key: cord-0928066-f4qydjpu
authors: Cocores, Alexandra N.; Monteith, Teshamae S.
title: Headache as a Neurologic Manifestation of Systemic Disease
date: 2022-03-18
journal: Curr Treat Options Neurol
DOI: 10.1007/s11940-022-00704-9
sha: 9877bde8688cbbe596c22c1ae9e4c595b8d2408b
doc_id: 928066
cord_uid: f4qydjpu

PURPOSE OF REVIEW: This is an update of headache attributed to systemic disease and current therapeutic strategies. Clinical scenarios are discussed. RECENT FINDINGS: The diagnosis of headache attributed to metabolic or systemic disorder appears in the Appendix of International Classification of Headache Disorders, Third Edition, and requires further evaluation and validation. However, recent studies characterizing headache appear in the literature. Specific treatment includes addressing underlying systemic disorders, managing concurrent primary headache, and treating comorbidities that may exacerbate headache. Evidence for specific treatment trials for headache as a symptom is lacking, including headaches post-COVID19 infection. Calcitonin gene-related peptide receptor antagonists and 5-HT(1F) receptor agonists are attractive options for migraine with vascular comorbidities, but long-term studies are needed. SUMMARY: Headache is commonly encountered as a manifestation or complication of systemic disease. Further research is needed to validate headache associated with systemic disorders and to determine optimal treatment strategies.

Currently, headache attributed to a systemic disorder appears in the Appendix of the ICHD-3, thus requiring further research and validation. The goals of this review are to discuss important systemic diseases that may manifest with headache, with focus on their epidemiology, diagnostic criteria, recent findings, and current treatment strategies. The review pays special attention to migraine and systemic diseases. We will also discuss the management of complex clinical scenarios relevant to neurology practice ( Table 2) . Systemic disease is defined as one that affects several organs and tissues, or the body as a whole. Moreover, headache may occur commonly as a manifestation secondary to numerous systemic conditions and to their therapies. Both primary and secondary headache disorders are diagnosed according to the International Classification of Headache Disorders-3 (ICHD3), published in 2018 [1] . It is helpful to have an anatomical and functional understanding of pain producing structures of the cranium or cranio-cervical region (i.e., dura, venous sinuses, intracranial arteries) that contribute to pain in systemic disease and lead to trigeminovascular activation. Secondary headache may present with a spectrum of clinical phenotypes that resemble primary headache disorders. There are specific indicators that are helpful for identifying secondary headaches such as temporal association and parallel severity, but these are less helpful for systemic disease-induced headaches.

The first objective in the diagnostic evaluation of a headache presentation is the determination of whether the symptom is due to a primary or secondary condition. A detailed and methodical clinical history must be actively elicited from the patient, with specific attention to red flag warning signs (SNNOOP10) [2] in Table 1 and medications known to cause headache. A neurologic examination should be performed, with vital signs, and a general exam focused on systemic complaints. Diagnostic investigations will depend on the suspected underlying disorder.

The presence of "green" flags is reassuring for confirming the diagnosis of primary headache disorders such as migraine, tension-type, and cluster headache. In addition, a history of pre-existing or a family history of headache is helpful for the diagnosis. It is important to note that although migraine is a central nervous system disorder, it can be associated with widespread systemic manifestations due to migraine. Migraine is defined by the presence of a moderate to severe throbbing head pain, hypersensitivities, and gastrointestinal symptoms. However, during the premonitory phase, patients may report fatigue as well as several homeostatic alternations including thirst, frequency of urination, and appetite changes that are possibly associated with the hypothalamus and locus coeruleus [3] . Migraine, as a primary headache, may be associated with comorbidities including systemic disease with a worse prognosis. Several systemic conditions may act as risk factors for transformation from episodic to chronic migraine [4] . This is important because longitudinal cohort studies such as the Chronic Migraine Epidemiology and Outcomes (CaMEO) and American Migraine Prevalence and Prevention (AMPP) studies have established more severe headache-related disability in those with chronic versus episodic migraine, with up to a 3.63 times greater rate of disability days per month [5, 6] . In a further analysis of the CaMEO study, when comparing individuals with migraine and the highest comorbidity burden with the subgroup with the fewest, there was a greater proportion of individuals with severe disability [7] . Further research is needed to assess prognostic and biological differences in migraine management based on comorbidity profiles. Based on the literature, we discuss several systems in which headache may be associated with systemic disorders or associated with primary headache, most commonly migraine.

