Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.

The autosomal dominant spinocerebellar ataxias (SCAs) consist of a highly heterogeneous group of rare movement disorders characterized by progressive cerebellar ataxia variably associated with ophthalmoplegia, pyramidal and extrapyramidal signs, dementia, pigmentary retinopathy, seizures, lower motor neuron signs, or peripheral neuropathy. Over 41 different SCA subtypes have been described evidencing the high clinical and genetic heterogeneity. We previously reported a novel spinocerebellar ataxia type subtype, SCA37, linked to an 11-Mb genomic region on 1p32, in a large Spanish ataxia pedigree characterized by ataxia and a pure cerebellar syndrome distinctively presenting with early-altered vertical eye movements. Here we demonstrate the segregation of an unstable intronic ATTTC pentanucleotide repeat mutation within the 1p32 5' non-coding regulatory region of the gene encoding the reelin adaptor protein DAB1, implicated in neuronal migration, as the causative genetic defect of the disease in four Spanish SCA37 families. We describe the clinical-genetic correlation and the first SCA37 neuropathological findings caused by dysregulation of cerebellar DAB1 expression. Post-mortem neuropathology of two patients with SCA37 revealed severe loss of Purkinje cells with abundant astrogliosis, empty baskets, occasional axonal spheroids, and hypertrophic fibres by phosphorylated neurofilament immunostaining in the cerebellar cortex. The remaining cerebellar Purkinje neurons showed loss of calbindin immunoreactivity, aberrant dendrite arborization, nuclear pathology including lobulation, irregularity, and hyperchromatism, and multiple ubiquitinated perisomatic granules immunostained for DAB1. A subpopulation of Purkinje cells was found ectopically mispositioned within the cerebellar cortex. No significant neuropathological alterations were identified in other brain regions in agreement with a pure cerebellar syndrome. Importantly, we found that the ATTTC repeat mutation dysregulated DAB1 expression and induced an RNA switch resulting in the upregulation of reelin-DAB1 and PI3K/AKT signalling in the SCA37 cerebellum. This study reveals the unstable ATTTC repeat mutation within the DAB1 gene as the underlying genetic cause and provides evidence of reelin-DAB1 signalling dysregulation in the spinocerebellar ataxia type 37.

Monitoring CD49d Receptor Occupancy: A Method to Optimize and Personalize Natalizumab Therapy in Multiple Sclerosis Patients.

BACKGROUND: In natalizumab-treated relapsing-remitting MS (RRMS) patients, various extended interval dosing strategies are under evaluation to minimize severe treatment-associated side effects, mainly progressive multifocal leukoencephalopathy development. Up to now, it has not been presented any approach, even in form of assay design, to determine the optimal percentage of CD49d receptor occupancy (RO) associated with a favorable clinical, radiological, and immunological response. METHODS: A multiparametric quantitative flow cytometry method was settled to measure CD49d RO on peripheral blood lymphocytes. The analytical protocol was tested in a 6-month follow-up from 19 RRMS patients treated with the natalizumab standard dosing of every 4 weeks or an extended-interval dosing of every 6 weeks. RESULTS: Extended natalizumab dose schedule promoted an increase of CD49d molecules per cell surface and a reduction of CD49d RO levels. The reduction observed on CD49d RO was not only depending on dose schedule but also on individual parameters such as body mass. Interestingly, individual clinical outcome was apparently the same between the different dose schedules or even better with the extended interval dosing. CONCLUSIONS: Following up CD49d RO levels with a well-regulated monitoring work scheme is crucial to further identify over-/under-treated patients and to define a safe, personalized natalizumab regimen. © 2017 International Clinical Cytometry Society.

Fatigue Improvement after Switching Multiple Sclerosis Treatment from Interferon-ß to Glatiramer Acetate in Clinical Practice.

BACKGROUND/AIMS: The immunomodulatory effect of glatiramer acetate may help in reducing multiple sclerosis (MS)-related fatigue; however, evidence to prove this notion especially after switching from another immunomodulatory therapy is limited. We assessed the 6-month effect of glatiramer acetate on MS-related fatigue in patients switching from interferon-ß (IFN-ß) in clinical practice. METHODS: This was an observational study including 54 patients with relapsing-remitting MS that showed moderate/severe fatigue primarily caused by MS before switching from IFN-ß to glatiramer acetate and received glatiramer acetate for ≥6 months in daily practice. Study data were retrospectively collected through chart review at treatment switch and over the following 6 months on glatiramer acetate. RESULTS: Over the 6-month administration of glatiramer acetate, scores on the Modified Fatigue Impact Scale decreased: overall (p < 0.001), physical scale (p < 0.001), cognitive scale (p < 0.001), and psychosocial scale (p < 0.001). The Work Productivity and Activity Impairment Questionnaire showed improvements in work (p = 0.009) and other daily activity impairment (p < 0.001). Health-related quality of life as per the Multiple Sclerosis Impact Scale also improved: physical score (p < 0.001) and psychological score (p < 0.001). CONCLUSION: Patients with moderate/severe fatigue switching from IFN-ß to glatiramer acetate may benefit from fatigue improvements that contribute to reduce their work/activity impairment and improve their quality of life.

