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SPG4 is an autosomal dominant pure form of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. HSP is considered an upper motor neuron disorder characterized by progressive spasticity and weakness of the lower limbs caused by degeneration of the corticospinal tract. In other neurodegenerative motor disorders, the thalamus and basal ganglia are affected, with a considerable impact on disease progression. However, only a few works have studied these brain structures in HSP, mainly in complex forms of this disease. Our research aims to detect potential alterations in the volume and shape of the thalamus and various basal ganglia structures by comparing 12 patients with pure HSP and 18 healthy controls. We used two neuroimaging procedures: automated segmentation of the subcortical structures (thalamus, hippocampus, caudate nucleus, globus pallidus, and putamen) in native space and shape analysis of the structures. We found a significant reduction in thalamic volume bilaterally, as well as an inward deformation, mainly in the sensory-motor thalamic regions in patients with pure HSP and a mutation in SPG4. We also observed a significant negative correlation between the shape of the thalamus and clinical scores (the Spastic Paraplegia Rating Scale score and disease duration). Moreover, we found a 'Group × Age' interaction that was closely related to the severity of the disease. No differences in volume or in shape were found in the remaining subcortical structures studied. Our results suggest that changes in structure of the thalamus could be an imaging biomarker of disease progression in pHSP.

This study proposes and clinically tests intramuscular electrical stimulation below motor threshold to achieve prolonged reduction of wrist flexion/extension tremor in Essential Tremor (ET) patients. The developed system consisted of an intramuscular thin-film electrode structure that included both stimulation and electromyography (EMG) recording electrodes, and a control algorithm for the timing of intramuscular stimulation based on EMG (closed-loop stimulation). Data were recorded from nine ET patients with wrist flexion/extension tremor recruited from the Gregorio Marañón Hospital (Madrid, Spain). Patients participated in two experimental sessions comprising: 1) sensory stimulation of wrist flexors/extensors via thin-film multichannel intramuscular electrodes; and 2) surface stimulation of the nerves innervating the same target muscles. For each session, four of these patients underwent random 60-s trials of two stimulation strategies for each target muscle: 1) selective and adaptive timely stimulation (SATS) - based on EMG of the antagonist muscle; and 2) continuous stimulation (CON) of target muscles. Two patients underwent SATS stimulation trials alone while the other three underwent CON stimulation trials alone in each session. Kinematics of wrist, elbow, and shoulder, together with clinical scales, were used to assess tremor before, right after, and 24 h after each session. Intramuscular SATS achieved, on average, 32% acute (during stimulation) tremor reduction on each trial, while continuous stimulation augmented tremorgenic activity. Furthermore, tremor reduction was significantly higher using intramuscular than surface stimulation. Prolonged reduction of tremor amplitude (24 h after the experiment) was observed in four patients. These results showed acute and prolonged (24 h) tremor reduction using a minimally invasive neurostimulation technology based on SATS of primary sensory afferents of wrist muscles. This strategy might open the possibility of an alternative therapeutic approach for ET patients.

Objectives: To compare the characteristics of patients undergoing treatment with continuous intestinal infusion of levodopa-carbidopa (CIILC) for advanced Parkinson's disease and the data on the effectiveness and safety of CIILC in the different autonomous communities (AC) of Spain., Methods: A retrospective, longitudinal, observational study was carried out into 177 patients from 11 CAs who underwent CIILC between January 2006 and December 2011. We analysed data on patients' clinical and demographic characteristics, variables related to effectiveness (changes in off time/on time with or without disabling dyskinesia; changes in Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale scores; non-motor symptoms; and Clinical Global Impression scale scores) and safety (adverse events), and the rate of CIILC discontinuation., Results: Significant differences were observed between CAs for several baseline variables: duration of disease progression prior to CIILC onset, off time (34.9-59.7%) and on time (2.6-48.0%; with or without disabling dyskinesia), Hoehn and Yahr score during on time, Unified Parkinson's Disease Rating Scale-III score during both on and off time, presence of≥ 4 motor symptoms, and CIILC dose. Significant differences were observed during follow-up (> 24 months in 9 of the 11 CAs studied) for the percentage of off time and on time without disabling dyskinesia, adverse events frequency, and Clinical Global Impression scores. The rate of CIILC discontinuation was between 20-40% in 9 CAs (78 and 80% in remaining 2 CAs)., Conclusions: This study reveals a marked variability between CAs in terms of patient selection and CIILC safety and effectiveness. These results may have been influenced by patients' baseline characteristics, the availability of multidisciplinary teams, and clinical experience., (Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To describe the clinical and electromyographic characteristics of blepharospasm caused by selective involvement of the pars pretarsalis of the orbicularis oculi muscle., Methods: Clinical assessment and simultaneous electromyographic recordings from levator palpebrae superioris and pars orbitaria and pretarsalis of orbicularis oculi muscles were performed in patients with blepharospasm and primary failure to botulinum toxin injections. Patients with selective abnormal electromyographic activity of the pars pretarsalis of the orbicularis oculi muscle were identified and treated with selective pretarsal injections of botulinum toxin., Results: We found 24 patients with pretarsal blepharospasm confirmed by the electromyographic assessment. All of them were functionally blind. Three clinical-electromyographic patterns were identified: (a) Impairment of eyelid opening; (b) Increased blinking; (c) Spasms of eye closure combined with varying degrees of excessive blinking and impairment of eye-opening. Pretarsal injections of botulinum toxin induced a significant improvement in all patients and 50 % regained normal or near-normal vision. The clinical improvement was sustained after repeated pretarsal injections., Conclusions: Pretarsal blepharospasm can be suspected on clinical grounds and it can be confirmed by electromyographic recordings., Significance: Recognition of this type of blepharospasm is important because of its excellent response to botulinum toxin injections applied into the pretarsal part of the orbicularis oculi muscle., Competing Interests: Declaration of Competing Interest F. Grandas received honoraria for lecturing from Allergan S.A. The other authors: none., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

