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Multiple sclerosis (MS) is a progressive neurologic disorder that can profoundly influence mobility, independence and quality of life. Gait dysfunction in MS is common, resulting in an increased risk of losing walking ability. Robotic exoskeletons have been developed to offer a new form of locomotor training. The aim of our study was to investigate the effectiveness of the powered exoskeleton (Ekso) in improving gait and balance in patients affected by MS. Twenty patients with MS (mean ± SD: age = 43.7 ± 10.3 years; 66.7% male) were enrolled in this retrospective study. They were divided into two groups, matched for demographic data (age and sex) and medical characteristics (disease duration and Expanded Disability Status Scale), but differing for the type of rehabilitation training performed. Group 1 [experimental group (EG)] received gait training with the Ekso device, whereas group 2 (control group) performed traditional gait training. Although both trainings led to a significant improvement in the ability to walk and balance, only in the EG a significant improvement in walking speed (10 Meter Walk test; P = 0.002), in person's mobility (Timed Up and Go test; P = 0.002), and in the perception of mental well-being (MSQoL-M; P = 0.004), with a good usability and acceptance of the device, was found. Powered exoskeletons could be considered a valuable tool to improve functional outcomes and get the therapeutic goal in patients with MS.

Background. Multiple sclerosis (MS) is an autoimmune and demyelination disease of the central nervous system that causes progressive accumulation of disability over time. Recent studies have highlighted the correlation between metabolic disorders and cognitive dysfunctions. The present study aims to evaluate the correlation between components of the lipid profile and cognitive dysfunctions in patients affected by MS.Methods. 90 MS inpatients were included in this study. We divided the sample into three subgroups to evaluate the influence of the presence of dyslipidemia: G1 (patients with dyslipidemia), G2 (patients without dyslipidemia), G3 (patients with a higher than normal lipid value). Patients underwent rehabilitation treatment which included conventional physiotherapy, speech therapy, psychological support, cognitive rehabilitation, nutritional therapy, robotic rehabilitation, cognitive rehabilitation, and virtual reality.Results. The results showed that the three subgroups had a significant improvement in global cognitive functioning (MOCA p

Lung cancer represents the world’s most common cause of cancer death. In recent years, we moved from a generic therapeutic strategy to a personalized approach, based on the molecular characterization of the tumor. In this view, liquid biopsy is becoming an important tool for assessing the progress or onset of lung disease. Liquid biopsy is a non-invasive procedure able to isolate circulating tumor cells, tumor educated platelets, exosomes and free circulating tumor DNA from body fluids. The characterization of these liquid biomarkers can help to choose the therapeutic strategy for each different case. In this review, the authors will analyze the main aspects of lung cancer and the applications currently in use focusing on the benefits associated with this approach for predicting the prognosis and monitoring the clinical conditions of lung cancer disease.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is a rare and heterogeneous acquired sensory-motor polyneuropathy with autoimmune pathogenesis. Intravenous immunoglobulins (IVIG) are a well-established therapy for CIDP: it is well known that at least two-thirds of these patients need these infusions for several years. More recently, Subcutaneous Immunoglobulins (SCIg) have been proved to be effective: this finding has been confirmed either in isolated cases or in few randomized trials. However, it appeared that the longest SCIg treatment follow up lasted no longer than 48 months. We report herein the results of a long-term SCIg treatment with a follow up period up to 7 years (84 months), considering safety, tolerability and patients’ perception of SCIg treatment in a CIDP population. We studied 17 patients (10 M; 7 F) with a diagnosis of CIDP, defined according to the EFNS/PNS criteria, successfully treated with IVIG every 4/6 weeks before being switched to SCIg treatment. Clinical follow-up included, apart from a routinely clinical assessment, the administration of Medical Research Council (MRC) sum-score, the Overall Neuropathy Limitation Scale (ONLS) and the Life Quality Index questionnaire (LQI). The results showed that, in the majority of this pre-selected group of CIDP patients (16/17), SCIg were well tolerated and were preferred over IVIG. Strength and motor functions remained stable or even improved during the long term follow-up (up to 84 months) with benefits on walking capability and resistance, manual activity performances and fatigue reduction.

Introduction: The approval of 9-δ-tetrahydocannabinol (THC)+cannabidiol (CBD) oromucosal spray (Sativex®) in Italy as an add-on medication for the management of moderate to severe spasticity in multiple sclerosis (MS) has provided a new opportunity for MS patients with drug-resistant spasticity. We aimed to investigate the improvement of MS spasticity-related symptoms in a large cohort of patients with moderate to severe spasticity in daily clinical practice. Materials and methods: MS patients with drug-resistant spasticity were recruited from 30 Italian MS centers. All patients were eligible for THC:CBD treatment according to the approved label: ≥ 18 years of age, at least moderate spasticity (MS spasticity numerical rating scale [NRS] score ≥ 4) and not responding to the common antispastic drugs. Patients were evaluated at baseline (T0) and after 4 weeks of treatment (T1) with the spasticity NRS scale and were also asked about meaningful improvements in 6 key spasticity-related symptoms. Results: Out of 1615 enrolled patients, 1432 reached the end of the first month trial period (T1). Of these, 1010 patients (70.5%) reached a ≥ 20% NRS score reduction compared with baseline (initial responders; IR). We found that 627 (43.8% of 1432) patients showed an improvement in at least one spasticity-related symptom (SRSr group), 543 (86.6%) of them belonging to the IR group and 84 (13.4%) to the spasticity NRS non-responders group. Conclusion: Our study confirmed that the therapeutic benefit of cannabinoids may extend beyond spasticity, improving spasticity-related symptoms even in non-NRS responder patients. © 2020, Fondazione Società Italiana di Neurologia.

Multiple Sclerosis (MS) is an inflammatory degenerative disease of the central nervous system. Cognitive impairment is a frequent feature of MS at both the earlier and later stages of the disease, and it tends to worsen over time. Cognitive rehabilitation (CR) is becoming a standard component of neurorehabilitation in patients with MS. The aim of this study is to evaluate the effect of computerized CR, by using the Italian software ERICA, on cognitive and daily life performance in MS patients with mild to moderate cognitive impairment. We studied 40 individuals affected by MS, randomized into either traditional CR group (TCRG: n = 20), which performed a conventional cognitive training, or the computer-assisted CR group (CCRG: n = 20), which performed PC-based CR. The cognitive dysfunctions were investigated through a complete neuropsychological battery, administered before (T0) and after (T1) each different training. Both the trainings were well-tolerated and led to improvement in cognitive function. Notably, the CCRG had a significant effect in improving memory, attention, and processing speed, as compared to TCRG. ERICA training could be a valuable tool for the CR in patients affected by MS. Further studied are needed to confirm these promising results and evaluate the long-term effects.

