Autonomic Dysfunction

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Continuing Education Activity

The autonomic nervous system (ANS) includes all regions implicated in controlling autonomic, unconscious, and involuntary functions in total body homeostasis. In general, the full range of physiologic functions are ultimately necessary for human survival and allow us to interact with the external environment in a wide range of conditions. Together with the slow-acting, long-lasting effects of the endocrine system, the ANS exerts its fast-acting, short-lived effects on the most diverse functions of the body, controlling visceral smooth muscle activation in vascular beds and other tubular organs and secretion of glands. In this activity, we will share a general overview of these different functions in health and how their malfunction affects daily life.

Objectives:

  • Summarize the most common etiologic and risk factors for developing autonomic dysfunction.
  • Outline the most common presentation and management considerations for patients with autonomic diseases.
  • Identify how to evaluate the levels of ANS dysfunction.
  • Explain the importance of improving care coordination amongst the interprofessional team to enhance care delivery for patients with autonomic sphere symptoms and disorders.

Introduction

The autonomic nervous system (ANS) is a subcomponent of the peripheral nervous system (PNS) that regulates involuntary physiologic processes, including blood pressure, heart rate, respiration, digestion, and sexual arousal. It comprises sympathetic, parasympathetic, and enteric nervous systems, which are three anatomically distinct divisions. The sympathetic nervous system (SNS), as well as the parasympathetic nervous system (PNS), contain afferent fibers that provide sensory input and efferent fibers that provide motor output to the central nervous system (CNS). The SNS and PNS motor pathways incorporate a two-neuron series: a pre-ganglionic neuron with a cell body in the CNS and a post-ganglionic neuron with a cell body in the periphery that innervates target tissues[1]. The enteric nervous system (ENS) is a large, web-like structure capable of functioning independently of the remainder of the nervous system.[2][3] It is chiefly responsible for regulating digestive processes and contains over a hundred million neurons of over fifteen morphologies, greater than the sum of all other peripheral ganglia.[4][5]

The autonomic nervous system (ANS) includes all regions implicated in controlling “autonomic,” unconscious, and involuntary functions in total body homeostasis. In general, the full range of physiologic functions are ultimately necessary for human survival and allow us to interact with the external environment in a wide range of conditions. Together with the slow-acting, long-lasting effects of the endocrine system, the ANS exerts its fast-acting, short-lived effects on the following functions (among others):

  • Perfusion of the whole body through regulation of heart rate and blood pressure
  • Homoeothermic role through sweating control and shivering, 
  • Processing of nutrients through control and coordination of different parts of the gut and glands,
  • Urinary motility, and
  • Pupil movement, focusing, and lacrimation.

Table 1. Autonomic nervous system functions[3]

       Organ Sympathetic activation Parasympathetic activation

Eye

    Ciliary muscle

    Pupils

 

 Relax (far vision)

 Dilation (dilator muscle)

 

Constrict (near vision)

Constriction (sphincter muscle)

Lacrimal gland

Salivary glands

 Slight secretion

 Slight secretion

Secretion

Secretion

Heart

    Contractility (muscle)

    Rate (sinus node)

 

Increase

Increase

 

Decreased or none

Decrease

Lungs Bronchodilation Bronchoconstriction
Gastrointestinal tract Decrease motility Increase motility
Kidney Antidiuresis (decreased output) None

Urinary bladder

    Detrusor muscle

    Sphincter

 

Relaxation

Contraction

 

Contraction

Relaxation

Penis Ejaculation Erection
Clitoris, labia minora None Swelling/ Erection

Nipples

None Erection

Sweat glands

Secretion Palmar sweating

Piloerector muscles

Contraction None

Blood vessels

    Large arteries

    Arterioles

    Precapillary sphincters

    Venules

    Large veins

    Coronary arteries

 

Constriction

Constriction 

Constriction 

Constriction 

Constriction, volume mobilization

Dilatation

 

None

None

None

None

None

None

Muscle

    Muscle spindles

    Arterioles

    Metabolism

 

 

Decreased sensitivity

Dilatation

Increased

 

 

None

None

NOne

Liver

Glycolysis, glucose mobilization

Glycogen synthesis

Fat tissue Lipolysis None
Immune system Suppressed Activated

Dysfunction of one or more subdivisions of the ANS, when accompanying other diseases, is linked to a worse prognosis of the latter. In some circumstances or when severe, dysfunction of ANS itself results in symptoms and disability, which may, in turn, prompt treatment.[6][7][8][9][10]

