Distonía mioclónica y ataxia cerebelosa en la autoinmunidad antiglutámico-descarboxilasa / Myoclonus-dystonia and cerebellar ataxia in association with anti-glutamic acid decarboxylase autoimmunity

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Hemorragia subaracnoidea de la convexidad cerebral causada por telangiectasia hereditaria hemorrágica / Convexity subarachnoid haemorrhage secondary to hereditary haemorrhagic telangiectasia

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Meningitis aséptica y anticuerpos anti-Beta-2-glicoproteína-1 en el síndrome de Sweet / Aseptic meningitis and anti-Beta-2-glycoprotein 1 antibodies in Sweet syndrome

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Migralepsia y migraña en el puerperio / Migralepsy and migraine in the puerperal period

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[Myths and evidence on the use of botulinum toxin: neuropharmacology and dystonia]. / Mitos y evidencias en el empleo de la toxina botulinica: neurofarmacologia y distonias.

INTRODUCTION: Botulinum toxin type A (BTA) is a bacterial endotoxin, whose therapeutic use has had a dramatic impact on different neurological disorders, such as dystonia and spasticity. AIM: To analyze and summarize different questions about the use of BTA in our clinical practice. DEVELOPMENT: A group of experts in neurology developed a list of topics related with the use of BTA. Two groups were considered: neuropharmacology and dystonia. A literature search at PubMed, mainly for English language articles published up to June 2016 was performed. The manuscript was structured as a questionnaire that includes those questions that, according to the panel opinion, could generate more controversy or doubt. The initial draft was reviewed by the expert panel members to allow modifications, and after subsequent revisions for achieving the highest degree of consensus, the final text was then validated. Different questions about diverse aspects of neuropharmacology, such as mechanism of action, bioequivalence of the different preparations, immunogenicity, etc. were included. Regarding dystonia, the document included questions about methods of evaluation, cervical dystonia, blepharospasm, etc. CONCLUSION: This review does not pretend to be a guide, but rather a tool for continuous training of residents and specialists in neurology, about different specific areas of the management of BTA.

TITLE: Mitos y evidencias en el empleo de la toxina botulinica: neurofarmacologia y distonias.Introduccion. La toxina botulinica de tipo A (TBA) ha supuesto una verdadera revolucion terapeutica en neurologia, y en la actualidad es el tratamiento rutinario en las distonias focales y la espasticidad. Objetivo. Plantear, revisar y responder cuestiones controvertidas en relacion con la neurofarmacologia de la TBA y su uso en las distonias en la practica clinica habitual. Desarrollo. Un grupo de expertos en trastornos del movimiento reviso una lista de temas controvertidos relacionados con la farmacologia de la TBA y su uso en las distonias. Revisamos la bibliografia e incluimos articulos relevantes especialmente en ingles, pero tambien, si su importancia lo merece, en castellano y en frances, hasta junio de 2016. El documento se estructuro como un cuestionario que incluyo las preguntas que podrian generar mayor controversia o duda. El borrador inicial del documento fue revisado por los miembros del panel y se realizaron las modificaciones necesarias hasta alcanzar el mayor grado de consenso. Incluimos preguntas sobre diferentes aspectos de la neurofarmacologia, especialmente el mecanismo de accion, la bioequivalencia de los diferentes preparados y la inmunogenicidad. En relacion con el subapartado de las distonias, se incluyeron aspectos sobre la evaluacion y el tratamiento de las distonias focales. Conclusiones. Esta revision no pretende ser una guia, sino una herramienta practica destinada a neurologos y medicos internos residentes interesados en esta area, dentro de diferentes ambitos especificos del manejo de la TBA.

Hallazgo de hipertrofia de la capa de fibras nerviosas de la retina en pacientes con ataxia de Charlevoix-Saguenay / Finding of retinal nerve fiber layer hypertrophy in ataxia of Charlevoix-Saguenay patients

OBJETIVO/MÉTODO: Se presenta la evaluación neurooftalmológica de cinco pacientes con ataxia espástica de Charlevoix-Saguenay (ARSACS). RESULTADOS/CONCLUSIONES: Los pacientes mostraron alteración en el campo visual, aumento de la visualización de la CFNR en las estereofotografías, nervio óptico de morfología normal en la evaluación con Heidelberg Retina Tomograph e incremento marcado del espesor de la CFNR en la tomografía de coherencia óptica (119-220 μm). Encontramos evidencia de que la hipertrofia de CFNR puede ser un hallazgo funduscópico alternativo a la persistencia de fibras de mielina descrita en la bibliografía previa. Se aconseja realizar una revisión de los criterios diagnósticos de la ARSACS

