Real-world evidence following a mandatory treatment break after a 1-year prophylactic treatment with calcitonin gene-related peptide (pathway) monoclonal antibodies.

BACKGROUND: Current German and European guidelines suggest migraine patients undertake a treatment break after 9 to 12 months of treatment with CGRP (pathway) monoclonal antibodies. METHODS: Clinical routine data of highly resistant migraine patients were analyzed before treatment with CGRP monoclonal antibodies (baseline), after 12 months of treatment, and following a treatment break between November 2018 and December 2020 in the West German Headache Centre, University Hospital Essen, Germany. Monthly migraine days (MMD), monthly headache days (MHD), and days of acute medication intake (AMD) were assessed. RESULTS: Complete clinical data from 46 migraine patients (14 episodic migraine (EM), 32 chronic migraine (CM) patients) treated with erenumab (n = 40), galcanezumab (n = 4), and fremanezumab (n = 2) were analyzed. The mean number of MMDs among EM and CM patients after 12 months of CGRP antibody treatment increased during the treatment break by 5.18 (SE 0.92, p < .001) and 5.06 (SE 1.22, p = .003) days, respectively. There was an increased intake of acute medications among episodic (4.72, SE 0.87, p = .004) and chronic migraine patients (3.01, SE 1.08, p = .013) during treatment break. Eighty-three percent of patients (n = 38) were dissatisfied with the mandatory treatment break. All patients continued with a CGRP (pathway) monoclonal antibody after the mandatory treatment break. CONCLUSION: A mandatory break in CGRP (pathway) monoclonal antibody therapy had a negative short-term impact on migraine patients.

Reduced vestibular perception thresholds in persistent postural-perceptual dizziness- a cross-sectional study.

BACKGROUND: Persistent postural-perceptual dizziness (PPPD) is the most common functional vestibular disorder. A multisensory mismatch altered by psychological influences is considered to be an important pathophysiological mechanism. Increased cortical and subcortical excitability may play a role in the pathophysiology of PPPD. We hypothesized that decreased motion perception thresholds reflect one mechanism of the abnormal vestibular responsiveness in this disorder. We investigated the vestibular perception thresholds and the vestibular ocular reflex with a rotatory chair experiment to gain insights in the processing and adaption to vestibular provocation. METHODS: In this cross-sectional study 26 female PPPD patients and 33 healthy female age matched controls (HC) were investigated sitting in a motorized rotary chair shielded regarding visual and acoustic stimuli. The chair was rotated for 20 minutes with slowly increasing velocity to a maximum of 72°/s. We functionally tested motion perception thresholds and vegetative responses to rotation as well as vestibular-ocular reflex thresholds. We additionally investigated several psychological comorbidities (i.e. depression, anxiety, somatosensory amplification) using validated scores. Conventional dizziness scores were obtained to quantify the experienced dizziness and impact on daily life. RESULTS: PPPD patients showed a significant reduced vestibulo-perceptual threshold (PPPD: 10.9°/s vs. HC: 29.5°/s; p<0.001) with increased motion sensitivity and concomitant vegetative response during and after the chair rotation compared to healthy controls. The extent of increased vestibular sensitivity was in correlation with the duration of the disease (p=0.043). No significant difference was measured regarding nystagmus parameters between both groups. CONCLUSION: PPPD patients showed increased vegetative response as well as decreased vestibulo-perceptual thresholds which are related to disease duration. This is of interest as PPPD might be sustained by increased vestibular excitability leading to motion intolerance and induction of dizziness when exposed to movement.

CGRP antibody therapy in patients with drug resistant migraine and chronic daily headache: a real-world experience.

BACKGROUND: Calcitonin gene-related peptide (CGRP) (receptor) antibodies (erenumab, fremanezumab and galcanezumab) are increasingly used in prophylactic treatment of migraine. In the approval studies, severely affected patients with migraine and chronic daily headache without any headache free days were excluded. Thus, less is known about the effectiveness of CGRP antibody treatment in this cohort. METHODS: Clinical routine data of 32 patients with migraine and daily headache were analysed after three months of treatment with a CGRP antibody (16 erenumab, 7 galcanezumab, 9 fremanezumab), including changes of monthly headache days (MHD) monthly migraine days (MMD) and monthly acute medication intake (AMD) as well as migraine characteristics. Statistical analysis was performed with the Wilcoxon-Test. Migraine characteristics were analysed descriptively. RESULTS: The number of MHD was significantly reduced (mean reduction (standard error), p-value): (-4.2 (1.3), p = 0.009) as well as MMD (-4.3 (1.6), p = 0.033). Four patients (13 %) reached a 50 % reduction regarding MHD and 8 patients (25 %) regarding MMD, migraine duration and intensity improved under therapy. CONCLUSIONS: Despite the low responder rate, CGRP antibodies can be effective at least in a few cases of severely affected patients with drug resistant migraine and chronic daily headache. TRIAL REGISTRATION: Retrospective registered.