Endometriosis can take one of three forms depending on its clinical presentation and management: endometriotic ovarian cyst (ovarian endometrioma), superficial or peritoneal endometriosis and deep infiltrating endometriosis (DIE).1Among them, DIE is considered the most aggressive, and the patient is often affected by more than one type together. The therapeutic methodology should not be influenced by a combination of different types of endometriotic lesion. According to the clinical context and the patient's needs, the treatment of this pathology can be medical or surgical. Although medical therapy could improve endometriosis-associated symptoms, it never offers a definite treatment for symptomatic patients, who often require surgical treatment. The rationale behind endometriosis surgical treatment is to achieve the complete removal of all lesions through a one-step surgical procedure; to obtain promising long-term results for pelvic pain, recurrence rate, and fertility; and to protect the functionality of the involved organs. Achieving these results depends on the total removal of the pathology from the pelvis, in an attempt to preserve, as much as possible, the healthy tissues surrounding the site of the disease. The choice of a surgical approach rather than medical therapy is subject to the patient's expectations, such as pregnancy desire, the effectiveness of treatment compared to possible complications, the type of pain and its intensity, and the location and severity of the disease. In this context, surgical management using a multidisciplinary endometriosis team is an important factor for achieving good outcomes.

Objective: To identify baseline factors associated with disease activity in patients with relapsing–remitting multiple sclerosis (RRMS) under teriflunomide treatment. Methods: This was an independent, multi-centre, retrospective post-marketing study. We analysed data of 1,507 patients who started teriflunomide since October 2014 and were regularly followed in 28 Centres in Italy. We reported the proportions of patients who discontinued treatment (after excluding 32 lost to follow-up) and who experienced clinical disease activity, i.e., relapse(s) and/or confirmed disability worsening, as assessed by the Expanded Disability Status Scale (EDSS). Decision tree-based analysis was performed to identify baseline factors associated with clinical disease activity during teriflunomide treatment. Results: At database lock (September 2020), approximately 29% of patients (430 out of 1,475) discontinued teriflunomide because of disease activity (~ 46%), adverse events (~ 37%), poor tolerability (~ 15%), pregnancy planning (~ 2%). Approximately 28% of patients experienced disease activity over a median follow-up of 2.75years: ~ 9% had relapses but not disability worsening; ~ 13% had isolated disability worsening; ~ 6% had both relapses and disability worsening. The most important baseline factor associated with disease activity(especially disability worsening) was an EDSS > 4.0 (p < 0.001). In patients with moderate disability level (EDSS 2.0–4.0), disease activity occurred more frequently in case of ≥ 1 pre-treatment relapses (p = 0.025). In patients with milder disability level (EDSS < 2.0), disease activity occurred more frequently after previous exposure to ≥ 2 disease-modifying treatments (p = 0.007). Conclusions: Our study suggests a place-in-therapy for teriflunomide in naïve patients with mild disability level or in those who switched their initial treatment for poor tolerability. Adverse events related with teriflunomide were consistent with literature data, without any new safety concern.

Motor impairment is the most common symptom in multiple sclerosis (MS). Thus, a variety of new rehabilitative strategies, including robotic gait training, have been implemented, showing their effectiveness. The aim of our study was to investigate whether an intensive robotic gait training, preceding a traditional rehabilitative treatment, could be useful in improving and potentiating motor performance in MS patients. Forty-five patients, who fulfilled the inclusion criteria, were enrolled in this study and randomized into either the control group (CG) or the experimental group (EG). A complete clinical evaluation, including the Expanded Disability Severity Scale, the Functional Independence Measure, the Hamilton Rating Scale for Depression, the time up and go test (TUG), and the Tinetti balance scale, was performed at baseline (T0), after 6 week (T1), at the end of rehabilitative training (T2), and 1 month later (T3). A significant improvement was observed in the EG for all the outcome measures, whereas the CG showed an improvement only in TUG. In contrast, from T1 to T2, only CG significantly improved in all outcomes, whereas the EG had an improvement only regarding TUG. From T2 to T3, no significant differences in Functional Independence Measure scores emerged for both the groups, but a significant worsening in Tinetti balance scale and TUG was observed for the CG and in TUG for the EG. Our study provides evidence that robotic rehabilitationn coupled with two-dimensional virtual reality may be a valuable tool in promoting functional recovery in patients with MS.

Studies on the prevalence of sexual dysfunction (SD) in multiple sclerosis (MS) have shown that 40% to 80% of women and 50% to 90% of men have had sexual complaints. Sexual function is often disregarded during consultation with healthcare professionals, and SD is frequently underdiagnosed. The aim of this study was to investigate the prevalence of SD and its relationship to sociodemographic and disease-related factors, with regard to disability state, in a hospital cohort of MS patients, by using a semistructured interview.Of 130 screened outpatients, 87 met the inclusion criteria and completed the study. The mean age of the participants was 39.3 ± 8.3 years, with a disease duration of 8.3 ± 5.4 years and a mean Expanded Disability Status Scale (EDSS) score of 2.04 ± 0.19. Sexual function was evaluated by means of a semistructured interview, investigating a patient's 3 main life areas: sociodemographic information, illness perception, and sexuality.Approximately 70% of the patients complained at least 1 SD (decreased libido, erectile dysfunction, premature or retarded ejaculation, painful penetration), and 22% of them reported the disorder as frequent. The disease duration was associated with lower satisfaction in sexual function, and lack of sexual interest was the most common problem having a negative correlation with EDSS.Healthcare professionals involved in MS, should assess patients for SD. Further studies should be fostered to better quantify SD etiology, the degree of sexual impairment, and its impact on patients' quality of life to "overcome" this problem.

Objectives To describe the effects of osteopathic manipulative treatment in patients affected by Multiple Sclerosis (MS). Design and setting This is a pilot study involving 20 MS patients attending the IRCCS Neurolesi “Bonino-Pulejo”, Messina, Italy. Intervention The clinical evaluation was performed before starting rehabilitation treatment (T0) and after 8 weeks of treatment (T1). The CG sample undergo a conventional rehabilitation training (CRT), 5 times/week for 60 min (for a total of 40 sessions), the EG performed the same CRT (but with a different frequency, i.e. 3 times/week, for a total of 24 sessions) and a specific OMT 2 times/week for 60 min (for a total of 16 sessions). Main outcome measures We analyzed the scores recorded in the following main scales: Expanded Disability Status Scale (EDSS), 10 m walking test (10mWT), Hamilton anxiety rating scale (HRS-A), and the Fatigue severity scale (FSS). Results Our data showed a reduction in the FSS score for the EG (40 ± 1,41 at T0 vs 37 ± 2,32 at T1; p = 0.04) but not in the CG (41 ± 2,41 at TO vs 39 ± 2,6 at T1) with an intergroup difference p Conclusions Our data raise idea that OMT might be useful in rehabilitative setting in MS patients, with particular regard to anxiety and fatigue.

Multiple sclerosis (MS) can adversely affect several domains of cognitive function, including attention, information processing, memory and learning, executive functions and visuospatial skills. In recent years, technological innovations have proven effective in improving motor and cognitive impairment in neurological patients, including those affected by MS.The study aims to evaluate cognitive outcomes after rehabilitation training with the Virtual Reality rehabilitation system (VRRS) in patients suffering from MS.All patients were randomized into either the control group (CG: 15 patients) receiving conventional cognitive rehab or the experimental group (EG) using virtual reality (VR) (15 patients). Both groups underwent the same amount of cognitive training, 3 times a week for 8 weeks. They were submitted to neuropsychological assessment before (T0) and after the rehabilitation treatment (T1).Our data showed that both conventional and VR cognitive rehabilitation approaches improved mood (p 0.001) and visuospatial skills. However, only in the EG a significant improvement in specific cognitive domains (p 0.001), including learning ability, short-term verbal memory, lexical access ability, as well as quality of life related to mental states, was found.The present study demonstrated that VR can be a motivational and effective tool for cognitive recovery in MS patients.

