Clinical Case

A 26-year-old woman with history of multiple concussions developed orthostatic lightheadedness and frequent syncopal events. Concurrently, she also developed a constant, low-grade headache with migrainous features and significant worsening in the upright position that improved while supine. Autonomic reflex screen demonstrated postural tachycardia along with a hypertensive response to tilt; this suggested a hyperadrenergic state which was corroborated by standing and supine catecholamine testing. She was diagnosed with hyperadrenergic POTS. Additional lab evaluation for causes of a hyperadrenergic state and POTS mimics or exacerbating conditions demonstrated two elevated urine mast cell markers in a 24-h collection. She achieved adequate control of POTS-related symptoms with a regimen of nadolol, gabapentin, midodrine, famotidine, fexofenadine, and cromolyn in addition to lifestyle measures. However, headache persisted, including the strong orthostatic phenotype despite improvement in other orthostatic symptoms. Neuroimaging did not demonstrate signs of intracranial hypotension or epidural fluid collection, but due to clinical symptoms, an empiric lumbar blood patch was performed. This resulted in significant improvement in headache. Her daily, constant headache resolved, and acute attacks were less severe.

Introduction

Autonomic dysfunction is at the forefront of the pathogenesis of multiple primary and secondary headache disorders. The central autonomic network, as well as peripheral sympathetic and parasympathetic efferents, is responsible for generating headache and cranial autonomic symptoms (CAS) in migraine and cluster headache. Additionally, more widespread systemic autonomic dysfunction may be present in those with primary headache disorders. Other disorders of systemic autonomic dysfunction that result in orthostatic intolerance are also associated with unique headache syndromes. This paper will discuss the pathophysiology involving central and peripheral autonomic pathways in primary and secondary headache disorders with an emphasis on recent findings and advancements in understanding the complex interconnection.

To adequately discuss these topics, a review of the baroreflex and trigeminovascular systems is necessary. The baroreflex maintains perfusion of blood to the brain when the body is upright by modulating heart rate, blood pressure, and vascular tone. The afferent arm of the baroreflex is modulated by stretch mechanoreceptors in the carotid sinus and aortic arch which are innervated by the glossopharyngeal and vagus nerves, respectively, and synapse at the nucleus tractus solitarius (NTS) in the medulla [1, 2]. The efferent portion of the baroreflex has three main components. When blood pressure is elevated, the stretch mechanoreceptors are activated which results in downstream stimulation of the NTS and activation of inhibitory interneurons that synapse at the caudal ventrolateral medulla. This ultimately modulates the rostral ventrolateral medulla, which inhibits sympathetic activity and results in vasodilation [1, 2]. Bradycardia is also induced by a connection between the NTS and preganglionic vagal cardiac ganglion cells in the nucleus ambiguus [1, 2]. A third efferent mechanism regulates the supraoptic and paraventricular hypothalamic nuclei via inhibition of noradrenergic cells in the medullarly reticular formation, ultimately inhibiting vasopressin release [1, 2]. Low blood pressure results in decreased stimulation of stretch mechanoreceptors and increased sympathetic outflow causing vasoconstriction of splanchnic and skeletal muscle and tachycardia [1, 2]. Damage or dysfunction along this pathway can result in labile blood pressures and headache. The vestibular sympathetic reflex may also contribute to cardiac and vascular tone via projections to the rostral and caudal ventrolateral medulla, as seen in several animal studies [3,4,5], and is triggered by position change. When there is dysfunction along the vestibular sympathetic pathway, a change in posture can lead to vasovagal syncope with bradycardia and hypotension [6].

Another important pathway involving the autonomic nervous system and generation of headache is the trigeminovascular system. The trigeminovascular system is connected to the trigemino-autonomic reflex which mediates CAS in migraine and trigeminal autonomic cephalalgias (TACs). CAS include lacrimation, conjunctival injection, ptosis, eyelid swelling, nasal congestion or rhinorrhea, facial sweating, and ear fullness. During a headache attack, pain-sensing trigeminal afferent neurons innervating the meninges, meningeal blood vessels, large intracranial blood vessels, and dural venous sinuses originating from the ophthalmic branch of trigeminal nerve (V1) are activated, and together with pain-sensing afferents of the dorsal horn of C1 and C2, synapse at the trigeminocervical complex (TCC) in the brainstem [7, 8]. Neurons from the TCC project to the superior salivatory nucleus in the pons where preganglionic parasympathetic neurons are activated and travel with cranial nerve VII, particularly the greater petrosal nerve, and synapse in the sphenopalatine ganglion [7]. Postganglionic parasympathetic fibers then leave the sphenopalatine ganglion and act on the lacrimal glands, nasal, and palatal mucosa resulting in lacrimation, nasal congestion, or rhinorrhea [7]. The parasympathetic efferents also project to the meninges and intracranial arteries releasing calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide-38 (PACAP-38) causing vasodilation and mast cell degranulation which further perpetuate pain [9].

