[Galcanezumab for episodic and chronic cluster headache]. / Galcanezumab bei episodischem und chronischem Clusterkopfschmerz.

BACKGROUND: Cluster headache (CH) is a highly debilitating headache disorder characterized by frequent attacks of excruciating unilateral pain accompanied by cranial autonomic symptoms. Calcitonin gene-related peptide (CGRP) is implicated in the pathophysiology of CH. OBJECTIVES: Preventive efficacy and tolerability of the anti-CGRP antibody galcanezumab in patients with episodic (eCH) and chronic CH (cCH). Review of the study results and the challenges in developing drugs for the preventive treatment of CH. MATERIALS AND METHODS: In two international multicenter phase III trials galcanezumab 300 mg given subcutaneously every 4 weeks was compared with placebo. The double-blind study period (8 weeks in eCH, 12 weeks in cCK) was preceded by a baseline period in both trials. The primary endpoint was the reduction in weekly attack frequency. RESULTS: In the eCH trial, 106 patients were randomized to either galcanezumab (n = 49) or placebo (n = 57). The mean weekly attack frequency during the first 3 weeks decreased by 52% in the galcanezumab group compared with 27% in the placebo group (p = 0.036). In the cCH trial, 237 patients were randomized to galcanezumab (n = 117) or placebo (n = 120). The primary endpoint was not met in this study. The reduction in mean weekly attack rate was 5.4 with galcanezumab versus 4.6 with placebo (p = 0.334). Galcanezumab was well tolerated in both studies. CONCLUSIONS: Galcanezumab had a significant effect in the prevention of eCH attacks but not in cCH. Possible reasons for this discrepancy are discussed.

Characterizing cognitive-motor impairments in patients with myotonic dystrophy type 1.

Myotonic Dystrophy Type 1 (DM1) is the most frequent hereditary, adult-onset muscular dystrophy. Nevertheless, DM1-associated cognitive-motor impairments have not been fully characterized so far. This study aimed at profiling cognitive and locomotor dysfunctions in these patients. In addition, cognitive-motor interactions were assessed using a dual-task paradigm. Comprehensive cognitive-motor impairment profiles were generated for 19 patients with DM1 and 19 healthy subjects by thorough clinical, biomechanical and neuropsychological examinations. Detailed gait analysis was performed using a 3D motion capture system, whereas cognitive function was assessed using a standardized neuropsychological test battery. Patients with DM1 showed impaired functional mobility, gait velocity and endurance. DM1-related gait pathology was mainly characterized by enhanced dynamic instability, gait variability, and restricted ankle dorsiflexion. Patients' cognitive impairments particularly concerned attentional functions. Dual-task conditions induced gait deviations that slightly differed between patients and controls. DM1-associated cognitive impairments correlated with reduced functional mobility and impaired ankle dorsiflexion. Patients with DM1 revealed significant impairments of walking function, balance and cognitive performance. Differential cognitive-motor interference and significant interactions between cognitive and motor dysfunctions point towards a prominent role of cognition in gait performance of patients with DM1.

Positive effects of fampridine on cognition, fatigue and depression in patients with multiple sclerosis over 2 years.

OBJECTIVE: To assess the effects of PR-fampridine on cognitive functioning, fatigue and depression in patients with multiple sclerosis (PwMS). METHODS: Thirty-two PwMS were included in this trial. Cognitive performance was assessed in an open-label and randomized double-blind, placebo-controlled study design using a comprehensive neuropsychological test battery as well as questionnaires examining depression and fatigue. RESULTS: We found significant improvements in cognitive measures assessing alertness (tonic alertness, p = 0.0244 and phasic alertness, p = 0.0428), psychomotor speed (p = 0.0140) as well as verbal fluency (p = 0.0002) during open-label treatment with PR-fampridine. These effects of performance were paralleled by patients' perception of reduced fatigue (physical, p = 0.0131; cognitive, p = 0.0225; total, p = 0.0126). Fampridine-induced improvements in phasic alertness (p = 0.0010) and measures of fatigue (physical, p = 0.0014; cognitive, p = 0.0003; total, p = 0.0005) were confirmed during randomized, double-blind, placebo-controlled assessment in the second year. In addition, we found positive effects of PR-fampridine on depressive symptoms (p = 0.0049). We demonstrated persisting beneficial effects of PR-fampridine on fatigue in PwMS over a period of more than 2 years. Drug responsiveness regarding cognitive performance and fatigue was not limited to walking responders. CONCLUSIONS: Our data demonstrate significant positive effects of treatment with PR-fampridine over 2 years on different cognitive domains as well as fatigue and depression in a cohort of PwMS. These findings imply that PR-fampridine should be considered as symptomatic treatment improving aspects of cognition, fatigue and depression in PwMS.

Subcortical Shape Changes, Hippocampal Atrophy and Cortical Thinning in Future Alzheimer's Disease Patients.