Several cerebellar functions related to upper limb motor control have been studied using non-invasive brain stimulation paradigms. We have recently shown that transcranial alternating current stimulation (tACS) may be a promising approach in shaping the plasticity of cerebellum-brain pathways in a safe and effective manner. This study aimed to assess whether cerebellar tACS at different frequencies may tune M1-leg excitability and modify gait control in healthy human subjects. To this end, we tested the effects of different cerebellar tACS frequencies over the right cerebellar hemisphere (at 10, 50, and 300 Hz, besides a sham-tACS) on M1-leg excitability, cerebellum-brain inhibition (CBI), and gait parameters in a sample of 25 healthy volunteers. Fifty and 300 Hz tACS differently modified M1-leg excitability and CBI from both lower limbs, without significant gait perturbations. We hypothesize that tACS aftereffect may depend on a selective entrainment of distinct cerebellar networks related to lower limb motor functions. Therefore, cerebellar tACS might represent a useful tool to modulate walking training in people with cerebellum-related gait impairment, given that tACS may potentially reset abnormal cerebellar circuitries.

Multiple sclerosis (MS) is a demyelinating disease of autoimmune originate. A large proportion of patient present with cognitive deficits that negatively affect their quality of life, thus, a proper cognitive rehabilitation is mandatory. The aim of this study is to evaluate the effect of semi-immersive virtual reality training (sVRT) on neuropsychological and motor recovery individuals suffering from MS. We enrolled 60 MS patients, randomized into either the control group (CG: 30) undergoing a conventional cognitive training, or the experimental group (EG: 30), which performed sVRT. Cognitive and motor outcomes were investigated through clinical and neuropsychological scales before (T0) and at the end (T1) of each different training. Only in the EG, we observed a significant improvement in cognitive parameters and motor scores. Our data demonstrate that VR cognitive training could potentiate MS patients' rehabilitation outcome, with positive results on both motor and cognitive performance.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, affecting ambulation even in people with only mild neurological signs. Patients with MS frequently experience spasticity, which contributes significantly to impair their motor functions, including ambulation, owing to muscle stiffness, spasms, and pain.To clarify the role of delta-9-tetrahydrocannabinol(THC):cannabidiol(CBD) oromucosal spray, coupled to robot-aided gait training (RAGT) using the Lokomat©Pro to improve functional ambulation in patients with MS.We compared 20 patients with MS, who were treated with THC:CBD oromucosal spray in add-on to the ongoing oral antispastic therapy (OAT) (group A), with 20 individuals with MS (matched for clinical-demographic characteristics) who were treated only with OAT (group B). Both the groups underwent RAGT using the Lokomat-Pro (three 45-minute sessions per week). Our primary outcome measures were the Functional Independence Measure (FIM) and the 10 meters walking test (10MWT). As secondary outcome measures we evaluated the brain cortical excitability by using Transcranial Magnetic Stimulation. Both parameters were taken before and after the end of the RAGT.FIM improved in group A more than in group B (p0.001). Moreover, 10MWT decreased in group A more than in group B (p0.001). These clinical findings were paralleled by a more evident reshape of intracortical excitability in both upper and lower limbs, as suggested by motor evoked potential amplitude increase (p0.001), intracortical inhibition strengthening (p0.001), and intracortical facilitation decrease (p=0.01) in group A as compared to group B.Our results suggest that the combined THC:CBD-RAGT approach could be useful in improving gait performance in patients with MS.

The cerebellum regulates several motor functions through two main mechanisms, the cerebellum-brain inhibition (CBI) and the motor surround inhibition (MSI). Although the exact cerebellar structures and functions involved in such processes are partially known, Purkinje cells (PC) and their surrounding interneuronal networks may play a pivotal role concerning CBI and MSI. Cerebellar transcranial alternating current stimulation (tACS) has been proven to shape specific cerebellar components in a feasible, safe, effective, and non-invasive manner. The aim of our study was to characterize the cerebellar structures and functions subtending CBI and MSI using a tACS approach. Fifteen healthy individuals underwent a cerebellar tACS protocol at 10, 50, and 300 Hz, or a sham-tACS over the right cerebellar hemisphere. We measured the tACS aftereffects on motor-evoked potential (MEP) amplitude, CBI induced by tACS (tiCBI) at different frequencies, MSI, and hand motor task performance. None of the participants had any side effect related to tACS. After 50-Hz tACS, we observed a clear tiCBI-50Hz weakening (about +30%, p 0.001) paralleled by a MEP amplitude increase (about +30%, p = 0.001) and a reduction of the time required to complete some motor task (about -20%, p = 0.01), lasting up to 30 min. The 300-Hz tACS induced a selective, specific tiCBI-300Hz and tiCBI-50Hz modulation in surrounding muscles (about -15%, p = 0.01) and MSI potentiation (about +40%, p 0.001). The 10-Hz tACS and the sham-tACS were ineffective (p 0.6). Our preliminary data suggest that PC may represent the last mediator of tiCBI and that the surrounding interneuronal network may have an important role in updating MSI, tiCBI, and M1 excitability during tonic muscle contraction, by acting onto the PC. The knowledge of these neurophysiological issues offers new cues to design innovative, non-invasive neuromodulation protocols to shape cerebellar-cerebral functions.

The differential diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD) is not always straightforward, and the rate of progression of MCI to dementia is not negligible. Thus, there is a need for para-clinical approaches that can improve the differential diagnosis and identify patients that are at risk of progression. There is a growing interest, at present, in the role of the deterioration of brain oscillations as a predictor of MCI-to-AD conversion. For this reason, we experimentally modulated γ-band oscillations (GBO) in a sample of MCI and AD patients and an age-matched healthy elderly group, using a transcranial alternating current stimulation (tACS) protocol that was applied to different cortical sites. We correlated the after-effects of tACS on the GBO and the neuropsychological data, in an attempt to differentiate MCI from AD patients and identify, among the MCI patients, those that could be at potential risk of MCI-to-dementia conversion. MCI patients showed a partial GBO increase and improvement in some neuropsychological tests whereas AD individuals did not show significant tACS after-effects. Notably, some MCI subjects lacked significant neuropsychological and electrophysiological after-effects, similar to AD individuals. In a two-year follow-up, such MCI individuals had converted into AD. Therefore, our data suggest that tACS may support the clinical differential diagnosis of MCI and AD and identify MCI patients who could be at risk of developing dementia. This prediction index may help the clinician to adopt a better prevention/follow-up strategy in such a disabling neurodegenerative disease.