While the parasympathetic nervous system is dominant in the generation of headache and many cranial autonomic symptoms, activation of the sympathetic nervous system is also thought to be pro-nociceptive [9]. As it relates to CAS, postganglionic sympathetic fibers traveling as a plexus around the internal carotid artery may become compressed due to perivascular edema from neurogenic inflammation in the cavernous sinus during migraine or TAC attacks. This results in miosis and/or ptosis due to sympathetic hypofunction, although increased parasympathetic tone may also play a role [10, 11].

While CAS are predominantly generated by peripheral efferents of the autonomic nervous system, the TCC also sends projections to several brainstem nuclei that are part of the central autonomic network including the locus coeruleus, raphe nucleus, and periaqueductal gray, as well as the thalamus, hypothalamus, and the cortex for pain processing and perception which subsequently exert a descending modulation on the TCC [7, 8, 12]. In migraine, the periaqueductal gray, locus coeruleus, and raphe nucleus modulate cerebral blood flow, intensity of sensory phobias, pain signaling, and cortical hyperexcitability [7].

Autonomic Dysfunction in Primary Headache Disorders

Migraine

The premonitory and headache phases of migraine are innately connected to the central and peripheral autonomic network. While the connection to the autonomic nervous system during the headache phase is discussed above, Dodick describes a state of increased parasympathetic tone in the hypothalamus during the premonitory phase that is triggered by disruptions in homeostasis (altered sleep wake cycles, emotional stress, etc.) and activates pre-ganglionic parasympathetic neurons in the superior salivatory nucleus. From there, post-ganglionic parasympathetic neurons release pro-inflammatory and vasodilatory neuropeptides triggering activation of meningeal nociceptors [8, 9]. Functional MRI studies have confirmed activation of the hypothalamus and central autonomic network during the premonitory phase of migraine as well as enhanced connections between these areas interictally [13, 14].

Cranial autonomic symptoms are known to occur in the premonitory and headache phases of migraine with a variable prevalence of 27–82% [15,16,17,18,19,20,21] although several recent studies examined only unilateral symptoms, likely leading to underreporting [15,16,17]. CAS have been associated with more severe attacks when unilateral [15,16,17], prolonged attacks [15, 21] and are associated with increased functional disability [20]. Some studies have also reported increased association of CAS with symptoms suggesting central sensitization, such as photophobia [15], phonophobia [21], and allodynia [15] though there is significant variability in design and data collection across these studies. Compared to cluster headache, CAS in migraine have been reported to be more likely bilateral, mild-to-moderate severity, and inconsistent from one attack to the next [19]. In a recent cross-sectional study of 373 episodic and chronic migraine patients in Japan, 42.4% reported at least one CAS and those with CAS had more severe attacks, allodynia, phonophobia and, possibly unique to this population, osmophobia [22]. Furthermore, more than half reported bilateral CAS [22]. A cross-sectional study of 904 patients in Iran reported that 56.2% of participants with episodic migraine and 70% of those with chronic migraine had CAS [23]. Similar to previous studies, unilateral headache and increased severity were more prevalent in those with CAS, but investigators also found chronic migraine, blurred vision, and increased headache frequency were more prevalent in migraine with CAS [23]. Friedman and Evans have proposed that blurred vision may be a symptom of autonomic dysfunction due to imbalance in sympathetic and parasympathetic signaling resulting in dry eye [24]. Togha et al. reported blurred vision in 17.9% of participants and the proportion was significantly higher in those with CAS [23], which may support the above proposed hypothesis.

