Does sex influence the natural history of idiopathic adult-onset dystonia?

BACKGROUND: Several earlier studies showed a female predominance in idiopathic adult-onset dystonia (IAOD) affecting the craniocervical area and a male preponderance in limb dystonia. However, sex-related differences may result from bias inherent to study design. Moreover, information is lacking on whether sex-related differences exist in expressing other dystonia-associated features and dystonia spread. OBJECTIVE: To provide accurate information on the relationship between sex differences, motor phenomenology, dystonia-associated features and the natural history of IAOD. METHODS: Data of 1701 patients with IAOD from the Italian Dystonia Registry were analysed. RESULTS: Women predominated over men in blepharospasm, oromandibular, laryngeal and cervical dystonia; the sex ratio was reversed in task-specific upper limb dystonia; and no clear sex difference emerged in non-task-specific upper limb dystonia and lower limb dystonia. This pattern was present at disease onset and the last examination. Women and men did not significantly differ for several dystonia-associated features and tendency to spread. In women and men, the absolute number of individuals who developed dystonia tended to increase from 20 to 60 years and then declined. However, when we stratified by site of dystonia onset, different patterns of female-to-male ratio over time could be observed in the various forms of dystonia. CONCLUSIONS: Our findings provide novel evidence on sex as a key mediator of IAOD phenotype at disease onset. Age-related sexual dimorphism may result from the varying exposures to specific age-related and sex-related environmental risk factors interacting in a complex manner with biological factors such as hormonal sex factors.

Does thyroid diseases contribute to the natural history of idiopathic adult-onset dystonia? Data from the Italian Dystonia Registry.

A few earlier observations and recent controlled studies pointed to the possible contribution of thyroid diseases in idiopathic adult-onset dystonia (IAOD). The aim of this study was to investigate the association between thyroid status and clinical characteristics of IAOD, focusing on dystonia localization, spread, and associated features such as tremors and sensory tricks. Patients were identified from those included in the Italian Dystonia Registry, a multicentre dataset of patients with adult-onset dystonia. The study population included 1518 IAOD patients. Patients with hypothyroidism and hyperthyroidism were compared with those without any thyroid disease. In the 1518 IAOD patients, 167 patients (11%; 95% CI 9.5-12.6%) were diagnosed with hypothyroidism and 42 (2.8%; 95% CI 1.99-3.74) with hyperthyroidism. The three groups were comparable in age at dystonia onset, but there were more women than men in the groups with thyroid disease. Analysing the anatomical distribution of dystonia, more patients with blepharospasm were present in the hyperthyroidism group, but the difference did not reach statistical significance after the Bonferroni correction. The remaining dystonia-affected body sites were similarly distributed in the three groups, as did dystonia-associated features and spread. Our findings provided novel information indicating that the high rate of thyroid diseases is not specific for any specific dystonia subpopulation and does not appear to influence the natural history of the disease.

Oromandibular dystonia: from onset to spread a multicenter italian study.

BACKGROUND: Detailed information about the epidemiological and phenomenological differences among the aetiological subtypes of oromandibular dystonia (OMD) is lacking. Moreover, the OMD tendency to spread to other body sites has never been investigated. AIM: To compare the main demographic and clinical features of OMD in different aetiological groups and assess the risk of spread. MATERIALS AND METHODS: We retrospectively analysed data from patients contained in the Italian Dystonia Registry. The risk of spread was assessed by Kaplan Meyer curves and Cox regression analysis. RESULTS: The study included 273 patients (175 women) aged 55.7 years (SD 12.7) at OMD onset. Female predominance was observed. Idiopathic dystonia was diagnosed in 241 patients, acquired dystonia in 22. In 50/273 patients, dystonia started in the oromandibular region (focal OMD onset); in 96/273 patients the onset involved the oromandibular region and a neighbouring body site (segmental/multifocal OMD onset); and in 127/273 patients OMD was a site of spread from another body region. Sensory trick (ST) and positive family history predominated in the idiopathic group. No dystonia spread was detected in the acquired group, whereas spread mostly occurred within the first five years of history in 34% of the focal OMD onset idiopathic patients. Cox regression analysis revealed ST as a significant predictor of spread (HR, 12.1; 95% CI, 2.5 - 18.8; P = 0.002). CONCLUSION: This large study provides novel information about the clinical phenomenology of idiopathic and acquired OMD. We pointed out a possible role of oestrogens in favouring dystonia development. Moreover, we described for the first time the association between ST and dystonia spread, revealing possible common pathophysiological mechanisms. Our findings may be suggested as a referral point for future pathophysiological and therapeutic studies on OMD.

