[Show abstract][Hide abstract] ABSTRACT: Purpose To assess effects of age and baseline axial length on best-corrected visual acuity (BCVA) in patients (pts) with myopic CNV receiving intravitreal aflibercept (IVT-AFL).Methods MYRROR was a 48 week, double-masked, sham-controlled, Phase 3 multicentre study (NCT01249664). Pts were randomised 3:1 to IVT AFL or sham/IVT-AFL (sham to Week 20 [W20]; IVT-AFL from W24 to W48). Post hoc analyses assessed effects of baseline pt age and axial length on mean BCVA change at W24 and W48. Subgroups were based on median cut-offs (age: ≤62 y vs >62 y; axial length: ≤28.6 mm vs >28.6 mm).Results 121 pts were analysed (IVT-AFL, n=90 / sham/IVT-AFL, n=31). With age ≤62 y, mean BCVA changes were 13.0/14.7 letters (W24/W48) for IVT-AFL vs -0.8/ 8.1 for sham/IVT-AFL. With age >62 y, changes were 11.1/12.2 letters for IVT-AFL vs -3.6/-1.2 for sham/IVT-AFL. With axial length ≤28.6 mm, mean BCVA changes were 12.6/13.8 letters (W24/W48) for IVT-AFL vs -2.1/1.7 for sham/IVT-AFL. With axial length >28.6 mm, changes were 11.6/13.2 letters for IVT-AFL vs -2.0/7.0 for sham/IVT-AFL. Correlation coefficients based on age were -0.234 and -0.215 (W24/W48) (both P<0.05); coefficients based on axial length were non significant. Ocular AEs were mainly mild and occurred at a similar rate with IVT-AFL and sham/IVT-AFL (37.4% vs 38.7%; most common, respectively: conjunctival haemorrhage [11.0%] and punctate keratitis [12.9%]). 7 (5.7%) pts had a serious AE (all IVT-AFL; only one SAE in study eye [macular hole]). No deaths were reported.Conclusion IVT-AFL was well tolerated and associated with clinically meaningful BCVA improvements in pts stratified by age or baseline axial length. Treatment benefits may be greater among younger myopic CNV pts. Baseline axial length did not appear to affect outcomes. Commercial interest
[Show abstract][Hide abstract] ABSTRACT: Purpose To evaluate visual acuity outcomes in patients (pts) with myopic CNV receiving intravitreal aflibercept (IVT-AFL) or sham injection in the international, 48 week, Phase 3 MYRROR trial (NCT01249664).Methods Pts were randomised 3:1 to IVT AFL or sham/IVT-AFL (sham to Week 20; IVT-AFL from Week 24 to Week 48). We report on exploratory post hoc analyses evaluating proportions of pts achieving visual gains (ETDRS letters) and the associated time course.Results 121 pts were analysed (IVT-AFL, n=90/ sham/IVT-AFL, n=31). At Week 24, 63.3% and 38.9% of IVT-AFL pts had gained ≥10 or ≥15 letters from baseline. In the sham/IVT-AFL group, 12.9% and 9.7% had gained ≥10 or ≥15 letters from baseline. By Week 48, the proportion of IVT-AFL pts gaining ≥10 or ≥15 letters was 68.9% and 50.0%, respectively. At Week 48 in the sham/IVT-AFL group (i.e., 24 weeks after IVT-AFL initiation), 41.9% and 29.0% of pts had gained ≥10 or ≥15 letters from baseline, respectively. Ocular AEs were mainly mild and occurred at a similar rate with IVT-AFL and sham/IVT-AFL (37.4% vs 38.7%; most common, respectively: conjunctival haemorrhage [11.0%] and punctate keratitis [12.9%]). 7 (5.7%) pts had a serious AE (all IVT-AFL; only one SAE in study eye [macular hole]). No deaths were reported.Conclusion The proportion of IVT-AFL pts who gained ≥10 or ≥15 letters by Week 24 was well maintained and even slightly increased at Week 48. Clinically meaningful benefits from IVT-AFL were also observed at Week 48 in the sham/IVT-AFL group. However, the proportion of gainers did not reach the extent seen in the initial IVT-AFL group, suggesting that earlier IVT-AFL treatment should be recommended. Commercial interest
[Show abstract][Hide abstract] ABSTRACT: Sporadic, genetically complex essential tremor (ET) is one of the most common movement disorders and may lead to severe impairment of the quality of life. Despite high heritability, the genetic determinants of ET are largely unknown. We performed the second genome-wide association study (GWAS) for ET to elucidate genetic risk factors of ET.
Using the Affymetrix Genome-Wide SNP Array 6.0 (1000K) we conducted a two-stage GWAS in a total of 990 subjects and 1,537 control subjects from Europe to identify genetic variants associated with ET.
