Dysfunction of the autonomic nervous system, or dysautonomia, is an uncommon disease that remains at the frontier in medical diagnosis and management. Although there are several types of dysautonomia, including Shy–Drager syndrome, pure autonomic failure, and the like, for the purpose of this article, the diagnosis and management of postural orthostatic tachycardia syndrome will act as the model for the rest of these disorders, although the other dysautonomias can have much more severe symptoms. Postural orthostatic tachycardia syndrome is estimated to occur with a prevalence of at least 500,000 patients in the United States of America.Reference Kanjwal, Kosinski and Grubb1 Despite its frequency as the most common dysautonomia, postural orthostatic tachycardia syndrome is not widely recognised as a true disease by many care providers. Responses to postural orthostatic tachycardia syndrome vary from not being aware of its existence to denying its existence to actively refusing to offer care to these patients:
• it is not my organ system,
• it is not a cardiac problem,
• those patients are just crazy,
• managing those patients would drive me crazy,
• I have no experience using those drugs.
The purpose of this article, therefore, is to provide a basic framework for evaluating and managing patients with postural orthostatic tachycardia syndrome, so as to spread knowledge of the existence of this syndrome as well as newer therapeutic options.
Postural orthostatic tachycardia syndrome, also known as chronic orthostatic intolerance, is the most common but least severe of the dysautonomic disorders; it will serve as the model for evaluation and management of the other dysautonomias. Despite the overall relative lack of severity as compared to other dysautonomias, patients with postural orthostatic tachycardia syndrome can be quite overwhelmed with their symptoms. Often, they have a history of being high achievers in academics, athletics, or both, which makes the difference in their clinical status even more dramatic. Also, there can be depression or anxiety associated with these symptoms, from either a chronic state of disease or possibly associated with the syndrome itself. There is a frequent history of an initiating viral syndrome, such as a mononucleosis-like illness, from which the patient feels that there has been no clinical recovery. In fact, many patients have positive serology for Epstein–Barr virus. The other common association is that of some aspect of hypermobility of the joints, either in Ehlers–Danlos syndrome or a less severe “joint hypermobility syndrome”.Reference Kanjwal, Saeed, Karabin, Kanjwal and Grubb2 Rarely, it can also be associated with mitochondrial myopathies. In general, children tend to have postural orthostatic tachycardia syndrome as an isolated syndrome; in contrast, adults can manifest it as either an isolated syndrome or in conjunction with a paraneoplastic process, porphyria, syringomyelia, diabetes mellitus, or fibromyalgia. Postural orthostatic tachycardia syndrome is more common in females over males by a ratio of five to one, with most patients having onset symptoms in adolescence. It can also be seen in younger children, and can be present in members of the family. Some sources have suggested that as many as 80% of patients have spontaneous resolution by age 19 to 24 years,Reference Grubb3 although this may be an optimistic estimate.
Diagnosis
Overall, these patients can have variable dysfunction of the autonomic nervous system that is more severe than that seen in typical neurocardiogenic syncope. Symptoms include:
• dizziness,
• syncope,
• tachycardia,
• palpitations,
• non-cardiac pain in the chest,
• headache (migraine and/or tension),
• severe debilitating fatigue,
• difficulty with concentration (“brain fog”),
• photophobia,
• phonophobia,
• chronic pain,
• intolerance of heat,
• diaphoresis,
• abnormal sudomotor function,
• cool extremities,
• pooling of blood and mottling,
• intolerance of exercise,
• early satiety,
• delayed gastric emptying,
• nausea and emesis,
• constipation, diarrhoea, or cycling between the two,
• chronic pain, and
• dysfunction of the bladder.
The symptoms are often worsened with upright position, and can also be exacerbated during menses as well as in the autumn, the so-called “October slide”. Symptoms can also vary daily, weekly, or monthly. This constellation of waxing and waning symptoms can be confusing to many providers, and can be missed by those clinicians not familiar with this syndrome. They present to cardiologists for evaluation of their complaints of syncope, dizziness, palpitations, or pain in the chest. However, the patients often do not respond to routine therapeutic interventions for these symptoms. Subsequently, either the clinicians or the patients and families tire of the inability to gain control of the symptoms, with the patients leaving to find another clinician who may be able to help in the diagnosis and management of their care. In all, as the aetiology of postural orthostatic tachycardia syndrome is not clear, the approach to its management thus has been to manage its symptoms until a “spontaneous remission” occurs.