We would like to submit the following erratum to our recently published paper [...].

Safinamide is an approved drug for the treatment of fluctuations in Parkinson's disease (PD). Scarce data are available on its use in clinical practice. A group of Spanish movement disorders specialists was convened to review the use of safinamide across different clinical scenarios that may guide neurologists in clinical practice. Eight specialists with recognized expertise in PD management elaborated the statements based on available evidence in the literature and on their clinical experience. The RAND/UCLA method was carried, with final conclusions accepted after a 2-round modified Delphi process. Higher level of agreement between panellists was reached for the following statements. Safinamide significantly improves mean daily ON time without troublesome dyskinesias [corrected]. Adjunctive treatment with safinamide is associated with motor improvements in patients with mid-to-late PD. The efficacy of safinamide on motor fluctuations is maintained at long-term, with no increase over time in dyskinesias severity. The clinical benefits of safinamide on pain and depression remain unclear. Safinamide presents a similar incidence of adverse events compared with placebo. The efficacy and safety of safinamide shown in the pivotal clinical trials are reproduced in clinical practice, with improvement of parkinsonian symptoms, decrease of daily OFF time, control of dyskinesias at the long term, and good tolerability and safety.

We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2, and HTT genes in several neurodegenerative diseases. The study included 1126 patients with Alzheimer's disease (AD), 440 patients with frontotemporal dementia (FTD), and 610 patients with Parkinson's disease. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. In addition, in the FTD cohort, we determined the number of HTT CAG repeats. The frequency of HTT IAs was higher in patients with FTD (6.9%) versus controls (2.9%) and in the C9orf72 expansion noncarriers (7.2%) versus controls (2.9%), although the difference was nonsignificant after correction for multiple testing. Compared with controls, progressive nonfluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs (13.6% vs. 2.9% controls). For the ATXN2 gene, we observed an increase in IA frequency in AD cases (AD 4.1% vs. controls 1.8%) and in the behavioral FTD group (4.8% vs. 1.8%). For the ATXN1 gene, we found a significant increase of IAs in patients with PNFA (18.6%) versus controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Postural instability in Parkinson's disease (PD) is commonly assessed by the pull test. This clinical test may be biased by the variability of the pull force applied. Our objective was to study the postural responses elicited by reproducible pull forces in healthy subjects and PD patients at different stages of the disease. We performed a multimodal approach that included a systematic analysis of the pull force needed to reach the backward limit of stability (FBLoS) assessed by mechanically produced forces, the displacements of the center of pressure (CoP) recorded on a force platform, and the latencies and patterns of activation of the stabilizing muscles. Comparisons between groups were performed by univariate and multivariate statistical analyses. Sixty-four healthy subjects and 32 PD patients, 22 Hoehn-Yahr (H-Y) stages I-II and 10 H-Y stage III, were studied. In healthy subjects, FBLoS decreased with aging and was lower in females. Mean (SD) FBLoS was 98.1 (48.9) Newtons (N) in healthy subjects, 70.5 (39.8) N in PD patients H-Y stages I-II, and 37.7 (18.9) N in PD patients H-Y stage III. Compared to healthy subjects and when adjusted for age and gender, PD patients H-Y stages I-II exhibited the following: (a) a reduced FBLoS; (b) larger CoP displacements and higher velocities for the same applied force; and (c) combined ankle and hip strategies elicited by less intense pull forces. All of these abnormalities were more pronounced in H-Y stage III PD patients compared to H-Y stages I-II PD patients. In conclusion, patients in the early stages of PD already exhibit a degree of postural instability due to inefficient postural adjustments, and they can more easily be destabilized by small perturbations than healthy subjects. This balance impairment becomes more pronounced in more advanced PD. In the pull test, pull force to step back should be a variable to consider when testing balance in clinical practice., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2019 Javier Ricardo Pérez-Sánchez and Francisco Grandas.)

