Lack of validation of variants associated with cervical dystonia risk: a GWAS replication study.

BACKGROUND: A recent genome-wide association study (GWAS) has identified a putative association, not statistically confirmed, of cervical dystonia within several regions in a British population. Hence, the authors proposed dysfunction of the ion channel NALCN (for sodium leak channel, nonselective) as a plausible cause of cervical dystonia. The objective of our study was to investigate the association of five single nucleotide polymorphisms (SNPs) previously reported with high signals as putative genetic risk factors for cervical dystonia in a British GWAS, including two located in the NALCN gene region. METHODS: We performed a case-control association study in a Spanish population. The SNPs selected for genotyping were two SNPS in the NALCN gene (rs61973742 and rs1338041), one SNP in the OR4X2 gene (rs67863238), one SNP in the COL4A1 region (rs619152), and one intergenic SNP (rs1249277). Genomic DNA was collected from 252 patients with cervical dystonia, with a mean age of 55.3 ± 14.1 years (mean age at onset, 43.5 ± 15.7 years), and 342 unrelated control subjects with a mean age of 56.3 ± 14.3 years. Genotyping of SNPs was performed using TaqMan assays and SimpleProbe assays. RESULTS: The SNP rs619152 had to be excluded because of assay failure. No significant differences were found in allele distribution between cases and controls for all analyzed SNPs. Therefore, we found no association with cervical dystonia for the analyzed SNPs in our Spanish population. CONCLUSIONS: We did not find any evidence supporting the association of NALCN with cervical dystonia, indicating that this gene is not implicated in the pathogenesis of this disorder in our cervical dystonia population.

BDNF Val66Met polymorphism in primary adult-onset dystonia: a case-control study and meta-analysis.

BACKGROUND: A polymorphism in brain-derived neurotrophic factor (BDNF) (Val66Met) has been reported as a risk factor in primary dystonia. However, overall the results have been inconclusive. Our aim was to clarify the association of Val66Met with primary dystonia, and with the most prevalent clinical subtypes, cervical dystonia and blepharospasm. METHODS: We conducted a Spanish multicenter case-control study (including 680 primary dystonia patients and 788 healthy controls) and performed a meta-analysis integrating our study and six previously published studies (including a total of 1,936 primary dystonia patients and 2,519 healthy controls). RESULTS: We found no allelic or genotypic association with primary dystonia, cervical dystonia, or blepharospasm risks, for the allele A (Met) from a BDNF Val66Met polymorphism in our case-control study. This was confirmed by results from our meta-analysis in white and mixed ethnic populations in any genetic model. CONCLUSION: We did not find any evidence supporting the association of the BDNF Val66Met polymorphism with primary dystonia.

Mesencephalic area measured by transcranial sonography in the differential diagnosis of parkinsonism.

BACKGROUND: Transcranial B-mode sonography (TCS) has become an important tool in the differential diagnosis of parkinsonism given that current technology enables an adequate assessment of brain structures. In this study we aimed at evaluating the usefulness of midbrain area measured by TCS in the differential diagnosis between Parkinson's Disease (PD) and Progressive Supranuclear Palsy (PSP). METHODS: Patients with a diagnosis of PD or PSP according to current clinical criteria were recruited. PSP patients were classified as Richardson's syndrome and PSP-parkinsonism. TCS was performed and the mesencephalic area and third ventricle width were measured offline by an examiner blinded to clinical diagnosis. RESULTS: TCS was performed in 60 patients (75% PD, 25% PSP). Eight patients (13,3%) had inadequate acoustic window. Patients with PSP had a smaller mesencephalic area (3.58 cm(2) vs 5.28 cm(2), p < 0.001). A mesencephalic area ≥4.27 cm(2) discriminates PD from PSP with a positive predictive value 100%. Patients with PSP also had a higher third ventricle diameter (8.84 mm vs 5.11 mm, p < 0.001). Within the PSP group patients with Richardson's syndrome had a wider third ventricle than patients with PSP-Parkinsonism phenotype (9.57 mm vs 7 mm, p = 0.01), but no differences were found in the mesencephalic area between both phenotypes. CONCLUSIONS: Measurement of the mesencephalic area and the third ventricle width by TCS is a non-invasive, easily accessible technique that is useful in the differential diagnosis between PD and PSP, at least in the late stages of the disease.

