Uso de la infusión intestinal continua de levodopa-carbidopa en pacientes con enfermedad de Parkinson avanzada en España. Subanálisis por comunidades autónomas / Continuous intestinal infusion of levodopa-carbidopa in patients with advanced Parkinson's disease in Spain: Subanalysis by autonomous community

OBJETIVOS: Comparar las características de los pacientes con enfermedad de Parkinson avanzada en tratamiento con infusión intestinal continua de levodopa-carbidopa (IICLC) y los datos de efectividad y seguridad de IICLC entre diferentes comunidades autónomas (CC. AA.). MÉTODOS: Estudio longitudinal observacional y retrospectivo. Se incluyeron 177 pacientes de 11 CC. AA. que iniciaron tratamiento con IICLC entre enero de 2006 y diciembre de 2011. Se compararon las características clínicas y demográficas, las variables de efectividad (cambios en el tiempo OFF, ON con y sin discinesias discapacitantes, cambios en la escala de Hoehn y Yahr y puntuación de la Unified Parkinson's Disease Rating Scale, síntomas no motores e Impresión Clínica Global) y seguridad (acontecimientos adversos), y la tasa de suspensión de IICLC. RESULTADOS: Se hallaron diferencias significativas entre las CC. AA. en diversas variables basales: duración de la enfermedad hasta el inicio de IICLC, tiempo OFF (34,9-59,7%) y ON (con o sin discinesias; 2,6-48,0%), Hoehn y Yahr en ON, Unified Parkinson's Disease Rating Scale-III en ON y OFF, presencia de ≥ 4 síntomas motores y dosis de IICLC. En el seguimiento (> 24 meses en 9 de 11 CC. AA.) hubo diferencias significativas en el porcentaje de tiempo OFF, tiempo ON sin discinesias discapacitantes, frecuencia de acontecimientos adversos e Impresión Clínica Global. La tasa de suspensión fue de entre 20-40% en todas las CC. AA., excepto en 2 (78 y 80%). CONCLUSIONES: Este estudio muestra una amplia variabilidad en la selección de los pacientes y en la efectividad y seguridad de IICLC entre las diferentes CC. AA. Podrían influir las características basales de los pacientes, la disponibilidad de un equipo multidisciplinar y la experiencia clínica

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

Continuous intestinal infusion of levodopa-carbidopa in patients with advanced Parkinson's disease in Spain: Subanalysis by autonomous community. / Uso de la infusión intestinal continua de levodopa-carbidopa en pacientes con enfermedad de Parkinson avanzada en España. Subanálisis por comunidades autónomas.

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

[Quantitative gait analysis in patients with advanced Parkinson's disease]. / Analisis cuantitativo de la marcha en pacientes con enfermedad de Parkinson avanzada.

AIM: To describe the gait disorders and postural instability in a group of patients with advanced Parkinson's disease (PD). PATIENTS AND METHODS: Gait was analysed in patients in advanced stages of PD on medication. Using a computerised analysis system, we studied the kinematic variables: cadence, number of correct gait cycles (HFPS cycles), total number of cycles, duration of the phases of the cycle, electromyography and a goniometric study of the knee and the ankle. The clinical appraisal of balance and postural instability was completed with the Tinetti and Timed Up and Go tests. RESULTS: The analysis showed alterations in the spatio-temporal parameters with respect to the ranges considered to be normal: reduction of the HFPS cycles, increase in the total number of cycles and alteration of the cadence in many patients. It also revealed that the mean cadence was kept within the limits of normal values, an increase in the duration of the contact phase, reduction of monopodal support and alteration of the joint range of motion of the knee and the ankle. Likewise, changes are also observed in the scores obtained on the clinical scales, which show an increase in the risk factor for falls and mild dependence. CONCLUSION: Quantification by objective analysis of the kinetic and kinematic variables in patients with PD can be used as a tool to establish the influence of the different therapeutic alternatives in gait disorders.