Individuals who regularly experience gastrointestinal symptoms have a higher prevalence of headache [8] . ICHD-3 does not define headache secondary to gastrointestinal disorders. However, nausea and vomiting are defining features of migraine, and both abdominal pain and cyclic vomiting are migraine subtypes that are often misdiagnosed. Patients with irritable bowel syndrome have been shown to have increased risk of coexisting headache; the comorbidity may be explained by shared pathological mechanisms of migraine [9] . Gastroparesis has also been reported with migraine [10] . The benefits of probiotics are understudied for migraine.

For systemic disease, a small study found that a gluten-free diet in four patients with celiac disease decreased reported migraine frequency, duration, and intensity; this may suggest a shared pathogenic relationship but needs further investigation [11] . In inflammatory bowel disease, a heightened immune response increases levels of pro-inflammatory cytokines which may contribute to the increased prevalence of headache among these patients [12] . In terms of medications, proton pump inhibitors, notably esomeprazole and lansoprazole, may cause headache especially in susceptible individuals.

Headache is common in hypertensive urgency, occurring in 42% of patients in one study [13] . According to ICHD-3, headache should be attributed to hypertension only if measured systolic blood pressure ≥ 180 mm Hg and/or diastolic pressure ≥ 120 mm Hg, and there is evidence of causation by either development in temporal relation to the onset of hypertension or significant worsening or improvement in parallel with relative worsening or improvement in blood pressure.

Regardless of the underlying reason for the hypertensive crisis, the headache is often bilateral in location and pulsating in quality [1] , and the mechanism causing head pain during acute hypertension is thought to be the same. Pathologic changes occur at the limit of compensatory cerebrovascular vasoconstriction, which acts to prevent hyperperfusion as blood pressure rises [14] . This presentation may be complicated by posterior reversible encephalopathy syndrome (PRES). One prospective study found headache occurred in 73% of PRES cases [15] .

Based on ambulatory blood pressure monitoring correlations with headache diaries, blood pressure variations in those with mild and moderate chronic arterial hypertension did not correlate with occurrence of headache [16, 17] . In a recent prospective study of 29,040 women without hypertension with a mean follow-up for 12.2 years, women with migraine were found to have a higher relative risk of developing hypertension (with aura 9%, without aura 21%, past history 15%) than those without migraine [18] . In the Northern Manhattan Study, hypertension, predominantly uncontrolled and of long duration, was associated with migraine with and without aura, in a predominantly Hispanic community-based cohort [19] . In addition, headache is an adverse side effect of cardiovascular medications use to treat angina and hypertension, including nitrates (nitroglycerin), calcium channel blockers, and angiotensin-converting enzyme inhibitors; these often display a dose-dependent effect.

Headache is a common symptom of autonomic dysregulation. When headache occurs in a patient with complete or incomplete spinal cord injury, the patient should be presumed to have autonomic dysreflexia until proven otherwise. Headache can also be a presentation of autonomic dysfunction as seen in orthostatic hypotension, including postural orthostatic tachycardia syndrome (POTS).

A coat-hanger distribution of pain affecting the neck and shoulders may be indicative of orthostatic hypotension. In one study of patients with POTS, two-thirds of patients interviewed experienced orthostatic headache, more so in those less than 30 years old; almost all patients interviewed experienced migraine headache [20] . Another study found that in adolescents with headache and lightheadedness referred for tilt table testing, headache type did not predict POTS diagnosis, although new-onset motion sickness and dizziness preceding orthostatic headaches were significantly associated with presence of POTS [21] . In patients presenting with these features, this diagnosis should be considered; and the comorbid headache in those with POTS should be managed accordingly. Treatment includes a high-salt diet, propranolol, fludrocortisone, midodrine, and possibly exercise training. Patients with comorbid migraine may particularly benefit from beta-blockers [22] .

Migraine has been associated with an increased risk of cardiovascular disease; it is estimated there are approximately 2.6 million adults with episodic migraine and one or more cardiovascular event, condition, or procedure in the USA [23] . The risk of ischemic stroke in individuals with migraine with aura is doubled; the underlying risk factors may be due to endothelial dysfunction, thromboembolism, hormonal influences, and genetic disposition.

An individual's risk of vascular events should be considered when prescribing migraine prevention and abortive treatments. Treatments may be chosen to target both disease processes; in hypertensive patients, the use of beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers for migraine prophylaxis may be helpful.