The diagnosis of postural orthostatic tachycardia syndrome remains relatively simple: it is made byReference Kanjwal, Kosinski and Grubb1 the finding of orthostatic intolerance associated with:
• a pulse greater than 120 beats per minute in the first 10 minutes of upright position; or
• an elevation in pulse greater than 30 beats per minute in the first 10 minutes of upright position.
The orthostatic intolerance may be symptomatic only; there may be no hypotension noted. In some cases, there is even a hypertensive response. These findings, combined with various historical features mentioned above, are typically sufficient to make the diagnosis. Mottling of the distal extremity and abnormal sudomotor responses can often be seen clinically, but besides a fatigued appearance, little else is often seen in the clinic. Reflex neurovascular dystrophy can be another associated finding. It is also helpful to assess mobility of the joints, with referral for genetic evaluation for possible Ehlers–Danlos syndrome, if there is sufficient suspicion. Some practitioners will perform upright tilt table testing, including those who also assess supine and upright levels of serum catecholamines. These tests, however, have not been shown to be particularly helpful in improving diagnostic accuracy or in aiding with management or prognosis. If concern exists for a mitochondrial myopathy, metabolic evaluation, including assessment of mitochondrial deoxyribonucleic acid, can be helpful. As these patients are frequently seen by their primary care providers and often by other specialists, other laboratory studies, including testing of the blood, imaging of the brain, Holter monitoring, echocardiography, exercise stress testing, and the like, have typically been performed; they are also typically normal, with the exception of the aforementioned panel of serology for Epstein–Barr virus and occasionally a non-specific elevation of the anti-nuclear antibody.
Treatment
Education of patients and families
Management of these patients can be difficult as well as rewarding. Possessing the ability to help a patient to return to school, or even to feel less symptomatic, after months or even years of disability, is quite gratifying. Conversely, failure of improvement can also occur after numerous trials of medication, leading to frustration among patient, parent, and provider. It is therefore helpful to perform extensive education up front with these patients and their families. This education involves several interlocking pieces: the first is the understanding that improvement of symptoms will not necessarily be immediate with therapy. Different therapies work differently among different patients, so patience and perseverance between both provider and patient and family is paramount. Second, giving a tiered approach to achieving goals for improvement can also be helpful:
• Helping patients to be able to manage their activities of daily living is the first level of intervention.
• Next is ensuring that they are able to achieve an education.
• The last tier can be characterised by “the fun stuff”, including participation in athletics, going out with friends, and other social activities important to maintaining an independent lifestyle.
Finally, giving the patient and families other resources for education and for community is important; these resources are available at several websites on the Internet, including the Dysautonomia Information Network (www.dinet.org) and the Dysautonomia Youth Network of America (www.dynakids.org). The National Dysautonomia Research Foundation (www.ndrf.org) is a clearing house for information for further studies into postural orthostatic tachycardia syndrome and other dysautonomias.
Therapy
Interventions for patients with postural orthostatic tachycardia syndrome typically fall into two broad categories: non-pharmacological and pharmacological. Non-pharmacological therapies are varied, but are based primarily on ensuring adequate status of intravascular fluid. Intake of fluid of between 48 and 80 ounces a day, along with salt, is a mainstay of this therapy. Salt can be supplied by salty snacks. Some practitioners give tablets of salt, which can cause some abdominal discomfort, and may not provide any greater benefit compared to increased dietary intake of salt. Some patients are not able to drink adequate fluid for various reasons, thus requiring fluid from a parenteral source. Parenteral supplementation of fluid is associated with risks, including infection and thrombosis, so encouragement of oral intake is preferred. Avoiding the skipping of meals as well as the intake of caffeine is also important, to prevent hypoglycaemia and diuresis. Elevating the head of the bed, such as with blocks of cinder, may be useful in decreasing hypotension in the morning. Prolonged standing, extreme heat, intake of alcohol, and other factors that can incite worsening symptoms should also be avoided. Special attention should be paid to ensuring appropriate sleep, as adolescents, and their parents, often ignore lack of sleep as an exacerbating factor. Exercises to strengthen the legs to assist with venous return are important. Physical therapy can be helpful with these exercises, especially in those patients with hypermobility of the joints, so as to protect the joints from damage. Finally, compression stockings may assist with counteracting the effects of peripheral vasodilation and thus reducing hypotension. These compression stockings should extend from the toes to above the waist and should give at least 30 millimetres of mercury of compression.
