CHAPTER 41: DISORDERS OF THE AUTONOMIC NERVOUS SYSTEM

The autonomic nervous system (ANS) innervates the entire neuraxis and influences all organ systems. It regulates blood pressure (BP), heart rate, sleep, and bladder and bowel function. It operates automatically; its full importance becomes recognized only when ANS function is compromised, resulting in dysautonomia. Hypothalamic disorders that cause disturbances in homeostasis are discussed in Chap. 23.

The activity of the ANS is regulated by central neurons responsive to diverse afferent inputs. After central integration of afferent information, autonomic outflow is adjusted to permit the functioning of the major organ systems in accordance with the needs of the whole organism. Connections between the cerebral cortex and the autonomic centers in the brainstem coordinate autonomic outflow with higher mental functions.

The preganglionic neurons of the parasympathetic nervous system leave the central nervous system (CNS) in the third, seventh, ninth, and tenth cranial nerves as well as the second and third sacral nerves, while the preganglionic neurons of the sympathetic nervous system exit the spinal cord between the first thoracic and the second lumbar segments (Fig. 41-1). These are thinly myelinated. The postganglionic neurons, located in ganglia outside the CNS, give rise to the postganglionic unmyelinated autonomic nerves that innervate organs and tissues throughout the body. Responses to sympathetic and parasympathetic stimulation are frequently antagonistic (Table 41-1), reflecting highly coordinated interactions within the CNS; the resultant changes in parasympathetic and sympathetic activity provide more precise control of autonomic responses than could be achieved by the modulation of a single system.

Acetylcholine (ACh) is the preganglionic neurotransmitter for both divisions of the ANS as well as the postganglionic neurotransmitter of the parasympathetic neurons; the preganglionic receptors are nicotinic, and the postganglionic are muscarinic in type. Norepinephrine (NE) is the neurotransmitter of the postganglionic sympathetic neurons, except for cholinergic neurons innervating the eccrine sweat glands.

CLASSIFICATION

Disorders of the ANS may result from pathology of either the CNS or the peripheral nervous system (PNS) (Table 41-2). Signs and symptoms may result from interruption of the afferent limb, CNS processing centers, or efferent limb of reflex arcs controlling autonomic responses. For example, a lesion of the medulla produced by a posterior fossa tumor can impair BP responses to postural changes and result in orthostatic hypotension (OH). OH can also be caused by lesions of the spinal cord or peripheral vasomotor nerve fibers (e.g., diabetic autonomic neuropathy). Lesions of the efferent limb cause the most consistent and severe OH. The site of reflex interruption is usually established by the clinical context in which the dysautonomia arises, combined with judicious use of ANS testing and neuroimaging studies. The presence or absence of CNS signs, association with sensory or motor polyneuropathy, medical illnesses, medication use, and family history are often important considerations. Some syndromes do not fit easily into any classification scheme.

SYMPTOMS OF AUTONOMIC DYSFUNCTION

Clinical manifestations can result from loss of function, overactivity, or dysregulation of autonomic circuits. Disorders of autonomic function should be considered in patients with unexplained OH, syncope, sleep dysfunction, altered sweating (hyperhidrosis or hypohidrosis), impotence, constipation or other gastrointestinal symptoms (bloating, nausea, vomiting of old food, diarrhea), or bladder disorders (urinary frequency, hesitancy, or incontinence). Symptoms may be widespread or regional in distribution. An autonomic history focuses on systemic functions (BP, heart rate, sleep, fever, sweating) and involvement of individual organ systems (pupils, bowel, bladder, sexual function). The autonomic symptom profile is a self-report questionnaire that can be used for formal assessment. It is also important to recognize the modulating effects of age. For example, OH typically produces lightheadedness in the young, whereas cognitive slowing is more common in the elderly. Specific symptoms of orthostatic intolerance are diverse (Table 41-3). Autonomic symptoms may vary dramatically, reflecting the dynamic nature of autonomic control over homeostatic function. For example, OH might be manifest only in the early morning, following a meal, with exercise, or with raised ambient temperature, depending on the regional vascular bed affected by the dysautonomia.