Unresponsive wakefulness syndrome (UWS) is a chronic disorder of consciousness (DOC) characterized by a lack of awareness and purposeful motor behaviors, owing to an extensive brain connectivity impairment. Nevertheless, some UWS patients may retain residual brain connectivity patterns, which may sustain a covert awareness, namely functional locked-in syndrome (fLIS). We evaluated the possibility of bringing to light such residual neural networks using a non-invasive neurostimulation protocol. To this end, we enrolled 15 healthy individuals and 26 DOC patients (minimally conscious state-MCS- and UWS), who underwent a γ-band transcranial alternating current stimulation (tACS) over the right dorsolateral prefrontal cortex. We measured the effects of tACS on power and partial-directed coherence within local and long-range cortical networks, before and after the protocol application. tACS was able to specifically modulate large-scale cortical effective connectivity and excitability in all the MCS participants and some UWS patients, who could be, therefore, considered as suffering from fLIS. Hence, tACS could be a useful approach in supporting a DOC differential diagnosis, depending on the level of preservation of the cortical large-scale effective connectivity.

Tafamidis is a transthyretin (TTR) stabilizer able to prevent TTR tetramer dissociation. There have been a few encouraging studies on Tafamidis efficacy in early-onset inherited transthyretin amyloidosis (ATTR) due to Val30Met mutation. However, less is known about its efficacy in later disease stages and in non-Val30Met mutations. We performed a multi-center observational study on symptomatic ATTR patients prescribed to receive Tafamidis. We followed up patients according to a standardized protocol including general medical, cardiological and neurological assessments at baseline and every 6 months up to 3 years. Sixty-one (42 males) patients were recruited. Only 28 % of enrolled subjects had the common Val30Met mutation, mean age of onset was remarkably late (59 years) and 18 % was in advanced disease stage at study entry. Tafamidis proved safe and well-tolerated. One-third of patients did not show significant progression along 36 months, independently from mutation type and disease stage. Neurological function worsened particularly in the first 6 months but progression slowed significantly thereafter. Autonomic function remained stable in 33 %, worsened in 56 % and improved in 10 %. Fifteen percent of patients showed cardiac disease progression and 30 % new onset of cardiomyopathy. Overall, Tafamidis was not able to prevent functional progression of the disease in 23 (43 %) subjects, including 16 patients who worsened in their walking ability and 12 patients who reached a higher NYHA score during the follow-up period. A higher mBMI at baseline was associated with better preservation of neurological function. In conclusion, neuropathy and cardiomyopathy progressed in a significant proportion of patients despite treatment. However, worsening of neurological function slowed after the first 6 months and also subjects with more advanced neuropathy, as well as patients with non-Val30Met mutation, benefited from treatment. Body weight preservation is an important favorable prognostic factor.

Alemtuzumab is a highly effective treatment for relapsing-remitting multiple sclerosis (MS). Its molecular target is CD 52, a GPI-anchored protein. Herein, we describe the case of a 40-year-old man with MS treated with alemtuzumab, who developed cerebral sinus thrombosis. In the literature, alemtuzumab was associated with venous thrombosis, attributed to a paroxysmal nocturnal hemoglobinuria (PNH)-like mechanism. In our case, no PNH clones were detected. Other common causes of cerebral venous thrombosis, like infections and thrombophilia, were excluded, thus the pathogenic mechanism remains obscure.

Multiple sclerosis (MS) is a demyelinating neurodegenerative disease with lesions involving the central nervous system. Clinical symptoms consist of disturbances in motor activity (e.g., weakness, spasticity, and tremor), sensory functioning (e.g., pain), visual functions (e.g., diplopia and optic neuritis), besides different cognitive (attention deficit and executive dysfunction) and behavioral abnormalities. This review aims to evaluate the role of VR tools in cognitive and motor rehabilitation of MS patients. Studies performed between 2010 and 2017 and fulfilling the selected criteria were searched on PubMed, Scopus, Cochrane and Web of Sciences databases, by combining the terms "VR rehabilitation" and "MS". Our findings showed that, following the use of VR training, MS patients presented a significant improvement in motor (especially gait and balance) and cognitive function (with regard to executive and visual-spatial abilities, attention and memory skills). This review supports the idea that rehabilitation through new VR tools could positively affect MS patients' outcomes, by boosting motivation and participation with a better response to treatment.

Rationale:Friedrich ataxia (FA) is the most common inherited neurodegenerative cerebellar ataxic syndrome. In patients with FA, physiotherapy is highly recommended to improve motor function outcome. Cerebellar transcranial direct current stimulation (tDCS) has been demonstrated to be effecti

Background Stroke can cause severe brain lesions, leading to multiple cognitive, emotional and motor disorders. In fact, it is one of the main causes of death and disability worldwide, with a negative impact on quality of life for both patient and caregiver. Home automation (also known as domotics) could allow stroke patients to manage and improve their daily lives. Objective The aim of our pilot study was to evaluate the effects of domotics on cognitive functions and personal/social autonomy in patients with stroke. Methods We enrolled 40 patients affected by chronic stroke undergoing neurorehabilitation at IRCCS Centro Neurolesi (Messina, Italy), between June 2017 and March 2019. All of the patients were randomized into either the control group (undergoing traditional training based on face-to-face interaction between therapist and patient, and practical activities), or the experimental group (undergoing Home Automation training). Each participant was evaluated before and immediately after the training period. Each different training consisted of 3 sessions per week for eight weeks (i.e. a total of 24 sessions), each session lasting about 60 min. For both the conventional and experimental trainings, treatments were performed in groups, and all the patients were provided with the same amount of treatment. Results Patients in the experimental group showed a greater improvement in cognitive and social performance, as compared to the control group. Conclusion Our study shows that domotics could be effective in improving social and cognitive functioning, autonomy and functional recovery in patients affected by chronic stroke.

The use of neurorobotic devices may improve gait recovery by entraining specific brain plasticity mechanisms, which may be a key issue for successful rehabilitation using such approach. We assessed whether the wearable exoskeleton, Ekso™, could get higher gait performance than conventional overground gait training (OGT) in patients with hemiparesis due to stroke in a chronic phase, and foster the recovery of specific brain plasticity mechanisms. We enrolled forty patients in a prospective, pre-post, randomized clinical study. Twenty patients underwent Ekso™ gait training (EGT) (45-min/session, five times/week), in addition to overground gait therapy, whilst 20 patients practiced an OGT of the same duration. All individuals were evaluated about gait performance (10 m walking test), gait cycle, muscle activation pattern (by recording surface electromyography from lower limb muscles), frontoparietal effective connectivity (FPEC) by using EEG, cortico-spinal excitability (CSE), and sensory-motor integration (SMI) from both primary motor areas by using Transcranial Magnetic Stimulation paradigm before and after the gait training. A significant effect size was found in the EGT-induced improvement in the 10 m walking test (d = 0.9, p