Evaluación de la sustancia negra mediante ultrasonografía transcraneal / Evaluation of the substantia nigra by means of transcranial ultrasound imaging

Objetivo. Describir la prevalencia de la hiperecogenicidad de la sustancia negra en dos muestras de pacientes, unos con diagnóstico de enfermedad de Parkinson (EP) según los criterios de la United Kingdom Parkinson’s Disease Society, y una población control, con el fin de establecer los propios valores de referencia para nuestro laboratorio de neurosonología. Sujetos y métodos. Se seleccionaron dos muestras de pacientes compuestos por controles sanos sin enfermedad neurodegenerativa y pacientes con EP. Se realizaron mediciones planimétricas del área de ecogenicidad de la sustancia negra en ambos grupos. Se consideró la mayor área de ecogenicidad medida en cada lado en cada paciente. Se realizaron estadísticos descriptivos de la muestra. Se construyó la curva ROC para mostrar la precisión global, la sensibilidad y la especificidad del Doppler transcraneal en comparación con el diagnóstico clínico de EP. Resultados. Se analizaron en total 45 pacientes con EP y 91 controles. Empleando nuestro propio punto de co e (percentil 90 de los controles = 0,22 cm2), presentaban hiperecogenicidad de la sustancia negra un 73,33% de los pacientes con EP y un 8,79% de los controles (p = 0). Se pudo apreciar un área bajo la curva del 93%, lo que expresa una buena precisión global del Doppler transcraneal en el diagnóstico de EP. Conclusiones. La evaluación ultrasonográfica de la sustancia negra consigue detectar en nuestro laboratorio diferencias significativas entre los sujetos con EP y los sujetos normales. Los valores obtenidos en nuestro laboratorio están ligeramente por debajo de los establecidos como referencia internacional, y ofrecen unos excelentes valores de especificad y una aceptable sensibilidad en nuestro medio (AU)

Aim. To describe the prevalence of hyperechogenicity of the substantia nigra in two samples of patients: one group who had been diagnosed with Parkinson’s disease (PD) in accordance with United Kingdom Parkinson’s Disease Society criteria and a control population, so as to be able to establish the reference values for our neurosonology laboratory Subjects and methods. Two samples of patients consisting of healthy controls with no neurodegenerative disease and patients with PD were selected. Planimetric measurements of the area of echogenicity in the substantia nigra were performed in both groups. The greatest area of echogenicity measured on each side of each patient was considered. Descriptive statistics of the sample were carried out. The ROC curve was constructed in order to show the overall precision, sensitivity and specificity of transcranial Doppler ultrasonography in comparison to the clinical diagnosis of PD. Results. Altogether 45 patients with PD and 91 controls were analysed. Using our own cut-off point (percentile 90 of the controls = 0.22 cm2), hyperechogenicity of the substantia nigra was observed in 73.33% of patients with PD and 8.79% of the controls (p = 0). An area below the curve of 93% was seen, which represents good overall precision for transcranial Doppler ultrasonography in the diagnosis of PD. Conclusions. The evaluation of the substantia nigra conducted in our laboratory using ultrasound imaging reveals significant differences between subjects with PD and normal subjects. The values obtained in our laboratory are slightly below those established as an international reference and offer excellent values for specificity and an acceptable level of sensitivity in our locale (AU)

[Evaluation of the substantia nigra by means of transcranial ultrasound imaging]. / Evaluacion de la sustancia negra mediante ultrasonografia transcraneal.

AIM. To describe the prevalence of hyperechogenicity of the substantia nigra in two samples of patients: one group who had been diagnosed with Parkinson's disease (PD) in accordance with United Kingdom Parkinson's Disease Society criteria and a control population, so as to be able to establish the reference values for our neurosonology laboratory. SUBJECTS AND METHODS. Two samples of patients consisting of healthy controls with no neurodegenerative disease and patients with PD were selected. Planimetric measurements of the area of echogenicity in the substantia nigra were performed in both groups. The greatest area of echogenicity measured on each side of each patient was considered. Descriptive statistics of the sample were carried out. The ROC curve was constructed in order to show the overall precision, sensitivity and specificity of transcranial Doppler ultrasonography in comparison to the clinical diagnosis of PD. RESULTS. Altogether 45 patients with PD and 91 controls were analysed. Using our own cut-off point (percentile 90 of the controls = 0.22 cm2), hyperechogenicity of the substantia nigra was observed in 73.33% of patients with PD and 8.79% of the controls (p = 0). An area below the curve of 93% was seen, which represents good overall precision for transcranial Doppler ultrasonography in the diagnosis of PD. CONCLUSIONS. The evaluation of the substantia nigra conducted in our laboratory using ultrasound imaging reveals significant differences between subjects with PD and normal subjects. The values obtained in our laboratory are slightly below those established as an international reference and offer excellent values for specificity and an acceptable level of sensitivity in our locale.

