Innervating every organ system in the body, the autonomic nervous system sustains biological homeostasis at rest and in response to stress through an intricate network of central and peripheral neurons that function automatically. Autonomic disorders are frequently encountered in clinical practice. Their presentations are diverse, ranging from common to rare, from benign to severe, from localized to generalized, from episodic to continuous, from transient to progressive. They can manifest in a number of ways. Deafferentation of central autonomic centers can disrupt the magnitude or timing of peripheral autonomic effectors. Lesions of autonomic efferent neurons can reduce or nullify autonomic responses. Drugs or antibodies that act on receptors on autonomic neurons can produce a variety of physiologic phenomena from hyperfunction to hypofunction or loss of function. The complex clinical manifestations of autonomic disorders may at first seem enigmatic.
To make sense of autonomic disorders, the clinical evaluation of the patient with autonomic symptoms requires an organized approach. It cannot be overstated that the most important element of the autonomic evaluation is a careful, detailed, nonhurried medical history. Second is the autonomic component of the neurologic examination, and third is laboratory evaluation directed toward the individual patient’s presentation. The goals of evaluation are to identify whether an autonomic disorder is present, to localize and define its distribution, and to gauge its severity. Of particular importance is to detect serious and treatable disorders.
AUTONOMIC MEDICAL HISTORY
Taking the autonomic history is a sophisticated cognitive service that, to be done properly, requires knowledge of neuroanatomy, neurophysiology, neuropharmacology, neurologic diseases, and related general medical conditions. As the autonomic nervous system is integrative, the clinical approach to autonomic disorders should be holistic, not only in its consideration of the complexity of the body but also in its understanding of the patient as a person.
Seldom does the patient with an autonomic concern present with a single, clearly articulated symptom of a readily identified diagnosis that can be easily reversed with treatment. Patients come to the neurologist with nonlinear narratives of multiple symptoms entwined with compelling personal stories. The skillful neurologist will listen attentively, remaining alert to subtle clues, questioning the patient for additional information, and placing the details into context in order to organize the facts into a coherent framework that makes sense out of what may begin as a jumble of experiences.
The art of taking an autonomic history includes taking a full review of autonomic systems and identifying relevant details while knowing which incidental minutiae to exclude. Taking an autonomic history can resemble a dance in which the neurologist and the patient gather information in partnership. Skillful in history taking, the neurologist knows when to direct the discussion so that important areas of inquiry are covered. Expert in the art of medicine, the neurologist also knows when to allow the patient to lead, telling the story in his or her unique way. Patients recall their medical symptoms biographically and subjectively in narratives that should not be expected to conform to the outline of a medical textbook. The adroit neurologist is able to distill disjointed historical fragments into a logical collection of facts, some of which explain, whereas others lead to further questions. When taking notes, it can be helpful to organize the history into sections on a page rather than constrain the patient to follow the neurologist’s sequence of thought or the electronic medical record’s structure for data entry. If the patient digresses as another symptom comes to mind, the neurologist’s pen (or keystrokes) should be nimble enough to move back and forth across categories, filling in details as they emerge. At the end, it may be helpful to summarize key elements of the history back to the patient to ensure they have been understood correctly.
Discerning the Context
As when taking any neurologic history, it is important to define the context in which symptoms occur. Additionally, knowledge of the anatomy, functional organization, and biochemistry of the autonomic nervous system can, like a lens, bring fuzzy facts into sharper focus.
A crucial part of taking the history is to delineate the temporal course of the patient’s symptoms. Did the symptoms begin at a specific point in time, did they evolve gradually, or have they always been present? How rapidly did they develop? If they began suddenly, what else was happening at the time? Was a new medication started? Did the patient have an antecedent viral illness, potential toxic exposure, dietary change, or stressful life event? As time goes on, are the symptoms improving or worsening?
Further questions explore modifying factors. Are the symptoms more pronounced in the early morning or evening, while standing, during or after meals or exercise, or when the weather is cold or hot? How long can the patient stand without discomfort, and of what does the discomfort consist? With continued standing, do the symptoms improve or worsen? Patients with orthostatic intolerance may have difficulty standing for more than a few minutes at a kitchen sink, in a warm shower, or in a waiting line. Some patients will report being able to continue standing only if they shift their weight back and forth from one leg to the other.
The history should explore the complete list of prescribed and over-the-counter medications as well as dietary supplements, as these frequently can affect autonomic function (table 2-1). Because of individual genetic differences in metabolic enzymes, some patients are exquisitely sensitive to certain drugs. Interactions between drugs also can produce unexpected and occasionally serious adverse effects. Which treatments have helped and which have not, at what doses, and for how long? What, if any, side effects were encountered?
Also important is defining the impact of symptoms on the patient’s quality of life. What activities can the patient no longer perform, or, if ability is limited, for how long can the patient perform them? Has transient loss of consciousness resulted in physical injury? Has impaired thermoregulation led to heat intolerance? Has increased sweating led to social withdrawal? Has autonomic impairment created obstacles to relationships, education, or employment? Does the severely debilitated patient have access to adequate social and financial resources for care?
Dysautonomias are syndromic, depending on the part of the autonomic nervous system involved (table 2-2). Specific clinical syndromes can be recognized as they cluster into patterns of presentation, which are described in the next few sections. These patterns reflect the organization of the peripheral autonomic nervous system, which consists of sympathetic, parasympathetic, and enteric divisions. Specific autonomic disorders can affect these systems selectively or in combination.
