Erenumab escalation in migraine - double dose without additional benefit - a retrospective experience.

BACKGROUND: Erenumab is a monoclonal antibody specifically targeting the CGRP-receptor. Several studies showed efficacy and safety in patients with migraine. Less is known regarding dosage increase, especially in a difficult to treat patients. The aim of the study is to evaluate the increased dosage under real world conditions with particular focus on 70 mg non-responders. METHODS: In a retrospective analysis, patients treated in tertiary headache centers (Halle or Jena, Germany) receiving 70 mg erenumab for at least 3 months with a dosage increase to 140 mg were analyzed. Data were evaluated regarding headache days, intake of acute medication, previous prophylaxis, and medication overuse. Baseline and all treatment intervals were determined as three-month periods. RESULTS: Datasets of 52 migraine patients (90.4% women) aged between 22 and 78 years (mean 50.4 years, SD 12.1 years) were analyzed. At baseline (mean headache-days 15.67 ± 6.37) 51.9% met criteria for chronic migraine and 56% were currently overusing acute medication. While therapy with 70 mg showed significant improvement in headache days and 50% response, further improvement was not achieved for therapy escalation to 140 mg. The same applies to the secondary endpoints and covers the entire study population as well as the subgroups of chronic and episodic migraine. The 50% response of the 70 mg non-responders for escalation was only 5.14%. CONCLUSIONS: In this difficult-to-treat patient cohort we reconfirmed the effectiveness of erenumab, but could not detect any additional benefit for a dosage escalation from 70 mg to 140 mg erenumab.

Trigeminal neuralgia.

Trigeminal neuralgia (TN) is a facial pain disorder characterized by intense and paroxysmal pain that profoundly affects quality of life and presents complex challenges in diagnosis and treatment. TN can be categorized as classical, secondary and idiopathic. Epidemiological studies show variable incidence rates and an increased prevalence in women and in the elderly, with familial cases suggesting genetic factors. The pathophysiology of TN is multifactorial and involves genetic predisposition, anatomical changes, and neurophysiological factors, leading to hyperexcitable neuronal states, central sensitization and widespread neural plasticity changes. Neurovascular compression of the trigeminal root, which undergoes major morphological changes, and focal demyelination of primary trigeminal afferents are key aetiological factors in TN. Structural and functional brain imaging studies in patients with TN demonstrated abnormalities in brain regions responsible for pain modulation and emotional processing of pain. Treatment of TN involves a multifaceted approach that considers patient-specific factors, including the type of TN, with initial pharmacotherapy followed by surgical options if necessary. First-line pharmacological treatments include carbamazepine and oxcarbazepine. Surgical interventions, including microvascular decompression and percutaneous neuroablative procedures, can be considered at an early stage if pharmacotherapy is not sufficient for pain control or has intolerable adverse effects or contraindications.

Headache Attributed to a Substance or Its Withdrawal.

Identification of substances that may cause or trigger headache is important to start effective treatment early to prevent unnecessary suffering, deterioration in quality of life, and the development of chronic pain. Treatment in case of medication overuse and other chronic headache should be decisive and effective. Drug withdrawal and introduction of effective prophylactic medication for the underlying headache disorder should be the primary treatment strategy. Typical headache-inducing substances are nitric oxide, phosphodiesterase, cocaine, alcohol, histamine, carbon oxide, and calcitonin gene-related peptide. The withdrawal of caffeine, estrogen, and opioids is most often associated with the development of headache.

Cognitive deficits in patients with peripheral vestibular dysfunction.

