Medication-overuse headache: a narrative review.

Medication-overuse headache (MOH), which potentially involves 1-2% of the population, is defined as a headache, on ≥ 15 days a month affected, along with overuse of one or other acute attack medications. MOH presents with significant challenges in the headache community, particularly in clinical settings raising various questions about its pathophysiology. Through a review of the current literature and our clinical experience, we have explored the mechanisms through which MOH may occur, provide an understanding of the current state of treatment and detail some possible views on the understanding and treatment of this condition. We evaluate the variations in treatment methods offered globally and understanding of the disorder. Above all interventions, patient education is crucial, which is underscored by an analysis of the academic publications. Given the condition is preventable, early intervention is imperative and patient awareness is highlighted as key. Globally, there is no uniform treatment methodology, which may be advantageous as approaches need to take local circumstances into account.

What visuospatial perception has taught us about the pathophysiology of vestibular migraine.

PURPOSE OF REVIEW: A decade has passed since vestibular migraine (VM) was formally established as a clinical entity. During this time, VM has emerged amongst the most common cause of episodic vertigo. Like all forms of migraine, VM symptoms are most prominent during individual attacks, however many patients may also develop persistent symptoms that are less prominent and can still interfere with daily activities. RECENT FINDINGS: Vestibular inputs are strongly multimodal, and because of extensive convergence with other sensory information, they do not result in a distinct conscious sensation. Here we review experimental evidence that supports VM symptoms are linked to multisensory mechanisms that control body motion and position in space. SUMMARY: Multisensory integration is a key concept for understanding migraine. In this context, VM pathophysiology may involve multisensory processes critical for motion perception, spatial orientation, visuospatial attention, and spatial awareness.

Effectiveness and safety profile of greater occipital nerve blockade in cluster headache: a systematic review.

BACKGROUND: Greater occipital nerve (GON) blockade is a short-term preventive therapy for cluster headache (CH). We conducted a systematic review to evaluate the effectiveness and safety of GON blockade in patients with CH. METHODS: On 23 October 2020, we searched MEDLINE, Embase, Embase Classic, PsycINFO, CINAHL, CENTRAL and Web of Science databases from their inception date. Studies included participants with a CH diagnosis who received corticosteroid and local anaesthetic suboccipital region injections. Outcomes were change in the frequency/severity/duration of attacks; proportion of participants responding to treatment, time to attack freedom from an attack, change in attack bout length and/or the presence of adverse effects after GON blockade. Risk of bias was assessed with the Cochrane Risk of Bias V.2.0 (RoB2)/Risk of Bias in Non-randomized Studies - of Interventions (ROBINS- I) tools and a specific tool for case reports/series. RESULTS: Two RCTs, eight prospective and eight retrospective studies, and four case reports were included in the narrative synthesis. Every effectiveness study found a significant response in one or more of frequency/severity/duration of individual attacks or proportion of patients responding to treatment (47.8%-100.0%). There were five instances of potentially irreversible adverse effects. A higher injectate volume and use of concurrent prophylaxis may be associated with an increased likelihood of response. Methylprednisolone may have the best safety profile of available corticosteroids. DISCUSSION: GON blockade is safe and effective for CH prevention. Higher injectate volumes may improve likelihood of response, and the likelihood of serious adverse events may be reduced by using methylprednisolone. PROSPERO REGISTRATION NUMBER: CRD42020208435.

From basic mechanisms to therapeutic perspectives in cluster headache.

PURPOSE OF REVIEW: The pathophysiological understanding of cluster headache has evolved significantly over the past years. Although it is now well known that the trigeminovascular system, the parasympathetic system and the hypothalamus play important roles in its pathomechanism, we increasingly understand the functional role several neurotransmitters and hormones play in the communication between these structures. RECENT FINDINGS: This work will give an overview of the current understanding of the role of calcitonin gene-related peptide, vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, melatonin and orexins in cluster headache. On the basis of recent evidence, this study will also review the relevance of the monoclonal calcitonin gene-related peptide antibody galcanezumab as well as the sleep-regulating hormone melatonin in the treatment of cluster headache. SUMMARY: Herein, we aim to review the basic mechanisms implicated in the pathophysiology of cluster headache and how the increased mechanistic understanding may lead to the discovery of novel therapeutic targets.

Erenumab in chronic migraine: Experience from a UK tertiary centre and comparison with other real-world evidence.

