Anatomic and Physiologic Remarks
The principal role of the autonomic nervous system (ANS) is the maintenance of homeostasis by regulating and integrating the activities of essentially all organs. The ANS has been divided into the central autonomic system also called central autonomic network (CAN) or the preganglionic system, and the peripheral or postganglionic system, which includes the parasympathetic, sympathetic, and enteric systems. ANS regulates internal organs and controls heart rate, blood pressure, sweating, digestion, respiration, pupillary reactivity, urination, and sexual arousal.
The ANS has three main branches: the sympathetic nervous system, the parasympathetic nervous system, and the enteric nervous system. The sympathetic and parasympathetic systems have opposite actions ( Table 22.1 ). The sympathetic system is the “fight or flight” system, while the parasympathetic is the “rest and digest” system. The enteric nervous system controls gut functions, and although it is relatively autonomous, it has numerous connections with the central nervous system.
| Organ/System | Sympathetic(Fight or Flight) | Parasympathetic(Rest and Digest) |
|---|---|---|
| Pupil | Dilatation | Constriction (CN III) |
| Salivary gland | Inhibition | Stimulation (CN VII, IX) |
| Heart | Increases | Decrease (CN X) |
| Vessels | Constricts most vessels except dilates vessels of the skeletal muscles during exercise | Minimal or no effect |
| Sweat glands | Stimulates sweating | No innervation |
| Bronchi | Relaxation | Constriction (CN X) |
| Digestion | Inhibition (CG), decreased activity of glands and muscles of digestive system, vasoconstriction and sphincter contraction | Stimulation (CN X). Increased motility and secretion in the digestive system, relaxes sphincter |
| Liver | Stimulation of glucose production (CG) | No effect |
| Adrenal glands | Stimulation | |
| Bladder |
| Contraction of detrusor (sacral) |
| Penis | Ejaculation (IMG) | Erection (sacral) |
| Vagina, clitoris | Contraction | Erection |
| Coagulation | Increases | |
| Fat tissue | Stimulates lipolysis |
Autonomic fibers are small, lightly myelinated Aδ fibers and unmyelinated C fibers. Sympathetic preganglionic fibers originate in the intermediolateral nucleus of the spine at the T1–L2 level. The fibers synapse at the sympathetic ganglia, which send the postganglionic (postsynaptic) fibers to the effector organs. Parasympathetic preganglionic fibers originate in the cranial nuclei and at the sacral portion of the spine.
The CAN is composed of structures dispersed throughout the central nervous system. CAN structures include the insular cortex, cingular gyrus, amygdala, hypothalamus, thalamus, brain stem nuclei, and ventrolateral medulla. Integration centers are composed of neurons with autonomic and nonautonomic functions. For example, the periventricular nucleus of the hypothalamus integrates autonomic functions with the energy balance.
The CAN controls autonomic functions and at the same time modulates a number of other functions, including emotional, attentional, behavioral, endocrine, respiratory, vestibular, sexual, and pain responses. The CAN is connected with all organs through the parasympathetic and sympathetic nerves innervations. Many CAN centers are defined by their function rather than by distinct anatomic or histologic landmarks. For example, the reticular formation in the brain stem is a complex network of nuclei that integrate and coordinate many vital brain systems without having precise boundaries of nuclei. Most structures of the CAN are bilaterally and reciprocally interconnected, and usually a bilateral lesion is needed to produce a well-defined and lasting effect.
Neurotransmitters and Neuromodulators
The main excitatory neurotransmitters in the ANS are amino acid glutamate and aspartate, and the inhibitory neurotransmitter is γ-aminobutyric acid. These transmitters elicit fast, short-lasting responses mediated specific ion channel receptors. The neurotransmitters that are characteristic for ANS functions are catecholamines (norepinephrine and epinephrine) and acetylcholine. Preganglionic sympathetic and parasympathetic neurons utilize acetylcholine. Postganglionic neurons of the parasympathetic nervous system utilize acetylcholine via cholinergic fibers. Postganglionic neurons of the sympathetic nervous system release norepinephrine upon activation via adrenergic fibers. The adrenal medulla is the major source of epinephrine, which is released into the blood. A number of additional, especially peptidergic neurotransmitters were described in the central autonomic network with a profound effect upon autonomic functions. Many of these transmitters interact with the principal transmitters and modulate autonomic responses, through G protein–coupled specific receptors.
