Ictus isquémico e infección por SARS-CoV-2, ¿asociación casual o causal? / Ischaemic stroke and SARS-CoV-2 infection: A causal or incidental association?

INTRODUCCIÓN: Se ha comunicado la asociación de ictus isquémico y COVID-19, con mayor frecuencia en aquellos pacientes más graves. Sin embargo, se desconoce en qué medida podría estar en relación con la inflamación sistémica y la hipercoagulabilidad producidas en el contexto de la infección. MÉTODOS: Descripción de 4 pacientes atendidos en nuestro centro por ictus isquémico y diagnóstico de COVID-19, clasificándolos según el grado de probabilidad causal entre el estado de hipercoagulabilidad y el ictus isquémico. Revisión de la literatura sobre los posibles mecanismos implicados en la etiopatogenia del ictus isquémico en este contexto. RESULTADOS: Dos pacientes se consideraron con alta probabilidad causal: presentaban infartos corticales, sin enfermedad cardioembólica ni arterial significativa, con parámetros de inflamación sistémica e hipercoagulabilidad; las otras 2 pacientes eran de edad avanzada y el ictus isquémico se consideró cardioembólico, con una probable asociación casual de COVID-19. CONCLUSIONES: La inflamación sistémica, junto con la posible acción directa del virus, provocaría disfunción endotelial, generando un estado de hipercoagulabilidad que podría considerarse una causa potencial de ictus isquémico. Sin embargo, puesto que los mecanismos del ictus pueden ser múltiples, se precisan estudios más amplios que evalúen esta hipótesis. Mientras tanto, el estudio etiológico del ictus en pacientes con COVID-19 debe ser sistemático atendiendo a los protocolos vigentes, con las adaptaciones necesarias en relación con las circunstancias clínicas y epidemiológicas de la actual pandemia

INTRODUCTION: Ischaemic stroke has been reported in patients with COVID-19, particularly in more severe cases. However, it is unclear to what extent this is linked to systemic inflammation and hypercoagulability secondary to the infection. METHODS: We describe the cases of 4 patients with ischaemic stroke and COVID-19 who were attended at our hospital. Patients are classified according to the likelihood of a causal relationship between the hypercoagulable state and ischaemic stroke. We also conducted a review of studies addressing the possible mechanisms involved in the aetiopathogenesis of ischaemic stroke in these patients. RESULTS: The association between COVID-19 and stroke was probably causal in 2 patients, who presented cortical infarcts and had no relevant arterial or cardioembolic disease, but did show signs of hypercoagulability and systemic inflammation in laboratory analyses. The other 2 patients were of advanced age and presented cardioembolic ischaemic stroke; the association in these patients was probably incidental. CONCLUSIONS: Systemic inflammation and the potential direct action of the virus may cause endothelial dysfunction, resulting in a hypercoagulable state that could be considered a potential cause of ischaemic stroke. However, stroke involves multiple pathophysiological mechanisms; studies with larger samples are therefore needed to confirm our hypothesis. The management protocol for patients with stroke and COVID-19 should include a complete aetiological study, with the appropriate safety precautions always being observed

Ischaemic stroke and SARS-CoV-2 infection: A causal or incidental association? / Ictus isquémico e infección por SARS-CoV-2, ¿asociación casual o causal?

INTRODUCTION: Ischaemic stroke has been reported in patients with COVID-19, particularly in more severe cases. However, it is unclear to what extent this is linked to systemic inflammation and hypercoagulability secondary to the infection. METHODS: We describe the cases of 4 patients with ischaemic stroke and COVID-19 who were attended at our hospital. Patients are classified according to the likelihood of a causal relationship between the hypercoagulable state and ischaemic stroke. We also conducted a review of studies addressing the possible mechanisms involved in the aetiopathogenesis of ischaemic stroke in these patients. RESULTS: The association between COVID-19 and stroke was probably causal in 2 patients, who presented cortical infarcts and had no relevant arterial or cardioembolic disease, but did show signs of hypercoagulability and systemic inflammation in laboratory analyses. The other 2 patients were of advanced age and presented cardioembolic ischaemic stroke; the association in these patients was probably incidental. CONCLUSIONS: Systemic inflammation and the potential direct action of the virus may cause endothelial dysfunction, resulting in a hypercoagulable state that could be considered a potential cause of ischaemic stroke. However, stroke involves multiple pathophysiological mechanisms; studies with larger samples are therefore needed to confirm our hypothesis. The management protocol for patients with stroke and COVID-19 should include a complete aetiological study, with the appropriate safety precautions always being observed.

