Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions.

BACKGROUND: SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability. METHODS: We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor. FINDINGS: A higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n = 85) compared with controls (1.1%, n = 5) (p < 0.0001) whereas GAA250-299 alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA250-299 repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA≥300 carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of +18 repeats per generation (r2 = 0.44; p < 0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r2 = 0.63; p < 0.0001)), resulting in the transmission bias observed in SCA27B pedigrees. INTERPRETATION: SCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA250-299 repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling. FUNDING: This work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL.

Trial of Botulinum Toxin for Isolated or Essential Head Tremor.

BACKGROUND: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. METHODS: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. RESULTS: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. CONCLUSIONS: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).

Quantification of Head Tremors in Medical Conditions: A Comparison of Analyses Using a 2D Video Camera and a 3D Wireless Inertial Motion Unit.

This study compares two methods to quantify the amplitude and frequency of head movements in patients with head tremor: one based on video-based motion analysis, and the other using a miniature wireless inertial magnetic motion unit (IMMU). Concomitant with the clinical assessment of head tremor severity, head linear displacements in the frontal plane and head angular displacements in three dimensions were obtained simultaneously in forty-nine patients using one video camera and an IMMU in three experimental conditions while sitting (at rest, counting backward, and with arms extended). Head tremor amplitude was quantified along/around each axis, and head tremor frequency was analyzed in the frequency and time-frequency domains. Correlation analysis investigated the association between the clinical severity of head tremor and head linear and angular displacements. Our results showed better sensitivity of the IMMU compared to a 2D video camera to detect changes of tremor amplitude according to examination conditions, and better agreement with clinical measures. The frequency of head tremor calculated from video data in the frequency domain was higher than that obtained using time-frequency analysis and those calculated from the IMMU data. This study provides strong experimental evidence in favor of using an IMMU to quantify the amplitude and time-frequency oscillatory features of head tremor, especially in medical conditions.

Trans-Spinal Direct Current Stimulation for Managing Primary Orthostatic Tremor.

BACKGROUND: Primary orthostatic tremor (POT) is a rare disorder, characterized by 13 to 18 Hz tremor in the legs when standing and is often refractory to medical treatment. Epidural spinal cord stimulation has been proposed as an alternative treatment. However, this approach is invasive, which limits its application. OBJECTIVE: Trans-spinal direct current stimulation (tsDCS) is a non-invasive method to modulate spinal cord circuits. The aim of this proof-of-concept study was to investigate the potential beneficial effect of tsDCS in POT. METHODS: We conducted a double-blind, sham-controlled study in 16 patients with POT. In two separate visits, patients received sham tsDCS first followed by active (either cathodal or anodal) tsDCS. The primary outcome was the change in time in standing position. Secondary outcomes comprised quantitative assessment of tremor, measurement of corticospinal excitability including short-latency afferent inhibition, and clinical global impression-improvement (CGI-I). Measurements were made at baseline, after sham tsDCS, 0-30 min, and 30-60 min after active conditions. RESULTS: Cathodal-tsDCS reduced tremor amplitude and frequency and lowered corticospinal excitability whereas anodal-tsDCS reduced tremor frequency only. CGI-I scores positively correlated with the time in standing position after both active tsDCS conditions. CONCLUSION: A single session of tsDCS can improve instability in POT. This opens a new vista for experimental treatment options using multiple sessions of spinal DC stimulation. © 2021 International Parkinson and Movement Disorder Society.

Repetitive transcranial magnetic stimulation for functional tremor: A randomized, double-blind, controlled study.

