Publications by authors named "Francisco Grandas"

38 Publications

Thalamic atrophy in patients with pure hereditary spastic paraplegia type 4.

J Neurol 2021 Jan 28. Epub 2021 Jan 28.

Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.

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.
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http://dx.doi.org/10.1007/s00415-020-10387-4DOI Listing
January 2021

Neurological complications of COVID-19 in hospitalized patients: The registry of a neurology department in the first wave of the pandemic.

Eur J Neurol 2021 Jan 21. Epub 2021 Jan 21.

Department of Neurology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Objective: To describe the spectrum of neurological complications observed in a hospital-based cohort of COVID-19 patients who required a neurological assessment.

Methods: We conducted an observational, monocentric, prospective study of patients with a COVID-19 diagnosis hospitalized during the 3-month period of the first wave of the COVID-19 pandemic in a tertiary hospital in Madrid (Spain). We describe the neurological diagnoses that arose after the onset of COVID-19 symptoms. These diagnoses could be divided into different groups.

Results: Only 71 (2.6%) of 2750 hospitalized patients suffered at least one neurological complication (77 different neurological diagnoses in total) during the timeframe of the study. The most common diagnoses were neuromuscular disorders (33.7%), cerebrovascular diseases (CVDs) (27.3%), acute encephalopathy (19.4%), seizures (7.8%), and miscellanea (11.6%) comprising hiccups, myoclonic tremor, Horner syndrome and transverse myelitis. CVDs and encephalopathy were common in the early phase of the COVID-19 pandemic compared to neuromuscular disorders, which usually appeared later on (p = 0.005). Cerebrospinal fluid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction was negative in 15/15 samples. The mortality was higher in the CVD group (38.1% vs. 8.9%; p = 0.05).

Conclusions: The prevalence of neurological complications is low in patients hospitalized for COVID-19. Different mechanisms appear to be involved in these complications, and there was no evidence of direct invasion of the nervous system in our cohort. Some of the neurological complications can be classified into early and late neurological complications of COVID-19, as they occurred at different times following the onset of COVID-19 symptoms.
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http://dx.doi.org/10.1111/ene.14748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013314PMC
January 2021

Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia.

Neurobiol Aging 2021 03 2;99:99.e15-99.e22. Epub 2020 Sep 2.

Instituto de Investigación Sanitaria del Principado de Asturias - ISPA, Oviedo, Spain; Servicio de Neurología, Hospital Universitario Central de Asturias, Oviedo, Spain.

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.08.018DOI Listing
March 2021

Upper trunk brachial plexopathy as a consequence of prone positioning due to SARS-CoV-2 acute respiratory distress syndrome.

Muscle Nerve 2020 11 10;62(5):E76-E78. Epub 2020 Sep 10.

Neurology Department, ALS-Neuromuscular Diseases Unit, Hospital General Universitario Gregorio, Marañón, Madrid, Spain.

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http://dx.doi.org/10.1002/mus.27055DOI Listing
November 2020

Intramuscular stimulation of muscle afferents attains prolonged tremor reduction in essential tremor patients.

IEEE Trans Biomed Eng 2020 Aug 19;PP. Epub 2020 Aug 19.

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 Maran 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.
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http://dx.doi.org/10.1109/TBME.2020.3015572DOI Listing
August 2020

Serotonin syndrome in two COVID-19 patients treated with lopinavir/ritonavir.

J Neurol Sci 2020 08 27;415:116944. Epub 2020 May 27.

Movement Disorders Unit, Neurology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

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http://dx.doi.org/10.1016/j.jns.2020.116944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255189PMC
August 2020

Erratum: Pagonabarraga, J.; et al. A Spanish Consensus on the Use of Safinamide for Parkinson's Disease in Clinical Practice. 2020, , 176.

Brain Sci 2020 05 22;10(5). Epub 2020 May 22.

Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain.

We would like to submit the following erratum to our recently published paper [...].
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http://dx.doi.org/10.3390/brainsci10050313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288153PMC
May 2020

Pretarsal blepharospasm: Clinical and electromyographic characteristics.

Clin Neurophysiol 2020 Jul 2;131(7):1678-1685. Epub 2020 Apr 2.

Clinical Neurophysiology Service, Hospital General Universitario Gregorio Marañón, Facultad de Medicina, Universidad Complutense, Madrid, Spain.

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.
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http://dx.doi.org/10.1016/j.clinph.2020.03.016DOI Listing
July 2020

A Spanish Consensus on the Use of Safinamide for Parkinson's Disease in Clinical Practice.

Brain Sci 2020 03 18;10(3). Epub 2020 Mar 18.

Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain.

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.
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http://dx.doi.org/10.3390/brainsci10030176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139287PMC
March 2020

Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease.

Neurobiol Aging 2020 03 1;87:139.e1-139.e7. Epub 2019 Nov 1.