Nomenclature Remarks
Neuropathy is a broader term that signifies damage to the whole neuronal system. Neuronopathy is a form of neuropathy that results from a degeneration of the neuronal cell body. Ganglionopathy is a neuronopathy with damage to the ganglionic cells, either sensory or autonomic.
Malfunction of the autonomic system is called autonomic dysfunction or dysautonomia. The term “dysautonomia” is an umbrella term that covers any type of autonomic dysfunction. Autonomic failure is a type of dysautonomia that manifests clinically as autonomic hypoactivity. By definition, the isolated failure of one system leads to unopposed action of the other. For example, isolated damage of the parasympathetic “rest” system leads to unopposed action of the sympathetic “fight” system with a net effect of sympathetic overactivity, such as hypertension. Thus the term “autonomic failure” is used when the autonomic hypofunction dominates. A typical example of autonomic failure is neurogenic orthostatic hypotension (NOH). In autonomic hyperactivity, the net effect of the lesion is parasympathetic or sympathetic overactivity, such as in several types of hypertension. Dysautonomia can be continuous or paroxysmal (intermittent); acute, subacute or chronic; and preganglionic (affecting the central nervous system), postganglionic (peripheral), or mixed, affecting both central and peripheral nervous system.
Many small sensory fibers are located in close proximity to autonomic fibers and are frequently damaged together with autonomic fibers; therefore sensory and autonomic symptoms accompany each other, as is seen in mixed small fiber neuropathies. If the pain prevails, the term “painful small fiber neuropathy” is used; for predominantly autonomic symptoms, the term “autonomic neuropathy” is used. Probably the most common are mixed small fiber neuropathies with variable proportion of sensory and autonomic complaints.
Autonomic Symptoms
The ANS acts unconsciously via efferent (motor) fibers; therefore autonomic dysfunction manifests as an organ malfunction. For example, damage of vasomotor fibers may result in neurogenic orthostatic hypotension (OH). In contrast, activity of sensory small fibers can be felt, and thus their dysfunction may result in a variety of neuropathic complaints including pain or burning sensation.
Dysautonomia is associated with numerous symptoms. They can be divided into orthostatic, nonorthostatic, and diffuse ( Box 22.1 ). Orthostatic symptoms are typically associated with cerebral hypoperfusion (typically manifesting as lightheadedness and dizziness) and/or sympathoexcitation (typically manifesting aspalpitation and restlessness). Frequent nonorthostatic symptoms include gastrointestinal and urinary problems, cold or hot intolerance, excessive sweating or loss of sweating, and erectile dysfunction in males. Common additional nonspecific complaints include fatigue, headaches, brain fog, and insomnia. The majority of patients present with a combination of orthostatic and nonorthostatic symptoms.
Orthostatic
Lightheadedness or dizziness
Syncope
Impending fainting sensation (presyncope)
Palpitations
Sense of weakness
Restlessness
Tremulousness
Nausea
Shortness of breath
Pallor,
Vertigo
Chest pain
Exacerbation by heat, exercise, meals, menses
Visual loss
Exercise intolerance
Neck pain
Nonorthostatic
Dysphagia, odynophagia, heartburn, reflux
Nausea, vomiting
Early satiety, bloating
Diarrhea, constipation
Abdominal pain
Bladder symptoms: incomplete emptying, incontinence
Pupillary symptoms
Dry eyes or mouth
Impotence, erectile dysfunction
Changes in skin color and texture
Hair loss
Hyperemia, cold, pale feet
Excessive sweating
Loss of sweating
Cold or hot intolerance
Erectile dysfunction
Diffuse
Fatigue
Sleep disturbances
Migraine
Brain fog
Sensory Symptoms
Damage of small sensory fibers is typically associated with burning pain on the feet or hands and less frequently with lightning-like or lancinating pain, aching, or uncomfortable paresthesia (dysesthesias) or with pain to nonpainful stimuli (allodynia). Chest pain and dyspnea are also frequent.
Examination
History Taking
Guidelines for taking a medical history and performing a medical examination should be followed. A careful past medical history and a detailed review of medications are necessary. Dysautonomia due to medication effect is very common in elderly people; therefore a detailed review of the use of any medication that can interact with the ANS is of utmost importance. Many medications interact with the ANS, including common drugs used for therapy for depression and pain with anticholinergic effect and antihypertensive/urinary medications with antiadrenergic effect.
