be administered.

Objective: To evaluate the neural basis of subjective fatigue in subjects with multiple sclerosis (MS) using a connectionist framework., Methods: Seventy seven subjects with relapsing-remitting MS were recruited in the study and underwent subjective fatigue evaluations and a diffusion MRI scan. Firstly, local white matter Fractional Anisotropy values were correlated with subjective fatigue scores using a voxel-wise approach. The long-range loss of connectivity due to structural damage in the white matter voxels thus associated with subjective fatigue was then assessed using the Network Modification (NeMo) package., Results: A voxel-wise regression analysis with fatigue scores revealed a significant association between structural damage and fatigue levels in two discrete white matter clusters, both included in the left cingulate bundle. The connectivity analysis revealed that damage in these clusters was associated with loss of structural connectivity in the anterior and medial cingulate cortices, dorsolateral prefrontal areas and in the left caudate., Discussion: Our data point to the cingulum bundle and its projections as the key network involved in subjective fatigue perception in MS. More generally, these results suggest the potential of the connectionist framework to generate coherent models of the neural basis of complex symptomatology in MS., (© The Author(s), 2014.)

Rhinitis is a very common disease and represents a health problem for both children and adults globally. Rhinitis can be allergic or occur without any IgE-mediated sensitization to aeroallergens. Common symptoms include nasal congestion, postnasal drainage, nasal itching, rhinorrhea and sneezing. The most effective drugs for the treatment of rhinitis are antihistamines and topical glucocorticoids. MP29-02 (Dymista(®)) is a novel intranasal formulation combining the second-generation antihistamine, azelastine hydrochloride, with fluticasone propionate in a single device that has recently been developed. Here, we review the efficacy and safety profile of this intranasal formulation in the treatment of allergic and nonallergic rhinitis.

