RESUMEN
INTRODUCTION: The aims of this study were to validate the French version of the SCales for Outcomes in Parkinson's Disease-PsychoSocial (SCOPA-PS) in individuals with Parkinson's disease (PD) who underwent deep brain stimulation of the subthalamic nucleus (DBS-STN), to confirm the unifactorial structure of this questionnaire, and to establish its psychometric properties. METHODS: Routinely used psychological questionnaires (BDI-II, STAI-Y, PDQ-39, UPDRS III) and the SCOPA-PS were used for a cross-sectional observational study of 154 PD patients. SCOPA-PS acceptability, scaling assumption, reliability, ordinal confirmatory factor analysis and validity were assessed. RESULTS: The ICC for two-week test-retest reliability was 0.88. SEM was 8.42. In confirmatory factor analysis, the one-factor model showed an acceptable fit to the data (Chi(2)/df=2.130; CFI=0.976; RMSEA=0.086). No floor or ceiling effects were observed. Skewness was 0.33. Item-total correlation coefficients ranged from 0.47 to 0.71. Cronbach's alpha was 0.86. SCOPA-PS SI correlated with PDQ-39 SI (rs=0.83) and with state-anxiety and depression (rs=0.56 and 0.69 respectively). The SCOPA-PS SI was higher in more depressed patients and in those with the most severe PD motor symptoms. CONCLUSION AND DISCUSSION: SCOPA-PS French version is a one-factor scale with satisfactory psychometric properties consistent with other language versions. This short scale can be used to evaluate the psychosocial component of QoL in PD patients treated with DBS-STN.
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Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/psicología , Escalas de Valoración Psiquiátrica , Calidad de Vida , Anciano , Estudios Transversales , Femenino , Francia , Humanos , Lenguaje , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Escalas de Valoración Psiquiátrica/normas , Psicometría , Reproducibilidad de los Resultados , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios/normasAsunto(s)
Centros Médicos Académicos , COVID-19/transmisión , Infección Hospitalaria/diagnóstico , Anciano , COVID-19/prevención & control , Prueba de COVID-19 , Infección Hospitalaria/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Paris/epidemiología , Factores de Riesgo , SARS-CoV-2RESUMEN
BACKGROUND: The global healthcare system has been overwhelmed by the Coronavirus disease-2019 (COVID-19). In order to mitigate the risk of spread of the virus, most elective surgical procedures have been cancelled especially during the lockdown periods. The purpose of this study was to assess the financial impact of the COVID outbreak due to the supposed reduced workload from our neurosurgery department in 2020. METHODS: Number of neurosurgical procedures (NSP) within the Department of Neurosurgery and their associated estimated income were retrospectively reviewed globally and month wise from administrative records of billing in 2020 and 2019 based on the Diagnosis related group (DRG) and severity of illness (4 levels). RESULTS: Overall, 824 and 818 inpatient surgical procedures were performed in 2019 and 2020 respectively. The total estimate revenue generated from inpatient surgeries was moderately decreased (3%): 9 498 226.41 euros in 2020 versus 9 817 361.65 euros in 2019 without significant difference across DRG (P=0.96) and severity of illness. CONCLUSIONS: Our data suggests a moderate negative impact of the COVID-19 pandemic had on neurosurgical and financial activity. However, a more in-depth medico-economic analysis need to be performed to assess the real financial impact.
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COVID-19 , Neurocirugia , COVID-19/epidemiología , Control de Enfermedades Transmisibles , Humanos , Procedimientos Neuroquirúrgicos , Pandemias , Estudios RetrospectivosRESUMEN
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7-Nitroindazole (7-NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS) that blocks MPTP neurotoxicity in mice. We now show that 7-NI protects against profound striatal dopamine depletions and loss of tyrosine hydroxylase-positive neurons in the substantia nigra in MPTP-treated baboons. Furthermore, 7-NI protected against MPTP-induced motor and frontal-type cognitive deficits. These results strongly implicate a role of nitric oxide in MPTP neurotoxicity and suggest that inhibitors of neuronal NOS might be useful in treating Parkinson's disease.