Sulci and gyri are topological cerebral landmarks in individual subjects: a study of brain navigation during tumour resection.

Surgical resection of brain tumours aims at the maximal safe resection of the pathological tissue with minimal functional impairment. To achieve this objective, reliable anatomical landmarks are indispensable to navigate into the brain. The neuronavigation system can provide information to target the location of the patient's lesion, but after the craniotomy, a brain shift and relaxation mismatch with it often occur. By contrast, sulci/gyri are topological cerebral landmarks in individual patients and do shift with the brain parenchyma during lesion removal, but remain independent from brain shift in relation to the sulci/gyri. Here, we present a case report of a novel strategy based on anatomical landmarks to guide intraoperative brain tumour resection, without using a standard neuronavigation system. A preoperative brain mapping of the peri-tumoural sulci by the MRI and surface reconstruction was followed by confirmation of the anatomical landmarks for the motor cortex using navigated transcranial magnetic stimulation. The resulting location was used as a seed for diffusion tensor imaging tractography to reconstruct the corticospinal tracts. These selected cortical landmarks (sulci/gyri) delimited the margins of the two lesions and the specific location under which the corticospinal tract courses, thus facilitating monitoring of the peri-tumoural region during brain resection. In this case, 96% of the brain tumour from the pericentral somatomotor region was successfully removed without chronic post-operative motor impairments. This approach is based on cortical anatomy that is fixed during surgery and does not suffer from the brain shift that could misplace the lesion according to the neuronavigation system.

Boosting and consolidating the proprioceptive cortical aftereffect by combining tendon vibration and repetitive TMS over primary motor cortex.

Tendon vibration of a limb elicits illusory movements in the direction that the vibrated muscle would be stretched, followed by a transient perception of movement in the opposite direction, that was demonstrated to correspond to a "cortical" aftereffect (Goodwin et al. Science 175:1382-1384, 1972). Primary motor cortex (M1) excitability of the non-vibrated antagonist muscle of the vibrated muscle increased during vibration and decreased thereafter. The cortical aftereffect is of interest when considering the possibility to use tendon vibration in rehabilitation for restoring unbalance activity between antagonistic muscles but, due to its short-lasting duration, has not been explored so far. We investigated the possibility to consolidate the cortical aftereffect by combining tendon vibration with a concomitant high-frequency 5-Hz repetitive transcranial magnetic stimulation (rTMS) protocol. The distal tendon of the flexor carpi radialis muscle (FCR) was vibrated and concomitantly a 2-min 5-Hz rTMS protocol was administered on the left hemi-scalp hot spot of the vibrated FCR or its antagonist muscle (extensor carpi radialis (ECR)). We found that this protocol induced a pattern of unbalanced M1 excitability between vibrated muscle and its antagonist with increased excitability of the FCR and decreased excitability of ECR cortical areas, which persisted up to 30 min.

Normal sensorimotor plasticity in complex regional pain syndrome with fixed posture of the hand.