Neuroimaging studies support the involvement of the cerebello-cortical and striato-cortical motor loops in motor sequence learning. Here, we investigated whether the gain of motor sequence learning could depend on a-priori resting-state functional connectivity (rsFC) between motor areas and structures belonging to these circuits. Fourteen healthy subjects underwent a resting-state functional magnetic resonance imaging session. Afterward, they were asked to reproduce a verbally-learned sequence of finger opposition movements as fast and as accurately as possible. All subjects increased their movement rate with practice, by reducing the touch duration and/or intertapping interval. The rsFC analysis showed that, at rest, the left and right primary motor cortex (M1) and left and right supplementary motor area (SMA) were mainly connected with other motor areas. The covariate analysis taking into account the different kinematic parameters indicated that the subjects achieving greater movement rate increase were those showing stronger rsFC of the left M1 and SMA with the right lobule VIII of the cerebellum. Notably, the subjects with greater intertapping interval reduction showed stronger rsFC of the left M1 and SMA with the association nuclei of the thalamus. Conversely, the regression analysis with the right M1 and SMA seeds showed only a few significant clusters for the different covariates not located in the cerebellum and thalamus. No common clusters were found between the right M1 and SMA. All of these findings indicated important functional connections at rest of those neural circuits responsible for motor learning improvement, involving the motor areas related to the hemisphere directly controlling the finger movements, the thalamus and cerebellum., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Studies in the 1970s and 1980s reported that bacterial lysates (BL) had a prophylactic effect on recurrent respiratory tract infections (RRTI). However, controlled clinical study procedures have evolved substantially since then. We performed a trial using updated methods to evaluate the efficacy of Lantigen B®, a chemical BL. This double blind, placebo controlled, multi-center clinical trial had the primary objective of assessing the capacity of Lantigen B to significantly reduce the total number of infectious episodes in patients with RRTI. Secondary aims were the RRTI duration, the frequency and the severity of the acute episodes, the use of drugs and the number of missed workdays. In the subgroup of allergic patients with RRTI, the number of allergic episodes (AE) and the use of anti-allergic drugs were also evaluated. One hundred and sixty patients, 79 allocated to the treated group (TG) and 81 to the placebo group (PG), were enrolled; 30 were lost during the study and 120 (79 females and 38 males) were evaluated. The PG had 1.43 episodes in the 8-months of follow-up while the TG had 0.86 episodes (p=0.036). A similar result was observed in the allergic patients (1.80 and 0.86 episodes for the PG and the TG, respectively, p=0.047). The use of antibiotics was reduced (mean 1.24 and 2.83 days of treatment for the TG and the PG). Logistic regression analysis indicated that the estimated risk of needing antibiotics and NSAIDs was reduced by 52.1 and 30.6%, respectively. With regard to the number of AE, no significant difference was observed between the two groups, but bronchodilators, antihistamines and local corticosteroids were reduced by 25.7%, 56.2% and 41.6%, respectively, in the TG. Lantigen B significantly reduced the number of infectious episodes in patients with RRTI. This finding suggests a first line use of this drug for the prophylaxis of infectious episodes in these patients., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Patients with Multiple Sclerosis (PwMS) with severe sensorimotor and cognitive deficits show reduced ability in motor sequence learning. Conversely, in PwMS with minimal disability (EDSS≤2), showing only subtle neurological impairments and no particular deficits in everyday life activities, motor sequence learning has been poorly addressed. Here, we investigated whether PwMS with minimal disability already show a specific impairment in motor sequence learning and which component of this process can be first affected in MS. We implemented a serial reaction time task based on thumb-to-finger opposition movements in response to visual stimuli. Each session included 14 blocks of 120 stimuli presented randomly or in ten repetitions of a 12-item sequence. Random (R) and sequence (S) blocks were temporally alternated (R1, R2, S1/S5, R3, S6/S10, R4). Random blocks were designed to evaluate the motor component; sequence blocks, beside the motor component, allowed to discriminate the procedural performance. Twenty-two PwMS and 22 control healthy subjects were asked to perform the task under implicit or explicit instructions (11 subjects for each experimental condition). PwMS with minimal disability improved motor performance in random blocks reducing response time with practice with a trend similar to control subjects, suggesting that short-term learning of simple motor tasks is nearly preserved at this disease stage. Conversely, they found difficulties in sequence-specific learning in implicit and explicit condition, with more pronounced impairment in the implicit condition. These findings could suggest an involvement of different circuits in implicit and explicit sequence learning that could deteriorate at different disease stages., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Upper limb impairments can occur in patients with multiple sclerosis, affecting daily living activities; however there is at present no definite agreement on the best rehabilitation treatment strategy to pursue. Moreover, motor training has been shown to induce changes in white matter architecture in healthy subjects. This study aimed at evaluating the motor behavioral and white matter microstructural changes following a 2-month upper limb motor rehabilitation treatment based on task-oriented exercises in patients with multiple sclerosis. Thirty patients (18 females and 12 males; age=43.3 ± 8.7 years) in a stable phase of the disease presenting with mild or moderate upper limb sensorimotor deficits were randomized into two groups of 15 patients each. Both groups underwent twenty 1-hour treatment sessions, three times a week. The "treatment group" received an active motor rehabilitation treatment, based on voluntary exercises including task-oriented exercises, while the "control group" underwent passive mobilization of the shoulder, elbow, wrist and fingers. Before and after the rehabilitation protocols, motor performance was evaluated in all patients with standard tests. Additionally, finger motor performance accuracy was assessed by an engineered glove. In the same sessions, every patient underwent diffusion tensor imaging to obtain parametric maps of fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. The mean value of each parameter was separately calculated within regions of interest including the fiber bundles connecting brain areas involved in voluntary movement control: the corpus callosum, the corticospinal tracts and the superior longitudinal fasciculi. The two rehabilitation protocols induced similar effects on unimanual motor performance, but the bimanual coordination task revealed that the residual coordination abilities were maintained in the treated patients while they significantly worsened in the control group (p=0.002). Further, in the treatment group white matter integrity in the corpus callosum and corticospinal tracts was preserved while a microstructural integrity worsening was found in the control group (fractional anisotropy of the corpus callosum and corticospinal tracts: p=0.033 and p=0.022; radial diffusivity of the corpus callosum and corticospinal tracts: p=0.004 and p=0.008). Conversely, a significant increase of radial diffusivity was observed in the superior longitudinal fasciculi in both groups (p=0.02), indicating lack of treatment effects on this structure, showing damage progression likely due to a demyelination process. All these findings indicate the importance of administering, when possible, a rehabilitation treatment consisting of voluntary movements. We also demonstrated that the beneficial effects of a rehabilitation treatment are task-dependent and selective in their target; this becomes crucial towards the implementation of tailored rehabilitative approaches., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Subjective and objective memory deficits represent a frequent and ill-understood aspect of multiple sclerosis (MS), and a significant cause of disability and quality of life reduction. The aim of the study is to verify the role of hippocampal and temporal associative fibers' damage in MS-related memory complaints. To reach this aim, 25 patients with low disability relapsing-remitting MS and 19 healthy controls were included in the study. All subjects underwent 3D T1 structural imaging and Diffusion Tensor Imaging. Additionally, MS patients underwent neuropsychological evaluation of objective (Selective Reminding Test and Spatial Recall Test) and of subjective (Perceived Deficit Questionnaire, Retrospective and Prospective Memory Subscales) memory deficits. Normalized hippocampal volume (NHV) and mean Fractional Anisotropy (FA) for the uncinate fasciculus (UF) and for the ventral division of the cingulum bundle (VCB) were calculated for all subjects. We showed that, compared to controls, MS subjects presented with reduced right NHV and with reduced mean FA bilaterally in the UF and the VCB. In the MS group, verbal memory scores correlated with left NHV, spatial memory scores correlated with right NHV, while perceived retrospective and prospective memory deficits correlated with left VCB and left UF mean FA respectively. Our data confirm an early involvement of memory-related brain structures in MS patients. Our data suggest that verbal and nonverbal memory as well as perceived retrospective and prospective memory deficits are related to alterations of discrete anatomical structures in the low-disability phase of MS., (Copyright © 2013 Wiley Periodicals, Inc.)

