Headache in Dysautonomia & “Long COVID”/PASC

Autonomic Disorders

Headache is a common symptom of autonomic disorders (also termed dysautonomia) and long COVID, which is also known as post-acute sequelae of SARS-CoV-2 infection (PASC). Dysautonomia refers to dysfunction of the autonomic nervous system (ANS) and encompasses a wide variety of defined autonomic disorders. The most common autonomic disorders are postural orthostatic tachycardia syndrome (POTS), neurocardiogenic syncope (NCS) (also known as vasovagal syncope), and orthostatic hypotension (OH). Diagnostic criteria for POTS, NCS, and OH are outlined in Table 1.^1,2 Orthostatic intolerance (OI) is the hallmark of the common autonomic disorders and is also a diagnostic term used when objective tests do not confirm diagnosis of a common autonomic disorder in a clinical setting of symptoms precipitated by an upright position and relieved by recumbency.

There are many clinical features of common autonomic disorders, which typically include OI, lightheadedness/dizziness, palpitations, syncope, presyncope, headache, fatigue, and cognitive complaints (commonly referred to as “brain fog”). The ANS comprises the sympathetic, parasympathetic, and enteric nerves and is responsible for numerous physiologic functions, including cardiovascular control of heart rate and blood pressure, gastric motility and secretion, bladder function, respiration, temperature control, and distribution of blood flow to all organs and tissues. The ANS also mediates the “fight or flight” response to both external and internal stimuli in order to maintain homeostasis.³ There is evidence that ANS is involved in the process of inflammation, whereas the vagus nerve, which carries the parasympathetic nervous system output, is a major constituent of the inflammatory neural reflex, which controls innate immune responses and inflammation during pathogen invasion and tissue injury.⁴ Sympathetic overactivity may be associated with a proinflammatory state, whereas increased parasympathetic activity may have anti-inflammatory properties.⁵

Long COVID/PASC

Although many people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recover completely, a significant number of people who had COVID-19, the disease caused by SARS-CoV-2 infection, have long-lasting symptoms and signs persisting for at least 4 weeks. These long-lasting symptoms are commonly referred to as long COVID, postCOVID, or long-haul COVID and are termed by the National Institutes of Health as PASC.⁶ The Centers for Disease Control and Prevention define postCOVID conditions as the wide range of health consequences present 4 or more weeks after infection with SARS-CoV-2,⁷ and the World Health Organization (WHO) refers to postCOVID conditions as those occurring in individuals with confirmed or suspected SARS-CoV-2 infection, usually within 3 months of the acute COVID-19 episode, that last for at least 2 months and cannot be explained by an alternative diagnosis.⁸

PASC can present with a variety of nonspecific symptoms and signs that closely resemble those of dysautonomia,⁹ including but not limited to, OI, palpitations, tachycardia, syncope, presyncope, OH, labile blood pressures, dizziness, fatigue, and exercise intolerance.⁹ The most common autonomic diagnosis associated with PASC appears to be POTS, which is often triggered by a viral infection.^10,11 Neurologic manifestations of PASC commonly include headache, cognitive impairment, neuropathic pain, and sleep disturbance. Gastrointestinal dysfunction and allergic symptoms suggestive of mast-cell activation, are also common. Although the mechanisms of PASC and postCOVID autonomic dysfunction are still being investigated, several possible etiologies have been suggested including autoimmunity, inflammation, immunologic T-cell changes, endothelial dysfunction, prothrombotic state, mast cell activation, and small fiber neuropathy.^12-16

Epidemiology & Etiology

Before the COVID-19 pandemic, many millions in the US had autonomic disorders, with approximately 500,000 to 3 million, including 1 in 100 teenagers living with POTS.¹⁷ The prevalence of POTS and other common autonomic disorders, however, has become significantly higher due to millions of people developing postCOVID autonomic disorders as part of PASC. At least 80% of persons with POTS are women, age 15 to 50 years, but POTS is also seen in people under age 12 years and over age 50. Although POTS is characterized by orthostatic tachycardia and OI, neurologic symptoms (eg, headache, fatigue, dizziness, cognitive dysfunction, and sleep disturbances) are highly prevalent. Headache, specifically migraine, is the most common comorbidity of POTS, present in at least 40% of cases.¹⁸