The onset of the presenting problem is important diagnostically and must be documented (sudden, gradual, insidious) as well as the duration (acute, subacute, chronic), progression (rapidly or slowly progressive, static, regressive), and severity (mild, moderate, severe) of illness. Patients need to be questioned about the use of drugs, alcohol, diet, supplements, toxic exposures, history of Lyme disease, and history of travel and risk behavior. Dysautonomia features include the simultaneous involvement of multiple organ systems, fluctuations of symptoms from day to day or from position to position, history of hypermobility, multiple allergies, poor healing, or frequent infections. The patient’s voiding and gastrointestinal history and any voiding or gastrointestinal complaints can be helpful for assessment of neurogenic bladder and gastric motility disorders.
Physical Examination
Specific features of the autonomic examination are postural variations in the blood pressure and heart rate, pupillary light reactions, skin temperature and color, and patterns of sweating. The dryness of the skin or excessive sweating, cold distal limbs, and pupillary changes point to dysautonomia. The blood pressure and heart rate must be measured with the patient in the supine position, preferentially after at least 10 minutes of rest, and during standing. The vital signs should be obtained at the first minute and third minute at a minimum. If postural tachycardia syndrome or delayed OH is suspected, the heart rate and blood pressure should be checked up to the 10th minute or longer of standing. Ideally, both blood pressure and heart rate should be checked every minute of standing. This approach can detect OH, which can occur at any time during standing. OH without a compensatory rise in heart rate usually indicates autonomic failure. A reduced or elevated core temperature may indicate central dysautonomia with abnormal hypothalamic functions. Dry mouth and dry eyes are common in dysautonomia affecting the sudomotor system. Pupillary abnormalities are also common in autonomic neuropathies.
The neurologic evaluation should assess the function of the small fibers, which transmit pain and temperature sensation. Pain and temperature sensation in the distal leg are abnormal in small fiber neuropathy (SFN). Sensation to light touch can be affected, but it is nonspecific, since it is carried by both large and small fibers. Vibration sense and proprioception, modalities that are transmitted by large fibers, should be normal in small fiber neuropathies unless there is concomitant involvement of large fibers. Deep tendon reflexes should be normal, and there should not be a muscle weakness in SFN.
Laboratory Evaluation
Laboratory evaluation complements the history and physical examination. Patients with suspected dysautonomia might benefit from a thyroid function test, 12-lead electrocardiogram, hematocrit, 24-hour ambulatory blood pressure monitoring, transthoracic echocardiogram, exercise stress testing, and carotid sinus massage. If orthostatic vital signs are normal and the clinical suspicion of orthostatic intolerance is high, autonomic testing can be considered.
Established autonomic cardiovascular reflex function tests include deep breathing, Valsalva maneuver, and the tilt test. The deep breathing test evaluates parasympathetic cardiovagal function. The Valsalva maneuver and tilt test measure predominantly sympathetic adrenergic function. Monitoring of cerebral blood flow with end-tidal CO 2 during the tilt tests is essential for differential diagnosis of postural tachycardia syndrome (POTS), hypocapnic cerebral hypoperfusion(HYCH), orthostatic cerebral hypoperfusion syndrome (OCHOS), and syncope. A neuronal autoimmunity panel ( Table 22.2 ) may be ordered for suspected autoimmune dysautonomia or SFN.
| Antibody | Underlying Tumor DiseaseAutonomic Syndromes |
|---|---|
| NMO/AGP4 |
|
| Anti-Hu/ANNA-1 |
|
| ANNA-2 |
|
| ANNA-3 |
|
| AGNA-1 | Autonomic neuropathy, pseudoobstruction |
| CRMP-5/Anti-CV2 |
|
| Anti-Yo/PCA-1 |
|
| PCA-2 |
|
| PCA-TR |
|
| CRMP-5 IgG | Small cell lung carcinoma |
| Antiamphiphysin |
|
| P/Q-type voltage-gated calcium channel |
|
| N -type voltage-gated calcium channel |
|
| Ganglionic (α3) acetylcholine receptor |
|
| Muscarinic (M3) acetylcholine receptor |
|
| VGKC |
|
| CASPR2 |
|
| LGIi (glioma inactivated 1 protein-IgG) |
|
| TS-HDS | Painful small fiber neuropathy |
| FGFR3 | Sensory small fiber neuropathy |
| Striated muscle antibody |
|
| GAD65 | Thymoma, renal cell carcinoma, breast cancer, colon adenocarcinoma variable |
Postganglionic sudomotor functions can be evaluated by the quantitative sudomotor axon test (QSART), electrochemical skin conductance (ESC), or sympathetic skin response (SSR). Skin biopsies can be used for direct evaluation of small nerve fiber damage. Epidermal nerve fiber density (ENFD) evaluates sensory fibers and sweat gland nerve fiber density (SGNFD) evaluates autonomic sudomotor fibers. Gastroenterology motility studies can be considered for evaluation of gastric motility disorders when enteric neuropathy is suspected. Urodynamic studies may be used to assess neurogenic bladder.