OBJECTIVES: The objective of this study was to compare the effect on functional tremor of active versus sham repetitive transcranial magnetic stimulation and investigate whether the addition of hypnosis might help to prolong any repetitive transcranial magnetic stimulation-induced therapeutic effect. METHODS: We compared the effect of 5 consecutive daily sessions of active/sham repetitive transcranial magnetic stimulation on functional tremor, at 1 and 2 months, in a randomized, double-blind, 2-arm, parallel-controlled study. In a second open-label phase, all patients underwent 3 weekly sessions of hypnosis combined with single sessions of real repetitive transcranial magnetic stimulation. The primary outcome was a change in the Psychogenic Movement Disorder Rating Scale at month 1 when compared with baseline. Secondary outcomes were changes in the Psychogenic Movement Disorder Rating Scale and Tremor subscores, the 36-item Short Form Health Survey, the Self-Report Hospital Anxiety and Depression Scale, the Hamilton Depression Rating Scale, and the Clinical Global Impression Scale assessed at months 1, 2, 6, and 12. RESULTS: A total of 33 outpatients affected by functional tremor were screened, and 18 outpatients fulfilling the inclusion criteria (8 men, 10 women) were randomized. One month after the intervention, the mean Psychogenic Movement Disorder Rating Scale score had decreased in both groups, but the differences from baseline were only significant in the active repetitive transcranial magnetic stimulation group (P < .001). This remained significant at month 2 (P < .001). The significant decrease of the Psychogenic Movement Disorder Rating Scale and Tremor subscores were maintained at months 6 and 12 for the active repetitive transcranial magnetic stimulation group. For the control group, the Psychogenic Movement Disorder Rating Scale score had returned almost to its baseline value by month 2 and remained unchanged at months 6 and 12. CONCLUSION: Repetitive transcranial magnetic stimulation could represent a valuable therapeutic option in the management of functional tremor. © 2019 International Parkinson and Movement Disorder Society.

Incobotulinum toxin A in Parkinson's disease with foot dystonia: A double blind randomized trial.

INTRODUCTION: Plantar flexion of toe dystonia is very painful and leads to difficulties in walking. The objective of this study was to investigate the effect of incobotulinum toxin A (Xeomin) in the treatment of this type of dystonia in parkinsonian patients, using a randomized, double blind, placebo-controlled trial. METHODS: 45 parkinsonian patients with painful dystonic plantar flexion of toes were injected either with incobotulinum toxin A (Btx group), or with placebo in two muscle targets: the Flexor digitorum longus and the Flexor digitorum brevis. Three groups were compared: the first group received placebo in the Flexor digitorum longus and 100UI of Btx in the Flexor digitorum brevis (n = 16); the second group received 100 UI of Btx in the Flexor digitorum longus and placebo in the Flexor digitorum brevis (n = 13); and the third group, 2 injections of placebo (n = 16). The patients were injected in the same way twice with an interval of 3 months. The primary endpoint was measured six weeks after injections with the Clinical Global Impression (CGI) of change. Dystonia severity and associated pain were also assessed. RESULTS: Mean CGI was improved in the Btx group compared to the placebo group (P = 0.039). A significant reduction of pain and dystonia severity were observed in patients treated with Btx compared to baseline but no improvement was noted when compared to placebo group. No difference of efficacy was highlighted between the two injection sites. CONCLUSIONS: Btx injections are effective for improving clinical state of parkinsonian patients with plantar flexion of toe dystonia.

Botulinum toxin injection in laryngeal dyspnea.

Data, regarding the use of botulinum toxin (BT-A) in laryngeal dyspnea, are scarce, coming from some cases reports in the literature, including Vocal fold paralysis, laryngeal dystonia, vocal cord dysfunction also called paradoxical motion of the vocal fold (PMVF), and post-neuroleptic laryngeal dyskinesia. There is no consensus regarding the muscles and the doses to inject. The aim of this study is to present a retrospective review of patients treated in our ENT Department by BT-A injection in this indication. This study is a retrospective study describing patients who underwent an injection of botulinum toxin for laryngeal dyspnea in the ENT Department from 2005 to 2015 years. The inclusion criteria were a dyspnea associated with a laryngeal dysfunction, confirmed by flexible fiberoptic nasopharyngolaryngoscopy. Information concerning the causes of the dyspnea, the botulinum toxin BT-A injections procedure, post-injection follow-up, and respiratory outcome were collected for all patients included. In the group of 13 patients included, the main cause identified as principal factor linked with the short breath was: a bilateral VF paralysis (Patel et al., Otolaryngol Head Neck Surg 130:686-689, 7), laryngeal dystonia (Balkissoon and Kenn, Semin Respir Crit Care Med 33:595-605, 2), Anxiety syndrome associated with unilateral vocal fold paralysis or asthma (Marcinow et al., Laryngoscope 124:1425-1430, 3), and an isolated asthma (Zwirner et al., Eur Arch Otorhinolaryngol 254:242-245, 1). Nine out of the thirteen patients were improved by the injections. A BT-A-induced stable benefit for four patients led them to stop the injections in the follow-up. Good outcome was observed in five other patients (main cause: bilateral VP paralysis), allowing a progressive lengthening of the delay between BT-A injections. Four patients did not report a positive risk/benefit ratio after BT-A injections; two of them (with bilateral VF paralysis), because of respiratory side effects and lack of benefit without the side effects for the two others. This failure of effect was not related with BT-A doses injected. This study provides support for using BT-A injections as a symptomatic treatment of periodic laryngeal dyspnea, regardless of the etiologic context. From our data, we suggest that a small starting dose (of around 4 U BT-A Botox®) could be enough for a first injection to obtain a good benefit. The target muscle should be determined by the EMG analysis.