An initial experience with intraoperative O-Arm for deep brain stimulation surgery: can it replace post-operative MRI?

Deep brain stimulation (DBS) is used to treat movement disorders, severe psychiatric disorders, and neuropathic pain, among other diseases. Advanced neuroimaging techniques allow direct or indirect localization of the target site, which is verified in many centers by the intraoperative recording of unitary neuronal activity. Intraoperative image acquisition technology (e.g., O-Arm) is increasingly used for accurate electrode positioning throughout the surgery. The aim of our study is to analyze the initial experience of our team in the utilization of O-Arm for planning DBS and monitoring its precision and accuracy throughout the procedure. The study included 13 patients with movement disorders. All underwent DBS with the intraoperative O-arm image acquisition system (iCT) and Medtronic StealthStation S7 cranial planning system, placing a total of 25 electrodes. For each patient, we calculated the difference between real and theoretic x, y, z coordinates, using the paired Student's t test to evaluate absolute and directional differences and the one-sample Student's t test to analyze differences in Euclidean distances. No statistically significant differences were found in absolute, directional, or Euclidean distances between intended and actual x, y, and z coordinates, based on iCT scan. Our experience confirms that utilization of the O-Arm system in DBS provides accurate and precise verification of electrode placements throughout the procedure. Recent studies found no significant differences between iCT and postoperative MRI, the current gold standard. Further prospective studies are warranted to test the elimination of postoperative MRI when this system is used.

Mortalidad asociada al ictus en un hospital andaluz de tercer nivel. Análisis y reflexiones / Stroke-related mortality in a tertiary care hospital in Andalusia: Analysis and reflections

Objetivos: El ictus constituye una causa muy frecuente de muerte, especialmente en el sur de España; se analiza la mortalidad intrahospitalaria asociada a ictus en un hospital andaluz de tercer nivel. Métodos: Registro de pacientes con ictus como diagnóstico en su informe de defunción en el Hospital Virgen de las Nieves de Granada durante 2013. Se utilizan además datos globales sobre altas en ictus y se comparan con iguales variables en síndrome coronario agudo (SCA). Resultados: Altas con diagnóstico de ictus 825 (96 defunciones, 11,6%); 562 isquémicos (44 fallecidos, 7,8%); 263 hemorrágicos (52 muertes, 19,7%). Los hemorrágicos, por tanto, tuvieron mayor mortalidad (OR = 2,9) y más precoz durante el ingreso (mediana 4 vs. 7 días, global 6 días), aunque los isquémicos fueron más ancianos y más pluripatológicos. Altas con SCA 617 (36 fallecidos, 5,8%); OR de mortalidad en ictus/SCA = 2,1. Un 23% de los fallecidos con ictus estaban anticoagulados cuando lo presentaron. El 60% de los ictus isquémicos y el 20% de los ictus hemorrágicos fallecidos tenían fibrilación auricular; solo el 35% de los pacientes con ictus isquémico y fibrilación auricular estaban anticoagulados. Conclusiones: El ictus supera al SCA en ingresos y mortalidad intrahospitalaria. El ictus hemorrágico supera al isquémico en mortalidad asociada. La anticoagulación crónica es frecuente en pacientes con ictus fatal; 2 tercios de los pacientes con ictus isquémico mortal y fibrilación auricular no estaban anticoagulados. Según nuestros resultados, optimizar la prevención en pacientes con fibrilación auricular podría impactar favorablemente sobre la mortalidad intrahospitalaria asociada al ictus (AU)

Objectives: Stroke is a very common cause of death, especially in southern Spain. The present study analyses in-hospital mortality associated with stroke in an Andalusian tertiary care hospital. Methods: We gathered the files of all patients who had died at Hospital Universitario Virgen de las Nieves in Granada in 2013 and whose death certificates indicated stroke as the cause of death. We also gathered stroke patients discharge data and compared them to that of patients with acute coronary syndrome (ACS). Results: A total of 825 patients had a diagnosis of stroke (96 deaths, 11.6%); of these, 562 had ischaemic stroke (44 deaths, 7.8%) and 263 haemorrhagic stroke (52 deaths, 19.7%). Patients with haemorrhagic stroke therefore showed greater mortality rate (OR = 2.9). Patients in this group died after a shorter time in hospital (median, 4 vs 7 days; mean, 6 days). However, patients with ischaemic stroke were older and presented with more comorbidities. On the other hand, 617 patients had a diagnosis of ACS (36 deaths, 5.8%). The mortality odds ratio (MOR) was 2.1 (stroke/SCA). Around 23% of the patients who died from stroke were taking anticoagulants. 60% of the deceased patients with ischaemic stroke and 20% of those with haemorrhagic stroke had atrial fibrillation (AF); 35% of the patients with ischaemic stroke and AF were taking anticoagulants. Conclusions: Stroke is associated with higher admission and in-hospital mortality rates than SCA. Likewise, patients with haemorrhagic stroke showed higher mortality rates than those with ischaemic stroke. Patients with fatal stroke usually had a history of long-term treatment with anticoagulants; 2 thirds of the patients with fatal ischaemic stroke and atrial fibrillation were not receiving anticoagulants. According to our results, optimising prevention in patients with AF may have a positive impact on stroke-related in-hospital mortality (AU)

