Headaches are one of the most prevalent disorders worldwide, typically affecting more women than men and when recurrent, can be disabling.1,2 While the presentation and underlying causes of headaches are diverse and poorly understood, the International Headache Society (IHS) broadly classifies headaches as either primary or secondary. Primary headaches include symptom-based headaches with examples including migraine, tension-type headache, trigeminal autonomic cephalalgias and cluster headache, whereas secondary headaches — or etiology-based headaches — are often related to a pre-existing condition, such as trauma or injury to the head and/or neck, cranial or cervical vascular disorder, substance use (eg, medication), infection, disrupted homeostasis, or psychiatric disorder.3
The recently updated, third edition (beta version) of the International Classification of Headache Disorders (ICHD-3 Beta) provides a comprehensive update of the different types of headache, the criteria that distinguish them, and key considerations for diagnosis.3 The goal here is to focus on secondary headaches with an underlying etiology related to disorders of homeostasis, particularly in light of recent studies that suggest that headaches associated with homeostasis may predict medical morbidity.
The current nomenclature of headaches attributed to disorder of homeostasis includes headaches that resolve or significantly improve following treatment or spontaneous re-establishment of homeostasis. According to the ICHD-3 Beta, headaches secondary to a disruption of homeostasis include those attributed to hypoxia and/or hypercapnia (ie, high altitude, diving, or sleep apnea), dialysis, arterial hypertension, hypothyroidism, fasting, cardiac cephalalgia, and other factors affecting homeostasis.
Headaches caused by disorder of homeostasis have a significant female preponderance with an estimated lifetime prevalence of approximately 22% of the general population based on limited population-based studies.4,5
Although the underlying pathophysiology of homeostasis-related headaches is not yet clearly defined, the nervous and endocrine systems are thought to be involved through the maintenance of homeostasis. Therefore, dysfunction of the endocrine system may lead to various neurologic manifestations, including headaches.6 In fact, in individuals with prediabetes or established diabetes, one of the early signs of hyperglycemia or hypoglycemia is headache,7 and fewer headaches are associated with tightly controlled diabetes.8
It thus appears that early and effective treatment of endocrine or hormonal imbalance can relieve neurologic symptoms associated with headaches. This then raises the question: Can manifestation of headaches can be regarded as a warning sign for homeostatic imbalance or disorder, similar to acute or chronic pain serving as a warning for body injury? Can homeostasis-related headaches therefore confer a survival advantage? A recent review explored these questions.4
High altitude (or hypobaric hypoxia) headache affects approximately 80% of individuals who ascend to high altitude and is thought to be due to hypoxia-induced changes in cerebral blood flow.9-11 Hypoxia as a trigger for migraine attacks was demonstrated in a randomized, double-blind, sham-controlled study in which a state of hypoxia increased lactate in a specific region of the brain and cranial arteritis.12
With this knowledge, it may be possible to minimize or prevent migraine attacks by better managing a state of hypoxia. Habitual morning headaches may be suggestive of sleep apnea and thus may prompt clinicians to screen for sleep apnea. Morning headaches, however, are associated with other sleep disorders including cervicogenic headache and analgesic-overdose headache.13,14
Headache is common among individuals undergoing hemodialysis. The variables that have been associated as triggers include osmotic encephalopathy, which is thought to be linked to dialysis disequilibrium syndrome; caffeine withdrawal; and electrolyte abnormalities.15,16 These variable can be associated with poor outcomes if not clinically managed. Consequently, dialysis headache may be used as a warning to closely monitor and better treat risk factors associated with hemodialysis, potentially leading to improved outcomes.
The prevalence of headache attributed to hypothyroidism has been shown to be comparable among patients with either subclinical or overt hypothyroidism and with comparable improvement in headache when treated with levothyroxine.17 An association between pain sensitivity, thyroid status, and alteration in serotonin level and regulation have been speculated as underlying pathologic mechanisms.18-20 The latter was demonstrated in rats in which diminished serotonin levels were observed after thyroidectomy.20 Clearly, further research is needed to elucidate the precise role of serotonin in hypothyroidism. These observations and studies suggest, however, that headache may act as a clinical marker to screen for individuals with subclinical hypothyroidism.
The significance of the association of headache with fasting may be a warning for hypoglycemia, caffeine withdrawal or dehydration, since under these circumstances, the headache is resolved with consumption of glucose, caffeine, or water.21 In fact, severe hypoglycemia and dehydration can be fatal, particularly in the elderly or among individuals for whom fasting is integral to religious practices. Under these circumstances, headache can be a warning sign to break a fast to avert poor outcomes.