Strength and fine dexterity recovery profiles after a primary motor cortex insult and effect of a neuronal cell graft.

The aim of this study was to set up (a) a large primary motor cortex (M1) lesion in rodent and (b) the conditions for evaluating a long-lasting motor deficit in order to propose a valid model to test neuronal replacement therapies aimed at improving motor deficit recovery. A mitochondrial toxin, malonate, was injected to induce extensive destruction of the forelimb M1 cortex. Three key motor functions that are usually evaluated following cerebral lesion in the clinic-strength, target reaching, and fine dexterity-were assessed in rats by 2 tests, a forelimb grip strength test and a skilled reaching task (staircase) for reaching and dexterity. The potential enhancement of postlesion recovery induced by a neuronal cell transplantation was then explored and confirmed by histological analyses. Both tests showed a severe functional impairment 2 days post lesion, however, reaching remained intact. Deficits in forelimb strength were long lasting (up to 3 months) but spontaneously recovered despite the extensive lesion size. This natural grip strength recovery could be enhanced by cell therapy. Histological analyses confirmed the presence of grafted cells 3 months postgraft and showed partial tissue reconstruction with some living neuronal cells in the graft. In contrast, fine dexterity never recovered in the staircase test even after grafting. These results suggest that cell replacement was only partially effective and that the forelimb M1 area may be a node of the sensorimotor network, where compensation from secondary pathways could account for strength recovery but recovery of forelimb fine dexterity requires extensive tissue reconstruction.

Distinctive features of NREM parasomnia behaviors in parkinson's disease and multiple system atrophy.

OBJECTIVE: To characterize parasomnia behaviors on arousal from NREM sleep in Parkinson's Disease (PD) and Multiple System Atrophy (MSA). METHODS: From 30 patients with PD, Dementia with Lewy Bodies/Dementia associated with PD, or MSA undergoing nocturnal video-polysomnography for presumed dream enactment behavior, we were able to select 2 PD and 2 MSA patients featuring NREM Parasomnia Behviors (NPBs). We identified episodes during which the subjects seemed to enact dreams or presumed dream-like mentation (NPB arousals) versus episodes with physiological movements (no-NPB arousals). A time-frequency analysis (Morlet Wavelet Transform) of the scalp EEG signals around each NPB and no- NPB arousal onset was performed, and the amplitudes of the spectral frequencies were compared between NPB and no-NPB arousals. RESULTS: 19 NPBs were identified, 12 of which consisting of 'elementary' NPBs while 7 resembling confusional arousals. With quantitative EEG analysis, we found an amplitude reduction in the 5-6 Hz band 40 seconds before NPBs arousal as compared to no-NPB arousals at F4 and C4 derivations (p<0.01). CONCLUSIONS: Many PD and MSA patients feature various NREM sleep-related behaviors, with clinical and electrophysiological differences and similarities with arousal parasomnias in the general population. SIGNIFICANCE: This study help bring to attention an overlooked phenomenon in neurodegenerative diseases.

Anodal tDCS Combined With Radial Nerve Stimulation Promotes Hand Motor Recovery in the Acute Phase After Ischemic Stroke.

BACKGROUND AND OBJECTIVE: The question of the best therapeutic window in which noninvasive brain stimulation (NIBS) could potentiate the plastic changes for motor recovery after a stroke is still unresolved. Most of the previous NIBS studies included patients in the chronic phase of recovery and very few in the subacute or acute phase. We investigated the effect of transcranial direct current stimulation (tDCS) combined with repetitive peripheral nerve stimulation (rPNS) on the time course of motor recovery in the acute phase after a stroke. METHODS: Twenty patients enrolled within the first few days after a stroke were randomized in 2 parallel groups: one receiving 5 consecutive daily sessions of anodal tDCS over the ipsilesional motor cortex in association with rPNS and the other receiving the same rPNS combined with sham tDCS. Motor performance (primary endpoint: Jebsen and Taylor Hand Function Test [JHFT]) and transcranial magnetic stimulation cortical excitability measures were obtained at baseline (D1), at the end of the treatment (D5), and at 2 and 4 weeks' follow-up (D15 and D30). RESULTS: The time course of motor recovery of the 2 groups of patients was different and positively influenced by the intervention (Group × Time interaction P = .01). The amount of improvement on the JHFT was greater at D15 and D30 in the anodal tDCS group than in the sham group. CONCLUSION: These results show that early cortical neuromodulation with anodal tDCS combined with rPNS can promote motor hand recovery and that the benefit is still present 1 month after the stroke.