TITLE: Analisis cuantitativo de la marcha en pacientes con enfermedad de Parkinson avanzada.Objetivo. Describir las alteraciones de la marcha e inestabilidad postural en un grupo de pacientes con enfermedad de Parkinson (EP) avanzada. Pacientes y metodos. Se analizo la marcha de pacientes con EP en estadio avanzado on medicacion. Por medio de un sistema de analisis computarizado del movimiento, se estudiaron las variables cinematicas: cadencia, numero de ciclos con apoyo correcto (ciclos HFPS), numero de ciclos totales, duracion de las fases del ciclo, electromiografia, y goniometria de rodilla y tobillo. La valoracion clinica del equilibrio y la inestabilidad postural se completo con los tests Tinetti y Timed Up and Go. Resultados. El analisis mostro alteraciones en los parametros espaciotemporales con respecto a los rangos de normalidad: disminucion de los ciclos HFPS, aumento del numero total de ciclos y alteracion de la cadencia en muchos pacientes, y conservacion de la cadencia media dentro de los limites de la normalidad, aumento de la duracion de la fase de apoyo, disminucion del apoyo monopodal y alteracion del rango articular de la rodilla y el tobillo. Asimismo, se observo una alteracion en las puntuaciones obtenidas en las escalas clinicas, que mostraban un aumento del factor de riesgo de caidas y dependencia leve. Conclusion. La cuantificacion mediante analisis objetivo de las variables cineticas y cinematicas en los pacientes con EP puede emplearse como herramienta para establecer la influencia de las distintas alternativas terapeuticas en el trastorno de la marcha.

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.

Estimulación cerebral profunda: 12 años de experiencia y 250 pacientes intervenidos con un seguimiento de más de un año / Deep brain stimulation: 12 years experience and 150 patients treated with a follow-up of over a year

Introduction. Deep brain stimulation (DBS) is a widely accepted clinical technique. The main motor symptoms are significantly reduced. The success of the technique depends on the experience of the neurosurgeon, neurologist and neurophysiologist who carry it out. The presentation of extensive series is needed to confirm and further currently held knowledge. Aim. To demonstrate the clinical benefits of a long series of patients treated by a single group with a minimum follow-up of one year and to report new neurophysiological data. Patients and methods. The study examined a total of 250 patients with different diagnoses: most of them with Parkinson’s disease, tremor and dystonia. The nuclei that were chosen were located by magnetic resonance imaging, computerised axial tomography and neurophysiological registers. Neurophysiological exclusion criteria, such as reflex control of heart rate, sympathetic skin response and auditory startle reflex, are employed in order to exclude patients with Parkinson-plus. Results. The motor sub-scale (part III) of the Unified Parkinson’s Disease Rating Scale improves by 64% in the off-medication status with sub-thalamic stimulation at one year after surgery. One year after DBS, patients with dystonia show a significant decrease on the Burke-Fahn-Marsden dystonia scale. The improvement on the scales continues, with a mean descent of 65% in the second year after surgery. Conclusions. DBS is a suitable technique for the treatment of movement disorders. The neuronal activity of the sub-thalamus and the internal globus pallidus presents its own characteristics that reflect the motor symptoms of the patients. Surface electromyography proves to be useful for quantifying the patients’ improvement (AU)

Introducción. La estimulación cerebral profunda (ECP) es una técnica de gran aceptación clínica. Los principales síntomas motores se reducen significativamente. El éxito de la técnica radica en la experiencia del neurocirujano, neurólogo y neurofisiólogo que lo llevan a cabo. La presentación de series extensas es necesaria para confirmar y extender los actuales conocimientos. Objetivo. Demostrar los beneficios clínicos de una larga serie de pacientes intervenidos por un único grupo con un seguimiento mínimo de un año y presentar nuevos datos neurofisiológicos. Pacientes y métodos. Se han estudiado 250 pacientes con diversos diagnósticos; la mayoría con enfermedad de Parkinson, temblor y distonía. Los núcleos elegidos se localizan por resonancia magnética, tomografía axial computarizada y registros neurofisiológicos. Se utilizan criterios de exclusión neurofisiológicos, como el control reflejo de la frecuencia cardíaca, la respuesta simpaticocutánea y el reflejo de sobresalto auditivo, para excluir pacientes con Parkinson-plus. Resultados. La subescala motora (parte III) de la Unified Parkinson’s Disease Rating Scale mejora un 64% en situación off de medicación con la estimulación del subtálamo al año de la cirugía. Los pacientes con distonía muestran, un año después de la ECP, en la escala de distonía Burke-Fahn-Marsden, un descenso significativo. La mejoría en las escalas persiste, con un descenso medio del 65% en el segundo año después de la cirugía. Conclusiones. La ECP es una técnica apropiada para el tratamiento de los trastornos del movimiento. La actividad neuronal del subtálamo y del globo pálido interno presenta características propias que reflejan la sintomatología motora de los pacientes. La electromiografía superficial demuestra ser útil para cuantificar la mejoría de los pacientes (AU)

[Deep brain stimulation: 12 years' experience and 150 patients treated with a follow-up of over a year]. / Estimulación cerebral profunda: 12 años de experiencia y 250 pacientes intervenidos con un seguimiento de más de un año.

