Listening to the neurological teams for multiple sclerosis: the SMART project.

OBJECTIVE: Aim of the research was to define the quality of life of Italian neurologists and nurses' professional caring for multiple sclerosis, to understand their living the clinical practice and identify possible signals of compassion fatigue. MATERIAL AND METHODS: One hundred five neurologists and nurses from 30 Italian multiple sclerosis centres were involved in an online quali-quantitative survey on the organization of care, combined with the Satisfaction and Compassion Fatigue Test and a collection of narratives. Descriptive statistics of the quantitative data were integrated with the results obtained by the narrative medicine methods of analysis. RESULTS: Most of the practitioners were neurologists, 46 average years old, 69% women, 43% part time dedicated to multiple sclerosis. An increased number of patients in the last 3 years were referred in 29 centres. Differences were found between neurologists and nurses. Physicians showed higher risks of burnout, reporting intensive working paces, lack of medical personnel, and anxiety caused by the precarious employment conditions. Nurses appeared more satisfied, although the reference to the lack of spaces, and the cross professional roles risk of compassion fatigue. Both positive and negative relationships of care were depicted as influencing the professional quality of life. CONCLUSION: The interviewed neurological teams need to limit the risk of compassion fatigue, which appeared from the first years of the career. The prevalence of the risk among neurologists suggests more awareness among scientific societies and health care managers on the risk for this category, as first step to prevent it.

Neural correlates of fatigue in multiple sclerosis: a combined neurophysiological and neuroimaging approach (R1).

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 <3.5, divided into two groups on the basis of their fatigue severity scale (FSS) scoring (cutoff ≥ 4). All the patients underwent a neurological evaluation, a brain MRI acquisition (including DTI study) and a neurophysiological assessment by means of TMS in a pre-movement facilitation paradigm. Our data showed a significant mean diffusivity (MD) increase (p=0.036) in left thalamo-frontal reconstructions in the MS patients with fatigue compared to those classified as non-fatigued. Moreover, significant correlations were observed between FSS scale and MD as well as planar coefficient (CP) values extracted from frontal-thalamic connections bilaterally. Instead, the pre-movement facilitation showed a significant difference between the groups with particular regard to the Reaction Time- MEP50ms amplitude (p=0.03). Our work confirms that fatigue is associated with a disruption of brain networks involved in motor preparation processes, depending on several frontal-thalamic pathways. Such findings can have an important role when dealing with fatigue management in MS patients and could be eventually used as prognostic marker of MS course.

Should we care about sativex-induced neurobehavioral effects? A 6-month follow-up study.

OBJECTIVE: Sativex® is an exclusive cannabinoid-based drug approved for the treatment of spasticity due to Multiple Sclerosis (MS). The most common side effects include dizziness, nausea, and somnolence. However, it is still under debate whether the drug could cause negative cognitive effects. The aim of our study was to investigate the effect of Sativex® on functional and psychological status in cannabis-naïve MS patients. PATIENTS AND METHODS: All the study participants (i.e. 40 patients affected by MS) underwent a specific clinical and neuropsychological assessment to investigate spasticity and associated symptoms, besides the cognitive and psychiatric domains commonly impaired in MS, before and after 1 and 6 months of Sativex® administration. RESULTS: After the treatment, we did not observe any significant neurobehavioral impairment in all the patients, but one. CONCLUSIONS: Our findings suggest that Sativex® treatment does not significantly affect the cognitive and neurobehavioral functions. However, the study supports the relevance of an extensive neuropsychological evaluation in MS patients selected for the drug administration, in an attempt to early detect the uncommon but important neurobehavioral side effects.

Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity.

BACKGROUND: The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting. METHODS: We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0-10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months. RESULTS: A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3-2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%). CONCLUSIONS: Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.

Risk of atrial fibrillation among bisphosphonate users: a multicenter, population-based, Italian study.

UNLABELLED: Bisphosphonate treatment is used to prevent bone fractures. A controversial association of bisphosphonate use and risk of atrial fibrillation has been reported. In our study, current alendronate users were associated with a higher risk of atrial fibrillation as compared with those who had stopped bisphosphonate (BP) therapy for more than 1 year. INTRODUCTION: Bisphosphonates are widely used to prevent bone fractures. Controversial findings regarding the association between bisphosphonate use and the risk of atrial fibrillation (AF) have been reported. The aim of this study was to evaluate the risk of AF in association with BP exposure. METHODS: We performed a nested case-control study using the databases of drug-dispensing and hospital discharge diagnoses from five Italian regions. The data cover a period ranging from July 1, 2003 to December 31, 2006. The study population comprised new users of bisphosphonates aged 55 years and older. Patients were followed from the first BP prescription until an occurrence of an AF diagnosis (index date, i.e., ID), cancer, death, or the end of the study period, whichever came first. For the risk estimation, any AF case was matched by age and sex to up to 10 controls from the same source population. A conditional logistic regression was performed to obtain the odds ratio with 95% confidence intervals (CI). The BP exposure was classified into current (<90 days prior to ID), recent (91-180), past (181-364), and distant past (≥365) use, with the latter category being used as a reference point. A subgroup analysis by individual BP was then carried out. RESULTS: In comparison with distant past users of BP, current users of BP showed an almost twofold increased risk of AF: odds ratio (OR) = 1.78 and 95% CI = 1.46-2.16. Specifically, alendronate users were mostly associated with AF as compared with distant past use of BP (OR, 1.97; 95% CI, 1.59-2.43). CONCLUSION: In our nested case-control study, current users of BP are associated with a higher risk of atrial fibrillation as compared with those who had stopped BP treatment for more than 1 year.