Deep brain stimulation of the subthalamic nucleus improves pain in Parkinson's disease.

BACKGROUND: In Parkinson's disease (PD), chronic pain is a common symptom which markedly affects the quality of life. Some physiological arguments proposed that Deep Brain Stimulation of the Subthalamic Nucleus (STN-DBS) could improve pain in PD. METHODS: We investigated in 58 PD patients the effect of STN-DBS on pain using the short McGill Pain Questionnaire and other pain parameters such as the Bodily discomfort subscore of the Parkinson's disease Questionnaire 39 and the Unified Parkinson's Disease Rating Scale section II (UPDRS II) item 17. RESULTS: All pain scores were significantly improved 12 months after STN-DBS. This improvement was not correlated with motor improvement, depression scores or L-Dopa reduction. CONCLUSIONS: STN-DBS induced a substantial beneficial effect on pain in PD, independently of its motor effects and mood status of patients.

Borderline personality disorder and rTMS: a pilot trial.

A randomized, controlled study was carried out to assess the effect of a series of 10 sessions of high-frequency rTMS to the right DLPFC in 10 Borderline Personality Disorder patients. Patients in the rTMS group showed improvements in anger, affective instability (Borderline Personality Disorder Severity Index) and planning (Tower Of London). Two smoking cessations were observed.

Does abnormal interhemispheric inhibition play a role in mirror dystonia?

The presence of mirror dystonia (dystonic movement induced by a specific task performed by the unaffected hand) in the dominant hand of writer's cramp patients when the nondominant hand is moved suggests an abnormal interaction between the 2 hemispheres. In this study we compare the level of interhemispheric inhibition (IHI) in 2 groups of patients with writer's cramp, one with the presence of a mirror dystonia and the other without as well as a control group. The level of bidirectional IHI was measured in wrist muscles with dual-site transcranial magnetic stimulation with a 10-millisecond (short IHI) and a 40-millisecond (long IHI) interstimulus interval during rest and while holding a pen in 9 patients with mirror dystonia 7 without mirror dystonia, and 13 controls. The group of patients without mirror dystonia did not differ from the controls in their IHI level. In contrast, IHI was significantly decreased in the group of patients with mirror dystonia in comparison with the group without mirror dystonia and the controls in both wrist muscles of both the dystonic and unaffected hand whatever the resting or active condition (P = 0.001). The decrease of IHI level in the group of patients with mirror dystonia was negatively correlated with the severity and the duration of the disease: the weaker the level of IHI, the more severe was the disease and the longer its duration. Interhemispheric inhibition disturbances are most likely involved in the occurrence of mirror dystonia. This bilateral deficient inhibition further suggests the involvement of the unaffected hemisphere in the pathophysiology of unilateral dystonia.

Neuronal activity correlated with checking behaviour in the subthalamic nucleus of patients with obsessive-compulsive disorder.

Doubt, and its behavioural correlate, checking, is a normal phenomenon of human cognition that is dramatically exacerbated in obsessive-compulsive disorder. We recently showed that deep brain stimulation in the associative-limbic area of the subthalamic nucleus, a central core of the basal ganglia, improved obsessive-compulsive disorder. To understand the physiological bases of symptoms in such patients, we recorded the activity of individual neurons in the therapeutic target during surgery while subjects performed a cognitive task that gave them the possibility of unrestricted repetitive checking after they had made a choice. We postulated that the activity of neurons in this region could be influenced by doubt and checking behaviour. Among the 63/87 task-related neurons recorded in 10 patients, 60% responded to various combinations of instructions, delay, movement or feedback, thus highlighting their role in the integration of different types of information. In addition, task-related activity directed towards decision-making increased during trials with checking in comparison with those without checking. These results suggest that the associative-limbic subthalamic nucleus plays a role in doubt-related repetitive thoughts. Overall, our results not only provide new insight into the role of the subthalamic nucleus in human cognition but also support the fact that subthalamic nucleus modulation by deep brain stimulation reduced compulsive behaviour in patients with obsessive-compulsive disorder.