Background: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA., Objectives: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients., Methods: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction., Results: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001)., Conclusions: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Background: Levodopa-carbidopa intestinal gel (LCIG) is effective in the treatment of advanced Parkinson's disease (PD). However, the patients' profile that might benefit from treatment with LCIG has not been characterized., Objective: This retrospective study explored the influence of disease duration (DD) on the effectiveness of LCIG and identified factors associated with treatment discontinuation in a cohort of advanced PD patients., Methods: Patients initiating LCIG therapy between Jan-2006 and Dec-2011 in 18 Spanish centers were included. Effectiveness in treating motor symptoms (MSs), non-motor symptoms (NMSs), and adverse events (AEs) occurrence was compared in DD≥10 or <10 years and LCIG continuation/discontinuation groups. Factors associated with LCIG discontinuation were evaluated using univariate and multivariate analyses., Results: Overall, 177 PD patients were included (52.5% male; mean age 70.6±8.4 years; mean LCIG duration 35.6±18.6 months). Patients with DD≥10 years (n = 125) experienced less reduction in "off" time (-29%) than those with DD <10 years (-38%; n = 51; p = 0.021), and reported more severe AEs (32.8% vs. 17.6%; p = 0.043). DD did not significantly influence changes in NMSs or discontinuation rates. Fifty-four patients discontinued LCIG therapy, factors associated with discontinuation were higher percentages of waking day in the "off" state (OR, 1.028; 95% CI, 1.002-1.055; p = 0.0360) and in the "on" state with troublesome dyskinesia (OR, 1.032; 95% CI, 1.002-1.064; p = 0.0376) at baseline., Conclusions: Advanced PD patients with DD <10 years might benefit more from treatment with LCIG than patients with a longer DD. Although MSs severity at baseline was statistically associated with LCIG discontinuation, the probability was very low with little clinical significance.

«Apuntes en Neurologia» is an initiative in which prominent national and international leaders, with broad academic recognition, came together to synthesise the most outstanding clinical aspects within their area of interest and to discuss the latest developments in a more accessible language. Understanding the factors that affect the onset and progression of any neurological disease through a review is important to be able to develop strategies to reduce the burden of these diseases. Moreover, knowledge of the clinical aspects is essential to solve the problems of daily clinical practice. The data collected here reflect the weight of evidence and some of them anticipate a promising future in the treatment of these diseases. This first edition focuses on common paroxysmal neurological disorders such as migraine, epilepsy and sleep disorders, as well as neurodegenerative disorders such as Parkinson's disease and cognitive impairment. These are clearly different pathologies, although some of them such as migraine and epilepsy, may share clinical symptoms. Sleep disorders, however, are important manifestations of neurodegenerative diseases that are sometimes clinically apparent long before the onset of other neurological symptoms. After recalling pathophysiology and diagnosis, the current review focuses on bringing together the main advances in five of the major neurological diseases.

Inertial measurement units (IMUs) have a long-lasting popularity in a variety of industrial applications from navigation systems to guidance and robotics. Their use in clinical practice is now becoming more common, thanks to miniaturization and the ability to integrate on-board computational and decision-support features. IMU-based gait analysis is a paradigm of this evolving process, and in this study its use for the assessment of Parkinson's disease (PD) is comprehensively analyzed. Data coming from 25 individuals with different levels of PD symptoms severity and an equal number of age-matched healthy individuals were included into a set of 6 different machine learning (ML) techniques, processing 18 different configurations of gait parameters taken from 8 IMU sensors. Classification accuracy was calculated for each configuration and ML technique, adding two meta-classifiers based on the results obtained from all individual techniques through majority of voting, with two different weighting schemes. Average classification accuracy ranged between 63% and 80% among classifiers and increased up to 96% for one meta-classifier configuration. Configurations based on a statistical preselection process showed the highest average classification accuracy. When reducing the number of sensors, features based on the joint range of motion were more accurate than those based on spatio-temporal parameters. In particular, best results were obtained with the knee range of motion, calculated with four IMUs, placed bilaterally. The obtained findings provide data-driven evidence on which combination of sensor configurations and classification methods to be used during IMU-based gait analysis to grade the severity level of PD.

Safinamide is a new add-on drug to levodopa for the treatment of Parkinson's disease (PD) with motor fluctuations. Due to the recent incorporation of safinamide into routine clinical practice, no post-authorisation phase IV studies on the safety of safinamide have been conducted to date. This study provides clinical management guidelines for safinamide based on the opinion of a group of experts in movement disorders. This project was developed in 2 phases: 16 local meetings in phase 1 and a national meeting in phase 2. The meetings followed a pre-established agenda. The present clinical practice guidelines are based on the main conclusions reached during the national meeting. The group concluded that safinamide is effective in reducing motor and non-motor fluctuations. PD patients with mild-to-moderate fluctuations benefit most from treatment, although the drug may also improve the clinical status of patients with advanced PD. The dose of other dopaminergic drugs may be reduced after introducing safinamide, which would contribute to reducing such adverse reactions as impulse control disorder. At doses higher than those usually prescribed, safinamide may also improve dyskinesia. The experts agreed that safinamide is well tolerated and causes few adverse reactions when compared with placebo., (Copyright © 2018. Publicado por Elsevier España, S.L.U.)