Instituto de Investigación Sanitaria del Principado de Asturias -ISPA, Oviedo, Spain; Servicio de Neurología, Hospital Universitario Central de Asturias, Oviedo, Spain.

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.10.017DOI Listing
March 2020

Early Postural Instability in Parkinson's Disease: A Biomechanical Analysis of the Pull Test.

Parkinsons Dis 2019 24;2019:6304842. Epub 2019 Oct 24.

Movement Disorders Unit, Neurology Department, Hospital General Universitario Gregorio Marañón, C./Doctor Esquerdo 46, 28007 Madrid, Spain.

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.
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http://dx.doi.org/10.1155/2019/6304842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854961PMC
October 2019

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism.

Mov Disord 2019 10 21;34(10):1547-1561. Epub 2019 Aug 21.

Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.

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.
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http://dx.doi.org/10.1002/mds.27812DOI Listing
October 2019

Impact of Disease Duration in Effectiveness of Treatment with Levodopa-Carbidopa Intestinal Gel and Factors Leading to Discontinuation.

J Parkinsons Dis 2019 ;9(1):173-182

Department of Neurology, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain.

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.
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http://dx.doi.org/10.3233/JPD-181324DOI Listing
May 2020

IMU-Based Classification of Parkinson's Disease From Gait: A Sensitivity Analysis on Sensor Location and Feature Selection.

IEEE J Biomed Health Inform 2018 11 13;22(6):1765-1774. Epub 2018 Aug 13.

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.
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http://dx.doi.org/10.1109/JBHI.2018.2865218DOI Listing
November 2018

Effect of subthalamic nucleus deep brain stimulation on balance in Parkinson's disease: A static posturographic analysis.

Gait Posture 2017 02 29;52:374-380. Epub 2016 Dec 29.

Movement Disorders Unit, Neurology Department, Hospital General Universitario Gregorio Marañón, Calle Doctor Esquerdo n°46, 28007, Madrid, Spain. Electronic address:

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.
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http://dx.doi.org/10.1016/j.gaitpost.2016.12.025DOI Listing
February 2017

Long-term effectiveness of levodopa-carbidopa intestinal gel in 177 Spanish patients with advanced Parkinson's disease.

Neurodegener Dis Manag 2016 08 21;6(4):289-98. Epub 2016 Jul 21.

AbbVie Spain S.L.U. Avenida De Burgos 91, 28050 Madrid, Spain.

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.
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http://dx.doi.org/10.2217/nmt-2016-0021DOI Listing
August 2016

Long-term Thalamic Deep Brain Stimulation for Essential Tremor: Clinical Outcome and Stimulation Parameters.

Mov Disord Clin Pract 2016 Nov-Dec;3(6):567-572. Epub 2016 Mar 1.

Movement Disorders Deep Brain Stimulation Group Hospital General Universitario Gregorio Marañón Madrid Spain.

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 ]).

Results: The mean reduction in FTM-TRS score was 73.4% at 6 months after VIM-DBS surgery ( < 0.001) and 50.1% at the last visit ( < 0.001). The gradual worsening of FTM-TRS scores over time fit a linear regression model (coefficient of determination [R] = 0.887; < 0.001). Stimulation adjustments to optimize tremor control required a statistically significant increase in voltage ( = 0.01), pulse width ( = 0.01), frequency ( = 0.02), and TEED ( = 0.008). TEED fit a third-order polynomial curve model throughout the follow-up period (R = 0.966; < 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.
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http://dx.doi.org/10.1002/mdc3.12337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178759PMC
March 2016

Paroxysmal Kinesigenic Dystonia in a Lesch-Nyhan Disease Variant.

Mov Disord Clin Pract 2014 Jun 23;1(2):123-124. Epub 2014 May 23.

Movement Disorders Unit Hospital General Universitario Gregorio Marañón Madrid Spain.

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http://dx.doi.org/10.1002/mdc3.12034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6183184PMC
June 2014

Subcutaneous infusions of apomorphine: a reappraisal of its therapeutic efficacy in advanced Parkinson's disease.

Expert Rev Neurother 2013 Dec 25;13(12):1343-53. Epub 2013 Oct 25.

Movement Disorders Research Unit, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain.

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.
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http://dx.doi.org/10.1586/14737175.2013.839235DOI Listing
December 2013

Peripheral neuropathy in Parkinson's disease: levodopa exposure and implications for duodenal delivery.

Parkinsonism Relat Disord 2013 May 27;19(5):501-7 ; discussion 501. Epub 2013 Feb 27.

Department of Neurology, St. Joseph Krankenhaus Berlin-Weißensee, Gartenstr. 1, 13088 Berlin, Germany.

