A rational approach to migraine diagnosis and management in primary care.

Migraine is a chronic neurologic disease estimated to affect approximately 50 million Americans. It is associated with a range of symptoms, which contribute to disability and substantial negative impacts on quality of life for many patients. Still, migraine continues to be underdiagnosed, undertreated, and optimising treatment for individual patients has proven difficult. As many migraine patients will be seen first in primary care settings, internists and other primary care providers are ideally positioned to improve diagnosis and migraine management for many patients. In this review, we discuss some of the challenges in diagnosing migraine and suggest strategies to overcome them, summarise the current understanding of migraine pathophysiology and clinical evidence on acute and preventive treatment options, and offer practical approaches to diagnosis and contemporary management of migraine in the primary care setting.Key messagesMigraine is a prevalent disease with substantial impact. Primary care providers are ideally positioned to improve care for migraine patients with streamlined approaches to diagnosis and management.A stepwise diagnostic approach to migraine involves taking a thorough headache history, excluding secondary headache, and identifying primary headache disorder using screening tools or ICHD-3 criteria.The FDA approved seven new migraine therapies from 2018 to 2020 (four monoclonal antibodies, two gepants, one ditan), expanding acute and preventive therapeutic options.

Hypervigilance, Allostatic Load, and Migraine Prevention: Antibodies to CGRP or Receptor.

Migraine involves brain hypersensitivity with episodic dysfunction triggered by behavioral or physiological stressors. During an acute migraine attack the trigeminal nerve is activated (peripheral sensitization). This leads to central sensitization with activation of the central pathways including the trigeminal nucleus caudalis, the trigemino-thalamic tract, and the thalamus. In episodic migraine the sensitization process ends with the individual act, but with chronic migraine central sensitization may continue interictally. Increased allostatic load, the consequence of chronic, repeated exposure to stressors, leads to central sensitization, lowering the threshold for future neuronal activation (hypervigilance). Ostensibly innocuous stressors are then sufficient to trigger an attack. Medications that reduce sensitization may help patients who are hypervigilant and help to balance allostatic load. Acute treatments and drugs for migraine prevention have traditionally been used to reduce attack duration and frequency. However, since many patients do not fully respond, an unmet treatment need remains. Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide involved in nociception and in the sensitization of peripheral and central neurons of the trigeminovascular system, which is implicated in migraine pathophysiology. Elevated CGRP levels are associated with dysregulated signaling in the trigeminovascular system, leading to maladaptive responses to behavioral or physiological stressors. CGRP may, therefore, play a key role in the underlying pathophysiology of migraine. Increased understanding of the role of CGRP in migraine led to the development of small-molecule antagonists (gepants) and monoclonal antibodies (mAbs) that target either CGRP or the receptor (CGRP-R) to restore homeostasis, reducing the frequency, duration, and severity of attacks. In clinical trials, US Food and Drug Administration-approved anti-CGRP-R/CGRP mAbs were well tolerated and effective as preventive migraine treatments. Here, we explore the role of CGRP in migraine pathophysiology and the use of gepants or mAbs to suppress CGRP-R signaling via inhibition of the CGRP ligand or receptor.

Migraine is a neurological disease affecting one in eight people. Symptoms include nausea and/or sensitivity to light and sound, and a throbbing headache. Although certain genes may increase the likelihood of migraine, environmental stimuli and molecules that increase the sensitivity of brain blood vessels and their innervations also play a role. During a migraine attack, nerves in the brain are activated, leading to increased sensitivity to stimuli, lowering the future threshold for activation, and making patients hypervigilant. Chronic, repeated exposure to certain stimuli can also lower this activation threshold, such that relatively innocuous stimuli can trigger an attack. Excessive use of certain migraine treatments can increase headache frequency over time and produce unwanted side effects; thus, selective agents are needed that specifically target the systems and pathways affected in migraine pathophysiology. Calcitonin gene-related peptide (CGRP), produced and released by nerve cells, is important in migraine pathophysiology. CGRP binds smooth muscle cell receptors, dilating blood vessels supplying the brain, and also binds to peripheral nerve cells that transmit pain signals to the spinal cord and brain. CGRP levels are elevated during a migraine attack. Medications targeting the CGRP pathway may decrease sensitivity and potentially normalize responses in hypervigilant patients. Two commercially available oral drugs that block CGRP receptors ('gepants') have reduced symptoms during migraine attacks in clinical trials. Four monoclonal antibodies (proteins that bind a specific molecule) have also been developed that target CGRP or the receptor and have been shown to significantly reduce the number of migraine days per month. Role of CGRP in Migraine.

Real-World Treatment Profiles, Clinical Outcomes, and Healthcare Resource Utilization of Patients with Migraine Prescribed Erenumab: A Multicenter Chart-Review Study of US Headache Centers.