Stroke-related mortality in a tertiary care hospital in Andalusia: Analysis and reflections. / Mortalidad asociada al ictus en un hospital andaluz de tercer nivel. Análisis y reflexiones.

OBJECTIVES: Stroke is a very common cause of death, especially in southern Spain. The present study analyses in-hospital mortality associated with stroke in an Andalusian tertiary care hospital. METHODS: We gathered the files of all patients who had died at Hospital Universitario Virgen de las Nieves in Granada in 2013 and whose death certificates indicated stroke as the cause of death. We also gathered stroke patients discharge data and compared them to that of patients with acute coronary syndrome (ACS). RESULTS: A total of 825 patients had a diagnosis of stroke (96 deaths, 11.6%); of these, 562 had ischaemic stroke (44 deaths, 7.8%) and 263 haemorrhagic stroke (52 deaths, 19.7%). Patients with haemorrhagic stroke therefore showed greater mortality rate (OR=2.9). Patients in this group died after a shorter time in hospital (median, 4 vs 7 days; mean, 6 days). However, patients with ischaemic stroke were older and presented with more comorbidities. On the other hand, 617 patients had a diagnosis of ACS (36 deaths, 5.8%). The mortality odds ratio (MOR) was 2.1 (stroke/SCA). Around 23% of the patients who died from stroke were taking anticoagulants. 60% of the deceased patients with ischaemic stroke and 20% of those with haemorrhagic stroke had atrial fibrillation (AF); 35% of the patients with ischaemic stroke and AF were taking anticoagulants. CONCLUSIONS: Stroke is associated with higher admission and in-hospital mortality rates than SCA. Likewise, patients with haemorrhagic stroke showed higher mortality rates than those with ischaemic stroke. Patients with fatal stroke usually had a history of long-term treatment with anticoagulants; 2 thirds of the patients with fatal ischaemic stroke and atrial fibrillation were not receiving anticoagulants. According to our results, optimising prevention in patients with AF may have a positive impact on stroke-related in-hospital mortality.

Abnormal thermography in Parkinson's disease.

BACKGROUND: An autonomic denervation and abnormal vasomotor reflex in the skin have been described in Parkinson's disease (PD) and might be evaluable using thermography with cold stress test. METHODS: A cross-sectional pilot study was undertaken in 35 adults: 15 patients with PD and abnormal [(123)I]-metaiodobenzylguanidine cardiac scintigraphy and 20 healthy controls. Baseline thermography of both hands was obtained before immersing one in cold water (3 ± 1 °C) for 2 min. Continuous thermography was performed in: non-immersed hand (right or with lesser motor involvement) during immersion of the contralateral hand and for 6 min afterward; and contralateral immersed hand for 6 min post-immersion. The region of interest was the dorsal skin of the third finger, distal phalanx. RESULTS: PD patients showed a lower mean baseline hand temperature (p = 0.037) and greater thermal difference between dorsum of wrist and third finger (p = 0.036) and between hands (p = 0.0001) versus controls, regardless of the motor laterality. Both tests evidenced an adequate capacity to differentiate between groups: in the non-immersed hand, the PD patients did not show the normal cooling pattern or final thermal overshoot observed in controls (F = 5.29; p = 0.001), and there was an AUC of 0.897 (95%CI 0.796-0.998) for this cooling; in the immersed hand, thermal recovery at 6 min post-immersion was lesser in patients (29 ± 17% vs. 55 ± 28%, p = 0.002), with an AUC of 0.810 (95%CI 0.662-0.958). CONCLUSIONS: PD patients reveal abnormal skin thermal responses in thermography with cold stress test, suggesting cutaneous autonomic dysfunction. This simple technique may be useful to evaluate autonomic dysfunction in PD.

Change of the melanocortin system caused by bilateral subthalamic nucleus stimulation in Parkinson's disease.