Etiology

A myriad of the factors can cause autonomic dysfunction, and more than one can concur even in the same patient. Due to the expansive nature of the autonomic nervous system, it can be affected by a wide range of conditions[11][12][13]. The most common factors known to cause autonomic dysfunction include the following:

Inherited

  • Amyloidosis, Fabry disease, hereditary sensory autonomic neuropathy, porphyrias
  • Genetic disorders like familial dysautonomia and dopamine-beta-hydroxylase deficiency

Acquired 

  • Autoimmune: Guillain-Barre, Autoimmune autonomic ganglionopathy, Lambert-Eaton myasthenic syndrome, rheumatoid arthritis, Sjogren, systemic lupus erythematosus
  • Abnormal reflex responses in carotid sinus hypersensitivity, vasovagal syncope, and other neuro-meditated syncopes; and probably in postural tachycardia syndrome (PoTS)
  • Abnormal sweating responses, as in generalized or focal hyperhidrosis, are related to excessive activation.
  • Metabolic/ Nutritional: Diabetes mellitus, vitamin B12 deficiency
  • Degenerative neurologic diseases: Parkinson disease, multiple system atrophy/Shy-Drager syndrome, pure autonomic failure presenting or suffering from orthostatic hypotension, fixed heart rate responses
  • Infections: Botulism, Chagas disease, human immunodeficiency virus (HIV), leprosy, Lyme disease, tetanus
  • Neoplasia: Brain tumors, paraneoplastic syndromes
  • Pharmacologic effects of several drugs that interfere with normal autonomic function and provoke symptoms include alpha- and beta-blocker-triggered orthostatic hypotension
  • Toxin/drug-induced: Alcohol, amiodarone, chemotherapy
  • Traumatic or tumoral spinal cord injuries at different levels and presenting with the so-called autonomic dysreflexia
  • Uremic neuropathy/chronic liver diseases

Medications That Exacerbate Orthostatic Hypotension

  • Diuretics: furosemide, torsemide, thiazide
  • Nitric oxide-mediated vasodilators: nitroglycerine, hydralazine, sildenafil
  • Adrenergic antagonists:
    • Alpha-1-adrenergic blockers: alfuzosin, terazosin
    • Beta-adrenergic blockers: propranolol
  • Alpha -2-adrenergic agonists: tizanidine, clonidine
  • Renin-angiotensin system inhibitors: lisinopril, valsartan
  • Dopamine antagonists:
    • Phenothiazines: chlorpromazine
    • Atypical antipsychotics: olanzapine, risperidone, quetiapine
  • Calcium channel blockers: verapamil, diltiazem
  • Selective serotonin receptor reuptake inhibitors: paroxetine
  • Antidepressants: trazodone, amitriptyline

Epidemiology

Autonomic dysfunction, taken as a whole, is not infrequent. The most common autonomic dysfunction occurs in the cardiovascular control sphere and consists of an abnormal vasovagal response that leads to syncope. Other common manifestations are related to postural tachycardia syndrome (POTS) or changes seen with Parkinson disease and other parkinsonisms. Compared to other areas of autonomic control, urinary incontinence, as observed in multiple sclerosis and other nervous system disorders, is unspecific but not rare. Some symptoms of autonomic disturbance, such as the facial vasomotor and ocular symptoms in trigeminal autonomic headaches, are of secondary significance but help in diagnosis.[14][15][16][17]

Orthostatic hypotension occurs in patients with neurodegenerative disorders such as Parkinson disease, multiple system atrophy, pure autonomic failure, and in individuals with ganglionopathies that affect autonomic nerves and peripheral neuropathy. The prevalence of orthostatic hypotension is proportional to age, and it is more common in institutionalized than community-dwelling elderly[18]. POTS is more prevalent in women. Syncope is highly prevalent in the general population, and the majority of syncope is due to reflex syncope. The frequency of reflex syncope is higher during adolescence and in individuals over 55 years. Carotid sinus hypersensitivity, defecation, and cough syncope occur almost exclusively in the elderly population.[18]

Pathophysiology

Pathophysiology in ANS depends upon the affected area. Both anatomically related, as well as isolated regions, can be affected. In the cardiovascular system, three pathophysiological syndromes are typically associated with chronic dysfunction of the ANS. These are Postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension with supine hypertension, and reflex cardiovascular syndromes. Hyperhidrosis and hypohidrosis are the main features of temperature control. Fixed mydriasis and myosis, also known as Adie's pupil and Horner syndrome in the eye, are also seen.

