[Clinical experience in the treatment of motor fluctuations in Parkinson's disease. Delphi consensus of a group of experts in movement disorders]. / Experiencia clínica en el tratamiento de las fluctuaciones motoras en la enfermedad de Parkinson. Consenso Delphi de un grupo de expertos en trastornos del movimiento.

INTRODUCTION: Motor fluctuations are one of the most common complications of Parkinson's disease and their treatment is still a complex matter. Therefore, from the Neurology Movement Disorders Group we present our clinical experience in the treatment of these complications, with the intention of it being useful in decision-making in daily clinical practice. DEVELOPMENT: Nineteen questions were developed based on a literature review and an open survey answered by members of this group. These issues were discussed in two phases, using the Delphi methodology. Considering the results of the survey, levodopa dose adjustment and dopamine agonists are the option with the best efficacy/tolerability ratio in the treatment of motor fluctuations. Rotigotine is useful in the motor fluctuations associated with gastroparesis, and intermittent subcutaneous apomorphine has positive effects in patients with unpredictable off periods. The most relevant adverse effect associated with dopamine agonists is impulse control disorder. Catechol-O-methyltransferase inhibitors are useful in the initial stages of motor fluctuations, especially in wearing off. Monoamine oxidase inhibitors are generally drugs that are well-tolerated and useful in motor fluctuations. If these measures are not effective, second-line treatments should be indicated on a case-by-case basis. CONCLUSION: The clinical profile of patients with Parkinson's disease is paramount in deciding the most appropriate therapy for the treatment of motor fluctuations.

TITLE: Experiencia clínica en el tratamiento de las fluctuaciones motoras en la enfermedad de Parkinson. Consenso Delphi de un grupo de expertos en trastornos del movimiento.Introducción. Las fluctuaciones motoras son una de las complicaciones más frecuentes en la enfermedad de Parkinson y su tratamiento sigue siendo complejo. Por ello, desde el Grupo de Trastornos del Movimiento de la Asociación Madrileña de Neurología presentamos nuestra experiencia clínica en el tratamiento de estas complicaciones, con la intención de que sea de utilidad en la toma de decisiones en la práctica clínica diaria. Desarrollo. Se elaboraron 19 preguntas a partir de una revisión bibliográfica y una encuesta abierta respondida por los miembros de dicho grupo. Dichas cuestiones se debatieron en dos fases, utilizando la metodología Delphi. Considerando los resultados de la encuesta, el ajuste de la dosis de levodopa y los agonistas dopaminérgicos son la opción con mejor relación eficacia/tolerabilidad en el tratamiento de las fluctuaciones motoras. La rotigotina es útil en las fluctuaciones motoras asociadas a gastroparesia, y la apomorfina subcutánea intermitente, en pacientes con off impredecible. El efecto adverso más relevante asociado a los agonistas dopaminérgicos es el trastorno del control de impulsos. Los inhibidores de la catecol-O-metiltransferasa son útiles en las fluctuaciones motoras de inicio, especialmente en el wearing off. Los inhibidores de la monoaminooxidasa son fármacos, en general, bien tolerados y útiles en las fluctuaciones motoras. En caso de que estas medidas no resulten eficaces, se deben indicar terapias de segunda línea de manera individualizada. Conclusión. El perfil clínico del paciente con enfermedad de Parkinson es primordial para decidir la terapia más adecuada en el tratamiento de las fluctuaciones motoras.

[Neuroprotection in Parkinson's disease: analysis though group of experts' methodology]. / Neuroprotección en la enfermedad de Parkinson: análisis a través de la metodología de informadores clave.

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

[Neural transplants en Parkinson disease: clinical results of 10 years of experience. Group of Neural Transplants of the CPH]. / Transplantes neurales en la enfermedad de Parkinson: resultados clínicos tras 10 años de experiencia. Grupo de Trasplantes Neurales de la CPH.

INTRODUCTION: At the end of the 1970s people considered the possibility that transplants might be useful to replace degenerate specific cell populations, such as the mesencephalic dopaminergic neurones in Parkinson's disease (PD). Since then this has become an experimental alternative treatment for patients with degenerative diseases. The history of transplants of catecholamine producing tissues within the brain of patients with PD started in 1985, when Backlund et al published the results of the first implants of autologous adrenal medulla in two patients with Parkinsonism. Since then, many patients throughout the world have benefited from the results obtained using this method. Two main types of tissue have been used in this method: autologous adrenal medulla and human foetal ventral mesencephalic tissue. DEVELOPMENT: In this paper we first review the clinical effects of the diverse types of transplant done to date. Then in the second part we give a summary of the clinical results obtained by our group with the different types of transplant carried out. We explain their evolution, original hypothesis and justify the reasons which led us to use three different types of donor material: autologous adrenal medulla, fetal tissue and adrenal medulla co-incubated with peripheral nerve. Then, after showing that the clinical improvement is different depending on the type of tissue transplanted, we comment on the probable reason for the improvement seen in patients with implants. CONCLUSION: The transplantation of nervous tissue seems to us to be no longer an experimental alternative for the treatment of PD but has become an effective, lasting treatment for patients with Parkinson's disease.