INTRODUCTION: Deep brain stimulation (DBS) is a widely accepted clinical technique. The main motor symptoms are significantly reduced. The success of the technique depends on the experience of the neurosurgeon, neurologist and neurophysiologist who carry it out. The presentation of extensive series is needed to confirm and further currently held knowledge. AIM: To demonstrate the clinical benefits of a long series of patients treated by a single group with a minimum follow-up of one year and to report new neurophysiological data. PATIENTS AND METHODS: The study examined a total of 250 patients with different diagnoses: most of them with Parkinson's disease, tremor and dystonia. The nuclei that were chosen were located by magnetic resonance imaging, computerised axial tomography and neurophysiological registers. Neurophysiological exclusion criteria, such as reflex control of heart rate, sympathetic skin response and auditory startle reflex, are employed in order to exclude patients with Parkinson-plus. RESULTS: The motor sub-scale (part III) of the Unified Parkinson's Disease Rating Scale improves by 64% in the off-medication status with sub-thalamic stimulation at one year after surgery. One year after DBS, patients with dystonia show a significant decrease on the Burke-Fahn-Marsden dystonia scale. The improvement on the scales continues, with a mean descent of 65% in the second year after surgery. CONCLUSIONS: DBS is a suitable technique for the treatment of movement disorders. The neuronal activity of the sub-thalamus and the internal globus pallidus presents its own characteristics that reflect the motor symptoms of the patients. Surface electromyography proves to be useful for quantifying the patients' improvement.

Deep brain stimulation in the globus pallidus to treat dystonia: electrophysiological characteristics and 2 years' follow-up in 10 patients.

Deep brain stimulation (DBS) was applied in the internal segment of the globus pallidus (GPi) to treat dystonia in 10 patients. One year after surgery the Burke-Fahn-Marsden movement scores were significantly lower than preoperative values (P=0.01). Two years after surgery the mean decrease reached 65% (P=0.001) with no motor symptoms worsening. Single unity activity was recorded in the operating room: GPi cells discharged with tonic (n=19; 29%), irregular (n=32; 48%), or burst-like activity (n=15; 23%) and fired with a mean discharge rate of 39 Hz+/-22. Some neurons demonstrated an oscillatory activity with periods lasting several seconds. Pairs of pallidal cells (n=8) recorded simultaneously displayed discharge synchronization. Movement modulated 64.4% of the cells tested, with increases in firing in 89% of cells and decreases in firing in 10% of cells. GPi cells responded to flexion and extension movements and to several passive manipulations indicating an important sensory role in dystonia. GPi neurons fired in advance of the electromyography (EMG) when the surface EMG was recorded simultaneously with the neuronal activity. Spectral analysis of the co-contracting muscles during dystonia demonstrated prominent high peaks at a low frequency band (20 Hz) during involuntary and voluntary movements. The high amplitude EMG profile recorded at rest diminished to very low values with GPi stimulation, allowing an ease of voluntary contractions. We conclude that DBS in the GPi is a reliable surgical technique for dystonia. GPi cells discharge with distinct electrophysiological characteristics that may explain some of the symptoms in dystonia. EMG recording in the operating room helps to determine which DBS contacts produce the best benefit.

Anti-heat shock protein 90beta antibodies are detected in patients with multiple sclerosis during remission.

Antibodies against heat shock protein 90beta (Hsp90beta) recognize the antigen on the surface of oligodendrocyte precursor cells and induce a decrease in the oligodendrocyte population of cell cultures. This study investigated the presence of anti-Hsp90beta antibodies in patients with multiple sclerosis (MS) during remission. Anti-Hsp90beta antibodies were detected in the cerebrospinal fluid (CSF) of patients with a specific and sensitive western blot procedure using Hsp90beta from cell membrane fraction. The number of patients with anti-Hsp90beta antibodies detected in the CSF was significantly greater in MS patients than in control patients with other neurological diseases, which included patients with other inflammatory neurological diseases. CSF anti-Hsp90beta antibody levels were significantly higher in MS patients than in control patients. The presence of anti-Hsp90beta antibodies in the CSF of MS patients during remission could suggest a potential pathogenic role for these autoantibodies in MS.