According to label, triptans are contraindicated in uncontrolled arterial hypertension, coronary artery disease, and after a cerebrovascular event. However, 5HT 1F and CGRP antagonists are new specific and non-vasoconstrictive acute medications that may be safer for treating migraine in individuals with high cardiovascular risks. For example, in one study, there was no statistical difference in lasmiditan efficacy or frequency of likely cardiovascular adverse events based on presence of cardiovascular risk factors [24] . For CGRP antagonists, also known as gepants, both ubrogepant and rimegepant are migraine specific acute treatment options, while rimegepant and atogepant are approved for prevention [25] . With regard to prevention using antibodies against CGRP or its receptor, although CGRP plays a role in regulation of blood pressure [26] , no serious cardiovascular concerns have been disclosed with any of these drugs [27] ; still, erenumab has been linked with new-onset or worsening hypertension. A recent review outlines potential risks of migraine treatment in vascular disease and discusses these options in detail [28] .

In any woman presenting with headache during pregnancy or the puerperium, it is imperative to first consider secondary etiologies although primary headache is common. In one retrospective analysis of women presenting to a tertiary care center, 73% were diagnosed with a secondary headache disorder. The most common was a post-dural puncture headache, followed by postpartum preeclampsia and other cerebrovascular disorders.

Headache is considered one of the most common neurologic manifestations of hypertension in pregnancy and is important to further evaluate given the tendency for hypertensive disorders lead to significant morbidity and mortality [29] . In one case-control study, headache was significantly more frequent in those with pre-eclampsia than in controls (OR 4.95) [30] .

Headache has also been found to be the most frequent symptom (87%) preceding stroke in a review of preeclampsia pregnancy-related deaths [31] . The headache that occurs is usually bilateral in location, pulsating in quality, and aggravated by physical activity [1] . Treatment of the pre-eclampsia or eclampsia will result in resolution of the headache. Meta-analyses and prospective studies suggest occurrence of headache does not portend adverse outcomes and should not be used as a diagnostic "severe feature" [32, 33] .

Estrogen-containing medications, including oral contraceptives, patch, vaginal ring, and hormone replacement, although can improve headache in some cases is known to cause or worsen headache in susceptible patients. On the other hand, valproic acid used for migraine prevention can lead to polycystic ovarian syndrome.

Headache can be commonly seen with a number of respiratory disorders such as OSA, asthma, and COPD. In addition, when respiratory disease and psychiatric disorder coexist, high rates of chronic migraine are observed [7] . We focus on OSA, a condition that commonly presents in neurology clinics.

Obstructive sleep apnea (OSA) may be the cause of a headache present on awakening from sleep, with usually a bilateral location, pressing quality, and a duration of less than 4 h. Headaches recur on at least 15 days per month and are not usually accompanied by nausea, photophobia, or phonophobia [1] . The prevalence is 12-18% in those with sleep apnea [34] . Other sleeprelated respiratory disorders and primary sleep disorders may also present with headache upon awakening and should remain in differential diagnosis.

The prevalence of morning headache has been shown in some studies to be higher in those with severe compared to moderate OSA based on apnea-hypopnea index (AHI) grading [35, 36] . Others have not found significant increased risk of morning headache based on AHI, blood oxygen saturation parameters, or arousal index [35, 37] . suggesting that oxygen desaturation alone cannot explain the pathophysiology of this secondary headache disorder [34] . Both headache and sleep disorder may be manifestations of the same systemic dysfunction of homeostasis, attributed to hypoxia and/or hypercapnia, although this remains to be elucidated [38] .

Headache associated with OSA may resolve after treatment initiation after diagnosis with a polysomnography [39] . In one study, CPAP therapy improved both sleep apnea and headache in only a third of participants [40] , although in another, nasal CPAP resolved headache in 90% of participants [36] .

OSA appears to occur at the same rate in migraine as the general population [41] , but is worth addressing in migraine patients as it is a modifiable vascular risk factor [42] . Snoring and other sleep disorders are risk factors for migraine progression [43] . Screening, diagnosis, and management of these sleep disturbances may be a crucial component of the therapeutic plan for migraine management.

Headache can be associated with multiple endocrine disorders and can vary in phenotype and pathophysiology such as intracranial hypertension or worsening migraine. Endocrinopathies should be considered in cases of chronic cluster headache or other trigeminal autonomic cephalalgias [44] .

Headache can be associated with both hyperthyroidism, hypothyroidism, and Hashimoto's thyroiditis. Headache secondary to hypothyroidism occurs in about one-third of patients diagnosed with the endocrinological derangement [45] A prior history of migraine is more frequent in these patients [45, 46] . The underlying mechanism for headache attributed to hypothyroidism remains unclear.