BACKGROUND AND PURPOSE: Chronic migraine is a highly disabling primary headache disorder that is the most common diagnosis of patients seen at tertiary headache centres. Typical oral preventive therapies are associated with many limitations that impact their therapeutic utility. Erenumab was the first available calcitonin gene-related peptide monoclonal antibody in the UK. It had proven efficacy in migraine prevention in clinical trials and limited real-world data in tertiary settings. METHODS: We audited our first 92 patients (n = 73 females) with severely disabling chronic migraine who were given monthly erenumab 70 mg sc for 6 months between December 2018 and December 2019. RESULTS: At 3 months, monthly migraine days were significantly reduced by a median of 4 days, and all other variables also showed significant improvement. The improvement was not affected by baseline analgesic use status. More than half of our patients experienced a clinically meaningful improvement in migraine days. No serious adverse events were reported. CONCLUSIONS: Our real-world data with erenumab demonstrate it is effective and well tolerated in managing patients with chronic migraine in a tertiary care setting.

New Generation Gepants: Migraine Acute and Preventive Medications.

Migraine is a debilitating disease whose clinical and social impact is out of debate. Tolerability issues, interactions, contraindications, and inefficacy of the available medications make new options necessary. The calcitonin-gene-related peptide (CGRP) pathway has shown its importance in migraine pathophysiology and specific medications targeting this have become available. The first-generation CGRP receptor antagonists or gepants, have undergone clinical trials but their development was stopped because of hepatotoxicity. The new generation of gepants, however, are efficacious, safe, and well tolerated as per recent clinical trials. This led to the FDA-approval of rimegepant, ubrogepant, and atogepant. The clinical trials of the available gepants and some of the newer CGRP-antagonists are reviewed in this article.

Devices for Episodic Migraine: Past, Present, and Future.

PURPOSE OF REVIEW: Historically, therapies for migraine have generally involved pharmacological treatments using non-selective or selective analgesics and preventive treatments. However, for many patients these treatments are not effective, while others prefer to use non-pharmacological-based therapies. To fill this need, over the last 15 years, neuromodulatory devices have entered the market for migraine treatment. Here, we will review the most recent findings for the use of these devices in the treatment of migraine. RECENT FINDINGS: Non-invasive vagus nerve stimulation and spring-pulse transcranial magnetic stimulation are both cleared for the treatment of migraine, supported by preclinical studies that validate efficacy and mechanism of action, and complemented with clinical trial data. Other options also authorized for use include transcutaneous supraorbital nerve stimulation and remote electrical neuromodulation. Various options are available to treat migraine using authorized neuromodulatory devices. These data support their efficacy in the treatment of episodic migraine, although further studies are necessary to elucidate their mechanism of action and to provide rigor to clinical trial data.

Evaluation of treatment response and symptom progression in 400 patients with visual snow syndrome.

AIMS: To gather information on useful medications to treat visual snow syndrome (VSS) as well as to validate an instrument to assess its clinical severity and the course of the disorder over time. METHODS: Four hundred patients with VSS were included in this web-based prospective questionnaire study. All subjects completed a treatment questionnaire and a clinical diary. The first allowed evaluation of the effects of previous medications on visual snow, while the second measured VSS symptoms daily over the course of 30 days. RESULTS: Patients commonly reported previous use of medications such as antidepressants, antiepileptics, antibiotics and benzodiazepines. However, none of these drug classes was beneficial for the majority of patients. Recreational drugs and alcohol worsened visual snow symptoms in several reports. Vitamins and benzodiazepines had high therapeutic ratios, although in most cases they did not change the course of VSS.The monthly diary confirmed that the static in VSS is a consistent symptom over time. It also showed that indoor and fluorescent lights have a worse effect on symptoms when compared with natural outdoor lighting. CONCLUSIONS: The study confirms clinical experience that medications are generally ineffective in VSS, with the exception of vitamins and perhaps benzodiazepines, which could be beneficial in some patients. The 30-day diary represents a useful tool to measure symptom progression over time, which could be used in future trials on VSS.

Indomethacin-responsive headaches-A narrative review.