Several studies have further investigated autonomic function in migraine by examining changes in the eyes. In a recent prospective study of 24 episodic migraine patients and 24 controls, smaller pupil size was found ictally (consistent with previous studies [25,26,27]) along with significantly increased accommodative response during attacks, both of which suggest sympathetic hypofunction [28]. In another study of 36 patients with migraine (chronic, episodic, and probable), those with migraine and lower photophobia threshold showed smaller dark-adapted pupils interictally suggesting sympathetic hypofunction. However, at the photophobia threshold they found larger pupil size suggesting mixed autonomic dysfunction [29]. Impairment of parasympathetic pupillary constriction latency and sympathetic pupillary re-dilation was also noted and correlated with more severe migraine disease, further supporting mixed sympathetic and parasympathetic dysfunction in those with migraine [29]. Cortez et al. studied pupillary cycle time, which assesses sympathetic and parasympathetic pathways to the eye, as a potential biomarker for migraine [30]. Pupillary cycle time is tested by shining light on the edge of the pupil with subsequent parasympathetically driven constriction outside the margin of the light. Once outside the margin of the light, the pupil dilates via sympathetic activation back within in the margin of the stimulus [30]. A fixed number of cycles are completed and the time to completion was recorded. Significantly prolonged pupil cycle time in subjects with probable, episodic, and chronic migraine was found compared to controls which again suggests mixed cranial sympathetic and parasympathetic dysfunction. A positive correlation between prolonged pupil cycle time and number of CAS in all types of migraine types was also identified [30]. Measurement of pupillary cycle time may prove to be a noninvasive way of diagnosing migraine when the clinical presentation is unclear. In the future, it would be of interest to know if pupil cycle time could also differentiate between other primary headache disorders with CAS.

Visceral symptoms, such as nausea, vomiting, constipation, diarrhea, stomach fullness, bloating, belching, frequent defecation, and frequent urination also occur in various phases of migraine [31] and are at least in part due to autonomic dysfunction. Connections between the vagus nerve and the NTS provide much of the autonomic basis for gastrointestional symptoms experienced in migraine, though the pathophysiology is likely more complex and includes alterations in serotonergic signaling and effects of inflammatory neuropeptides [32]. A prospective, cross-sectional study of 605 patients with migraine (including episodic, chronic, and with/without aura) found those with visceral symptoms had more prolonged and severe attacks and those without aura had higher prevalence of visceral symptoms during all phases of migraine [33]. Visceral symptoms were most prevalent ictally (71%), yet 52% of participants had at least one symptom during the premonitory phase and 36% after the attack [33].

Table 1 outlines the cranial and systemic autonomic symptoms and diagnostic findings in migraine as well as the other primary and secondary headache disorders described below.

Table 1 Cranial and systemic autonomic symptoms and corresponding diagnostic findings of select headache and autonomic disorders. N/A, information not available
Full size table

Cluster Headache

The posterior hypothalamus is an initiator and modulator of cluster headache, as demonstrated by PET imaging studies showing activation in the ipsilateral posterior hypothalamus in nitroglycerin-induced attacks [34]. Additional brainstem nuclei, such as the locus coeruleus, raphe nucleus, and periaqueductal gray (PAG) also play a role in the pathophysiology of cluster headache by regulating pain input and vascular tone similar to migraine [14, 35]. Activation of the trigeminal autonomic reflex as discussed previously is the basis for CAS experienced during TAC attacks and the distribution of pain is attributed to involvement of the trigeminovascular system [11].

In addition to CAS, systemic autonomic dysfunction may be present in cluster headache, but studies thus far have demonstrated inconsistent findings likely due to variability of study designs. Additionally, various tests are unable to be performed during an acute cluster headache attack due to the debility experienced by the patient. Barloese performed a narrative review of 22 studies focusing on cardiovascular autonomic changes in cluster headache and suggested there may be increased parasympathetic tone and reduced sympathetic tone during cluster attacks along with subclinical autonomic dysfunction interictally [36]. The studies were grouped into those that evaluated cluster headache by ECG and Holter monitoring, those using specific tests of the autonomic nervous system (Valsalva, head up tilt, etc.), and those utilizing spectral analysis and measurement of baroreflex sensitivity, although there was overlap between measurements used in several of the studies. It is not noted if all studies were performed during an active cluster phase. While this review provides a much-needed summary of studies investigating systemic autonomic dysfunction in cluster headache, clear conclusions could not be made from the data gathered. Following the review by Barloese in 2016, a prospective study of 19 subjects with cluster headache demonstrated prolonged latency of skin responses on the affected side of the face interictally, suggesting local (post-ganglionic) sympathetic hypofunction [37]. Standardized testing and study designs are needed to further elucidate the relationship of systemic autonomic dysfunction and cluster headache.