Patients with headache as a component of their manifestations of hypothyroidism will not differ clinically with respect to the remainder of symptoms compared to those without headache (with the exception of hoarseness which was more frequent in those with headache) [46] . Presenting complaints including fatigue, constipation, cold intolerance, skin changes, decreased concentration, and examination may reveal bradycardia, diminished pules, increased BMI, or delayed relaxation of deep tendon reflexes.

Correction of the hormone derangement with levothyroxine will result in relief or complete remission of headache in the majority of patients; headache has shown to decrease in intensity and duration within the first 2 weeks of treatment [45] . The degree of hypothyroidism (subclinical versus overt disease) does not seem to affect potential for improvement with levothyroxine treatment [46] .

Metabolic syndrome may be associated with migraine [47] , but not diabetes [48] . Individuals with migraine who are obese or overweight may be at risk of experiencing increased frequency of attacks and progressing from episodic to chronic migraine. In the CaMEO study, chronic as opposed to episodic migraineurs were 34% more likely to be obese. As obesity is a potential modifiable risk factor, clinicians should consider weight management as a particularly useful component of the migraine treatment plan. Therapy should include nutritional and dietary education, exercise strategies, and behavioral interventions. Weight loss may be challenging in some patients with systemic disorders such as PCOS. If migraine and obesity are comorbid, weight neutral drugs such as topiramate should be considered and common drugs associated with weight gain (valproate, amitriptyline, propranolol, etc.) avoided.

For pseudotumor cerebri, headache is a direct consequence of increased intracranial pressure. However, systemic inflammation associated with obesity can be migraine-triggering so treating with migraine prophylaxis and specific therapies is beneficial. Weight loss, correction of metabolic disturbance, removal of the inciting agent, or treatment of the underlying causative disorder may not be sufficient to normalize the high intracranial pressure. Additionally, diuretics are often required to relieve headache and other symptoms and to prevent vision loss.

Headache is a common manifestation of autoimmune disorders, with focused or systemic inflammation. Conditions that may cause headache may vary from systemic lupus erythematosus (SLE) and related conditions, vasculitis which may be primary or secondary, or systemic vasculitides. Treatment with steroids of immunomodulators may not be enough to treat headache; systematic treatment with analgesics are often needed. Migraine has previously been shown to be more prevalent in patients with primary Sjogren's syndrome, scleroderma, SLE, and rheumatoid arthritis as compared to controls; there may be a significant association between Raynaud's phenomenon and migraine [49] . In addition to steroids (and analgesics), steroid-sparing agents are often necessary for prolonged remission.

Temporal arteritis should be considered in older patients greater than 50 with new-onset headache. Temporal arteritis is commonly associated with polymyalgia rheumatica and jaw claudication. The headache of temporal arteritis is sometimes missed because the headache be present beyond the temples, also involving the frontal, vertex, and occipital regions [50] . In addition to blindness, patients may have vascular complications such as ischemic stroke if not effectively treated with steroids urgently. We suggest an initial treatment with the equivalent of prednisone 1 mg/kg (maximum 60 mg/day) administered in a single daily dose and pulse intravenous methylprednisolone for patients at risk of with established visual loss [51] .

Neurologic manifestations are relatively rare in the multisystem granulomatous disorder of systemic sarcoidosis, but patients may develop headache and stroke-like symptoms during presentation [52] and reported migraine headache more commonly than healthy controls [53] .

In neurosarcoidosis, headache was the second most commonly reported feature (32%) after cranial neuropathy (55%) [54] . For patients in which headache was the presenting manifestation of neurosarcoidosis, half had clinical characteristics suggestive of Tolosa-Hunt syndrome while in the remainder headache was tension-type and without other neurologic symptoms [55] . Classical imaging finding include leptomeningeal, pituitary, hypothalamic, and the brain parenchymal involvement. Steroids are first-line treatment, which may improve secondary headache, and the addition of steroid-sparing agents is often necessary [56] .