While evidence is emerging linking headache with disorders of homeostasis, this is complicated by observations and studies that show persistence of headache despite re-establishment of homeostasis. The obvious question that arises is whether an imbalance of homeostasis is one of several causes of the presenting headache. A study reported that despite treatment of hypothyroidism, 21% of patients continued to experience headache 12 months after treatment.17 Confounding conditions such as underlying chronic migraine, sleep apnea, or other conditions that may predispose to headaches may also be present. Clearly, robust research is needed before cause and effect can be concluded with certainty.
Summary and Clinical Applicability
While headaches associated with homeostasis are recognized as a diverse diagnostic category, research that might inform treatment of homeostasis-related headaches is emerging. An improved understanding of the link between headache and homeostasis might allow earlier diagnosis and better management or treatment of conditions that trigger imbalance in homeostasis, thereby circumventing the morbidity and mortality that can result from diagnostic and treatment delays.
- World Health Organization. Headache disorders Fact sheet. Updated April 2016. Accessed January 24, 2017.
- Centers for Disease Control and Prevention. QuickStats: Percentage of Adults Who Had Migraines or Severe Headaches, Pain in the Neck, Lower Back, or Face/Jaw,* by Sex — National Health Interview Survey, 2009. Accessed January 24, 2017.
- Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, third edition (beta version). Cephalalgia. 2013;33(9):629-808.
- Grewal P, Smith JH. When headache warns of homeostatic threat: the metabolic headaches. Curr Neurol Neurosci Rep. 2017;17(1):1.
- Rasmussen BK, Olesen J. Symptomatic and nonsymptomatic headaches in a general population. Neurology. 1992;42(6):1225-1231.
- Yu J. Endocrine disorders and the neurologic manifestations. Ann Pediatr Endocrinol Metab. 2014;19(4):184-190.
- Cherney K. Is diabetes to blame for your headache? Published online May 5, 2016. Available at: http://www.healthline.com/health/diabetes/headache#Overview1. Accessed January 24, 2017.
- Siegel LB, Wang SJ. Headache attributed to disorder of homeostasis. Last updated February 22, 2012. Available at: http://www.medlink.com/article/headache_attributed_to_disorder_of_homeostasis. Accessed January 24, 2017.
- Wilson MH, Davagnanam I, Holland G, et al. Cerebral venous system and anatomical predisposition to high-altitude headache. Ann Neurol. 2013;73(3):381-389.
- Bian SZ, Jin J, Li QN, et al. Hemodynamic characteristics of high-altitude headache following acute high altitude exposure at 3700 m in young Chinese men. J Headache Pain. 2015;16:527.
- Lawley JS, Oliver SJ, Mullins PG, Macdonald JH. Investigation of whole-brain white matter identifies altered water mobility in the pathogenesis of high-altitude headache. J Cereb Blood Flow Metab. 2013;33(8):1286-1294.
- Arngrim N, Schytz HW, Britze J, et al. Migraine induced by hypoxia: an MRI spectroscopy and angiography study. Brain. 2016;139(Pt 3):723-737.
- Alberti A, Mazzotta G, Gallinella E, Sarchielli. Headache characteristics in obstructive sleep apnea syndrome and insomnia. Acta Neurol Scand. 2005;111(5):309-316.
- Chen PK, Fuh JL, Lane HY, Chiu PY, Tien HC, Wang SJ. Morning headache in habitual snorers: frequency, characteristics, predictors and impacts. Cephalalgia. 2011;31(7):829-836.
- Stojimirovic B, Milinkovic M, Zidverc-Trajkovic J, et al. Dialysis headache in patients undergoing peritoneal dialysis and hemodialysis. Ren Fail. 2015;37(2):241-244.
- Goksel BK, Torun D, Karaca S, et al. Is low blood magnesium level associated with hemodialysis headache? Headache. 2006 Jan;46(1):40-45.
- Lima Carvalho MF, de Medeiros JS, Valença MM. Headache in recent onset hypothyroidism: Prevalence, characteristics and outcome after treatment with levothyroxine. [published online July 7, 2016] Cephalalgia. pii: 0333102416658714
- Kakked G, Bhatt N, Lakhani J, Prakash S. Electromyographic evaluation of blink reflex as a tool for early diagnosis of neurological dysfunction in patients of hypothyroidism. Ann Neurosci. 2013;20(3):95-98.
- Yi J, Zheng JY, Zhang W, Wang S, Yang ZF, Dou KF. Decreased pain threshold and enhanced synaptic transmission in the anterior cingulate cortex of experimentalhypothyroidism mice. Mol Pain. 2014 18;10:38.
- Zhang Q, Feng JJ, Yang S, Liu XF, Li JC, Zhao H. Lateral habenula as a link between thyroid and serotoninergic system modiates depressive symptoms in hypothyroidism rats. Brain Res Bull. 2016;124:198-205.
- Torelli P, Manzoni GC. Fasting headache. Curr Pain Headache Rep. 2010;14(4):284-291.