The use of new tools to detect Parkinson's Disease (PD) from speech articulatory movements can have a considerable impact in the diagnosis of patients. In this study, a novel approach involving speaker recognition techniques with allophonic distillation is proposed and tested separately in four parkinsonian speech databases (205 patients and 186 controls in total). This new scheme provides values between 72% and 94% of accuracy in the automatic detection of PD, depending on the database, and improvements up to 9% respect to baseline techniques. Results not only point towards the importance of the segmentation of the speech for the differentiation of parkinsonian and control speakers but confirm previous findings about the relevance of plosives and fricatives in the detection of parkinsonian dysarthria.

Introduction: Variant detection protocols for clinical next-generation sequencing (NGS) need application-specific optimization. Our aim was to analyze the performance of single nucleotide variant (SNV) and copy number (CNV) detection programs on an NGS panel for a rare disease., Methods: Thirty genes were sequenced in 83 patients with hereditary spastic paraplegia. The variant calls obtained with LifeScope, GATK UnifiedGenotyper and GATK HaplotypeCaller were compared with Sanger sequencing. The calling efficiency was evaluated for 187 (56 unique) SNVs and indels. Five multiexon deletions detected by multiple ligation probe assay were assessed from the NGS panel data with ExomeDepth, panelcn.MOPS and CNVPanelizer software., Results: There were 48/51 (94%) SNVs and 1/5 (20%) indels consistently detected by all the calling algorithms. Two SNVs were not detected by any of the callers because of a rare reference allele, and one SNV in a low coverage region was only detected by two algorithms. Regarding CNVs, ExomeDepth detected 5/5 multi-exon deletions, panelcn.MOPs 4/5 and only 3/5 deletions were accurately detected by CNVPanelizer., Conclusions: The calling efficiency of NGS algorithms for SNVs is influenced by variant type and coverage. NGS protocols need to account for the presence of rare variants in the reference sequence as well as for ambiguities in indel calling. CNV detection algorithms can be used to identify large deletions from NGS panel data for diagnostic applications; however, sensitivity depends on coverage, selection of the reference set and deletion size. We recommend the incorporation of several variant callers in the NGS pipeline to maximize variant detection efficiency.

Background: The effect of subthalamic deep brain stimulation on balance in Parkinson's disease remains unclear., Objective: To evaluate the effect of subthalamic nucleus stimulation on balance in Parkinson's disease using posturography., Methods: 16 patients (9 women) who underwent subthalamic deep brain stimulation [mean age 59.6 years (46-70); mean disease duration 15.6 years (7-25); mean duration of subthalamic stimulation 32.1 months (3.0-69.6)] and 13 healthy age-matched controls were evaluated using a static posturography analysis. Patients were assessed under four conditions: 1) off medication/off stimulation; 2) off medication/on stimulation; 3) on medication/off stimulation and 4) on medication/on stimulation in ten experimental paradigms, some reproducing common situations of daily living. The displacement of the centre of pressure was analyzed using 14 posturographic parameters. The Mann-Whitney test was used to compare patients with controls. The Wilcoxon signed rank test was used to compare patients under different clinical conditions., Results: Patients off medication/off stimulation showed larger and more rapid displacements of the centre of pressure than controls in most paradigms (p<0.05), particularly when performing a dual task. Subthalamic stimulation alone reduced the lateral excursion and anterior-posterior velocity of the centre of pressure in quite stance paradigms (p<0.05). Subthalamic stimulation combined with antiparkinsonian medication did not induce statistically significant changes in posturagraphic measures in any experimental paradigm., Conclusions: Although subthalamic stimulation alone may induce some positive effect on balance, subthalamic stimulation in addition to antiparkinsonian medication, which is the usual treatment in clinical practice, did not modify balance as assessed by static posturography in patients with Parkinson's disease., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aim: To assess long-term effectiveness and tolerability of levodopa-carbidopa intestinal gel (LCIG) in Spanish patients with advanced Parkinson's disease., Patients & Methods: This was an observational, multicenter, cross-sectional, retrospective study., Results: Data of 177 patients were analyzed. LCIG treatment led to a reduction in the percentage of daily 'off' time (16.2 vs 47.6% before LCIG), an increase in the percentage of daily 'on' time without disabling dyskinesia (55.6 vs 21.6%). Most patients experienced improvements in freezing of gait, tremor, dizziness, fatigue or flat mood. Adverse events related to levodopa, gastrostomy and technical issues were reported in 36.2, 42.4 and 43.5% of patients, respectively., Conclusion: This study confirms the long-term effectiveness and safety profile of LCIG in patients with advanced Parkinson's disease.