The sympathetic nervous system comprises noradrenergic, adrenergic, and cholinergic systems, in which the primary chemical messengers are norepinephrine, epinephrine, and acetylcholine, respectively. Sympathetic noradrenergic and cholinergic neurons, which are nonmyelinated and slowly conducting, derive from thoracolumbar chain ganglia. Sympathetic adrenergic neurons are myelinated and rapidly conducting and pass through the sympathetic ganglia without synapsing to innervate the adrenal medulla.
Parasympathetic neurons arise from the brainstem or sacral spinal cord and are myelinated, rapidly conducting, and cholinergic. Their ganglia are near or embedded in their target organs.
Enteric neurons, which derive from neural crest cells, are embedded in the lining of the gastrointestinal tract and consist of two types of ganglia. The myenteric plexus, which controls gastrointestinal motility, receives parasympathetic innervation from the vagus nerve and sympathetic innervation from postganglionic neurons. The submucous plexus, which provides secretomotor innervation, receives parasympathetic innervation only. Both can function independently of the brain, spinal cord, and sympathetic and parasympathetic nerves, although are influenced by them.
Sympathetic Noradrenergic Disorders
Failure of the sympathetic noradrenergic system presents with orthostatic hypotension, which can be disabling. Upon standing, gravity pulls intravascular fluid downward, causing 500 mL to 800 mL of blood to be displaced to splanchnic and proximal lower extremity vascular beds (figure 2-1). In healthy people, the autonomic nervous system promptly compensates for this. The unloading of carotid sinus baroreceptors initiates an increase in sympathetic noradrenergic outflow, causing an increase in peripheral vasoconstrictor tone and cardiac output that compensates for the displacement of blood, thereby sustaining blood pressure and cerebral blood flow. When neurotransmission of norepinephrine at sympathetic postganglionic nerve terminals innervating peripheral blood vessels is deficient, blood pressure drops upon standing. The patient may report dizziness, lightheadedness, weakness, fatigue, graying or dimming of vision, difficulty focusing thoughts, or no symptoms. Severe sympathetic noradrenergic failure is among the neurologic deficits that characterizes multiple system atrophy (case 2-1).
A 63-year-old man presented with the recent onset of hoarseness, lightheadedness after exercising, and urinary incontinence. On further questioning, he reported he had also experienced a gradual decline in mobility, with slowness of gait, loss of balance when turning, and occasional falling; urinary urgency; erectile failure; loss of fine motor hand coordination; and dream enactment behavior. His blood pressure while seated during check-in was reported to be normal at 150/78 mm Hg.
On examination, his blood pressure taken by the neurologist with the patient supine was 190/94 mm Hg and his heart rate was 70 beats/min; after 1 minute of standing, his blood pressure was 84/62 mm Hg and his heart rate was 76 beats/min. Despite the drop in blood pressure, the patient reported that he had no symptoms while standing, although he insisted on sitting down. Other findings included facial hypomimia, hypophonia with admixed dysphonia and ataxia of speech, hypometric saccades, postural instability, anterocollis, poor tandem gait, cogwheel rigidity, and intact tendon reflexes and primary sensory modalities. Autonomic testing demonstrated failure of sudomotor, cardiovagal, and noradrenergic responses.
This case exemplifies the sporadic, neurodegenerative, and fatal α-synucleinopathy multiple system atrophy, which is characterized by progressive autonomic failure in combination with parkinsonian or cerebellar features. Its variable presentations may mimic Parkinson disease or late-onset cerebellar ataxia. Multiple system atrophy may be distinguished from dementia with Lewy bodies, in most cases, by the more severe degree of autonomic failure and absence of dementia or visual hallucinations in multiple system atrophy. The hallmark neuropathologic finding is proteinaceous oligodendroglial cytoplasmic inclusions. Brain MRI may disclose atrophy of the pons, cerebellum, or striatum. Nocturnal inspiratory stridor, if present, should be treated as it can lead to sudden death.
Measures to treat neurogenic orthostatic hypotension include hydration, avoidance of triggers such as rapid postural changes or large meals, elimination of medications that can worsen hypotension, physical countermaneuvers to increase muscle pumping of venous blood, waist-high compressive garments to reduce venous pooling, or an abdominal binder to compress splanchnic vessels. Medications effective for neurogenic orthostatic hypotension include the α-adrenoceptor agonist midodrine and the norepinephrine prodrug droxidopa.
A surprising aspect of orthostatic hypotension is that some patients do not report symptoms despite profound drops in blood pressure, although they will usually insist on sitting down, which promptly restores blood pressure adequate for cerebral perfusion. The absence of expressed symptoms may reflect accommodation to a chronic condition or a reduced ability of the hypoperfused brain to register or describe symptoms. What is important to appreciate is that symptoms alone are unreliable in the diagnosis of orthostatic hypotension. Orthostatic hypotension is defined not by symptoms but by an abnormal change in blood pressure.
The history should explore relationship with factors such as heat exposure, exercise, and meals, as they can transiently exacerbate orthostatic hypotension. Symptoms tend to be worse during the morning hours when patients may be relatively dehydrated. Clarifying the history of medications is also important, as vasodilators, diuretics, and alpha-blockers can unmask or worsen orthostatic hypotension.