BACKGROUND AND PURPOSE: Previous studies demonstrated cognitive deficits in patients with peripheral vestibulopathy (PVP) with dysfunction of spatial navigation and orientation, but also documented cognitive decline in nonspatial abilities. This study evaluates cognitive deficits in patients with unilateral vestibulopathy (UVP) as well as bilateral vestibulopathy (BVP) in multiple cognitive domains using common screening tests to reliably detect these deficits in clinical practice. METHODS: This prospective study compared patients with UVP and BVP to age- and sex-matched healthy controls (HC). Tests included the Alzheimer's Disease Assessment Scale (ADAS), Mini-Mental Status Examination (MMSE), Trail Making Test Part A and B, Clock Drawing Task, Executive Interview-25 (EXIT25), Dementia Detection (DemTect), and the Judgment of Line Orientation (JLO). The Montgomery-Åsberg Depression Rating Scale was used to control for depression. Videonystagmography objectively reconfirmed PVP. The Vertigo Symptoms Scale and the Dizziness Handicap Inventory were used to assess for symptom severity and restrictions of activities of daily living. RESULTS: Eighty-one patients (65 UVP, 16 BVP) were compared to 55 HC. Patients showed impairment in ADAS, MMSE, DemTect, EXIT25, and JLO. No differences between UVP and BVP were detected. The relative risk (RR) estimates of developing cognitive deficits following PVP were increased. The RR for the ADAS was higher in BVP (RR = 4.91, 95% confidence interval [CI] = 1.87-12.9, p = 0.001) than in UVP (RR = 3.75, 95% CI = 1.65-8.51, p = 0.002), but was similar for the MMSE and DemTect between groups. CONCLUSIONS: Patients with PVP showed deficits in multiple cognitive domains including nonspatial cognitive abilities. Vestibulopathy could be a risk factor for the development of cognitive impairment.

No structural brain alterations in new daily persistent headache - a cross sectional VBM/SBM study.

OBJECTIVE: To identify grey matter alterations in patients suffering new daily persistent headache to enrich the pathophysiological concept of this rare headache disorder characterised by a distinct, clearly remembered onset and its instant chronification. METHOD: Magnetic resonance-based voxel-based and surface-based morphometry was used to investigate 23 patients suffering from new daily persistent headache and 23 age- and gender-matched healthy controls with 1.5 Tesla MRI.Independent statistical analysis was performed at three sites using statistical parametric mapping, as well as FSL(FMRIB Software Library)-based approaches. RESULTS: No grey matter changes were detected using this sophisticated and cross-checked method. CONCLUSION: The absence of structural brain changes in patients with new daily persistent headache contribute to the recent discussion regarding structural alterations in primary headache disorders in general and does not provide evidence for grey matter changes being associated with the pathophysiology of new daily persistent headache. Future research will have to determine the underlying pathophysiological mechanisms of this disorder.

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.

Delayed headache after COVID-19 vaccination: a red flag for vaccine induced cerebral venous thrombosis.

BACKGROUND: Headache is a frequent symptom following COVID-19 immunization with a typical onset within days post-vaccination. Cases of cerebral venous thrombosis (CVT) have been reported in adenovirus vector-based COVID-19 vaccine recipients. FINDINGS: We reviewed all vaccine related CVT published cases by April 30, 2021. We assessed demographic, clinical variables and the interval between the vaccination and onset of headache. We assessed whether the presence of headache was associated with higher probability of death or intracranial hemorrhage. We identified 77 cases of CVT after COVID-19 vaccination. Patients' age was below 60 years in 74/77 (95.8%) cases and 61/68 (89.7%) were women. Headache was described in 38/77 (49.4%) cases, and in 35/38 (92.1%) was associated with other symptoms. Multiple organ thrombosis was reported in 19/77 (24.7%) cases, intracranial hemorrhage in 33/77 (42.9%) cases and 19/77 (24.7%) patients died. The median time between vaccination and CVT-related headache onset was 8 (interquartile range 7.0-9.7) days. The presence of headache was associated with a higher odd of intracranial hemorrhage (OR 7.4; 95% CI: 2.7-20.8, p < 0.001), but not with death (OR: 0.51, 95% CI: 0.18-1.47, p = 0.213). CONCLUSION: Delayed onset of headache following an adenovirus vector-based COVID-19 vaccine is associated with development of CVT. Patients with new-onset headache, 1 week after vaccination with an adenovirus vector-based vaccine, should receive a thorough clinical evaluation and CVT must be ruled out.