Background: The reasons underlying the loss of efficacy of deep brain stimulation (DBS) of the thalamic nucleus ventralis intermedius (VIM-DBS) over time in patients with essential tremor are not well understood., Methods: Long-term clinical outcome and stimulation parameters were evaluated in 14 patients with essential tremor who underwent VIM-DBS. The mean ± standard deviation postoperative follow-up was 7.7 ± 3.8 years. At each visit (every 3-6 months), tremor was assessed using the Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) and stimulation parameters were recorded (contacts, voltage, frequency, pulse width, and total electrical energy delivered by the internal generator [TEED 1sec ])., Results: The mean reduction in FTM-TRS score was 73.4% at 6 months after VIM-DBS surgery ( P < 0.001) and 50.1% at the last visit ( P < 0.001). The gradual worsening of FTM-TRS scores over time fit a linear regression model (coefficient of determination [R 2 ] = 0.887; P < 0.001). Stimulation adjustments to optimize tremor control required a statistically significant increase in voltage ( P = 0.01), pulse width ( P = 0.01), frequency ( P = 0.02), and TEED 1sec ( P = 0.008). TEED 1sec fit a third-order polynomial curve model throughout the follow-up period (R 2 = 0.966; P < 0.001). The initial exponential increase (first 4 years of VIM-DBS) was followed by a plateau and a further increase from the seventh year onward., Conclusions: The current findings suggest that the waning effect of VIM-DBS over time in patients with essential tremor may be the consequence of a combination of factors. Superimposed on the progression of the disease, tolerance can occur during the early years of stimulation.

Histological image analysis plays a key role in understanding the effects of disease and treatment responses at the cellular level. However, evaluating histology images by hand is time-consuming and subjective. While semi-automatic and automatic approaches for image segmentation give acceptable results in some branches of histological image analysis, until now this has not been the case when applied to skeletal muscle histology images. We introduce Charisma, a new top-down cell segmentation framework for histology images which combines image processing techniques, a supervised trained classifier and a novel robust clump splitting algorithm. We evaluate our framework on real-world data from intensive care unit patients. Considering both segmentation and cell property distributions, the results obtained by our method correspond well to the ground truth, outperforming other examined methods., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Subcutaneous infusion of apomorphine is a useful treatment for motor and nonmotor complications in Parkinson's disease patients and improves the patient's quality of life. An adequate selection of suitable candidates is crucial for obtaining the best results with this therapy. Parkinsonian patients with severe biphasic dyskinesias, demented or having experienced serious neuropsychiatric side effects with other dopamine agonists should not be offered this treatment. The therapeutic effect of continuous apomorphine infusion is reviewed and practical recommendations on its use are provided.

Freezing of gait is an episodic gait disorder that may occur in patients with Parkinson's disease. The risk factors for this disorder are poorly understood. To determine the relevant risk factors for this condition, we screened 160 consecutive patients with Parkinson's disease for freezing of gait and assessed 36 potentially related variables. Freezers and non-freezers were compared using statistical univariate analysis, followed by bivariate and multivariate logistic regression, receiver operating characteristics curves and Kaplan-Meier estimates. Seventy-one patients (44.4%) reported freezing of gait. At onset, the mean disease duration was 8.1±6.3years. Freezers experienced falls more frequently than non-freezers (57.7% vs 23.6%, p<0.001). Disease duration was the independent variable most associated with freezing of gait (OR=1.10, 95% CI=1.01-1.19, p=0.020). Its specificity was 77%, but its sensitivity was low, and Hoehn and Yahr staging and the UPDRS (part III) score showed similar accuracy to that of disease duration in predicting freezers. Previous antiparkinsonian treatments and predominant motor signs (tremor/akinesia-rigidity subtypes) at the onset of Parkinson's disease were not related to freezing of gait. Patients who developed Parkinson's disease before the age of 60years experienced freezing of gait earlier than older patients (log-rank, p<0.005). Freezing of gait is a common and disabling motor complication of Parkinson's disease that is related to the progression of the disease. It is not primarily associated with dopamine replacement therapy and may occur early in young patients., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Dopamine dysregulation syndrome is a complication of the dopaminergic treatment for Parkinson's disease, probably related to sensitization of the mesolimbic dopamine system. The relationship between dopamine dysregulation syndrome and deep brain stimulation of the subthalamic nucleus remains unclear. We report three patients with Parkinson's disease who developed de novo dopamine dysregulation syndrome after deep brain stimulation of the subthalamic nucleus. We hypothesized that the combined effect of dopaminergic replacement therapy and deep brain stimulation on the limbic territory of the subthalamic nucleus could have precipitated the dopamine dysregulation syndrome in these patients, by inducing hyperstimulation of the mesolimbic dopamine system. The outcome of postoperative dopamine dysregulation syndrome is poor despite deep brain stimulation adjustments, attempts to reduce the dose of dopaminergic drugs and the addition of quetiapine or antidepressants., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Falls are a major source of disability in Parkinson's disease. Risk factors for falling in Parkinson's disease remain unclear. To determine the relevant risk factors for falling in Parkinson's disease, we screened 160 consecutive patients with Parkinson's disease for falls and assessed 40 variables. A comparison between fallers and nonfallers was performed using statistical univariate analyses, followed by bivariate and multivariate logistic regression, receiver-operating characteristics analysis, and Kaplan-Meier curves. 38.8% of patients experienced falls since the onset of Parkinson's disease (recurrent in 67%). Tinetti Balance score and Hoehn and Yahr staging were the best independent variables associated with falls. The Tinetti Balance test predicted falls with 71% sensitivity and 79% specificity and Hoehn and Yahr staging with 77% sensitivity and 71% specificity. The risk of falls increased exponentially with age, especially from 70 years onward. Patients aged >70 years at the onset of Parkinson's disease experienced falls significantly earlier than younger patients.