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Inhibidores Enzimáticos/farmacología , Indazoles/farmacología , Neuronas/enzimología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Modelos Animales de Enfermedad , Dopamina/metabolismo , Ácido Homovanílico/metabolismo , Hipocinesia , Masculino , Actividad Motora , Examen Neurológico , Neuronas/efectos de los fármacos , Óxido Nítrico Sintasa/metabolismo , Papio , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/enzimología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/enzimología , Grabación de Cinta de VideoRESUMEN
Substitutive therapy using fetal striatal grafts in animal models of Huntington disease (HD) have already demonstrated obvious beneficial effects on motor indices. Using a new phenotypic model of HD recently designed in primates, we demonstrate here complete and persistent recovery in a frontal-type cognitive task two to five months after intrastriatal allografting. The striatal allografts also reduce the occurrence of dystonia, a major abnormal movement associated with HD. These results show the capacity of fetal neurons to provide a renewed substrate for both cognitive and motor systems in the lesioned adult brain. They also support the use of neural transplantation as a potential therapy for HD.
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Trasplante de Tejido Encefálico , Cognición , Cuerpo Estriado/trasplante , Trasplante de Tejido Fetal , Enfermedad de Huntington/psicología , Enfermedad de Huntington/cirugía , Animales , Apomorfina/farmacología , Cuerpo Estriado/fisiología , Enfermedad de Huntington/inducido químicamente , Macaca fascicularis , Imagen por Resonancia Magnética , Actividad Motora/efectos de los fármacos , Nitrocompuestos , Propionatos , Trasplante HomólogoRESUMEN
Lentiviral delivery of glial cell line-derived neurotrophic factor (lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.
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Dihidroxifenilalanina/análogos & derivados , Dopamina/metabolismo , Terapia Genética , Degeneración Nerviosa/prevención & control , Factores de Crecimiento Nervioso , Proteínas del Tejido Nervioso/genética , Enfermedad de Parkinson/terapia , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Envejecimiento , Animales , Antígenos CD/análisis , Dihidroxifenilalanina/metabolismo , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Vectores Genéticos , Factor Neurotrófico Derivado de la Línea Celular Glial , Lentivirus/genética , Macaca mulatta , Neostriado/metabolismo , Neostriado/patología , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/uso terapéutico , Neuronas/enzimología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , Trastornos Parkinsonianos/terapia , Desempeño Psicomotor , Sustancia Negra/metabolismo , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The survival outcome of patients suffering from gliomas is directly linked to the complete surgical resection of the tumour. To help the surgeons to delineate precisely the boundaries of the tumour, we developed an intraoperative positron probe with background noise rejection capability. The probe was designed to be directly coupled to the excision tool such that detection and removal of the radiolabelled tumours could be simultaneous. The device consists of two exchangeable detection heads composed of clear and plastic scintillating fibres. Each head is coupled to an optic fibre bundle that exports the scintillating light to a photodetection and processing electronic module placed outside the operative wound. The background rejection method is based on a real-time subtraction technique. The measured probe sensitivity for (18)F was 1.1 cps kBq(-1) ml(-1) for the small head and 3.4 cps kBq(-1) ml(-1) for the large head. The mean spatial resolution was 1.6 mm FWHM on the detector surface. The gamma-ray rejection efficiency measured by realistic brain phantom modelling of the surgical cavity was 99.4%. This phantom also demonstrated the ability of the probe to detect tumour discs as small as 5 mm in diameter (20 mg) for tumour-to-background ratios higher than 3:1 and with an acquisition time around 4 s at each scanning step. These results indicate that our detector could be a useful complement to existing techniques for the accurate excision of brain tumour tissue and more generally to improve the efficiency of radio-guided cancer surgery.
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Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/cirugía , Aumento de la Imagen/instrumentación , Tomografía de Emisión de Positrones/instrumentación , Cirugía Asistida por Computador/instrumentación , Transductores , Diseño de Equipo , Análisis de Falla de Equipo , Humanos , Miniaturización , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Integración de SistemasRESUMEN
A higher than expected frequency of suicide has been reported among patients undergoing subthalamic nucleus deep brain stimulation (STN DBS) for advanced Parkinson's disease (PD). We conducted a retrospective survey of 200 patients with PD who underwent STN DBS. Two patients (1%) committed suicide and four (2%) attempted suicide, despite clear motor improvements. Suicidal patients did not differ from non-suicidal patients with respect to age, disease duration or preoperative depressive and cognitive status. Suicidal behaviour was associated with postoperative depression and/or altered impulse regulation. Suicidal behaviour is a potential hazard of STN DBS, calling for careful preoperative assessment and close postoperative psychiatric and behavioural follow-up.