BACKGROUND: Movement disorders associated with complex regional pain syndrome type I have been a subject of controversy over the last 10 years regarding their nature and pathophysiology, with an intense debate about the functional (psychogenic) nature of this disorder. The aim of this study was to test sensorimotor plasticity and cortical excitability in patients with complex regional pain syndrome type I who developed a fixed posture of the hand. METHODS: Ten patients with complex regional pain syndrome type I in the right upper limb and a fixed posture of the hand (disease duration less than 24 months) and 10 age-matched healthy subjects were enrolled. The following parameters of corticospinal excitability were recorded from the abductor pollicis brevis muscle of both hands by transcranial magnetic stimulation: resting and active motor thresholds, short-interval intracortical inhibition and facilitation, cortical silent period, and short- and long-latency afferent inhibition. Sensorimotor plasticity was tested using the paired associative stimulation protocol. RESULTS: Short-interval intracortical inhibition and long-latency afferent inhibition were reduced only in the affected right hand of patients compared with control subjects. Sensorimotor plasticity was comparable to normal subjects, with a preserved topographic specificity. CONCLUSIONS: Our data support the view that motor disorder in complex regional pain syndrome type I is not associated with abnormal sensorimotor plasticity, and it shares pathophysiological abnormalities with functional (psychogenic) dystonia rather than with idiopathic dystonia. © 2016 International Parkinson and Movement Disorder Society.

Intraoperative Neurophysiological Monitoring in Spine Surgery: A Significant Tool for Neuronal Protection and Functional Restoration.

Although there is recent evidence for the role of intraoperative neurophysiological monitoring (IONM) in spine surgery, there are no uniform opinions on the optimal combination of the different tools. At our institution, multimodal IONM (mIONM) approach in spine surgery involves the evaluation of somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) with electrical transcranial stimulation, including the use of a multipulse technique with multiple myomeric registration of responses from limbs, and a single-pulse technique with D-wave registration through epi- and intradural recording, and free running and evoked electromyography (frEMG and eEMG) with bilateral recording from segmental target muscles. We analyzed the impact of the mIONM on the preservation of neuronal structures and on functional restoration in a prospective series of patients who underwent spine surgery. We observed an improvement of neurological status in 50 % of the patients. The D-wave registration was the most useful intraoperative tool, especially when MEP and SEP responses were absent or poorly recordable. Our preliminary data confirm that mIONM plays a fundamental role in the identification and functional preservation of the spinal cord and nerve roots. It is highly sensitive and specific for detecting and avoiding neurological injury during spine surgery and represents a helpful tool for achieving optimal postoperative functional outcome.

Intraoperative neurophysiological mapping and monitoring in spinal tumor surgery: sirens or indispensable tools?

Spinal tumor (ST) surgery carries the risk of new neurological deficits in the postoperative period. Intraoperative neurophysiological monitoring and mapping (IONM) represents an effective method of identifying and monitoring in real time the functional integrity of both the spinal cord (SC) and the nerve roots (NRs). Despite consensus favoring the use of IONM in ST surgery, in this era of evidence-based medicine, there is still a need to demonstrate the effective role of IONM in ST surgery in achieving an oncological cure, optimizing patient safety, and considering medicolegal aspects. Thus, neurosurgeons are asked to establish which techniques are considered indispensable. In the present study, the authors focused on the rationale for and the accuracy (sensitivity, specificity, and positive and negative predictive values) of IONM in ST surgery in light of more recent evidence in the literature, with specific emphasis on the role of IONM in reducing the incidence of postoperative neurological deficits. This review confirms the role of IONM as a useful tool in the workup for ST surgery. Individual monitoring and mapping techniques are clearly not sufficient to account for the complex function of the SC and NRs. Conversely, multimodal IONM is highly sensitive and specific for anticipating neurological injury during ST surgery and represents an important tool for preserving neuronal structures and achieving an optimal postoperative functional outcome.

A local signature of LTP-like plasticity induced by repetitive paired associative stimulation.