Pharmacological interventions ultimately combine a number of standard and non-standard medications, with many of the non-standard medications used “off-label”. These off-label uses take advantage of the actual effects that the biochemical actions produce, such as the direct increase of serotonin, noradrenaline, or acetylcholine, or the side effects of their increase. It is important to be familiar with the effects and side effects of these medications, especially as some patients with postural orthostatic tachycardia syndrome can be more sensitive to standard therapeutic doses as compared to normal patients. In fact, it may be helpful to start with lower doses of medications, and increase them as tolerated. Therapy for dizziness, palpitations, and near-syncope includes fludrocortisone, a salt-sparing mineralocorticoid, and midodrine, an alpha-adrenergic agonist.Reference Grubb3 Side effects for fludrocortisone include oedema, rash, headache, hypokalaemia, hypomagnesaemia, and the potential for adrenal suppression and Cushingoid findings at higher doses. The side effects associated with midodrine include tingling of the scalp and goose bumps in the first 30 minutes of therapy that typically resolve. Hypertension while in a supine position can also be seen. It is important to know that midodrine should be administered every 4 hours. Anecdotally, it is suggested that the version of midodrine sold under the brand name may have fewer side effects than the generic version, although this finding has not been consistently demonstrated. Low-dose beta-blocker, such as propranolol, has been demonstrated to reduce symptoms of palpitations and tachycardia.Reference Raj, Black and Biaggioni4 The low-dose beta-blocker may also be useful in the prophylaxis of headache, although hypotension can be a dose-limiting restriction. Because of this hypotension, it may be helpful to use a more cardiac-specific beta-blocker, such as metoprolol, starting at a very low dose, and slowly increasing the dose, in a method similar to that of patients with congestive cardiac failure.
Fatigue and decreased ability to concentrate are increasingly being treated with stimulants, similar to treatment for attention deficit-hyperactivity disorder. These medications include methylphenidate and mixed amphetamine salts. Long acting formulations of these medications, either oral or transcutaneous, are available. These formulations can reduce the need for more frequent dosing, though they tend to be more expensive. The side effects from these medications include decreased appetite, decreased ability to sleep, jitteriness at higher doses, modest retardation of the velocity of growth, and modest increases in pulse and systemic arterial pressure; a latent tic disorder can also be uncovered. These side effects can be dose limiting, but are reversible with lowered dose or discontinuation of the medication. Occasionally, an interesting anecdotal side effect of these medications that can be seen is better tolerance to some of the other systemic symptoms of postural orthostatic tachycardia syndrome. One other downside to these medications is their classification as controlled substances, which leads to the need for frequent refills of prescriptions. Other medications that have been used for this domain include atomexetine and armodafonil.
Gastrointestinal symptoms associated with dysautonomia are often by-products of slowed motility secondary to poor autonomic control. Pyridostigmine, a medication often used in the therapy of myasthenia gravis, has been used for general therapy of postural orthostatic tachycardia syndrome. The best use of pyridostigmine, however, may be in patients with gastrointestinal problems. As pyridostigmine is a pro-cholinergic agent, side effects include increased intestinal motility, diarrhoea, urination, salivation, and lacrimation. Increasingly, it has been anecdotally recognised that many patients with gastrointestinal involvement have bacterial overgrowth in the small intestine. This bacterial overgrowth can be diagnosed with a “lactulose breath test”. If this test is positive, therapy with rifaximin, an antibiotic that remains in the intestinal tract, followed by treatment with zinc, probiotics, and pyridostigmine, may improve these gastrointestinal symptoms.
The selective serotonin reuptake inhibitors, such as citalopram and escitalopram, selective noradrenaline reuptake inhibitors, such bupropion, and combination medications, such as duloxetine, can be useful for central stabilisation of the sympathetic nervous system, as well as for treatment of anxiety and depression associated with postural orthostatic tachycardia syndrome.Reference Grubb3Duloxetine is also approved for therapy of chronic pain. The aforementioned selective serotonin reuptake inhibitors tend to have fewer side effects as compared with earlier generation selective serotonin reuptake inhibitors, but can still have nausea, headache, and insomnia, or somnolence. The selective noradrenaline reuptake inhibitors can lower the threshold for seizures, and have more typical side effects, including dry mouth and insomnia.