Autonomic dysfunction may result from any disease that affects the peripheral or central components of ANS. Primary autonomic dysfunction involves primary (idiopathic) degeneration of autonomic postganglionic fibers without other neurologic abnormalities. Orthostatic hypotension is associated with autonomic dysfunction and motor and cerebellar abnormalities in diseases involving a central degenerative process, as described in the Shy–Drager syndrome. A central degenerative disease process involving preganglionic neuronal degeneration, presenting with orthostatic hypotension and typical parkinsonian symptoms, has been described.[19]

Orthostatic hypotension is defined as a sustained reduction of systolic blood pressure of at least 20 mmHg or diastolic blood pressure of 10 mmHg within three minutes of standing or head-up tilt to at least 60 degrees on the tilt table. The magnitude of fall in blood pressure depends on baseline blood pressure. In patients with supine hypertension, a reduction of 30 mmHg in systolic blood pressure may be an appropriate criterion for orthostatic hypotension. Immediately upon standing, gravitationally mediated redistribution of the blood volume and pooling of 300 to 800 ml of blood in lower limbs and splanchnic venous capacitance system occurs, which leads to a reduction of venous return and cardiac filling pressure. During standing, contraction of skeletal muscles of the lower body prevents excessive pooling and increases venous return to the heart. Orthostatic hypotension is caused by an excessive fall of cardiac output or by inadequate or defective vasoconstrictor mechanisms.

Neurally mediated (reflex) syncope includes vasovagal, carotid sinus, situational (cough, swallowing, micturition) syncope. It refers to a diverse group of conditions in which there is a relatively sudden change in ANS activity leading to a drop in blood pressure, heart rate, and cerebral perfusion. Neurally mediated syncope is best understood as a reflex with afferent, central, and efferent pathways, and the use of 'neurocardiogenic syncope' should be abandoned because the origin of the reflex is rarely in the heart.

Postural tachycardia syndrome (POTS) is defined as a sustained heart rate increment of 30 beats per minute within 10 minutes of standing or head-up tilt in the absence of orthostatic hypotension. For individuals of ages 12 to 19 years, the requirement is at least 40 beats per minute. POTS may be accompanied by symptoms of autonomic overactivity and cerebral hypoperfusion that are relieved by recumbency. The pathophysiology and etiology of POTS are unknown but are likely heterogeneous. POTS is associated with recent viral illness, chronic fatigue syndrome, deconditioning, and limited or restricted autonomic neuropathy.[18]

Diabetic neuropathy is a kind of nerve pathology that may occur for those with diabetes mellitus. Hyperglycemia interferes with a nerve's ability to send signals and weakens the walls of the vasa nervorum blood vessels that supply nerves with nutrients and oxygen. Diabetic neuropathy can affect the nerves of the ANS, especially general visceral afferent (GVA) fibers, resulting in gastroparesis and decreased blood pressure regulation.[20] GVA fibers affected by diabetic neuropathy reduce the response of their corresponding general visceral efferent (GVE).

Parkinson disease is a progressive neurodegenerative disease characterized by bradykinesia and hypokinesia combined with rest tremor and rigidity. Constipation, dysphagia, sialorrhea, rhinorrhea, urinary difficulties, and sexual dysfunction are the common nonmotor problems related to autonomic dysfunction in Parkinson disease.[21][22] These signs and symptoms are also present in multiple system atrophy (MSA), making it hard to distinguish between the two disorders. However, the autonomic symptoms in MSA are generally more severe than in Parkinson disease. As the disease progresses, MSA tends to be less responsive to levodopa and is often associated with pyramidal and cerebellar findings.

History and Physical

A detailed account of symptoms in each area should guide us to list possible diseases with autonomic dysfunction. Emphasis should be placed on obtaining a good history and comprehensive examination of cardiovascular, urinary, neurological, and sudomotor manifestations. A key feature of autonomic dysfunction, either orthostatic syncope or presyncope, should guide us to suspicion of cardiovascular autonomic dysfunction. In this scenario, the usual orthostatic symptoms consist of lightheadedness, visual blurring or tunnel vision, neckache (coat-hanger pain), nausea, palpitations, tremulousness, weakness, and dizziness. Other symptoms include exercise intolerance, fatigue, shortness of breath, chest pain, anxiety, hyperventilation, acral coldness or pain, concentration difficulty, and headaches.[18] The alternating sweating intensity in different areas of the body, typically a length-dependent distal hypohidrosis with sparing of palms and soles, can raise suspicion for a sudomotor autonomic lesion. Urgency and incontinence tend to relate to a neurogenic bladder more than retention.