Allergen immunotherapy (AIT) has a clear evidence of efficacy and safety, as shown by a number of meta-analyses. However, a number of issues limit the use of AIT, many of them being not actually supported by solid data from the literature. In particular, several contraindications to AIT deserve to be argued, being needed to accurately balance in single cases the benefits versus the disadvantages. This concerns comorbidities, such as autoimmune diseases and malignancies, concomitant drug treatments, particularly β-blockers and angiotensin-converting enzyme inhibitors, pregnancy, patient's age, the severity of asthma, allergen polysensitization and the period of starting the treatment. Another important aspect producing misconceptions on AIT is the quality of the allergen extracts, because currently a patient with respiratory allergy to a given source may be prescribed to treat his allergyby products with very different quality. Improving characterization and standardization of allergen extracts will pave the way to the general acknowledgment of AIT as an effective treatment.

Rationale and Objectives: There have been a large number of case-control studies using diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS). The objective of this study was to perform an individual patient data (IPD) meta-analysis for the estimation of the diagnostic accuracy measures of DTI in the diagnosis of ALS using corticospinal tract data., Materials and Methods: MEDLINE, EMBASE, CINAHL, and Cochrane databases (1966-April 2011) were searched. Studies were included if they used DTI region of interest or tractography techniques to compare mean cerebral corticospinal tract fractional anisotropy values between ALS subjects and healthy controls. Corresponding authors from the identified articles were contacted to collect individual patient data. IPD meta-analysis and meta-regression were performed using Stata. Meta-regression covariate analysis included age, gender, disease duration, and Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores., Results: Of 30 identified studies, 11 corresponding authors provided IPD and 221 ALS patients and 187 healthy control subjects were available for study. Pooled area under the receiver operating characteristic curve (AUC) was 0.75 (95% CI: 0.66-0.83), pooled sensitivity was 0.68 (95% CI: 0.62-0.75), and pooled specificity was 0.73 (95% CI: 0.66-0.80). Meta-regression showed no significant differences in pooled AUC for each of the covariates. There was moderate to high heterogeneity of pooled AUC estimates. Study quality was generally high. Data from 19 of the 30 eligible studies were not ascertained, raising possibility of selection bias., Conclusion: Using corticospinal tract individual patient data, the diagnostic accuracy of DTI appears to lack sufficient discrimination in isolation. Additional research efforts and a multimodal approach that also includes ALS mimics will be required to make neuroimaging a critical component in the workup of ALS., (Copyright © 2013 AUR. Published by Elsevier Inc. All rights reserved.)

Objective: To address the disability impact on fine hand motor functions in patients with Multiple Sclerosis (MS) by quantitatively measuring finger opposition movements, with the aim of providing a new "score" integrating current methods for disability assessment., Methods: 40 MS patients (Expanded Disability Status Scale (EDSS): 0-7) and 80 healthy controls (HC) performed a repetitive finger-to-thumb opposition sequence with their dominant hand at spontaneous and maximal velocity, and uni- and bi-manually metronome-paced. A sensor-engineered glove was used to measure finger motor performance. Twenty-seven HC were tested twice, one month apart, to assess test-retest reliability., Results: The motor parameters showed a good reproducibility in HC and demonstrated significantly worse performance in MS patients with respect to HC. A multivariate model revealed that rate of movement in the spontaneous velocity condition and inter-hand interval (IHI), indicating bimanual coordination, contributed independently to differentiate the two groups. A finger motor impairment score based on these two parameters was able to discriminate HC from MS patients with very low EDSS scores (p<0.001): a significant difference was already evident for patients with EDSS = 0. Further, in the MS group, some motor performance parameters correlated with the clinical scores. In particular, significant correlations were found between IHI and EDSS (r = 0.56; p<0.0001), MS Functional Composite (r = -0.40; p = 0.01), Paced Auditory Serial Addition (r = -0.38; p = 0.02). No motor performance parameter correlated with Timed 25-Foot Walk., Conclusions: A simple, quantitative, objective method measuring finger motor performance could be used to define a score discriminating healthy controls and MS patients, even with very low disability. This sensitivity might be of crucial importance for monitoring the disease course and the treatment effects in early MS patients, when changes in the EDSS are small or absent.