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Estimulación Encefálica Profunda/efectos adversos , Enfermedad de Parkinson/mortalidad , Enfermedad de Parkinson/terapia , Complicaciones Posoperatorias/mortalidad , Núcleo Subtalámico/fisiopatología , Intento de Suicidio/estadística & datos numéricos , Suicidio/estadística & datos numéricos , Anciano , Causas de Muerte , Estudios de Cohortes , Estudios Transversales , Estimulación Encefálica Profunda/mortalidad , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/mortalidad , Trastorno Depresivo/fisiopatología , Trastornos Disruptivos, del Control de Impulso y de la Conducta/diagnóstico , Trastornos Disruptivos, del Control de Impulso y de la Conducta/mortalidad , Trastornos Disruptivos, del Control de Impulso y de la Conducta/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Destreza Motora/fisiología , Examen Neurológico , Pruebas Neuropsicológicas , Enfermedad de Parkinson/fisiopatología , Inventario de Personalidad , Complicaciones Posoperatorias/fisiopatología , Resultado del TratamientoRESUMEN
The use of optogenetics or photobiomodulation in non-human primate (NHP) requires the ability to noninvasively stimulate large and deep cortical brain tissues volumes. In this context, the optical and geometrical parameters of optodes are critical. Methods and general guidelines to optimize these parameters have to be defined. OBJECTIVE: We propose the design of an optode for safe and efficient optical stimulation of a large volume of NHP cortex, down to 3-5 mm depths without inserting fibers into the cortex. APPROACH: Monte Carlo simulations of optical and thermal transport have been carried out using the Geant4 application for tomographic emission (GATE) platform. Parameters such as the fiber diameter, numerical aperture, number of fibers and their geometrical arrangement have been studied. Optimal hardware parameters are proposed to obtain homogeneous fluence above the fluence threshold for opsin activation without detrimental thermal effects. MAIN RESULTS: The simulations show that a large fiber diameter and a large numerical aperture are preferable since they allow limiting power concentration and hence the resulting thermal increases at the brain surface. To obtain a volume of 200-500 mm3 of brain tissues receiving a fluence above the opsin activation threshold for optogenetics or below a phototocixity threshold for photobiomodulation, a 4 fibers configuration is proposed. The optimal distance between the fibers was found to be 4 mm. A practical implementation of the optode has been performed and the corresponding fluence and thermal maps have been simulated. SIGNIFICANCE: The present study defines a method to optimize the design of optode and the choice of stimulation parameters for optogenetics and more generally light delivery to deep and large volumes of tissues in NHP brain with a controlled irradiance dosimetry. The general guidelines are the use of silica fibers with a large numerical aperture and a large diameter. The combination of several fibers is required if large volumes need to be stimulated while avoiding thermal effects.
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Corteza Cerebral/fisiología , Optogenética/instrumentación , Estimulación Luminosa/instrumentación , Primates/fisiología , Animales , Simulación por Computador , Calor , Fibras Minerales , Método de Montecarlo , Corteza Motora/fisiología , Opsinas/metabolismo , Optogenética/métodos , Estimulación Luminosa/métodos , Estimulación FísicaRESUMEN
Dissecting neural circuitry in non-human primates (NHP) is crucial to identify potential neuromodulation anatomical targets for the treatment of pharmacoresistant neuropsychiatric diseases by electrical neuromodulation. How targets of deep brain stimulation (DBS) and cortical targets of transcranial magnetic stimulation (TMS) compare and might complement one another is an important question. Combining optogenetics and tractography may enable anatomo-functional characterization of large brain cortico-subcortical neural pathways. For the proof-of-concept this approach was used in the NHP brain to characterize the motor cortico-subthalamic pathway (m_CSP) which might be involved in DBS action mechanism in Parkinson's disease (PD). Rabies-G-pseudotyped and Rabies-G-VSVg-pseudotyped EIAV lentiviral vectors encoding the opsin ChR2 gene were stereotaxically injected into the subthalamic nucleus (STN) and were retrogradely transported to the layer of the motor cortex projecting to STN. A precise anatomical mapping of this pathway was then performed using histology-guided high angular resolution MRI tractography guiding accurately cortical photostimulation of m_CSP origins. Photoexcitation of m_CSP axon terminals or m_CSP cortical origins modified the spikes distribution for photosensitive STN neurons firing rate in non-equivalent ways. Optogenetic tractography might help design preclinical neuromodulation studies in NHP models of neuropsychiatric disease choosing the most appropriate target for the tested hypothesis.
