Effect of Exoskeleton-Assisted Rehabilitation Over Prefrontal Cortex in Multiple Sclerosis Patients: A Neuroimaging Pilot Study.

Application of a passive and fully articulated exoskeleton, called Human Body Posturizer (HBP), has been demonstrated to improve mobility, response accuracy and ambulation in multiple sclerosis (MS) patients. By using functional magnetic imaging (fMRI) during a visuomotor discrimination task, we performed a pilot study to evaluate the effect of HBP over the neural correlates of motor and cognitive functions which are typically impaired in MS patients. Specifically, we tested the effect of a 6-week multidisciplinary rehabilitation intervention on two groups of MS patients: a control group who followed a standard physiotherapeutic rehabilitation protocol, and an experimental group who used the HBP during physical exercises in addition to the standard protocol. We found that, after treatment, the experimental group exhibited a significant lower activity (as compared to the control group) in the inferior frontal gyrus. This post-treatment activity reduction can be explained as a retour to a normal range, being the amount of iFg activity observed in the experimental patients very similar to that observed in healthy subjects. These findings indicate that the use of HBP during rehabilitation intervention normalizes the prefrontal activity, mitigating the cortical hyperactivity associated to MS.

Effectiveness of a sensor-based technology in upper limb motor recovery in post-acute stroke neurorehabilitation: a randomized controlled trial.

Sensor-based technological therapy devices could be a possible neurorehabilitation strategy for motor rehabilitation in patients with stroke during the post-acute hospitalization, especially for treating upper extremities function limitations. The audio-visual feedback devices are characterized by interactive therapy games that allow training the movement of shoulders, elbows, and wrist, measuring the strength and the active range of motion of upper limb, registering data in an electronic database to quantitatively monitoring measures and therapy progress. This study aimed to investigate the effects of sensor-based motor rehabilitation in add-on to the conventional neurorehabilitation for improving the upper limb functions in patients with subacute stroke. Thirty-seven patients were enrolled in the study and randomly assigned to the experimental group and the control group. The training consisting of twelve sessions of upper limb training compared with twelve sessions of upper limb sensory-motor training, without robotic support. Both rehabilitation programs were performed for 40 minutes three times a week, for 4 weeks, in addition to conventional therapy. All patients were evaluated at the baseline (T0) and after 4 weeks of training (T1). The within-subject analysis showed a statistically significant improvement in both groups in all clinical scales. The analysis of effectiveness revealed that, compared with baseline (T0), the improvement percentage in the Modified Barthel Index was greater in the experimental group than the control group. The use of a sensor-based training with audio-video-feedback could be a useful complementary strategy for improving upper limb motor functions in patients with stroke during post-acute neurorehabilitation.

Prevalence of dysphagia in a consecutive cohort of subjects with MS using fibre-optic endoscopy.

INTRODUCTION: Multiple sclerosis (MS) refers to chronic inflammation of the central nervous system including the brain and spinal cord. Dysphagia is a symptom that represents challenges in clinical practice. The aim of the present study was to evaluate the prevalence of dysphagia in an Italian cohort of subjects with MS using the Dysphagia Outcome Severity Score (DOSS), based on fibre-optic endoscopy, and determine factors that correlate with the presence of swallowing problems. MATHERIALS AND METHODS: Data were collected in a multicentre study from a consecutive sample of MS patients, irrespective of self-reported dysphagia. The study included 215 subjects. Possible scores for DOSS range from 7 to 1, with 7 indicating normal swallowing. RESULTS: One hundred twenty-four (57.7%) subjects demonstrated abnormal swallowing and 57 (26.5%) of these had swallowing problems that required nutrition/diet modifications when evaluated objectively with fibre-optic endoscopy. Subjects with dysphagia were more severely disabled and more often had a progressive form of MS, compared to MS subjects with normal swallowing. In subjects with EDSS, < 4, 8 (13.3%), had a DOSS < 4. Seventy-five percent of subjects older than 60 years of age had dysphagia. CONCLUSION: In this sample of MS patients, more nearly 60% showed swallowing problems.

Individualized quality of life of severely affected multiple sclerosis patients: practicability and value in comparison with standard inventories.