Early symptoms may be overlooked. Impotence, although not specific for autonomic failure, often heralds autonomic failure in men and may precede other symptoms by years. A decrease in the frequency of spontaneous early morning erections may occur months before loss of nocturnal penile tumescence and development of total impotence. Bladder dysfunction may appear early in men and women, particularly in those with a CNS etiology. Cold feet may indicate increased peripheral vasomotor constriction. Brain and spinal cord disease above the level of the lumbar spine results first in urinary frequency and small bladder volumes and eventually in incontinence (upper motor neuron or spastic bladder). By contrast, PNS disease of autonomic nerve fibers results in large bladder volumes, urinary frequency, and overflow incontinence (lower motor neuron flaccid bladder). Measurement of bladder volume (postvoid residual) is a useful bedside test for distinguishing between upper and lower motor neuron bladder dysfunction in the early stages of dysautonomia. Gastrointestinal autonomic dysfunction typically presents as severe constipation. Diarrhea may develop (typically in diabetes mellitus) due to rapid transit of contents or uncoordinated small-bowel motor activity, or on an osmotic basis from bacterial overgrowth associated with small-bowel stasis. Impaired glandular secretory function may cause difficulty with food intake due to decreased salivation or eye irritation due to decreased lacrimation. Occasionally, temperature elevation and vasodilation can result from anhidrosis because sweating is normally important for heat dissipation (Chap. 23). Lack of sweating after a hot bath, during exercise, or on a hot day can suggest sudomotor failure.

OH (also called orthostatic or postural hypotension) is perhaps the most disabling feature of autonomic dysfunction. The prevalence of OH is relatively high, especially when OH associated with aging and diabetes mellitus is included (Table 41-4). OH can cause a variety of symptoms, including dimming or loss of vision, lightheadedness, diaphoresis, diminished hearing, pallor, and weakness. Syncope results when the drop in BP impairs cerebral perfusion. Other manifestations of impaired baroreflexes are supine hypertension, a heart rate that is fixed regardless of posture, postprandial hypotension, and an excessively high nocturnal BP. Many patients with OH have a preceding diagnosis of hypertension or have concomitant supine hypertension, reflecting the great importance of baroreflexes in maintaining postural and supine normotension. The appearance of OH in patients receiving antihypertensive treatment may indicate overtreatment or the onset of an autonomic disorder. The most common causes of OH are not neurologic in origin; these must be distinguished from the neurogenic causes (Table 41-5). Neurocardiogenic and cardiac causes of syncope are considered in Chap. 11.

APPROACH TO PATIENT

MULTIPLE SYSTEM ATROPHY

Multiple system atrophy (MSA) is an entity that comprises autonomic failure (OH or a neurogenic bladder) and either parkinsonism (MSA-p) or a cerebellar syndrome (MSA-c) (Chap. 36). MSA-p is the more common form; the parkinsonism is atypical in that it is usually unassociated with significant tremor or a response to levodopa. Symptomatic OH within 1 year of onset of parkinsonism predicts eventual development of MSA-p in 75% of patients. There is a very high frequency of impotence in men. Although autonomic abnormalities are common in advanced Parkinson’s disease (Chap. 36), the severity and distribution of autonomic failure are more severe and generalized in MSA. Brain magnetic resonance imaging (MRI) is a useful diagnostic adjunct: in MSA-p, iron deposition in the striatum may be evident as T2 hypointensity, and in MSA-c, cerebellar atrophy is present with a characteristic T2 hyperintense signal (“hot cross buns sign”) in the pons (Fig. 41-2). Cardiac postganglionic adrenergic innervation, measured by uptake of fluorodopamine on positron emission tomography, is markedly impaired in the dysautonomia of Parkinson’s disease (PD) but is usually normal in MSA. Neuropathologic changes include neuronal loss and gliosis in many CNS regions, including the brainstem, cerebellum, striatum, and intermediolateral cell column of the thoracolumbar spinal cord.

MSA is uncommon, with a prevalence estimated at 2–5 per 100,000 individuals. Onset is typically in the mid-fifties, men are slightly more often affected than women, and most cases are sporadic. The diagnosis should be considered in adults over the age of 30 years who present with OH or urinary incontinence and either parkinsonism that is poorly responsive to dopamine replacement or a cerebellar syndrome. MSA generally progresses relentlessly to death 7–10 years after onset, but survival beyond 15 years has been reported. Factors that predict a worse prognosis include rapid progression of disability, bladder dysfunction, female gender, the MSA-p subtype, and an older age at onset. Attempts to slow the progression of MSA have thus far been unsuccessful, including trials of lithium, growth hormone, riluzole, rasagiline, minocycline, and a recent trail of rifampicin.