The pathophysiology of POTS is thought to be hetero-geneous and traditionally classified as neuropathic, hypo-volemic, and hyperadrenergic although for many, these subtypes may be arbitrary and not mutually exclusive.¹⁹ POTS and migraine share some overlapping clinical features, including autonomic symptoms and signs, and both may be viewed as central nervous system (CNS) disorders with shared pathophysiology that may involve neuroinflammation and activation of the central autonomic networks.²⁰ Recently, autoimmunity emerged as a major mechanism of POTS, considering findings that people with POTS have a higher prevalence of nonspecific autoimmune markers and comorbid autoimmune disorders compared with the general population.²¹ More specific to the autonomic nervous system, antibodies to ganglionic N-type and P/Q type acetylcholine receptors; α1, β1, and β2 adrenergic receptors; muscarinic M2 and M4 receptors; angiotensin II type 1 receptors; and opioid-like 1 receptors have been identified in persons with POTS,²⁰ suggesting that various autoantibodies could play a role in the pathophysiology of POTS.

It is unknown how many people in the US are living with PASC, but estimates range from 7% to 87% among those who had SARS-CoV-2 infection.^22-24 Estimates in the UK suggest that, as of February 2022, 2.1% of the UK population has been experiencing persistent symptoms for at least 4 weeks after SARS-CoV-2 infection.²⁵

Because headache is a common symptom of autonomic disorders and PASC, neurologists and other headache specialists encounter a significant number of persons with autonomic disorders and PASC when they present for evaluation of headache in conjunction with other neurologic and nonneurologic complaints. Identification, diagnosis, and treatment of autonomic disorders in people with headaches are essential to providing comprehensive care and reducing the symptom burden and functional impairment in individuals with headaches who may have comorbid dysautonomia.

PASC-Associated Headache & Autonomic Dysfunction

Although studies on persistent headache characteristics attributed to COVID-19 are not yet available, clinical observations by neurologists indicate many different headache types are present, some with migraine-like features.²⁶ Studies have found SARS-CoV-2 proteins in trigeminal nerve branches and the trigeminal ganglion, raising a possibility of acquired activation of the trigeminovascular system by SARS-CoV-2 infection.^27,28

Isolated case reports and 2 large case series of new-onset ANS disorders after COVID-19 have been reported, and autonomic dysfunction appears to be one of the underlying mechanisms of PASC in general.^29,30 In a series of 20 cases of postCOVID POTS and other autonomic disorders, there was a history of occasional autonomic symptoms (eg, dizziness, syncope or palpitations) in 30%, remote history of concussion in 20%, and a history of preexisting migraine in 15%.¹⁰ Persons with a history of migraine who recovered from severe COVID-19 were found to have more long-term fatigue, but not headache, as postCOVID sequelae than those without a history migraine.³¹ Headache at the onset of acute COVID-19 was associated with a previous history of migraine and development of persistent postCOVID tension-type-like headache and fatigue.³² Studies on pathophysiology and risk factors for PASC are ongoing, and clinical experience suggests that a preexisting history of migraine, minor autonomic symptoms, or concussion—another known trigger of dysautonomia—might be possible risk factors for PASC-associated autonomic disorders and headache. Because randomized controlled therapeutic trials are not yet available to guide treatment choices or decisions, the general approach to PASC is to treat postCOVID headache as the primary headache it most closely resembles (eg, migraine, tension-type, or cervicogenic headache phenotypes) and to treat postCOVID autonomic symptoms with the treatment approach for common autonomic disorders. The choice to initiate preventive therapies for postCOVID headache can be based on overall headache frequency, severity, presence of other PASC-associated symptoms, and principles of shared decision-making.

