Additional effect of erenumab for patients with chronic migraine treated with onabotulinumtoxin A—real-world data from a preliminary cohort study

BackgroundThis preliminary retrospective cohort study investigates the potential additive prophylactic effect of erenumab, a fully human monoclonal antibody that blocks the calcitonin gene-related peptide receptor, in combination with ongoing onabotulinumtoxin A (onaBoNT-A) treatment in patients suffering from chronic migraine.MethodsThe study included 218 patients and investigated the effects of adding erenumab to the existing treatment regimen. The primary outcome was the MIDAS (Migraine Disability Assessment) score assessed 3 months after the introduction of erenumab.ResultsThe results indicated a significant improvement of the MIDAS score, suggesting a reduction in migraine-related disability following the addition of erenumab to onaBoNT-A. In the inter group comparison, dual therapy showed a significantly greater reduction of the MIDAS when compared to a switch from onaBoNT-A to erenumab monotherapy, but not compared to initiation of onaBoNT-A monotherapy. It is hypothesized that the observed additive effects are due to the independent modes of action of erenumab and onabotulinumtoxin A.ConclusionThis study suggests that the combination of erenumab with onaBoNT-A may offer an improved approach for the treatment of chronic migraine in selected patients. However, the results highlight the need for prospective, controlled studies to validate these findings and determine the optimal combination of treatments tailored to the individual patient

Jurisdiction of Tribunals to Settle Intra-EU Investment Treaty Disputes

The European Court of Justice (ECJ) made a ground-breaking shift away from the current system of investor-State dispute settlement (ISDS) by rendering its judgment in the matter of Achmea v Slovak Republic. However, since March 2018, a large and ever-growing number of investment tribunals have found that the Achmea judgment does not deprive them of arbitral jurisdiction. Against this background, the aim of the present article is to analyse the effects of the Achmea judgment on the jurisdiction of tribunals to settle intra-European Union (EU) investment treaty disputes. By taking due account of the reasoning conducted by the ECJ, the scope of the Achmea jurisprudence will be clarified. It is concluded that the incompatibility of intra-EU ISDS with EU law concerns all intra-EU investment treaties, including article 26 of the Energy Charter Treaty (ECT). On this basis, we ask whether, and to what extent, the applicability of the Achmea judgment is relevant to arbitral jurisdiction. Considering the law applicable to the arbitration agreement, we conclude that International Centre for Settlement of Investment Disputes (ICSID) tribunals and those seated outside the EU remain competent to settle intra-EU investment disputes. In contrast, the Achmea judgment renders ISDS clauses contained in intra-EU investment treaties inoperable if the tribunal is seated within the EU. The article closes with an outlook that puts these conclusions into perspective by considering recent developments such as the EU Member States' ratification of a multilateral termination treaty

Impact of the number of conditioning pulses on motor cortex excitability: a transcranial magnetic stimulation study

Conditioning transcranial magnetic stimulation (TMS) with subthreshold conditioning stimulus followed by supra-threshold test stimulus at inter-stimulus intervals (ISI) of 1-5 ms results in inhibition (SICI), while ISI at 10-15 ms results in facilitation (ICF). One concerning issue, applying ICF/SICI protocols on patients is the substantial protocol variability. Here, we hypothesized that increasing the number of CS could result in more robust ICF/SICI protocols. Twenty healthy subjects participated in the study. Motor-evoked potentials (MEP) were obtained from conditioning TMS with a varying number of conditioning stimuli in 3, 4, 10, and 15 ms ISI over the primary motor cortex. MEP amplitudes were then compared to examine excitability. TMS with 3, 5, and 7 conditioning stimuli but not with one conditioning stimulus induced ICF. Moreover, 10 ms ISI produced stronger ICF than 15 ms ISI. Significant SICI was only induced with one conditioning stimulus. Besides, 3 ms ISI resulted in stronger SICI than 4 ms ISI. Only a train of conditioning stimuli induced stable ICF and may be more advantageous than the classical paired pulse ICF paradigm

Cerebellar Involvement in DYT-THAP1 Dystonia.

DYT-THAP1 dystonia is known to present a variety of clinical symptoms. To the best of our knowledge, this is the first case with DYT-THAP 1 dystonia and clinical signs of cerebellar involvement studied with transcranial magnetic stimulation in vivo. We report a case of a 51-year-old male DYT-THAP1 mutation carrier with dystonia, who additionally developed ataxia 1.5 years ago. To study cerebellar involvement in our patient, we used a TMS protocol called cerebellar inhibition (CBI). The lack of CBI in our patient strongly suggests cerebellar involvement. According to our findings, cerebellar syndrome may be part of the phenotypical spectrum of DYT-THAP1 mutations

Paired associative stimulation demonstrates alterations in motor cortical synaptic plasticity in patients with hepatic encephalopathy

Objective: Hepatic encephalopathy (HE) is a potentially reversible brain dysfunction caused by liver failure. Altered synaptic plasticity is supposed to play a major role in the pathophysiology of HE. Here, we used paired associative stimulation with an inter-stimulus interval of 25 ms (PAS25), a transcranial magnetic stimulation (TMS) protocol, to test synaptic plasticity of the motor cortex in patients with manifest HE. Methods: 23 HE-patients and 23 healthy controls were enrolled in the study. Motor evoked potential (MEP) amplitudes were assessed as measure for cortical excitability. Time courses of MEP amplitude changes after the PAS25 intervention were compared between both groups. Results: MEP-amplitudes increased after PAS25 in the control group, indicating PAS25-induced synaptic plasticity in healthy controls, as expected. In contrast, MEP-amplitudes within the HE group did not change and were lower than in the control group, indicating no induction of plasticity. Conclusion: Our study revealed reduced synaptic plasticity of the primary motor cortex in HE. Significance: Reduced synaptic plasticity in HE provides a link between pathological changes on the molecular level and early clinical symptoms of the disease. This decrease may be caused by disturbances in the glutamatergic neurotransmission due to the known hyperammonemia in HE patients.Comment: number of pages: 33; number of tables: 1; number of figures: 5; References: 9