+++
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 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).
++
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.
++
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.
++
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).
++
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.
++
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.
++
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.
++
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: Autonomic Failure
Management of autonomic failure is aimed at specific treatment of the cause and alleviation of symptoms. Of particular importance is the removal of drugs or amelioration of underlying conditions that cause or aggravate the autonomic symptoms, especially in the elderly. For example, OH can be caused or aggravated by angiotensin-converting enzyme inhibitors, calcium channel-blocking agents, tricyclic antidepressants, levodopa, alcohol, or insulin. A summary of drugs that can cause OH by class, putative mechanism, and magnitude of the BP drop is shown in Table 41-6.
PATIENT EDUCATION Only a minority of patients with OH require drug treatment. All patients should be taught the mechanisms of postural normotension (volume status, resistance and capacitance bed, autoregulation) and the nature of orthostatic stressors (time of day and the influence of meals, heat, standing, and exercise). Patients should learn to recognize orthostatic symptoms early (especially subtle cognitive symptoms, weakness, and fatigue) and to modify or avoid activities that provoke episodes. Other helpful measures may include keeping a BP log and dietary education (salt/fluids). Learning physical counter-maneuvers that reduce standing OH and practicing postural and resistance training are helpful measures.
SYMPTOMATIC TREATMENT Nonpharmacologic approaches are summarized in Table 41-9. Adequate intake of salt and fluids to produce a voiding volume between 1.5 and 2.5 L of urine (containing >170 meq/L of Na+) each 24 h is essential. Sleeping with the head of the bed elevated will minimize the effects of supine nocturnal hypertension. Prolonged recumbency should be avoided when possible. Patients are advised to sit with legs dangling over the edge of the bed for several minutes before attempting to stand in the morning; other postural stresses should be similarly approached in a gradual manner. One maneuver that can reduce OH is leg-crossing with maintained contraction of leg muscles for 30 s; this compresses leg veins and increases systemic resistance. Compressive garments, such as compression stockings or abdominal binders, are helpful on occasion but uncomfortable for many patients. For transient worsening of OH, drinking two 250-mL (8-oz) glasses of water can raise standing BP 20–30 mmHg for about 2 h, beginning ~20 min after the fluid load. The patient can increase intake of salt and fluids (bouillon treatment), increase use of physical counter-maneuvers (elevate the legs when supine), or temporarily resort to a full-body stocking (compression pressure 30–40 mmHg).
Anemia should be corrected with erythropoietin, administered subcutaneously at doses of 25–75 U/kg three times per week. The hematocrit increases after 2–6 weeks. A weekly maintenance dose is usually necessary. However, the increased intravascular volume that accompanies the rise in hematocrit can exacerbate supine hypertension.
If these measures are not sufficient, pharmacologic treatment may be necessary. Midodrine, a directly acting α1-agonist that does not cross the blood-brain barrier, is effective. It has a duration of action of 2–4 h. The usual dose is 5–10 mg orally tid, but some patients respond best to a decremental dose (e.g., 15 mg on awakening, 10 mg at noon, and 5 mg in the afternoon). Midodrine should not be taken after 6:00 P.M. Side effects include pruritus, uncomfortable piloerection, and supine hypertension especially at higher doses. Droxidopa (Northera) was recently approved by the FDA for treatment of neurogenic OH associated with PAF, PD, or MSA; oral droxidopa is converted to NE and in short-term clinical trails was effective in decreasing symptoms of OH. Pyridostigmine (Mestinon) appears to improve OH without aggravating supine hypertension by enhancing ganglionic transmission (maximal when orthostatic, minimal when supine). Fludrocortisone will reduce OH but aggravates supine hypertension. At doses between 0.1 mg/d and 0.3 mg bid orally, it enhances renal sodium conservation and increases the sensitivity of arterioles to NE. Susceptible patients may develop fluid overload, congestive heart failure, supine hypertension, or hypokalemia. Potassium supplements are often necessary with chronic administration of fludrocortisone. Sustained elevations of supine BP >180/110 mmHg should be avoided. Supine hypertension (>180/110 mmHg) can be self-treated by avoiding the supine position (e.g., sleeping in a recumbent chair) and reducing fludrocortisone. A daily glass of wine, if requested by the patient, can be taken shortly before bedtime. If these simple measures are not adequate, drugs to be considered include oral hydralazine (25 mg qhs), oral nifedipine (Procardia; 10 mg qhs), or a nitroglycerin patch.
A promising drug combination (atomoxetine and yohimbine) has been studied for use in human subjects with severe OH not responsive to other agents, as can occur is some patients with diabetes and severe autonomic neuropathy not responsive to other medications. The atomoxetine blocks the NE reuptake transporter, and yohimbine blocks α2 receptors that mediate the sympathetic feedback loop for downregulation of BP in response to atomoxetine. The result is a dramatic increase in BP and standing tolerance. This combination is not FDA approved for this purpose. It is possible that the limited drug duration of action can be used to withdraw drug treatment when the patient anticipates becoming supine (e.g., before sleep).
Postprandial OH may respond to several measures. Frequent, small, low-carbohydrate meals may diminish splanchnic shunting of blood after meals and reduce postprandial OH. Prostaglandin inhibitors (ibuprofen or indomethacin) taken with meals or midodrine (10 mg with the meal) can be helpful. The somatostatin analogue octreotide can be useful in the treatment of postprandial syncope by inhibiting the release of GI peptides that have vasodilator and hypotensive effects. The subcutaneous dose ranges from 25 μg bid to 200 μg tid.
++