The purpose of this study was to assess the feasibility of measuring different permeability parameters with T1-weighted dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in order to investigate the blood brain-barrier permeability associated with different brain tumors. The Patlak algorithm and the extended Tofts-Kety model were used to this aim. Twenty-five adult patients with tumors of different histological grades were enrolled in this study. MRI examinations were performed at 1.5 T. Multiflip angle, fast low-angle shot, and axial 3D T1-weighted images were acquired to calculate T1 maps, followed by a DCE acquisition. A region of interest was placed within the tumor of each patient to calculate the mean value of different permeability parameters. Differences in permeability measurements were found between different tumor grades, with higher histological grades characterized by higher permeability values. A significant difference in transfer constant (K (trans)) values was found between the two methods on high-grade tumors; however, both techniques revealed a significant correlation between the histological grade of tumors and their K (trans) values. Our results suggest that DCE acquisition is feasible in patients with brain tumors and that K (trans) maps can be easily obtained by these two algorithms, even if the theoretical model adopted could affect the final results.

Motor performance recovery after a demanding finger motor task does not follow the excitability dynamics of primary motor cortex (M1), which remains depressed also when performance is restored. Thus, other neural circuits are supposed to cope with central fatigue, re-establishing adequate motor performance levels. A hint that the basal ganglia (BG) can be involved in this process is provided by studies showing an association of central fatigue with the BG. To investigate this possibility, we conducted an fMRI study with simultaneous motor performance recording in 20 healthy volunteers at different stages of a demanding finger motor task: baseline, central fatigue induced by 5-min sequence repetition, performance recovery after a short rest period. When motor performance was recovered, we observed a significant activation with respect to baseline in subcortical structures belonging to different BG circuits (putamen and globus pallidus), involving the limbic system functionally interacting with the BG (amygdala). Then, to assess whether the BG activation was exclusively related to the fatigue and recovery processes or to increasing automatism in motor performance, a control fMRI experiment based on a shorter motor task duration was carried out on 14 healthy subjects. In this case, the task repetition did not induce decreased performance, and no significant effect on the BOLD signal change was found in BG regions of interest with respect to baseline. All these findings suggest that motor and non-motor BG circuits run parallel and converge in a common motor path to successfully compensate motor performance deterioration in a central fatigue condition., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To prospectively evaluate longitudinal changes in white matter lesions (WMLs) in migraineurs with aura, by magnetic resonance imaging (MRI), and to correlate WMLs modifications with patients' clinical characteristics., Methods: Forty-one consecutive migraineurs with aura were followed for a mean time of 33.2 months. Patients underwent MRI at baseline and follow-up and were evaluated for cerebrovascular risk factors. Presence of WMLs on MRI was assessed by two neuroradiologists., Results: WMLs were present in 26 subjects (63.4%) at baseline MRI. At follow-up a total of 8 patients had new WMLs (19.5%). There was a significant correlation between aura duration and number of new WMLs, and between the number of migraine attacks with aura and new WMLs., Conclusions: Our study demonstrates that in migraine with aura WMLs number can progress over time and suggests an association between aura features and WMLs progression. Studies with a higher number of patients are required to confirm these findings., (Copyright © 2012 by the American Society of Neuroimaging.)

Subjective fatigue is a typical symptom in Multiple Sclerosis (MS) even in the earliest stages of the disease. The relationship between persistent fatigue and motor task performance is still unclear. Aim of this study was to better investigate this relationship at both the motor behavioral and neuroanatomical levels. Towards this goal, we combined a quantitative evaluation of an undemanding finger motor task with concurrent brain functional magnetic resonance imaging (fMRI) in a group of MS patients with minimal disability but reporting persistent subjective fatigue. We found an unexpected significant positive correlation between persistent subjective fatigue and task-related temporal accuracy, revealing a "fatigue-motor performance paradox". fMRI analysis indicated that this association is potentially mediated by cerebellar and orbitofrontal cortex activity, suggesting a role of these regions in developing subjective fatigue. Our data point to a possible adaptive role for fatigue as the subjective correlate of increased resource demand for motor activities.

