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The formation of neutralizing antibodies (NAbs) directed specifically against the active neurotoxin part of the botulinum neurotoxin (BoNT) complex is often cited as a major cause of secondary non-responsiveness (SnR) to treatment. This systematic and meta-analytic review evaluates the frequency of NAbs among patients treated with BoNT therapy for any clinical indication. A comprehensive database search strategy was designed to retrieve relevant clinical data from the published literature up to April 2013. All English-language publications that analyzed NAbs prevalence in more than ten patients were included, regardless of BoNT formulation, assay method, and study design. For the meta-analysis, patients were divided into three categories: secondary nonresponse (SnR) patients, clinically responding patients and all patients, independently of BoNT responsiveness. The meta-analysis included 61 studies reporting data for 8525 patients; 4972 dystonic patients, 1170 patients with spasticity, 294 patients with urologic indications, 396 patient with hyperhidrosis, 1659 patients with glabellar line, and 34 patients with hypersalivation. Among the ‘‘all patients’’ group NAbs frequency was 20%for dystonia, 5.9%for spasticity, and 2.7% for urologic patients and 1.1% for other conditions. The prevalence of NAbs was lower (3.5%) among clinically responding patients and higher in 53.5%SnR patients. About a half of patients with SnR do not have NAbs. NAbs was high among patients treated with RIMA but it was not associated with clinical non-responsiveness. Meta-analysis of the frequency of NAbs and SnR are limited by the heterogeneity of study design and reported outcomes. Indeed the analysis of several factors that can influence the development of NAbs, i.e.,MHCof patients, frequency and site of injection, injection technique, cumulative dose, and toxin denaturation, was not specifically evaluated due to the paucity and heterogeneity of data. The identification of all these missing data should be taken into account in order to improve the methodology of future studies.

Freezing of gait (FOG) is a disabling disorder that often affects Parkinson's disease (PD) patients in advanced stages of the disease. To study structural gray matter (GM) and white matter (WM) changes in PD patients with and without FOG, twenty-one PD patients with FOG (PD-FOG), 16 PD patients without FOG (PD-nFOG) and 19 healthy subjects (HS) underwent a standardized MRI protocol. For the gray matter evaluation, cortical volume (CV), cortical thickness (CTh), and surface area (SA) were analyzed using the FreeSurfer pipeline. For the white matter evaluation, DTI images were analyzed using tracts constrained by underlying anatomy (TRACULA) toolbox in FreeSurfer. PD-FOG patients exhibited lower CTh than HS in the mesial surface of both cerebral hemispheres, including the superior frontal gyrus, paracentral lobule, posterior cingulate cortex, precuneus and pericalcarine cortex, and in the right dorsolateral prefrontal cortex. Moreover, significant WM changes were observed in PD-FOG patients in comparison with HS in the superior longitudinal fasciculus, uncinate fasciculus, cingulum cingulate gyrus and inferior longitudinal fasciculus (prevalently in the right hemisphere) and in the frontal radiations of the corpus callosum. DTI abnormalities in specific WM bundles correlated significantly with cognitive measures. The damage of multiple cortical areas involved in high-level gait control together with WM disruption between motor, cognitive and limbic structures may represent the anatomical correlate of FOG.

Freezing of gait (FOG) is a leading cause of falls and fractures in Parkinson’s disease (PD). The episodic and rather unpredictable occurrence of FOG, coupled with the variable response to l-DOPA of this gait disorder, makes the objective evaluation of FOG severity a major clinical challenge in the therapeutic management of patients with PD. The aim of this study was to examine and compare gait, clinically and objectively, in patients with PD, with and without FOG, by means of a new wearable system. We also assessed the effect of l-DOPA on FOG severity and specific spatiotemporal gait parameters in patients with and without FOG. To this purpose, we recruited 28 patients with FOG, 16 patients without FOG, and 16 healthy subjects. In all participants, gait was evaluated clinically by video recordings and objectively by means of the wearable wireless system, during a modified 3-m Timed Up and Go (TUG) test. All patients performed the modified TUG test under and not under dopaminergic therapy (ON and OFF therapy). By comparing instrumental data with the clinical identification of FOG based on offline video-recordings, we also assessed the performance of the wearable system to detect FOG automatically in terms of sensitivity, specificity, positive and negative predictive values, and finally accuracy. TUG duration was longer in patients than in controls, and the amount of gait abnormalities was prominent in patients with FOG compared with those without FOG. l-DOPA improved gait significantly in patients with PD and particularly in patients with FOG mainly by reducing FOG duration and increasing specific spatiotemporal gait parameters. Finally, the overall wireless system performance in automatic FOG detection was characterized by excellent sensitivity (93.41%), specificity (98.51%), positive predictive value (89.55%), negative predictive value (97.31%), and finally accuracy (98.51%). Our study overall provides new information on the beneficial effect of l-DOPA on FOG severity and specific spatiotemporal gait parameters as objectively measured by a wearable sensory system. The algorithm here reported potentially opens to objective long-time sensing of FOG episodes in patients with PD.

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