PURPOSE: Individualized quality of life (QoL) measures differ from traditional inventories in that QoL domains/weights are not predetermined, but identified by the individual. We assessed practicability of the Schedule for the Evaluation of Individual QoL-Direct Weighting (SEIQoL-DW) interview in severely affected multiple sclerosis (MS) patients; the key QoL dimensions identified; and the correlation of the SEIQoL-DW index score with standard patient-reported outcome measures (PROMs). METHODS: Participants were people with severe MS who performed the baseline visit of the PeNSAMI trial (ISRCTN73082124). The SEIQoL-DW was administered at the patient's home by a trained examiner. Patients then received the following PROMs: the Core-Palliative care Outcome Scale (Core-POS), the Palliative care Outcome Scale-Symptoms-MS (POS-S-MS), the European Quality of Life Five Dimensions-3L (EQ-5D-3L), and the Hospital Anxiety and Depression Scale (HADS). RESULTS: Of 59 enrolled patients, 11 (19 %) did not receive the SEIQoL-DW (and the other PROMs) because of severe cognitive compromise or inability to communicate. SEIQoL-DW administration was completed and deemed valid in all 48 cases (mean age 60 years, 58 % women, median Expanded Disability Status Scale score 8.5). Mean SEIQoL-DW index score was 59.1 (SD 25.5). The most commonly nominated SEIQoL-DW areas were family (94 % of the patients), relationships, and leisure activities (both 65 %). Core-POS and POS-S-MS contained 70 % of the SEIQoL-DW-nominated areas. Nevertheless, correlations between SEIQoL-DW index, Core-POS, and POS-S-MS (and the other PROMs) were negligible. CONCLUSIONS: Individualized QoL can be assessed in severely affected MS patients, providing information that is not tracked by the standard inventories Core-POS, POS-S-MS, EQ-5D-3L, and HADS.

Infratentorial lesion volume correlates with sensory functional system in multiple sclerosis patients: a 3.0-Tesla MRI study.

PURPOSE: This study sought to correlate lesion volume in infratentorial areas using 3.0-T proton-density (PD)-weighted images with disability scales and appropriate functional system scores in patients with multiple sclerosis (MS). MATERIALS AND METHODS: We examined 20 consecutive patients (13 women and 7 men) with a median age of 47 years (range 26-70). Neurological examination included the Expanded Disability Status Scale and its functional systems, the Barthel Index (BI) and the Rivermead Mobility Index (RMI). MRI scans were performed on a system operating at 3.0 T using a quadrature birdcage head coil. Acquired images imported as Digital Imaging and Communication in Medicine (DICOM) files, and the region of interest (ROI) files were converted to Neuroimaging Informatics Technology Initiative (NIfTI) format and normalised to the Montreal Neurological Institute (MNI) standard template. An automated segmentation algorithm was used to distinguish between supratentorial and infratentorial areas. Normalisation to the magnetisation-prepared rapid acquisition with gradient echo (MPRAGE) T1-weighted sequence allowed lesion volume estimation in the different anatomical areas. RESULTS: A significant correlation was found between infratentorial lesion volume and the sensory functional system score (rho=0.76, p=0.002). No significant correlation was found between supratentorial lesion volume and Expanded Disability Status Scale (EDSS), RMI and BI scores. CONCLUSIONS: The described method, by means of anatomical assignment of MS lesions, allows detection of significant correlation coefficients between clinical and MRI lesion burden in MS patients at the infratentorial level.

Validation of the DYMUS questionnaire for the assessment of dysphagia in multiple sclerosis.

Swallowing problems can complicate the course of multiple sclerosis (MS). However, no validated questionnaire for the assessment of dysphagia in MS is currently available. We previously developed a 10-item DYsphagia in Multiple Sclerosis questionnaire (DYMUS). In the present study, this questionnaire was submitted to a validation process. Thirteen Italian MS centres took part in this research in which DYMUS was administered to 1734 consecutive MS patients during routine checkups outside relapse. The questionnaire showed very good internal consistency (Cronbach's alpha = 0.914). It was then subdivided into two subscales, both of which also showed very good internal consistency: Cronbach's alpha was 0.885 for the 'dysphagia for solids' subscale and 0.864 for the 'dysphagia for liquids' subscale. The DYMUS questionnaire was found to be an easy and reliable tool for detecting dysphagia and also for the preliminary selection of patients requiring more specific instrumental analyses, and those suitable for aspiration prevention programmes.

Identifying neuropathic pain in patients with multiple sclerosis: a cross-sectional multicenter study using highly specific criteria.