When evaluating the patient who has difficulty standing, the neurologist should keep in mind a differential diagnosis that includes orthostatic hypotension as well as nonautonomic conditions such as vertigo, postural instability, ataxia, weakness of leg muscles that support the body against gravity, and osteoarthritis with weight-bearing musculoskeletal pain. Unlike orthostatic hypotension, vertigo manifests as a sensation of movement that is typically rotational and may occur not only when standing but also when the patient turns over while reclining in bed. Postural instability and ataxia, unlike orthostatic hypotension, improve if the patient touches furniture or leans against a wall to restore balance. Lower extremity muscle weakness may be more evident during leg exertion, such as rising from a chair or ascending stairs, than when standing still. Other manifestations of sympathetic noradrenergic failure can include male ejaculatory failure, eyelid ptosis, and lack of piloerection in response to cold.
Sympathetic noradrenergic hyperactivity, on the other hand, can cause palpitations, increased blood pressure and heart rate, pupillary dilatation, or piloerection. Pallor may occur due to cutaneous blood vessel constriction. The history should explore any use of stimulant medications, including agents used to promote weight loss or increase mental energy. When evaluating the patient who has episodic and highly labile hypertension, the neurologist should inquire about any past history of irradiation to the neck (eg, in the treatment of cancer), as damage to the carotid baroreceptors can cause disinhibition of central sympathetic outflow. Sympathetic noradrenergic episodic hyperactivity is also a hallmark of autonomic dysreflexia (case 2-2).
A 38-year-old man with C7 paraplegia resulting from a motor vehicle collision 1 year earlier was hospitalized for the sudden onset of left face and arm weakness with headache. His blood pressure was 200/110 mm Hg and heart rate was 55 beats/min. Head CT disclosed an acute right thalamic lacunar infarction. The onset of symptoms occurred during one of many episodes he had experienced over the past 3 months consisting of hypertension, bradycardia, facial flushing, blurry vision, sweating in the face and arms, cold hands, and piloerection in the trunk and legs.
Urinary bladder catheterization obtained 500 mL of cloudy, blood-tinged urine, after which his blood pressure subsided to 140/76 mm Hg. Following a course of antibiotics for urinary tract infection and a daily program of intermittent self-catheterization to prevent bladder distension, no further episodes of hypertension occurred.
This case illustrates the condition of autonomic dysreflexia, which occurs to some degree in 90% of patients with severe spinal cord injuries above the level of T6. Autonomic dysreflexia can rise to the level of a medical emergency that, if not treated, may lead to myocardial infarction, stroke, or cerebral hemorrhage. These patients lack descending neural inhibition of spinal cord reflexes and peripheral receptors. Sudden episodes of noradrenergic hyperfunction are triggered by sensory stimuli such as bladder distension, urinary tract infection, kidney stones, constipation, fecal impaction, ingrown toenail, or pressure sores. Medical procedures can also trigger this response. The hypertension activates the carotid baroreceptors, causing vagally mediated bradycardia. Treatment consists of removal of the noxious stimulus, which may be mild or initially inapparent. Short-acting antihypertensive agents such as nifedipine or captopril may be required if blood pressure remains elevated after removal of the offending stimulus.
Sympathetic Adrenergic Disorders
Failure of the sympathetic adrenergic system, which causes epinephrine (adrenaline) to be released from the adrenal medulla, can result in seemingly nonspecific symptoms of fatigue. Sympathetic adrenergic hyperactivity is manifested by palpitations, pallor, a queasy stomach due to inhibition of peristalsis, and dilated pupils. Circulating epinephrine also activates palmar and plantar eccrine and axillary apocrine glands and plays a role in emotional sweating.
Sympathetic Cholinergic Disorders
Failure of the sympathetic cholinergic system causes hypohidrosis or anhidrosis, which can impair thermoregulatory sweating, as acetylcholine is the primary neurochemical messenger at eccrine neuroeffector junctions. When anhidrosis is extensive, patients do not tolerate hot weather, especially when exercising, and will report feeling hot, lightheaded, and tired. They may report headache or prickling paresthesia in hot environments. Under conditions of heat stress, patients who do not sweat may experience cutaneous flushing as a secondary mechanism to release heat. These patients can be at increased risk for heat exhaustion or the potentially serious condition of heatstroke. Compensatory hyperhidrosis may occur in body regions that retain sweat function. Involvement of postganglionic sudomotor neurons in diabetic autonomic neuropathy causes sympathetic cholinergic deficits that may be distal, radicular, or global in distribution (case 2-3).
A 51-year-old woman presented with dizziness that occurred when standing, particularly first thing in the morning when she took a shower or stood to dress. Her dizziness also occurred when she stood up after exercising and, on several occasions, led to momentary collapse without loss of consciousness. She did not endorse any sensation of rotation. Her past medical history was significant for a 10-year history of type 2 diabetes mellitus, and her medications included amitriptyline 50 mg at bedtime for burning feet.
Neurologic examination was notable for absent Achilles tendon jerks, decreased sensation to pinprick below the midcalves, normal strength, and no sign of nystagmus. Her blood pressure was 140/86 mm Hg supine, 132/84 mm Hg seated, and 90/62 mm Hg standing, with her heart rate in the low 80s in all postures.