OBJECTIVES - Determine whether bilateral subthalamic nucleus stimulation (STN-DBS) in Parkinson's disease (PD) is associated with an increase in neuropeptide Y (NPY) and/or resistance to inhibition by leptin in relation to post-surgery weight gain. MATERIALS AND METHODS - This prospective study included 20 patients who underwent bilateral STN-DBS and 17 who refused surgery. Data were obtained at baseline, 3 and 6 months on neurological and nutritional status, including determination of body mass index (BMI) and serum NPY and leptin levels. RESULTS - NPY and leptin levels changed over time, with a distinct pattern. The BMI increase at 6 months was greater in the surgical group (5.5 ± 6.3% vs 0.5 ± 3.5%; P = 0.035). Medical group exhibited a reduction in leptin level (-2.0 ± 4.3 ng/ml) and a consequent increase in NPY level (72.4 ± 58.7 pmol/ml). However, STN-DBS patients showed an increase in leptin (3.1 ± 5.0 ng/ml; P = 0.001 vs medical group) and also in NPY (12.1 ± 53.6 pmol/ml; P = 0.022 vs medical group) levels, which suggests resistance to inhibition by leptin. Rise in NPY level correlated with higher stimulation voltages. CONCLUSIONS - Bilateral STN-DBS causes disruption of the melanocortin system, probably related to diffusion of the electric current to the hypothalamus. This mechanism may in part explain the weight gain of patients with PD after surgery.

[Calamities in movement disorders]. / Catástrofes en trastornos del movimiento.

The field of movement disorders largely covers subacute or chronic diseases that are usually treated in outpatient clinics. However, the much less frequent acute disorders require urgent recognition and treatment. The present article reviews the entities that frequently require neurointensive management and whose development can prove "calamitous". These include neuroleptic malignant syndrome and related conditions, status dystonicus, and hemiballism.

Catástrofes en trastornos del movimiento / Calamities in movement disorders

Aunque el campo de los trastornos del movimiento incluye en su mayoría patologías subagudas o crónicas atendidas habitualmente en consultas externas, en ocasiones se presentan cuadros agudos cuyo reconocimiento y tratamiento urgentes son imperativos. En este artículo se revisan aquellas entidades que con frecuencia requieren un manejo neurointensivista y cuya evolución puede resultar “catastrófica”. Entre ellas se incluyen el síndrome neuroléptico maligno y otros cuadros relacionados, el estado distónico y el hemibalismo (AU)

The field of movement disorders largely covers subacute or chronic diseases that are usually treated in outpatient clinics. However, the much less frequent acute disorders require urgent recognition and treatment. The present article reviews the entities that frequently require neurointensive management and whose development can prove “calamitous”. These include neuroleptic malignant syndrome and related conditions, status dystonicus, and hemiballism (AU)

Efficacy and safety of pallidal stimulation in primary dystonia: results of the Spanish multicentric study.

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.

[Diagnostic value of cardiac 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy in Lewy body disorders]. / Valor diagnóstico de la gammagrafía cardíaca con 123I-metaiodobenzilguanidina en las enfermedades con cuerpos de Lewy.

INTRODUCTION: Lewy body disorders such as Parkinson's disease (PD) and Lewy body dementia (LBD) are associated with cardiac sympathetic denervation, which can be visualized on 123I-MIBG scintigraphy. Our objectives were to study the diagnostic value of this technique in Lewy body disorders and its relationship with PD clinical variables. PATIENTS AND METHODS: We studied 90 patients: 51 with PD, 19 with LBD, 9 with multiple system atrophy (MSA) and 11 controls. Scintigraphy images were qualitatively evaluated and early and delayed heart-to-mediastinum ratios (HMR) were calculated. The main confounding factors (ischemic heart disease, diabetes, hypertension and drugs) were controlled by multivariate linear regression analysis. We investigated correlations between scintigraphy variables and PD variables. RESULTS: The delayed HMR, which showed better discriminative ability was 2.03 +/- 0.32 in controls, 1.37 +/- 0.30 in PD (p<0.001 vs controls), 1.47+/-0.45 in LBD (p=0.001 vs controls) and 1.69+/-0.28 in MSA (p=0.02 vs controls; p=0.004 vs PD). This ratio was influenced by PD/LBD diagnosis (beta= -0.638; p<0.001) and to a lesser degree, by ischemic heart disease (beta= -0.244; p=0.028). Optimal cut-off value between PD/LBD and controls was 1.71 (83% sensitivity and 82% specificity). Within the PD group, those with a family history of PD/LB showed higher delayed HMR values (1.65+/-0.34 vs 1.30+/-0.24 without history; p<0.001) and proportion with normal scintigraphy (56% vs 5%; p=0.001). CONCLUSIONS: Cardiac 123I-MIBG scintigraphy is useful in the diagnosis of Lewy body disorders, although its value in PD is conditioned by having a family history of PD.