Diagnosing Dysautonomia

Diagnosis of common autonomic disorders begins with clinical suspicion and recognition of key features in people with headache. OI is the hallmark of common autonomic disorders, and since the ANS can affect multiple organs and body systems, a thorough history, review of systems, and physical exam are needed to identify whether an autonomic disorder is present and which symptom domains it affects.

Although some patients may endorse OI symptoms, many with headache do not when they present with a multitude of various complaints involving numerous organ systems and what may appear to be vague nonspecific complaints. It is important for neurologists to elicit a history of OI with targeted questions, such as:

• Do you have any difficulty standing or walking?
• Do you feel dizzy when you stand up?
• Do you feel that your heart is racing when you stand?
• Do your symptoms change when you are standing compared with lying down?

Physical examination in patients with autonomic disorders may demonstrate acrocyanosis (a purple-bluish discoloration of the extremities, likely caused by blood pooling and skin cyanosis), dry skin, or dry mouth. The neurologic exam may reveal dilated pupils poorly reactive to light and decreased temperature and pain sensation in the distal lower extremities compatible with small fiber neuropathy, which is comorbid with POTS. A 10-minute stand test with heart rate and blood pressure measurements obtained in the supine and standing positions after standing for 3, 5, 7, and 10 minutes should be done by a health care professional and is a part of the diagnostic criteria (Table 1). If a 10-minute stand test is negative or inconclusive, a tilt table test can be obtained to diagnose common autonomic disorders.

The Box lists clinical scenarios common in headache clinics that should prompt investigation for possible comorbid autonomic disorders.

Diagnostic Testing

Diagnosis of common autonomic disorders relies on thorough history, physical exam, and orthostatic heart rate and blood pressure measurements obtained from a 10-minute stand test performed at bedside. When a 10-minute stand test is negative or inconclusive and suspicion for an autonomic disorder is high, obtaining a tilt-table test to confirm a diagnosis of POTS, NCS or OH, is recommended. A tilt-table test is performed at 60 to 70 degrees of tilt for at least 10 minutes using plethysmographic blood pressure and heart rate monitoring for continuous beat-to-beat assessment during head-up tilt. If possible, withdraw all medications that may affect heart rate and blood pressure for at least 4 half-lives before the tilt-table test to minimize blunting of the vital signs. A tilt-table test is also useful to delineate the etiology of undiagnosed episodes of altered consciousness or awareness and may be helpful in differentiating anoxic reflex syncope from epilepsy and psychogenic nonepileptic seizures. The tilt-table test has up to 90% specificity and 32% to 85% sensitivity for syncope and is recommended for evaluation of POTS, NCS, OH, and psychogenic pseudosyncope by the European Federation of Autonomic Societies and the European Academy of Neurology and is also endorsed by the American Autonomic Society, when the initial assessment does not yield a definite or highly likely diagnosis.³³

If there is suspicion for an uncommon autonomic disorder not listed in Table 1, or if there is a need to further quantify the extent of the ANS involvement, other autonomic function tests (eg, deep breathing, Valsalva maneuver, quantitative sudomotor axon reflex test (QSART), thermoregulatory sweat test, and a skin biopsy for evaluation of small fiber neuropathy) may be obtained.³⁴ These tests can be very valuable and informative for diagnostic purposes, but access and availability of autonomic laboratories equipped to perform these tests are limited, presenting a significant barrier to diagnostic evaluation for people with suspected autonomic disorders.

In addition to MRI of the brain for evaluation of headache, other diagnostic testing that can be considered in patients with suspected autonomic disorders is EMG to rule out large-fiber neuropathy; a sleep study for possible sleep disorder; gastric emptying and motility testing to assess for gastroparesis; urodynamic tests to evaluate for neurogenic or overactive bladder; genetic tests to rule out classical and vascular Ehlers-Danlos syndrome (EDS), and serum and urine mast cells mediators for suspected mast cell activation syndrome.³⁴ Because POTS has a strong autoimmune basis, evaluation for autoimmune and inflammatory disorders should be considered.^20,34