Management is symptomatic for neurogenic OH (see below), sleep disorders including laryngeal stridor, and gastrointestinal (GI) and urinary dysfunction. GI management includes frequent small meals, soft diet, stool softeners, and bulk agents. Gastroparesis is difficult to treat; metoclopramide stimulates gastric emptying but worsens parkinsonism by blocking central dopamine receptors. The peripheral dopamine (D₂ and D₃) receptor antagonist domperidone has been used patients with various GI conditions in many countries and is now available in the United States through the U.S. Food and Drug Administration’s (FDA) Expanded Access to Investigational Drugs program.

Autonomic dysfunction is also a common feature in dementia with Lewy bodies (Chap. 35); the severity is usually less than that found in MSA or PD. In multiple sclerosis (MS; Chap. 45), autonomic complications reflect the CNS location of MS involvement and generally worsen with disease duration and disability.

SPINAL CORD

Spinal cord lesions from any cause may result in focal autonomic deficits or autonomic hyperreflexia (e.g., spinal cord transection or hemisection) affecting bowel, bladder, sexual, temperature-regulation, or cardiovascular functions. Quadriparetic patients exhibit both supine hypertension and OH after upward tilting. Autonomic dysreflexia describes a dramatic increase in BP in patients with traumatic spinal cord lesions above the T6 level, often in response to stimulation of the bladder, skin, or muscles. A distended or obstructed bladder, suprapubic palpation, catheter insertion, and urinary infection are common triggers. Associated symptoms can include facial flushing, headache, hypertension, or piloerection. Potential complications include intracranial vasospasm or hemorrhage, cardiac arrhythmia, and death. Awareness of the syndrome, identifying the trigger, and careful monitoring of BP during procedures in patients with acute or chronic spinal cord injury are essential. In patients with supine hypertension, BP can be lowered by tilting the head upward or sitting the patient up. Vasodilator drugs may be used to treat acute elevations in BP. Clonidine can be used prophylactically to reduce the hypertension resulting from bladder stimulation. Dangerous increases or decreases in body temperature may result from an inability to experience the sensory accompaniments of heat or cold exposure or control peripheral vasoconstriction or sweating below the level of the spinal cord injury.

PERIPHERAL NERVE AND NEUROMUSCULAR JUNCTION DISORDERS

Peripheral neuropathies (Chap. 53) are the most common cause of chronic autonomic insufficiency. Polyneuropathies that affect small myelinated and unmyelinated fibers of the sympathetic and parasympathetic nerves commonly occur in diabetes mellitus, amyloidosis, chronic alcoholism, porphyria, and Guillain-Barré syndrome. Neuromuscular junction disorders with autonomic involvement include botulism and Lambert-Eaton syndrome (Chap. 55).

Diabetes mellitus

Autonomic neuropathy in patients with diabetes increases the mortality rate 1.5- to 3-fold, even after adjusting for other cardiovascular risk factors. Estimates of 5-year mortality risk among these patients range from 15 to 53%. Although many deaths are due to secondary vascular disease, there are patients who specifically suffer cardiac arrest due to autonomic neuropathy. The autonomic involvement is also predictive of other complications including renal disease, stroke, and sleep apnea.

Amyloidosis

Autonomic neuropathy occurs in both sporadic and familial forms of amyloidosis. The AL (immunoglobulin light chain) type is associated with primary amyloidosis or amyloidosis secondary to multiple myeloma. The ATTR type, with transthyretin as the primary protein component, is responsible for the most common form of inherited amyloidosis. Although patients usually present with a distal painful polyneuropathy accompanied by sensory loss, autonomic insufficiency can precede the development of the polyneuropathy or occur in isolation. The diagnosis can be made by protein electrophoresis of blood and urine, tissue biopsy (abdominal fat pad, rectal mucosa, or sural nerve) to search for amyloid deposits, and genetic testing for transthyretin mutations in familial cases. Treatment of familial cases with liver transplantation can be successful. The response of primary amyloidosis to melphalan and stem cell transplantation has been mixed. Death is usually due to cardiac or renal involvement. Postmortem studies reveal amyloid deposition in many organs, including two sites that contribute to autonomic failure: intraneural blood vessels and autonomic ganglia. Pathologic examination reveals a loss of both unmyelinated and myelinated nerve fibers.