Evaluation

Testing the most disturbing or salient features of autonomic dysfunction is often necessary to confirm a diagnosis and give objective evidence supporting pharmacologic treatment.[23][24][25]

Bedside evaluation of the ANS consists primarily of observing cardiovascular reflexes, casual sweating patterns, and pupillary changes.[19] Bedside tests such as orthostatic blood pressure measurement and heart rate (while supine and after three minutes standing) are the most commonly used tests. When the bedside tests are not informative, but suspicion of an abnormal cardiovascular autonomic function is high, tilt table tests with natural cardiovascular stimuli such as Valsalva maneuver, hyperventilation, or cold pressor, are needed. 

Sympathetic skin responses can add objective information, and a thermoregulatory sweat test might be a good option if the symptoms of altered sweating predominate.

Vesical ultrasonography and urodynamic studies help diagnose and choose the best pharmacologic approach for urinary dysfunction in autonomic dysfunction.

Other tests are not as useful in changing the management but may play a role in supporting an explanation for the patient's symptoms or as adjunctive for syndromic diagnosis. Blocking eyedrop tests and pupillometry for pupillary abnormalities are examples of such tests.

Some tests do help in management. For example, positive testing for autoantibodies, antibodies against alfa-3-acetylcholine receptors helps support immunosuppressive therapy.

Indications of Tilt Table Test[26]:

  • High suspicion of orthostatic hypotension despite an initial negative evaluation (for example, Parkinson disease).[27]
  • Patients who have a significant motor impairment that precludes them from having standing vital signs obtained.[27]
  • Monitor the span of an autonomic disorder and its response to therapy.[28]

Responses to Head-Up Tilt-Table testing[29]:

Normal

Heart rate increases by 10 to 15 beats per minute

Diastolic blood pressure increases by 10 mm Hg or more

Dysautonomia

Immediate and continuing drop in systolic and diastolic blood pressure

No compensatory increase in heart rate

Neurogenic syncope

Symptomatic, sudden drop in blood pressure

Simultaneous bradycardia

Occurs after 10 minutes or more of testing

Orthostatic hypotension

Systolic blood pressure decreases by 20 mm Hg or more

                              or

Diastolic blood pressure decreases by 10 mm Hg or more

Postural orthostatic tachycardia syndrome

Heart rate increases by at least 30 beats per minute

                              or

Persistent tachycardia of more than 120 beats per minute

Treatment / Management

Treatment, when indicated, can be organized into three levels. Treatment strategies are aimed at etiology, physiopathology, and symptoms.

  1. Symptom management is the most frequently used and must first address the most bothersome symptoms while keeping the whole picture in mind. Physical measures like exercise, tailored physiotherapy, pressure stockings can help in some cardiovascular autonomic dysfunctions. Sunglasses can be used for mydriatic pupils. Also, a wide range of non-pharmacologic and pharmacologic measures are beneficial, as described below.
  2. The pathophysiologic aspect can be addressed in the case of immune-mediated disorders. Immunotherapy, such as steroids and other immune suppressor drugs, intravenous immunoglobulins, and plasma exchange, is employed in immune-mediated disorders management strategies.
  3. Finally, etiology must always be addressed. It is essential to treat certain situations, such as the malignancy found in paraneoplastic and autoimmune autonomic neuropathy. However, it is imperative to taper or withdraw the drugs interfering with the ANS in drug-induced, symptomatic autonomic failure in some other situations. 

Management of Orthostatic Hypotension

Non Pharmacological Measures

  • Discontinue exacerbating medications.
  • Use of compression stockings and abdominal binders.
  • Increase salt and water intake: Drinking 500 mL of water upon awakening and reaching 1.5 to 3 L per day is a reasonable target.[30][31][32] Salt tablets or high sodium-containing foods also may be beneficial. While the optimal dose varies with the patients, a typical target dose of 6 to 10 g/day of sodium or a target urinary sodium level of 150 to 200 mEq is used.[30][31][32][26]
  • Modify lifestyle and daily activities: Slow changing of postures, for example, from supine to sitting and standing to increase the orthostatic tolerance. Avoiding Valsalva-like maneuvers and limiting walking in hot and humid weather, minimize hot showers and saunas as exposure to warm temperatures can cause skin vasodilation and worsen orthostatic hypotension.[33]
  • Engaging in an exercise program in a sitting or recumbent position is better tolerated than standing.

Pharmacotherapy

Pharmacological intervention is needed if the above measures are insufficient in preventing symptoms and complications of orthostatic hypotension. The two medications approved by US Food and Drug Administration (FDA) to treat symptomatic neurogenic orthostatic hypotension are:

  1. The alpha-adrenergic agonist, midodrine, and
  2. The norepinephrine precursor, droxidopa[34]

A synthetic mineralocorticoid, Fludrocortisone, is widely used to treat orthostatic hypotension, is not specifically approved by the FDA for treating neurogenic orthostatic hypotension, and can lead to sustained hypertension in the supine position and other adverse effects. Fludrocortisone can augment intravascular volume and provide symptom relief.