INTRODUCTION: Erenumab, a first-in-class monoclonal antibody targeting the calcitonin gene-related peptide pathway, was approved by the US Food and Drug Administration in 2018 for the prevention of migraine in adults. There is limited data available on its impact in real-world settings. The study aim was to characterize the real-world treatment profiles, clinical outcomes, and healthcare resource utilization of patients prescribed erenumab from select major US headache centers. METHODS: A retrospective chart review of patients with migraine treated with erenumab for at least 3 months across five major headache centers was conducted. Data was collected from patient charts between April 2019 and April 2020 and included patient and clinical characteristics, migraine medication use, and outpatient visits. The date of the first prescription fill of erenumab was defined as the index date. The baseline period comprised the 3 months prior to the index date and the study period comprised the at least 3 months on erenumab treatment. RESULTS: Data from a total of 1034 patients with chronic migraine with a mean of 9.3 months of erenumab treatment were analyzed. Patients were on average 48 years old, 86% were female, and 79% were white. Patients had a mean of 5 preventive treatment failures prior to erenumab initiation. Patients used a mean of 2 preventive treatments (excluding erenumab) and 2 acute treatments during baseline and study periods. Among patients with effectiveness data, 45% of patients had improvement in physician-reported migraine severity and 35% experienced at least 50% reduction in mean headache/migraine days per month. The average number of monthly outpatient visits was 0.43 and 0.30 before and after erenumab initiation, respectively. CONCLUSION: In this predominantly refractory chronic migraine population treated in select headache centers, patients had fewer headache/migraine days per month and outpatient visits after initiating erenumab. However, patients largely continued to be managed via a polypharmacy approach after erenumab initiation.

Wallenda/DLK protein levels are temporally downregulated by Tramtrack69 to allow R7 growth cones to become stationary boutons.

Dual leucine zipper kinase (DLK) promotes growth cone motility and must be restrained to ensure normal development. PHR (Pam/Highwire/RPM-1) ubiquitin ligases therefore target DLK for degradation unless axon injury occurs. Overall DLK levels decrease during development, but how DLK levels are regulated within a developing growth cone has not been examined. We analyzed the expression of the fly DLK Wallenda (Wnd) in R7 photoreceptor growth cones as they halt at their targets and become presynaptic boutons. We found that Wnd protein levels are repressed by the PHR protein Highwire (Hiw) during R7 growth cone halting, as has been observed in other systems. However, as R7 growth cones become boutons, Wnd levels are further repressed by a temporally expressed transcription factor, Tramtrack69 (Ttk69). Previously unobserved negative feedback from JNK also contributes to Wnd repression at both time points. We conclude that neurons deploy additional mechanisms to downregulate DLK as they form stable, synaptic connections. We use live imaging to probe the effects of Wnd and Ttk69 on R7 bouton development and conclude that Ttk69 coordinates multiple regulators of this process.

Podosome-regulating kinesin KIF1C translocates to the cell periphery in a CLASP-dependent manner.

The kinesin KIF1C is known to regulate podosomes, actin-rich adhesion structures that remodel the extracellular matrix during physiological processes. Here, we show that KIF1C is a player in the podosome-inducing signaling cascade. Upon induction of podosome formation by protein kinase C (PKC), KIF1C translocation to the cell periphery intensifies and KIF1C accumulates both in the proximity of peripheral microtubules that show enrichment for the plus-tip-associated proteins CLASPs and around podosomes. Importantly, without CLASPs, both KIF1C trafficking and podosome formation are suppressed. Moreover, chimeric mitochondrially targeted CLASP2 recruits KIF1C, suggesting a transient CLASP-KIF1C association. We propose that CLASPs create preferred microtubule tracks for KIF1C to promote podosome induction downstream of PKC.

Diagnosing and understanding adult headache.

Primary headaches are the most common headache disorders. The most common forms are tension-type headaches, migraine, and cluster headache. Knowing the clinical presentation coupled with taking a thorough history taking and performing a thorough physical examination usually helps in arriving at a correct diagnosis. Special attention should be paid to unusual clinical presentations. Further diagnostic work-up should be performed in the presence of atypical and worrisome signs.

An attenuating role of a WASP-related protein, WASP-B, in the regulation of F-actin polymerization and pseudopod formation via the regulation of RacC during Dictyostelium chemotaxis.

The WASP family of proteins has emerged as important regulators that connect multiple signaling pathways to regulate the actin cytoskeleton. Dictyostelium cells express WASP, as well as a WASP related protein, WASP-B, endoded by wasB gene. WASP-B contains many of the domains present in WASP. Analysis of wild type, wasB null cells revealed that WASP-B is required for proper control of F-actin polymerization in response to a cAMP gradient. Due to the lack of tight control on actin polymerization, wasB null cells exhibited higher level of F-actin polymerization. wasB(-) cells extend more de novo pseudopods laterally and their average life span is longer than those of wild type cells, causing more turns and inefficient chemotaxis. YFP-WASP-B appears to be uniformly distributed in the cytosol and shows no translocation to cortical membrane upon cAMP stimulation. Active RacC pull-down assay reveals that the level of active RacC in wasB(-) cells is significantly higher than wild type cells. Moreover, the distribution of active RacC is not localized in wasB(-) cells. We conclude that chemotaxis defects of wasB(-) cells are likely to result from the aberrant regulation of RacC activation and localization.