Schizencephaly is regarded as a malformation of cortical development (due to abnormal neuronal organization) and may be associated with continuous involuntary hand movements. The mechanisms underlying these movements are not clear and both dystonia and epilepsia partialis continua have been considered in previously reported cases. We describe a young patient affected by schizencephaly and continuous involuntary movements of the contralateral hand. Functional MRI showed bilateral cerebral activation, while the subject performed tapping movements with the affected hand and no significant difference in the activation pattern after diazepam infusion. Standard and back-averaged EEG showed no alterations. The results obtained from these investigations and the clinical features of the involuntary movements are not in favor of an epileptic genesis, while support the diagnosis of secondary dystonia.

In vitro neuronal cultures exhibit spontaneous electrophysiological activity that can be modulated by chemical stimulation and can be monitored over time by using Micro-Electrode Arrays (MEAs), devices composed by a glass substrate and metal electrodes. Dissociated networks respond to transmitters, their blockers and many other pharmacological substances, including neurotoxic compounds. In this paper we present results related to the effects, both acute (i.e. 1 hour after the treatment) and chronic (3 days after the treatment), of increasing glutamatergic transmission induced by the application of rising concentrations of glutamate and its agonists (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid - AMPA, N-methyl-D-aspartate - NMDA and AMPA together with cyclothiazide - CTZ). Increase of available glutamate was obtained in two ways: 1) by direct application of exogenous glutamate and 2) by inhibiting the clearance of the endogenously released glutamate through DL-threo-β-benzyloxyaspartate (TBOA). Our findings show that fine modulations (i.e. low concentrations of drug) of the excitatory synaptic transmission are reflected in the electrophysiological activation of the network, while intervention leading to excessive direct stimulation of glutamatergic pathways (i.e. medium and high concentrations of drug) results in the abolishment of the electrophysiological activity and eventually cell death. The results obtained by means of the MEA recordings have been compared to the analysis of cell viability to confirm the excitotoxic effect of the applied drug. In conclusion, our study demonstrates that MEA-coupled cortical networks are very sensitive to pharmacological manipulation of the excitatory ionotropic glutamatergic transmission and might provide sensitive endpoints to detect acute and chronic neurotoxic effects of chemicals and drugs for predictive toxicity testing., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Training one hand on a motor task results in performance improvements in the other hand, also when stimuli are randomly presented (nonspecific transfer). Corpus callosum (CC) is the main structure involved in interhemispheric information transfer; CC pathology occurs in patients with multiple sclerosis (PwMS) and is related to altered performance of tasks requiring interhemispheric transfer of sensorimotor information. To investigate the role of CC in nonspecific transfer during a pure motor reaction-time task, we combined motor behavior with diffusion tensor imaging analysis in PwMS. Twenty-two PwMS and 10 controls, all right-handed, were asked to respond to random stimuli with appropriate finger opposition movements with the right (learning) and then the left (transfer) hand. PwMS were able to improve motor performance reducing response times with practice with a trend similar to controls and preserved the ability to transfer the acquired motor information from the learning to the transfer hand. A higher variability in the transfer process, indicated by a significantly larger standard deviation of mean nonspecific transfer, was found in the PwMS group with respect to the control group, suggesting the presence of subtle impairments in interhemispheric communication in some patients. Then, we correlated the amount of nonspecific transfer with mean fractional anisotropy (FA) values, indicative of microstructural damage, obtained in five CC subregions identified on PwMS's FA maps. A significant correlation was found only in the subregion including posterior midbody (Pearson's r = 0.74, P = 0.003), which thus seems to be essential for the interhemispheric transfer of information related to pure sensorimotor tasks., (Copyright © 2010 Wiley-Liss, Inc.)