Sensitized rotatory motion perception and increased susceptibility to motion sickness in vestibular migraine: A cross-sectional study.

BACKGROUND AND PURPOSE: Vestibular migraine (VM) patients are ictally and interictally hypersensitive for self-motion and visual perception. Increased cortical excitability of the vestibular system represented by lowered motion perception thresholds might play an important role in the pathophysiology of VM. We aimed to compare motion perception thresholds and the vegetative response to rotatory motion, as well as the vestibulo-ocular reflex (VOR) during rotation in VM patients compared to healthy controls (HC). METHODS: In this cross-sectional study, 28 female VM patients in the interictal state and 33 age- and gender-matched HC were investigated sitting in a motorized rotary chair shielded regarding visual and acoustic stimuli for 20 min with slowly increasing velocity (maximum = 72°/s). The motion perception threshold was indicated by the participants by pushing a button. During and after rotation, participants rated the presence and extent of motion sickness using a sickness rating scale. RESULTS: We detected lower motion perception thresholds (7.54°/s vs. 23.49°/s; p < 0.001) in VM patients compared to HC but no difference at the basic VOR thresholds. Furthermore, the patients showed enhanced susceptibility to motion sickness during and after the rotation. CONCLUSIONS: We provide evidence for decreased motion perception thresholds and pronounced susceptibility to motion sickness in VM patients in the interictal state, which could indicate alterations in higher levels of vestibular processing. Future studies should determine whether this could be the pathophysiological hallmark of VM either as a unique disease entity or in differentiation from other forms of migraine.

Erenumab in highly therapy-refractory migraine patients: First German real-world evidence.

BACKGROUND: Calcitonin gene related peptide (CGRP) monoclonal antibodies (mAB) are the first specific migraine prophylactic medication. Erenumab is the only CGRP mAB targeting the CGRP receptor. Clinical data regarding efficacy and tolerability of erenumab in highly therapy-refractory patients are not available, yet, although many patients treated with CGRP mAB under real world conditions can be considered as highly therapy-refractory. METHODS: Clinical routine data of highly therapy-refractory migraine patients treated with erenumab 70 mg for 3 months between November 2018 and December 2019 in the West German Headache Center, University Hospital Essen, Germany, were analysed. Monthly migraine days (MMD), monthly headache days (MHD) and days of acute medication intake (AMD) were assessed. Statistical analysis was performed using the Wilcoxon test. Descriptive statistics were performed to evaluate changes of vegetative symptoms, acute medication response, side effects, as well as treatment satisfaction. RESULTS: Complete clinical data were available for 26 episodic (EM) and 74 chronic (CM) migraineurs. Sixty-six % (n = 49) of CM patients had an additional medication overuse headache (MOH). After 3 months 57.7% of EM patients and 41.9% of CM patients had a 50% or greater reduction of MMD. The mean number of MMD was reduced by 3.43 (SE 1.26) in EM, and by 4.72 (SE 0.87) in CM. Thirty-nine patients (52.7%) returned from chronic to episodic course of migraine. After 3 months, 23 patients (46.9%) were not suffering from a MOH anymore. CONCLUSIONS: Erenumab seems to be a promising therapeutic option in highly therapy-refractory migraine patients. TRIAL REGISTRATION: Retrospective registered.

Impaired wound healing in a migraine patient as a possible side effect of calcitonin gene-related peptide receptor antibody treatment: A case report.

INTRODUCTION: Wound healing disturbances as possible side effects of calcitonin gene-related peptide (CGRP) antibody treatment have been discussed previously but not yet described in humans. Basic research suggests that calcitonin gene-related peptide plays an important role in keratinocyte migration, vascularization and immune response and lack of calcitonin gene-related peptide may lead to impaired wound healing. CASE: A 51-year-old female migraine patient was treated with the CGRP receptor antibody erenumab for 6 months, which led to a relevant reduction of migraine days. During the treatment, two periods of severely impaired wound healing occurred after a trivial skin injury without spatial relation to the injection site. Skin biopsy confirmed a deep perivascular and interstitial lymphohistiocytic infiltrate with admixed eosinophils, ulceration of the epithelium, a heavy edema of the papillary dermis and focally thrombosed vessels. CONCLUSION: Impaired wound healing might be relevant side effects of CGRP antibody therapy and anamnesis within the course of treatment should also include possible observation of impaired wound healing or planned surgery.