Alcoholic neuropathy

Abnormalities in parasympathetic vagal and efferent sympathetic function are usually mild in alcoholic polyneuropathy. OH is usually due to brainstem involvement, rather than injury to the PNS. Impotence is a major problem, but concurrent gonadal hormone abnormalities may play a role in this symptom. Clinical symptoms of autonomic failure generally appear only when the stocking-glove polyneuropathy is severe, and there is usually coexisting Wernicke’s encephalopathy (Chap. 33). Autonomic involvement may contribute to the high mortality rates associated with alcoholism (Chap. 63).

Porphyria

Autonomic dysfunction is most extensively documented in acute intermittent porphyria but can also occur with variegate porphyria and hereditary coproporphyria. Autonomic symptoms include tachycardia, sweating, urinary retention, abdominal pain, nausea and vomiting, insomnia, hypertension, and (less commonly) hypotension. Another prominent symptom is anxiety. Abnormal autonomic function can occur both during acute attacks and during remissions. Elevated catecholamine levels during acute attacks correlate with the degree of tachycardia and hypertension that is present.

Guillain-Barré syndrome

BP fluctuations and arrhythmias from autonomic instability can be severe (Chap. 54). It is estimated that between 2 and 10% of patients with severe Guillain-Barré syndrome suffer fatal cardiovascular collapse. GI autonomic involvement, sphincter disturbances, abnormal sweating, and pupillary dysfunction can also occur. Demyelination has been described in the vagus and glossopharyngeal nerves, the sympathetic chain, and the white rami communicantes. Interestingly, the degree of autonomic involvement appears to be independent of the severity of motor or sensory neuropathy. Acute autonomic and sensory neuropathy is a variant that spares the motor system and presents with neurogenic OH and varying degrees of sensory loss. It is treated similarly to Guillain-Barré syndrome, but prognosis is less favorable, with persistent severe sensory deficits and variable degrees of OH in many patients.

Autoimmune autonomic ganglionopathy (AAG)

This disorder presents with the subacute development of autonomic disturbances including OH, enteric neuropathy (gastroparesis, ileus, constipation/diarrhea), flaccid bladder, and cholinergic failure (e.g., loss of sweating, sicca complex, and a tonic pupil). A chronic form of AAG resembles pure autonomic failure (see below). Autoantibodies against the ganglionic ACh receptor (A₃ AChR), which are present in approximately half of patients, are considered diagnostic of AAG. Pathology shows preferential involvement of small unmyelinated nerve fibers, with sparing of larger myelinated ones. Onset of the neuropathy follows a viral infection in approximately half of cases. Up to one-third of untreated patients experience significant functional improvement over time. Immunotherapies that have been reported to be helpful include plasmapheresis, intravenous immune globulin, glucocorticoids, azathioprine, rituximab, and mycophenolate mofetil. OH, gastroparesis, and sicca symptoms can be managed symptomatically.

AAG can also occur on a paraneoplastic basis, with adenocarcinoma or small-cell carcinoma of the lung, lymphoma, or thymoma being the most common (Chap. 50). In the paraneoplastic cases, distinctive additional features, such as cerebellar involvement or dementia, may be present (see Tables 50-1, 50-2, and 50-3). The neoplasm may be occult and possibly suppressed by the autoantibody.

Botulism

Botulinum toxin binds presynaptically to cholinergic nerve terminals and, after uptake into the cytosol, blocks ACh release. This acute cholinergic neuropathy presents as motor paralysis and autonomic disturbances that include blurred vision, dry mouth, nausea, unreactive or sluggishly reactive pupils, constipation, and urinary retention.

PURE AUTONOMIC FAILURE (PAF)

This sporadic syndrome consists of postural hypotension, impotence, bladder dysfunction, and impaired sweating. The disorder begins in midlife and occurs in women more often than men. The symptoms can be disabling, but the disease does not shorten life span. The clinical and pharmacologic characteristics suggest primary involvement of postganglionic sympathetic neurons. A severe reduction in the density of neurons within sympathetic ganglia results in low supine plasma NE levels and noradrenergic supersensitivity. Some patients who are initially labeled with this diagnosis subsequently go on to develop AAG or MSA. Skin biopsies can demonstrate phosphorylated α-synuclein inclusions in postganglionic sympathetic adrenergic and cholinergic nerve fibers from some individuals with PAF, distinguishing them from AAG and suggesting that PAF is a synucleinopathy; patients with PD also have α-synuclein inclusions in sympathetic nerve biopsies.

POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME (POTS)

This syndrome is characterized by symptomatic orthostatic intolerance without OH, accompanied by either an increase in heart rate to >120 beats/min or an increase of 30 beats/min with standing that subsides on sitting or lying down. Women are affected approximately five times more often than men, and most develop the syndrome between the ages of 15 and 50. Presyncopal symptoms (lightheadedness, weakness, blurred vision) combined with symptoms of autonomic overactivity (palpitations, tremulousness, nausea) are common. Recurrent unexplained episodes of dysautonomia and fatigue also occur. The pathogenesis is unclear, but there is increasing evidence for sympathetic denervation distally in the legs with preserved cardiovascular function. Hypovolemia, venous pooling, impaired brainstem regulation, or increased sympathetic activity may play a role. Optimal treatment is uncertain, but expansion of fluid volume with water, salt, and fludrocortisone can be helpful as initial interventions. If this approach is inadequate, then midodrine, pyridostigmine, phenobarbital, beta blockers, or clonidine can be tried. Reconditioning and a sustained exercise program are important adjuncts to treatment.

INHERITED DISORDERS

There are five known hereditary sensory and autonomic neuropathies (HSAN I–V). The most important autonomic variants are HSAN I and HSAN III. HSAN I is dominantly inherited and often presents as a distal small-fiber neuropathy (burning feet syndrome) associated with sensory loss and foot ulcers. The most common responsible gene, on chromosome 9q, is SPTLC1. SPTLC is an important enzyme in the regulation of ceramide. Cells from HSAN I patients with the mutation produce higher-than-normal levels of glucosyl ceramide, perhaps triggering apoptosis. HSAN III (Riley-Day syndrome; familial dysautonomia) is an autosomal recessive disorder of Ashkenazi Jewish children and adults and is much less prevalent than HSAN I. Decreased tearing, hyperhidrosis, reduced sensitivity to pain, areflexia, absent fungiform papillae on the tongue, and labile BP may be present. Episodic abdominal crises and fever are common. Pathologic examination of nerves reveals a loss of sympathetic, parasympathetic, and sensory neurons. The defective gene, IKBKAP, may prevent normal transcription of important molecules in neural development.

PRIMARY HYPERHIDROSIS

This syndrome presents with excess sweating of the palms of the hands and soles of the feet beginning in childhood or early adulthood. The condition tends to improve with age. The disorder affects 0.6–1.0% of the population. The etiology is unclear, but there may be a genetic component because 25% of patients have a positive family history. The condition can be socially embarrassing (e.g., shaking hands) or even disabling (e.g., inability to write without soiling the paper). Topical antiperspirants are occasionally helpful. More useful are potent anticholinergic drugs such as glycopyrrolate (1–2 mg PO tid). T2 ganglionectomy or sympathectomy is successful in >90% of patients with palmar hyperhidrosis. The advent of endoscopic transaxillary T2 sympathectomy has lowered the complication rate of the procedure. The most common postoperative complication is compensatory hyperhidrosis, which improves spontaneously over months. Other potential complications include recurrent hyperhidrosis (16%), Horner’s syndrome (<2%), gustatory sweating, wound infection, hemothorax, and intercostal neuralgia. Local injection of botulinum toxin has also been used to block cholinergic, postganglionic sympathetic fibers to sweat glands in patients with palmar hyperhidrosis. This approach is limited by the need for repetitive injections (the effect usually lasts 4 months before waning).

ACUTE SYMPATHETIC OVERACTIVITY SYNDROMES

The physician may be confronted occasionally with an acute state of sympathetic overactivity.

An autonomic storm is an acute state of sustained sympathetic surge that results in variable combinations of alterations in BP and heart rate, body temperature, respiration, and sweating. Causes of autonomic storm include brain and spinal cord injury, toxins and drugs, autonomic neuropathy, and chemodectomas (e.g., pheochromocytoma). Brain injury is the most common cause of autonomic storm and typically follows severe head trauma and postresuscitation encephalopathy anoxic-ischemic brain injury. Autonomic storm can also occur with other acute intracranial lesions such as hemorrhage, cerebral infarction, rapidly expanding tumors, subarachnoid hemorrhage, hydrocephalus, or (less commonly) an acute spinal cord lesion. The most consistent setting is that of an acute intracranial catastrophe of sufficient size and rapidity to produce a massive catecholaminergic surge. The surge can cause seizures, neurogenic pulmonary edema, and myocardial injury. Manifestations include fever, tachycardia, hypertension, tachypnea, hyperhidrosis, pupillary dilatation, and flushing. Lesions of the afferent limb of the baroreflex can result in milder recurrent autonomic storms; many of these follow neck irradiation.