Management of Dysautonomia

Therapeutic approaches to autonomic disorders include nonpharmacologic and pharmacologic treatment modalities aimed at reducing symptom severity and functional impairment. Nonpharmacologic treatment consists of increased fluid intake of at least 2.5 L/day and salt (sodium chloride) consumption of at least 7 g/day via diet and/or supplemental sodium chloride.³⁵ Compression garments (eg, waist-high stockings and abdominal binders) can be effective.³⁵ Avoiding dehydration, heat, prolonged sitting or standing, and medications that can exacerbate orthostatic symptoms is advised. A supine or sitting exercise program (eg, swimming, recumbent bike or a rowing machine) is encouraged, but pacing and slow incremental increases in exercise need to be considered because many persons with autonomic disorders have significant exercise intolerance and postexertional malaise. Importantly, for many, nonpharmacologic therapy alone may be insufficient to improve symptoms, and medications may be required.

Pharmacotherapy (Table 2) includes first-line medications, including β-blockers, which decrease resting and postural tachycardia by reducing sympathetic overactivity; fludrocortisone, a mineralocorticoid that augments retention of water and sodium and expands plasma volume; midodrine, which is an α1 agonist that causes vasoconstriction and increased peripheral resistance; and other commonly used medications for the OI, tachycardia, and fatigue (eg, pyridostigmine, ivabradine, clonidine, modafinil, methylphenidate, or selective serotonin reuptake inhibitors (SSRIs).³⁵ In some people with POTS that is medication resistant or in those with severe nausea, vomiting, or other gastrointestinal symptoms, intravenous saline can be used effectively on as-needed basis.³⁵ Immunotherapy may be considered for severe POTS and other autonomic disorders with positive autoimmune markers nonresponsive to standard pharmacotherapy.³⁶ Noninvasive vagus nerve stimulation—an effective treatment for migraine and cluster headache—may be considered for POTS, because it has a potential anti-inflammatory effect via activation of the vagus nerve and reduction of proinflammatory cytokines.^37,38

Studies of pharmacotherapy for people with migraine and autonomic disorders are lacking, but β blockers, (eg, propranolol or atenolol; Table 2) are particularly valuable. Importantly, a low dose is used to control POTS symptoms, which may be suboptimal for preventive migraine treatment, but higher doses of β blockers may not be well tolerated in persons with POTS, who are typically sensitive to medications. In the author’s experience, fludrocortisone can sometimes trigger or worsen a headache, whereas tricyclic antidepressants (eg, amitriptyline and nortriptyline) at low doses are usually well tolerated. High doses of tricyclic antidepressants should be avoided in autonomic disorders because these may worsen OI, presyncope, postural tachycardia, or OH. Clinical observations suggest that treatment of POTS can often improve migraine attack frequency and severity, and conversely, when chronic migraine is effectively managed with preventive treatment, symptoms of POTS may also improve concurrently. The observation of parallel improvement of POTS and migraine in response to treatment reinforces the concept of shared pathophysiology of both disorders.

Summary

Both autonomic disorders and PASC are commonly associated with headache and may present a diagnostic and therapeutic challenge, considering the diverse and overlapping clinical features discussed. A high degree of clinical suspicion is needed to identify autonomic disorders in persons with headache in conjunction with other manifestations (eg, dizziness, lightheadedness, tachycardia, palpitations, fatigue, and exercise intolerance). OI is the hallmark of common autonomic disorders and needs to be elicited via questions tailored to identifying symptoms and signs exacerbated by standing and relieved by recumbency. A 10-minute stand test or a tilt-table test are used to confirm a clinically suspected diagnosis, whereas more detailed autonomic function tests can be utilized to quantify the extent of the autonomic involvement or the presence of less common autonomic disorders. Treatment involves nonpharmacologic and pharmacologic approaches, with β blockers offering a preferred treatment option for OI, especially if accompanied by tachycardia, and preventive headache treatment. Randomized controlled trials are needed to determine the most effective treatment approaches in people with headache and autonomic disorders and those with PASC-associated headache and autonomic dysfunction.