Utility of 18F-fluorodeoxyglucose positron emission tomography in presurgical evaluation of patients with epilepsy: A multicenter study

OBJECTIVE: 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) is widely used in presurgical assessment in patients with drug-resistant focal epilepsy (DRE) if magnetic resonance imaging (MRI) and scalp electroencephalography (EEG) do not localize the seizure onset zone or are discordant. METHODS: In this multicenter, retrospective observational cohort study, we included consecutive patients with DRE who had undergone FDG-PET as part of their presurgical workup. We assessed the utility of FDG-PET, which was defined as contributing to the decision-making process to refer for resection or intracranial EEG (iEEG) or to conclude surgery was not feasible. RESULTS: We included 951 patients in this study; 479 had temporal lobe epilepsy (TLE), 219 extratemporal epilepsy (ETLE), and 253 epilepsy of uncertain lobar origin. FDG-PET showed a distinct hypometabolism in 62% and was concordant with ictal EEG in 74% in TLE and in 56% in ETLE (p < .001). FDG-PET was useful in presurgical decision-making in 396 patients (47%) and most beneficial in TLE compared to ETLE (58% vs. 44%, p = .001). Overall, FDG-PET contributed to recommending resection in 78 cases (20%) and iEEG in 187 cases (47%); in 131 patients (33%), FDG-PET resulted in a conclusion that resection was not feasible. In TLE, seizure-freedom 1 year after surgery did not differ significantly (p = .48) between patients with negative MRI and EEG-PET concordance (n = 30, 65%) and those with positive MRI and concordant EEG (n = 46, 68%). In ETLE, half of patients with negative MRI and EEG-PET concordance and three quarters with positive MRI and concordant EEG were seizure-free postsurgery (n = 5 vs. n = 6, p = .28). SIGNIFICANCE: This is the largest reported cohort of patients with DRE who received presurgical FDG-PET, showing that FDG-PET is a useful diagnostic tool. MRI-negative and MRI-positive cases with concordant FDG-PET results (with either EEG or MRI) had a comparable outcome after surgery. These findings confirm the significance of FDG-PET in presurgical epilepsy diagnostics

Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

Melusin - candidate gene in context of cardiac hypertrophy and primary cardiomyopathies

Titelblatt und Inhaltsverzeichnis Einleitung Material und Methoden Ergebnisse Diskussion Literaturverzeichnis AnhangMit vorliegender Arbeit wurde das Zytoskelett-assoziierte Protein Melusin als Kandidatengen primärer Kardiomyopathien untersucht. Melusin ist wesentlich involviert in die Hypertrophieentwicklung nach mechanischer Belastung. Bei Kardiomyopathien sind hypertrophe Reaktionen von größter pathogenetischer Wichtigkeit. Daher etablierten wir zunächst eine auf PCR, SSCP-Analyse und Sequenzierung beruhende Screening-Methode des Melusin-Gens und untersuchten daraufhin 192 an einer primären HCM bzw. DCM erkrankte, nicht verwandte Probanden auf Vorliegen einer Mutation im Melusin. Unter den 106 HCM-Patienten fanden wir eine Mutation, die aufgrund eines Aminosäureaustauschs funktionelle Relevanz besitzen könnte. In der Familie der betroffenen Patientin wurden weitere Merkmalsträger identifiziert. Eine eindeutige Zuordnung zur klinischen Ausprägung einer HCM konnte nicht beobachtet werden, was allerdings an der Altersabhängigkeit des Auftretens von initialen Krankheitssymptomen oder einer inkompletten Penetranz liegen könnte. In einem Intron wurde eine weitere Mutation bei einem HCM-Patienten entdeckt. In der Gruppe der untersuchten DCM- Patienten fand sich keine Variante. Auch das Fehlen weiterer genetischer Alterationen im Melusin-Gen ist wichtiges Ergebnis vorliegender Untersuchung. So kann man aufgrund der genetisch hohen Konservierung von einer besonderen Bedeutung des Melusin in Kardiomyozyten ausgehen. Die Rolle des Melusin bei der Genese von Hypertrophie im Rahmen der primären Kardiomyopathien kann mittels vorliegender Ergebnisse nicht abschließend beurteilt werden. Ein Eingebundensein des Melusin in die Hypertrophie-Pathogenese in humanem Myokard erscheint jedoch wahrscheinlich; um Licht in die genaue Bedeutung des Melusin zu bringen, sind allerdings weitere Untersuchungen notwendig. Interessante Studienziele sind u.a. eine mögliche Interaktion des Melusin mit Hsp90, dem Calcineurin-Signalweg und dem Komplex um T-cap/MLP. Zur Regulierung des Melusin werden Informationen über das Bindungsverhalten ans Integrin in vivo benötigt. Diesbezügliche Erkenntnisse könnten nicht nur zum näheren Verständnis der Signalwege sondern auch bezüglich einer therapeutischen Beeinflussung kardialer Hypertrophie, die nicht nur bei Kardiomyopathien klinisch von höchster Relevanz ist, hilfreich sein.The goal of this work was to examine the cytoskeleton-associated protein melusin as candidate gene of primary cardiomyopathies. Melusin is a muscle- specific â1-integrin interacting protein, involved in cardiac hypertrophy growth in response to chronic pressure overload. Hypertrophic pathways play a pivotal role in the development of cardiomyopathies. Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are major causes of severe heart failure and sudden death. They are caused by a variety of mutant genes encoding protein components of the cardiac sarcomere like Actin, Myosin and components of Z-disc like titin. Methods: Isolation of deoxyribonucleic acid (DNA), polymerase chain reaction (PCR) and single -strand conformation polymorphism analysis were performed. Single-strand conformation polymorphism analysis was used for mutation screening, followed by DNA-sequencing. Restriction digests were performed as a second proof of mutation. Results: Melusin was analyzed in 106 unrelated patients with HCM and 86 unrelated patients with DCM. We identified one mutation in a HCM-patient. This mutation was not found in 190 control subjects. The mutation occurred in exon 1, in a region of high conservation during evolution. It leads to an amino acid change. We obtained family history and examined blood relatives to construct pedigree. Two healthy children and a clinically still unaffected brother of the patient with echocardiographical HCM are also mutation-carriers. Statistical analysis was not significant. A second variant occurred in an intron. Discussion: We identified a melusin-mutation in a patient with HCM, occurring in one of two cysteine/histidine rich domains (CHORDs) at the N-terminal portion of the protein. Another variant in an exon was not found, which indicates a high conservation of melusin and importance of protein in cardiomyocytes. These observations suggest that the melusin mutation may cause HCM via altered signalling hypertrophy pathways, as it was shown that melusin overexpressing mice have a mild cardiac hypertrophy in basal conditions (Acetis et al. 2005). Possible pathways are via interaction of melusin and hsp90, calcineurin pathway and the complex Titin/T-cap/MLP. In conclusion, we suppose that melusin plays an important role in the regulation of cardiomyocyte growth and the development of hypertrophy in cardiomyopathies. Further investigations are necessary to explore the exact relationship between this Melusin abnormality and hypertrophic cardiomyopathy