Headache attributed to SLE may occur but is not considered as a presenting or prominent symptom of the disease and is not sufficiently validated to be defined in the ICHD-3. Still, headache is commonly one of the nonspecific symptoms with which an SLE patient may present. Some studies reveal migraine, especially with aura, is more common in patients with SLE than controls [57] , although others show no significant difference [58] . In a cohort of 1732 patients, there was no association between headache and immunosuppressant drugs or the presence of specific autoantibodies [59] . Importantly, SLE patients may be hypercoagulable and are therefore at risk of cerebral venous sinus thrombosis (CVST). There is insufficient data on headache treatment, but acetazolamide may be considered as well as standard migraine treatments (i.e., tricyclic anti-depressants, topiramate, onabotuli-numtoxinA injections, SNRIs). In SLE patients, serious headache may be an important indicator of CNS infection or cerebral vasculitis.

Rheumatologic diseases including sarcoidosis, Behcet's disease, Sjogren's syndrome, SLE, and granulomatosis with polyangiitis may result in headache due to meningeal involvement, though aseptic meningitis can also be due to other etiologies such as drug-induced (most commonly due to NSIADs, antibiotics, IVIG, and monoclonal antibodies) or neoplastic processes [60] . Patients may suffer accompanying nausea, neck stiffness, and photophobia. CSF reveals pleocytosis with no evidence of bacterial infection, fungal infection, or malignancy; MRI may reveal meningeal enhancement [61] . In the case of CSF high pressures, serial lumbar punctures, acetazolamide, or topiramate may be helpful. This condition may be self-limiting; however, shunting may be necessary in severe cases of chronic meningitis with impending blindness.

In US populations, connective tissue disorders are a common (16-38%) cause of for patients found to have spontaneous intracranial hypotension [62] . In Marfan syndrome, Ehlers-Danlos syndrome, autosomal dominant polycystic kidney disease, and benign joint mobility syndrome, dural weakness may predispose to CSF leakage. Therefore, one should evaluate for subtle manifestations of a variety of connective tissue disorder in these cases and if present an epidural blood patch may be therapeutic [63] . An updated diagnostic criteria for this headache was proposed in 2017 [64] . In those already diagnosed with a connective tissue disease, postural headaches should raise suspicion of spinal meningoceles with or without CSF leak [65] .

Patients with iron deficiency anemia (IDA) have a high frequency of headache, and specifically migraine; one questionnaire-based study revealed almost 80% of IDA patients had headache during their lifetime and 36% met criteria for migraine [66] . A recent case-control study found an association between IDA, hemoglobin levels, and serum ferritin levels and the incidence of migraine in female but not male patients [67] . One randomized controlled trial found a significant improvement in headache after iron supplementation in iron-deficient blood donors [68] .

Headache and facial pain may be common in patients with sickle cell disease (SCD); primary etiologies are common, but secondary etiologies must be investigated given potential for significant morbidity and mortality. Secondary causes of headache and facial pain in SCD include vascular etiology, bone infarcts (including facial, skull, and subperiosteal), orbital compression syndrome, osteomyelitis, dental and periodontal, PRES, and neuropathic pains [69] . At least in children with SCD, headache or migraine was associated with lower hemoglobin and higher pain event rates, but not silent cerebral infarction [70] . In a large case-control study, headache was of increased prevalence in children but not adults with SCD. Regular blood transfusions have not been shown to reduce headache frequency [71] .

Patients with suspicion for a hypercoagulable state who present with headache must be evaluated for secondary causes of headache. The most common presenting feature of CVST is headache (up to 89.4%) [72] . The headache in CVST is most frequently subacute, diffuse, and increases in intensity over time; it worsens with maneuvers that increase ICP and may be refractory to common analgesics [73] . In one large population-based case-control study, those with the combination of headache and high intrinsic coagulation protein levels were shown to have an increased risk of ischemic stroke than was based on the effect of headache or high levels alone [74] . Estrogen-containing oral contraceptives should be avoided as well as non-steroidal anti-inflammatory drugs with concomitant anti-coagulation use.

Headache may present as a manifestation of systemic or CNS infection, including rhinosinusitis, influenza syndromes, meningitis, encephalitis, or brain abscesses. Headache attributed to infectious meningitis or encephalitis should be suspected when associated with fever, neck stiffness, light sensitivity, nausea, and vomiting. The ICHD-3 recognizes headache attributed to systemic infection or new daily persistent headache (NDPH), which becomes continuous within 24 hours of onset and is commonly preceded by a viral prodrome. The treatment of NDPH may be challenging but includes including muscle relaxants, triptans, tricyclic antidepressants, onabotulinumtoxinA, SSRIs/SNRIs, and antiepileptic drugs [75] .