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Conectoma , Red Nerviosa/anatomía & histología , Red Nerviosa/fisiología , Optogenética/métodos , Potenciales de Acción , Animales , Genes Reporteros , Vectores Genéticos , Lentivirus/genética , Macaca mulatta , Imagen por Resonancia Magnética , Masculino , Corteza Motora/anatomía & histología , Corteza Motora/fisiología , Opsinas/análisis , Opsinas/genética , Núcleo Subtalámico/anatomía & histología , Núcleo Subtalámico/fisiología , Transducción GenéticaRESUMEN
OBJECTIVE: Pain management in patients having a subarachnoid haemorrhage was assessed in French intensive care unit of neurosurgical centres. STUDY DESIGN: Nationwide survey. METHODS: A standardized postal questionnaire was sent to senior doctor of every neurosurgical centres in France inquiring pain scores assessment, analgesics used and their routes of administration, centre's opinion about efficacy of pain management. RESULTS: Of the 34 centres, 24 returned completed questionnaires. Fifty four per cent of the centres evaluated pain intensity with a non valid pain score. In the case of patients in the comatose, pain was not evaluated in fifty four per cent of the centres. Paracetamol and morphine were the most currently used analgesics drugs. Morphine was administered subcutaneously by 75% of the centres. Six centres used also PCA. Thirty-seven percent of the centres were reluctant to use opioids and 75% to use NSAIDS. CONCLUSION: The majority of the centres considered pain management in patient suffering from subarachnoid haemorrhage (SAH) was not optimal and stressed the need to establish a well validated pain rating scale dedicated to SAH patients.
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Analgésicos/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/etiología , Hemorragia Subaracnoidea/fisiopatología , Antiinflamatorios no Esteroideos/uso terapéutico , Francia , Encuestas Epidemiológicas , Humanos , Morfina/uso terapéutico , Narcóticos/uso terapéutico , Dimensión del DolorRESUMEN
Huntington's disease (HD) is an inherited disorder characterized by cognitive impairments, motor deficits, and progressive dementia. These symptoms result from progressive neurodegenerative changes mainly affecting the neostriatum. This pathology is fatal in 10 to 20 years and there is currently no treatment for HD. Early in the course of the disease, initial clinical manifestations are due to striatal neuronal dysfunction, which is later followed by massive neuronal death. A major therapeutic objective is therefore to reverse striatal dysfunction prior to cell death. Using a primate model reproducing the clinical features and the progressive neuronal degeneration typical of HD, we tested the therapeutic effects of direct intrastriatal infusion of ciliary neurotrophic factor (CNTF). To achieve a continuous delivery of CNTF over the full period of evaluation, we took advantage of the macroencapsulation technique. Baby hamster kidney (BHK) cells previously engineered to produce human CNTF were encapsulated into semipermeable membranes and implanted bilaterally into striata. We show here that intracerebral delivery of low doses of CNTF at the onset of symptoms not only protects neurons from degeneration but also restores neostriatal functions. CNTF-treated primates recovered, in particular, cognitive and motor functions dependent on the anatomofunctional integrity of frontostriatal pathways that were distinctively altered in this HD model. These results support the hypothesis that CNTF infusion into the striatum of HD patients not only could block the degeneration of neurons but also alleviated motor and cognitive symptoms associated with persistent neuronal dysfunction.
