Accepted

Calcitonin gene-related peptide (CGRP), a 37 amino-acid neuropeptide found mostly in peptidergic sensory C-fibers, has been suggested to be implicated in the pathogenesis of migraine, which is one of the most common neurological disorders seen in medical practice, affecting almost 16% of the US population. While previously thought to be a vascular condition, migraine attacks are the result of neurogenic inflammation and peripheral/central sensitization through dysfunctional activation of the trigeminovascular system. To date, two classes of therapeutic agents have been developed to interrupt the function of CGRP: CGRP-targeted monoclonal antibodies (mAbs) and small-molecule antagonists (gepants). There are currently four CGRP-targeted mAbs and three gepants that are US Food and Drug Administration (FDA) approved for the treatment of migraine. Multiple phase II and III studies have established the efficacies and tolerability of these treatments. Previously, we reviewed the fundamental role of CGRP in migraine pathogenesis. Here, we discuss in depth the clinical evidence (randomized controlled trials and real-world studies), safety, and tolerability of CGRP-targeted mAbs and gepants for treating migraine.

Temporomandibular disorders (TMDs) are a prominent reason for visits to medical providers. The presentation of headaches within this population remains a challenging diagnosis, given the prevalence and overlap of symptomatology of both conditions. The literature demonstrates an undeniable association between headaches and TMD. Regardless of causality and etiology, the literature supports that prompt diagnosis and treatment results in improvement or resolution of symptoms, including headaches. Treatment of TMD headaches should begin with conservative measures, including medical management with NSAIDs, heat therapy, and muscle-stretching exercises.

Cluster headache (CH) is a highly debilitating headache disorder characterized by frequent attacks of excruciating unilateral pain accompanied by cranial autonomic symptoms. Calcitonin gene-related peptide (CGRP) is implicated in the pathophysiology of CH.

Headache is a common symptom in pregnancy. The differential diagnosis for headache in pregnancy is broad and includes conditions that range in acuity and severity. Most headaches in pregnancy are migraine or tension-type headaches. However, pregnant women are at an increased risk of vascular causes of headache due to hormone changes and increased hypercoagulability in pregnancy. A careful history, physical examination, and possible diagnostic workup should be performed. Treatment of headache in pregnancy varies according to the etiology, but care should be taken when performing diagnostic studies and considering pharmacologic treatments, given the possible risk to the mother and fetus.

Imaging plays an important role in identifying the cause of the much less common secondary headaches. Such headaches may be caused by a variety of pathologic conditions which can be categorized as intracranial and extracranial. Idiopathic intracranial hypertension imaging findings include "empty sella," orbital changes, and dural venous sinus narrowing. Intracranial hypotension (ICH) is frequently caused by CSF leaks. Imaging findings include loss of the CSF spaces, downward displacement of the brain, as well as dural thickening and enhancement. Severe cases of ICH may result in subdural hematomas. A variety of intracranial and skull base tumors may cause headaches due to dural involvement. Extracranial tumors and lesions that frequently present with headaches include a variety of sinonasal tumors as well as mucoceles. Neurovascular compression disorders causing headaches include trigeminal and glossopharyngeal neuralgia. Imaging findings include displacement and atrophy of the cranial nerve caused by an adjacent arterial or venous structure.

Patients often report symptoms of headache and dizziness concomitantly. Symptoms of dizziness can be explored with a comprehensive vestibular assessment, allowing for the investigation of central and peripheral vestibular system contributions to symptoms of dizziness. Patients who report both symptoms of headache and dizziness demonstrate abnormalities of the vestibular system which can be measured quantitatively. Completion of comprehensive vestibular testing can help to guide diagnosis and strategies for intervention.

Pediatric headache is a common medical complaint managed across multiple subspecialties with a myriad of unique factors (clinical presentation and disease phenotype) that make accurate diagnosis particularly elusive. A thorough understanding of the stepwise approach to headache disorders in children is essential to ensure appropriate evaluation, timely diagnosis, and efficacious treatment. This work aims to review key components of a comprehensive headache assessment as well as discuss primary and secondary headache disorders observed in children, with a particular focus on clinical pearls and "red flag" symptoms necessitating ancillary diagnostic testing.