Her fingerstick glucose levels during symptoms were not low; rather, her diabetic control had been suboptimal with a recent hemoglobin A1c of 8.0%. Autonomic testing disclosed quantitative sudomotor axon reflex test (QSART) responses that were reduced in volume at distal sites. Heart rate variability to deep breathing was subnormal for age. Beat-to-beat blood pressure responses to the Valsalva maneuver demonstrated prolonged pressure recovery and absent overshoot.
This case typifies the cause of autonomic neuropathy that is most common in the developed world and increasing in prevalence in the developing world. This patient has a diabetic peripheral neuropathy with evidence of sensory, motor, and autonomic involvement. Her greatest symptoms, in addition to acral neuropathic pain, are caused by neurogenic orthostatic hypotension. Autonomic neuropathy occurs in approximately 70% of patients with long-term diabetes mellitus, and 20% will develop a clinically consequential cardiovascular autonomic neuropathy, which is associated with a twofold increased risk of silent myocardial ischemia and mortality. Treatment of orthostatic hypotension should begin with hydration, each morning replacing water lost during the night and, unless contraindicated by hypertension or renal disease, sodium supplementation to expand intravascular volume. Medications such as amitriptyline that can worsen orthostatic hypotension should be discontinued; in this case, gabapentin would be a reasonable alternative. Symptomatic orthostatic hypotension refractory to conservative measures may be treated with an abdominal binder, waist-high compressive stockings, or the α-adrenergic agonist midodrine 5 mg to 10 mg 2 to 3 times a day during upright activities.
It is important to ask about medications that can inhibit sweating, which fall into two classes. Anticholinergic drugs, of which there are many, reduce sweating by inhibiting the release of acetylcholine. Dry mouth is a common side effect in patients taking anticholinergic medications. Carbonic anhydrase inhibitors such as topiramate and acetazolamide may block sweat production in the eccrine secretory coil.
Sympathetic cholinergic hyperactivity causes hyperhidrosis (increased sweating), which is more often noticed by patients than is hypohidrosis. Hyperhidrosis may be focal, involving the palms and soles, or it may be generalized, often concentrated in the head, neck, and upper chest. Here also the medication history is important, as hyperhidrosis is a common side effect of opioids, selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Heavy sweating along with confusion, agitation, muscle twitching, dilated pupils, increased blood pressure, tachycardia, and diarrhea can signify serotonin syndrome in a patient who has increased the dose of a serotonergic agent.
Parasympathetic Nervous System Disorders
Failure of the cranial component of the parasympathetic nervous system can result in dry mouth, pupillary dilatation, increased heart rate, decreased heart rate variability, and constipation. Failure of the sacral component can result in urinary bladder retention or male erectile failure. Parasympathetic failure occurs along with sympathetic noradrenergic failure in multiple system atrophy (case 2-1).
Parasympathetic hyperactivity can manifest as increased salivation, slower heart rate, nausea, and urinary frequency or urgency. Following injury to the facial nerve from Bell’s palsy or parotid gland surgery, the patient may experience focal gustatory sweating over the cheek as the result of aberrant reinnervation of facial eccrine glands by parasympathetic fibers that formerly innervated the salivary glands.
Enteric Nervous System Disorders
Disturbances of the enteric nervous system encompass a range of clinical presentations that can include nausea, bloating, early satiety, or reflux in the patient with gastroparesis. The patient with esophageal achalasia may report difficulty swallowing, regurgitation, or chest pain. Constipation is a common symptom with many potential causes; when severe, intestinal hypomotility should be considered. Colonic pseudoobstruction from myenteric plexus denervation, for example, causes severe constipation and abdominal distension in the absence of mechanical obstruction.
AUTONOMIC PHYSICAL EXAMINATION
The ascertainment of objective neurologic examination findings is an indispensable part of the evaluation of autonomic disorders. As with other neurologic subspecialties, the autonomic neurologic examination has areas of emphasis to be explored in detail (table 2-3). The physical examination should be informed by an intelligently gathered autonomic history.
Orthostatic Vital Signs
When evaluating the patient who develops symptoms upon standing that are relieved by sitting down, the physical examination is incomplete without measurement of blood pressure and heart rate while standing and comparison to baseline values obtained seated or supine. Orthostatic hypotension cannot be diagnosed on the basis of symptoms any more than hypertension can be. Orthostatic hypotension is defined not by subjective symptoms, which are frequently nonspecific or even absent, but objectively by a sustained reduction in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing. The condition that the reduction be sustained is intended to exclude the transient reduction in blood pressure that can occur in healthy people during the first 20 to 30 seconds of standing and then recovers. For this reason, it is best to measure the standing blood pressure after the patient has been standing for at least 1 minute. When the patient is unable to stand for a full minute, it may be necessary to measure the blood pressure more quickly.
The neurologic assessment seeks to distinguish whether orthostatic hypotension is neurogenic. The systolic blood pressure drop from supine to standing is frequently greater and the heart rate increase is less pronounced when orthostatic hypotension is neurogenic. One reason for this is that neurogenic orthostatic hypotension is often accompanied by supine hypertension, defined as systolic blood pressure of ≥140 mm Hg or diastolic blood pressure of ≥90 mm Hg measured after at least 5 minutes of rest in the supine position. These factors were taken into account in the development of the diagnostic criteria for multiple system atrophy, which assigns greater diagnostic confidence to a reduction in systolic blood pressure of at least 30 mm Hg or diastolic blood pressure of at least 15 mm Hg in the context of other phenotypic features such as parkinsonism or cerebellar ataxia.