Patients not responding to nonpharmacological measures such as volume augmentation, supine norepinephrine levels must be checked. If the supine norepinephrine level is <220 pg/mL, either midodrine or droxidopa is used, and for other patients, another sympathomimetic, atomoxetine (norepinephrine transporter (NET) inhibitor), can be used as initial pharmacotherapy.[35]

Adjunctive or Alternative Therapeutic Options

  • Caffeine
  • Nonsteroidal anti-inflammatory drugs
  • Pyridostigmine
  • Erythropoietin
  • Experimental agents: yohimbine, desmopressin, dihydroergotamine, metoclopramide, norepinephrine infusion (data regarding these agents is limited)

Management of autonomic dysfunction in Parkinson disease:

  • Constipation: therapies like Polyethylene glycol, probiotics, and lubiprostone have been studied and found to be more effective than placebo.[36]
  • Sialorrhea(drooling): for patients with mild symptoms, the initial step would be to use hard candy or chewing gum to encourage swallowing may decrease drooling in social situations.[37][38] Treatment with Botulinum toxin injection into the salivary glands can be effective for patients with more severe symptoms of drooling. Glycopyrrolate is also effective in severe drooling and has only a limited ability to cross the blood-brain barrier, which reduces the risk of central anticholinergic side effects.
  • Rhinorrhea: Ipratropium nasal spray, an anticholinergic agent, is effective.[39]
  • Sexual dysfunction:
    •  Men with erectile dysfunction may benefit from treatment with sildenafil one hour before sex.[40] Sildenafil should be used cautiously in patients with orthostatic hypotension. Tadafil and vardenafil are effective as well.
    • Women may benefit from urinating before sexual activity and vaginal lubricants.
  • Orthostatic hypotension: It may occur as a feature of the disease itself or due to the medications used to treat Parkinson disease, including dopamine agonists, levodopa, and monoamine oxidase type B (MAO B) inhibitors.

Differential Diagnosis

Differential Diagnosis of orthostatic hypotension[41][28]:

  • Cardiovascular: Anemia, cardiac arrhythmia, congestive heart failure, myocardial infarction, myocarditis, pericarditis, valvular heart disease, venous insufficiency
  • Drugs: Alcohol, antiadrenergic medications, antianginals, antiarrhythmics, antidepressants, antihypertensives, antiparkinsonian agents, diuretics, narcotics, neuroleptics, sedatives
  • Endocrine: Adrenal insufficiency, diabetes insipidus, hypoaldosteronism, hyperglycemia, hypokalemia, hypothyroidism
  • Intravascular volume depletion: Blood loss, dehydration, shock, pregnancy/postpartum
  • Miscellaneous: Acquired immunodeficiency syndrome (AIDS), anxiety, panic disorder, eating disorders, prolonged bed rest

Prognosis

The importance of autonomic dysfunction secondary to other diseases is related to the prognosis of the primary disease process, the severity of orthostatic symptoms, and its response to treatment. The primary forms of autonomic dysfunction, both peripheral and central, have a generally poor prognosis, especially those associated with parkinsonian symptoms or movement disorders. The mean age of onset of these primary syndromes is in the 6th decade, and survival five years after the neurologic symptoms is less than 50%.

Complications

Orthostatic hypotension, particularly when symptomatic, can lead to falling, which has significant associated morbidity, particularly in a frail elderly population.[42][43] According to several population-based studies, orthostatic hypotension is a risk factor for cardiovascular and all-cause mortality, usually due to associated diseases and underlying causes.[31][44] Orthostatic hypotension has been associated with the development of dementia and cognitive impairment, though the mechanisms underlying this association are uncertain. Recurrent episodes of hypotension and cerebral hypoperfusion may result in neuronal injury. It is associated with periventricular white matter lesion burden, which in turn is a marker of vascular cognitive impairment.[45] In addition, cognitive impairment and orthostatic hypotension can be both prodromal manifestations of an underlying neurodegenerative disease, such as dementia with Lewy bodies.[46]

Pearls and Other Issues

Autonomic dysfunction is a prevalent health problem that remains underdiagnosed, undertreated, and underappreciated across healthcare systems. In most cases, patients tend to have a late diagnosis when their symptoms are chronic and long-standing. The lack of acknowledgment from the general population and the medical community, diagnostic testing set in the development, and a finite set of extensively tested and validated drugs to offer, among other causes, make the field one of the most promising for research.

