Spinocerebellar ataxia type 37 is an adult-onset dominant ataxia characterised by altered vertical eye movements. Corral-Juan et al. demonstrate that an ATTTC expansion mutation within the DAB1 gene ...is the genetic cause of SCA37, present the first neuropathological findings, and provide evidence of cerebellar dysregulation of Reelin-DAB1 and PI3K/AKT signalling.
Abstract
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.
IMPORTANCE: In nonurban areas with limited access to thrombectomy-capable centers, optimal prehospital transport strategies in patients with suspected large-vessel occlusion stroke are unknown. ...OBJECTIVE: To determine whether, in nonurban areas, direct transport to a thrombectomy-capable center is beneficial compared with transport to the closest local stroke center. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, population-based, cluster-randomized trial including 1401 patients with suspected acute large-vessel occlusion stroke attended by emergency medical services in areas where the closest local stroke center was not capable of performing thrombectomy in Catalonia, Spain, between March 2017 and June 2020. The date of final follow-up was September 2020. INTERVENTIONS: Transportation to a thrombectomy-capable center (n = 688) or the closest local stroke center (n = 713). MAIN OUTCOMES AND MEASURES: The primary outcome was disability at 90 days based on the modified Rankin Scale (mRS; scores range from 0 no symptoms to 6 death) in the target population of patients with ischemic stroke. There were 11 secondary outcomes, including rate of intravenous tissue plasminogen activator administration and thrombectomy in the target population and 90-day mortality in the safety population of all randomized patients. RESULTS: Enrollment was halted for futility following a second interim analysis. The 1401 enrolled patients were included in the safety analysis, of whom 1369 (98%) consented to participate and were included in the as-randomized analysis (56% men; median age, 75 IQR, 65-83 years; median National Institutes of Health Stroke Scale score, 17 IQR, 11-21); 949 (69%) comprised the target ischemic stroke population included in the primary analysis. For the primary outcome in the target population, median mRS score was 3 (IQR, 2-5) vs 3 (IQR, 2-5) (adjusted common odds ratio OR, 1.03; 95% CI, 0.82-1.29). Of 11 reported secondary outcomes, 8 showed no significant difference. Compared with patients first transported to local stroke centers, patients directly transported to thrombectomy-capable centers had significantly lower odds of receiving intravenous tissue plasminogen activator (in the target population, 229/482 47.5% vs 282/467 60.4%; OR, 0.59; 95% CI, 0.45-0.76) and significantly higher odds of receiving thrombectomy (in the target population, 235/482 48.8% vs 184/467 39.4%; OR, 1.46; 95% CI, 1.13-1.89). Mortality at 90 days in the safety population was not significantly different between groups (188/688 27.3% vs 194/713 27.2%; adjusted hazard ratio, 0.97; 95% CI, 0.79-1.18). CONCLUSIONS AND RELEVANCE: In nonurban areas in Catalonia, Spain, there was no significant difference in 90-day neurological outcomes between transportation to a local stroke center vs a thrombectomy-capable referral center in patients with suspected large-vessel occlusion stroke. These findings require replication in other settings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02795962
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.
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-β (IFN-β) in clinical practice.
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-β 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.
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).
Patients with moderate/severe fatigue switching from IFN-β to glatiramer acetate may benefit from fatigue improvements that contribute to reduce their work/activity impairment and improve their quality of life.
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