BACKGROUND: Indomethacin is a nonsteroidal anti-inflammatory drug whose mechanism of action in certain types of headache disorders remains unknown. The so-called indomethacin-responsive headache disorders consist of a group of conditions with a very different presentation that have a particularly good response to indomethacin. The response is so distinct as to be used in the definition of two: hemicrania continua and paroxysmal hemicrania. METHODS: This is a narrative literature review. PubMed and the Cochrane databases were used for the literature search. RESULTS: We review the main pharmacokinetic and pharmacodynamics properties of indomethacin useful for daily practice. The proposed mechanisms of action of indomethacin in the responsive headache disorders, including its effect on cerebral blood flow and intracranial pressure, with special attention to nitrergic mechanisms, are covered. The current evidence for its use in primary headache disorders, such as some trigeminal autonomic cephalalgias, cough, hypnic, exertional or sexual headache, and migraine will be covered, as well as its indication for secondary headaches, such as those of posttraumatic origin. CONCLUSION: Increasing understanding of the mechanism(s) of action of indomethacin will enhance our understanding of the complex pathophysiology that might be shared by indomethacin-sensitive headache disorders.

Emerging Targets for Migraine Treatment.

BACKGROUND: While understanding the pathophysiology of migraine has led to CGRP-based treatments, other potential targets have also been implicated in migraine. OBJECTIVES: To catalog new promising targets for the treatment of migraine. METHODS: We completed a literature review focusing on 5HT1F, PACAP, melatonin, and orexins. RESULTS: The 5HT1F receptor agonist lasmiditan, following two positive randomized placebo-controlled trials, was FDA-approved for the acute treatment of migraine. PACAP-38 has shown analogous evidence to what was obtained for CGRP with its localization in key structures, provocation tests, and positive studies when antagonizing its receptor in animal models, although a PAC-1 receptor monoclonal antibody study was negative. Melatonin has undergone several randomized controlled trials showing a positive trend. Filorexant is the only dual orexin receptor antagonist, which was tested in humans with negative results. CONCLUSIONS: Further and ongoing studies will determine the utility of these new therapies with lasmiditan and melatonin having demonstrated efficacy for the treatment of migraine.

Targets for migraine treatment: beyond calcitonin gene-related peptide.

PURPOSE OF REVIEW: Despite the development of several medications for the acute and preventive treatment of migraine, there are still many patients in whom lack of efficacy, tolerability, interactions or contraindications make other options necessary. CGRP-based drugs have opened the door to a new era of migraine-targeted treatments. Beyond CGRP, there are other promising targets covered here. RECENT FINDINGS: For the acute treatment of migraine, 5-HT1F receptor agonists, ditans, are now available. Unlike triptans, 5-HT1B/1D receptor agonists, cardiovascular disease is not a contraindication for the use of ditans. The first study on a monoclonal antibody targeting PAC1 receptor was negative, although this may not be the end for the pituitary adenylate cyclase-activating polypeptide (PACAP) pathway as a target. SUMMARY: Following positive phase-III clinical trials, lasmiditan is the first ditan to be FDA-approved. PACAP has experimental evidence suggesting a role in migraine pathophysiology. As for CGRP, the presence of PACAP in key migraine structures along with positive provocative tests for both PACAP-38 and PACAP-27 indicate this pathway may still be a pharmacological target. Glutamate-based targets have long been considered in migraine. Two clinical trials with memantine, an NMDA-R antagonist, for the preventive treatment of migraine have now been published. The hypothalamus has also been implicated in migraine pathophysiology: the potential role of orexins in migraine is discussed. Acid-sensing ion channels, as well as amylin-blocking drugs, may also become migraine treatments in the future: more research is warranted.

Exploding head syndrome (a.k.a. episodic cranial sensory shock) responds to single-pulse transcranial magnetic stimulation.

We present the case of a patient with a sleep disturbance attributed to the exploding head syndrome, recently redefined as episodic cranial sensory shock. The patient, who suffered with concomitant migraine, was treated for headache prevention with daily single-pulse transcranial magnetic stimulation (sTMS). Following treatment, he reported a significant reduction in the episodes of exploding head syndrome, albeit not of his migraine. Neurologists could consider sTMS in the management of patients troubled by episodic cranial sensory shock, as it is a safe and noninvasive treatment that might provide benefit for this benign but occasionally bothersome parasomnia.