BACKGROUND: Pain is a common and heterogeneous complication of multiple sclerosis (MS). In this multicenter, cross sectional study, we aimed at investigating the prevalence of pain in MS using highly specific criteria for distinguishing the different types of pain. MATERIALS AND METHODS: After a structured interview, in patients with pain, clinical examination and DN4 questionnaire were used for distinguishing neuropathic and nociceptive pain. In subjects with neuropathic pain, the Neuropathic Pain Symptom Inventory was used for differentiating neuropathic pain symptoms. RESULTS: We enrolled 1249 participants (832 F, 417 M, mean age 33.9 years, mean disease duration 8 years, mean EDSS 3.2); based on clinical evaluation and DN4 score 429 patients (34.34%) were classified with pain (470 pain syndromes): 286 nociceptive pain syndromes and 184 neuropathic pain syndromes. Multivariate analysis showed that pain was associated with age, gender and disease severity and that neuropathic pain was distinctly associated with EDSS. CONCLUSIONS: Our study, providing definite information on the prevalence, characteristics and variables associated with neuropathic pain due to MS, shows that a more severe disease course is associated with a higher risk of neuropathic pain. Our findings might, therefore, provide a basis for improving the clinical management of this common MS complication.

Depressive Symptoms Correlate with Disability and Disease Course in Multiple Sclerosis Patients: An Italian Multi-Center Study Using the Beck Depression Inventory.

BACKGROUND: Depression occurs in about 50% of patients with multiple sclerosis. The aims of this study was to investigate the prevalence of depressive symptoms in a multicenter MS population using the Beck Depression Inventory II (BDI II) and to identify possible correlations between the BDI II score and demographic and clinical variables. METHODS: Data were collected in a multi-center, cross-sectional study over a period of six months in six MS centers in Italy using BDI II. RESULTS: 1,011 MS patients participated in the study. 676 subjects were female, with a mean age of 34 years (SD 10.8), mean EDSS of 3.3 (0-8.5) and mean disease duration of 10.3 years (range 1-50 years). 668 (%) subjects scored lower than 14 on the BDI II and 343 (33.9%) scored greater than 14 (14 cut-off score). For patients with BDI>14 multivariate analysis showed a significant difference between EDSS and disease course. BDI II scores for subjects with secondary progressive (SP) MS were significantly different from primary progressive (PP) patients (p < 0.001) but similar to relapsing-remitting (RR) patients. Considering subjects with moderate to severe depressive symptoms (BDI II score from 20-63), in relation to disease course, 11.7% (83/710) had RR MS, 40.7% (96/236) SP and 13.6% (6/44) PP. CONCLUSIONS: Using the BDI II, 30% of the current sample had depressive symptoms. BDI II score correlates with disability and disease course, particularly in subjects with SP MS. The BDI II scale can be a useful tool in clinical practice to screen depressive symptoms in people with MS.

FAS-ligand regulates differential activation-induced cell death of human T-helper 1 and 17 cells in healthy donors and multiple sclerosis patients.

Functionally distinct T-helper (Th) subsets orchestrate immune responses. Maintenance of homeostasis through the tight control of inflammatory Th cells is crucial to avoid autoimmune inflammation. Activation-Induced Cell Death (AICD) regulates homeostasis of T cells, and it has never been investigated in human Th cells. We generated stable clones of inflammatory Th subsets involved in autoimmune diseases, such as Th1, Th17 and Th1/17 cells, from healthy donors (HD) and multiple sclerosis (MS) patients and we measured AICD. We find that human Th1 cells are sensitive, whereas Th17 and Th1/17 are resistant, to AICD. In particular, Th1 cells express high level of FAS-ligand (FASL), which interacts with FAS and leads to caspases' cleavage and ultimately to cell death. In contrast, low FASL expression in Th17 and Th1/17 cells blunts caspase 8 activation and thus reduces cell death. Interestingly, Th cells obtained from healthy individuals and MS patients behave similarly, suggesting that this mechanism could explain the persistence of inflammatory IL-17-producing cells in autoimmune diseases, such as MS, where their generation is particularly substantial.

The immune response to mycobacterial 70-kDa heat shock proteins frequently involves autoreactive T cells and is quantitatively disregulated in multiple sclerosis.