Background The Armeo Power, a rehabilitation exoskeleton that allows early treatment of motor disabilities, provides intelligent arm support in a large 3-dimensional work space, thus enabling patients to perform intensive, repetitive, and goal-oriented exercises. This device could efficiently induce new connections and facilitate plasticity phenomena potentiation. Knowledge of the potential brain plasticity reservoir after brain damage constitutes a prerequisite for an optimal rehabilitation strategy. Objective To identify potential neurophysiologic markers predicting the responsiveness of stroke patients to upper limb robotic treatment. Design Prospective cohort study. Setting Behavioral and Robotic Neurorehabilitation Laboratory of IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy. Patients We enrolled 35 patients who had sustained a first-ever ischemic supratentorial stroke at least 2 months before enrollment and had unilateral hemiplegia. Methods All patients underwent 40 Armeo Power training sessions that lasted 1 hour each (ie, 5 times a week for 8 weeks). Main Outcome Measurements We assessed the spasticity and motor function of the upper limb by means of the Modified Ashworth scale and Fugl-Meyer assessment, respectively. Moreover, we evaluated the cortical excitability and plasticity potential of the bilateral primary motor areas in response to the repetitive paired associative stimulation paradigm using transcranial magnetic stimulation and Armeo Power kinematic parameters. Results The patients who showed significant repetitive paired associative stimulation aftereffects at baseline exhibited an evident increase of cortical plasticity in the affected hemisphere (motor evoked potential amplitude increase, P = .03), a decrease of interhemispheric inhibition (affected hemisphere cortical silent period duration decrease, P = .01; unaffected hemisphere cortical silent period duration increase, P = .004; repetitive paired associative stimulation aftereffect increase, P = .008). Such findings were paralleled by clinical improvements (Fugl-Meyer, P = .04) and Armeo Power kinematic improvements (elbow flexion/extension, P = .02; shoulder range of movement, P = .002). Conclusions Our data suggest that use of Armeo Power may improve upper limb motor function recovery as predicted by reshaping of cortical and transcallosal plasticity, according to the baseline cortical excitability. Level of Evidence IV

Background: Tilt-table equipped with the dynamic foot-support (ERIGO) and the functional electric stimulation could be a safe and suitable device for stabilization of vital signs, increasing patient’s motivation for further recovery, decreasing the duration of hospitalization, and accelerating the adaptation to vertical posture in bedridden patients with brain-injury. Moreover, it is conceivable that verticalization may improve cognitive functions, and induce plastic changes at sensory motor and vestibular system level that may in turn facilitate motor functional recovery. Objective: To test the safety and effectiveness of ERIGO treatment on motor and cognitive functions, cortical plasticity within vestibular and sensory-motor systems in a bedridden post-stroke sample. Methods: 20 patients were randomly divided in two groups that performed ERIGO training (30 sessions) (G1) or physiotherapist-assisted verticalization training (same duration) (G2), beyond conventional neurorehabilitation treatment. Motor and cognitive functions as well as sensory-motor and vestibular system plasticity were investigated either before (T0) or after (T1) the rehabilitative protocols. Results: Both the verticalization treatments were well-tolerated. Notably, the G1 patients had a significant improvement in cognitive function (p = 0.03), global motor function (p = 0.006), sensory-motor (p < 0.001) and vestibular system plasticity (p = 0.02) as compared to G2. Conclusions: ERIGO training could be a valuable tool for the adaptation to the vertical position with a better global function improvement, as also suggested by the sensory-motor and vestibular system plasticity induction.

Fingolimod is the first oral disease-modifying drug approved for the treatment of multiple sclerosis. The drug is usually well tolerated, and common adverse effects include bradycardia, headache, influenza, diarrhea, back pain, increased liver enzyme levels, and cough. Fingolimod is thought to provide therapeutic benefit by preventing normal lymphocyte egress from lymphoid tissues, thus reducing the infiltration of autoaggressive lymphocytes into the central nervous system. However, because the drug acts on different sphingosine-1-phosphate receptors, it may induce several biological effects by influencing endothelial cell-cell adhesion, angiogenesis, vascular development, and cardiovascular function. We describe a patient with multiple sclerosis who, after 3 weeks of fingolimod administration, developed purplish blotches over the dorsal surface of the distal phalanges of the second and fifth digits and the middle phalanx of the fourth ray, itching, and edema on his left hand, without other evident clinical manifestations. When fingolimod therapy was discontinued, the clinical picture regressed within a few days but reappeared after a rechallenge test. Physicians should be aware of unexpected peripheral vascular adverse effects due to fingolimod use, and patients with vascular-based acropathies should be carefully screened and monitored when taking this drug.

Although gait abnormality is one of the most disabling events following stroke, cognitive, and psychological impairments can be devastating. The Lokomat is a robotic that has been used widely for gait rehabilitation in several movement disorders, especially in the acute and subacute phases. The aim of this study was to evaluate the effectiveness of gait robotic rehabilitation in patients affected by chronic stroke. Psychological impact was also taken into consideration. Thirty patients (13 women and 17 men) affected by chronic stroke entered the study. All participants underwent neurological examination with respect to ambulation, Ashworth, Functional Independence Measure, and Tinetti scales to assess their physical status, and Hamilton Rating Scale for Depression, Psychological General Well-being Index, and Coping Orientation to Problem Experienced to evaluate the Lokomat-related psychological impact before and after either a conventional treatment or the robotic training. During each rehabilitation period (separated by a no-treatment period), patients underwent a total of 40 1 h training sessions (i.e. five times a week for 8 weeks). After the conventional treatment, the patients did not achieve a significant improvement in the functional status, except balance (P

Cognitive impairment occurs frequently in post-stroke patients. This study aimed to determine the effects of a virtual reality training (VRT) with BTs-Nirvana (BTsN) on the recovery of cognitive functions in stroke patients, using the Interactive-Semi-Immersive Program (I-SIP).We enrolled 12 subjects (randomly divided into two groups: experimental group (EG); and control group (CG)), who attended the Laboratory of Robotic and Cognitive Rehabilitation of IRCCS Neurolesi of Messina from January to June 2016. The EG underwent a VRT with BTsN, whereas CG received a standard cognitive treatment. Both the groups underwent the same conventional physiotherapy program. Each treatment session lasted 45 minutes and was repeated three times a week for 8 weeks. All the patients were evaluated by a specific clinical-psychometric battery before (T0), immediately (T1), and one month (T2) after the end of the training.At T1, the EG presented a greater improvement in the trunk control test (p = 0.03), the Montreal Cognitive Assessment (p = 0.01), the selective attention assessment scores (p = 0.01), the verbal memory (p = 0.03), and the visuospatial and constructive abilities (p = 0.01), as compared to CG. Moreover, such amelioration persisted at T2 only in the EG.According to these preliminary data, VRT with I-SIP can be considered a useful complementary treatment to potentiate functional recovery, with regard to attention, visual-spatial deficits, and motor function in patients affected by stroke.