Other medications that have been used for the therapy of postural orthostatic tachycardia syndrome include buspirone, clonidine, and erythropoietin. One medication that stands out as being helpful for insomnia is melatonin, which can be a helpful adjunct to appropriate sleep hygiene and may be associated with fewer side effects than prescription medications for insomnia.
Overall, patients and families need to be aware that polypharmacy may be required to control symptoms associated with postural orthostatic tachycardia syndrome. Also, patients may need varying doses or even wholesale changes to medical regimens with seasonal variation or temporal progression of symptoms. It is incumbent upon the practitioner to be aware of changes in symptoms and to be willing to wean medications appropriately while considering other avenues of therapy. It may also be helpful to make only a few changes at a time in a therapeutic regimen to prevent clouding of the interpretation of salutary or adverse effects and their assignment to specific medications. One approach that can also be helpful is to have the patient enumerate the three worst symptoms, and aim the therapeutic assault at those. It is important to realise that those three symptoms may change over time, and that flexibility in management is necessary.
Meeting the challenges of school
On account of the severity of their symptoms, these patients frequently have difficulty in completing their school assignments, due to fatigue, brain fog, headaches, or severe dizziness that interferes with their ability to concentrate on their work. Some patients may even be too sick to attend school. Tardy arrivals, early departures, and frequent absenteeism are all common in these patients. The physician may need to help support the attempts of the family to work with the school system to bolster the education of the patient. The ability to stay in school is the desired goal for the educational plan of the patient. Staying in school gets the patient out of the house and out of more of a “sick role”, allows for more socialisation, and leads to the patient enjoying more of a normal lifestyle. Use of an individualised educational plan can both:
• bring the medical problems of the patient to the attention of the teachers and administration of the school; and
• help the patient in numerous adaptive ways to be able to stay in school.
The physician, as the medical coordinator who understands the problems with postural orthostatic tachycardia syndrome, can enumerate the medical problems in a letter and help facilitate strategies for the patient. Some of these strategies include:
• having two sets of books, so that one set stays at home and less weight is carried by the patient;
• allowing frequent access to both water intake and bathroom use;
• giving the patient an elevator key, so as to avoid stairs;
• having extra time to transit between classes;
• having extra time to complete homework and tests;
• providing a friend to walk with the patient between classes or to the bathroom; giving forbearance for potentially frequent absences;
• allowing the patient to start classes slightly later, such as at second period; and
• building in more study hall time, if necessary.
Occasionally, the symptoms of the student are severe enough as to preclude attending school full time. Other options for education include part-time school, homebound education, and virtual schooling.
Research for the future
As postural orthostatic tachycardia syndrome is both underdiagnosed and so poorly understood, it is a disease that provides an excellent opportunity to perform research. The most important studies would be those that aim to elucidate an aetiology and a pathophysiology of postural orthostatic tachycardia syndrome. This knowledge would lead to better, and potentially, more complete interventions. In the interim, characterisation of the optimal use of the presently used medications as well as the addition of new therapeutic regimens is needed to better manage the symptoms associated with postural orthostatic tachycardia syndrome.
Summary
In total, the role of the cardiologist in the evaluation and management of dysautonomia is similar to that of the evaluation and management of any other disease. The provider should make the effort to learn about the disease and its treatment. These patients should be accepted into the care of the practitioner, and be diagnosed and treated appropriately. Provision of patience and support is paramount. Advocacy for and education of the patient, family, providers of primary care, and other referral sources remains an important method of allowing better recognition of and care for the patient. Aggressive and creative therapeutic intervention, with the sometimes unavoidable use of polypharmacy, can lead to wide-ranging improvement of symptoms. It cannot be overstated that the ability to help a patient with severe disability to feel as if they are normal, or much closer to it, remains both very rewarding for providers who care for these children and adolescents and a central tenet of the practice of medicine.
Acknowledgement
The author would like to thank Jeffrey P. Jacobs, MD, for his excellent editorial support.