PURPOSE/METHODS: To present the neuro-ophthalmology examination in 5 spastic ataxia of Charlevoix-Saguenay (ARSACS) patients showing significant increases in retinal nerve fiber layer (RNFL) thickness. RESULTS/CONCLUSIONS: All patients showed abnormal visual fields, normal optic discs with increased visibility of RNFL in color stereo-photographs, normal examination with Heidelberg Retina Tomography instrument, and moderate to markedly increased RNFL thickness in Cirrus Optical Coherence Tomography evaluation (average thickness: 119 to 220 microns). We found evidence that RNFL hypertrophy may be an alternative funduscopic finding to the hypermyelinated retinal fibers in previous reports. A revision of ARSACS diagnostic criteria, particularly with regard to retinal alterations, is necessary

[Finding of retinal nerve fiber layer hypertrophy in ataxia of Charlevoix-Saguenay patients]. / Hallazgo de hipertrofia de la capa de fibras nerviosas de la retina en pacientes con ataxia de Charlevoix-Saguenay.

PURPOSE/METHODS: To present the neuro-ophthalmology examination in 5 spastic ataxia of Charlevoix-Saguenay (ARSACS) patients showing significant increases in retinal nerve fiber layer (RNFL) thickness. RESULTS/CONCLUSIONS: All patients showed abnormal visual fields, normal optic discs with increased visibility of RNFL in color stereo-photographs, normal examination with Heidelberg Retina Tomography instrument, and moderate to markedly increased RNFL thickness in Cirrus Optical Coherence Tomography evaluation (average thickness: 119 to 220 microns). We found evidence that RNFL hypertrophy may be an alternative funduscopic finding to the hypermyelinated retinal fibers in previous reports. A revision of ARSACS diagnostic criteria, particularly with regard to retinal alterations, is necessary.

Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients.

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.

Single-blind, placebo-controlled pilot study of pregabalin for ataxia in cortical cerebellar atrophy.

OBJECTIVE: To preliminarily compare the efficacy of pregabalin with that of placebo on the cerebellar signs caused by cortical cerebellar atrophy (CCA). A deficiency of gamma-aminobutyric acid (GABA) has been described in the cerebellum in CCA, and pregabalin has been shown to enhance GABA release in rat hippocampus. PATIENTS AND METHODS: Two consecutive patients with clinical diagnoses of CCA took part in the study. A placebo and pregabalin, 225 mg per day, were administered in a single-blind scheme during 15 day periods to every patient; cerebellar function was evaluated with the Scale for the Assessment and Rating of Ataxia (SARA) at the end of each period. A video recording of the SARA items performed by the first patient accompanies this article. RESULTS: Total SARA scores of 19 and 15 were obtained for the patients after placebo administration. The SARA scores decreased to 11 and 8, respectively, with the administration of pregabalin; an important amelioration of the ataxia was also evident. Both patients preferred continuing treatment with pregabalin when the trial was over. CONCLUSION: Pregabalin was superior to placebo in the improvement of the cerebellar signs caused by CCA. Further studies are needed to confirm the present results.

[An update on neurochemistry and pharmacological therapy of the cerebellar ataxias]. / Actualización en neuroquímica y terapéutica farmacológica de las ataxias cerebelosas.

AIM: To review the available neurochemical data on the different cerebellar ataxias, and the therapeutic trials undertaken in the last twenty-five years. DEVELOPMENT: The cerebellar ataxias have been classified according to the compromised structures in cortical cerebellar atrophies, olivopontocerebellar atrophies, spinocerebellar atrophies, and degenerations of the dentate nucleus and efferent tracts of the cerebellum. Episodic ataxias have been included, as they are eminently treatable. No nosological, nor genetic classification has been followed in this article. In each section, the (frequently fragmentary) neurochemical data is presented first, followed by the most relevant attempts at pharmacological therapy undertaken in the last twenty-five years. As can be observed from the reviewed data, neurochemical principles have rarely been applied in the majority of the analysed clinical trials. An outline of the physiological neurotransmission of the cerebellum is given at the beginning of this article. CONCLUSION: A systematic search for treatable ataxias is emphasized, as a response to the severity of the degenerative conditions. The use of GABAergic drugs is proposed in ataxias associated with a deficiency of GABA in the brain, and that of glutamatergic agents, for ataxias associated with glutamate deficiency. The use of serotoninergic and cholinergic drugs is ruled out due to insufficient neurochemical evidence. It is proposed that research on remedies for the cerebellar ataxias should be based on either molecular data, or on neurochemical data, in its defect. To this end, the study of animal or experimental models of ataxia, the use of objective methods for the measurement of ataxia, and the recruitment of homogenous study populations, are all recommended.