Introduction: Traumatic brain injury (TBI) in the elderly is becoming an increasingly frequent phenomenon. Studies have mainly analyzed the influence of age as a continuous variable and have not specifically looked at geriatric patients as a group. The aim of this study is to map the magnitude and characteristics of geriatric TBI and to identify factors contributing to their poorer outcome., Material and Methods: Based on the ICD-9 register of the University Hospitals Leuven demographic and clinical variables of TBI were analyzed (2002-2008). The influence of older age on physiological variables was assessed using the Brain-IT database., Results: The elderly (aged ≥65 years) accounted for 38.2% of non-concussion TBI and 32.6% of ICU admissions, representing the largest age group. The elderly had a significantly lower ICP (median 10.06 mmHg versus median 14.52 mmHg; p = 0.048), but no difference in their measure of autoregulation (daily mABP/ICP correlation coefficient) compared with 20-35 year-olds. TBI was caused by a fall in 78.9% of elderly patients and 42.3% suffered a mass lesion. 72.1% had cardiovascular comorbidity. Complications did not differ from their younger counterparts., Discussion: Geriatric TBI is a significant phenomenon. Poorer outcomes are not yet sufficiently explained by physiological monitoring data, but reduced vascular versatility is likely to contribute. More research is needed in order to develop specific management protocols.

Introduction: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal-recessive disease due to mutations of the 27α-hydroxylase. It is characterized by cataracts, xanthomas, and neurological manifestations. Polyneuropathy has been reported, although it is unclear whether it is axonal or demyelinating., Methods: We report clinical and neurophysiological results of 13 patients with CTX diagnosed in Spain., Results: In 8 patients (62%), peripheral neuropathy was demonstrated (4 demyelinating, 3 axonal, and 1 mixed; 3 predominantly motor and 5 sensorimotor). All patients had clinical signs/symptoms of peripheral neuropathy. Upper limb somatosensory evoked potentials (SSEPs) were affected in 38% of patients, and lower limb SSEPs in 67%. Fifty percent of patients had delayed brainstem auditory evoked potentials, and 43% had affected visual evoked potentials., Discussion: In this series, polyneuropathy was predominantly sensorimotor and demyelinating. Neurophysiological studies correlated only partially with clinical follow-up. Therefore, we recommend neurophysiological follow-up studies only if clinical symptoms are present., (Copyright © 2011 Wiley Periodicals, Inc.)

Hemiballism is a relatively rare hyperkinetic movement disorder characterized by involuntary, violent, coarse and wide-amplitude movements involving ipsilateral arm and leg. Although classically related to lesions in the subthalamic nucleus, in clinical-radiological series of hemiballism most patients had lesions outside this nucleus, involving mainly other basal ganglia structures. It has been suggested that abnormal neuronal firing patterns in the internal segment of the globus pallidus may be related to the pathogenesis of hemiballism. Stroke is the most common cause, but in recent years an increasing number of patients with hemiballism associated with nonketotic hyperglycemia or with complications of human immunodeficiency virus (HIV) infection have been reported. Contrarily to what was stated in older literature, hemiballism has, in general, a relatively good prognosis. Depending on the underlying causes, many patients may experience spontaneous improvements or remissions. Treatment should be directed to the cause of hemiballism. Symptomatic treatment includes the use of drugs, particularly blockers of striatal D2 dopamine receptors and tetrabenazine. Surgical treatment, especially pallidotomy, is a therapeutic option for the minority of patients with severe persistent disabling hemiballism., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Dopamine dysregulation syndrome is a complication of the dopaminergic treatment in Parkinson's disease that may be very disabling due to the negative impact that compulsive medication use may have on patients' social, psychological, and physical functioning. The relationship between subthalamic nucleus deep brain stimulation and dopamine dysregulation syndrome in patients with Parkinson's disease remains unclear. Deep brain stimulation may improve, worsen, or have no effect on preoperative dopamine dysregulation syndrome. Moreover, dopamine dysregulation syndrome may appear for the first time after deep brain stimulation of the subthalamic nucleus. The outcome of postoperative dopamine dysregulation syndrome is poor despite stimulation and medication adjustments. Here we review the phenomenology and neurobiology of this disorder, discuss possible mechanisms that may underlie the diverse outcomes of dopamine dysregulation syndrome after subthalamic nucleus deep brain stimulation, and propose management strategies.