Drugs and toxins may also be responsible, including sympathomimetics such as phenylpropanolamine, cocaine, amphetamines, and tricyclic antidepressants; tetanus; and, less often, botulinum toxin. Cocaine, including “crack,” can cause a hypertensive state with CNS hyperstimulation. Tricyclic overdose, such as from amitriptyline, can cause flushing, hypertension, tachycardia, fever, mydriasis, anhidrosis, and a toxic psychosis. The hyperadrenergic state associated with Guillain-Barré syndrome can produce a moderate autonomic storm. Pheochromocytoma presents with a paroxysmal or sustained hyperadrenergic state, headache, hyperhidrosis, palpitations, anxiety, tremulousness, and hypertension. Neuroleptic malignant syndrome refers to a syndrome of muscle rigidity, hyperthermia, and hypertension in psychotic patients treated with phenothiazines (Chap. 36). Management of autonomic storm includes ruling out other causes of autonomic instability, including malignant hyperthermia, porphyria, and seizures. Sepsis and encephalitis need to be excluded with appropriate studies. An electroencephalogram (EEG) should be done to search for seizure activity; MRI of the brain and spine is often necessary. The patient should be managed in an intensive care unit. Management with morphine sulphate (10 mg every 4 h) and labetalol (100–200 mg twice daily) may be helpful. Supportive treatment may need to be maintained for several weeks. For chronic and milder autonomic storm, propranolol and/or clonidine can be effective.

MISCELLANEOUS

Other conditions associated with autonomic failure include infections, malignancy, poisoning (organophosphates), and aging. Disorders of the hypothalamus can affect autonomic function and produce abnormalities in temperature control, satiety, sexual function, and circadian rhythms (Chap. 51).

REFLEX SYMPATHETIC DYSTROPHY AND CAUSALGIA

The failure to identify a primary role of the ANS in the pathogenesis of these disorders has resulted in a change of nomenclature. The terms complex regional pain syndrome (CRPS) types I and II are now used in place of reflex sympathetic dystrophy (RSD) and causalgia.

CRPS type I is a regional pain syndrome that often develops after tissue injury and most commonly affects one limb. Examples of associated injury include minor shoulder or limb trauma, fractures, myocardial infarction, or stroke. Allodynia (the perception of a nonpainful stimulus as painful), hyperpathia (an exaggerated pain response to a painful stimulus), and spontaneous pain occur. The symptoms are unrelated to the severity of the initial trauma and are not confined to the distribution of a single peripheral nerve. CRPS type II is a regional pain syndrome that develops after injury to a specific peripheral nerve, often a major nerve trunk. Spontaneous pain initially develops within the territory of the affected nerve but eventually may spread outside the nerve distribution.

Pain (usually burning or electrical in quality) is the primary clinical feature of CRPS. Vasomotor dysfunction, sudomotor abnormalities, or focal edema may occur alone or in combination but must be present for diagnosis. Limb pain syndromes that do not meet these criteria are best classified as “limb pain—not otherwise specified.” In CRPS, localized sweating (increased resting sweat output) and changes in blood flow may produce temperature differences between affected and unaffected limbs.

CRPS type I (RSD) has been classically divided into three clinical phases. Phase I consists of pain and swelling in the distal extremity occurring within weeks to 3 months after the precipitating event. The pain is diffuse, spontaneous, and either burning, throbbing, or aching in quality. The involved extremity is warm and edematous, and the joints are tender. Increased sweating and hair growth develop. In phase II (3–6 months after onset), thin, shiny, cool skin appears. After an additional 3–6 months (phase III), atrophy of the skin and subcutaneous tissue plus flexion contractures complete the clinical picture. Autonomic testing or bone scans are occasionally useful when the diagnosis is in doubt.

The natural history of typical CRPS may be more benign and more variable than previously recognized. A variety of surgical and medical treatments have been developed, with conflicting reports of efficacy. Clinical trials suggest that early mobilization with physical therapy or a brief course of glucocorticoids may be helpful for CRPS type I or II. Other medical treatments include the use of adrenergic blockers, nonsteroidal anti-inflammatory drugs, calcium channel blockers, phenytoin, opioids, and calcitonin. Stellate ganglion blockade is a commonly used invasive technique that often provides temporary pain relief, but the efficacy of repetitive blocks is uncertain.

TREATMENT