VEMPs and Dysautonomia Assessment in Definite Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS): a Case Series Study.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recently described slowly progressive ataxia with severe imbalance due to the compromise of three of the four sensory inputs for balance, leaving only vision unaffected. Bilateral vestibulopathy is present but saccular and utricular function, measured by vestibular evoked myogenic potentials (VEMPs), has not been widely studied in these patients. Dysautonomia has been reported but is not among the diagnostic criteria. We performed a database analysis to identify patients evaluated between 2003 and 2019 with probable diagnosis of CANVAS by using key words "bilateral vestibulopathy and/or cerebellar ataxia and/or sensory polyneuropathy." Five out of 842 met all conditions. Patients underwent neurological/neurootological exam, brain MRI, visually enhanced vestibulo-ocular reflex (VVOR) exam by high-speed video-oculography using video-Head Impulse Test (vHIT), VEMPs, neurophysiological studies, and genetic tests to exclude other causes of ataxia. Dysautonomia was addressed by the standardized survey of autonomic symptoms. All patients had clinically definite CANVAS as brain MRI showed vermal cerebellar atrophy, neurophysiological studies showed a sensory neuronopathy pattern (absent sensory action potentials), VVOR was abnormal bilaterally, and genetic tests ruled out other causes of ataxia including SCA 3 and Friedreich ataxia. Patients had at least 3 dysautonomic symptoms, including xerostomia/xerophthalmia (5/5). VEMP results varied among patients, ranging from normal to completely abnormal. We found inconsistent results with VEMPs. The utilization of VEMPs in more CANVAS cases will determine its utility in this syndrome. Dysautonomia may be included in the diagnostic criteria.

Eptinezumab for the preventive treatment of migraine.

Our knowledge of the pathophysiology of migraine and the molecules implicated in the disorder have evolved over time. Among these, calcitonin gene-related peptide has shown a crucial role that led to the development of therapies specifically targeting the molecule. Four monoclonal antibodies targeting the calcitonin gene-related peptide pathway are currently available after the US FDA approval of eptinezumab for the indication of migraine prevention. This is the only one of the class to be administered intravenously. The pharmacology of eptinezumab and the four studies that led to the approval, two Phase II and two Phase III clinical trials, are reviewed in this paper. Eptinezumab has demonstrated efficacy, tolerability and safety in patients with episodic and chronic migraine. Studies including migraineurs who have failed previous preventives, and comparison with other options administered quarterly, as well as real-world experience data will all be welcome.

18F-FDG-PET Imaging Patterns in Autoimmune Encephalitis: Impact of Image Analysis on the Results.

Brain positron emission tomography imaging with 18Fluorine-fluorodeoxyglucose (FDG-PET) has demonstrated utility in suspected autoimmune encephalitis. Visual and/or assisted image reading is not well established to evaluate hypometabolism/hypermetabolism. We retrospectively evaluated patients with autoimmune encephalitis between 2003 and 2018. Patients underwent EEG, brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) sampling and autoantibodies testing. Individual FDG-PET images were evaluated by standard visual reading and assisted by voxel-based analyses, compared to a normal database. For the latter, three different methods were performed: two based on statistical surface projections (Siemens syngo.via Database Comparison, and 3D-SSP Neurostat) and one based on statistical parametric mapping (SPM12). Hypometabolic and hypermetabolic findings were grouped to identify specific patterns. We found six cases with definite diagnosis of autoimmune encephalitis. Two cases had anti-LGI1, one had anti-NMDA-R and two anti-CASPR2 antibodies, and one was seronegative. 18F-FDG-PET metabolic abnormalities were present in all cases, regardless of the method of analysis. Medial-temporal and extra-limbic hypermetabolism were more clearly depicted by voxel-based analyses. We found autoantibody-specific patterns in line with the literature. Statistical surface projection (SSP) methods (Neurostat and syngo.via Database Comparison) were more sensitive and localized larger hypermetabolic areas. As it may lead to comparable and accurate results, visual analysis of FDG-PET studies for the diagnosis of autoimmune encephalitis benefits from voxel-based analysis, beyond the approach based on MRI, CSF sample and EEG.

An Update on Imaging in Idiopathic Intracranial Hypertension.