Background: Dystonia is a complex clinical syndrome originated by a wide range of aetiologies. The diagnosis of dystonia is made after the evaluation of aetiological, phenomenological and genetic factors. Medications, except in patients with dopa-responsive dystonia, are of limited efficacy. Botulinum toxin injections are not applicable to patients with generalised dystonia, since many muscular groups contribute to disability. Clinical studies in children and adults with primary generalised dystonia (PGD) have reported beneficial effects of bilateral GPi deep brain stimulation (DBS) in both motor symptoms and disability produced by dystonia as well as a favourable impact of DBS in the health-related quality of life (HRQoL). Some clinical aspects of GPi stimulation in primary dystonia still remain controversial such as the influence of disease duration or age at onset in determining the postoperative clinical outcome., Results: The authors report the results of a multicentric study designed to assess the tolerability and clinical effects of bilateral pallidal DBS on motor impairment, functional disability, quality of life, pain and mood in patients with medically refractory primary generalised or segmental dystonia.

Objective: To study the possible relationship between central levodopa influx and short-term antiparkinsonian and dyskinetic responses to levodopa in patients with Parkinson disease., Methods: The clinical response to a single oral dose of standard and controlled-release levodopa/carbidopa was assessed in 12 patients with Parkinson disease complicated with motor fluctuations and dyskinesias. Plasma concentrations of levodopa and large neutral amino acids were determined, and the theoretical central levodopa influx was calculated using a model based on competitive inhibition of substrates to cross the blood-brain barrier., Results: The mean (SD) central levodopa influxes at the onset of the antiparkinsonian clinical effect were 19.7 (10.9 x 10(-3) and 19.1 (7.4 x 10(-3) nmol min(-1) g(-)1 (P >0.1) for standard and controlled-release levodopa, respectively. The mean (SD) central levodopa influxes at the onset of choreic dyskinesias were 20.1 (8.2 x 10 (-3) and 19.9 (10.8 x 10(-3) nmol min (-1) g(-)1 (P 9 0.1) for standard and controlled-release levodopa, respectively. During the tests, choreic dyskinesias were associated with a central levodopa influx of 10 x 10(-3) nmol min(-1) g(-1) or greater, and foot dystonia occurred with a central levodopa influx less than 9 x 10(-3) nmol min(-1) g(-1)., Conclusions: The clinical response to levodopa in patients with advanced Parkinson disease may be related to central levodopa influx. We found no differences in the central levodopa influx threshold for clinical improvement with different levodopa formulations. The central levodopa influxes at the onset of choreic dyskinesias and antiparkinsonian effect were similar. Choreic dyskinesias and foot dystonia were associated with high and low central levodopa influx, respectively.

Introduction: Currently used antiparkinsonian drugs neither stop nor slow-down the progressive nature of the disease. The final phase of PD is characterized by the presence of symptoms and signs resistant to dopaminergic agents, such as depression, dementia, freezing and falls. Therefore, it is urgent to develop therapies able to positively modify this outcome. Despite neuroprotection is a research priority in PD, no effective strategies have been found so far., Method: A key informants study was conducted. A group of experts in PD fulfilled a questionnaire of 10 questions to explore the most important topics related to neuroprotection. Afterwards a consensus about the current situation of neuroprotection in PD was established and future directions of development were suggested., Results: Most of the answers emphasized the need of new concepts, the limitations of animal models and the difficulties in the difficulties in demonstrating a neuroprotective effects in humans owing to a lack of biomarkers. Some of the experts believe that we are already exerting a disease modifying effect., Conclusions: The concept of neuroprotection should be widened. Animal models should be improved. A reliable biomarker to start neuroprotective therapies long before the appearance of motor symptoms and to evaluate the neuroprotective effect of any therapy should be urgently developed.