Consultations With Specialists
A consultation with a specialist is warranted if a patient presents with a severe dysautonomia that had an acute or subacute onset and/or is rapidly progressing. A referral for autonomic testing is also recommended for patients with established diagnoses whose symptoms are responding poorly to therapy.
Classification of Autonomic and Related Disorders
There are several classification schemes, but from the clinical point of view, dysautonomia can be conceptually divided into orthostatic intolerance syndromes, central dysautonomia, and small fiber neuropathies. According to another classification system, primary dysautonomia includes orthostatic intolerance syndromes, small fiber neuropathies with autonomic involvement, and pure autonomic failure (PAF). Secondary dysautonomia includes a number of other conditions in which dysautonomia coexists with other symptoms or signs.
Orthostatic Intolerance Syndromes
The term “orthostatic intolerance” is a broad term but has a specific meaning in autonomic neurology. It is used to describe symptoms that occur upon standing, and are relieved by recumbence that cannot be explained by other disorders, such as cardiovascular or pulmonary disease. Orthostatic symptoms that may occur with cardiovascular, respiratory, metabolic, or systemic disorders are not considered part of orthostatic intolerance syndromes. Common orthostatic intolerance syndromes are presyncope, neurally mediated syncope, NOH, postural tachycardia syndrome, hypocapnic cerebral hypoperfusion, and orthostatic cerebral hypoperfusion syndrome ( Table 22.3 and Fig. 22.1 ).
| Name | Definitions |
|---|---|
| POTS |
|
| HYCH |
|
| Syncope, neurally mediated |
|
| Presyncope | Probably common and poorly understood syndrome that may correspond to incomplete syncope, HYCH, or OCHOS. |
| Neurogenic OH |
|
| OCHOS | Orthostatic decline in cerebral blood flow velocity without OH and without hypocapnia |
| IST |
|
| PST | A transient and exaggerated heart rate increment ≥30 bpm occurring before the third minute of the tilt test or active standing. OH is absent. |
| Orthostatic hypertension syndrome | A postural increase of systolic blood pressure by at least 20 mm Hg or above 120% where the supine baseline is equal to 100% |
| Psychogenic pseudosyncope | Apparent loss of consciousness without global cerebral hypoperfusion |
| Baroreflex failure |
|
Presyncope
Presyncope, also known as near syncope, is a sensation of feeling faint, lightheaded, or dizzy without fainting. Presyncope is a very common and poorly understood syndrome. Dysautonomia is among multiple potential causes of presyncope, including cardiac and noncardiac.
Neurally Mediated Syncope
Syncope is a transient loss of consciousness due to global cerebral hypoperfusion ( Table 22.3 ).
Syncope is very common, with a lifetime cumulative incidence of 35%, affecting more females, in 66% of cases of the neurally mediated subtype. Neurally mediated (reflex) syncope is triggered by still poorly understood reflex associated with a withdrawal of sympathetic traffic, resulting in vasodilation, a reduction in peripheral resistance, venous return, and preload, resulting in systemic hypotension and reduced cardiac output. Neurally mediated syncope can be further divided into cardiovagal (vasovagal, cardioinhibitory), vasodepressor, and the most common mixed type of syncope. Evaluation is focused to rule out cardiac syncope because of the difference in treatment and prognosis of cardiac syncope. Isolated neurally mediated syncope has good prognosis except when associated with autonomic failure and OH. Treatment of neurally mediated syncope includes both nonpharmacologic and pharmacologic approaches ( Box 22.2 ). Proamatine can be effective in preventing vasovagal syncope. Cardiac syncope may be life threatening.
Nonpharmacologic
Education about the condition
Avoidance of precipitating factors in situational syncope
Physical therapy
Countermaneuvers: crossing, squatting or tensing of lower extremities at the onset of prodromes
Pharmacotherapy
Proamatine is modestly effective for vasovagal syncope
Conflicting results have been shown for beta-blockers or fludrocortisone
Paroxetine for patients with concurrent psychiatric illness
Permanent Dual-Chamber Pacing
Usually reserved for patients with severe asystole
Postural Tachycardia Syndrome
POTS is one of the most common forms of orthostatic intolerance, and it is estimated to affect up 3 million Americans. POTS affects more females (female-to-male ratio: 5:1) and ages from adolescence (>15) to adulthood (<50 years). POTS is associated with the orthostatic intolerance and the presence of excessive tachycardia upon standing ( Table 22.3 ).
