Swiss QUality of life and healthcare impact Assessment in a Real-world Erenumab treated migraine population (SQUARE study): interim results.

BACKGROUND: The fully human monoclonal antibody erenumab, which targets the calcitonin gene-related peptide (CGRP) receptor, was licensed in Switzerland in July 2018 for the prophylactic treatment of migraine. To complement findings from the pivotal program, this observational study was designed to collect and evaluate clinical data on the impact of erenumab on several endpoints, such as quality of life, migraine-related impairment and treatment satisfaction in a real-world setting. METHODS: An interim analysis was conducted after all patients completed 6 months of erenumab treatment. Patients kept a headache diary and completed questionnaires at follow up visits. The overall study duration comprises 24 months. RESULTS: In total, 172 adults with chronic or episodic migraine from 19 different sites across Switzerland were enrolled to receive erenumab every 4 weeks. At baseline, patients had 16.6 ± 7.2 monthly migraine days (MMD) and 11.6 ± 7.0 acute migraine-specific medication days per month. After 6 months, erenumab treatment reduced Headache Impact Test (HIT-6™) scores by 7.7 ± 8.4 (p < 0.001), the modified Migraine Disability Assessment (mMIDAS) by 14.1 ± 17.8 (p < 0.001), MMD by 7.6 ± 7.0 (p < 0.001) and acute migraine-specific medication days per month by 6.6 ± 5.4 (p < 0.001). Erenumab also reduced the impact of migraine on social and family life, as evidenced by a reduction of Impact of Migraine on Partners and Adolescent Children (IMPAC) scores by 6.1 ± 6.7 (p < 0.001). Patients reported a mean effectiveness of 67.1, convenience of 82.4 and global satisfaction of 72.4 in the Treatment Satisfaction Questionnaire for Medication (TSQM-9). In total, 99 adverse events (AE) and 12 serious adverse events (SAE) were observed in 62 and 11 patients, respectively. All SAE were regarded as not related to the study medication. CONCLUSIONS: Overall quality of life improved and treatment satisfaction was rated high with erenumab treatment in real-world clinical practice. In addition, the reported impact of migraine on spouses and children of patients was reduced. TRIAL REGISTRATION: BASEC ID 2018-02,375 in the Register of All Projects in Switzerland (RAPS).

Impact on monthly migraine days of discontinuing anti-CGRP antibodies after one year of treatment - a real-life cohort study.

OBJECTIVE: This study aims to analyse the effect of the discontinuation of anti-calcitonin gene-related peptide antibodies on monthly migraine days after 12 treatment months. BACKGROUND: Anti-calcitonin gene-related peptide antibodies have been a game changer in migraine prophylaxis. However, high treatment costs warrant reducing treatment duration to the essential minimum. METHODS: We collected data of patients with migraine who had received anti-calcitonin gene-related peptide antibodies and had received treatment for 12 months. RESULTS: We included 52 patients. The average number of monthly migraine days was 16 ± 7 days at baseline, 6 ± 6 in the third, and 5 ± 4 in the 12th treatment month. After treatment interruption, the number of monthly migraine days was 6 ± 4 days in the first month, 9 ± 4 days in the second, and 11 ± 5 days in the third month. Most patients (88.9%) restarted treatment. CONCLUSION: Only little of the therapeutic effect of anti-calcitonin gene-related peptide antibodies outlasts their pharmacological effect. After treatment interruption, migraine frequency rose in most patients, and prophylaxis was required again in most cases.Limiting treatment to benefitting patients and confirming the need for prophylaxis periodically is reasonable. However, our data does not support the need for prescheduled treatment discontinuation after 12 months and a fixed duration of the treatment interruption of 3 months.

Disownership of body parts as revealed by a visual scale evaluation. An observational study.