Heat shock proteins (HSP) are the most conserved molecules known to date that may also function as immune targets during infection. Hence, theoretically there is a high chance of cross-reactive responses to epitopes shared by host and microbe HSP. If not properly regulated, these responses may contribute to the pathogenesis of autoimmune disease. To determine if immune responses to HSP could contribute to the pathogenesis of multiple sclerosis, we raised T lymphocyte lines specific for the purified protein derivative of Mycobacterium tuberculosis (PPD) from patients with multiple sclerosis, patients with tuberculosis and from healthy individuals. These lines were then screened for their proliferative response to a M. tuberculosis 70-kDa heat shock protein (M.tb.HSP70). The relative frequency of the recognition of highly conserved sequences of M.tb.HSP70 compared to variable ones was also assessed by mapping experiments on those PPD specific T lymphocyte lines which also recognized the mycobacterial 70-kDa heat shock protein. In patients with multiple sclerosis, we observed a significantly higher estimated frequency of PPD-specific T lines responding to M.tb.HSP70 compared to healthy individuals and patients with tuberculosis. Furthermore, mapping experiments using recombinant proteins representing mycobacterial and human HSP70 sequences and a panel of synthetic peptides encompassing the whole sequence of Mycobacterium leprae HSP70, showed that the response to conserved epitopes of HSP70 is a frequent event in each of the three conditions studied, often leading to the cross-recognition of microbial and human sequences. These findings implicate the 70-kDa heat shock proteins as potential autoantigens in multiple sclerosis.

Demyelinating plaques in relapsing-remitting and secondary-progressive multiple sclerosis: assessment with diffusion MR imaging.

BACKGROUND AND PURPOSE: Conventional MR imaging does not provide specific information that can be reliably associated with the pathologic substrate and clinical status of patients with multiple sclerosis (MS). Our goals were 1) to determine whether the orientationally averaged water diffusion coefficient () can be used to distinguish between plaques of different severity in these patients and 2) to assess possible correlations between values and disease duration, Expanded Disability Status Scale (EDSS) score, and signal intensity on T1-weighted MR images. METHODS: Twenty patients (10 with relapsing-remitting MS and 10 with secondary-progressive MS) and 11 healthy volunteers underwent a combined conventional and diffusion-weighted MR study of the brain. , a parameter that is proportional to the trace of the diffusion tensor, was computed by averaging the apparent diffusion coefficients measured in the x, y, and z directions. measurements were obtained for selected areas of white matter plaques. Differences in among the three groups were tested using analysis of variance. RESULTS: was significantly higher (1.445 +/- 0.129 x 10(-3) mm2/s) in secondary-progressive lesions than in relapsing-remitting lesions (0.951 +/- 0.08), and both values were higher than in normal white matter (0.732 +/- 0.02). There was a significant negative correlation between and the degree of hypointensity on T1-weighted images, and a positive correlation between and both EDSS score and disease duration. CONCLUSION: Our findings suggest that is useful for distinguishing MS lesions of different severities, which are associated with different degrees of clinical disability.

Anatomical and functional correlates of cognitive deficit in multiple sclerosis.

This brief article reviews the present state of knowledge concerning the relationship between structural and functional cerebral abnormalities and the cognitive deficits associated with multiple sclerosis. Currently available neuroimaging techniques have substantially contributed to a better understanding of the latter, suggesting that cortical-subcortical disconnection is the most likely cause of the cognitive disturbance. Longitudinal studies are needed to determine the natural history of the cognitive deficit and its relationship to the cerebral changes detected by neuroimaging techniques.

Suicides and the third age.

The phenomenon of suicide represents a complex problem, the specific aspects of which should be examined by a multifactorial analysis, particularly in the elderly subjects. Although the research on risk factors continues to grow, only a limited knowledge is available on the biological changes increasing the risk for suicide. Similarly, limited information is at our disposal about the contributing psychosocial processes extending beyond the demographic factors. Although the best explored population is the elderly using primary care services, no proven interventions are known for the time being, although some efforts to test certain approaches reaching these older adults are under way. Apparently even more, continued efforts are needed to change the attitudes toward the mental illnesses and their treatments in general, in order to reach the older adults who are still outside of the health care services.

The leisure time and the third age: the experience of a geriatric day hospital.

Leisure time represents an important part of the so-called 'successful aging' and contributes to overcome the problems related to the reduction of the social roles, favoring a better subjective adaptation to old age. In this work we observed the elderly population frequenting our Day Hospital, by estimating the affective sphere (geriatric depression scale, GDS), the autosufficiency (activity of daily living, ADL; and instrumental activity of daily living, IADL) and the schooling years in correlation with the type and length of leisure time activities during the day. These data have been compared with those of the national statistics (ISTAT). The analyses revealed a very wide diffusion of the utilization of mass media and a large interindividual differentiation of the modes of using leisure time. The correlations between the indices of affectivity and autosufficiency show an effect on the types of leisure time activities, while the scholarity of the subjects has no influence on it. These results suggest considering leisure time as an indispensable part of the relational life of elderly subjects, having an important 'valency' for the affective sphere and the individual expectations and needs.

