Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial

Introduction

Uric acid is an antioxidant with neuroprotective effects in experimental models of stroke. We assessed whether uric acid therapy would improve functional outcomes at 90 days in patients with acute ischaemic stroke.

Methods

URICO-ICTUS was a randomised, double-blind, placebo-controlled, phase 2b/3 trial that recruited patients with acute ischaemic stroke admitted to ten Spanish stroke centres. Patients were included if they were aged 18 years or older, had received alteplase within 4·5 h of symptom onset, and had an eligible National Institutes of Health Stroke Scale (NIHSS) score (>6 and ≤25) and premorbid (assessed by anamnesis) modified Rankin Scale (mRS) score (≤2). Patients were randomly allocated (1:1) to receive uric acid 1000 mg or placebo (both infused intravenously in 90 min during the infusion of alteplase), stratified by centre and baseline stroke severity. The primary outcome was the proportion of patients with excellent outcome (ie, an mRS score of 0—1, or 2 if premorbid score was 2) at 90 days, analysed in the target population (all randomly assigned patients who had been correctly diagnosed with ischaemic stroke and had begun study medication). The study is registered with ClinicalTrials.gov, numberNCT00860366.

Findings

Between July 1, 2011, and April 30, 2013, we randomly assigned 421 patients, of whom 411 (98%) were included in the target population (211 received uric acid and 200 received placebo). 83 (39%) patients who received uric acid and 66 (33%) patients who received placebo had an excellent outcome (adjusted risk ratio 1·23 [95% CI 0·96—1·56]; p=0·099). No clinically relevant or statistically significant differences were reported between groups with respect to death (28 [13%] patients who received uric acidvs 31 [16%] who received placebo), symptomatic intracerebral haemorrhage (nine [4%] vs six [3%]), and gouty arthritis (one [<1%]vs four [2%]). 516 adverse events occurred in the uric acid group and 532 in the placebo group, of which 61 (12%) and 67 (13%), respectively, were serious adverse events (p=0·703).

Interpretation

The addition of uric acid to thrombolytic therapy did not increase the proportion of patients who achieved excellent outcome after stroke compared with placebo, but it did not lead to any safety concerns.

Lancet Neurology 2014

Breaking News: A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study

Background

Autoimmunity might be associated with or implicated in sleep and neurodegenerative disorders. We aimed to describe the features of a novel neurological syndrome associated with prominent sleep dysfunction and antibodies to a neuronal antigen.

Methods

In this observational study, we used clinical and video polysomnography to identify a novel sleep disorder in three patients referred to the Sleep Unit of Hospital Clinic, University of Barcelona, Spain, for abnormal sleep behaviours and obstructive sleep apnoea. These patients had antibodies against a neuronal surface antigen, which were also present in five additional patients referred to our laboratory for antibody studies. These five patients had been assessed with polysomnography, which was done in our sleep unit in one patient and the recording reviewed in a second patient. Two patients underwent post-mortem brain examination. Immunoprecipitation and mass spectrometry were used to characterise the antigen and develop an assay for antibody testing. Serum or CSF from 298 patients with neurodegenerative, sleep, or autoimmune disorders served as control samples.

Findings

All eight patients (five women; median age at disease onset 59 years [range 52—76]) had abnormal sleep movements and behaviours and obstructive sleep apnoea, as confirmed by polysomnography. Six patients had chronic progression with a median duration from symptom onset to death or last visit of 5 years (range 2—12); in four the sleep disorder was the initial and most prominent feature, and in two it was preceded by gait instability followed by dysarthria, dysphagia, ataxia, or chorea. Two patients had a rapid progression with disequilibrium, dysarthria, dysphagia, and central hypoventilation, and died 2 months and 6 months, respectively, after symptom onset. In five of five patients, video polysomnography showed features of obstructive sleep apnoea, stridor, and abnormal sleep architecture (undifferentiated non-rapid-eye-movement [non-REM] sleep or poorly structured stage N2, simple movements and finalistic behaviours, normalisation of non-REM sleep by the end of the night, and, in the four patients with REM sleep recorded, REM sleep behaviour disorder). Four of four patients had HLA-DRB1*1001 and HLA-DQB1*0501 alleles. All patients had antibodies (mainly IgG4) against IgLON5, a neuronal cell adhesion molecule. Only one of the 298 controls, who had progressive supranuclear palsy, had IgLON5 antibodies. Neuropathology showed neuronal loss and extensive deposits of hyperphosphorylated tau mainly involving the tegmentum of the brainstem and hypothalamus in the two patients studied.