Some patients with orthostatic intolerance who do not have orthostatic hypotension will exhibit an excessive increase in heart rate when standing. The postural tachycardia syndrome (POTS) is defined as a sustained heart rate increment of ≥30 beats/min within 10 minutes of standing or head-up tilt in the absence of orthostatic hypotension. Transient acceleration of heart rate during the first 15 to 30 seconds of standing is normal. For patients younger than 20 years of age, a heart rate increment of ≥40 beats/min is required to diagnose postural tachycardia syndrome.
When obtaining orthostatic vital signs, the patient should rest in the supine posture for at least 2 minutes before baseline measurements are taken. Standing measurements are best taken after at least 1 minute of standing, as the autonomic response to standing takes 20 to 30 seconds to equilibrate. If orthostatic hypotension is not present but, on the basis of the history, is strongly suspected, then repeating standing measurements at 2 to 5 minutes may be informative.
In addition to blood pressure and heart rate, further physical signs may be present upon standing. The patient with profound orthostatic hypotension (eg, systolic blood pressure <80 mm Hg) may begin to lean forward, which decreases the vertical distance between the heart and the circle of Willis, thereby increasing blood flow to the brain. The patient with orthostatic intolerance may shift weight from one leg to the other, activating the muscle pump as contracting the skeletal muscles compresses veins and assists venous return to the heart.
A key diagnostic distinction is whether orthostatic hypotension is neurogenic. The majority of orthostatic hypotension occurs in patients with a normally functioning autonomic nervous system and is due to factors such as dehydration, cardiac pump failure, deconditioning, or vasoactive drugs. Approximately one-third of persistent orthostatic hypotension is neurogenic, resulting from the deficient neurotransmission of norepinephrine, which is the primary neurotransmitter released at sympathetic postganglionic nerve terminals. Patients with neurogenic orthostatic hypotension may lack the reflex tachycardia that occurs in other causes of orthostatic hypotension and, as discussed below, have impaired blood pressure responses to the Valsalva maneuver. Further, systolic blood pressure changes correlate more closely with noradrenergic failure than diastolic blood pressure changes, measurement of which can be less accurate.
Pupillary light reflexes should be examined in a darkened room with the patient gazing into the distance to avoid the pupillary constriction that occurs during convergence. An oculosympathetic deficit decreases pupillary size and is more apparent in dim light, whereas an oculoparasympathetic deficit increases pupillary size and is more apparent in bright light.
A unilateral oculosympathetic deficit comprising ptosis, miosis, and facial anhidrosis (Horner syndrome) can be an important clue to an apical lung tumor, carotid artery dissection, cervical myelopathy, or lateral medullary stroke. Oculoparasympathetic deficits cause an enlarged, tonic pupil. A unilateral or bilateral tonic pupil may occur as an isolated finding (Adie pupil), with tendon hyporeflexia (Holmes-Adie syndrome), or with tendon hyporeflexia and anhidrosis (Ross syndrome).
Facial flushing occurs in many conditions, including emotional arousal, menopause, rosacea, sunburn, anticholinergic or antiestrogen medication use, mastocytosis, carcinoid syndrome, polycythemia vera, or niacin use, or as a constitutional trait. Patients with global anhidrosis who are unable to sweat will flush in response to heat stress as a way of liberating heat. Facial pallor is a distinctive sign often preceding neurally mediated syncope.
Hemifacial flushing in response to heat stress, exercise, or sudden emotion in the patient with a contralateral sympathetic deficit is known as harlequin syndrome. The asymmetry of color across the face can be quite striking with a vertical line demarcating red from white (figure 2-2). The patient may regard the flushing side as abnormal, but it is the sympathetically denervated pale and dry half of the face that is truly abnormal.
Distal arteriolar vasoconstriction may manifest as cold hands or feet in some patients with autonomic neuropathies. Vasomotor instability leading to venous pooling may cause red or purple erythema in the distal lower extremities.
Dryness of the eyes may cause slight redness of the conjunctivae and inability of contact lenses to remain in place. This frequently occurs in Sjögren syndrome, which is one of the causes of autonomic neuropathy. Decreased eye blinking in Parkinson disease can also lead to dry eyes. Sjögren syndrome also causes deficient salivation, although the most common cause of dry mouth is anticholinergic medication. The tongue may appear dry and the lips cracked.
Dryness of areas of the skin that do not sweat is more easily detected by palpation than visualization. When gently stroked, anhidrotic skin (unless lubricated with lotion) feels rough as compared to smooth skin in which normal baseline sweating is present. Asymmetries can be defined by palpation analogous to mapping sensory deficits.
Focal hyperhidrosis is most easily visualized in a dimly lit room by shining a bright light positioned just above the examiner’s eyes perpendicularly to the patient’s skin. Sweat droplets reflecting the light will render the skin shiny. Sweat droplets can be inspected more closely with a magnifying glass or otoscope.