The disownership of body parts, that most frequently occurs on the left side of the body, contralateral to right-hemispheric lesions, is an infrequent disorder, as usually assessed by interviews asking for dichotomic "yes/no" responses. This observational study in right-brain-damaged stroke patients investigated the efficacy of a continuous Visual Analog Scale (VAS) to detect body disownership after right brain damage, compared to dichotomic questions. Thirty-two right-handed right-brain-damaged stroke patients were given a Standardized Interview (SI), asking "Whose hand/arm/leg is this?", followed by a VAS (asking patients to mark on a vertical line their agreement with the statement that a body part belonged to them). The neural correlates of this disorder and measures of extra-personal and personal spatial neglect were also assessed. Control data were recorded from 18 neurologically unimpaired right-handed participants. During the interview, no patient showed disownership of body parts. Conversely, on the VAS eight out of 32 (25%) patients' scores, but none of the controls' scores, indicated a judgement of disownership for left body parts, with a left-right difference larger than that of control participants. VAS-detected disownership was not systematically associated with extra-personal and personal unilateral spatial neglect. Lesion sites associated with disownership of left body parts included the caudate nucleus and the anterior part of the internal capsule. To conclude, the VAS task, compared to the interview, is a novel tool to detect disownership of left body parts in right brain-damaged patients. A revised classification of body-ownership disorders is proposed. The present variant, assessed and detected by the VAS task, is termed Covert disownership and distinguished from the Overt disownership assessed by a SI.

Somatosensory and auditory deviance detection for outcome prediction during postanoxic coma.

OBJECTIVE: Prominent research in patients with disorders of consciousness investigated the electrophysiological correlates of auditory deviance detection as a marker of consciousness recovery. Here, we extend previous studies by investigating whether somatosensory deviance detection provides an added value for outcome prediction in postanoxic comatose patients. METHODS: Electroencephalography responses to frequent and rare stimuli were obtained from 66 patients on the first and second day after coma onset. RESULTS: Multivariate decoding analysis revealed an above chance-level auditory discrimination in 25 patients on the first day and in 31 patients on the second day. Tactile discrimination was significant in 16 patients on the first day and in 23 patients on the second day. Single-day sensory discrimination was unrelated to patients' outcome in both modalities. However, improvement of auditory discrimination from first to the second day was predictive of good outcome with a positive predictive power (PPV) of 0.73 (CI = 0.52-0.88). Analyses considering the improvement of tactile, auditory and tactile, or either auditory or tactile discrimination showed no significant prediction of good outcome (PPVs = 0.58-0.68). INTERPRETATION: Our results show that in the acute phase of coma deviance detection is largely preserved for both auditory and tactile modalities. However, we found no evidence for an added value of somatosensory to auditory deviance detection function for coma-outcome prediction.

How Do You Feel? Subjective Perception of Recovery as a Reliable Surrogate of Cognitive and Functional Outcome in Cardiac Arrest Survivors.

OBJECTIVES: To show that subjective estimate of patient's condition is related to objective cognitive and functional outcome in cardiac arrest survivors. DESIGN: Longitudinal cohort study. SETTING: ICU and Neuropsychology Service in two hospitals in Switzerland. PATIENTS: Fifty survivors included from a prospective cohort of 138 patients admitted at the ICU for cardiopulmonary arrest. INTERVENTIONS: Comprehensive cognitive and functional evaluation at 6 months follow-up. MEASUREMENTS AND MAIN RESULTS: Subjectively, 70% of survivors reported satisfactory recovery and 29% reported no complaints. Objectively, 76% were classified as good neurologic outcome (Cerebral Performance Category 1), 26% as having no symptoms (modified Rankin Scale 0), and 38% as upper good recovery (Glasgow Outcome Scale Extended 1). Cognitive assessment detected substantial cognitive impairment in 26%, primarily concerning processing speed, language, long-term memory, and executive functions. Subjective complaints severity correlated significantly with objective cognitive impairment (rS = 0.64; p < 0.001). Finally, patients reporting unsatisfactory recovery displayed lower functional scores than those reporting satisfactory recovery (e.g., quality of life satisfaction: 64% vs 81%; Z = 2.18; p = 0.03) and more cognitive impairment (three vs one cognitive domains impaired; Z = -3.21; p < 0.001), concerning in particular learning and long-term verbal and visual memory. CONCLUSIONS: Long-term subjective and objective outcome appears good in the majority of cardiac arrest survivors. Specific functional and cognitive impairments were found in patients reporting unsatisfactory recovery. Subjective recovery was strongly correlated with objective assessment.