Valor diagnóstico de la gammagrafíacardíaca con 123I-metaiodobenzilguanidinaen las enfermedades con cuerpos de Lewy / Diagnostic value of cardiac 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy in Lewy body disorders

Introducción. Enfermedades con cuerpos de Lewy (ECL), como laenfermedad de Parkinson (EP) y la demencia con cuerpos de Lewy(DCL), asocian una denervación simpática cardíaca que puede evidenciarsemediante gammagrafía con 123I-metaiodobenzilguanidina(123I-MIBG). Nuestros objetivos fueron estudiar su valor diagnósticoen las ECL y su relación con variables clínicas de la EP.Pacientes y métodos. Estudiamos 90 pacientes: 51 con EP, 19 conDCL, 9 con atrofia multisistémica (AMS) y 11 controles. Se realizó valoracióncualitativa de la gammagrafía y se calcularon los índices corazón/mediastino (ICM) precoz y tardío. Los principales factores deconfusión (cardiopatía isquémica, diabetes, hipertensión y fármacos)se controlaron mediante regresión lineal multivariante. Efectuamoscorrelaciones entre las variables gammagráficas y del grupo con EP.Resultados. El ICM tardío, con mayor capacidad discriminativa,fue 2,03±0,32 en los controles, 1,37±0,30 en EP (p<0,001 vs controles),1,47±0,45 en DCL (p=0,001 vs controles) y 1,69±0,28 enAMS (p=0,02 vs controles; p=0,004 vs EP). En este índice influía eldiagnóstico de ECL (ß=–0,638; p<0,001) y en menor grado la cardiopatíaisquémica (ß=–0,244; p=0,028). Identificamos el valor 1,71como mejor punto de corte entre ECL y controles (sensibilidad 83%y especificidad 82%). Dentro del grupo con EP, aquellos con antecedentesfamiliares de EP mostraron mayores ICM tardío (1,65±0,34 vs1,30±0,24 sin antecedentes; p<0,001) y proporción de gammagrafíasnormales (56% vs 5%; p=0,001).Conclusiones. La gammagrafía cardíaca con 123I-MIBG es útilen el diagnóstico de ECL, si bien, en la EP su valor está condicionadopor el hecho de tener historia familiar de la enfermedad (AU)

Introduction. Lewy body disorders such as Parkinson’s disease(PD) and Lewy body dementia (LBD) are associated withcardiac sympathetic denervation, which can be visualized on123I-MIBG scintigraphy. Our objectives were to study the diagnosticvalue of this technique in Lewy body disorders and its relationshipwith PD clinical variables.Patients and methods. We studied 90 patients: 51 with PD,19 with LBD, 9 with multiple system atrophy (MSA) and 11 controls.Scintigraphy images were qualitatively evaluated and earlyand delayed heart-to-mediastinum ratios (HMR) were calculated.The main confounding factors (ischemic heart disease, diabetes,hypertension and drugs) were controlled by multivariate linearregression analysis. We investigated correlations between scintigraphyvariables and PD variables.Results. The delayed HMR, which showed better discriminativeability was 2.03 ± 0.32 in controls, 1.37 ± 0.30 in PD(p<0.001 vs controls), 1.47±0.45 in LBD (p=0.001 vs controls) and1.69±0.28 in MSA (p=0.02 vs controls; p=0.004 vs PD). This ratiowas influenced by PD/LBD diagnosis (ß=–0.638; p<0.001)and to a lesser degree, by ischemic heart disease (ß = –0.244;p=0.028). Optimal cut-off value between PD/LBD and controlswas 1.71 (83% sensitivity and 82% specificity). Within the PDgroup, those with a family history of PD/LB showed higher delayedHMR values (1.65±0.34 vs 1.30±0.24 without history; p<0.001)and proportion with normal scintigraphy (56% vs 5%; p=0.001).Conclusions. Cardiac 123I-MIBG scintigraphy is useful in thediagnosis of Lewy body disorders, although its value in PD isconditioned by having a family history of PD (AU)

Do alpha-synuclein aggregates in autonomic plexuses predate Lewy body disorders?: a cohort study.