Autonomic dysreflexia is a severe, potentially life-threatening condition affecting the cardiovascular system of patients exposed to various risk factors - ranging from painful/noxious stimuli to more subtle conditions (e.g., bowel or bladder obstructions). It can lead to cardiac ischemia, brain hemorrhage, seizures, and even death. Therefore, clinicians should remain cognizant, depending on the specific patient and clinical constellation of symptoms.

Enhancing Healthcare Team Outcomes

The diagnosis and management of autonomic dysfunction are complex and usually require an interprofessional team comprising specialists such as a neurologist, endocrinologist, internist, urologist, and cardiologist. The treatment is symptomatic and usually requires medications, which also have adverse effects. The outcomes and quality of life with autonomic dysfunction are poor.[47][48]


Article Details

Article Author

Rahul Gujarathi

Article Editor:

Matthew Varacallo

Updated:

9/4/2022 8:02:58 PM

PubMed Link:

Autonomic Dysfunction

References

[1]

Waxenbaum JA,Reddy V,Varacallo M, Anatomy, Autonomic Nervous System StatPearls. 2021 Jan;     [PubMed PMID: 30969667]

[2]

Sternini C, Organization of the peripheral nervous system: autonomic and sensory ganglia. The journal of investigative dermatology. Symposium proceedings. 1997 Aug;     [PubMed PMID: 9487007]

[3]

Karemaker JM, An introduction into autonomic nervous function. Physiological measurement. 2017 May;     [PubMed PMID: 28304283]

[4]

Lake JI,Heuckeroth RO, Enteric nervous system development: migration, differentiation, and disease. American journal of physiology. Gastrointestinal and liver physiology. 2013 Jul 1;     [PubMed PMID: 23639815]

[5]

Siéssere S,Vitti M,Sousa LG,Semprini M,Iyomasa MM,Regalo SC, Anatomic variation of cranial parasympathetic ganglia. Brazilian oral research. 2008 Apr-Jun;     [PubMed PMID: 18622477]

[6]

Ziemssen T,Siepmann T, The Investigation of the Cardiovascular and Sudomotor Autonomic Nervous System-A Review. Frontiers in neurology. 2019     [PubMed PMID: 30809183]

[7]

Hong CT,Chan L,Wu D,Chen WT,Chien LN, Association Between Parkinson's Disease and Atrial Fibrillation: A Population-Based Study. Frontiers in neurology. 2019     [PubMed PMID: 30804869]

[8]

James LA,Levin MA,Lin HM,Deiner SG, Association of Preoperative Frailty With Intraoperative Hemodynamic Instability and Postoperative Mortality. Anesthesia and analgesia. 2019 Jun     [PubMed PMID: 31094800]

[9]

Chung SJ,Bae YJ,Jun S,Yoo HS,Kim SW,Lee YH,Sohn YH,Lee SK,Seong JK,Lee PH, Dysautonomia is associated with structural and functional alterations in Parkinson disease. Neurology. 2019 Feb 22;     [PubMed PMID: 30796135]

[10]

Spallone V, Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet. Diabetes     [PubMed PMID: 30793549]

[11]

Mustafa HI,Fessel JP,Barwise J,Shannon JR,Raj SR,Diedrich A,Biaggioni I,Robertson D, Dysautonomia: perioperative implications. Anesthesiology. 2012 Jan     [PubMed PMID: 22143168]

[12]

McLeod JG, Investigation of peripheral neuropathy. Journal of neurology, neurosurgery, and psychiatry. 1995 Mar     [PubMed PMID: 7897405]

[13]

Ludwig PE,Varacallo M, Neuroanatomy, Central Nervous System (CNS) null. 2018 Jan     [PubMed PMID: 28723039]

[14]

Barboza CA,Fukushima AR,Carrozzi N,Machi JF,Dourado PMM,Mostarda CT,Irigoyen MC,Nathanson L,Morris M,Caperuto EC,Rodrigues B, Cholinergic Stimulation by Pyridostigmine Bromide Before Myocardial Infarction Prevent Cardiac and Autonomic Dysfunction. Scientific reports. 2019 Feb 21     [PubMed PMID: 30792425]

[15]

Nattero-Chávez L,Redondo López S,Alonso Díaz S,Garnica Ureña M,Fernández-Durán E,Escobar-Morreale HF,Luque-Ramírez M, Association of Cardiovascular Autonomic Dysfunction With Peripheral Arterial Stiffness in Patients With Type 1 Diabetes. The Journal of clinical endocrinology and metabolism. 2019 Jul 1     [PubMed PMID: 30786000]