POTS has been associated in a subset of patients with mast cell disorders including hereditary tryptasemia, hypermobile Ehlers-Danlos syndrome, and hypermobility spectrum disorder.
Nonorthostatic symptoms are common in POTS, including gastrointestinal, insomnia, impaired cognitive functions, depression, and anxiety. POTS is a syndrome with multiple causes, including neuropathy, hypovolemia, and hyperadrenergic state. POTS can be diagnosed at the office by observing symptomatic excessive tachycardia in the standing position without OH. Autonomic testing can be used to get a more detailed evaluation of POTS, including its subtypes. Therapy for POTS is complex and includes education and a variety of nonpharmacologic approaches ( Box 22.3 ). Pharmacotherapy is usually reserved for more advanced POTS.
Neurogenic Orthostatic Hypotension
OH is defined as a decrease in systolic blood pressure of ≥20 mm Hg or a decrease in diastolic blood pressure of ≥10 mm Hg ( Table 22.3 ). Although OH is common (prevalence: 5%–30%) and has numerous causes, OH is rare. It results from impaired sympathetic vasoconstriction. OH is associated with sympathetic and parasympathetic failure, which can be confirmed by an autonomic testing. OH can be seen in Parkinson disease (37%–58%), multiple system atrophy (75%), PAF (100%), diabetic (7.4%–8.4%) and nondiabetic small fiber neuropathies, and acute dysautonomia. Box 22.4 and Table 22.4 summarize nonpharmacologic and pharmacologic treatment of OH and related postprandial hypotension.
Nonpharmacologic
Education about the condition
Avoidance of precipitating factors/triggers
Diet:
Bolus ingestion of 500 mL water
Small frequent meals
Daily >8 g of sodium (1 g of salt = 0.4 g of sodium)
Daily >1. 5 L of fluids
Compression stockings, pantyhose size, pressure 20–40 mm Hg
Compression garment (leggings)
Corset
Physical therapy
Physical countermaneuvers: leg crossing, squatting, tiptoeing, bending forward
Physical maneuvers: Squatting, genuflection-contraction, knee flexion, toe raise, neck flexion, abdominal contraction, thigh contraction, combination
Sleeping with head-up tilt 30 degrees
Pharmacotherapy
Fludrocortisone, proamatine, pyridostigmine, droxydopa, yohimbine, atomoxetine, ephedrine, erythropoetin
| Name | Main Features |
|---|---|
|
|
|
|
|
|
|
|
| Atomoxetine |
|
| Ephedrine |
|
| Erythropoietin |
|
Hypocapnic Cerebral Hypoperfusion
HYCH is a form of orthostatic intolerance with reduced orthostatic cerebral blood flow velocity due to hypocapnia but without excessive tachycardia or OH ( Table 22.2 ).
Clinical presentations are similar to that of POTS except that the postural tachycardia is absent. HYCH affect predominantly females of age <50 years, and typical complaints are orthostatic dizziness, shortness of breath, chronic fatigue, and a variety of other autonomic symptoms. Autonomic testing shows similar patterns in HYCH and POTS except that excessive tachycardia is absent in HYCH. Therefore HYCH and POTS may represent a spectrum of the same disorder. Treatment of HYCH is similar to POTS therapy with a combination of nonpharmacologic and pharmacologic approaches ( Box 22.3 ). Pyridostigmine and selective serotonin reuptake inhibitors may improve shortness of breath.