In recent reports of hospitalized patient diagnosed with COVID-19, headache was reported in 11-34% of hospitalized patients [76] . The CDC includes headache in an expanded list of possible symptoms. One hospital found COVID-19-related headaches to be of new onset, moderate to severe intensity, and bilateral with a pulsating or pressing quality in the temporoparietal, forehead, and periorbital regions; headache was poorly responsive to common analgesics and was limited to the active phase of illness [76] . Based on others' experience, in the acute phase, headache can appear as attributed to systemic viral infection, associated with cough headache, or tension-type; headache may emerge during a second phase of cytokine storming [77] . In patients with prior diagnosis of migraine disorder, severe persistent headache may be an early symptom [78] . Headaches associated with personal protective equipment among frontline healthcare workers may occur as a new onset or an exacerbation of a pre-existing headache disorder [79] . Remdesivir is indicated for moderate to severe COVID-19 infection with respiratory compromise; however, headache specific recommendations are lacking. Initially, renin-angiotensin system inhibitors, for hypertension and migraine prevention, were thought to potentially complicate outcomes; however, new studies suggest no evidence of harm. NSAIDs were also advised to use with caution; however, there is no evidence to support and may provide analgesia for severe headaches. Furthermore, mechanistic and therapeutic studies are needed for better management of persistent headache along with other symptoms, also known as long COVID or post-acute sequelae SARS-CoV-2 infection.

In acute stage of Lyme disease, many patients have nonspecific symptoms including headache, fatigue, arthralgia, and myalgia. Recent-onset headache occurred in more than half in a study of patient's hospitalization for neurologic Lyme disease; with the majority of these meeting criteria for meningitis or encephalitis with abnormal CSF evaluations [80] . There have been cases published of Lyme disease presenting with Raeder paratrigeminal neuralgia [81, 82] . In the chronic stage, nonspecific symptoms such as persistent headache do not indicate active infection [83] . Persistent headache due to lyme may be difficult to treat and may respond to NSAIDs, anti-depressants, SNRIs, or anti-convulsants. Stabbing headache if present may respond to gabapentin, pregabalin, or NSAIDs.

Headaches are the most commonly reported form of pain among patients with human immunodeficiency virus (HIV) [84] . The etiology of headache in patients with HIV infection may be multifactorial; a secondary etiology for headache can occur at any time during infection. Headache related directly to Fig. 1 Headache attributed to systemic disease is best treated by addressing the underlying disorders and treating headache symptomatically. When headache persists, migraine treatments may be helpful if migraine co-exists or if the phenotype resembles migraine. The description of pain may be useful to guide treatment such as the presence of neuropathic symptoms which may indicate use of anti-convulsants, tricyclic anti-depressants, or serotonin norepinephrine reuptake inhibitors.

the HIV infection includes an acute meningitis seen during seroconversion, during symptomatic HIV, and after an AIDS-defining illness. Alternatively, headache may be a manifestation of an underlying opportunistic process, infectionrelated malignancy, medications used for treatment, and immune restoration inflammatory syndrome [85] . In patients with migraine and HIV, triptans should be used cautiously as they may interact with antiretroviral therapies.

Headache associated with systemic disorder may be due to new-onset headache, an exacerbation of pre-existing headache disorder, or treatment. When treating the systemic disorder does not resolve headache, the treatment approach should be based on the phenotype it most resembles and management of underlying primary headache disorders such as migraine (Fig. 1 ) [25] . Treatment may vary between acute and preventive pharmacological options depending on disability but are considered off label. Lifestyle (physical activity, sleep hygiene, dietary factors) or non-pharmacological interventions such as relaxation therapy, cognitive behavioral therapy, or neuromodulation devices should be considered.

Many complex systemic disorders that are associated with headache are often excluded in clinical trials; real-world studies are needed to determine safe and efficacious treatment options. Overlapping conditions can contribute to increased cumulative disease burden, and treatment of headache may improve outcomes and quality of life. A comprehension approach with coordination of care is essential.

Teshamae Monteith has received personal compensation for serving on advisory boards for Biohaven, Allegan/Abbvie, Lundbeck, Amgen, Teva, and Impel Neuropharmaceuticals. She has also served as a site principal investigator without direct compensation for Teva, Eli Lilly, Electrocore, Amgen, and Novartis. She has received grant support from Abbvie and Amgen and compensation for educational or writing activities from Massachusetts Medical Society, Neurodiem, and Medscape. Alexandra Cocores does not have any conflicts of interest.

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Cardiac cephalalgia: severe, non-exertional headache presenting as unstable angina

Treatment of pheochromocytoma in adults

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