Repetitive paired associative stimulation (rPAS) repeatedly pairs electrical nerve stimulation (ENS) with transcranial magnetic stimulation (TMS) of the contralateral motor hand area (M1) at 5 Hz frequency. So far, there are only few studies concerning the effects of PAS on the modulation of EEG power. Hence, aim of the present study was to investigate rPAS long term after-effects on cortical excitability looking at EEG power spectra. In four experimental sessions, separated by 2 weeks interval, 12 awake subjects received rPAS of the right median nerve and left M1 at a fixed interval (ISI) of 25 ms (real condition), 5 Hz-TMS on left M1, 5 Hz-ENS, of the right median nerve, and rPAS with changing ISI (sham condition). We measured peak-to-peak MEP amplitude, evoked from the target muscle (right abductor pollicis brevis muscle) at rest and the absolute power (POW) in four frequency bands: α (8-12 Hz), ß (13-30), θ (4-7) and δ (1-3), under rest conditions. All these parameters were evaluated in three detection blocks: baseline, immediately after and after 30' from the end of the conditioning protocol. Real rPAS induced a long-lasting homotopic cortical excitability modulation, as indexed by MEP amplitude increase, that was paralleled by a long-lasting reduction of α/ß-POW and by a widespread θ-δ-POW modulation. rPAS applied over the sensory-motor cortex induced an LTP-like plasticity, as indexed by a robust reduction in the α/ß POW positively correlated with the MEP amplitude increase. rPAS25ms may be a useful tool for motor neurorehabilitation promoting a sensory-motor coupling within ß oscillations.

Cognitive processess and cognitive reserve in multiple sclerosis.

Multiple Sclerosis (MS) is characterized by motor, cognitive, and neuropsychiatric symptoms, which can occur independently. While MS is traditionally considered an inflammatory disease of the white matter, degeneration of gray matter is increasingly recognized as an important contributor to the progressive cognitive decline. A protective factor against the progression of cognitive dysfunction in MS could be the cognitive reserve, defined as resistance to brain dysfunction. Aim of the present study is to evaluate the role of cognitive reserve for different aspects of cognitive dysfunction of patients with MS. We found that patients with MS and lower cognitive reserve have poorer neuropsychological performance and slower information speed processing. These findings support the notion that intellectual reserve may protect some aspects of cognitive function in patients with MS.

Cortical plasticity in patients with Parkinson's disease a window for therapeutic non-invasive neuromodulation.

Several evidences in animal models have consistently an alteration of cortico-striatal plasticity, which is related to the degeneration of the substantia nigra. An alteration of plasticity have also been reported in humans by recording evoked field potentials in the substantia nigra pars reticulata of PD patients undergoing subthalamic nucleus (STN) stimulation where high-frequency (HF) in the OFF state did not induce a lasting change in field potential amplitude in the substantia nigra. In addition protocols of non-invasive brain stimulation, such as paired associative stimulation (PAS) and theta-burst stimulation (TBS), can be used to investigate cortical plasticity of the human primary motor cortex. Despite data reported in literature are apparently controversial with some studies showing a reduced or increased or even normal LTP and LTD like plasticity, recent evidences suggest the hypothesis that these different pat- terns of cortical plasticity likely depend on the stage of the disease and on the concomitant administration of L-DOPA. The current review will provide an up-to-date of these issues on cortical plasticity in PD discussing the clinical implications in rehabilitation. In addition in the last section we will review the state of art of non invasive neuro- modulation as adjuvant treatment in the advanced stage of the disease.

The role of ethnicity and native-country income in multiple sclerosis: the Italian multicentre study (MS-MigIT).