Neuroinflammation and neuroprotection: an update on (future) neurotrophin-related strategies in multiple sclerosis treatment.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), characterized by inflammation, demyelination and axonal loss underlying progressive clinical disability. The chronic inflammatory tissue damage involving myelin and axons is driven by autoreactive T cells and represents a key mechanism in the immunopathogenesis of MS. Over the last few years, evidence from MS and experimental models of neuroinflammation has suggested that autoimmune responses could exert neuroprotective effects through the release of neurotrophins by autoreactive T cells. Specifically, the role of the Brain-derived neurotrophic factor (BDNF) in facilitating brain tissue repair in experimental traumatic injury has been well recognized. Support for this hypothesis comes from recent studies showing that glatiramer acetate, a currently approved treatment for MS, promotes the expansion of T cell clones crossing the blood-brain barrier and releasing BDNF in situ. A small subset of autoreactive T cells expresses the high-affinity full-length receptor for BDNF (TrkB-TK) in the periphery. In MS patients, T cells show reduced susceptibility to activation-induced apoptosis, a crucial mechanism eliminating autoreactive T clones and contributing to peripheral immunologic tolerance. These findings suggest the existence of a dual effect exerted by BDNF, which not only provides neuroprotection in the CNS but also promotes the survival of autoreactive T cells through an autocrine/paracrine loop. The aim of this review is to discuss the neuroprotective effects of currently approved immunomodulatory treatments for MS and their role in regulating neurotrophin production. We will also describe novel therapeutic strategies arising from new insights on "neuroprotective autoimmunity".

Endolaparoscopic rendezvous treatment: a satisfying therapeutic choice for cholecystocholedocolithiasis.

BACKGROUND: There are many different strategies for the treatment of the main bile duct lithiasis. When lithiasis of the biliary tract is suspected at a preoperative stage, we can treat patients with sequential treatment: endoscopic netrograde cholangiopancreatography followed by laparoscopic cholecystectomy. If common bile duct-lithiasis is recognized at an intraoperative stage, many options for treatment exist, one of which is intraoperative retrograde endoscopic sphincterotomy (ES) (laparoendorendezvous). METHODS: We report our experience using the aforementioned technique with 58 patients affected by cholelithiasis and complex Common bile duct disease who underwent laparoscopic cholecystectomy and intraoperative ES consecutively from March 1996 to May 2000. Of the 58 patients, 43 were affected by cholecystocholedocolithiasis: 12 by previously described lithiasis plus stenosant papillitis, 2 also by a pancreas head cancer, and 1 by cancer of the papilla. RESULTS: The combined technique was performed in 86% of the cases. Six patients required conversion to open surgery. In two other patients, laparoscopic choledocotomy was performed with positioning of a Kehr-tube for an ampulla-impacted lithiasis. CONCLUSIONS: Intraoperative ES offers a valid approach to the treatment of cholecystocholedocolithiasis in one session. Furthermore, it represents a valid alternative to transcholedocical laparoscopic treatment of cholelithiasis and complex common bite duct pathology.

The spasticity evaluation test (SeT): a pilot study.

This paper addresses the development of an apparatus designed to evaluate clinically the presence of spasticity affecting the elbow. The biomechanical contributions due to the lever-arm muscles and to the gravity force are accounted for using software algorithms that express gravity force and lever arm as functions of the elbow angle and are able to provide information on the force exerted by the muscles at a known speed. The preliminary data indicate that the device can be applied easily in the clinical setting. Further studies are required to demonstrate conclusively the validity and reliability of this device in quantifying spasticity at the elbow.

Effects of felbamate on brain polyamine changes following transient cerebral ischemia in the Mongolian gerbil.

We sought to determine whether treatment with felbamate was capable to reduce the accumulation of putrescine induced by transient forebrain ischemia in the Mongolian gerbil. Gerbils underwent 10 min ligation of common carotid arteries followed by recirculation. Immediately after the release of the arterial occlusion, felbamate (75 and 150 mg kg(-1) i.p.) was administered. Putrescine and polyamine levels were measured in hippocampus and striatum at 1, 8, 24 and 48 h after recirculation. Putrescine levels appeared enhanced already 8 h after the release of the arterial occlusion and kept increasing up to 48 h in the hippocampus and striatum. No significant changes in spermidine levels during recirculation were detected. Conversely, spermine appeared to decrease in the hippocampus while it did not show changes in the striatum. Felbamate significantly reduced the ischemia induced changes in putrescine brain content only at the dose of 150 mg kg(-1) i.p.