Evidence of trace conditioning in comatose patients revealed by the reactivation of EEG responses to alerting sounds.

Trace conditioning refers to a learning process occurring after repeated presentation of a neutral conditioned stimulus (CS+) and a salient unconditioned stimulus (UCS) separated by a temporal gap. Recent studies have reported that trace conditioning can occur in humans in reduced levels of consciousness by showing a transfer of the unconditioned autonomic response to the CS+ in healthy sleeping individuals and in vegetative state patients. However, no previous studies have investigated the neural underpinning of trace conditioning in the absence of consciousness in humans. In the present study, we recorded the EEG activity of 29 post-anoxic comatose patients while presenting a trace conditioning paradigm using neutral tones as CS+ and alerting sounds as UCS. Most patients received therapeutic hypothermia and all were deeply unconscious according to standardized clinical scales. After repeated presentation of the CS+ and UCS couple, learning was assessed by measuring the EEG activity during the period where the UCS is omitted after CS+ presentation. Specifically we assessed the 'reactivation' of the neural response to UCS omission by applying a decoding algorithm derived from the statistical model of the EEG activity in response to the UCS presentation. The same procedure was used in a group of 12 awake healthy controls. We found a reactivation of the UCS response in absence of stimulation in eight patients (five under therapeutic hypothermia) and four healthy controls. Additionally, the reactivation effect was temporally specific within trials since it manifested primarily at the specific latency of UCS presentation and significantly less before or after this period. Our results show for the first time that trace conditioning may manifest as a reactivation of the EEG activity related to the UCS and even in the absence of consciousness.

Prediction of awakening from hypothermic postanoxic coma based on auditory discrimination.

OBJECTIVE: Most of the available clinical tests for prognosis of postanoxic coma are informative of poor outcome. Previous work has shown that an improvement in auditory discrimination over the first days of coma is predictive of awakening. Here, we aimed at evaluating this test on a large cohort of patients undergoing therapeutic hypothermia and at investigating its added value on existing clinical measures. METHODS: We recorded electroencephalographic responses to auditory stimuli in 94 comatose patients, under hypothermia and after rewarming to normal temperature. Auditory discrimination was semiautomatically quantified by decoding electroencephalographic responses to frequently repeated versus rare sounds. Outcome prediction was based on the change of decoding performance from hypothermia to normothermia. RESULTS: An increase in auditory discrimination from hypothermia to normothermia was observed for 33 of 94 patients. Among them, 27 awoke from coma, resulting in a positive predictive value of awakening of 82% (95% confidence interval = 0.65-0.93). Most nonsurvivors showing an improvement in auditory discrimination had incident status epilepticus. By excluding them, 27 of 29 patients with improvement in auditory discrimination survived, resulting in a considerable improvement of the predictive value for awakening (93%, with 95% confidence interval = 0.77-0.99). Importantly, this test predicted the awakening of 13 of 51 patients for whom the outcome was uncertain based on current tests. INTERPRETATION: The progression of auditory discrimination from hypothermia to normothermia has a high predictive value for awakening. This quantitative measure provides an added value to existing clinical tests and encourages the maintenance of life support. Ann Neurol 2016;79:748-757.

Intermittent hemodialysis treatment in cefepime-induced neurotoxicity: case report, pharmacokinetic modeling, and review of the literature.