AUTONOMIC LABORATORY EVALUATION
The patient suspected of having an autonomic neuropathy should undergo routine laboratory investigations for peripheral neuropathy. Tests to consider in the routine evaluation of orthostatic hypotension include serum electrolytes, glucose, hemoglobin A1c, complete blood cell count, serum protein electrophoresis, morning cortisol, thyroid-stimulating hormone (TSH), vitamin B12, and supine and standing catecholamines (drawn through an indwelling IV catheter or needle after 30 minutes of supine rest and after 10 minutes of standing). When neurologic examination discloses sensory or motor deficits, nerve conduction studies and EMG are useful in diagnosing a peripheral neuropathy that may also involve autonomic fibers.
Further tests to consider in special cases include α3-ganglionic nicotinic acetylcholine receptor antibodies (autoimmune autonomic ganglionopathy), α-galactosidase (Fabry disease), subcutaneous fat pad biopsy or genetic testing (transthyretin amyloid neuropathy), SSA and SSB antibodies (Sjögren syndrome), plasma free metanephrines (pheochromocytoma), 24-hour urine 5-hydroxyindoleacetic acid (carcinoid syndrome), or plasma histamine (mast cell degranulation disorder). A Schirmer test to measure tear production and the rose bengal test of conjunctival integrity are helpful in evaluating dry eyes. Gastrointestinal motility studies are useful in evaluating gastroparesis and colonic inertia. Urinary bladder denervation (neurogenic bladder) can be quickly assessed by measuring postvoid residual volumes by straight catheterization or suprapubic ultrasound, whereas more detailed information can be obtained by urodynamic studies.
The development of noninvasive autonomic function tests has considerably enhanced the neurologic evaluation of autonomic disorders beyond what the history and physical examination achieve. The types of testing vary among centers, which may emphasize physiologic, neurochemical, or neuroimaging batteries of tests. Most neurology practices that perform autonomic testing focus on standard tests of sudomotor (sympathetic cholinergic), cardiovagal (parasympathetic), and noradrenergic (sympathetic cardiovascular) function.
In 2014, the American Academy of Neurology published a position statement on autonomic testing, including the recommendation that physicians who interpret autonomic test results have appropriate training in autonomic disorders. The United Council of Neurologic Subspecialties has established an autonomic disorders board examination as a method to certify such expertise (www.ucns.org).
A number of tests have been developed for assessing sudomotor dysfunction. Well-established normative values and clinical guidelines exist for the quantitative sudomotor axon reflex test (QSART), which evaluates sudomotor nerves at four standard sites in a quantitative and reproducible manner. The test involves iontophoresis of acetylcholine at the skin surface, which activates an axon reflex mediated by the postganglionic sympathetic sudomotor axon. The impulse generated travels antidromically, reaching a branch point in the peripheral nerve, and from there travels orthodromically to evoke a sudomotor response in adjacent eccrine glands. The evoked response is measured by the moisture detected over time in a capsule placed over the skin. QSART and variations thereof are a sensitive method for detecting small fiber peripheral neuropathies and are recommended in the evaluation of autonomic neuropathy in diabetes mellitus.
The thermoregulatory sweat test evaluates the anatomic distribution of sweating as the patient’s body is gradually heated under conditions of controlled temperature and humidity. Whereas an abnormal QSART localizes to the postganglionic sudomotor neuron or eccrine sweat gland, an abnormal thermoregulatory sweat test results from a lesion anywhere along the thermoregulatory pathway from the brain to the spinal cord, to preganglionic nerves, to sympathetic ganglia, and to postganglionic nerves. Visualization of sweating patterns is aided by topical application of a dye that changes color when wet, such as alizarin red mixed in cornstarch and sodium carbonate. Starch iodine is sometimes used to evaluate focal sudomotor disorders. Some laboratories use the sympathetic skin response, which detects emotional rather than thermoregulatory sweating, or silicone impression techniques, which evaluate localized sweating.
It is important to perform sudomotor tests in the absence of medications that inhibit sweating, which is mediated by M3 acetylcholine receptors. Otherwise a medication effect may be indistinguishable from an autonomic neuropathy. Among M3 receptor antagonists are numerous medications, the most potent of which include atropine, hyoscyamine, oxybutynin, glycopyrrolate, amitriptyline, diphenhydramine, and tolterodine. Carbonic anhydrase inhibitors, including topiramate, zonisamide, and acetazolamide, may also inhibit sweating, particularly in children. Patients vary in the degree to which drugs alter sudomotor responses. A reasonable practice is to withhold these medications for three to five elimination half-lives, when safe to do so, in preparation for sudomotor testing.
The parasympathetic (vagus nerve) influence on heart rate is assessed by the heart rate response to deep breathing or by the Valsalva ratio. The R-R intervals on a single-lead ECG tracing are converted to beat-to-beat heart rate, which is traced along with respiration. Heart rate response to deep breathing is measured by having the patient inspire and expire deeply at a frequency of 6 breaths/min. The mean of a series of differences in maximum and minimum heart rate is a sensitive index of cardiovagal function. Its magnitude declines with advancing age, and it is suppressed by sympathetic activation. Sensitivity is greatest when the patient is supine and relaxed.
For the Valsalva maneuver, the recumbent patient is asked to exhale against resistance and maintain a column of mercury at 30 mm Hg to 40 mm Hg for 15 seconds. The Valsalva ratio is derived from the beat-to-beat heart rate tracing and consists of the maximum heart rate divided by the lowest heart rate within 30 seconds of peak heart rate.