OBJECTIVE: To determine the prevalence of alpha-synuclein (AS) aggregates in abdominopelvic autonomic plexuses in the general population and to evaluate the relationship between this finding and the subsequent development of neurologic dysfunction. METHODS: First, surgical specimens from 100 patients (ages 44 to 84) undergoing a wide resection of an abdominopelvic organ were examined by anti-AS immunostaining. Second, 16 patients (6 AS+ and 10 randomly selected AS-) participated in yearly double-blinded neurologic assessments. RESULTS: AS aggregates were found in autonomic plexuses in 9% of the whole sample (95% CI 3.4 to 14.6%) but were more common in vesicoprostatic (26%) than in digestive tract (4%) specimens. At 16 months after the biopsy, no prevalent cases of Parkinson disease, dementia, or autonomic failure were diagnosed among participants. One AS+ patient had previously been diagnosed with REM sleep behavior disorder. Seven of 10 control subjects but none of the 6 AS+ patients had a diagnosis of hypertension (p = 0.01). During phase IV of Valsalva maneuver, AS+ group exhibited a longer blood pressure recovery time (p = 0.03), with one patient showing absence of blood pressure overshoot. Cardiac [(123)I]metaiodobenzylguanidine uptake was reduced in the AS+ group (p = 0.03). Striatal [(123)I]ioflupane uptake was abnormally low in only one AS+ patient. At 30 months after the biopsy, lower cardiac and striatal uptake values tended to correlate with higher Unified Parkinson's Disease Rating Scale III scores (p = 0.07). CONCLUSION: The common presence of alpha-synuclein aggregates in peripheral autonomic neurons may represent an early presymptomatic phase in the development of Lewy body disorders.

[Cell therapy and other neuroregenerative strategies in Parkinson's disease (II)]. / Terapia celular y otras estrategias neurorregenerativas en la enfermedad de Parkinson (II).

OBJECTIVE: To review, from a mainly clinical standpoint, the different strategies applied to regenerate or restore the nigrostriatal dopaminergic system in Parkinson's disease (PD). A previous first part focused on the results of adrenal medulla and human fetal mesencephalic transplants, and this second part addresses transplants of other cell types, administration of trophic factors, and gene therapy. DEVELOPMENT: As an alternative to human fetal mesencephalic neurons, other donor cells types (porcine mesencephalic neurons, retinal pigment epithelial cells) with similar 'dopaminergic' action mechanism have been tried, although with heterogeneous results. Transplantation of carotid body cell aggregates may be a promising therapy because of its neurotrophic action mechanism. The perspectives of cell therapies based on genetically modified cells and precursor cells of different origin are also reviewed. Among other neuroregenerative approaches, the clinical outcomes of direct administration of neurotrophic factors and the perspectives for in vivo gene therapy are also addressed. CONCLUSIONS: The objective of neuroregenerative therapy for PD should include trophic restoration of damaged neuronal systems, since improvement in striatal dopaminergic function is not sufficient. After the recent failure of the direct (intraventricular or intraputaminal) administration of glial cell line-derived neurotrophic factor (GDNF), attention of researchers has focused on indirect methods, including transplantation of GDNF-producing cells (carotid body cell aggregates or different genetically modified cells), and in vivo gene therapy.

Terapia celular y otras estrategias neurorregenerativas en la enfermedad de Parkinson (II) / Cell therapy and other neuroregenerative strategies in parkinson’s disease (II)

Objetivo. Revisar, desde una perspectiva fundamentalmente clínica, las diferentes estrategias que tienen como finalidad la regeneración o restauración del sistema dopaminérgico nigroestriatal en la enfermedad de Parkinson (EP). En una primera parte se analizaron los resultados de los trasplantes de médula adrenal y de mesencéfalo fetal humano, y en este artículo se continúa con los trasplantes de otras estirpes celulares, la administración de factor estróficos y la terapia génica. Desarrollo. Como alternativa al trasplante fetal humano se han planteado otros procedimientos con similar mecanismo de acción 'dopaminérgico' (xenotrasplante porcino, células retinianas microencapsuladas), aunque con resultados poco consistentes. El trasplante de agregados celulares del cuerpo carotídeo podría ser una terapia prometedora por su mecanismo de acción neurotrófico. Se revisan también las perspectivas de la terapia celular basada en células modificadas genéticamente y en células precursoras de distinta procedencia. Entre otras estrategias neurorregenerativas, se analizan los resultados clínicos dela administración directa de factores neurotróficos y las perspectivas de la terapia génica in vivo. Conclusiones. El objetivo de una auténtica terapia neurorregenerativa para la EP debería ser, no sólo incrementar la función dopaminérgica estriatal, sino promoverla restauración trófica de los sistemas neuronales dañados. Tras el reciente fracaso de los métodos de administración directa(intraventricular e intraputaminal) de factor neurotrófico derivad o de una línea celular glial (GDNF), ha cobrado una mayor relevancia la investigación de otros métodos indirectos, como el trasplante de células productoras de GDNF -agregados celulares del cuerpo carotídeo, distintas células modificadas genéticamente- y la terapia génica in vivo (AU)