Trasplantes neurales en la enfermedad de Parkinson: resultados clínicos tras 10 años de experiencia / Neural transplants in Parkinson's disease: clinical results after 10 years' experience

Introducción. A finales de la década de los 70 se planteó la posibilidad de que los trasplantes pudieran utilizarse para sustituir a poblaciones celulares específicas degeneradas, como es el caso de las neuronas dopaminérgicas mesencefálicas en la enfermedad de Parkinson (EP), y desde entonces se han convertido en una alternativa terapéutica experimental en pacientes con enfermedades degenerativas. La historia de los trasplantes de tejidos productores de catecolaminas en el interior del cerebro de pacientes con EP tuvo su origen en 1985, cuando Backlund et al publicaron los resultados de los primeros implantes de médula adrenal autóloga en dos pacientes parkinsonianos. Desde entonces, numerosos pacientes repartidos por todo el mundo se han beneficiado de los resultados obtenidos por este procedimiento, en el que se han utilizado, principalmente, dos tipos de tejido donante: médula adrenal autóloga y tejido del mesencéfalo ventral de fetos humanos. Desarrollo. En este artículo primeramente revisaremos los efectos clínicos de los diversos tipos de trasplante realizados hasta la actualidad, para, en una segunda parte, mostrar resumidamente los resultados clínicos obtenidos por nuestro grupo con los diferentes tipos de trasplante realizados. Explicaremos su evolución, la hipótesis de partida y justificaremos las razones que nos impulsaron a utilizar tres tipos diferentes de tejido donante: médula adrenal autóloga, tejido fetal y médula adrenal coincubada con nervio periférico. Después, tras mostrar que la mejoría clínica es diferente según el tipo de tejido trasplantado, comentaremos las causas probables de la mejoría observada en los pacientes implantados. Conclusión. El trasplante de tejido nervioso ha dejado de ser, para nosotros, una alternativa experimental en el tratamiento de la EP para convertirse en un tratamiento eficaz y duradero para los enfermos parkinsonianos (AU)

Subgroups of parkinsonian patients differentiated by peptidergic immunostaining of caudate nucleus biopsies.

In this study, Met-enkephalin (Met-enk), substance P (SP) and tyrosine hydroxylase (TH) immunostaining was assessed in caudate nucleus biopsies from 15 Parkinson's disease patients who were treated surgically. According to the combination of changes in Met-enk, SP and TH immunostaining, several subgroups of parkinsonian patients were disclosed. Group I: Patients showing low SP and normal Met-enk immunostaining, and variably reduced TH immunoreactivity. Group II: both SP and Met-enk immunostaining were apparently of normal intensity in these PD patients, but they showed the greatest decrease in TH labeling. Group III: PD patients that showed normal SP, very low Met-enk and variably reduced TH immunostaining. Low Met-enk immunostaining tended to correlate with the severity of the disease as judged by higher Unified Parkinson's disease Rating Scale and gait scores. These results suggest that different neurochemical phenotypes may exist among Parkinson's disease patients. Peptidergic deficits should be taken into account for therapeutic intervention.

The PDQ-39 Spanish version: reliability and correlation with the short-form health survey (SF-36).

BACKGROUND AND METHODS: The Parkinson's Disease Questionnaire (PDQ-39) was the first specific instrument for evaluation of the "health-related quality of life" (QoL) in Parkinson's disease patients. The PDQ-39 has been subjected to adaptation to Spanish language and culture (PDQ-39 Spanish version, PDQ-39SV) and this version has been validated in aspects of internal consistency and construct validity. The present study assess the test-retest reliability and the convergent validity of the PDQ-39SV with a generic QoL instrument (SF-36). RESULTS: Most of the PDQ-39 dimensions showed an adequate consistency-Cronbach's alpha > 0.7 for six dimensions. As a whole, test-retest reliability resulted satisfactory. Two dimensions-activities of daily living and emotional well-being- showed a low grade significant difference (paired Student t-test, p < 0.05) due to improvement in the second survey (at 10 to 14 days from the first one) perhaps related to adjustments of the treatment at the first visit. A strong association (Spearman r, p < 0.001), indicative of convergent validity, was obtained for the PDQ-39 dimensions and the relevant SF-36 scales, as well as for the physical and mental component summary scores of the SF-36. CONCLUSIONS: Taking into account these results and previous studies, it is concluded that the PDQ-39 SV is a reliable measure that has construct validity.