Fatigue, an overwhelming lack of physical or mental energy, is a common complaint in patients affected by multiple sclerosis (MS). Although different mechanisms have been proposed to explain MS-related fatigue, injury of distinct anatomical networks seems to be relevant in fatigue etiology. Particularly, theories point to fronto-striatal network pathological changes as a possible neural basis of fatigue. To investigate the role of fronto-striatal white matter structural alterations in fatigue perception we prospectively recruited 40 relapsing remitting patients with MS and 15 healthy controls. In patients with MS, fatigue was assessed using a validated measure, the Modified Fatigue Impact Scale (MFIS; Kos et al., 2005). Brain MRI scans were acquired for each subject enrolled with diffusion tensor imaging. Diffusion tensor data were correlated with MFIS scores using voxel-wise analysis of fractional anisotropy maps and fiber tractography algorithms. A significant cluster of voxels correlating with fatigue scores located in the deep left frontal white matter was identified. Fiber tractography revealed the cluster to be included in a complex fronto-frontal, fronto-striatal, fronto-occipital, and fronto-limbic network. Structural properties of the traced white matter fiber bundles correlated with fatigue perception and patients with clinically relevant fatigue were found to present reduced white matter integrity in the aforementioned tracts compared to those with lower levels of fatigue. Our observations show a significant involvement of different frontal networks in the pathophysiology of fatigue, thus accounting for the multifaceted nature of this disabling symptom.

Continuous recording of Visual Evoked Potentials (VEPs) and functional Magnetic Resonance Imaging (fMRI) exploits the VEPs high temporal resolution and the fMRI high spatial resolution. In this work, we present a new method of continuous VEPs/fMRI recording to study visual function in seven normal subjects. Our real-time artifact filtering is characterized by a procedure based on an analytical study of echo-planar imaging (EPI) sequence parameters related electro-encephalogram (EEG)-artifact shapes. The magnetic field artifacts were minimized by using a dedicated amagnetic device and by a subtraction algorithm that takes into account the EPI sequence parameters. No significant decrease in signal-to-noise ratio was observed in case of EEG recording simultaneously with MR acquisition; similarly, transient and steady-state VEPs parameters were comparable during fMRI acquisition and in the off-phase of fMRI recording. We also applied this method to one patient with optic neuritis, and, compared with controls, found different results. We suggest that our technique can be reliably used to investigate the function of human visual cortex and properly correlate the electrophysiological and functional neuroimaging related changes.

Background: The treatment effects in multiple sclerosis (MS) clinical trials are often estimated by monitoring disease activity by the count of "active" plaques on T2-weighted or gadolinium (Gd)-enhanced T1-weighted magnetic resonance imaging (MRI)., Objective: To evaluate the relationship between the treatment effects estimated on T2-weighted or Gd-enhanced T1-weighted MRI., Methods: Data were extracted from published randomized clinical trials in relapsing-remitting MS with frequent MRI, reporting both active T2 and Gd-enhancing lesions. A regression analysis was performed between the treatment effects estimated on the two different MRI endpoints., Results: A strong association was found between the treatment effect on Gd-enhancing lesions and on active T2 lesions (R(2) = 0.93), and the treatment effect estimates were almost the same (slope = 0.96)., Conclusion: Defining either active T2 or Gd-enhancing lesions as MRI endpoint seems to be not crucial for monitoring MRI activity in MS clinical trials. The choice of the best MRI endpoint should be based on different considerations (e.g., sensitivity, reproducibility, time for assessment, safety, and patients' comfort). Further monitoring active T2 lesions could allow less expensive trials, without requiring injection of Gd-based contrast agents.

Purpose: To evaluate whether artifacts caused by a stainless steel glaucoma drainage device can alter the interpretation of magnetic resonance imaging (MRI) scans of the optic nerve and brain., Design: Consecutive case series., Methods: Five patients (7 eyes) with Ex-PRESS devices (Optonol Ltd, Neve Ilan, Israel) positioned at the limbus were studied. For each subject, an axial T1-weighted, axial and coronal T2-weighted with fat saturation, and whole brain proton density (PD)/T2-weighted MRI scan was obtained. Standard MRI protocol was not optimized for the imaging of patients harboring Ex-PRESS implants. The effects of the device on PD/T2 pulse sequence imaging of the optic nerve and brain were rated from 1 (optic nerve margins unidentifiable or brain details altered) to 5 (excellent visualization of the optic nerve and brain)., Results: For optic nerve visualization, 1 optic nerve scored 2, 3 optic nerves scored 3, and 3 optic nerves scored 4 (mean, 3.3 +/- 0.8 standard deviation). For whole brain imaging, 4 patients scored 4 and 1 patient scored 5 (mean, 4.2 +/- 0.4 standard deviation)., Conclusions: Our data demonstrate that interpretation of MRI scans of the orbit and brain is unaffected by the artifacts caused by the Ex-PRESS shunt, whereas optic nerve imaging may be affected. We are unaware of previous reports of this finding and could find no reference to it in a computerized search using PubMed.