More recent studies have attempted to increase knowledge about the associated symptoms in cluster headache in a standardized manner. Wei and Goadsby conducted a single-blind, placebo-controlled, cross-over study of nitroglycerin-induced attacks in 24 patients with episodic and chronic cluster headache [38]. In the blinded arm, CAS were induced in 84% of participants and the most common CAS were nasal congestion, lacrimation and conjunctival injection [38]. CAS were experienced by 58% prior to the headache and 16% during the headache [38]. Findings were similar to previous studies with the most common CAS being nasal congestion/rhinorrhea in 41–89%, lacrimation in 59–91%, and conjunctival injection in 41–72% [39,40,41,42,43,44]. Snoer et al. also conducted a prospective diary study comparing retrospective attack descriptions of 57 episodic and chronic cluster subjects [45]. In this study, the most common reported CAS in prospective descriptions included lacrimation and conjunctival injection [45]. They also reported a high prevalence of migrainous symptoms similar between retrospective and prospective reports, although these symptoms were reported more by women than men [45]. Women also reported longer and more severe intensity which is important to highlight as women may be misdiagnosed with migraine based on these symptom descriptions [45].

Given frequently overlapping symptoms with migraine and other TACs, identifying physiological tests to assist in diagnosis is also needed. A recent study examined digital voice records and video laryngostroboscopy of male subjects with cluster headache (n = 20) and hemicrania continua (n = 13) [46]. They found significantly lower second harmonic values in cluster headache subjects during an attack manifested by a “creaky voice” along with significantly higher mild-to-moderate vocal cord edema and laryngopharyngeal reflux [46]. The findings were proposed as extracranial manifestations of autonomic dysfunction in cluster headache with disrupted vagal tone allowing relaxation of the esophageal sphincter and laryngeal edema [46].

Secondary Headache due to Systemic Autonomic Dysfunction

Orthostatic intolerance is a broad term to describe conditions associated with an inability to tolerate upright posture due to symptoms of lightheadedness, near fainting, cognitive impairment, headache, fatigue, nausea, palpitations, weakness, tremulousness, and others [6, 47]. Orthostatic hypotension, reflex syncope, and postural orthostatic tachycardia syndrome (POTS) are included under the umbrella of orthostatic intolerance.

Orthostatic Hypotension

Orthostatic hypotension is defined as persistently decreased systolic blood pressure of at least 20 mm Hg and diastolic blood pressure of 10 mm Hg from baseline within 3 min after standing with resultant lightheadedness, weakness, headache, neck pain, or cognitive symptoms [48]. Potential etiologies include hypovolemia, medications, cardiac disorders, and autonomic dysfunction [6]. Headache associated with orthostatic hypotension has been described as a dull ache with variable intensity in a coat-hanger distribution involving the cranium, occiput, neck, and shoulders that is provoked shortly after sitting or standing and improves after lying down [6, 49,50,51]. In a study comparing orthostatic hypotension in pure autonomic failure (PAF) and multiple system atrophy (MSA), the greater degree of orthostatic hypotension correlated positively with frequency of neck pain [50]. Ischemia of the neck muscles has been the main hypothesis for headache in orthostatic hypotension [50]. However, others have suggested a more complex interplay of activation of nociceptive pathways in the posterior fossa, epidural hypotension, and decreased headache threshold as a result of vagal dysfunction [6, 51].

Orthostatic hypotension is also seen in baroreflex failure, a condition that occurs due to damage or dysfunction anywhere along the afferent pathway from the stretch mechanoreceptors to the level of the medulla resulting in labile blood pressures. Additional symptoms include palpitations, flushing, diaphoresis, and findings of episodic tachycardia or bradycardia [1]. It is most often secondary to damage of carotid baroreceptors in the neck by radiation, surgery, or trauma but can also occur due to brainstem lesions, sensory neuropathies, or may be idiopathic [1]. Headache in baroreflex failure can occur during hypo- or hypertensive episodes though specific headache characteristics and frequency are not well defined.