Interpretation

IgLON5 antibodies identify a unique non-REM and REM parasomnia with sleep breathing dysfunction and pathological features suggesting a tauopathy.

Lancet Neurology 2014

Discovering rare diseases: DOOSE SYNDROME (Myoclonic astatic epilepsy)

Doose syndrome, otherwise traditionally known as myoclonic-astatic epilepsy, was first described as a unique epilepsy syndrome by Dr HermannDoose in 1970. In 1989, the International League Against Epilepsy classified it formally as a symptomatic generalized epilepsy, and 20 years later it was renamed 'epilepsy with myoclonic-atonic seizures'. In this review, we discuss the components of this unique disorder including its incidence, clinical features, and electroencephalographic findings. Recent evidence has suggested possible genetic links to the GEFS+ (generalized epilepsy with febrile seizures plus) family, and, additionally, some children with structural brain lesions can mimic the Doose syndrome phenotype. Treatment strategies such as corticosteroids, ethosuximide, and valproate have been described as only partially effective, but newer anticonvulsants, such as levetiracetam and zonisamide, may provide additional seizure control. The most effective treatment reported to date appears to be the ketogenic diet. Prognosis is quite varied in this disorder; however, many children can have a remarkably normal neurodevelopmental outcome.

Dev Med Child Neurol 2010

EEG-fMRI in myoclonic astatic epilepsy (Doose syndrome)

Objective: To identify neuronal networks underlying generalized spike and wave discharges (GSW) in myoclonic astatic epilepsy (MAE).

Methods: Simultaneous EEG-fMRI recordings were performed in 13 children with MAE. Individual GSW-associated blood oxygenation level–dependent (BOLD) signal changes were analyzed in every patient. A group analysis was performed to determine common syndrome-specific hemodynamic changes across all patients.

Results: GSW were recorded in 11 patients, all showing GSW-associated BOLD signal changes. Activation was detected in the thalamus (all patients), premotor cortex (6 patients), and putamen (6 patients). Deactivation was found in the default mode areas (7 patients). The group analysis confirmed activations in the thalamus, premotor cortex, putamen, and cerebellum and deactivations in the default mode network.

Conclusions: In addition to the thalamocortical network, which is commonly found in idiopathic generalized epilepsies, GSW in patients with MAE are characterized by BOLD signal changes in brain structures associated with motor function. The results are in line with animal studies demonstrating that somatosensory cortex, putamen, and cerebellum are involved in the generation of myoclonic seizures. The involvement of these structures might predispose to the typical seizure semiology of myoclonic jerks observed in MAE.

Neurology 2014

Phonologic errors as a clinical marker of the logopenic variant of PPA

Objective: To disentangle the clinical heterogeneity of nonsemantic variants of primary progressive aphasia (PPA) and to identify a coherent linguistic-anatomical marker for the logopenic variant of PPA (lv-PPA).

Methods: Key speech and language features of 14 cases of lv-PPA and 18 cases of nonfluent/agrammatic variant of PPA were systematically evaluated and scored by an independent rater blinded to diagnosis. Every case underwent a structural MRI and a Pittsburgh compound B (PiB)-PET scan, a putative biomarker of Alzheimer disease. Key speech and language features that showed association with the PiB-PET status were entered into a hierarchical cluster analysis. The linguistic features and patterns of cortical thinning in each resultant cluster were analyzed.