Clinical outcome of cotransplantation of peripheral nerve and adrenal medulla in patients with Parkinson's disease. Clínica Puerta de Hierro Neural Transplantation Group.

OBJECT: Transplants of adrenal medulla (AM) and fetal ventral mesencephalon (FVM) are currently being tested as therapeutic alternatives in patients with Parkinson's disease (PD). At the Clínica Puerta de Hierro in Madrid, a controlled clinical trial is underway to establish which donor tissue, if any, is the best for open surgical implantation in patients with PD. METHODS: Since 1987, varying degrees of clinical improvement have been achieved in Grade IV and V parkinsonian patients by implanting perfused AM and FVM into the right caudate nucleus. To investigate further whether implantation of different types of donor tissues results in qualitatively and quantitatively different degrees of recovery, four patients with Grade IV or V PD received implants of pre-coincubated autologous AM and intercostal nerve in the caudate nucleus. Four nonsurgically treated patients served as a control group. Three years posttransplantation, longer on phases (46.2%+/-10.4% of the day presurgery to 87.5%+/-10.4% of the day 36 months postsurgery) and improved symptoms in on and off phases persist in all four cases, with reduced dyskinesias (67.1%+/-9.2% of the day in on phases presurgery to 17%+/-13.8% of the day in on phases 36 months postsurgery). Progress appears to be stepwise, starting within weeks of tranplantation and becoming clinically significant in the 2nd and 3rd months (similar to our AM- and sooner than in our FVM-implanted patients), followed by a period of stability and, after a second wave of improvement 12 to 18 months posttransplantation (similar to FVM implants), has continued (87.5+/-7 points presurgery to 46+/-5.6 points 36 months postsurgery). In the experimental group, doses of levodopa have been reduced by more than 60% and dopamine agonist use has not resumed. In contrast, there have been no significant clinical changes in the control group. CONCLUSIONS: Implantation of tissue other than fetal tissue can promote a long-term improvement in the clinical symptomatology of seriously disabled parkinsonian patients. This finding is supported by the autopsy report of a patient with PD who had undergone grafting of AM plus peripheral nerve in which it was demonstrated that a large number of tyrosine hydroxylase-positive cells survive 1 year after implantation. In addition, there was a dense network of host dopaminergic fibers around the graft.

Long-term improvement in patients with severe Parkinson's disease after implantation of fetal ventral mesencephalic tissue in a cavity of the caudate nucleus: 5-year follow up in 10 patients. Clinica Puerta de Hierro Neural Transplantation Group.

Different groups worldwide have observed in recent years that stereotactic implantation of fetal tissue can ameliorate the clinical symptoms of Parkinson's disease. The authors therefore investigated whether implantation of fetal ventral mesencephalic (FVM) tissue via open surgery is also capable of producing an improvement and whether this improvement is transient or long lasting. The authors report their findings in a 5-year follow-up study in 10 patients with Hoehn and Yahr Grade IV or V Parkinson's disease in whom a single FVM graft was implanted in a cavity created in the right caudate nucleus. The results indicate that the implants improved motor function and that clinical recovery persisted in seven of the 10 patients 5 years after implantation. Amelioration was observed in both the on and off phases and was accompanied by a 64% reduction in the levodopa dose and withdrawal of the dopamine agonist. The on phase was prolonged from 39% of the waking day to 72%, with reduced intensity and duration of dyskinesias. All symptoms that were analyzed showed improvement, although they differed in intensity and time of onset. The course of improvement seemed to be stepwise, with significant improvement between 5 and 7 months postimplantation followed by two waves of progress peaking in Months 15 and 36. Withdrawal of cyclosporine in three patients after more than 2 years of administration produced a decline in the patients' clinical conditions. In conclusion, the results indicate that open surgery implantation of FVM tissue in the caudate nucleus improves the clinical condition of parkinsonian patients and that this improvement can persist for at least 5 years. In comparison with two earlier series reported by the authors, which involved implants of perfused adrenal medulla and coimplantation of adrenal medulla and peripheral nerve, the course and pattern of improvement in these implant recipients suggests that their recovery can be attributed to more than one factor.

Clinical experience with cotransplantation of peripheral nerve and adrenal medulla in patients with Parkinson's disease.