Propuesta alternativa al test de apomorfina habitual / Proposed alternative to standard apomorphine challenge test

La apomorfina en inyecciones subcutáneas intermitentes se emplea como tratamiento de rescate de los períodos off en la enfermedad de Parkinson moderada-avanzada y para cuando se requiera evaluar la respuesta dopaminérgica. No es recomendable como prueba diagnóstica en la enfermedad de Parkinson, porque tiene más efectos adversos y es inferior a la respuesta crónica con levodopa. Para calcular la dosis se hace un test con apomorfina, que, en general, conlleva bastante tiempo y pruebas con dosis diversas. Proponemos un test alternativo, con una sola inyección, con una dosis inicial mayor, de entre 2-4 mg, y pautar el tratamiento según la respuesta obtenida a esta dosis. Con ello se gana tiempo y, además, se pueden preestablecer mucho mejor los tiempos de atención (AU)

Subcutaneous apomorphine injection is used as a rescue treatment in the off periods in moderate and advanced Parkinson’s disease and also when required to assess the dopaminergic response. It is not recommended as a diagnostic tool in Parkinson’s disease because it has more side effects and is less specific than chronic response to levodopa. To calculate the dosage, an apomorphine challenge test is performed, generally taking quite time and testing several doses. We propose an alternative apomorphine challenge test, with a single injection and a higher initial dosage of 2-4 mg, as well as to schedule treatment according to the obtained response at that dosage. This procedure saves time and also allows a better planning of medical attention (AU

Levodopa en el tratamiento de la enfermedad de Parkinson: mitos y realidades / Levodopa in the treatment of Parkinson’s disease: myths and realties

Durante los últimos años hemos sido testigos de una utilización preferente de agonistas dopaminérgicos (AD) como tratamiento de la enfermedad de Parkinson (EP), con la intención de retrasar en lo posible el desarrollo de fluctuaciones y discinesias. Sin embargo, la levodopa continúa siendo el fármaco antiparkinsoniano más eficaz y, probablemente, el que mejora un mayor número de síntomas de la enfermedad. En este artículo se ha realizado una revisión exhaustiva de la literatura por parte de un grupo de neurólogos expertos y miembros del Grupo de Trastornos del Movimiento de la Sociedad Española de Neurología sobre los beneficios y riesgos del tratamiento con levodopa en pacientes con EP. La principal conclusión de este artículo es que la levodopa continúa siendo el tratamiento más eficaz para la EP. Aunque el riesgo y la incidencia de desarrollar discinesias se mantiene en un nivel menor en el grupo tratado inicialmente con AD, el número de pacientes que desarrollan discinesias incapacitantes es muy bajo en todos los estudios y similar para los AD y la levodopa, y las escalas de calidad de vida son también similares en ambos grupos, lo que cuestiona el impacto que estas complicaciones motoras tienen sobre la calidad de vida de los pacientes con EP. A la vista de estos resultados, deberíamos plantearnos si está justificado privar a los pacientes del buen control de los síntomas que proporciona la levodopa por el temor a que desarrollen discinesias o fluctuaciones motoras leves que no van a mermar su calidad de vida. A ello hay que añadir la posibilidad de que desarrollen efectos secundarios graves, que son más frecuentes con el uso de AD (AU)

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

[Proposed alternative to standard apomorphine challenge test]. / Propuesta alternativa al test de apomorfina habitual.

Subcutaneous apomorphine injection is used as a rescue treatment in the off periods in moderate and advanced Parkinson's disease and also when required to assess the dopaminergic response. It is not recommended as a diagnostic tool in Parkinson's disease because it has more side effects and is less specific than chronic response to levodopa. To calculate the dosage, an apomorphine challenge test is performed, generally taking quite time and testing several doses. We propose an alternative apomorphine challenge test, with a single injection and a higher initial dosage of 2-4 mg, as well as to schedule treatment according to the obtained response at that dosage. This procedure saves time and also allows a better planning of medical attention.

[Levodopa in the treatment of Parkinson's disease: myths and realties]. / Levodopa en el tratamiento de la enfermedad de Parkinson: mitos y realidades.

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

Diagnóstico clínico de la enfermedad de Parkinson. ¿Se podrá conocer la base genética de la enfermedad de Parkinson esporádica? / The clinical diagnosis of Parkinson's disease. Will it be possible to determine the genetic base of sporadic Parkinson's disease?

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[Familial idiopathic paroxysmal kinesigenic dyskinesia: its natural history and a descriptive study in three Spanish families]. / Discinesia paroxistica cinesigenica idiopatica familiar: evolucion natural y estudio descriptivo en tres familias espanolas.