Background Severe acquired brain injury (SABI) rehabilitation should be as intensive and long as to allow the patients get the best independence and quality of life (QoL), but facing with the rehabilitation socioeconomic burden. Telerehabilitation (TR) could supply frail subjects requiring long-term rehabilitation. Methods A multicenter, prospective, parallel design, single-blind trial will be conducted at the IRCCS Neurolesi Bonino Pulejo (Messina, Italy) and IRCCS Hospital San Camillo (Venice, Italy) involving patients suffering from SABI and requiring home motor and cognitive rehabilitation. We will investigate the use of TR, based on advanced Information and Communication Technology (ICT) solutions, taking into account that the supervision of rehabilitation at home will be enriched with the counseling and vital parameters monitoring. The enrolled patients will be balanced for pathology, and randomized in 2 groups, performing TR (G1) or standard rehabilitation training (G2), respectively, according to a pc-generated random assignment. TR will be delivered by means of an advanced video-conferencing system, whereas the patient will be provided with low-cost monitoring devices, able to collect data about his/her health status and QoL. In both the groups each treatment (either cognitive or motor, or both as per patient functional status) will last about 1 hour a day, 5 days/week, for 12 weeks. Two structured telephone interviews will be administered to the patients (when possible) and/or their caregivers, and to all the healthcare professionals involved in the patient management, 1 week after the beginning and at the end of the TR. All the patients will undergo a complete neurological and cognitive examination performed by skilled physicians and psychologists, blindly. Clinical evaluations will be administered blindly, before and after the treatments. Results the data of this study should demonstrate that TR is at least non-inferior in comparison with the same amount of usual territorial rehabilitative physical treatments, taking into account patients' functional recovery, psychological well-being, caregiver burden, and healthcare costs. Conclusion data coming from this study could demonstrate the usefulness of TR in facing the rehabilitation socioeconomic burden of managing patients with SABI, so to allow the patients get the best independence and quality of life (QoL).

The present study is aimed at further exploring structural and functional correlates of fatigue in Relapsing- Remitting Multiple Sclerosis (RRMS) patients by using a combined approach by means of transcranial magnetic stimulation (TMS) and a Diffusion Tensor Imaging (DTI). The physiopathology of fatigue in MS is still poorly understood, although a variety of pathogenic mechanisms has been proposed. Our working hypothesis is that diffuse microstructural white matter damage may subtend the cortico-subcortical functional disconnection described in patients with MS and fatigue. We enrolled 30 RRMS patients (mean age 39±13; age range 24-63 years) with mild neurological impairment Expanded Disability Status Scale

Multiple sclerosis (MS) is a chronic inflammatory disease and one of the leading causes of disability in young adults. Functional markers able to predict MS progression are still lacking. It is recognized that olfactory dysfunction may be an early symptom in MS. The aim of this study was to investigate whether alterations in olfactory event-related potentials could play a prognostic role in MS. Thirty patients affected by MS relapsing-remitting underwent an olfactory potential examination (T0). Three years after baseline (T1), 28 of 30 patients were clinically evaluated by expanded disability status scale. In addition, the number of Disease Modifying Therapies (DMTs) and the total number of relapses occurred in the last 3 years were collected. At T1, we observed a negative correlation between presence/absence of olfactory potentials and expanded disability status scale scores (rpb = -0.48; p = 0.009). A significant trend for a negative correlation between presence/absence of olfactory potentials and disease duration (rpb = -0.36; p = 0.06) and total number of relapses (rpb = -0.34; p = 0.08) was found. Only patients with olfactory potential absence showed a significant trend in the difference of the disability status scale (p = 0.06) between T0 and T1. In the sub-group of patients with reduced olfactory potential amplitude, we detected a trend for a negative correlation between the disability status scale and the amplitude of N1-P2 components more marked at T1 (r = -0.52; p = 0.06) than T0 (r = -0.47; p = 0.09). This is the first study that evaluated the prognostic role of olfactory event-related potentials in MS. Our results highlighted that olfactory alterations of MS patients were related to disability progression and, to a lesser extent, disease activity. The analysis of olfactory potential parameters confirmed the involvement in olfactory network damage of inflammatory and/or neurodegeneration processes which could predict the progressive course of the disease.

After experiencing a stroke in the right hemisphere, almost 50% of patients show unilateral spatial neglect (USN). Virtual Reality technologies offer impressive opportunities for both the rehabilitation and assessment of different cognitive deficits, including USN. A 57-year-old woman, affected by subarachnoid hemorrhage presented a severe left hemiparesis with severe cognitive and behavioral alterations, including temporal and spatial disorientation, reduction of attention and memory process, slowing ideation, USN, and depression of mood. She underwent two different rehabilitation trainings, including standard cognitive training (SCT) in addition to semi-immersive virtual training with her shadow (S-IVT_s) and SCT in addition to a Semi- immersive virtual training, without her shadow (S-IVT). The patient was assessed before and after each of the two different trainings, by using a specific psychometric battery and the event related potential, P300. Only at the end of the use of the S-IVT, we observed a significant improvement in the motor and cognitive function, with regard to USN. SCT in addition to S-IVT with Bts-Nirvana System may be a promising approach in improving attention process, spatial cognition, and mood in patients with post stroke USN, as also demonstrated by the electrophysiological parameters.

Background Cognitive impairment after stroke is common and can cause disability with a high impact on quality of life and independence. Cognitive rehabilitation is a therapeutic approach designed to improve cognitive functioning after central nervous system's injuries. Computerized cognitive rehabilitation (CCR) uses multimedia and informatics resources to optimize cognitive compromised performances. The aim of this study is to evaluate the effects of pc cognitive training with Erica software in patients with stroke. Methods We studied 35 subjects (randomly divided into 2 groups), affected by either ischemic or hemorrhagic stroke, having attended from January 2013 to May 2015 the Laboratory of Robotic and Cognitive Rehabilitation of Istituto di Ricerca e Cura a Carattere Scientifico Neurolesi in Messina. Cognitive dysfunctions were investigated through a complete neuropsychological battery, administered before (T0) and after (T1) each different training. Results At T0, all the patients showed language and cognitive deficits, especially in attention process and memory abilities, with mood alterations. After the rehabilitation program (T1), we noted a global cognitive improvement in both groups, but a more significant increase in the scores of the different clinical scales we administered was found after CCR. Conclusions Our data suggest that cognitive pc training by using the Erica software may be a useful methodology to increase the post-stroke cognitive recovery.

Background Many studies have demonstrated the usefulness of repetitive task practice by using robotic-assisted gait training (RAGT) devices, including Lokomat, for the treatment of lower limb paresis. Virtual reality (VR) has proved to be a valuable tool to improve neurorehabilitation training. The aim of our pilot randomized clinical trial was to understand the neurophysiological basis of motor function recovery induced by the association between RAGT (by using Lokomat device) and VR (an animated avatar in a 2D VR) by studying electroencephalographic (EEG) oscillations. Methods Twenty-four patients suffering from a first unilateral ischemic stroke in the chronic phase were randomized into two groups. One group performed 40 sessions of Lokomat with VR (RAGT + VR), whereas the other group underwent Lokomat without VR (RAGT-VR). The outcomes (clinical, kinematic, and EEG) were measured before and after the robotic intervention. Results As compared to the RAGT-VR group, all the patients of the RAGT + VR group improved in the Rivermead Mobility Index and Tinetti Performance Oriented Mobility Assessment. Moreover, they showed stronger event-related spectral perturbations in the high-γ and β bands and larger fronto-central cortical activations in the affected hemisphere. Conclusions The robotic-based rehabilitation combined with VR in patients with chronic hemiparesis induced an improvement in gait and balance. EEG data suggest that the use of VR may entrain several brain areas (probably encompassing the mirror neuron system) involved in motor planning and learning, thus leading to an enhanced motor performance. Trial registration Retrospectively registered in Clinical Trials on 21-11-2016, n. NCT02971371 .