Pallidal stimulation relieves myoclonus-dystonia syndrome.

A patient with myoclonus-dystonia syndrome was treated by implanting electrodes in the internal segment of the globus pallidus (GPi) and applying deep brain stimulation. Surgery was done in two sessions. The most affected limb was treated first and the other limb one year later. Neuronal recordings showed that most pallidal neurones discharged in bursts at a relatively low firing rate (mean (SD), 46 (18) Hz) compared with cells in the GPi in patients with Parkinson's disease. Neurones modified the rate and mode of discharge with dystonic postures and rapid involuntary contractions of limb muscles. Neurological examination at 24 months after surgery showed a decline of 47.8% and 78.5% in the Burke-Fahn-Marsden and disability rating scales, respectively.

Monitorización intraoperatoria del nervio facial: consideraciones anestésicas y neurofisiológicas / Electromiografía intraoperatoria. Bloqueantes neuro-musculares. Intraoperative facial nerve monitoring: anesthetic and neurophysiologic aspects

La monitorización intraoperatoria del componente motor del VII par o de cualquier otro par craneal debe ser rutinaria en cualquier tipo de cirugía, intra o extracraneal, que conlleve riesgo de lesionarlo. Se considera su cenit la monitorización del nervio facial y del acústico en otoneurocirugía del ángulo pontocerebeloso (schwanoma vestibular o del VIII par).La monitorización electromiográfica intraoperatoria del nervio facial debe utilizarse de forma rutinaria en la cirugía del schwanoma vestibular para disminuir el grado de disfunción neurológica postoperatoria y evitar la posible demanda legal. Aunque este tipo de monitorización requiere que el músculo no esté paralizado, es admisible utilizar bloqueantes neuromusculares intraoperatorios si su dosificación se realiza mediante una monitorización adecuada del grado de bloqueo neuromuscular periférico (AU)

Caspase inhibitors protect against neuronal apoptosis induced by cerebrospinal fluid from multiple sclerosis patients.

Neuronal apoptosis has recently been implicated in multiple sclerosis (MS). Apoptotic cell death of neurons is induced in cultures exposed to cerebrospinal fluid (CSF) from MS patients. Since caspases are essential in the regulation of apoptosis, direct evidence was sought linking caspases to CSF-induced neuronal death. Caspase activity was measured in cell extracts from MS CSF-treated cultured neurons by the cleavage of caspase-1 and caspase-3 substrates. Caspase-3 activity, but not caspase-1, was induced in neuronal cultures in response to MS CSF treatment. This caspase-3 activity was inhibited in vitro by Ac-YVAD-cmk and Ac-DEVD-cmk caspase inhibitors. Treatment of MS CSF-incubated neuronal cells with these caspase inhibitors completely preserved neuronal survival and largely attenuated DNA fragmentation detected in situ. These findings show that neuronal cells are rescued from MS CSF-induced death by caspase inhibitors and suggest ways to treat MS.

[Intraoperative monitoring of the facial nerve: anesthesia and neurophysiology considerations]. / Monitorización intraoperatoria del nervio facial: consideraciones anestésicas y neurofisiológicas.

Intraoperative monitoring of the motor component of the 7th cranial pair or any other nerve should be routine during any surgical procedure involving risk of neural damage, whether or not the skull is opened. This paper discusses the main indications for monitoring facial and acoustic nerves during ear and neurosurgery involving the pontocerebellar angle (for acoustic neuroma or in surgery on the 8th cranial pair). Intraoperative electromyographic monitoring of the facial nerve should be used routinely in acoustic neuroma surgery to reduce the degree of postoperative neurological impairment and avoid possible malpractice suits. Although such monitoring requires that the muscle remain unblocked, intraoperative neuromuscular relaxants can be used if doses are administered along with appropriate monitoring of the level of peripheral neuromuscular block.

[The effect of cerebrospinal fluid on neurone culture: implications in the pathogenesis of multiple sclerosis]. / Efecto del líquido cefalorraquídeo en los cultivos neuronales: implicaciones en la patogenia de la esclerosis múltiple.

In vitro studies have shown that the cerebrospinal fluid of patients with multiple sclerosis transports compounds which may affect the function or viability of central nervous system cell function. The presence of nerve ion channel blockers and other molecules, as yet unidentified, which may cause the death of nerve cells or oligodendrocytes has been shown, although their relevance and clinical correlation is still not clear. If their usefulness is proved, these methods may be useful in the search for inhibitors of the noxious effects of the substances mentioned.