INTRODUCTION: Paroxysmal kinesigenic dyskinesia (PKD) is a disorder that is characterised by brief episodes of involuntary movements triggered by other sudden movements. PATIENTS AND METHODS: Here we describe the cases of nine patients from three unrelated families who had PKD in its familial idiopathic form. RESULTS: The majority of the patients (77.7%) were males. The mean age at onset was 10.3 years. All the subjects presented sudden movements as factors that precipitated the crises, which lasted < 10 s in 88.8% of cases. Two thirds (66.6%) of the patients were treated with carbamazepine, phenytoin and valproic acid and all of them responded well. Spontaneous remission occurred in 62.5% of the patients over 20 years of age and in a further 25% there was a significant decrease in the number of crises. CONCLUSIONS: In our sample the proportion of patients who presented spontaneous remission was greater than in that reported in previous studies. As in other series, we found positive responses to antiepileptic drugs other than carbamazepine.

Discinesia paroxística cinesigénica idiopática familiar: evolución natural y estudio descriptivo en tres familias españolas / Familial idiopathic paroxysmal kinesigenic dyskinesia: its natural history and a descriptive study in three Spanish families

Introducción. La discinesia paroxística cinesigénica (DPC) es un trastorno caracterizado por episodios breves de movimientos involuntarios inducidos por movimientos súbitos. Pacientes y métodos. Se describe a nueve pacientes pertenecientes a tres familias no relacionadas, afectados de DPC en su forma idiopática familiar. Resultados. Un 77,7 % de los pacientes son varones. La edad media de inicio es 10,3 años. Todos los sujetos presentaban movimientos súbitos como desencadenante de la crisis. La duración de éstas fue < 10 s en el 88,8% de los casos. Un 66,6% de los pacientes recibió tratamiento con carbamacepina, fenitoína y ácido valproico; en todos los casos se obtuvo una buena respuesta. En el 62,5% de los pacientes mayores de 20 años se ha producido una remisión espontánea y en un 25% una disminución significativa del número de crisis. Conclusiones. En nuestra muestra hay una proporción mayor de pacientes que presentan una remisión espontánea respecto a lo descrito en estudios anteriores. Al igual que en otras series, encontramos respuestas positivas a otros fármacos antiepilépticos diferentes de la carbamacepina (AU)

Introduction. Paroxysmal kinesigenic dyskinesia (PKD) is a disorder that is characterised by brief episodes of involuntary movements triggered by other sudden movements. Patients and methods. Here we describe the cases of nine patients from three unrelated families who had PKD in its familial idiopathic form. Results. The majority of the patients (77.7%) were males. The mean age at onset was 10.3 years. All the subjects presented sudden movements as factors that precipitated the crises, which lasted < 10 s in 88.8% of cases. Two thirds (66.6%) of the patients were treated with carbamazepine, phenytoin and valproic acid and all of them responded well. Spontaneous remission occurred in 62.5% of the patients over 20 years of age and in a further 25% there was a significant decrease in the number of crises. Conclusions. In our sample the proportion of patients who presented spontaneous remission was greater than in that reported in previous studies. As in other series, we found positive responses to antiepileptic drugs other than carbamazepine (AU)

Oromandibular dystonia: A dental approach

Oromandibular dystonia consists of prolonged spasms of contraction of the muscles of the mouth and jaw. Primaryidiopathic forms and secondary forms exist. Secondary dystonia develops due to environmental factors;some cases of cranial dystonia after dental procedure have been reported, but the causal relationship betweenthese procedures and dystonia remains unclear. Traumatic situations in the mouth, such as poor aligned denturesor multiple teeth extractions may cause an impairment of proprioception of the oral cavity, leading to subsequentdevelopment of dystonia. The clinical characteristics of oromandibular dystonia are classified according to theaffected muscles. The muscles involved may be the muscles of mastication, muscles of facial expression, or themuscles of the tongue. At present, there is no known cure for OMD. The mainstay of treatment for most focaldystonia is botulinum toxin injections. It is important for the dentist to be familiar with oromandibular dystonia,as it can develop after dental treatment and is often misdiagnosed as a dental problem (AU)

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Oromandibular dystonia: a dental approach.

Oromandibular dystonia consists of prolonged spasms of contraction of the muscles of the mouth and jaw. Primary idiopathic forms and secondary forms exist. Secondary dystonia develops due to environmental factors; some cases of cranial dystonia after dental procedure have been reported, but the causal relationship between these procedures and dystonia remains unclear. Traumatic situations in the mouth, such as poor aligned dentures or multiple teeth extractions may cause an impairment of proprioception of the oral cavity, leading to subsequent development of dystonia. The clinical characteristics of oromandibular dystonia are classified according to the affected muscles. The muscles involved may be the muscles of mastication, muscles of facial expression, or the muscles of the tongue. At present, there is no known cure for OMD. The mainstay of treatment for most focal dystonia is botulinum toxin injections. It is important for the dentist to be familiar with oromandibular dystonia, as it can develop after dental treatment and is often misdiagnosed as a dental problem.