The effects of botulinum toxin injections into the cricopharyngeus muscle of patients with cricopharyngeus dysfunction associated with pharyngo-laryngeal weakness.

This prospective, open study was carried out in order to assess changes in the swallowing and dietary status after injection of Botulinum toxin A (BoNT-A) into the upper esophageal sphincter (UES) in a series of patients with cricopharyngeus (CP) muscle dysfunction associated with pharyngo-laryngeal weakness during at least 1 year follow-up after treatment. Patients who had a cricopharyngeus (CP) muscle dysfunction associated with pharyngo-laryngeal weakness and who were at risk for aspiration were included in the study. The upper border of the cricoid cartilage was identified and the CP muscle localized using a standard electromyogram (EMG). The dose of BoNT-A was determined depending on the results of EMG performed just before the injection. Outcomes were assessed by the penetration-aspiration scale (PAS), the level of residue in the pyriform sinus and the National Institute of Health-Swallow Safety Scale (NIH-SSS) on a video fluoroscopic swallowing (VFSS) assessment, the patient's subjective impressions of their ability to swallow by the Deglutition Handicap Index (DHI), and changes in dietary status by the Functional Oral Intake Scale. Eleven patients underwent the complete assessment of swallowing function at 1, 3, 6, and 12 months. After the first set of treatment, seven patients had a good response and four did not respond. A significant decrease in the PAS score (p = 0.03), the amount of residue (p = 0.04) and the NIH-SSS score (p = 0.03) was observed 3 months after the injection in comparison with the first VFSS before the treatment. A relapse of dysphagia occurred in 3 out of the 11 treated patients; at 3 and 4 months for 2 patients with a Wallenberg syndrome, and at 11 months for a patient with cranial nerve paralysis after a surgery for a glomus tumor. Two of them underwent a second injection. One patient had a good response and remained stable for at least 1 year. The second did not respond either to the second injection or to a myotomy of the cricopharyngeal muscle. The third one is waiting for further surgery (myotomy). Therefore, at the end of the study and after a follow-up of at least 12 months, 5 patients out of the 11 enrolled had a good result. Percutaneous injection of BoNT-A into the UES can be a useful solution to improve cricopharyngeal dysfunction, despite the underlying pharyngo-laryngeal weakness.

Factors influencing response to Botulinum toxin type A in patients with idiopathic cervical dystonia: results from an international observational study.

OBJECTIVES: Real-life data on response to Botulinum toxin A (BoNT-A) in cervical dystonia (CD) are sparse. An expert group of neurologists was convened with the overall aim of developing a definition of treatment response, which could be applied in a non-interventional study of BoNT-A-treated subjects with CD. DESIGN: International, multicentre, prospective, observational study of a single injection cycle of BoNT-A as part of normal clinical practice. SETTING: 38 centres across Australia, Belgium, Czech Republic, France, Germany, The Netherlands, Portugal, Russia and the UK. PARTICIPANTS: 404 adult subjects with idiopathic CD. Most subjects were women, aged 41-60 years and had previously received BoNT-A. OUTCOME MEASURES: Patients were classified as responders if they met all the following four criteria: magnitude of effect (≥25% improvement Toronto Western Spasmodic Torticollis Rating Scale), duration of effect (≥12-week interval between the BoNT-A injection day and subject-reported waning of treatment effect), tolerability (absence of severe related adverse event) and subject's positive Clinical Global Improvement (CGI). RESULTS: High rates of response were observed for magnitude of effect (73.6%), tolerability (97.5%) and subject's clinical global improvement (69.8%). The subjective duration of effect criterion was achieved by 49.3% of subjects; 28.6% of subjects achieved the responder definition. Factors most strongly associated with response were age (<40 years; OR 3.9, p<0.05) and absence of baseline head tremor (OR 1.5; not significant). CONCLUSIONS: Three of four criteria were met by most patients. The proposed multidimensional definition of response appears to be practical for routine practice. Unrealistically high patient expectation and subjectivity may influence the perception of a quick waning of effect, but highlights that this aspect may be a hurdle to response in some patients. CLINICAL REGISTRATION NUMBER: (NCT00833196; ClinicalTrials.gov).