The interaction of plasma sialylated and desialylated lipoproteins with collagen from the intima and media of uninvolved and atherosclerotic human aorta.

We have evaluated the binding of sialylated and desialylated lipoproteins to collagen isolated from the proteoglycan and musculoelastic layers of intima and media of uninvolved human aorta and atherosclerotic lesions. Comparing various collagen preparations from the uninvolved intima-media, the binding of sialylated apoB-containing lipoproteins was best to collagen from the intimal PG-rich layer. Binding of sialylated apoB-containing lipoproteins to collagen from this layer of fatty streak and fibroatheroma was 1.4- and 3.1-fold lower, respectively, in comparison with normal intima. Desialylated VLDL versus sialylated one exhibited a greater binding (1.4- to 3.0-fold) to all the collagen preparations examined. Desialylated IDL and LDL showed a higher binding than sialylated ones when collagen from the intimal layers of fibroatheroma was used. Binding of desialylated HDL to collagen from the intimal PG-rich layer of normal tissue, initial lesion, and fatty streak was 1.2- to 2.0-fold higher compared with sialylated HDL.

Specific roles of Target of rapamycin in the control of stem cells and their progeny in the Drosophila ovary.

Stem cells depend on intrinsic and local factors to maintain their identity and activity, but they also sense and respond to changing external conditions. We previously showed that germline stem cells (GSCs) and follicle stem cells (FSCs) in the Drosophila ovary respond to diet via insulin signals. Insulin signals directly modulate the GSC cell cycle at the G2 phase, but additional unknown dietary mediators control both G1 and G2. Target of rapamycin, or TOR, is part of a highly conserved nutrient-sensing pathway affecting growth, proliferation, survival and fertility. Here, we show that optimal TOR activity maintains GSCs but does not play a major role in FSC maintenance, suggesting differential regulation of GSCs versus FSCs. TOR promotes GSC proliferation via G2 but independently of insulin signaling, and TOR is required for the proliferation, growth and survival of differentiating germ cells. We also report that TOR controls the proliferation of FSCs but not of their differentiating progeny. Instead, TOR controls follicle cell number by promoting survival, independently of either the apoptotic or autophagic pathways. These results uncover specific TOR functions in the control of stem cells versus their differentiating progeny, and reveal parallels between Drosophila and mammalian follicle growth.

Self-directed learning of basic musculoskeletal ultrasound among rheumatologists in the United States.

OBJECTIVE: Because musculoskeletal ultrasound (MSUS) is highly user dependent, we aimed to establish whether non-mentored learning of MSUS is sufficient to achieve the same level of diagnostic accuracy and scanning reliability as has been achieved by rheumatologists recognized as international experts in MSUS. METHODS: A group of 8 rheumatologists with more experience in MSUS and 8 rheumatologists with less experience in MSUS participated in an MSUS exercise to assess patients with musculoskeletal abnormalities commonly seen in a rheumatology practice. Patients' established diagnoses were obtained from chart review (gout, osteoarthritis, rotator cuff syndrome, rheumatoid arthritis, and seronegative arthritis). Two examining groups were formed, each composed of 4 less experienced and 4 more experienced examiners. Each group scanned 1 predefined body region (hand, wrist, elbow, shoulder, knee, or ankle) in each of 8 patients, blinded to medical history and physical examination. Structural abnormalities were noted with dichotomous answers, and an open-ended answer was used for the final diagnosis. RESULTS: Less experienced and more experienced examiners achieved the same diagnostic accuracy (US-established diagnosis versus chart review diagnosis). The interrater reliability for tissue pathology was slightly higher for more experienced versus less experienced examiners (kappa = 0.43 versus kappa = 0.34; P = 0.001). CONCLUSION: Non-mentored training in MSUS can lead to the achievement of diagnostic accuracy in MSUS comparable to that achieved by highly experienced international experts. Reliability may increase slightly with additional experience. Further study is needed to determine the minimal training requirement to achieve proficiency in MSUS.

Sumatriptan 6 mg subcutaneous as an effective migraine treatment in patients with cutaneous allodynia who historically fail to respond to oral triptans.

The objective of the study was to assess the efficacy of 6 mg subcutaneous (s.c.) sumatriptan to treat migraine and the relationship between response of migraine and cutaneous allodynia in a population of migraine patients who historically failed to respond to oral triptan medications. This was an open-label study consisting of patients with migraines who historically failed to respond to oral triptan medications. Forty-three patients were asked to treat three migraine attacks with 6 mg s.c. sumatriptan. The primary efficacy endpoint was the percentage of patients achieving relief of headache at 2 h. Ninety-one percent of the patients responded to a single dose of s.c. sumatriptan 6 mg. Fifty percent of all patients were pain-free by 2 h and over 30% had a 24-h sustained pain-free response. When administered within 90 min from the onset of migraine (i.e., during the developing phase of cutaneous allodynia), s.c. 6 mg sumatriptan proved to be effective despite the occurrence of allodynia in a group of patients, who historically had failed to respond to oral triptan medications. These findings suggest that the window of opportunity to treat allodynic patients with injectable triptans may be longer (up to 2 h) than with oral triptans (up to 1 h).