OBJECTIVE: Multiple sclerosis (MS) is a complex disorder in which environmental and genetic factors interact modifying disease risk and course. This multicentre, case-control study involving 18 Italian MS Centres investigated MS course by ethnicity and native-country economic status in foreign-born patients living in Italy. METHODS: We identified 457 MS patients who migrated to Italy and 893 age- and sex-matched native-born Italian patients. In our population, 1225 (93.2%) subjects were White Europeans and White Northern Americans (WENA) and 89 (6.8%) patients were from other ethnical groups (OEG); 1109 (82.1%) patients were born in a high-income (HI) Country and 241 (17.9%) in a low-middle-income (LMI) Country. Medical records and patients interviews were used to collect demographic and disease data. RESULTS: We included 1350 individuals (973 women and 377 men); mean (SD) age was 45.0 (11.7) years. At onset, 25.45% OEG patients vs 12.47% WENA (p = 0.039) had > 3 STIR spine lesions. At recruitment, the same group featured mean (SD) EDSS score of 2.85 (2.23) vs 2.64 (2.28) (p = 0.044) reached in 8.9 (9.0) vs 12.0 (9.0) years (p = 0.018) and underwent 1.10 (4.44) vs. 0.99 (0.40) annual MRI examinations (p = 0.035). At disease onset, patients from LMI countries had higher EDSS score than HI patients (2.40 (1.43) vs 1.99 (1.17); p = 0.032). DISCUSSION: Our results suggested that both ethnicity and socio-economic status of native country shape MS presentation and course and should be considered for an appropriate management of patients. To the best of our knowledge, this is the first study reporting on the impact of ethnicity in MS at an individual level and beyond an ecological population-perspective.

Comparing Essential Tremor with and without Soft Dystonic Signs and Tremor Combined with Dystonia: The TITAN Study.

BACKGROUND: Tremor disorders remain as clinical diagnoses and the rate of misdiagnosis between the commonest non-parkinsonian tremors is relatively high. OBJECTIVES: To compare the clinical features of Essential Tremor without other features (pure ET), ET plus soft dystonic signs (ET + DS), and tremor combined with dystonia (TwD). METHODS: We compared the clinical features of patients with pure ET, ET + DS, and TwD enrolled in The ITAlian tremor Network (TITAN). Linear regression models were performed to determine factors associated with health status and quality of life. RESULTS: Three-hundred-eighty-three patients were included. Sex distribution was significantly different between the groups with males being more represented in pure ET and females in TwD. The initial site of tremor was different between the groups with about 40% of TwD having head tremor and ET + DS unilateral upper limb tremor at onset. This pattern mirrored the distribution of overt dystonia and soft dystonic signs at examination. Sensory trick, task-specificity, and position-dependence were more common, but not exclusive, to TwD. Pure ET patients showed the lowest degree of alcohol responsiveness and ET + DS the highest. Midline tremor was more commonly encountered and more severe in TwD than in the other groups. Regression analyses demonstrated that tremor severity, sex, age, and to a lesser degree the variable "group", independently predicted health status and quality of life, suggesting the existence of other determinants beyond tremor. CONCLUSIONS: Pure ET and TwD manifest with a phenotypic overlap, which calls for the identification of diagnostic biomarkers. ET + DS shared features with both syndromes, suggesting intra-group heterogeneity.

Integration of functional neuroimaging in CyberKnife radiosurgery: feasibility and dosimetric results.

OBJECT: The integration of state-of-the-art neuroimaging into treatment planning may increase the therapeutic potential of stereotactic radiosurgery. Functional neuroimaging, including functional MRI, navigated brain stimulation, and diffusion tensor imaging-based tractography, may guide the orientation of radiation beams to decrease the dose to critical cortical and subcortical areas. The authors describe their method of integrating functional neuroimaging technology into radiosurgical treatment planning using the CyberKnife radiosurgery system. METHODS: The records of all patients who had undergone radiosurgery for brain lesions at the CyberKnife Center of the University of Messina, Italy, between July 2010 and July 2012 were analyzed. Among patients with brain lesions in critical areas, treatment planning with the integration of functional neuroimaging was performed in 25 patients. Morphological and functional imaging data sets were coregistered using the Multiplan dedicated treatment planning system. Treatment planning was initially based on morphological data; radiation dose distribution was then corrected in relation to the functionally relevant cortical and subcortical areas. The change in radiation dose distribution was then calculated. RESULTS: The data sets could be easily and reliably integrated into the Cyberknife treatment planning. Using an inverse planning algorithm, the authors achieved an average 17% reduction in the radiation dose to functional areas. Further gain in terms of dose sparing compromised other important treatment parameters, including target coverage, conformality index, and number of monitor units. No neurological deficit due to radiation was recorded at the short-term follow-up. CONCLUSIONS: Radiosurgery treatments rely on the quality of neuroimaging. The integration of functional data allows a reduction in radiation doses to functional organs at risk, including critical cortical areas, subcortical tracts, and vascular structures. The relative simplicity of integrating functional neuroimaging into radiosurgery warrants further research to implement, standardize, and identify the limits of this procedure.