Objective. To review, from a mainly clinical standpoint, the different strategies applied to regenerate or restore the nigrostriatal dopaminergic system in Parkinson’s disease (PD). A previous first part focused on the results of adrenal medulla and human fetal mesencephalic transplants, and this second part addresses transplants of other cell types, administration of trophic factors, and gene therapy. Development. As an alternative to human fetal mesencephalic neurons, other donor cells types (porcine mesencephalic neurons, retinal pigment epithelial cells) with similar ‘dopaminergic’ action mechanism have been tried, although with heterogeneous results. Transplantation of carotid body cell aggregates may be a promising therapy because of its neurotrophic action mechanism. The perspectives of cell therapies based on genetically modified cells and precursor cells of different origin are also reviewed. Among other neuroregenerative approaches, the clinical outcomes of direct administration of neurotrophic factors and the perspectives for in vivo gene therapy are also addressed. Conclusions. The objective of neuroregenerative therapy for PD should include trophic restoration of damaged neuronal systems, since improvement in striatal dopaminergic function is not sufficient. After the recent failure of the direct (intraventricular orintraputaminal) administration of glial cell line-derived neurotrophic factor (GDNF), attention of researchers has focused on indirect methods, including transplantation of GDNF-producing cells (carotid body cell aggregates or different genetically modified cells), and in vivo gene therapy (AU)

[Cell therapy and other neuroregenerative strategies in Parkinson's disease (I)]. / Terapia celular y otras estrategias neurorregenerativas en la enfermedad de Parkinson (I).

OBJECTIVE: To review, from a mainly clinical standpoint, the different strategies applied to regenerate or restore the nigrostriatal dopaminergic system in Parkinson's disease. This first part focuses on the results of adrenal medulla and human fetal mesencephalic transplants, and a second part will address transplants of other cell types, administration of trophic factors, and gene therapy. DEVELOPMENT: Adrenal medulla transplants were abandoned because of their inconsistent results and high morbidity. Although fetal mesencephalic transplantation can produce long-term restoration of striatal dopamine deficiency, this neurochemical effect is clinically inadequate in presence of progressive neuronal loss. Other strategies with similar 'dopaminergic' action mechanism are not a therapeutic option in this setting. CONCLUSIONS: The objective of neuroregenerative therapy for Parkinson's disease should include trophic restoration of damaged neuronal systems, since improvement in striatal dopaminergic function is not sufficient. After the recent failure of the direct (intraventricular or intraputaminal) administration of glial cell line-derived neurotrophic factor (GDNF), attention of researchers has focused on indirect methods, including transplantation of GDNF-producing cells (carotid body cell aggregates or different genetically modified cells, including stem cells), and in vivo gene therapy.

Terapia celular y otras estrategias neurorregenerativas en la enfermedad de Parkinson (I) / Cell therapy and other neuroregenerative strategies in Parkinson’s disease (I)

Objetivo. Revisar, desde una perspectiva fundamentalmente clínica, las diferentes estrategias que tienen como finalidad la regeneración o restauración del sistema dopaminérgico nigroestriatal en la enfermedad de Parkinson. En esta primera parte se analizan los resultados de los trasplantes de médula adrenal y de mesencéfalo fetal humano, y se continúa en una segunda parte con los trasplantes de otras estirpes celulares, la administración de factores tróficos y la terapia génica. Desarrollo. Los trasplantes de médula adrenal se abandonaron por la inconsistencia de sus resultados y su elevada morbilidad. Los trasplantes de mesencéfalo fetal poseen capacidad para restaurar a largo plazo el déficit de dopamina estriatal; sin embargo, este efecto neuroquímico ha demostrado ser clínicamente insuficiente en presencia de una degeneración neuronal progresiva. En este contexto, otras estrategias con similar mecanismo de acción ‘dopaminérgico’ no suponen una alternativa. Conclusiones. El objetivo de una auténtica terapia neurorregenerativa para la enfermedad de Parkinson debería ser no sólo incrementar la función dopaminérgica estriatal, sino promover la restauración trófica de los sistemas neuronales dañados. Tras el reciente fracaso de los métodos de administración directa (intraventricular e intraputaminal) de factor neurotrófico derivado de una línea celular glial (GDNF), ha cobrado una mayor relevancia la investigación de otros métodos indirectos, como el trasplante de células productoras de GDNF (agregados celulares del cuerpo carotídeo, distintas células modificadas genéticamente) y la terapia génica in vivo