Actualización en neuroquímica y terapéutica farmacológica de las ataxias cerebelosas / An update on neurochemistry and pharmacological therapy of the cerebellar ataxias

Objetivo. Recopilar los datos neuroquímicos disponibles sobre las diferentes ataxias cerebelosas y los múltiples ensayos terapéuticos realizados hasta el momento actual. Desarrollo. Se han clasificado las ataxias cerebelosas, según las estructuras afectadas, en atrofias cerebelosas corticales, atrofias olivopontocerebelosas, atrofias espinocerebelosas, degeneraciones del núcleo dentado y vías eferentes del cerebelo, y se han incluido las ataxias episódicas al ser eminentemente tratables. No se ha seguido, por tanto, ninguna clasificación nosológica o genética. Primero se han expuesto en cada apartado los datos neuroquímicos, que han resultado incompletos en ocasiones, y a continuación, los intentos de terapéutica farmacológica más relevantes realizados en los últimos 25 años. Tal como se desprende de los datos presentados, los fundamentos neuroquímicos han sido escasamente atendidos en la mayor parte de los ensayos clínicos analizados. Se repasa la neurotransmisión fisiológica del cerebelo al comienzo del trabajo. Conclusión. Se plantea la búsqueda sistemática de ataxias tratables, ante la gravedad de las degenerativas. Se propugna el empleo de fármacos gabérgicos en ataxias que conllevan una deficiencia de GABA, y el de fármacos glutamatérgicos en otras con escasez de glutamato, y se desestima el uso de fármacos serotoninérgicos por carecer de base neuroquímica suficiente. La búsqueda de remedios curativos para las ataxias cerebelosas debería basarse en datos moleculares o, en su defecto, en otros de tipo neuroquímico. Para ello, se aconseja el estudio de modelos animales o experimentales, el empleo de métodos de medición objetiva de la ataxia y el reclutamiento de poblaciones de estudio homogéneas(AU)

Aim. To review the available neurochemical data on the different cerebellar ataxias, and the therapeutic trials undertaken in the last twenty-five years. Development. The cerebellar ataxias have been classified according to the compromised structures in cortical cerebellar atrophies, olivopontocerebellar atrophies, spinocerebellar atrophies, and degenerations of the dentate nucleus and efferent tracts of the cerebellum. Episodic ataxias have been included, as they are eminently treatable. No nosological, nor genetic classification has been followed in this article. In each section, the (frequently fragmentary) neurochemical data is presented first, followed by the most relevant attempts at pharmacological therapy undertaken in the last twenty-five years. As can be observed from the reviewed data, neurochemical principles have rarely been applied in the majority of the analysed clinical trials. An outline of the physiological neurotransmission of the cerebellum is given at the beginning of this article. Conclusion. A systematic search for treatable ataxias is emphasized, as a response to the severity of the degenerative conditions. The use of GABAergic drugs is proposed in ataxias associated with a deficiency of GABA in the brain, and that of glutamatergic agents, for ataxias associated with glutamate deficiency. The use of serotoninergic and cholinergic drugs is ruled out due to insufficient neurochemical evidence. It is proposed that research on remedies for the cerebellar ataxias should be based on either molecular data, or on neurochemical data, in its defect. To this end, the study of animal or experimental models of ataxia, the use of objective methods for the measurement of ataxia, and the recruitment of homogenous study populations, are all recommended (AU)

[P/Q-type voltage-dependent calcium channels in neurological disease]. / Canales de calcio dependientes de voltaje de tipo P/Q en neurología.