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Encéfalo/patología , Factor Neurotrófico Ciliar/genética , Terapia Genética/métodos , Enfermedad de Huntington/terapia , Animales , Encéfalo/metabolismo , Calbindinas , Línea Celular , Factor Neurotrófico Ciliar/administración & dosificación , Convulsivantes/farmacología , Cricetinae , Modelos Animales de Enfermedad , Femenino , Vectores Genéticos , Humanos , Inmunohistoquímica , Macaca fascicularis , Imagen por Resonancia Magnética , Destreza Motora , Manifestaciones Neuroconductuales , Nitrocompuestos , Propionatos/farmacología , Putamen/metabolismo , Ratas , Proteína G de Unión al Calcio S100/metabolismo , Succinato Deshidrogenasa/metabolismo , Factores de Tiempo , Transfección , TransgenesRESUMEN
Huntington's disease (HD) is a monogenic neurodegenerative disease that affects the efferent neurons of the striatum. The protracted evolution of the pathology over 15 to 20 years, after clinical onset in adulthood, underscores the potential of therapeutic tools that would aim at protecting striatal neurons. Proteins with neuroprotective effects in the adult brain have been identified, among them ciliary neurotrophic factor (CNTF), which protected striatal neurons in animal models of HD. Accordingly, we have carried out a phase I study evaluating the safety of intracerebral administration of this protein in subjects with HD, using a device formed by a semipermeable membrane encapsulating a BHK cell line engineered to synthesize CNTF. Six subjects with stage 1 or 2 HD had one capsule implanted into the right lateral ventricle; the capsule was retrieved and exchanged for a new one every 6 months, over a total period of 2 years. No sign of CNTF-induced toxicity was observed; however, depression occurred in three subjects after removal of the last capsule, which may have correlated with the lack of any future therapeutic option. All retrieved capsules were intact but contained variable numbers of surviving cells, and CNTF release was low in 13 of 24 cases. Improvements in electrophysiological results were observed, and were correlated with capsules releasing the largest amount of CNTF. This phase I study shows the safety, feasibility, and tolerability of this gene therapy procedure. Heterogeneous cell survival, however, stresses the need for improving the technique.
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Terapia Genética/métodos , Enfermedad de Huntington/genética , Enfermedad de Huntington/terapia , Fármacos Neuroprotectores/farmacología , Animales , Encéfalo/metabolismo , Línea Celular , Supervivencia Celular , Factor Neurotrófico Ciliar/química , Factor Neurotrófico Ciliar/genética , Codón , Cricetinae , Electrofisiología , Femenino , Técnicas de Transferencia de Gen , Humanos , Masculino , Neuronas/metabolismo , Polímeros/química , Retroviridae/genética , Factores de TiempoRESUMEN
The neuroprotective properties of cyclosporin A (CsA) are mediated by its ability to prevent mitochondrial permeability transition during exposure to high levels of calcium or oxidative stress. By using the mitochondrial toxin 3-nitropropionic acid (3NP), the present study assessed whether CsA could protect striatal neurons in vitro and in vivo. In vitro, 3NP produced a 20-30% reduction of striatal glutamic acid decarboxylase-immunoreactive (GAD-ir) neurons. A single treatment with CsA protected GAD-ir neurons from 3NP toxicity at lower (0.2 or 1.0 microM), but not at higher (5.0 microM) doses. Similar findings were seen when the cultures were treated twice with cyclosporin. In vivo experiments used the Lewis rat model of Huntington's disease (HD) in which a low 3NP dose was delivered subcutaneously through an osmotic minipump. Rats received unilateral or bilateral intrastriatal saline injections to disrupt the blood-brain barrier (BBB) and facilitate CsA reaching vulnerable neurons. In the first experiment, CsA treated 3NP-lesioned rats displayed significantly more dopamine-and adenosine-3;, 5;-monophosphate-regulated phosphoprotein (DARPP32-ir) neurons ipsilateral to BBB disruption compared to the contralateral intact striatum, indicating that disruption of the BBB maybe necessary for CsA's neuroprotective effects. In the second experiment, stereological counts of DARPP32-ir neurons revealed that CsA protected striatal neurons in a dose-dependent manner following bilateral disruption of the striatal BBB. Rats treated with the higher (15 or 20 mg/kg) but not lower (5 mg/kg) doses of CsA displayed greater numbers of DARRP32-ir striatal neurons relative to vehicle-treated 3NP-lesioned rats. Thus, under conditions in which CsA can gain access to striatal neurons, significant protection from 3NP toxicity is observed. Therefore, CsA or more lipophilic analogues of this compound, may be of potential therapeutic benefit by protecting vulnerable neurons from the primary pathological event observed in HD.