Objective. To review, from a mainly clinical standpoint, the different strategies applied to regenerate or restore the nigrostriatal dopaminergic system in Parkinson’s disease. This first part focuses on the results of adrenal medulla and human fetal mesencephalic transplants, and a second part will address transplants of other cell types, administration of trophic factors, and gene therapy. Development. Adrenal medulla transplants were abandoned because of their inconsistent results and high morbidity. Although fetal mesencephalic transplantation can produce long-term restoration of striatal dopamine deficiency, this neurochemical effect is clinically inadequate in presence of progressive neuronal loss. Other strategies with similar ‘dopaminergic’ action mechanism are not a therapeutic option in this setting. Conclusions. The objective of neuroregenerative therapy for Parkinson’s disease should include trophic restoration of damaged neuronal systems, since improvement in striatal dopaminergic function is not sufficient. After the recent failure of the direct (intraventricular or intraputaminal) administration of glial cell line-derived neurotrophic factor (GDNF), attention of researchers has focused on indirect methods, including transplantation of GDNF-producing cells (carotid body cell aggregates or different genetically modified cells, including stem cells), and in vivo gene therapy

Different patterns of medication change after subthalamic or pallidal stimulation for Parkinson's disease: target related effect or selection bias?

BACKGROUND: Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is favoured over bilateral globus pallidus internus (Gpi) DBS for symptomatic treatment of advanced Parkinson's disease (PD) due to the possibility of reducing medication, despite lack of definitive comparative evidence. OBJECTIVE: To analyse outcomes after one year of bilateral Gpi or STN DBS, with consideration of influence of selection bias on the pattern of postsurgical medication change. METHODS: The first patients to undergo bilateral Gpi (n = 10) or STN (n = 10) DBS at our centre were studied. They were assessed presurgically and one year after surgery (CAPIT protocol). RESULTS: Before surgery the Gpi DBS group had more dyskinesias and received lower doses of medication. At one year, mean reduction in UPDRS off medication score was 35% and 39% in the Gpi and STN groups, respectively (non-significant difference). Dyskinesias reduced in proportion to presurgical severity. The levodopa equivalent dose was significantly reduced only in the STN group (24%). This study high-lights the absence of significant differences between the groups in clinical scales and medication dose at one year. In the multivariate analysis of predictive factors for off-state motor improvement, the presurgical levodopa equivalent dose showed a direct relation in the STN and an inverse relation in the Gpi group. CONCLUSION: Differences in the patterns of medication change after Gpi and STN DBS may be partly due to a patient selection bias. Both procedures may be equally useful for different subgroups of patients with advanced PD, Gpi DBS especially for patients with lower threshold for dyskinesia.

[Clinical utility of deep brain stimulation in an advanced Parkinson's disease]. / Utilidad clínica de la estimulación cerebral profunda en la enfermedad de Parkinson avanzada.

INTRODUCTION: Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) have demonstrated efficacy in advanced Parkinson's disease (PD). We aimed to assess the clinical utility of these procedures in terms of the quality of life, and to determine the pre and postsurgical characteristics related to the outcome. METHOD: A prospective study was conducted on a cohort of 20 patients with advanced PD who underwent bilateral DBS: 14 in STN and 6 in GPi. They were assessed according to the CAPSIT-PD protocol before and after surgery, with a mean follow-up of 9 and 11 months, respectively. The main outcome variables were change in the UPDRS III score in off efficacy and the PDQ-39 quality of life questionnaire score (clinical utility). RESULTS: The STN group improved their UPDRS III in off by a mean of 35% (p = 0.001) and their PDQ-39 by 21% (p = 0.026). The GPi group improved their UPDRS III in off by 21% (p = 0.028) and their PDQ-39 by 37% (p = 0.116). The presurgical levodopa-equivalent dose was a positive predictor of the efficacy and clinical utility of STN DBS and a negative predictor of the efficacy of GPi DBS. In both groups, the clinical utility was determined by improvement in functional disability in off scales. CONCLUSIONS: Bilateral DBS demonstrated middle-term efficacy and clinical utility in the treatment of advanced PD. The presurgical levodopa-equivalent dose was a predictor of the efficacy and clinical utility of DBS.