Results: The cluster analysis revealed 3 coherent clinical groups, each of which was linked to a specific PiB-PET status. The first cluster was linked to high PiB retention and characterized by phonologic errors and cortical thinning focused on the left superior temporal gyrus. The second and third clusters were characterized by grammatical production errors and motor speech disorders, respectively, and were associated with low PiB brain retention. A fourth cluster, however, demonstrated nonspecific language deficits and unpredictable PiB-PET status.

Conclusions: These findings suggest that despite the clinical and pathologic heterogeneity of nonsemantic variants, discrete clinical syndromes can be distinguished and linked to specific likelihood of PiB-PET status. Phonologic errors seem to be highly predictive of high amyloid burden in PPA and can provide a specific clinical marker for lv-PPA.

Neurology 2014

Plasma FGF23 and the risk of stroke

Objective: To examine fibroblast growth factor 23 (FGF23) as a risk factor for incident stroke in a racially/ethnically diverse population-based urban cohort.

Methods: Stroke-free Northern Manhattan Study participants with FGF23 measurements (n = 2,525) were followed for a mean of 12 (±5) years to detect incident strokes. We used Cox proportional hazards models to estimate the association of baseline FGF23 with incident total, ischemic, and hemorrhagic stroke.

Results: Median FGF23 was 57 relative units (RU)/mL (interquartile range = 44–81 RU/mL). Each unit increase of natural log-transformed FGF23 conferred a 40% greater overall stroke risk after adjusting for estimated glomerular filtration rate and sociodemographic and vascular risk factors (hazard ratio = 1.4, 95% confidence interval 1.1–1.6, p = 0.004). Penalized spline analysis revealed a linear association with overall stroke risk at ≥90 RU/mL FGF23, compared with <90 RU/mL (hazard ratio = 1.5, 95% confidence interval = 1.2–2.1, p = 0.004). Greater FGF23 conferred a doubling of intracerebral hemorrhage (ICH) risk but no significant increased risk of ischemic stroke. The associations of elevated FGF23 levels with greater risks of overall stroke and ICH events were independent of phosphate and parathyroid hormone levels and were similar among participants without chronic kidney disease.

Conclusions: Elevated FGF23 was a risk factor for overall stroke and ICH events, in particular in a racially and ethnically diverse urban community, independent of chronic kidney disease.

Neurology 2014

PIGA mutations cause early-onset epileptic encephalopathies and distinctive features

Objective: To investigate the clinical spectrum caused by mutations in PIGA at Xp22.2, which is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, among patients with early-onset epileptic encephalopathies (EOEEs).

Methods: Whole-exome sequencing was performed as a comprehensive genetic analysis for a cohort of 172 patients with EOEEs including early myoclonic encephalopathy, Ohtahara syndrome, and West syndrome, and PIGAmutations were carefully investigated.

Results: We identified 4 PIGA mutations in probands showing early myoclonic encephalopathy, West syndrome, or unclassified EOEE. Flow cytometry of blood granulocytes from patients demonstrated reduced expression of GPI-anchored proteins. Expression of GPI-anchored proteins in PIGA-deficient JY5 cells was only partially or hardly restored by transient expression of PIGA mutants with a weak TATA box promoter, indicating a variable loss of PIGA activity. The phenotypic consequences of PIGA mutations can be classified into 2 types, severe and less severe, which correlate with the degree of PIGA activity reduction caused by the mutations. Severe forms involved myoclonus and asymmetrical suppression bursts on EEG, multiple anomalies with a dysmorphic face, and delayed myelination with restricted diffusion patterns in specific areas. The less severe form presented with intellectual disability and treatable seizures without facial dysmorphism.

Conclusions: Our study confirmed that PIGA mutations are one genetic cause of EOEE, suggesting that GPI-anchor deficiencies may be an underlying cause of EOEE.

Neurology 20'14