Role of Functional Neuroimaging in Primary Headache Disorders.

BACKGROUND: Key structures for the pathophysiology of primary headache disorders such as migraine, cluster headache, and other trigeminal autonomic cephalalgias were identified by imaging in the past years. OBJECTIVE: Available data on functional imaging in primary headache disorders are summarized in this review. MATERIAL AND METHODS: We performed a MEDLINE search on December 27th, 2020 using the search terms "primary headache" AND "imaging" that returned 453 results in English, out of which 137 were labeled reviews. All articles were evaluated for content and relevance for this narrative review. RESULTS: The structure depicted most consistently using functional imaging in different states of primary headaches (without and with pain) was the posterior hypothalamus. Whole-brain imaging techniques such as resting-state functional resonance imaging showed a wide-ranging association of cortical and subcortical areas with human nociceptive processing in the pathophysiological mechanisms underlying the different TACs. Similarities of distinct groups of primary headache disorders, as well as their differences in brain activation across these disorders, were highlighted. CONCLUSION: The importance of neuroimaging research from clinical practice point of view remains the reliable and objective distinction of each individual pain syndrome from one another. This will help to make the correct clinical diagnosis and pave the way for better and effective treatment in the future. More research will be necessary to fulfill this unmet need.

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.

Green Flags and headache: A concept study using the Delphi method.

OBJECTIVE: The aim of this study was to collect and rate Green Flags, that is, symptoms or pieces of information indicating that a patient is more likely to suffer from a primary than from a secondary headache. BACKGROUND: When assessing headaches, a central question to be answered is whether the pain is primary or secondary to another disorder. To maximize the likelihood of a correct diagnosis, relevant signs and symptoms must be sought, identified, and weighed against each other. METHODS: The project was designed as a Delphi study. In the first round, an expert panel proposed green flags that were rated anonymously in two subsequent rounds. Proposals with an average rating of 4.0 and higher on a scale from 0 to 5 reached consensus. RESULTS: Five Green Flags reached consensus: (i) "The current headache has already been present during childhood"; (ii) "The headache occurs in temporal relationship with the menstrual cycle"; (iii) "The patient has headache-free days"; (iv) "Close family members have the same headache phenotype"; and (v) "Headache occurred or stopped more than one week ago." CONCLUSIONS: We propose five Green Flags for primary headache disorders. None being a pathognomonic sign, we recommend searching for both Green Flags and Red Flags. If both are present, a secondary headache should be suspected. Overall, the application of the Green Flag concept in clinical practice is likely to increase diagnostic accuracy and improve diagnostic resource allocation. Prospective studies in clinical populations should be conducted to validate these Green Flags.

Secondary headache attributed to exposure to or overuse of a substance.

BACKGROUND: Secondary headaches attributed to exposure to or the overuse of a substance are classified under chapter eight in the International Classification of Headache Disorders 3rd edition. Three distinct sub-chapters consider: 1. Headache attributed to exposure to a substance, 2. Medication overuse headache, and 3. Headache attributed to substance withdrawal. Headache attributed to exposure to a substance refers to a headache with onset immediately or within hours after the exposure, while medication overuse headache is a headache occurring on 15 or more days per month that has developed as a consequence of regular usage of acute headache medication(s) for more than three consecutive months in a patient with a pre-existing primary headache disorder. The withdrawal of caffeine, oestrogen, and opioids is most often associated with the development of headache. DISCUSSION: Despite the current headache classification, there is no certainty of a causal relationship between the use of any substance and the development of headache. Some substances are likely to provoke headache in patients that suffer from a primary headache disorder like migraine, tension-type headache or cluster headache, while others were described to cause headache even in people that generally do not get headaches. Toxic agents, such as carbon monoxide (CO) are difficult to investigate systematically, while other substances such as nitric oxide (NO) were specifically used to induce headache experimentally. If a patient with an underlying primary headache disorder develops a headache, in temporal relation to exposure to a substance, which is significantly worse than the usual headache it is considered secondary. This is even more the case if the headache phenotype is different from the usually experienced headache characteristics. Medication overuse headache is a well-described, distinct disease entity with only marginally understood pathophysiology and associated psychological factors. Managing medication overuse headache patients includes education, detoxification, prophylactic treatments and treating comorbidities, which is reflected in available guidelines. Viewing medication overuse headache as a separate entity helps clinicians and researchers better recognise, treat and study the disorder. CONCLUSION: Identification of substances that may cause or trigger secondary headache is important in order to educate patients and health care professionals about potential effects of these substances and prevent unnecessary suffering, as well as deterioration in quality of life. Treatment in case of medication overuse and other chronic headache should be decisive and effective.

Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Prednisone is commonly used for initial short-term therapy of episodic cluster headaches before preventive medication such as verapamil becomes effective, but this strategy has not been tested in large randomised trials. We aimed to access the safety and efficacy of this treatment approach. METHODS: This study was a multicentre, randomised, double-blind, placebo-controlled trial done in ten specialised headache centres in Germany. Patients with episodic cluster headaches who were aged between 18 and 65 years and within a current pain episode for not more than 30 days, received 100 mg oral prednisone for 5 days followed by tapering of 20 mg every 3 days, or matching placebo (17 days total exposure). All patients received oral verapamil for long-term prevention, starting with 40 mg three times daily and increasing to 120 mg three times daily by day 19; patients then continued with verapamil 120 mg throughout the study. Randomisation was computer-generated at a 1:1 ratio by use of an interactive web-response system, with stratification according to age, sex, and participating site. Participants, investigators, and those assessing outcomes were unaware of treatment allocation. The primary endpoint was the mean number of attacks within the first week of treatment with prednisone compared with placebo. An attack was defined as a unilateral headache with moderate-to-severe intensity of at least five on a numerical rating scale. All efficacy and safety analyses were done in the modified intention-to-treat (mITT) population, which consisted of all patients who had been randomly assigned to a trial group and received at least one dose of prednisone or placebo. The study was stopped early due to slow recruitment and expired funding. The study was registered with EudraCT (2011-006204-13) and with the German Clinical Trials Register (DRKS00004716). FINDINGS: Between April 5, 2013, and Jan 11, 2018, 118 patients were enrolled in the study. Two patients dropped out immediately and 116 patients were randomly assigned (57 patients to prednisone and 59 patients to placebo); 109 patients were included in the mITT analysis (53 patients assigned to prednisone and 56 patients assigned to placebo). Participants in the prednisone group had a mean of 7·1 (SD 6·5) attacks within the first week compared with 9·5 (6·0) attacks in the placebo group (difference -2·4 attacks, 95% CI -4·8 to -0·03; p=0·002). Two serious adverse events occurred, both in the placebo group (inguinal hernia and severe deterioration of cluster headache). A total of 270 adverse events were observed: in the prednisone group, 37 (71%) of 52 patients reported 135 adverse events (most common were headache, palpitations, dizziness, and nausea) and in the placebo group, 39 (71%) of 55 patients had 135 adverse events (most common were nausea, dizziness, and headache). INTERPRETATION: Oral prednisone was an effective short-term preventive therapy in our population of patients with episodic cluster headache. Our findings support the use of prednisone as a first-line treatment in parallel to the up-titration of verapamil, although the efficacy of prednisone alongside other long-term prevention requires additional investigation. FUNDING: German Federal Ministry for Education and Research.

[Neurological complications of hepatitis C infections]. / Neurologische Komplikationen der Hepatitis-C-Infektion.