Power spectrum analysis of ECG signals has also been used to estimate cardiovagal function. Heart period (the reciprocal of heart rate) oscillations at approximately 0.25 Hz correlate with parasympathetic function, and patients with cardiovagal failure will show attenuation of the power spectrum at this frequency. Alterations are sometimes reported in conjunction with low-frequency power spectra as an index of “sympathovagal balance,” which is an oversimplified concept that is not universally accepted, as the meaning of the low-frequency power spectrum remains unclear.
Vasomotor Adrenergic Testing
Dynamic changes in blood pressure during the Valsalva maneuver are a valuable index of baroreflex-sympathoneural function. These changes occur too quickly to capture by arm cuff sphygmomanometry but require a finger cuff that tracks beat-to-beat blood pressure noninvasively. Whereas the term “adrenergic” function is often applied, baroreflex-sympathoneural function is noradrenergic (table 2-2) and should be distinguished from adrenomedullary adrenergic function.
The Valsalva maneuver is a key test for distinguishing neurogenic orthostatic hypotension from other causes of orthostatic hypotension. In patients with neurogenic orthostatic hypotension, the blood pressure responses to the Valsalva maneuver are impaired.
The Valsalva maneuver is divided into four phases (figure 2-3). In phase I, increased intrathoracic pressure at the onset of straining causes a brief mechanical rise in arterial pressure as the aorta is compressed. In early phase II, the thoracic pressure gradient reduces cardiac filling, leading to a decline in stroke volume and cardiac output. The sympathetic response is first seen in late phase II, as the progressive decline in beat-to-beat blood pressure unloads carotid baroreceptors, which signal the brainstem to drive sympathetic noradrenergic outflow. This causes an increase in peripheral vasoconstrictor tone, cardiac rate, and inotropic force. In a healthy person, blood pressure recovers nearly to baseline, but in baroreflex-sympathoneural failure, late phase II blood pressure recovery is deficient or absent. In phase III, release of straining and normalization of intrathoracic pressure causes a brief mechanical fall in blood pressure. In phase IV, cardiac filling returns to normal, but in the context of reflexively constricted peripheral vasculature, an overshoot in blood pressure occurs. The patient with baroreflex-sympathoneural failure lacks this blood pressure overshoot, and the time for blood pressure to recover to baseline (the pressure recovery time) is delayed.
Another measure of vasomotor adrenergic testing is the tilt-table test, which is useful in the assessment of orthostatic hypotension, orthostatic intolerance, and unexplained syncope. The methodology should include continuous beat-to-beat monitoring of blood pressure and heart rate. The conditions and duration of tilt-table testing are determined by the clinical question being asked. During passive head-up tilting to 70 degrees, a transient decrease in blood pressure and increase in heart rate normally occurs and recovers to baseline within 30 seconds. In patients with baroreflex-sympathoneural failure, blood pressure does not recover but may decline further, and the heart rate response is decreased. A tilt duration of 5 minutes is sufficient to establish neurogenic orthostatic hypotension, but in the evaluation of disorders of delayed orthostatic intolerance, including syncope, a longer duration of tilt is often necessary.
Tilt-table testing differs significantly from active standing. The table supports the patient in maintaining an upright posture, thus reducing activation of leg muscles that, when contracted, compress or pump the veins and facilitate return of blood to the heart. Its value lies in the ability to assess autonomic responses to orthostatic stress independently of skeletal muscle activation.
By contrast, active standing in healthy persons causes a larger transient decrease in blood pressure and increase in heart rate as compared to passive head-up tilt. The decrease in blood pressure during active standing is driven by reflex peripheral vasodilatation in response to activation of low-pressure cardiopulmonary baroreflexes as muscle contraction enables venous blood in the abdomen and lower extremities to return to the heart.
Access to personal autonomic nervous system data is no longer within the exclusive purview of clinicians and scientists. Increasingly, portable or wearable nonmedical devices are displaying heart rate or blood pressure data to patients in their daily lives. These devices can be useful diagnostically as they allow patients to correlate their symptoms with real-time cardiovascular data and in management as an indicator of their response to treatment. They also introduce potential problems for the patient who, lacking medical knowledge, misinterprets normal physiologic variations or artifacts as a dysautonomia. Frequent checking of heart rate or blood pressure values may exacerbate anxiety in patients predisposed to somatic hypervigilance.
In the medical office setting, a number of simplified automated testing devices have entered the market with claims of evaluating the autonomic nervous system without physician interpretation. Some of these devices include software that automatically generates a diagnosis or even treatment recommendations. Neurologists should be aware that such devices have not been scientifically validated, omit necessary components of testing, and are known to generate erroneous results.
EXPLAINING THE DIAGNOSIS
Drawing from knowledge about the autonomic nervous system to provide the patient with an explanation for baffling symptoms can be quite rewarding. It is crucial to understand the patient’s expectations. Establishing an autonomic diagnosis can potentially obviate the need for further medical testing in the search for other disorders. Whether symptoms can be explained or not, there is value in listening to patients and letting them know they have been heard and their symptoms have been taken seriously. Such discussions require not only knowledge but also the ability to express complex neurologic phenomena in plain language with humility and a nonjudgmental attitude.
Medical terminology can be confusing, particularly when practitioners use it differently. It must be remembered that orthostatic hypotension is a physical sign, not a symptom, and should be based on objective measurements of blood pressure. Further, the term dysautonomia is not a specific diagnosis, but rather a category, as is weakness or gait unsteadiness. An accurate diagnosis on which to base appropriate treatment decisions requires further clarification.