Reflex Syncope

Reflex syncope, described as spontaneous cerebral hypoperfusion with resultant transient loss of consciousness and postural tone followed by recovery [6], is also associated with headache. It is caused by transient baroreceptor dysfunction that triggers abrupt sympathetic hypofunction brought on by strong emotion or prolonged orthostasis [6]. However, the underlying mechanism for this sudden change in an otherwise normal functioning baroreflex is not fully understood. A case–control study of 16 adolescents with history of headache and syncope were evaluated during tilt-table testing and those who experienced syncope and postictal headache were found to have a larger pulsatile cerebral blood flow velocity during and after the tilt-table test [52]. Authors hypothesized that postsyncopal headache may be due to the wide fluctuation of blood flow which triggers nitric oxide release with downstream release of CGRP and activation of trigeminal nociceptors [52].

Autonomic Dysreflexia

Headache secondary to autonomic dysreflexia is characterized as sudden-onset severe headache in patients with spinal cord injuries (SCI) at or above T6 when systolic pressure is ≥ 30 mm Hg and/or diastolic pressure is ≥ 20 mm Hg from baseline [53]. The headache is often described as throbbing with radiation to the neck and may be unilateral or bilateral [54]. Headache as the presenting symptom ranges from 56 to 89% [55, 56]. Autonomic dysreflexia is a result of impaired communication between the sympathetic and parasympathetic systems above and below the level of the SCI [57]. The pathophysiology of headache in autonomic dysreflexia has not been determined but may be due to dilation of cerebral vessels secondary to increased prostaglandin E2 [54, 58], which activates the trigeminovascular pathway [58, 59].

Postural Orthostatic Tachycardia Syndrome

Postural orthostatic tachycardia syndrome (POTS) in adults is defined as sustained, excessive tachycardia of ≥ 30 beats per minutes (≥ 40 beats per minute in pediatric subjects) within 10 min on head-up tilt table test (HUTT) without orthostatic hypotension [48]. POTS is a heterogenous disorder associated with other conditions including but not limited to connective tissue and autoimmune disease [59]. Similarly, other conditions may mimic POTS such as anemia, thyroid dysfunction, mastocytosis, and adrenal dysfunction [59]. Symptoms include but are not limited to dizziness, lightheadedness, presyncope, and palpitations; many patients also experience fatigue and “brain fog” [59]. Headache in patients with POTS has a reported prevalence of 41–96% including primary headache disorders such as migraine and secondary headache disorders such as spontaneous intracranial hypotension (SIH) [60,61,62,63,64]. Consistent with previous findings [61, 64], headache was the most commonly reported neurological co-morbidity in a recent pediatric retrospective study of 134 patients with POTS. Migraine was reported in 43% of patients followed by 22% with nonspecific headache, 14% with chronic daily headache, and 4% with new daily persistent headache. Interestingly, orthostatic headache was only reported by 2% [65]. In another pediatric study of 112 predominantly female participants with orthostatic intolerance and abnormal HUTT, headache was the second most common presenting symptom (46%) [66]. While the relationship between primary headache disorders and POTS is not fully understood, Ojha et al. hypothesized that the high prevalence of pain syndrome comorbidities like migraine may be due to dysregulation at the level of the brainstem including the raphe nuclei or the locus coeruleus [61]. Although there is still a lot of work to be done to understand POTS and its associated co-morbidities, we tend to agree that at least part of the answer may be in the brainstem where there is overlap of key structures involved in both migraine and autonomic regulation.

POTS and SIH can both present with orthostatic or postural headache without findings of arterial hypotension. The similar presentations can be difficult to differentiate, and to complicate the matter further, POTS and SIH can co-occur. The connection between SIH and POTS is unclear, but theories include deconditioning and reduction in venous return to the inferior vena cava leading to epidural venous hypotension [67, 68]. If examined within the context of hypovolemia, a known mechanism of POTS, the epidural venous hypotension theory may offer a connection between the disorders [69, 70]. If there is low pressure in the inferior vena cava, due to a hypovolemic state, the pressure gradient will drive the flow of spinal fluid to the epidural space and veins resulting in reduced CSF volume [68]. Franzini et al. suggested that SIH may be due to aspiration of spinal fluid at arachnoid diverticula in those with predisposed weakness of the dura rather than an actual tear in the dura. This may explain normal imaging results frequently encountered in patients with orthostatic headache, as described in the clinical case above [68]. This theory for orthostatic headache is further supported by the increased prevalence of connective tissue disorders in POTS, such as joint hypermobility and Ehlers-Danlos syndrome (12–39%) [71,72,73], which increases the risk of SIH [74]. Another study of 113 pediatric patients with POTS and orthostatic hypotension hypothesized that cerebral hypoperfusion may be a potential cause of orthostatic headache based on findings of decreased cerebral oxygenated hemoglobin level on infrared spectroscopy oximetry more prominently in those with orthostatic headache on active stand testing [75].