INTRODUCTION: Voltage-dependent calcium channels (VDCC) are hetero-multimeric complexes that mediate calcium influx into cells in response to changes in membrane potential. The alpha1A subunit, encoded by the CACNA1A gene, is the pore-forming structure specific to the neuronal P/Q-type voltage-dependent calcium channels (P/QCC), present exclusively in neurons. The ancillary subunits beta, alpha2delta and gamma, which are common to other VDCC, modulate alpha1A activity. P/QCC are involved in neuronal plasticity and survival, and mediate fast neurotransmission in the central and peripheral nervous system. Their highest levels of expression are found in the Purkinje cell layer of the cerebellum and in the hippocampus. METHODS: Congenital and acquired disturbances of the P/QCCs lay behind some neurological diseases, such as spinocerebellar ataxia type 6, episodic ataxia type 2 and paraneoplastic cerebellar degeneration; familial hemiplegic migraine; generalized convulsive epilepsy, generalized absence epilepsy and myasthenic syndrome of Lambert-Eaton. CONCLUSION: In this article, the structure and modulation of normal P/QCCs, and the neurological diseases caused by disturbances in these are reviewed. Electrophysiological characterization of mutated P/QCCs has yielded decreased calcium conductance in every case, compared with wild type channels. Research about calcium channelopathies should clarify how altered channel function produces disease and lead to new treatments for these conditions.

The P/Q-type voltage-dependent calcium channel: a therapeutic target in spinocerebellar ataxia type 6.

BACKGROUND: Voltage-dependent calcium channels (VDCCs) are heteromultimeric complexes that mediate calcium influx into cells; the alpha 1A subunit is the pore-forming subunit specific to the neuronal P/Q-type VDCCs. Spinocerebellar ataxia type 6 (SCA 6) is caused by an abnormal expansion of a CAG repeat in CACNA1A, which encodes the alpha 1A subunit. Heterologous expression of mutated alpha 1A subunits resulted in increased channel inactivation in electrophysiological tests. Gabapentin and pregabalin interact with the alpha 2 delta subunit of the VDCCs and improved ataxia in cases of cortical cerebellar atrophy (CCA) and ataxia-telangiectasia. MATERIALS AND METHODS: A bibliographical review was performed in order to find out if gabapentin and pregabalin could prove useful in the treatment of SCA 6. RESULTS: Gabapentin and pregabalin slowed the rate of inactivation in recombinant P/Q-type VDCCs. SCA 6 shares neuropathological findings with CCA. CONCLUSIONS: On the basis of the neuropathological identity of SCA 6 with CCA, and of the effect of gabapentin and pregabalin on recombinant VDCCs the authors put forward the hypothesis that these drugs might prove beneficial in SCA 6, as the ataxia would be expected to improve. The authors hope that researchers working with this illness will be encouraged to undertake the appropriate clinical and experimental work.

[Adult-onset ataxia-telangiectasia. A clinical and therapeutic observation]. / Ataxia-telangiectasia del adulto. Observación clínica y terapéutica.

A case of adult-onset ataxia-telangiectasia (AT) is presented, with debut at the age of 18 years and survival into the fourth decade. The clinical picture included cerebellar ataxia, distal weakness and hypopalesthesia in the lower limbs, oculomotor apraxia, dysarthria, and conjunctival telangiectasiae. Carcinoembrionic antigen was raised in plasma. MR imaging showed atrophy of the cerebellar vermis and thinning of the spinal cord. Deficiencies of gamma-aminobutyric acid and glutamate have been found in the cerebellar cortex in a case of AT. These were attributed to the loss of Purkinje cells and granule cells. In spite of some ataxias having improved with the gabaergic drugs gabapentin and tiagabine, the administration of gabapentin, acetazolamide and a placebo, did not benefit this patient. Pregabalin, 225 mg/day, ameliorated the ataxia unexpectedly, with further improvement after the addition of tiagabine. The authors suggest that the beneficial effect observed might have been due, either to the higher affinity of pregabalin towards alpha2-delta, a subtype of the alpha2-delta subunit which forms part of the voltage-gated calcium channel; either to the profusion of this subtype in the Purkinje cell layer, or to its larger capacity to let calcium into the neuron; or to the combination of these. These differences with gabapentin could explain the higher power of pregabalin in the stimulation of the cerebellar structures, thus justifying the improvement of ataxia in this case of AT. A synergistic effect with pregabalin is proposed as the cause of the improvement obtained with the addition of tiagabine.