A multitude of symptoms does not necessarily mean that the patient’s symptoms are always psychological. Also, physiologic symptoms mediated through autonomic nerves or that arouse autonomic responses in the patient with an intact and normally functioning autonomic nervous system do not necessarily indicate a dysautonomia.
The approach to evaluating the patient with an autonomic disorder has never before been as scientifically grounded and diagnostically fruitful as it is today. Characterization of distinct autonomic disorders has led to the recognition of specific disease patterns in clinical practice. The availability of noninvasive autonomic reflex testing has provided objective measures of autonomic phenomena that can be difficult to discern on physical examination or to define adequately on the basis of a subjective history.
Despite these gains, each neurologic discovery has led to more questions to be answered. There remains an educational gap to be bridged so that more neurologists and other health care professionals can recognize autonomic disorders and know how to evaluate and manage them appropriately. Much remains to be done also in the development of more effective treatments for patients with autonomic disorders.
- Autonomic disorders are common and diverse in character and can present with sustained or episodic hypofunction or hyperfunction of sympathetic or parasympathetic systems.
- A thoughtful autonomic history is the most important component of the evaluation of the patient with autonomic symptoms. The art of the history consists in taking a jumble of clues and formulating a coherent set of questions and conclusions.
- Key aspects of the autonomic history are timing of onset, temporal course, associated illness or context, modifying factors, and use of medications and dietary supplements.
- The impact of autonomic symptoms on daily functioning and quality of life is important. Standing activities may be limited, and tolerance of heat or cold may be impaired. Social and job-related function may also be impaired.
- Dysautonomias are syndromic and cluster into recognizable patterns of presentation that help to organize the history and examination.
- Sympathetic noradrenergic failure causes neurogenic orthostatic hypotension, which is often worse in the morning, in hot environments, after exercise, or after meals.
- Sympathetic noradrenergic hyperactivity causes hypertension, tachycardia, palpitations, pupillary dilatation, and piloerection.
- Sympathetic adrenergic failure occurs in adrenal failure and presents with fatigue. Sympathetic adrenergic hyperactivity causes palpitations, dilated pupils, facial pallor, palmar sweating, and decreased intestinal motility.
- Sympathetic cholinergic failure causes hypohidrosis or anhidrosis. When severe or widespread, patients may be at risk for heat-related illness, including heatstroke. Anticholinergic medications or carbonic anhydrase inhibitors can contribute to anhidrosis.
- Sympathetic cholinergic hyperactivity causes increased sweating. Opioids, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors may contribute to sweating. Consider serotonin syndrome in the patient who has increased the dose of a serotonergic agent.
- Orthostatic hypotension is a sustained reduction in systolic blood pressure of >20 mm Hg within 3 minutes of standing, with or without symptoms. Orthostatic hypotension cannot be diagnosed by symptoms alone but requires measurement of blood pressure.
- Postural tachycardia syndrome is a sustained increase in heart rate during standing or head-up tilt ≥30 beats/min above baseline, or, for patients younger than 20 years of age, ≥40 beats/min above baseline. The tachycardia must not be in response to orthostatic hypotension.
- About one-third of orthostatic hypotension is neurogenic, as recognized by impaired blood pressure responses to the Valsalva maneuver and by deficient reflex tachycardia. Blood pressure drops in neurogenic orthostatic hypotension can also be more profound than orthostatic hypotension that does not have a neurogenic basis.
- Harlequin syndrome consists of strikingly unilateral facial flushing provoked by heat stress. The opposite side of the face, which remains pale, is abnormal and lacks sympathetic vasomotor innervation.
- Physicians who perform autonomic testing should be knowledgeable about the autonomic nervous system and its disorders.
- The quantitative sudomotor axon reflex test evaluates distal postganglionic sudomotor neurons innervating eccrine glands. This test is a sensitive method for detecting small fiber peripheral neuropathies, but the results can be confounded by medications that inhibit sweating. Such medications should be withheld in advance of testing when it is safe to do so.
- A sensitive test of cardiovagal function is the variation in heart rate with sinusoidal deep breathing, which assesses respiratory sinus arrhythmia. Another method is the Valsalva ratio, which is the maximum heart rate divided by the minimum heart rate in response to straining.
- The Valsalva maneuver consists of four phases. Phases I and III are mechanical and occur at the beginning and end of straining. Baroreflex-sympathoneural (noradrenergic cardiovascular) function is assessed by how quickly and completely the blood pressure recovers during phases II and IV and overshoots in phase IV in response to the drop in blood pressure early in phase II that occurs in response to straining.
- Not all tilt-table tests are the same, but the duration and conditions of the test are adjusted to the goals of the test. A duration of 5 minutes is sufficient to establish neurogenic orthostatic hypotension. Longer durations of tilt are needed when assessing orthostatic intolerance and syncope.
- Personal health devices that display autonomic data such as heart rate and blood pressure are increasingly available to patients. Such data have become part of the autonomic evaluation. The numbers can be useful, but they can also be misinterpreted.
- Dysautonomia is not a specific diagnosis but rather a broad category. No one universal treatment exists for “dysautonomia.” Treatment decisions must be directed to the patient’s specific diagnosis and condition.