[16]

Traunmüller C,Stefitz R,Gaisbachgrabner K,Hofmann P,Roessler A,Schwerdtfeger AR, Psychophysiological concomitants of burnout: Evidence for different subtypes. Journal of psychosomatic research. 2019 Mar     [PubMed PMID: 30782353]

[17]

Allen DR,Huang MU,Morris NB,Chaseling GK,Frohman EM,Jay O,Davis SL, Impaired Thermoregulatory Function during Dynamic Exercise in Multiple Sclerosis. Medicine and science in sports and exercise. 2019 Mar     [PubMed PMID: 30779715]

[18]

Freeman R,Wieling W,Axelrod FB,Benditt DG,Benarroch E,Biaggioni I,Cheshire WP,Chelimsky T,Cortelli P,Gibbons CH,Goldstein DS,Hainsworth R,Hilz MJ,Jacob G,Kaufmann H,Jordan J,Lipsitz LA,Levine BD,Low PA,Mathias C,Raj SR,Robertson D,Sandroni P,Schatz I,Schondorff R,Stewart JM,van Dijk JG, Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clinical autonomic research : official journal of the Clinical Autonomic Research Society. 2011 Apr     [PubMed PMID: 21431947]

[19]

Barbato AL,Walker HK,Hall WD,Hurst JW, Bedside Evaluation of the Autonomic System Clinical Methods: The History, Physical, and Laboratory Examinations. 1990     [PubMed PMID: 21250243]

[20]

Rathmann W,Enck P,Frieling T,Gries FA, Visceral afferent neuropathy in diabetic gastroparesis. Diabetes care. 1991 Nov     [PubMed PMID: 1797493]

[21]

Verbaan D,Marinus J,Visser M,van Rooden SM,Stiggelbout AM,van Hilten JJ, Patient-reported autonomic symptoms in Parkinson disease. Neurology. 2007 Jul 24     [PubMed PMID: 17646625]

[22]

Asahina M,Vichayanrat E,Low DA,Iodice V,Mathias CJ, Autonomic dysfunction in parkinsonian disorders: assessment and pathophysiology. Journal of neurology, neurosurgery, and psychiatry. 2013 Jun;     [PubMed PMID: 22942216]

[23]

Kadoya M,Koyama H, Sleep, Autonomic Nervous Function and Atherosclerosis. International journal of molecular sciences. 2019 Feb 13     [PubMed PMID: 30781734]

[24]

Baschieri F,Cortelli P, Circadian rhythms of cardiovascular autonomic function: Physiology and clinical implications in neurodegenerative diseases. Autonomic neuroscience : basic & clinical. 2019 Mar     [PubMed PMID: 30744907]

[25]

Bellon G,Venturin A,Masiero S,Del Felice A, Intra-articular botulinum toxin injection in complex regional pain syndrome: Case report and review of the literature. Toxicon : official journal of the International Society on Toxinology. 2019 Mar 1     [PubMed PMID: 30660558]

[26]

Lanier JB,Mote MB,Clay EC, Evaluation and management of orthostatic hypotension. American family physician. 2011 Sep 1     [PubMed PMID: 21888303]

[27]

Lahrmann H,Cortelli P,Hilz M,Mathias CJ,Struhal W,Tassinari M, EFNS guidelines on the diagnosis and management of orthostatic hypotension. European journal of neurology. 2006 Sep     [PubMed PMID: 16930356]

[28]

Gupta V,Lipsitz LA, Orthostatic hypotension in the elderly: diagnosis and treatment. The American journal of medicine. 2007 Oct     [PubMed PMID: 17904451]

[29]

Lamarre-Cliche M,Cusson J, The fainting patient: value of the head-upright tilt-table test in adult patients with orthostatic intolerance. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2001 Feb 6;     [PubMed PMID: 11232140]

[30]

Nwazue VC,Raj SR, Confounders of vasovagal syncope: orthostatic hypotension. Cardiology clinics. 2013 Feb     [PubMed PMID: 23217690]

[31]

Fedorowski A,Melander O, Syndromes of orthostatic intolerance: a hidden danger. Journal of internal medicine. 2013 Apr     [PubMed PMID: 23216860]

[32]

Shibao C,Lipsitz LA,Biaggioni I, ASH position paper: evaluation and treatment of orthostatic hypotension. Journal of clinical hypertension (Greenwich, Conn.). 2013 Mar     [PubMed PMID: 23458585]

[33]