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Cuerpo Estriado/efectos de los fármacos , Ciclosporina/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Propionatos/toxicidad , Ratas/fisiología , Animales , Muerte Celular/efectos de los fármacos , Células Cultivadas , Cuerpo Estriado/citología , Embrión de Mamíferos , Masculino , Nitrocompuestos , Ratas Endogámicas F344 , Ratas Endogámicas LewRESUMEN
The putative neuroprotective effect of riluzole was investigated in a rat model of progressive striatal neurodegeneration induced by prolonged treatment (three weeks, intraperitoneal) with 3-nitropropionic acid, an irreversible inhibitor of succinate dehydrogenase. Quantitative analysis of motor behaviour indicated a significant protective effect (60%) of riluzole (8 mg/kg/day) on 3-nitropropionic acid-induced motor deficits as assessed using two independent motor tests. Furthermore, quantitative analysis of 3-nitropropionic acid-induced lesions indicated a significant 84% decrease in the volume of striatal damage produced by 3-nitropropionic acid, the neuroprotective effect apparently being more pronounced in the posterior striatum and pallidum. In addition, it was checked that this neuroprotective effect of riluzole against systemic 3-nitropropionic acid did not result from a decreased bioavailability of the neurotoxin or a direct action of riluzole on 3-nitropropionic acid-induced inhibition of succinate dehydrogenase. We found that riluzole significantly decreased by 48% the size of striatal lesions produced by stereotaxic intrastriatal injection of malonate, a reversible succinate dehydrogenase inhibitor. Furthermore, the inhibition of cortical and striatal succinate dehydrogenase activity induced by systemic 3-nitropropionic acid was left unchanged by riluzole administration. The present results, consistent with a beneficial effect of riluzole in amyotrophic lateral sclerosis, suggest that this compound may be useful in the treatment of chronic neurodegenerative diseases.
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Antihipertensivos/toxicidad , Cuerpo Estriado/fisiopatología , Trastornos del Movimiento/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Propionatos/toxicidad , Riluzol/farmacología , Animales , Cuerpo Estriado/patología , Inyecciones Intraperitoneales , Masculino , Malonatos/toxicidad , Microinyecciones , Trastornos del Movimiento/mortalidad , Neurotoxinas/toxicidad , Nitrocompuestos , Ratas , Ratas Sprague-Dawley , Succinato Deshidrogenasa/antagonistas & inhibidores , Análisis de SupervivenciaRESUMEN
Impairment in energy metabolism is thought to be involved in the aetiology of Huntington's disease. In line with this hypothesis, chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid to rats and monkeys produces selective striatal lesions similar to Huntington's disease. The present study examined whether rats treated with varying regimen of 3-nitropropionic acid could present motor abnormalities reminiscent of Huntington's disease symptomatology, correlated with Huntington's disease specific striatal symptomatology. Subacute 3-nitropropionic acid treatment (15 mg/kg per day intraperitoneally for 10 days) produced dramatic motor symptoms associated with extensive neuronal loss and gliosis in the lateral striatum as well as severe hippocampal degeneration in 50% of the cases. In contrast, chronic 3-nitropropionic acid treatment (10 mg/kg per day subcutaneously for one month) led to more subtle excitotoxic-like lesions, selective for the dorsolateral striatum and more closely resembling Huntington's disease striatal pathology. Animals with these Huntington's disease-like lesions showed spontaneous motor symptoms including mild dystonia, bradykinesia and gait abnormalities, which were barely detectable on visual inspection but could be readily identified and quantified by computerized video analysis. In these chronic animals, the degree of striatal neuronal loss was significantly correlated with the severity of spontaneous motor abnormalities, as is the case in Huntington's disease. The present study demonstrates that chronic low-dose 3-nitropropionic acid treatment in rats results in a valuable model of both the histological features and motor deficits which occur in Huntington's disease. Despite the interanimal variability in terms of response to 3-nitropropionic acid treatment, this rat model may be particularly useful for evaluating the functional benefits of new therapeutic strategies for Huntington's disease, particularly those aiming to reduce the severity of motor symptoms.