Efecto del líquido cefalorraquídeo en los cultivos neuronales: implicaciones en la patogenia de la esclerosis múltiple / The effect of cerebrospinal fluid on neurone culture: implications in the pathogenesis of multiple sclerosis

Los estudios in vitro han permitido demostrar que el líquido cefalorraquídeo de los pacientes con esclerosis múltiple transporta compuestos que pueden modificar la funcionalidad de células del sistema nervioso central en cultivo o afectar su viabilidad. Así, se ha comprobado la existencia de bloqueadores de los canales iónicos neuronales y de otras moléculas, aún por identificar, que pueden originar muerte celular, bien de los oligodendrocitos o de las neuronas. Está por aclarar la relevancia de estos hallazgos y su correlación clínica. Si se comprueba su utilidad, estos métodos podrían emplearse en la búsqueda de inhibidores de los efectos nocivos de los compuestos comentados (AU)

Further supporting evidence of beneficial subthalamic stimulation in Parkinson's patients.

Twenty-two patients with Parkinson's disease were treated by implanting electrodes in the subthalamic nucleus. The follow-up evaluation was conducted at one (22 patients) and two years (9 patients). Significant improvement in the Unified PD Rating Scale scores was found. Tremor diminished 100% in the on drug/on stimulation and 70% off drug/on stimulation state. Rigidity decreased by 68% in the on drug/on stimulation and by 52% in off drug/on stimulation state. Subthalamic stimulation is reliable.

Axonal damage induced by cerebrospinal fluid from patients with relapsing-remitting multiple sclerosis.

The importance of axonal damage in multiple sclerosis (MS) has been recently stressed in proton magnetic resonance spectroscopy and pathological studies, but the exact mechanism producing this damage is unknown. The aim of our study was to ascertain whether soluble mediators present in the cerebrospinal fluid (CSF) of patients with relapsing-remitting MS could induce neuron injury in culture. Different biochemical and cytochemical parameters were determined in primary embryonal rat neuron cultures following 8 days of exposure to CSF. Cytotoxic activity was evaluated with a blue formazan production colorimetric assay. Morphological and immunocytochemical studies performed with antibodies against beta-tubulin revealed neuritic fragmentation, axonal damage and cellular shrinkage indicating apoptosis. Detection of apoptosis was carried out using the fluorescent DNA-binding dye Hoechst 33342, as well as by a Terminal deoxynucleotidyl transferase-mediated dUTP Nick End-Labeling assay. We observed that soluble factors in CSF from patients with "aggressive" MS i.e, those with poor recovery after relapses, induced neurite breakdown and neuronal apoptosis in cultures. Neuron injury is not related with blood-brain barrier dysfunction nor with IgG index. Interestingly, CSF from patients with "non-aggressive" MS i.e., relapsing-remitting patients with a good recovery after relapses, did not induce any damage. In conclusion, we report that CSF from patients with aggressive MS bears soluble mediators that induce axonal damage and apoptosis of neurons in culture. These mediators can be present during the first attack of the disease, and the neuronal damage caused could be related to the functional deficit of these MS patients.

Induction of apoptosis by cerebrospinal fluid from patients with primary-progressive multiple sclerosis in cultured neurons.

We have studied the noxious effect of cerebrospinal fluids (CSF) from patients with primary-progressive multiple sclerosis (MS) on cultured neurons. Cells were exposed to CSF for 8 days and the possible neuronal damage was determined. Morphological studies with phase-contrast microscopy showed cellular shrinkage indicating apoptosis. CSF-induced apoptosis as evidenced by the fluorescent DNA-binding dye Hoechst 33342, as well as by the TUNEL-reaction, was only present in primary-progressive MS patients with a worsening disease. This neuron injury did not correlate with blood-brain barrier dysfunction nor with intrathecal IgG synthesis. On the contrary, CSF from either stable primary-progressive or other non-inflammatory neurological diseases, did not induce any culture damage. Undetectable or low similar tumor necrosis factor-alpha (TNF-alpha) levels (range to 8.7 pg/ml) were found in the CSFs tested regardless they damage cultures or not. These results suggest that soluble factors, other than TNF-alpha, molecules transudated from blood or IgG, present in the CSF of active primary-progressive patients with MS induce neuronal apoptosis.