Relationship between bladder dysfunction and brain MRI in multiple sclerosis.

We studied 70 consecutive patients with definite multiple sclerosis (MS) to examine the relationship between magnetic resonance imaging (MRI) cerebral findings and urinary disturbances. Thirty-two subjects (46%) had urinary symptoms and 38 (54%) were asymptomatic. Patients with urinary symptoms exhibited greater overall functional disability. A significant correlation between the presence of midbrain lesions and urinary dysfunctions was found which may indicate an important role of the mesencephalic formation to preserve continence.

Quantitative assessment of cerebral blood flow in partial epilepsy using Xe-133 inhalation and SPECT.

The Xe-133 inhalation method was used to study rCBF in 12 patients with partial epilepsy during the interictal phase. SPECT images evidenced a focal CBF defect in 10 out of 12 patients, while quantitative analysis showed CBF abnormalities in all the patients. The focal CBF defect corresponded to the site of EEG abnormalities in nine patients. Additional low-flow areas beyond the EEG focus were found. Five patients presented a significant CBF decrease in the cerebellar hemisphere contralateral to the EEG focus. In five patients with unilateral EEG abnormalities, a CBF reduction was found in the contralateral cerebral hemisphere, mirror to the EEG focus. Finally, a widespread CBF decrease involving one or both cerebral hemispheres was observed in seven patients. Global and rCBF values were not correlated with age, duration of disease, frequency of seizures, secondary generalization, or specific therapy. SPECT may be useful in evaluating EEG epileptic foci, and quantitative SPECT allows the detection of functional effects of the epileptic focus on anatomically connected remote areas, probably due to the decrease of afferent inputs (diaschisis phenomenon).

Prevalence of patient-reported dysphagia in multiple sclerosis patients: an Italian multicenter study (using the DYMUS questionnaire).

OBJECTIVE: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with a chronic course. Dysphagia represents one of the current challenges in clinical practice for the management of MS patients. Dysphagia starts to appear in mildly impaired MS subjects (EDSS 2-3) and becomes increasingly common in the most severely disabled subjects (EDSS 8-9). The aim of the present study was to evaluate the frequency and characteristics of patient-reported dysphagia in MS patients with a multicenter study using the recently developed DYMUS (DYsphagia in MUltiple Sclerosis) questionnaire. DESIGN: Data were collected in a multi-centre, cross-sectional study using a face-to-face structured questionnaire for clinical characteristics and the DYMUS questionnaire. RESULTS: 1875 patients were interviewed. The current study has shown a correlation between patient-reported dysphagia and EDSS and disease course but not with age, gender and disease duration. Questionnaires were divided into "patient-reported dysphagia-yes" (587, 31.3%) and "patient-reported dysphagia-no" (1288, 68.7%). Compared with the patient-reported dysphagia-no group, patients in patient-reported dysphagia-yes group had higher EDSS score (mean EDSS 4.6 vs. 2.8; p<0.001) and had a longer disease duration (mean duration 13 years vs. 11 years; p<0.001), while there was no significant difference in gender (32.7% vs. 30.5% male and 67.3% vs. 69.5% female) and in age composition (46.18 vs. 42.05). CONCLUSIONS: This study represents the largest, multi-centre sample of MS patients evaluated for patient-reported dysphagia utilizing an ad-hoc questionnaire for this condition.

Prognostic factors in multiple sclerosis rehabilitation.

AIM: The aim of our study was to evaluate the effectiveness of inpatient multidisciplinary rehabilitation treatment in multiple sclerosis (MS) and identify reliable prognostic factors. METHODS: Two hundred patients were enrolled for this study (65% females), with a mean age of 49.77+11.32 years and a mean disease duration of 17.33+10.15 years. RESULTS: The results of rehabilitation were assessed in the whole sample, as well as by comparing three subgroups, divided according to their basal Expanded Disability Status Scale of Kurtzke (EDSS) score: a ''mild'' group (EDSS score 2-5.5), a ''moderate'' group (EDSS 6-6.5), and a ''severe'' group (EDSS 7-8.5). All three subgroups of patients showed a significant improvement in functional status in both the Barthel Index and Rivermead Mobility Index (Wilcoxon Test) at discharge. However the effectiveness observed in patients with mild and moderate MS in both ADL and mobility was significantly higher than that observed in patients with the severe form. CONCLUSIONS: A multidisciplinary rehabilitative approach should be recommended for patients with a short disease duration and a relatively moderate disability.