R3 nociceptive reflex in multiple sclerosis patients with paroxysmal symptoms treated with gabapentin.

Gabapentin (GBP) is a new, well-tolerated antiepileptic drug found to be effective for painful paroxysmal symptoms (PS) in multiple sclerosis (MS). The aim of this study was to obtain a neurophysiological evaluation of the effects of GBP on the nociceptive system of MS patients suffering PS. We studied 10 MS patients, 6 males, 4 females (mean age 47.3 years), suffering PS (3 had trigeminal neuralgia, 1 painful tonic spasms and 6 dysesthetic or paresthetic symptoms). Three patients were, at the same time, also being treated with carbamazepine. Pain was evaluated by means of the Visual Faces Scale. R3 nociceptive reflex was recorded after 2 weeks' treatment. R3 thresholds and latencies were evaluated and a statistical analysis was performed. A significant variation was found in R3 thresholds between the values recorded before and during GBP treatment; no significant variation was observed in R3 latencies.

Changes in somatosensory evoked potentials following forebrain ischemia in the gerbils: effects of felbamate.

Somatosensory evoked potentials (SEPs) as well as change following transient cerebral ischemia in the gerbil were characterized in this study. SEPs were measured in each gerbil before ischemia (day -1), during ischemia, 10 min, 2, 4, 8, 24, 48 h and 8 days after recirculation. During bilateral carotid occlusion, SEP amplitude was dramatically reduced and central conduction time was significantly increased. During recirculation these values showed an improvement when compared to ischemic but not to control values. Moreover at 8 days of recirculation they were still statistically different from control values. Felbamate administration at the dose of 150 mg kg(-1), immediately after recirculation was shown to ameliorate neurophysiological recovery following cerebral ischemia.

Nociceptive R3 reflex in relapsing-remitting multiple sclerosis patients.

Pain in multiple sclerosis (MS) patients has only recently been recognised as a genuine symptom of this disease. It is important to determine whether this pain is the consequence of another symptom of MS or whether it is due to a demyelinating lesion affecting pain pathways. A close relationship has been found between the R3 component of the blink reflex and the pain threshold. The aim of this work was to carry out an objective evaluation of the nociceptive system in MS patients by means of the R3 component of the blink reflex. The study was performed on 20 healthy volunteers and on 20 clinically defined relapsing-remitting MS patients with EDSS not > 3.5, normal R1 and R2 components of the blink-reflex, personal and family anamnesis negative for migraine and trigeminal neuralgia; the patients were not taking drugs at the time of the test. A significant difference was found, between healthy volunteers and patients, for R3 threshold, pain threshold and R3 latency.

Enhanced spasticity in primary progressive MS patients treated with interferon beta-1b.

Spasticity is a disabling symptom of MS that is enhanced during interferon beta-lb (IFNbeta-1b) treatment. Nineteen patients with primary progressive MS were treated with IFNbeta-1b; an additional 19 patients did not receive this treatment. Thirteen of the 19 patients treated with IFNbeta-1b had increased spasticity requiring increased antispasticity drug administration. This observation suggests that further studies are needed before interferons can be so widely used in primary progressive MS patients.

Pallidotomy improves quality of life in selected parkinsonian patients: an Italian report.

Pallidotomy has recently been reconfirmed as effective for otherwise intractable symptoms of Parkinson's disease. Nonetheless almost every aspect of its performance requires choices which are not fully established and may vary between centers. These include: 1) patient selection; 2) choice of imaging modality, 3) choice of anatomic landmarks for targeting the lesion, 4) choice of method for physiologic confirmation of location, 5) choice of lesion size and shape. We present two cases of pallidotomy procedures in Parkinsonian patients that in our knowledge are the first reported in Italy. Our experience and a careful review of the literature led to the following choices: 1) selection of Parkinsonian patients with dominant L-Dopa induced dyskinesia, akinetic and rigidity symptoms, 2) use of CT due to the distortion effects of MRI, 3) use of standard (Laitinen) coordinates combined with an image fusion method using MRI, 4) use of stimulation to gauge distance to internal capsule and optic tract, 5) production of vertical lesion covering internal segment of pallidum. At a 1-year follow-up the results include a 45% drop in UPDRS (Unified Parkinson's Disease Rating Scale) motor score and almost complete resolution of contralateral dopa induced dyskinesias in both patients.

[Our experience with lymphocytes activated against cancer: CTL cells]. / La nostra esperienza con linfociti attivati contro il cancro: le cellule CTL.

Our group, thanks to the considerable help offered by prof. S. Fujimoto, Chief of the Immunologic Oncology Department of the Kochi Medical School (Japan), developed a method of "in vitro" activation of cytotoxic T lymphocytes (CTL), which are directed against tumour-specific antigens MHC-linked of the tumor cells. A protocol of specific immunotherapy based on the use of the CTL cells appropriately manipulated as therapeutic agents is our goal. The protocol recognizes five essential points: 1) retrieve and culture of tumor cells; 2) retrieve of T Lymphocytes; 3) induction of CTL cells; 4) assay of CTL activity; 5) reinfusion of the activated CTL cells to the patient.