Simultaneous performance of motor and cognitive tasks may compete for common brain network resources in aging or patients with some neurological diseases, suggesting the occurrence of a cognitive-motor interference. While this phenomenon has been well described for multiple sclerosis (MS) patients, it never has been tested on asymptomatic subject with magnetic resonance imaging (MRI) findings suggestive of demyelinating disease (i.e., radiologically isolated syndrome: RIS). In this pilot study, 10 RIS subjects and 10 sex/age-matched healthy controls were tested by means of static posturography under eyes opened (single-task trial) and while performing two different cognitive tasks (semantic modified word list generation for first dual-task trial and phonemic semantic modified word list generation for second dual-task trial), to estimate the dual-task cost (DTC) of standing balance. In our sample, under cognitive interference (without any substantial differences between semantic and phonemic modified word list generation), the RIS group showed significance differences in CoP (center of pressure) total sway area, ellipse eccentricity, CoP sway path length, CoP median sway velocity along the AP (anteroposterior) axis and along the ML (mediolateral) axis, reflecting a higher negative DTC respect to healthy subjects (which have simply shown a statistical trend, failing to reach a significance, in some trials). The phenomenon of cognitive-motor interference might be unmasked by a dual-task posturography in RIS subjects, too. We hypothesize that this approach could be useful to early reveal the presence of a demyelinating disease and to reach a MS diagnosis in subjects otherwise classified as RIS.

BACKGROUND Multiple sclerosis (MS) is a demyelinating disease, affecting both the sensorimotor and cognitive systems. The typical pattern of cognitive impairment includes reduced speed of information processing, decreased phonological and semantic speech fluency, deficits in verbal and visual episodic memory, as well as attention and executive dysfunctions. We aimed to investigate the influence of the neurologic music therapy (NMT) on mood, motivation, emotion status, and cognitive functions in patients with MS. METHODS Thirty patients with MS were randomly divided in 2 groups: the control group (CG) undergoing conventional cognitive rehabilitation (CCR), 6 times a week for 8 weeks, and the experimental group (EG) undergoing CCR 3 times a week for 8 weeks plus NMT techniques, performed 3 times a week for 8 weeks. All the participants were submitted to the same amount of treatment. Each patient was evaluated before (baseline: T0) and immediately after the end of each training (T1). MAIN OUTCOMES MEASURES We used as main outcome measure: the brief repeatable battery of neuropsychological test to assess various cognitive abilities; and the multiple sclerosis quality of life-54 (MSQoL-54). RESULTS Both the groups benefit from 8 weeks of CR. In particular, the EG got better results in cognitive function, with regard to selective reminding test long term storage (P

Rationale: Multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system and it is associated with an impaired motor function status. The efficacy of rehabilitation in promoting functional recovery and increasing quality of life in MS patients has been demonstrated. Patient concerns: A 47-year-old woman was diagnosed with relapsing-remitting multiple sclerosis (RRMS) in November 2014 because of left upper limb hypoesthesia and weakness with difficulty in hand manipulation skills (there was a 1-point Expanded Disability Status Scale (EDSS) progression, i.e., 2.5 vs 1.5). Magnetic resonance image (MRI) showed a new frontal right cortical high-signal-intensity lesion. Diagnosis: Neurological and MRI examination were suggestive of MS diagnosis. Interventions: Patient was treated with robotic rehabilitation and evaluated by a Glove Analyzer for fMRI system (GAF). Functional MRI (fMRI) was acquired before and at the end of rehabilitative treatment performed with robotic device (Armeo-power). Outcomes: At the end of the rehabilitation program, most of the behavioral parameters, GAF and fMRI evaluation, showed a significative improvement. Moreover, fMRI showed a significantly increased functional activation within the sensory-motor network in the active, motor task. Lessons: Our findings suggest a possible restorative effect of robotics on brain networks. Moreover, we may argue that GAF may be a valuable tool in assessing functional recovery after upper limb rehabilitation, especially of associated to fMRI examination.

Even though robotic rehabilitation is very useful to improve motor function, there is no conclusive evidence on its role in reducing post-stroke spasticity. Focal muscle vibration (MV) is instead very useful to reduce segmental spasticity, with a consequent positive effect on motor function. Therefore, it could be possible to strengthen the effects of robotic rehabilitation by coupling MV. To this end, we designed a pilot randomized controlled trial (Clinical Trial NCT03110718) that included twenty patients suffering from unilateral post-stroke upper limb spasticity. Patients underwent 40 daily sessions of Armeo-Power training (1 hour/session, 5 sessions/week, for 8 weeks) with or without spastic antagonist MV. They were randomized into two groups of 10 individuals, which received (group-A) or not (group-B) MV. The intensity of MV, represented by the peak acceleration (a-peak), was calculated by the formula (2πf)2A, where f is the frequency of MV and A is the amplitude. Modified Ashworth Scale (MAS), short intracortical inhibition (SICI), and Hmax/Mmax ratio (HMR) were the primary outcomes measured before and after (immediately and 4 weeks later) the end of the treatment. In all patients of group-A, we observed a greater reduction of MAS (p = 0.007, d = 0.6) and HMR (p

Gait, coordination, and balance may be severely compromised in patients with multiple sclerosis (MS), with considerable consequences on the patient's daily living activities, psychological status and quality of life. For this reason, MS patients may benefit from robotic-rehabilitation and virtual reality training sessions. Aim of the present study was to assess the efficacy of robot-assisted gait training (RAGT) equipped with virtual reality (VR) system in MS patients with walking disabilities (EDSS 4.0 to 5.5) as compared to RAGT without VR. We enrolled 40 patients (randomized into two groups) undergoing forty RAGT±VR sessions over eight weeks. All the patients were assessed at baseline and at the end of the treatment by using specific scales. Effect sizes were very small and non-significant between the groups for Berg Balance Scale (-0.019, CI95% -2.403 to 2.365) and TUG (-0.064, 95%CI -0.408 to 0.536) favoring RAGT+VR. Effects were moderate-to-large and significant for positive attitude (-0.505, 95%CI -3.615 to 2.604) and problem-solving (-0.905, 95%CI -2.113 to 0.302) sub-items of Coping Orientation to Problem Experienced, thus largely favoring RAGT+VR. Our findings show that RAGT combined with VR is an effective therapeutic option in MS patients with walking disability as compared to RAGT without VR. We may hypothesize that VR may strengthen RAGT thanks to the entrainment of different brain areas involved in motor panning and learning.