Purpose: To describe the occurrence of abnormal hyperintensity in the dentate nucleus on T1-weighted magnetic resonance (MR) images in patients with multiple sclerosis (MS) as a neuroradiologic sign of gray matter involvement. Presence of the finding was evaluated for association with disability, clinical MS subtype, total lesion volume on T1- and T2-weighted MR images (lesion load), and brain atrophy., Materials and Methods: Written informed consent was waived by the Ethics Committee because of the retrospective nature of this single-center Institutional Review Board-approved study. MR examinations of 185 patients with MS were reviewed, and 119 patients were included for analysis. Two neuroimagers, who were blinded to clinical data, assessed the presence of a hyperintense dentate nucleus on T1-weighted MR images. The presence of this radiologic alteration was then evaluated in relation to MS subtype, clinical disability, T1 and T2 lesion load, and whole-brain atrophy measurements. Fisher exact, chi(2), and Mann-Whitney U tests were used to evaluate differences in clinical and imaging features between patients with and those without a T1 hyperintense dentate nucleus., Results: Twenty-three (19.3%) of the 119 patients had a hyperintense dentate nucleus on unenhanced T1-weighted MR images. This finding was related to the secondary progressive subtype of the disease, a higher score on the Expanded Disability Status Scale, a higher brain lesion load, and tissue loss. None of the patients with primary progressive MS had a hypterintense dentate nucleus., Conclusion: Hyperintensity of the dentate nucleus may be present on unenhanced T1-weighted MR images of patients with MS and is associated with the secondary progressive disease subtype and with increased clinical disability, lesion load, and brain atrophy.

Objective: The aim of this work was to evaluate whether the treatment effects on magnetic resonance imaging (MRI) markers at the trial level were able to predict the treatment effects on relapse rate in relapsing-remitting multiple sclerosis., Methods: We used a pooled analysis of all the published randomized, placebo-controlled clinical trials in relapsing-remitting multiple sclerosis reporting data both on MRI variables and relapses. We extracted data on relapses and on MRI "active" lesions. A regression analysis weighted on trial size and duration was performed to study the relation between the treatment effect on relapses and the treatment effect on MRI lesions. We validated the estimated relation on an independent set of clinical trials satisfying the same inclusion criteria but with a control arm other than placebo., Results: A set of 23 randomized, double-blind, placebo-controlled trials in relapsing-remitting multiple sclerosis was identified, for a total of 63 arms, 40 contrasts, and 6,591 patients. A strong correlation was found between the effect on the relapses and the effect on MRI activity. The adjusted R(2) value of the weighted regression line was 0.81. The regression equation estimated using the placebo-controlled trials gave a satisfactory prediction of the treatment effect on relapses when applied to the validation set., Interpretation: More than 80% of the variance in the effect on relapses between trials is explained by the variance in MRI effects. Smaller and shorter phase II studies based on MRI lesion end points may give indications also on the effect of the treatment on relapse end points.

We prospectively investigated pathological modifications in the corticospinal tract (CST), by diffusion tensor imaging (DTI) in 14 patients with sporadic amyotrophic lateral sclerosis (ALS) and 12 healthy volunteers. We used a validated automated method to accurately measure the in vivo thickness of the cerebral cortex. We found a reduction of precentral cortical ribbon thickness in ALS patients with respect to control subjects. DTI metrics demonstrated disorganization of the CST, as characterized by decreased fractional anisotropy (FA) and increased Apparent Diffusion Coefficient in ALS patients with respect to control subjects. Decreased mean FA values along the CST significantly correlated with clinical measures of pyramidal and bulbar impairment. Quantitative analysis of MR data shows that thinning of the motor cortex coexists with CST damage in ALS patients.

To assess the influence of white matter pathology on cortical reorganization, we probed the fronto-parietal attention network in Multiple Sclerosis (MS) patients by combining the Paced Visual Serial Addition Test (PVSAT) with fMRI-guided fiber tractography (FT). During the PVSAT, the control subjects activated the left inferior parietal lobule, superior temporal gyrus, precuneus, precentral gyrus, and medial and middle frontal gyri; while the precuneus and the inferior parietal lobule gyrus bilaterally, the left precentral and angular gyri and the right superior parietal lobule were activated in the MS group. At fMRI-guided FT, the superior longitudinal fasciculus (SLF) was the main white matter tract connecting areas active during the PVSAT. We then identified two subgroups of MS patients according to the SLF mean Fractional Anisotropy, used as indicator of integrity. The activations of the MS patients with a less damaged tract were in the left hemisphere, similarly to controls; while the patients with a more damaged SLF showed bilateral cortical activations. The MS subgroups, however, did not differ in PVSAT performance. This approach could be useful to investigate the relationship between brain structural and functional plastic changes and to identify different MRI endophenotypes related to the same level of cognitive impairment.