Cefepime is a broad-spectrum cephalosporin indicated for in-hospital treatment of severe infections. Acute neurotoxicity, an increasingly recognized adverse effect of this drug in an overdose, predominantly affects patients with reduced renal function. Although dialytic approaches have been advocated to treat this condition, their role in this indication remains unclear. We report the case of an 88-year-old female patient with impaired renal function who developed life-threatening neurologic symptoms during cefepime therapy. She was treated with two intermittent 3-hour high-flux, high-efficiency hemodialysis sessions. Serial pre-, post-, and peridialytic (pre- and postfilter) serum cefepime concentrations were measured. Pharmacokinetic modeling showed that this dialytic strategy allowed for serum cefepime concentrations to return to the estimated nontoxic range 15 hours earlier than would have been the case without an intervention. The patient made a full clinical recovery over the next 48 hours. We conclude that at least 1 session of intermittent hemodialysis may shorten the time to return to the nontoxic range in severe clinically patent intoxication. It should be considered early in its clinical course pending chemical confirmation, even in frail elderly patients. Careful dosage adjustment and a high index of suspicion are essential in this population.

Demyelination in mild cognitive impairment suggests progression path to Alzheimer's disease.

The preclinical Alzheimer's disease (AD) - amnestic mild cognitive impairment (MCI) - is manifested by phenotypes classified into exclusively memory (single-domain) MCI (sMCI) and multiple-domain MCI (mMCI). We suggest that typical MCI-to-AD progression occurs through the sMCI-to-mMCI sequence as a result of the extension of initial pathological processes. To support this hypothesis, we assess myelin content with a Magnetization Transfer Ratio (MTR) in 21 sMCI and 21 mMCI patients and in 42 age-, sex-, and education-matched controls. A conjunction analysis revealed MTR reduction shared by sMCI and mMCI groups in the medial temporal lobe and posterior structures including white matter (WM: splenium, posterior corona radiata) and gray matter (GM: hippocampus; parahippocampal and lingual gyri). A disjunction analysis showed the spread of demyelination to prefrontal WM and insula GM in executive mMCI. Our findings suggest that demyelination starts in the structures affected by neurofibrillary pathology; its presence correlates with the clinical picture and indicates the method of MCI-to-AD progression. In vivo staging of preclinical AD can be developed in terms of WM/GM demyelination.

Local landmark-based registration for fMRI group studies of nonprimary auditory cortex.

Interindividual functional and structural brain variability is a major problem in group studies, in which very focal activations are expected. Architectonic studies have shown that the human primary auditory area, which is located with a great constancy on Heschl's gyrus, is surrounded by several nonprimary auditory areas with surface areas of 40-310 mm(2). The small size of the latter makes them only partially accessible to fMRI group studies, because of imprecision in realignment when using currently available registration procedures. We describe here a new method for sulcal realignment using a non-rigid local landmark-based registration and show its application to the registration of fMRI acquisitions on the supratemporal plane. After an affine global voxel-based registration, which transforms all brains into the same standard space, we propose a non-rigid local landmark-based registration method based on thin-plate splines for matching the two sulci delimiting Heschl's gyrus of a given brain to the corresponding sulci of a reference brain. We show here that, in comparison with global affine and non-rigid approaches, our method leads in group studies to i) a much more precise alignment of Heschl's gyrus; and ii) a putatively optimal superposition of functionally corresponding areas on and around Heschl's gyrus.

Human auditory belt areas specialized in sound recognition: a functional magnetic resonance imaging study.

The human primary auditory cortex is surrounded by at least six other, anatomically distinct areas that process auditory information. We have investigated their specialization with respect to sound recognition or sound localization with triple epoch functional magnetic resonance imaging paradigm (recognition-localization-rest) in 18 normal individuals. In each study participant, the pattern of selective activation by the recognition or by the localization tasks was superimposed on the map of the nonprimary auditory areas, as identified in previous anatomical studies. Two areas, anterior lateral and anterior areas, were activated bilaterally in significantly more individuals by the recognition than by the localization task. They are proposed to be human homologues of macaque anterolateral auditory belt area.