Efficacy of future treatments depends on biomarkers identifying patients with mild cognitive impairment at highest risk for transitioning to Alzheimer's disease. Here, we applied recently developed analysis techniques to investigate cross-sectional differences in subcortical shape and volume alterations in patients with stable mild cognitive impairment (MCI) (n = 23, age range 59-82, 47.8% female), future converters at baseline (n = 10, age range 66-84, 90% female) and at time of conversion (age range 68-87) compared to group-wise age and gender matched healthy control subjects (n = 23, age range 61-81, 47.8% female; n = 10, age range 66-82, 80% female; n = 10, age range 68-82, 70% female). Additionally, we studied cortical thinning and global and local measures of hippocampal atrophy as known key imaging markers for Alzheimer's disease. Apart from bilateral striatal volume reductions, no morphometric alterations were found in cognitively stable patients. In contrast, we identified shape alterations in striatal and thalamic regions in future converters at baseline and at time of conversion. These shape alterations were paralleled by Alzheimer's disease like patterns of left hemispheric morphometric changes (cortical thinning in medial temporal regions, hippocampal total and subfield atrophy) in future converters at baseline with progression to similar right hemispheric alterations at time of conversion. Additionally, receiver operating characteristic curve analysis indicated that subcortical shape alterations may outperform hippocampal volume in identifying future converters at baseline. These results further confirm the key role of early cortical thinning and hippocampal atrophy in the early detection of Alzheimer's disease. But first and foremost, and by distinguishing future converters but not patients with stable cognitive abilities from cognitively normal subjects, our results support the value of early subcortical shape alterations and reduced hippocampal subfield volumes as potential markers for the early detection of Alzheimer's disease.

Cocaine users manifest impaired prosodic and cross-modal emotion processing.

BACKGROUND: A small number of previous studies have provided evidence that cocaine users (CU) exhibit impairments in complex social cognition tasks, while the more basic facial emotion recognition is widely unaffected. However, prosody and cross-modal emotion processing has not been systematically investigated in CU so far. Therefore, the aim of the present study was to assess complex multisensory emotion processing in CU in comparison to controls and to examine a potential association with drug use patterns. METHOD: The abbreviated version of the comprehensive affect testing system (CATS-A) was used to measure emotion perception across the three channels of facial affect, prosody, and semantic content in 58 CU and 48 healthy control (HC) subjects who were matched for age, sex, verbal intelligence, and years of education. RESULTS: CU had significantly lower scores than controls in the quotient scales of "emotion recognition" and "prosody recognition" and the subtests "conflicting prosody/meaning - attend to prosody" and "match emotional prosody to emotional face" either requiring to attend to prosody or to integrate cross-modal information. In contrast, no group difference emerged for the "affect recognition quotient." Cumulative cocaine doses and duration of cocaine use correlated negatively with emotion processing. CONCLUSION: CU show impaired cross-modal integration of different emotion processing channels particularly with regard to prosody, whereas more basic aspects of emotion processing such as facial affect perception are comparable to the performance of HC.

"Tell me how do I feel"--emotion recognition and theory of mind in symptomatic mesial temporal lobe epilepsy.

Specific interictal personality characteristics in epilepsy, sometimes referred to as "Waxman-Geschwind Syndrome", have been recognized for centuries and extensively described. Despite the persevering clinical impression that patients with mesial temporal lobe epilepsies (MTLE) suffer from problems in communication and interpersonal relations, uncertainties and controversies remain as to the precise origin of these psychosocial difficulties. Here, we investigated social-cognitive and decision-making abilities using a set of tasks that combine behavioural and psychological measures of social and emotional variables to answer the question of whether patients with MTLE are specifically impaired in social cognition compared to both an epilepsy and a healthy control group. MTLE patients, an epilepsy control group (extra-MTLE; patients with epilepsy, not originating within the frontal or mesial temporal lobe) and healthy controls (HC) were assessed according to their general cognitive status as well as with our Social Cognition Battery, which included tests of basic processes of social cognition, theory of mind, decision making, and various aspects of psychopathology and quality of life. MTLE patients were significantly impaired compared to HC on most measures of the Social Cognition Battery. MTLE patients were predominantly impaired in general emotion recognition compared to extra-MTLE patients. Performance in the epilepsy control group, although not significantly differing from performance in either the MTLE or the healthy control group, lay between these two groups. MTLE can be considered a significant risk factor for the development of deficits in social cognition beyond weaknesses that might be associated with epilepsy as a stigmatized chronic neurological disorder. The presence of deficits in social cognition may explain various behavioural symptoms that have historically driven concepts such as "epileptic personality" or "interictal personality disorder" and may indicate new routes for therapeutic interventions.

Alterations in functional connectivity of the amygdala in unilateral mesial temporal lobe epilepsy.

The aim of this work was to evaluate the relationship between ipsilateral amygdala dysfunction in unilateral mesial temporal lobe epilepsy (MTLE) and remote temporal, frontal, and parietal brain structures and to identify their association with theory of mind (ToM) abilities. Functional magnetic resonance imaging (fMRI) data were acquired from MTLE patients with unilateral hippocampal sclerosis (n = 28; 16 left-sided) and healthy controls (HC, n = 18) watching an animated fearful face paradigm. To explore functional connectivity, we used independent component analysis (ICA) of fMRI data to characterize possible amygdala network alterations that may be caused by lateralized amygdala dysfunction. We furthermore investigated the relationship between activation within the amygdala network and ToM task performance. The pattern of amygdalar BOLD activation observed in response to an animated fearful face paradigm was bilateral amygdalar activation in HC and amygdala activation lateralized to the contralateral side in MTLE patients. In HC, a hemispheric asymmetry of the amygdala network was present with amygdala co-activation in predominantly left temporolateral and frontal brain structures. In MTLE patients, the observed asymmetry of amygdala connectivity was modulated by the side of pathology and the extent of amygdalar connectivity to the parahippocampal gyrus and insula was related to ToM test performance. These findings suggest that ipsilateral amygdalar dysfunction in MTLE is associated with alterations in remote temporal and frontal brain areas. The study of psychiatric and neurological disorders via network analysis allows for a shift of focus away from viewing dysfunctions of individual structures to a pathological network that possibly gives rise to a variety of symptoms.