We discovered association of an intronic variant of the main glial glutamate transporter (SLC1A2) gene with ET in the first-stage sample (rs3794087, p = 6.95 × 10(-5), odds ratio [OR] = 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p = 1.25 × 10(-3), OR = 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087 obtained genome-wide significance (p = 3.44 × 10(-10), OR = 1.59) in the combined first- and second-stage sample. Genetic fine mapping using nonsynonymous single nucleotide polymorphisms (SNPs) and SNPs in high linkage disequilibrium with rs3794087 did not reveal any SNP with a stronger association with ET than rs3794087.
We identified SLC1A2 encoding the major glial high-affinity glutamate reuptake transporter in the brain as a potential ET susceptibility gene. Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET.
[Show abstract][Hide abstract] ABSTRACT: No clinical disorders have been caused by dysfunction of any of the 5 subtypes (M1-M5) of muscarinic receptors. We present a patient with a novel clinical syndrome that we suggest results from a deficiency of the muscarinic M3 receptor.
We conducted a comprehensive workup of autonomic function. The patient's disorder was compared to the phenotypic features of male M3 knockout mice. M3 protein quantity was assessed by Western blot and radioligand binding in peripheral blood lymphocytes. Tests for autoantibodies and genetic abnormalities were performed.
The disease pattern was characterized by disturbances in micturition, pupil constriction, body weight, and sudomotor function, with normal accommodation, gastrointestinal motility, salivation, and lacrimation, similar to features of male M3 knockout mice. M3 protein quantity was reduced. Genetic tests were unrevealing, but unspecific antinuclear antibodies were present.
The presented clinical syndrome suggests a deficiency of the muscarinic M3 receptor. These results and future evaluation of patients with autonomic deficits may provide insights into the site and functional role of the muscarinic M3 receptor in humans.
[Show abstract][Hide abstract] ABSTRACT: Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are progressive disabling neurological conditions usually fatal within 10 years of onset. Little is known about the economic costs of these conditions. This paper reports service use and costs from France, Germany and the UK and identifies patient characteristics that are associated with cost. 767 patients were recruited, and 760 included in the study, from 44 centres as part of the NNIPPS trial. Service use during the previous six months was measured at entry to the study and costs calculated. Mean six-month costs were calculated for 742 patients. Data on patient sociodemographic and clinical characteristics were recorded and used in regression models to identify predictors of service costs and unpaid care costs (i.e., care from family and friends). The mean six-month service costs of PSP were €24,491 in France, €30,643 in Germany and €25,655 in the UK. The costs for MSA were €28,924, €25,645 and €19,103 respectively. Unpaid care accounted for 68-76%. Formal and unpaid costs were significantly higher the more severe the illness, as indicated by the Parkinson's Plus Symptom scale. There was a significant inverse relationship between service and unpaid care costs.
PLoS ONE 01/2011; 6(9):e24369. DOI:10.1371/journal.pone.0024369 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: To provide a revised version of earlier guidelines published in 2006.
Background: Primary dystonias are chronic and often disabling conditions with a widespread spectrum mainly in young people.
Diagnosis: Primary dystonias are classified as pure dystonia, dystonia plus or paroxysmal dystonia syndromes. Assessment should be performed using a validated rating scale for dystonia. Genetic testing may be performed after establishing the clinical diagnosis. DYT1 testing is recommended for patients with primary dystonia with limb onset before age 30, and in those with an affected relative with early-onset dystonia. DYT6 testing is recommended in early-onset or familial cases with cranio-cervical dystonia or after exclusion of DYT1. Individuals with early-onset myoclonus should be tested for mutations in the DYT11 gene. If direct sequencing of the DYT11 gene is negative, additional gene dosage is required to improve the proportion of mutations detected. A levodopa trial is warranted in every patient with early-onset primary dystonia without an alternative diagnosis. In patients with idiopathic dystonia, neurophysiological tests can help with describing the pathophysiological mechanisms underlying the disorder.
Treatment: Botulinum toxin (BoNT) type A is the first-line treatment for primary cranial (excluding oromandibular) or cervical dystonia; it is also effective on writing dystonia. BoNT/B is not inferior to BoNT/A in cervical dystonia. Pallidal deep brain stimulation (DBS) is considered a good option, particularly for primary generalized or cervical dystonia, after medication or BoNT have failed. DBS is less effective in secondary dystonia. This treatment requires a specialized expertise and a multidisciplinary team.
European Journal of Neurology 01/2011; 18(1):5-18. DOI:10.1111/j.1468-1331.2010.03042.x · 4.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Involuntary eyelid closure (IEC) may occur after deep brain stimulation of the subthalamic nucleus (STN-DBS) in Parkinson's disease (PD) and is often categorised as apraxia of lid opening (ALO), albeit the appropriateness of this term is under debate. To gain insight into the hitherto undefined pathophysiology of IEC after STN-DBS, we performed a comprehensive clinical and electrophysiological characterisation of lid function in a total of six PD patients.
The study was carried out in six PD patients who developed IEC after STN-DBS. They underwent neurological examination and electromyography recording of activity in the orbicularis oculi muscle (OO) upon varying stimulation patterns. Intraoperative studies were performed in one patient.