Asunto(s)
Cuerpo Estriado/patología , Marcha/efectos de los fármacos , Enfermedad de Huntington/patología , Actividad Motora/efectos de los fármacos , Trastornos del Movimiento/fisiopatología , Propionatos/toxicidad , Análisis de Varianza , Animales , Cuerpo Estriado/efectos de los fármacos , Dihidrolipoamida Deshidrogenasa/análisis , Esquema de Medicación , Proteína Ácida Fibrilar de la Glía/análisis , Haplorrinos , Enfermedad de Huntington/inducido químicamente , Enfermedad de Huntington/fisiopatología , Masculino , Actividad Motora/fisiología , Trastornos del Movimiento/patología , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/patología , Neurotoxinas/toxicidad , Nitrocompuestos , Ratas , Ratas Sprague-Dawley , Valores de ReferenciaRESUMEN
The caudate nucleus and putamen form part of a complex but topographically connected circuitry that links the cortex, the basal ganglia and the thalamus. Within this complex system lie a series of functionally and anatomically segregated loops that allow the concurrent processing of a wide range of cognitive and motor information (Alexander et al., 1986; Alexander and Crutcher, 1990). As a constituent of these loops it has been shown that the striatum is involved in movement initiation, response selection and attentional processes (Robbins and Brown, 1990; Alexander, 1994; Lawrence et al., 1998). Although it is the medium spiny GABAergic projection neurones that are primarily lost in HD, it is not sufficient merely to replace the GABA. Instead it is crucial for striatal tissue transplants to integrate with the host tissue in such a way that the cortico-striatal-thalamic circuitry is restored and is functional. Rodent studies have progressed a long way in establishing the principle that striatal grafts can, at least partially, restore function and integrate appropriately with the host (Dunnett and Svendsen, 1993; Björklund et al., 1994; Sanberg et al., 1998) but the limited behavioural repertoire and the undifferentiated striatum meant that it was inevitable that studies should progress into primate models. Anatomical tracing studies have demonstrated that motor, premotor and somatosensory cortical areas send corticostriatal projections primarily to the putamen region in primates, whereas the head and body of the caudate nucleus mostly receive efferent input from associative cortical areas (Kemp and Powell, 1970; Kunzle, 1975, 1977, 1978; Selemon and Goldman-Rakic, 1985). Based on such anatomical, and functional, studies Alexander and colleagues have proposed the existence of at least five cortico-striatal-thalamic loops including a motor, a dorsolateral-prefrontal and an orbito-frontal loop (Alexander et al., 1986). The concentration of motor inputs to the putamen region suggests a particular involvement of this structure in the motor loop. Indeed, unilateral lesions of the putamen disrupt motor performance in the marmoset and generate apomorphine-induced dyskinesias in larger primates (Burns et al., 1995; Kendall et al., 2000). The implantation of striatal grafts into marmosets that had previously received unilateral putamen lesions ameliorated some of the motor impairments, which suggested at least partial restoration of the motor loop. In support of this we found direct evidence of host-graft cortico-striatal connectivity using an anterograde tracer injected in the primary motor cortical region (Kendall et al., 1998a). In larger primates, with lesions of the caudate and putamen, striatal [figure: see text] allografts and xenografts have been shown to reduce apomorphine-induced dyskinesias (Isacson et al., 1989; Hantraye et al., 1992; Palfi et al., 1998). The mechanism by which dyskinesias are elicited is not fully understood but alterations in firing patterns within both segments of the globus pallidus have been identified during dyskinetic movements (Matsumura et al., 1995). It seems likely that it would actually require re-establishment of afferent connections between the implanted putamen and the globus pallidus as well as of functioning dopamine receptors within the graft for the reduction in the dyskinetic profile to be observed. Certainly there is evidence, from rodent studies and the marmoset study described here, that close proximity of the graft to the globus pallidus yields better functional recovery (Isacson et al., 1986). In addition, anatomical tracing studies in rats have demonstrated connections between the implanted tissue and the host globus pallidus (Wictorin et al., 1989b, 1990) However, the relationship between graft placement and functional recovery remains to be fully substantiated.