Unlabelled: A literature review was conducted to assess risk of cardiac valve regurgitation (CVR) associated with use of ergot-derived and non-ergot dopamine agonists (DAs) in patients with Parkinson's disease (PD)., Inclusion Criteria: case-control/observational studies of >10 patients with PD treated with DAs, including a control group and assessment of incidence/risk of CVR. Of the 166 publications identified, 14 met all inclusion criteria and included 1,750 patients. In 11 of the studies, a significant increase in CVR frequency of any severity (at the aortic, mitral or tricuspid valve) in the ergot group vs. the non-ergot or control group was described. No study reported increased risk of CVR for non-ergot DAs, compared with controls. In the studies identified in the literature, the use of ergot-derived DAs (pergolide and cabergoline) in patients with PD was associated with increased risk of CVR. Increased risk of CVR was not associated with the use of non-ergot DAs.

Levodopa-induced dyskinesias (LID) are common and difficult to treat. This review focuses on three issues related to LID: clinical features, classification and rating, pathophysiology and pathogenesis, and management. The three primary clinical syndromes are OFF-period dystonia, peak-dose dyskinesia, and diphasic dyskinesia. Several other forms also occur, making the evaluation and choice of treatment complicated. A core component of the pathophysiology of LID is overactivity of the direct striatal output pathway. This pathway provides a direct GABAergic connection by which the striatum inhibits the output regions of the basal ganglia, i.e., the internal globus pallidus and the substantia nigra pars reticulata. Altering dopaminergic dosing and timing can abate dyskinesias, but usually impact the control of parkinsonism. Putative therapies to reduce the problem of dyskinesias could focus on the glutamatergic, GABAergic, alpha2 adrenergic, serotonergic (5HT1A, 5HT2A), opioid, histamine H3, adenosine A2A receptors, the monoamine transport or cannabinoid CB1 receptors systems. The only currently available drug with an evidence-based recommendation on efficacy for dyskinesia is amantadine. Therapy goals include the prevention of dyskinesia and treatment of dyskinesias that are troublesome clinically. New rating measures to assess severity and disability related to dyskinesia are in the process of development and clinimetric testing., (Copyright 2007 Movement Disorder Society)

Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the "pulsatile" dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of "wearing off" fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in "de novo" patients is underway. At present, the combination levodopa-carbidopa-entacapone is indicated when levodopa is judged necessary.

We report on a patient who presented a transient eyelid motor disorder characterized by bilateral reflex blepharospasm as the main clinical manifestation of a right-sided striatal infarction. This case emphasizes the role of the nondominant striatum in the pathophysiology of eyelid motor abnormalities.

To assess the patterns of drug use in Parkinson's disease in Spain, information about the clinical characteristics and current treatment of 1803 parkinsonian patients was obtained from a nationwide survey, involving 241 physicians with practice based on the different assistance levels of the Spanish National Healthcare System. Approximately 90% of the patients were treated with levodopa, regardless of the characteristics of their physicians, but the use of the other available antiparkinsonian treatments was highly influenced by the medical specialty and interest in movement disorders of the prescribing doctors., (Copyright 2002 Movement Disorder Society)

A case of gliomatosis cerebri which clinically presented with a syndrome of intracranial hypertension (ICH), involvement of bilateral sixth cranial nerves, and oppressive holocranial headache of one week of evolution. Cranial MR and CT were performed demonstrating diffuse hypodense cortical-subcortical lesions on tomography and in T1 sequences and hyperdense lesions in T2 sequences with irregular contrast enhancement. Intracranial pressure was measured by ventricular catheter with the appearance of high, maintained pressure waves (Lundberg A waves). Ventricular LCR study and cerebral angiography did not provide additional data. Meningeal and cerebral biopsies showed infiltration by pleomorphous glioma leading to the diagnosis of gliomatosis cerebri. The patient was treated with steroids, hyperosmolar agents, external LCR derivation and tumoral radiotherapy. Nonetheless, the patient dies at six months of initiation of the symptoms. Gliomatosis cerebri should be taken into account in the differential diagnosis of clinical pictures presenting with ICH.

Parkinson's disease is probably caused by a combination of genetic and environmental factors, which trigger a cascade of events that lead to the cell death of the dopamine-containing neurons of the substantia nigra pars compacta. These processes include oxidative stress, mitochondrial dysfunction, excitotoxicity with excess of nitric oxide formation, glial and inflammatory abnormalities and apoptosis. Dopamine agonists are chemical compounds that act directly on the dopamine receptors without any previous enzymatic biotransformation. Besides their symptomatic antiparkinsonian effect, these drugs may have neuroprotective properties in Parkinson's disease through different possible mechanisms: (a) stimulation of dopamine auoreceptors, reducing thereby dopamine turnover; (b) direct antioxidant effects; (c) reduction of excitotoxicity induced by excessive subthalamic nucleus firing; (d) inhibition of mitochondrial permeability; (e) induction of trophic factors. Dopamine agonists have already shown neuroprotective effects on dopaminergic cells against a variety of neurotoxins in several in vitro and in vivo studies. Clinical studies to detect changes in the progression of the underlying neurodegenerative process in patients with Parkinson's disease treated with dopamine agonists, by assessing the dopamine terminal function in the striatum by means of PET and SPECT techniques are under way.