Prevalence of hereditary transthyretin amyloid polyneuropathy in idiopathic progressive neuropathy in conurban areas.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare, genetically heterogenous, and clinically variable autosomal dominant disease that severely reduces life expectancy. As treatment options grow, a proper diagnostic approach is mandatory especially in non-endemic regions with diverse genetic backgrounds. METHODS: We examined 102 neuropathy patients at a German neuromuscular centre. Common causes of polyneuropathy were ruled out by medical history and extensive laboratory testing to define a cohort of patients with progressive polyneuropathy classified as idiopathic. Molecular genetic testing of the entire TTR gene was performed, and the detected amyloidogenic and non-amyloidogenic variants were associated with the observed clinical phenotypes and results of prior diagnostic testing. RESULTS: Two of 102 patients tested positive for amyloidogenic mutations (p.Ile127Val and p.Glu81Lys), while a variant of unknown significance, p.Glu26Ser, was found in 10 cases. In both positive cases, previous negative biopsy results were proved by gene sequencing to be false negative. In case of the p.Glu81Lys mutation we detected clinical presentation (combination of severe polyneuropathy and cardiomyopathy), ethnic background (patient of polish origin, mutation only reported in Japanese families before), and disease course clearly differed from well-known cases of the same mutation in the literature. CONCLUSIONS: In conclusion, transthyretin hereditary amyloid polyneuropathy (ATTR-PN) should be considered in cases of otherwise idiopathic polyneuropathy. Sequencing of the four exons of the TTR gene should be considered the key step in diagnosis, while tissue biopsy possibly leads to false negative results.

Cerebral gray matter changes in persistent postural perceptual dizziness.

BACKGROUND: Persistent postural perceptual dizziness (PPPD) is the most common vestibular syndrome in middle-aged patients. Multisensory maladjustment involving alterations of sensory response pattern including vestibular, visual and motion stimuli is thought to be a key pathophysiological correlate of this disorder. OBJECTIVE: We aimed to identify regional gray matter changes in PPPD patients that might be involved in the underlying pathophysiology of this disorder. METHODS: 42 PPPD patients and healthy age and gender matched controls were investigated using magnetic resonance imaging-based voxel-based morphometry. All patients fulfilled the current diagnostic criteria for PPPD, established by the Bárány-Society based on previous criteria for chronic subjective dizziness and phobic postural vertigo. RESULTS: PPPD patients showed gray matter volume decrease in the temporal cortex, cingulate cortex, precentral gyrus, hippocampus, dorsolateral prefrontal cortex, caudate nucleus and the cerebellum. A negative correlation of disease duration and gray matter volume was observed in the visual cortex, supplementary motor area and somatosensory processing structures. CONCLUSIONS: In patients with PPPD areas involved in multisensory vestibular processing show gray matter volume decrease. These brain regions resemble those previously described for other vestibular disorders. Longer duration of disease leads to a more pronounced gray matter alteration, which might represent maladaptive mechanisms within the course of disease.

Persistent Postural-Perceptual Dizziness: A Matter of Higher, Central Dysfunction?

OBJECTIVE: Persistent postural-perceptual dizziness (PPPD) is the most common vestibular disorder in the age group between 30 and 50 years. It is considered to be based on a multisensory maladjustment involving alterations of sensory response pattern including vestibular, visual and motion stimuli. Previous data supported a link between vestibular and pain mechanism. The aim of the study was to investigate whether other sensory inputs such as pain stimuli might be altered in terms of a more widespread central perception dysfunction in this disorder. METHODS: Nociceptive blink reflex was measured in 27 patients with PPPD and compared with 27 healthy, age and gender matched controls. The habituation of the R2 component of the blink reflex was evaluated as the percentage area-under-the curve (AUC) decrease in ten consecutive blocks of five averaged rectified responses. Additionally, clinical characteristics were evaluated. RESULTS: In patients with PPPD a lack of habituation was observed compared to healthy controls. Relative AUC decreased between the first and the tenth block by 19.48% in PPPD patients and by 31.63% (p = 0.035) in healthy controls. There was no correlation between clinical data (course of disease, comorbid depression, medication, trigger factors) or electrophysiological data (perception threshold, pain threshold, stimulus intensity) and habituation pattern. No trigeminal sensitization in terms of facilitation of absolute values could be detected. CONCLUSION: Our study results supports the hypothesis of the multisensory dimension of impaired sensory processing in patients with PPPD extends beyond vestibular/visual motion stimuli and reflexive postural/oculomotor control mechanisms to other sensory inputs such as pain perception in terms of a more generalized disturbed habituation pattern.

Central vestibular system modulation in vestibular migraine.

BACKGROUND: Vestibular migraine affects 1% of the general population, and 30%-50% of all migraine patients describe occasionally associated vertigo or dizziness. We aimed to identify brain regions altered in vestibular migraine in order to evaluate the connection between migraine and the vestibular system. METHODS: Seventeen patients with definite vestibular migraine were compared to 17 controls using magnetic resonance imaging-based voxel-based morphometry. RESULTS: We found grey matter (GM) volume reduction in the superior, inferior and middle (MT/V5) temporal gyrus as well as in the mid. cingulate, dorsolateral prefontal, insula, parietal and occipital cortex. A negative correlation of disease duration and GM volume was observed in areas associated with pain and vestibular processing. Moreover, there was a negative correlation between headache severity and prefrontal cortex volume. CONCLUSION: Alterations identified in vestibular migraine resemble those previously described for migraine, but also extend to areas involved in multisensory vestibular control and central vestibular compensation possibly representing the pathoanatomic connection between migraine and the vestibular system.