Introduction:Currently, none of the available multiple sclerosis (MS) disease-modifying medications has been shown to stop or reverse gait disability. Recently, the nabiximols has been tested for the treatment of spasticity and walking impairment in MS. Nabiximols (trade name Sativex) is an

This narrative review aims to provide an objective view of the noninvasive neuromodulation (NINM) protocols available for treating spasticity, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). On the basis of the relevant randomized controlled trials, we infer that NINM is more effective in reducing spasticity when combined with the conventional therapies than used as a stand-alone treatment. However, the magnitude of NINM after-effects depends significantly on the applied hemisphere and the underlying pathology. Being in line with these arguments, low-frequency rTMS and cathodal-tDCS over the unaffected hemisphere are more effective in reducing spasticity than high-frequency rTMS and anodal-tDCS over the affected hemisphere in chronic poststroke. However, most of the studies are heterogeneous in the stimulation setup, patient selection, follow-up duration, and the availability of the sham operation. Therefore, the available data on the usefulness of NINM in reducing spasticity need to be confirmed by larger and multicentric randomized controlled trials to gather evidence on the efficiency of NINM regimens in reducing spasticity in various neurologic conditions. Level of Evidence V

Measurements of the concentrations of γ-aminobutyric acid (GABA) and glutamate in the motor cortices and lentiform nuclei of dystonic patients using single-voxel (1)H magnetic resonance spectroscopy (MRS) have yielded conflicting results so far. This study aimed to investigate dynamic changes in metabolite concentrations after stimulation of the motor cortices in patients with upper limb dystonia. Using single-voxel MRS at 3 T, the concentrations of GABA, glutamate plus glutamine, and N-acetylaspartate were measured bilaterally in the primary sensorimotor cortex, lentiform nucleus, and occipital region before and after 5-Hz transcranial magnetic stimulation (TMS) over the dominant motor cortex. Data obtained from 15 patients with upper limb primary dystonia were compared with data obtained from 14 healthy volunteers. At baseline, there was no group difference in concentration of metabolites in any region. rTMS induced a local (in the stimulated motor cortex) decrease of N-acetylaspartate (P < .006) to the same extent in healthy volunteers and patients. GABA concentrations were modulated differently, however, decreasing mildly in patients and increasing mildly in healthy volunteers (P = .05). There were no remote effects in the lentiform nucleus in either group. The stimulation-induced changes in metabolite concentrations have been interpreted in view of the increased energy demand induced by rTMS. The dynamics of the GABA concentration were specifically impaired in dystonic patients. Whether these changes reflect changes in the extrasynaptic or synaptic GABA component is discussed.

We tested the hypothesis that fatigue in MS is related to a dysfunction in cortical areas involved in movement preparation. Thirty-three patients with clinically definite MS (16 with fatigue MS-F, 17 without fatigue MS-NF) and a relapsing-remitting course, matched for disease severity and duration, disability scores and level of depression were enrolled. They underwent a combined assessment with magnetic resonance imaging (MRI) and transcranial magnetic stimulation (TMS) and, for the electrophysiological study, were compared with 12 healthy controls. MRI was used to assess regional and total lesion-load volume (LL) on T1- and T2-weighted sequences and total brain volume on T1-weighted sequences. With TMS we tested central motor conduction time, short intracortical inhibition (SICI) and facilitation (ICF), pre-movement facilitation related to a simple reaction time paradigm and the effect of short trains of 5-Hz repetitive TMS (rTMS). No significant differences were found in total and regional LL between MS-F and MS-NF, except for a significant increase in frontal lobe LL in MS-F. Neurophysiological assessment did not disclose any difference of SICI and ICF among the three groups. The significant increase of MEP size produced by 5 Hz rTMS in controls was absent in both MS-NF and MS-F. MS-F lacked pre-movement facilitation compared with MS-NF and controls. The lack of pre-movement facilitation and the increased frontal lobe lesion load were significantly correlated to the FSS score, suggesting that central fatigue in MS is probably due to a dysfunction of cortical motor areas involved in movement preparation.

Objectives – Idiopathic inflammatory myopathies (IIM), including dermatomyositis (DM), polymyositis (PM), sporadic inclusion-body myositis (s-IBM) and focal myositis (FM) are a heterogeneous group of autoimmune disorders of skeletal muscle. An increased transglutaminase 2 (TG2) expression has been found in DM, PM and s-IBM. The aim of our study was to investigate TG2 expression in FM in comparison with other IIM. Materials and methods – We re-examined tissue material we have gathered in the course of our previous studies on IIM, investigating muscle expression of TG2 in patients with FM in comparison with DM, PM and s-IBM using immunocytochemistry and real-time RT-PCR. Results – Immunocytochemistry revealed an increased TG2 signal in endomysial vessels, in atrophic and degenerating/regenerating muscle fibres in PM, DM, s-IBM and FM; in s-IBM, some vacuoles were immunostained too. Real-time RT-PCR study confirmed a significantly increased expression of TG2 in all IIM muscles examined. Conclusions – Our study demonstrates the presence of TG2 in FM muscles. The study suggests that TG2 expression does not represent a distinctive marker to differentiate FM from generalized IIM. TG2 over-expression in inflamed skeletal muscle does not seem have a pathogenetic role in such a disease, but it could represent a way to contain the inflammatory process.

Cognitive impairment after stroke is quite common and can cause important disability with a relevant impact on quality of life. Cognitive rehabilitation (CR) and related assistive technology may improve functional outcomes. A 30-year-old woman came to our research institute for an intensive CR cycle following a right parieto-temporal stroke. Because the patient was in the chronic phase, we decided to use 3 different rehabilitative protocols: (a) traditional cognitive training (TCT), (b) computerized cognitive training (CCT), and (c) CCT combined with transcranial direct stimulation (CCT plus) with a 2-week interval separating each session. Cognitive and language deficits were investigated using an ad-hoc psychometric battery at baseline (T0), post-TCT (T1), post-CCT (T2), and post-CCT plus (T3). Our patient showed the best neuropsychological improvement, with regard to attention processes and language domain, after T3. Our data showed that CCT plus should be considered a promising tool in the treatment of poststroke neuropsychological deficits.

Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes syndrome (MELAS) is a rare inherited mitochondrial disorder, commonly due to the m.3243A>G mutation, which typically presents with seizures, headaches, and acute neurological stroke-mimicking deficits. At onset, there is often no general intellectual deterioration in these patients, although specific cognitive deficits in peculiar language domains, visual construction, attention, abstraction, or flexibility may be present. To date, there is no evidence for an effective treatment in individuals with MELAS. Herein, we describe the case of young woman affected by MELAS who underwent an intensive cognitive training by means of the following methods: (a) traditional cognitive training, (b) computerized cognitive training (CCT), and (c) CCT plus a low-intensity aerobic motor exercise. We compared her cognitive and psychological profile at baseline (T0) and at the end of each training (i.e., (Time 1, Time 2, and Time 3 [T3]) using a proper psychometric battery, and we found a greater improvement at T3. Our findings support the idea that the combined CCT with motor training could represent a valuable therapeutic opportunity in MELAS.

Objective . The aim of our study was to better investigate the role of Sativex® in improving pain in multiple sclerosis (MS) patients by means of either clinical or neurophysiological assessment. Setting. Pain is a common symptom of MS, affecting up to 70% of patients. Pain treatment is often unsatisfactory, although emerging drugs (including cannabinoids) are giving encouraging results. Clinical pain assessment in MS is very difficult, and more objective tools are necessary to better quantify this symptom and its potential response to the treatments. Subjects and Methods. We enrolled 20 MS patients (10 with and 10 without neuropathic pain), who underwent a specific clinical (such as visual analog scale) and neurophysiological assessment (by means of laser-evoked potentials and transcranial magnetic stimulation), before and after 4 weeks of Sativex administration. Results One month of drug administration in MS patients with neuropathic pain successfully reduced pain rating and improved quality of life. Interestingly, such effects were paralleled by an increase of fronto-central γ-band oscillation and of pain-motor integration strength. Conclusions. Our data suggest that Sativex may be effective in improving MS-related neuropathic pain, maybe through its action on specific cortical pathways.