Raj SR,Coffin ST, Medical therapy and physical maneuvers in the treatment of the vasovagal syncope and orthostatic hypotension. Progress in cardiovascular diseases. 2013 Jan-Feb     [PubMed PMID: 23472781]

[34]

Biaggioni I,Arthur Hewitt L,Rowse GJ,Kaufmann H, Integrated analysis of droxidopa trials for neurogenic orthostatic hypotension. BMC neurology. 2017 May 12;     [PubMed PMID: 28494751]

[35]

Palma JA,Norcliffe-Kaufmann L,Martinez J,Kaufmann H, Supine plasma NE predicts the pressor response to droxidopa in neurogenic orthostatic hypotension. Neurology. 2018 Oct 16;     [PubMed PMID: 30232253]

[36]

Seppi K,Ray Chaudhuri K,Coelho M,Fox SH,Katzenschlager R,Perez Lloret S,Weintraub D,Sampaio C,the collaborators of the Parkinson's Disease Update on Non-Motor Symptoms Study Group on behalf of the Movement Disorders Society Evidence-Based Medicine Committee., Update on treatments for nonmotor symptoms of Parkinson's disease-an evidence-based medicine review. Movement disorders : official journal of the Movement Disorder Society. 2019 Feb     [PubMed PMID: 30653247]

[37]

Pfeiffer RF, Gastrointestinal dysfunction in Parkinson's disease. Parkinsonism & related disorders. 2011 Jan     [PubMed PMID: 20829091]

[38]

Cloud LJ,Greene JG, Gastrointestinal features of Parkinson's disease. Current neurology and neuroscience reports. 2011 Aug     [PubMed PMID: 21499704]

[39]

Thomsen TR,Galpern WR,Asante A,Arenovich T,Fox SH, Ipratropium bromide spray as treatment for sialorrhea in Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society. 2007 Nov 15;     [PubMed PMID: 17876852]

[40]

Raffaele R,Vecchio I,Giammusso B,Morgia G,Brunetto MB,Rampello L, Efficacy and safety of fixed-dose oral sildenafil in the treatment of sexual dysfunction in depressed patients with idiopathic Parkinson's disease. European urology. 2002 Apr;     [PubMed PMID: 12074807]

[41]

Bradley JG,Davis KA, Orthostatic hypotension. American family physician. 2003 Dec 15     [PubMed PMID: 14705758]

[42]

van Hateren KJ,Kleefstra N,Blanker MH,Ubink-Veltmaat LJ,Groenier KH,Houweling ST,Kamper AM,van der Meer K,Bilo HJ, Orthostatic hypotension, diabetes, and falling in older patients: a cross-sectional study. The British journal of general practice : the journal of the Royal College of General Practitioners. 2012 Oct     [PubMed PMID: 23265229]

[43]

Gangavati A,Hajjar I,Quach L,Jones RN,Kiely DK,Gagnon P,Lipsitz LA, Hypertension, orthostatic hypotension, and the risk of falls in a community-dwelling elderly population: the maintenance of balance, independent living, intellect, and zest in the elderly of Boston study. Journal of the American Geriatrics Society. 2011 Mar     [PubMed PMID: 21391928]

[44]

Luukinen H,Koski K,Laippala P,Airaksinen KE, Orthostatic hypotension and the risk of myocardial infarction in the home-dwelling elderly. Journal of internal medicine. 2004 Apr     [PubMed PMID: 15049883]

[45]

Kruit MC,Thijs RD,Ferrari MD,Launer LJ,van Buchem MA,van Dijk JG, Syncope and orthostatic intolerance increase risk of brain lesions in migraineurs and controls. Neurology. 2013 May 21;     [PubMed PMID: 23616159]

[46]

Kaufmann H,Norcliffe-Kaufmann L,Palma JA,Biaggioni I,Low PA,Singer W,Goldstein DS,Peltier AC,Shibao CA,Gibbons CH,Freeman R,Robertson D,Autonomic Disorders Consortium., Natural history of pure autonomic failure: A United States prospective cohort. Annals of neurology. 2017 Feb     [PubMed PMID: 28093795]

[47]

Magkas N,Tsioufis C,Thomopoulos C,Dilaveris P,Georgiopoulos G,Doumas M,Papadopoulos D,Tousoulis D, Orthostatic hypertension: From pathophysiology to clinical applications and therapeutic considerations. Journal of clinical hypertension (Greenwich, Conn.). 2019 Feb 6;     [PubMed PMID: 30724451]

[48]

Grisanti LA, Diabetes and Arrhythmias: Pathophysiology, Mechanisms and Therapeutic Outcomes. Frontiers in physiology. 2018     [PubMed PMID: 30534081]