Corpus callosum (CC) is involved in the performance of bimanual motor tasks. We asked whether its functional role could be investigated by combining a motor behavioral study on bimanual movements in multiple sclerosis (MS) patients with a quantitative magnetic resonance diffusion tensor imaging (DTI) analysis of CC, which is shown to be damaged in this disease. MS patients and normal subjects were asked to perform sequences of bimanual finger opposition movements at different metronome rates; then we explored the structural integrity of CC by means of DTI. Significant differences in motor performance, mainly referred to timing accuracy, were observed between MS patients and control subjects. Bimanual motor coordination was impaired in MS patients as shown by the larger values of the interhand interval observed at all the tested metronome rates with respect to controls. Furthermore, DTI revealed a significant reduction of fractional anisotropy (FA), indicative of microstructural tissue damage, in the CC of MS patients. By correlating the mean FA values with the different motor behavior parameters, we found that the degree of damage in the anterior callosal portions mainly influences the bimanual coordination and, in particular, the movement phase preceding the finger touch. Finally, the described approach, which correlates quantitative measures of tissue damage obtained by advanced magnetic resonance imaging tools with appropriate behavioral measurements, may help the exploration of different aspects of motor performance impairment attributable to the disease.

The relationship between migraine with aura and patent foramen ovale (PFO) is still debatable. We report 2 cases of migraine with aura attacks after diagnostic microbubble injection for contrast transcranial Doppler (cTCD), in subjects with large PFO. In one case MR images, including diffusion weighted imaging and apparent diffusion coefficient, performed during aura did not show any signal abnormality. Patients with migraine with aura may have an attack during cTCD, probably by a "non-ischemic" mechanism.

We report the first application of brain functional Magnetic Resonance Imaging (fMRI) to congenital peripheral lymphedema patients before and after microsurgical treatment. Our aim was to evaluate the effects of limb shape change on cortical organization of the motor system and how the cortical sensorimotor network restructures after microsurgical therapy. We acquired fMRI during active motor and motor imagery tasks before surgery and six months after surgery in a patient with congenital lymphedema of the left leg. fMRI data revealed activation differences in primary and secondary motor areas between the two scanning sessions for both tasks and also between the patient's and a healthy volunteer's activations. We suggest that these alterations could be related to changes in body schema representation due to the congenital lymphedema.

The incidence of coeliac disease (CD) was calculated on 304 patients under eighteen who were born in the city of Turin and its province in the years 1975-1989; the prevalence on 494 patients who live in the Piedmont Region. The mean crude yearly incidence was 0.511/1000 (1:1957 live birth). It varied from year to year, reaching minimum values in the years 1984-1987. In a contemporary epidemiological study, the mean crude incidence of CD in Italy was 1.2/1000 (1:833 live birth) twice the rate observed in Turin. The prevalence of paediatric CD in Piedmont was 113 per million inhabitants. Since CD has a normal life expectancy, its prevalence may be expected to increase. In the provinces of Novara, Alessandria and Asti CD prevalence was lower than in the others. Mean age at onset was 6 mos in 1975 and increased to 34 mos in 1989. Mean age at diagnosis was 15 mos in 1981, and 7 yrs in 1989. Symptoms were more numerous and severe in patients under 12 mos of age, and became fewer and often atypical in older children. We can therefore speculate that the trend towards a decreasing incidence of CD in recent years my be due to delayed diagnosis.

Thirty children suffering from acute diarrhoea have been examined over a period of 10 months. Salmonellae were present in 16.6% of the cases, Campylobacter in 10%, E. coli in 60%, Rotavirus in 10%. The monthly incidence of the infections has been studied, verifying values which fall into line with those reported by other authors. It has also been observed that macroscopic blood, fecal leucocytes are present in diarrhoea by bacterial agents, while Kerry test is more indicative of infections by Rotavirus. We fall into line with those who believe that the "use of products without lactose should be reserved for selected cases".

We describe a 7-years boy by with a meningococcal sepsis due to Neisseria Meningitidis, with very serious evolution of cutaneous necrosis, initial D.I.C. and heart failure. The clinical picture do not improve with antibiotic therapy (CAF-penicillin), but the association ceftriaxone + tobramycin results in rapid improvement. The cutaneous necrosis, especially evident on gluteus, arms and legs, were treated locally with AgNO3 and penicillin-solution. After 4 weeks of treatment, also this cutaneous involvement improved and now the boy is healthy, without residual signs neither systemic nor cutaneous.