Coimplants of adrenal medulla (AM) and peripheral nerve (PN) in animal models of Parkinson's disease (PD) have shown that AM cells survive longer, tend to show neuronal phenotype, and enhance sprouting of host fibers. Since 1987, our implants of perfused AM and fetal ventral mesencephalon (FVM) in PD patients have achieved varying degrees of clinical improvement. If the donor tissue determines the improvement, different types of implants should result in qualitatively and quantitatively different degrees of improvement. The purpose of this study is to determine whether or not the clinical course, improvement slope, and reduction of medication observed in PD patients who undergo tissue transplantation (Tx) depend on the donor tissue type. In a pilot study, four grade IV-V PD patients received implants of precoincubated autologous AM and intercostal nerve in the caudate nucleus (open surgery). Clinical assessment was based on international scales (UPD) as reported for Tx of FVM and perfused AM. There were no systemic or neurologic complications. Four years post-Tx, longer On phases and improved PD symptoms (ADL and motor-UPD) in On and Off persist in four cases, with reduced dyskinesias. Progress appears to be stepwise, starting within weeks of Tx (similar to AM and sooner than our FVM implants), followed by a period of stability and, after a second wave of improvement 12-18 months post-Tx (similar to FVM implants), continues to date. L-dopa medication has been reduced by more than 60% and dopamine agonist use has not resumed. We conclude that our recipients continue to be clinically better than prior to Tx. The course of recovery after co-Tx of AM and PN differs from that of FVM or AM implants. This fact may be related to the etiological factors that produce the improvement.

[Preparation of a levodopa/carbidopa solution in ascorbic acid (citridopa) and chromatographic and electrochemical assessment of its stability over 24 hours]. / Preparación de una disolución de levodopa/carbidopa en ácido ascórbico (citrodopa) y valoración de su estabilidad durante 24 horas mediante cromatografía y detección electroquímica.

Levodopa/inhibitor improves motor function in parkinsonian patients. In its usual tablet form, however, its efficacy is reduced after several years, partially due to absorption deficiencies and changes in plasma kinetics; thus, other therapeutic strategies to provide a stable, easy to prepare formula are being sought. One such approach could be to dissolve L-dopa/carbidopa in ascorbic acid. This report describes the preparation method and demonstrates the stability of the sample using High pressure liquid cromatography (HPLC) with electrochemical detection. Regardless of the number of tablets the patient takes, the concentration of L-dopa/carbidopa/ascorbic acid remains constant (1/0.25/2 mg/ml). Thus, a patient taking 5 tablets of Sinemet Plus a day, would pulverize them in a glass, ceramic or marble mortar and add them to a measuring cup containing a 1 gram tablet of vitamin C (Redoxon) dissolved in 500 cc of cold water. This would be shaken or stirred until the Sinemet powder had dissolved. A few particles remaining in suspension after this process would be of no concern. The liquid would be stored in the refrigerator in an opaque or aluminum foil-covered glass bottle or, if possible, in several small dose-size vials. Using a measuring cup, a test tube and a syringe, the correct volume can be drawn out of the bottle and shaken well before drinking. The solution would be taken at regular intervals throughout the day (which vary from one patient to another) to maintain stable plasma L-dopa levels.

Bromazepam-induced dystonia.

Benzodiazepines are drugs with a good tolerance that are widely used for the treatment of anxiety. Extrapyramidal side-effects are unusual. Diazepam is effective for the treatment of drug-induced dystonias, nevertheless there are some reports of Diazepam-induced dystonia. We report a case history of a patient who developed oromandibular dystonia after taking Bromazepam. The possible mechanisms that cause drug-induced dystonia are described.

Grafting of perfused adrenal medullary tissue into the caudate nucleus of patients with Parkinson's disease. Clinica Puerta de Hierro Neural Transplantation Group.

The authors report results obtained in 20 severely affected patients with Parkinson's disease (Grade IV or V) who received an autotransplant of perfused adrenal medullary tissue. This study seems to indicate that these autoimplants can improve the parkinsonian symptomatology and induce amelioration in the patients' performance of routine activities. All the symptoms analyzed showed improvement, although it differed in intensity and time of onset. Moreover, this improvement was accompanied by a reduction in the daily intake of L-dopa, with discontinuance of dopamine agonists and amantadine. A number of medical complications were encountered, including three deaths, probably related to performing abdominal surgery in seriously affected parkinsonian patients who were unable to tolerate the discontinuance of their medication. The transient psychiatric disorders observed appeared to be related to the postoperative dose of L-dopa and/or anticholinergic agents administered, and diminished or disappeared when the doses were reduced. The reasons for improvement, which was bilateral, remain unknown, although one cause may be the surgical trauma (minicaudotomy) together with the implantation of adrenal medullary tissue, which may promote the sprouting of surviving dopaminergic fibers. Moreover, in this series, perfusion of adrenal medulla increased the capacity for revascularization of the tissue and may have reduced the damaging effects of warm ischemia on the cells. This, together with the existence of fenestrated vessels, could hypothetically have served as an access point for drugs, and if the implanted cells were viable, they might have served to store and manufacture different factors and/or transmitters. These results as well as those of other groups justify the development of a controlled international clinical trial.