Increasing STN-DBS intensity induced IEC in four patients, whereas it improved the condition in two. Needle EMG showed tonic hyperactivity of the OO in STN-DBS induced IEC, while variable patterns of OO activity (irregular and tonic) were seen in patients with STN-DBS-relieved IEC. Intraoperative analysis in one patient showed evidence for IEC being induced by activation of corticobulbar fibres.
We identified two groups of IEC after STN-DBS based on clinical and EMG patterns: (1) STN-DBS induced IEC associated with tonic OO overactivity and (2) STN-DBS relieved IEC presenting with variable EMG patterns. Our findings provide relevant information on pathophysiology of STN-DBS related IEC and implications for its therapeutic management.
Journal of neurology, neurosurgery, and psychiatry 09/2010; 81(9):1002-7. DOI:10.1136/jnnp.2009.196691 · 6.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Deep brain stimulation (DBS) of the internal globus pallidus (GPi) and ventral intermediate thalamic nucleus (VIM) are established treatment options in primary dystonia and tremor syndromes and have been reported anecdotally to be efficacious in myoclonus-dystonia (MD). We investigated short- and long-term effects on motor function, cognition, affective state, and quality of life (QoL) of GPi- and VIM-DBS in MD. Ten MD-patients (nine epsilon-sarcoglycan-mutation-positive) were evaluated pre- and post-surgically following continuous bilateral GPi- and VIM-DBS at four time points: presurgical, 6, 12, and as a last follow-up at a mean of 62.3 months postsurgically, and in OFF-, GPi-, VIM-, and GPi-VIM-DBS conditions by validated motor [unified myoclonus rating scale (UMRS), TSUI Score, Burke-Fahn-Marsden dystonia rating scale (BFMDRS)], cognitive, affective, and QoL-scores. MD-symptoms significantly improved at 6 months post-surgery (UMRS: 61.5%, TSUI Score: 36.5%, BFMDRS: 47.3%). Beneficial effects were sustained at long-term evaluation post-surgery (UMRS: 65.5%, TSUI Score: 35.1%, BFMDRS: 48.2%). QoL was significantly ameliorated; affective status and cognition remained unchanged postsurgically irrespective of the stimulation conditions. No serious long-lasting stimulation-related adverse events (AEs) were observed. Both GPi- and VIM-DBS offer equally effective and safe treatment options for MD. With respect to fewer adverse, stimulation-induced events of GPi-DBS in comparison with VIM-DBS, GPi-DBS seems to be preferable. Combined GPi-VIM-DBS can be useful in cases of incapaciting myoclonus, refractory to GPi-DBS alone.
Movement Disorders 08/2010; 25(11):1733-43. DOI:10.1002/mds.23312 · 5.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dystonia-plus syndromes represent a heterogeneous group of diseases, where dystonia is accompanied by other neurological features and gene mutations can be detected frequently. Symptomatic dystonias and complex neurodegenerative diseases with dystonia as part of the clinical presentation are excluded from this category. At present, the following disorders are categorized as dystonia-plus syndromes: Dopa-responsive dystonia (DRD) is a mostly pediatric-onset, neurometabolic disorder with two different modes of inheritance: in its autosomal-dominant form, heterozygous mutations of GTP-cyclohydrolase I (GCH1, DYT5) cause DRD with reduced penetrance and excellent and lasting response to levodopa. Autosomal-recessive (AR) forms of DRD are caused by homozygous or compound heterozygous mutations of the tyrosine hydroxylase (TH) or the sepiapterin reductase (SPR) gene. In AR-DRD, the phenotype is generally more severe including cognitive deficits and developmental delay. Diagnosis can be confirmed by analysis of CSF pterine metabolites. Alternatively, comprehensive genetic testing yields causative mutations in up to 80% of patients. Myoclonus-dystonia (M-D) is caused by heterozygous mutations of the epsilon-sarcoglycan gene (SGCE). Dystonia is generally only mild to moderate, and 'lightning-like' myoclonic jerks occur rarely at rest and can be triggered by complex motor tasks like writing and drawing. Both features together with an age at onset below 25 years strongly predict SGCE mutation in M-D and differentiate this genetic disease from other 'jerky' dystonias. The combination of dystonia and parkinsonism can only be rarely observed in non-degenerative syndromes. Besides DRD, two additional syndromes have been classified. Rapid-onset dystonia-parkinsonism (RPD, DYT12) is a rare disorder with an abrupt onset of symptoms over minutes to days, prominent bulbar involvement and parkinsonism with a lack of response to levodopa. Patients with this rare phenotype should be screened for mutation in the Na(+)/K(+) ATPase alpha3-subunit (ATP1A3) gene, even if family history is negative. Recently, a novel form of dystonia-parkinsonism (DYT16) has been found to be linked to mutations in the PRKRA gene, whose relation to basal ganglia disorders is yet unknown .
European Journal of Neurology 07/2010; 17 Suppl 1(Suppl 1):37-45. DOI:10.1111/j.1468-1331.2010.03049.x · 4.06 Impact Factor