Neuroimaging plays an essential role in the diagnostic workup of idiopathic intracranial hypertension with the aims to exclude secondary causes of elevated intracranial pressure and to identify imaging signs that are commonly observed in this disorder. As a valuable expansion of brain imaging, the imaging of the retina using optical coherence tomography has been of increasing value. In particular, this is the case with the latest devices that allow a more accurate distinction between a reduction in retinal nerve fiber layer thickness due to an improvement of papilledema or due to a worsening caused by optic nerve atrophy. Although optical coherence tomography does not yet replace the other elements of the diagnostic workup, it is likely to play an increasing role in diagnosis and follow-up of idiopathic intracranial hypertension. The review focuses on the main findings in neuroimaging, including structural and vascular alterations as well as on the relevance of optical coherence tomography.

Gepants, calcitonin-gene-related peptide receptor antagonists: what could be their role in migraine treatment?

PURPOSE OF REVIEW: Migraine is the second leading cause of years lived with disability after back pain. Poor tolerability, contraindications, drug-drug interactions and efficacy limited to a subpopulation make new approaches necessary for the acute and preventive treatment of migraine. The study of the calcitonin-gene-related peptide (CGRP) pathway over the last decades is a good example of translational medicine leading to directed therapies for patients. RECENT FINDINGS: After some of the first-generation CGRP receptor antagonists, gepants, were not fully developed because of hepatotoxicity, the second generation of gepants have shown efficacy, safety and tolerability in recent clinical trials. SUMMARY: Both rimegepant and ubrogepant have published positive randomized placebo-controlled clinical trials data. Vazegepant is the first intranasal gepant for the acute treatment of migraine and has announced a positive phase II/III study. Daily rimegepant use has preliminary data to suggest efficacy. Atogepant has shown efficacy in migraine prevention in a phase II/III study. Most importantly, hepatotoxicity has not been reported in specifically designed phase I studies or long-term extension studies, with rimegepant or ubrogepant, or in a preventive study with atogepant. Given the preventive effect, it seems likely that gepants will not lead to medication overuse headache. They will likely have no cardiovascular warnings. Because of the particular benefit gepants may represent for these groups of patients, specific studies in patients with medication overuse headache, as well as those with comorbid cardiovascular diseases, would be of considerable interest.

Elevated circulating metalloproteinase 7 predicts recurrent cardiovascular events in patients with carotid stenosis: a prospective cohort study.

BACKGROUND: Major adverse cardiovascular events are the main cause of morbidity and mortality over the long term in patients undergoing carotid endarterectomy. There are few reports assessing the prognostic value of markers of inflammation in relation to the risk of cardiovascular disease after carotid endarterectomy. Here, we aimed to determine whether matrix metalloproteinases (MMP-1, MMP-2, MMP-7, MMP-9 and MMP-10), tissue inhibitor of MMPs (TIMP-1) and in vivo inflammation studied by 18F-FDG-PET/CT predict recurrent cardiovascular events in patients with carotid stenosis who underwent endarterectomy. METHODS: This prospective cohort study was carried out on 31 consecutive patients with symptomatic (23/31) or asymptomatic (8/31) severe (> 70%) carotid stenosis who were scheduled for carotid endarterectomy between July 2013 and March 2016. In addition, 26 healthy controls were included in the study. Plasma and serum samples were collected 2 days prior to surgery and tested for MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein and erythrocyte sedimentation rate. 18F-FDG-PET/CT focusing on several territories' vascular wall metabolism was performed on 29 of the patients because of no presurgical availability in 2 symptomatic patients. Histological and immunohistochemical studies were performed with antibodies targeting MMP-10, MMP-9, TIMP-1 and CD68. RESULTS: The patients with carotid stenosis had significantly more circulating MMP-1, MMP-7 and MMP-10 than the healthy controls. Intraplaque TIMP-1 was correlated with its plasma level (r = 0.42 P = .02) and with 18F-FDG uptake (r = 0.38 P = .05). We did not find any correlation between circulating MMPs and in vivo carotid plaque metabolism assessed by 18F-FDG-PET. After a median follow-up of 1077 days, 4 cerebrovascular, 7 cardiovascular and 11 peripheral vascular events requiring hospitalization were registered. Circulating MMP-7 was capable of predicting events over and above the traditional risk factors (HR = 1.15 P = .006). When the model was associated with the variables of interest, the risk predicted by 18F-FDG-PET was not significant. CONCLUSIONS: Circulating MMP-7 may represent a novel marker for recurrent cardiovascular events in patients with moderate to severe carotid stenosis. MMP-7 may reflect the atherosclerotic burden but not plaque inflammation in this specific vascular territory.