Circular RNAs: A New Approach to Multiple Sclerosis.

Multiple sclerosis, a condition characterised by demyelination and axonal damage in the central nervous system, is due to autoreactive immune cells that recognise myelin antigens. Alteration of the immune balance can promote the onset of immune deficiencies, loss of immunosurveillance, and/or development of autoimmune disorders such as MS. Numerous enzymes, transcription factors, signal transducers, and membrane proteins contribute to the control of immune system activity. The "transcriptional machine" of eukaryotic cells is a complex system composed not only of mRNA but also of non-coding elements grouped together in the set of non-coding RNAs. Recent studies demonstrate that ncRNAs play a crucial role in numerous cellular functions, gene expression, and the pathogenesis of many immune disorders. The main purpose of this review is to investigate the role of circular RNAs, a previously unknown class of non-coding RNAs, in MS's pathogenesis. CircRNAs influence post-transcriptional control, expression, and functionality of a microRNA and epigenetic factors, promoting the development of typical MS abnormalities such as neuroinflammation, damage to neuronal cells, and microglial dysfunction. The increase in our knowledge of the role of circRNAs in multiple sclerosis could, in the future, modify the common diagnostic-therapeutic criteria, paving the way to a new vision of this neuroimmune pathology.

Efficacy and safety of once-weekly bortezomib in multiple myeloma patients.

In a recent phase 3 trial, bortezomib-melphalan-prednisone-thalidomide followed by maintenance treatment with bortezomib-thalidomide demonstrated superior efficacy compared with bortezomib-melphalan-prednisone. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions: 372 patients received once-weekly and 139 twice-weekly bortezomib. In this post-hoc analysis we assessed the impact of the schedule change on clinical outcomes and safety. Long-term outcomes appeared similar: 3-year progression-free survival rate was 50% in the once-weekly and 47% in the twice-weekly group (P > .999), and 3-year overall survival rate was 88% and 89%, respectively (P = .54). The complete response rate was 30% in the once-weekly and 35% in the twice-weekly group (P = .27). Nonhematologic grade 3/4 adverse events were reported in 35% of once-weekly patients and 51% of twice-weekly patients (P = .003). The incidence of grade 3/4 peripheral neuropathy was 8% in the once-weekly and 28% in the twice-weekly group (P < .001); 5% of patients in the once-weekly and 15% in the twice-weekly group discontinued therapy because of peripheral neuropathy (P < .001). This improvement in safety did not appear to affect efficacy. This study is registered at http://www.clinicaltrials.gov as NCT01063179.

Homo- and heterodimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part I: Synthesis.

Novel pro-apoptotic, homo- and heterodimeric Smac mimetics/IAPs inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold were prepared from monomeric structures connected through a head-head (8), tail-tail (9) or head-tail (10) linker. The selection of appropriate decorating functions for the scaffolds, and of rigid and flexible linkers connecting them, is described. The synthesis, purification and analytical characterization of each prepared dimer 8-10 is thoroughly described.

Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization.

Novel pro-apoptotic, homodimeric and heterodimeric Smac mimetics/IAPs inhibitors connected through head-head (8), tail-tail (9) or head-tail linkers (10), were biologically and structurally characterized. In vitro characterization (binding to BIR3 and linker-BIR2-BIR3 domains from XIAP and cIAP1, cytotoxicity assays) identified early leads from each dimer family. Computational models and structural studies (crystallography, NMR, gel filtration) partially rationalized the observed properties for each dimer class. Tail-tail dimer 9a was shown to be active in a breast and in an ovary tumor model, highlighting the potential of dimeric Smac mimetics/IAP inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold as potential antineoplastic agents.