Resultados de un seguimiento prolongado de pacientes con ictus isquémicos criptogénicos / Outcome of a prolonged follow-up of patients with cryptogenic infarct

Objetivo: Analizar la evolución de los pacientes con un infarto criptogénico (IC) tras un año de seguimiento. Método: De nuestro registro prospectivo de ictus, durante un período de 4 años, identificamos 121 pacientes consecutivos con un IC. Se recogieron datos de recurrencia del ictus, eventos cardiovasculares y otras incidencias tras un año de seguimiento. Analizamos los datos de nuestro estudio y se correlacionan con datos de revisión bibliográfica. Resultados: Edad media: 70.6 años, 53.7% de varones. La arteria cerebral media (ACM) fue el territorio más afectado (52 casos), 70% de ellos con afección cortical. Ningún paciente falleció durante el ingreso. Durante el período de seguimiento, se detectó fibrilación auricular (FA) en 7 pacientes (6.54%), su edad media fue 75 años y en cinco de ellos el IC había sido en el territorio de la ACM (cuatro superficiales y uno profundo). Tres pacientes (2.76%) sufrieron una recurrencia del ictus isquémico, en las semanas 15, 16 y 44 después del IC. En los tres casos el ictus fue nuevamente considerado criptogénico. Dos pacientes sufrieron un infarto agudo de miocardio y cuatro fallecieron (infarto de miocardio, neoplasia de esófago, neumonía y muerte súbita). Conclusión: En nuestra serie, la tasa de recurrencia y de episodios cardiovasculares en el primer año tras un IC es baja. Un 11% de los pacientes con un IC en el territorio cortical de la ACM presentaron FA en el año siguiente, por lo que detectamos un subgrupo de IC tributarios de estudios cardiológicos más extensos.

Resultados de un seguimiento prolongado de pacientes con ictus isquémicos criptogénicos / Outcome of a prolonged follow-up of patients with cryptogenic infarct

Objetivo: Analizar la evolución de los pacientes con un infarto criptogénico (IC) tras un año de seguimiento. Método: De nuestro registro prospectivo de ictus, durante un período de 4 años, identificamos 121 pacientes consecutivos con un IC. Se recogieron datos de recurrencia del ictus, eventos cardiovasculares y otras incidencias tras un año de seguimiento. Analizamos los datos de nuestro estudio y se correlacionan con datos de revisión bibliográfica. Resultados: Edad media: 70.6 años, 53.7% de varones. La arteria cerebral media (ACM) fue el territorio más afectado (52 casos), 70% de ellos con afección cortical. Ningún paciente falleció durante el ingreso. Durante el período de seguimiento, se detectó fibrilación auricular (FA) en 7 pacientes (6.54%), su edad media fue 75 años y en cinco de ellos el IC había sido en el territorio de la ACM (cuatro superficiales y uno profundo). Tres pacientes (2.76%) sufrieron una recurrencia del ictus isquémico, en las semanas 15, 16 y 44 después del IC. En los tres casos el ictus fue nuevamente considerado criptogénico. Dos pacientes sufrieron un infarto agudo de miocardio y cuatro fallecieron (infarto de miocardio, neoplasia de esófago, neumonía y muerte súbita). Conclusión: En nuestra serie, la tasa de recurrencia y de episodios cardiovasculares en el primer año tras un IC es baja. Un 11% de los pacientes con un IC en el territorio cortical de la ACM presentaron FA en el año siguiente, por lo que detectamos un subgrupo de IC tributarios de estudios cardiológicos más extensos.(AU)

Migraine treatment patterns and patient satisfaction with prior therapy: a substudy of a multicenter trial of rizatriptan effectiveness.

BACKGROUND: Migraine is a common, chronic, often disabling neurologic condition that is underdiagnosed and undertreated. OBJECTIVE: We undertook this questionnaire-based study as a substudy of a multicenter trial of rizatriptan effectiveness. Our goal was to assess the history of acute migraine medication use and the relationship between different migraine medication regimens and patient satisfaction with prior therapy. METHODS: This study was conducted at 85 neurology clinics throughout Spain from March Lo December 2001. It was planned prospectively as part of the screening visit for a multicenter trial of the effectiveness of rizatriptan therapy for migraine. Male and female patients >/=18 years of age were eligible for the primary trial, and hence for this study, if they had a history of migraine attacks and did not have a contraindication for triptan use. At the screening visit for the primary trial, a questionnaire was used by clinicians to record past and current use, and duration and order of use, of analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), ergot derivatives, and triptans; satisfaction with treatment was scored on a 5-point scale ranging from "very dissatisfied" to "very satisfied." RESULTS: Of 712 patients completing the questionnaire (mean [SD] age, 34 [10] years; range, 18-69 years), 75% were women and 94% experienced moderate or severe functional disability during migraine attacks. Analgesics were used by the majority of patients (81%) and for the longest mean [SD] duration (8.8 [7.6] years) but were associated with the least satisfaction (10% of patients "very satisfied" or "somewhat satisfied"). Triptans were used by the fewest patients (32%) and for the shortest mean duration (18 [1.6] years) but were associated with the highest rate of satisfaction (66%) compared with NSAIDs (27%) and ergot derivatives (31%). Regardless of duration or order of drug use, or sex or age of the patient, the likelihood of satisfaction with triptans was significantly greater (P < 0.001) than with nontriptan regimens, with an adjusted odds ratio (95% CI) of 16.8 (11.4-24.9) versus analgesics, 5.1 (3.6-7.1) versus NSAIDs, and 4.1 (2.8-6.0) versus ergot derivatives. CONCLUSIONS: Our results showed that analgesics, NSAIDs, and ergot derivatives were used for long durations but provided low satisfaction among patients. Triptans were rarely used as a first treatment choice; however, patients reported the highest treatment satisfaction scores after triptan therapy compared with ergot derivatives, NSAIDs, or analgesics.