While postural headache is common to POTS and SIH, other headache characteristics are more variable among the disorders. In a prospective study of 24 patients with POTS, 14 patients (58%) described orthostatic headache as frontal or holocranial with pressure-like or throbbing quality and moderate-to-severe intensity. [62]. Twenty-three subjects (96%) reported non-orthostatic headache, 20 of which met migraine criteria and 3 for probable migraine [62]. In a systematic review of 33 studies with 1694 subjects with SIH, headache was the most frequent reported symptom (97%) of which 92% were orthostatic [76]. Compared to orthostatic headache in POTS, headache in SIH was occipital, holocranial, and frontal with associated symptoms of nausea/vomiting, neck pain/stiffness, dizziness, hearing disturbances, tinnitus, hyperacusis, and aural fullness [76]. In a retrospective study comparing 9 patients with SIH and 48 patients with POTS, orthostatic headache was present in all with SIH and in 27% of those with POTS. Additionally, all patients with SIH had excessive tachycardia on HUTT meeting criteria for POTS [77]. Overall, orthostatic headache seems to be more prominent in SIH. One small study utilized transorbital ultrasound to help differentiate the two disorders and compared differences in optic nerve sheath diameter in upright and supine position in those with POTS with (n = 7) or without orthostatic headache (n = 7) and those with SIH (n = 8). They found a decrease in optic nerve sheath diameter during orthostatic stress in SIH, but not in POTS [78]. While no significant conclusions can be made, it highlights the need for additional non-invasive tests to differentiate these disorders.

Posttraumatic Headache

Autonomic dysfunction is a known complication of traumatic brain injury (TBI) but understanding the extent of dysautonomia is limited due to variability of autonomic testing, patient populations, and severity of TBI. Autonomic dysfunction in these patients is likely due to microscopic axonal shearing and subsequent uncoupling of the sympathetic and parasympathetic nervous systems as well as dysregulation of cerebral blood flow [79, 80]. In a cross-sectional cohort study examining subjects with persistent posttraumatic headache (PPTH) and migraine compared to controls, autonomic symptom burden was assessed using the COMPASS-31 questionnaire (a survey of gastrointestinal, vasomotor, secretomotor, orthostatic intolerance, bladder, and pupillomotor symptoms) [81]. Those with PPTH had significantly higher scores in all domains, particularly in orthostatic intolerance and bladder domains, compared to those with migraine and controls. In post hoc analyses, there was a positive relationship between total COMPASS-31 scores and number of lifetime TBIs [81]. The patients in this study did not undergo autonomic reflex testing [81]. Table 1 further outlines cranial and systemic autonomic findings in PTH and post-concussive syndrome though findings are limited by variable methodology across studies.

Conclusion

Migraine and cluster headache are innately connected with the autonomic nervous system. This connectivity is demonstrated by the presence of cranial autonomic symptoms as well as extracranial manifestations that involve the vocal cords, cardiovascular system, and GI tract. While there may be reduced systemic sympathetic tone in migraine and cluster headache, results of autonomic testing have been variable, and mixed systemic sympathetic and parasympathetic dysfunction are likely at play. With more time and understanding, standardized measurements of the clinical manifestations of autonomic dysfunction in primary headache disorders may improve diagnostic accuracy. Secondary headache in orthostatic hypotension, autonomic dysreflexia, POTS, and SIH is incredibly common, but the headache phenotype is variable. The mechanism of headache in these disorders is continuing to be characterized, but hypovolemia and weakened connective tissue may play a role in headache associated with POTS and SIH. Future research will benefit from standardized autonomic testing to further characterize systemic autonomic dysfunction and identify additional biomarkers that may assist in diagnosis overlapping headache and autonomic disorders.