Nonpharmacologic
Education about the condition
Avoidance of precipitating factors
Diet:
Daily >8 g of sodium (not for hyperadrenergic variant with elevated blood pressure)
(1 g of salt = 0.4 g of sodium)
Daily >1. 5 L of fluids
Compression stockings, pantyhose size, pressure 20–40 mm Hg
Compression garment (leggings)
Corset
Graded exercise training
Physical therapy
Reclined exercise, such as swimming, reconditioning program
Countermaneuvers
Stress management
Pharmacotherapy
Beta-blockers:
Hypovolemic form: fludrocortisone
Vasoconstrictors
Proamatine
Droxidopa
Pyridostigmine
Ivabradine
Hyperadrenergic form:
Clonidine 0.1–0.2 mg po twice a day or patch, can cause drowsiness
Alpha methyl dopa 125–250 mg po bid po, can cause drowsiness
Immunomodulation (IVIG) for autoimmune form
Orthostatic Cerebral Hypoperfusion Syndrome
OCHOS is associated with orthostatic intolerance and reduced orthostatic cerebral blood flow velocity without OH, bradycardia, hypocapnia, and excessive tachycardia ( Table 22.3 ). OCHOS may result from abnormal cerebral arteriolar vasoconstriction associated with cerebral autoregulatory failure. OCHOS has been described in postacute sequelae of COVID-19 and Long COVID disease. Our approach to therapy of OCHOS is the use of calcium channel blockers or angiotensin-converting enzyme blockers for patients with hypertension or prehypertension and volume expansion with salt, fluids, fludrocortisone, or the use of pressor medications in patients with low blood pressure.
Inappropriate Sinus Tachycardia
Inappropriate sinus tachycardia (IST) resembles POTS except that there is a persistent tachycardia (>100 bpm) at rest even in a supine position ( Table 22.3 ). Exercise or an upright position may induce exaggerated (“inappropriate”) tachycardia. The treatment of IST includes beta-blockers and ivabradine. Drug-refractory patients may need ablation. The long-term outcome is benign for most patients.
Paroxysmal Sinus Tachycardia
Paroxysmal sinus tachycardia is associated with a transient increase in the heart rate ≥30 bpm usually at the beginning of the tilt and can be due to underlying anxiety disorder ( Table 22.3 ).
Dysautonomia in neurodegenerative disorders
Typical neurodegenerative disorders associated with prominent dysautonomia are multiple system atrophy (MSA), Parkinson disease, and PAF ( Table 22.5 ). Postprandial hypotension can be part of dysautonomia in neurodegenerative disorders.
| Disorders | Comments |
|---|---|
| Parkinson disease |
|
| Multiple system atrophy |
|
| Pure autonomic failure |
|
Parkinson Disease
Parkinson disease (PD) affects more than 1 million Americans and is the second most common neurodegenerative disease after Alzheimer dementia. PD has average onset at approximately 60 years of age and survival of 15 years. Dysautonomia manifesting as a small fiber polyneuropathy is a frequent nonmotor complication, correlates with decreased activities of daily living and poor quality of life, and may indicate disease progression in PD. PD is associated with a generalized autonomic failure of variable severity. SFN affects all autonomic branches, including the adrenergic, the parasympathetic, and the sudomotor functions, including cardiac and sympathetic denervation. The most severe symptom of PD is OH due to adrenergic failure. OH affects about 58% of PD patients and is a major risk factor for falls and cognitive decline. OH can be associated with failure of cerebral autoregulation and reduced brain perfusion during standing up.
Multiple System Atrophy
MSA is an alpha-synucleinopathy with rapidly progressing symptoms that span multiple neurologic systems, including cognitive, autonomic, cerebellar, and both pyramidal and extrapyramidal motor pathways. The average age of onset is earlier than that of PD (58–61 years), and average survival is shorter (6.2–7.5 years). An early, prominent, and severe dysautonomia is characteristic of MSA and can precede motor symptoms by years. Autonomic symptoms are widespread and include sphincter dysfunction (urinary incontinence, constipation), erectile dysfunction, OH, respiratory stridor, and sweat gland dysfunction. Cognitive impairment is common and primarily affects the frontal/executive, visuospatial, memory, and emotional regulatory systems.
Pure Autonomic Failure
Pure autonomic failure (PAF) is a rare alpha-synucleinopathy that affects <0.003% of the population and has a good prognosis, with survival >20 years. PAF affects primarily autonomic fibers, without motor involvement. The most common manifestation is OH due to denervation of adrenergic postganglionic fibers, but parasympathetic fibers are also involved. A diagnosis of PAF should be considered in patients with chronic OH but mild or no neurologic or motor symptoms. Other presentations may include mild incoordination, supine hypertension, postprandial hypotension, constipation acral venous pooling, anhidrosis, urinary and sexual dysfunction, and anemia.
Orthostatic Hypotension Management
OH, a marker of more advanced autonomic failure, poses a serious risk to the brain due to failure of cerebral autoregulation and cerebral hypoperfusion and also poses a risk of ischemic injury to other organs. Management of OH includes nonpharmacologic and pharmacologic approaches ( Box 22.4 , Table 22.4 ). Table 22.6 shows treatment modalities for postprandial hypotension.
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