Asunto(s)
Trasplante de Tejido Encefálico/tendencias , Modelos Animales de Enfermedad , Enfermedad de Huntington/cirugía , Neostriado/trasplante , Primates/cirugía , Animales , Lesiones Encefálicas/inducido químicamente , Trasplante de Tejido Encefálico/métodos , Callithrix/anatomía & histología , Callithrix/fisiología , Callithrix/cirugía , Desnervación/efectos adversos , Desnervación/métodos , Evaluación de la Discapacidad , Supervivencia de Injerto/fisiología , Humanos , Enfermedad de Huntington/patología , Enfermedad de Huntington/fisiopatología , Macaca/anatomía & histología , Macaca/fisiología , Macaca/cirugía , Neostriado/patología , Neostriado/fisiopatología , Neostriado/cirugía , Neurotoxinas/efectos adversos , Primates/anatomía & histología , Primates/fisiología , Putamen/efectos de los fármacos , Putamen/fisiopatología , Putamen/cirugía , Recuperación de la Función/fisiología , Resultado del TratamientoRESUMEN
Since its description by Dandy in 1922, several techniques have been used to perform third ventriculostomy under endoscopic control. Except for the blunt technique, in which the endoscope is used by itself to create the opening in the floor of the third ventricle, the other techniques require more than one instrument to perforate the floor of the ventricle and enlarge the ventriculostomy. The new device described is a sterilizable modified forceps that allows both the opening of the floor and the enlargement of the ventriculostomy in a simple and effective way. The new device has the following characteristics: 1) the tip of the forceps is thin enough to allow the easy perforation of the floor of the ventricle; 2) the inner surface of the jaws is smooth to avoid catching vessels of the basal cistern; and 3) the outer surface of the jaws has indentations that catch the edges of the opening to prevent them from slipping along the instrument's jaws. The ventricle floor is opened by gentle pressure of the forceps, which is slowly opened so that the edges of the aperture are caught by the distal outer indentation of the jaws, leading to an approximately 4-mm opening of the floor. This device has been used successfully in 10 consecutive patients. This new device allows surgeons to perform third ventriculostomy under endoscopic control in a very simple, quick, and effective way, avoiding the need for additional single-use instruments.
Asunto(s)
Endoscopios , Endoscopía/métodos , Hidrocefalia/cirugía , Tercer Ventrículo/cirugía , Diseño de Equipo , Humanos , Procedimientos Neuroquirúrgicos/instrumentación , Procedimientos Neuroquirúrgicos/métodos , Instrumentos QuirúrgicosRESUMEN
The simultaneous occurrence of multiple sclerosis and transverse myelitis is known in the literature. Apart from the spinal symptoms, other neurological signs of brain involvement are usually found and magnetic resonance imaging (MRI) reveals disseminated foci in the brain. The positive evoked responses, the immunological abnormalities of the cerebrospinal fluid (CSF), and the oligoclonality together prove the presence of multiple sclerosis. In these cases the symptoms of transverse myelitis can separately precede other signs of multiple sclerosis, or appear as a relapse. Recurrent transverse myelitis as an independent entity, with negative MRI and CSF immunology, is an exciting topic in terms of the etiological factors and therapeutic considerations. The view in the literature is that the occurrence of transverse myelitis as an independent entity is rather rare. The present article reports the case of a female patient with recurrent spinal cord signs, and negative MRI and CSF immunology. During a ten-year follow-up observation period, symptoms of multiple sclerosis did not develop. Further studies of such cases are needed in order to clarify the etiological factors, the pathomechanism and the therapeutic considerations relating to this relatively new and probably independent clinical entity.
Asunto(s)
Esclerosis Múltiple/diagnóstico , Mielitis Transversa/diagnóstico , Adulto , Encéfalo/fisiología , Diagnóstico Diferencial , Potenciales Evocados Somatosensoriales , Potenciales Evocados Visuales , Resultado Fatal , Femenino , Humanos , Imagen por Resonancia Magnética , Esclerosis Múltiple/líquido cefalorraquídeo , Mielitis Transversa/líquido cefalorraquídeo , Mielitis Transversa/fisiopatología , Recurrencia , Médula Espinal/fisiopatologíaRESUMEN
Botulinum toxin produces a transient presynaptic focal block at the neuromuscular junction. Thus it induces muscle weakness which has a significant beneficial effect on hemifacial spasm. Fifty-four patients were treated and received at least 2 and at the most 22 consecutive injections over a 5-year period. Injections were repeated every 9 weeks on average. The interval between injections corresponded to the time elapsed between the last injection and the re-emergence of spasms. Nineteen patients abandoned the treatment for various reasons. The most frequent side-effect was a ptosis which was observed in 1 out of 6 injections. Ptosis is due to diffusion of the botulinum toxin over a territory larger than expected. The results obtained in 42 patients were analyzed: there was no effect in 7 patients (17%); 11 patients improved by less than 50%; 13 by 50 to 70% and 11 more than 75%.