Chronic hepatitis C virus (HCV) infection is a highly prevalent systemic disease, which can cause a variety of neurological complications. The HCV-associated symptoms can be differentiated into central and peripheral nervous systems as well as the musculature. Important pathomechanisms are HCV-associated autoimmunity (e.g. mixed cryoglobulinemia with polyneuropathy) and direct neurotoxic effects of the virus (e.g. HCV-associated cognitive deficits). Distal symmetric polyneuropathies, small fiber neuropathies and cognitive deficits are the most prevalent neurological manifestations. Furthermore, HCV infection is a risk factor for ischemic and hemorrhagic stroke as well as Parkinson's disease. As HCV infection has become a permanently curable disease in >90% of patients, early identification and antiviral treatment of HCV positive patients is of utmost importance.

Advances in diagnosis, classification, pathophysiology, and management of trigeminal neuralgia.

Trigeminal neuralgia is a very painful neurological condition with severe, stimulus-evoked, short-lasting stabbing pain attacks in the face. The past decade has offered new insights into trigeminal neuralgia symptomatology, pathophysiology, and treatment, leading to a change in the classification of the condition. An accurate diagnosis is crucial because neuroimaging interpretation and clinical management differ among the various forms of facial pain. MRI using specific sequences should be a part of the diagnostic workup to detect a possible neurovascular contact and exclude secondary causes. Demonstration of a neurovascular contact should not be used to confirm a diagnosis but rather to facilitate surgical decision making. Carbamazepine and oxcarbazepine are drugs of first choice for long-term treatment, whereas microvascular decompression is the first-line surgery in medically refractory patients. Advances in neuroimaging techniques and animal models will provide further insight into the causes of trigeminal neuralgia and its pathophysiology. Development of more efficacious treatment options is highly warranted.

High-intensity arm resistance training does not lead to better outcomes than low-intensity resistance training in patients after subacute stroke: A randomized controlled trial.

OBJECTIVE: To describe the effects of 2 levels of intensity of arm resistance training on grip strength, arm function, activities, participation, and adverse events in patients with subacute stroke. DESIGN: A randomized controlled and preregistered trial with concealed allocation, assessor blinding and intention-to-treat analysis. PATIENTS: Patients with subacute stroke and upper extremity hemiparesis. METHODS: After randomization the experimental group received a 3-week high-intensity arm resistance training (HIT). The control group completed a 3-week low-intensity arm resistance training (LIT). The primary outcome was grip strength. Secondary outcomes included the Motricity Index, Fugl-Meyer Assessment for the upper limb, Box and Block Test, Goal Attainment Scale, Modified Ashworth Scale, and adverse events. All outcomes were assessed at baseline and after 3 weeks of intervention. RESULTS: A total of 43 patients were investigated (HIT, n = 23; LIT, n = 20). All primary and secondary outcomes improved after the 3-week training, but no significant between-group differences were found. Adverse events occurred in 5% of training sessions (19/369). CONCLUSION: The results of this study did not show differential effects on any outcome of 2 forms of arm resistance training in patients with subacute stroke.

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-Updated series of 120 cases.

BACKGROUND: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. AIMS: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. METHODS: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. RESULTS: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0-3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. CONCLUSION: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.

Dipeptidyl-peptidase-like protein 6 encephalitis treated with immunotherapy.

This case describes a middle-aged man with anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis who exhibited the triad of memory loss, diarrhea, and tremor. The progression of his disease resembled neurodegenerative disease, and his first presentation at our department was 2 years after the first onset of symptoms. Antibodies against DPPX were positive in both serum and cerebrospinal fluid. No related tumor was found. The patient was initially treated with corticosteroid therapy and plasmapheresis. Despite moderate response to this treatment, corticosteroids were ceased because of adverse effects such as Cushing syndrome, deep vein thrombosis, and osteoporosis. After five cycles of treatment with rituximab, the patient experienced no further progression of neurologic symptoms and no adverse effects. The case adds to the understanding of the diagnosis, treatment, and potential prognosis of anti-DPPX encephalitis.