In advanced Parkinson's disease (PD) patients, continuous intra-duodenal infusion of levodopa/carbidopa intestinal gel (LCIG) is an established approach in the management of motor complications that cannot be further improved by conventional oral therapy. In general, tolerability of LCIG has resembled that of oral dopaminergic therapy; however, cases of symptomatic peripheral neuropathy (PN), sometimes severe, have been reported in patients receiving LCIG. Cases are generally a sensorimotor polyneuropathy with both subacute and chronic onsets, often associated with vitamin B12 and/or B6 deficiency. Rare cases clinically resemble Guillain-Barré syndrome. In the absence of prospectively collected data on possible associations between LCIG and PN, it is prudent to explore potential mechanisms that may explain a possible relationship. The PN may be linked to use of high-dose levodopa, promoting high levels of homocysteine and methylmalonic acid or reduced absorption of vitamins essential for homocysteine metabolism. Cases of LCIG-associated PN often have responded to vitamin supplementation without need for LCIG cessation, although LCIG cessation is sometimes necessary. It may be advisable to monitor vitamin B12/B6 status before and after patients start LCIG and be vigilant for signs of PN. Prospective, large-scale, long-term studies are needed to clarify whether vitamin supplementation and routine use of a catechol-O-methyltransferase inhibitor may help prevent PN in LCIG recipients and whether these measures should be routine practice in patients with PD on high-dose oral levodopa.
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http://dx.doi.org/10.1016/j.parkreldis.2013.02.006DOI Listing
May 2013

[Levodopa in the treatment of Parkinson's disease: myths and realties].

Rev Neurol 2012 Dec;55(11):669-88

Servicios de Neurología, Clínica Universidad de Navarra, Pamplona, Navarra, España.

In recent years we have witnessed a growing tendency to opt for the use of dopamine agonists (DA) as treatment for Parkinson's disease (PD), with the aim of delaying as far as possible the development of fluctuations and dyskinesias. Yet, levodopa continues to be the most effective antiparkinson drug and is probably the one that improves the greatest number of symptoms of the disease. This article reports on the results of a comprehensive review of the literature dealing with the benefits and risks of levodopa treatment in patients with PD which was conducted by a group of expert neurologists and members of the Spanish Neurology Society's Movement Disorder Group. The main conclusion reached in this article is that levodopa continues to be the most effective treatment for PD. Although the risk and incidence of developing dyskinesias remains at a lower level in the group initially treated with DA, the number of patients who develop disabling dyskinesias is very low in all the studies and is similar for DA and for levodopa. Scores on the quality of life scales are also similar in the two groups, which casts some doubt on the impact that these motor complications have on the quality of life of patients with PD. In view of these findings, we should consider whether there is any real justification for depriving patients of the good control of their symptoms offered by levodopa owing to the fear of developing dyskinesias or mild motor fluctuations that are not really going to have any negative effect on their quality of life. There is also the possibility of their developing severe side effects, which are more frequent with the use of DA.
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December 2012

[Subcutaneous continuous apomorphine infusion: treatment initiation and follow up].

Rev Neurol 2012 ;55 Suppl 1:S21-4

Hospital General Universitario Gregorio Maranon, 28007 Madrid, Espana.

Continuous apomorphine infusion has been an established treatment for advanced Parkinson's disease for over two decades. This article reviews the different methods for starting treatment and propose a consensus methodology for it, as well as for the modification of prior treatment, in order to standardize and reduce the variability of clinical practice.
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August 2014

Risk factors for freezing of gait in Parkinson's disease.

J Neurol Sci 2012 Sep 15;320(1-2):66-71. Epub 2012 Jul 15.

Movement Disorders Research Unit, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

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.
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http://dx.doi.org/10.1016/j.jns.2012.06.018DOI Listing
September 2012

Risk of falls in Parkinson's disease: a cross-sectional study of 160 patients.

Parkinsons Dis 2012 15;2012:362572. Epub 2012 Jan 15.

Unidad de Investigación en Trastornos del Movimiento, Instituto de Investigación Sanitaria Hospital Gregorio Marañón, 28007 Madrid, Spain.

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.
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http://dx.doi.org/10.1155/2012/362572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265111PMC
August 2012

Dopamine dysregulation syndrome and deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

Neurol Res Int 2011 2;2011:759895. Epub 2011 Nov 2.

Movement Disorders Research Unit, Hospital Universitario Gregorio Marañón, 28007 Madrid, Spain.

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.
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http://dx.doi.org/10.1155/2011/759895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216377PMC
August 2012

Dopamine dysregulation syndrome after deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

J Neurol Sci 2012 Jan 27;312(1-2):191-3. Epub 2011 Aug 27.

Movement Disorders Research Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

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.
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http://dx.doi.org/10.1016/j.jns.2011.08.014DOI Listing
January 2012

Hemiballismus.

Handb Clin Neurol 2011 ;100:249-60

Department of Neurology, Hospital Universitario Gregorio Marañón and Parkinson's Disease and Movement Disorders Unit, Hospital Beata Maria Ana, Madrid, Spain.

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.
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http://dx.doi.org/10.1016/B978-0-444-52014-2.00017-3DOI Listing
July 2011