Results of a Randomized Clinical Trial of Speech after Early Neurostimulation in Parkinson's Disease

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Behavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial

Background Although subthalamic stimulation is a recognised treatment for motor complications in Parkinson's disease, reports on behavioural outcomes are controversial, which represents a major challenge when counselling candidates for subthalamic stimulation. We aimed to assess changes in behaviour in patients with Parkinson's disease receiving combined treatment with subthalamic stimulation and medical therapy over a 2-year follow-up period as compared with the behavioural evolution under medical therapy alone. Methods We did a parallel, open-label study (EARLYSTIM) at 17 surgical centres in France (n=8) and Germany (n=9). We recruited patients with Parkinson's disease who were disabled by early motor complications. Participants were randomly allocated (1: 1) to either medical therapy alone or bilateral subthalamic stimulation plus medical therapy. The primary outcome was mean change in quality of life from baseline to 2 years. A secondary analysis was also done to assess behavioural outcomes. We used the Ardouin Scale of Behavior in Parkinson's Disease to assess changes in behaviour between baseline and 2-year follow-up. Apathy was also measured using the Starkstein Apathy Scale, and depression was assessed with the Beck Depression Inventory. The secondary analysis was done in all patients recruited. We used a generalised estimating equations (GEE) regression model for individual items and mixed model regression for subscores of the Ardouin scale and the apathy and depression scales. This trial is registered with ClinicalTrials.gov, number NCT00354133. The primary analysis has been reported elsewhere; this report presents the secondary analysis only. Findings Between July, 2006, and November, 2009, 251 participants were recruited, of whom 127 were allocated medical therapy alone and 124 were assigned bilateral subthalamic stimulation plus medical therapy. At 2-year follow-up, the levodopa-equivalent dose was reduced by 39% (-363.3 mg/day [SE 41.8]) in individuals allocated bilateral subthalamic stimulation plus medical therapy and was increased by 21% (245.8 mg/day [40.4]) in those assigned medical therapy alone (p<0.0001). Neuropsychiatric fluctuations decreased with bilateral subthalamic stimulation plus medical therapy during 2-year follow-up (mean change -0.65 points [SE 0.15]) and did not change with medical therapy alone (-0.02 points [0.15]); the between-group difference in change from baseline was significant (p=0.0028). At 2 years, the Ardouin scale subscore for hyperdopaminergic behavioural disorders had decreased with bilateral subthalamic stimulation plus medical therapy (mean change -1.26 points [SE 0.35]) and had increased with medical therapy alone (1.12 points [0.35]); the between-group difference was significant (p<0.0001). Mean change from baseline at 2 years in the Ardouin scale subscore for hypodopaminergic behavioural disorders, the Starkstein Apathy Scale score, and the Beck Depression Inventory score did not differ between treatment groups. Antidepressants were stopped in 12 patients assigned bilateral subthalamic stimulation plus medical therapy versus four patients allocated medical therapy alone. Neuroleptics were started in nine patients assigned medical therapy alone versus one patient allocated bilateral subthalamic stimulation plus medical therapy. During the 2-year follow-up, two individuals assigned bilateral subthalamic stimulation plus medical therapy and one patient allocated medical therapy alone died by suicide. Interpretation In a large cohort with Parkinson's disease and early motor complications, better overall behavioural outcomes were noted with bilateral subthalamic stimulation plus medical therapy compared with medical therapy alone. The presence of hyperdopaminergic behaviours and neuropsychiatric fluctuations can be judged additional arguments in favour of subthalamic stimulation if surgery is considered for disabling motor complications