Clinical manifestations

Presentation and course

As with acute autonomic neuropathies, the causes of chronic autonomic dysfunction share several common clinical features that vary depending on relative involvement of distal sympathetic, cholinergic, or adrenergic systems (Table 1). All organ systems have some autonomic fiber innervation so the clinical presentation will be variable depending on the pattern of organ system involvement and the pathological cause. The typical clinical features of the chronic autonomic neuropathies are indicated below. Contrary to common belief, most causes of sensorimotor or small fiber neuropathy affect autonomic fibers as well. In many cases, manifestations are length-dependent and affect mainly or exclusively distal sites. Loss of distal sweating, trophic changes, and vasomotor and temperature regulation consequences are evident. The vast majority of those conditions are not discussed in this section. Instead, entities that have disproportionate or exclusive autonomic manifestations are detailed.

Table 1. Clinical Features of Autonomic Nervous System Failures

Idiopathic distal small-fiber neuropathy. This chronic peripheral autonomic neuropathy is characterized by superficial burning pain on the sole and toe pads. It may be a manifestation of impaired glucose regulation or may be truly idiopathic. Clinical findings include allodynia, deep aching pain, sympathetic vasomotor changes, pallor alternating with rubor, cyanosis, and mottling (46). Examination usually reveals normal strength and mild impairment of sensation distally with reflexes often being normal. Diagnosis is made by clinical and laboratory exclusion of the many causes of small-fiber neuropathy, and by skin biopsies (24). Some may be undetected hereditary neuropathies or may have impaired glucose tolerance. In patients with neuropathy of undetermined etiology, 36% have impaired glucose tolerance. Patients with impaired glucose tolerance have earlier, milder forms of neuropathy in comparison to diabetic neuropathy, indicating a possible correlation between the severity of glucose dysregulation and the severity of neuropathy (60). Sodium channel mutations (Na(v)1.7 sodium channel mutations) have been associated with rare painful dysautonomic syndromes such as primary erythromelalgia and paroxysmal extreme pain disorder. Small fiber neuropathy with autonomic symptoms and chronic nonparoxysmal pain have been described in patients harboring gain-of-function mutations in Na(v)1.7 channel (16).

Pure cholinergic autonomic neuropathy. This disorder includes the following diseases:

Lambert-Eaton myasthenic syndrome. This is an acquired presynaptic disorder of neuromuscular transmission that involves reduction in the release of acetylcholine and occurs in about 3% of patients with small-lung cancer. It is characterized by proximal muscle weakness, reduced or absent deep tendon reflexes, and autonomic symptoms in 80% of patients (57). Common autonomic symptoms include dry mouth, impotence, constipation, orthostatic hypotension (adrenergic), and urinary difficulties (56).

Chagas disease. This condition is caused by Trypanosoma cruzi infection and is endemic in parts of South America. The disease is often asymptomatic but may be associated with parasympathetic greater than sympathetic neuropathy. Pathologically, Chagas disease is characterized by lymph node enlargement and inflammatory changes in cardiac muscle, skeletal muscle, nerve, and autonomic ganglia.

Chronic idiopathic anhidrosis. This disorder is an acquired selective and generalized loss of sweating without adrenergic or cardiovagal failure. Onset is often subacute and may be postviral; patients typically have near but not complete global sweating loss but no other findings. Most retain small patches of sweating that are insufficient for temperature control. These patients are heat intolerant and become hot, dizzy, flushed, dyspneic, and weak when exposed to heat or exercise. Orthostatic hypotension is absent. About half slowly improve and regain sweating, but many do not.

Sporadic primary amyloid neuropathy. A generalized acquired small fiber painful and autonomic neuropathy clinically characterizes primary amyloid neuropathy, also known as AL amyloid. It usually begins in the feet, with a predominance of pain and temperature loss, autonomic failure, and weight loss. It is generally a disease of middle to older age persons. Autonomic failure consisting of orthostatic hypotension, with presyncope or syncope, is a prominent feature early in the illness course and may be severe (46). Anhidrosis, impotence, and gastroparesis are common. Amyloidosis may be associated with polyneuropathy in 20% of subjects with light chain amyloid, and 25% of subjects may have carpal tunnel syndrome. In addition to involvement of the peripheral nervous system, virtually all other organs can be involved in both acquired and familial amyloidosis. It is characterized pathologically by Congo red positive deposits in connective tissue and vessel walls resulting in red-green birefringence under polarized light; however, diagnostic biopsy material may be problematic to find even in suspected cases. Fat pad, rectal, or organ biopsies are often performed. In some cases, muscle and nerve biopsy is needed to detect the amyloid and initiate treatment. Paraproteinemia, multiple myeloma, or light chain disease typically underlies the condition. The median survival was 13 to 35 months (27). Newer approaches to chemotherapy and bone marrow or stem cell transplant have improved survival. This topic is covered in more detail in other sections.

Familial amyloid polyneuropathy. This entity is typically an autosomal-dominant disorder. Its classifications are based on mutations of three proteins: TTR, apolipoprotein A1, and gelsolin. Most commonly inherited mutations occur in the transthyretin (prealbumin) gene; more than 100 mutations (mainly missense point mutations) of the transthyretin (TTR) gene have been described. In TTR-related familial amyloid polyneuropathy, formerly known as type 1 familial autonomic neuropathy, the most frequent mutation is Val30Met (18q11.2-q12.1). As in the sporadic form, autonomic symptoms are dominant and include hypotension, distal anhidrosis, impotence, urinary retention, and gastrointestinal dysfunction. In Thr49Ser mutation-related familial amyloid polyneuropathy, patients present with autonomic neuropathy, with a greater degree of cardiac involvement, especially fatal heart failure (06). Glu54Lys mutation has been associated with severe familial amyloid polyneuropathy, early vitreous opacity, and fatal heart failure. In apolipoprotein A1-related familial amyloid polyneuropathy, apolipoprotein A-1 (chromosome 11q23.3) is affected, with a point mutation of Gly26Arg, and presents similarly to TTRP familial amyloid polyneuropathy yet with less autonomic and earlier renal involvement. In gelsolin familial amyloid polyneuropathy, the most common point mutation is asparagine for aspartic acid at residue 187 on the gelsolin gene on chromosome 9. This systemic disorder is distinguished by ocular manifestations, such as corneal opacity due to amyloid infiltration, and involves some degree of autonomic dysfunction (46). Several effective treatments are now FDA-approved in the United States and other countries to treat TTR neuropathy. Vutrisiran (Amvuttra®), patisiran (Onpattro®), and inotersen (Tegsedi®) for approved for the treatment of hereditary TTR neuropathy in adults. Tafamidis (Vyndamax®) and tafamidis meglumine (Vyndaqel®) are FDA-approved for transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) but may have benefit for neuropathy or wild-type amyloid. There is some evidence that treatment can halt or possibly improve autonomic neuropathy symptoms and findings in these patients (15; 13).

Metabolic and nutritional causes of autonomic neuropathy.

Diabetic autonomic neuropathy. This entity frequently exists in combination with some degree of somatic nerve involvement. Of patients with neuropathy of undetected etiology, 20% have diabetes (60). Autonomic changes include cardiac parasympathetic impairment, orthostatic hypotension, abnormal sweat patterns, decreased cough response (12), gastric motor abnormalities, bladder dysfunction (up to 50%), and erectile dysfunction. Clinical autonomic failure increases with the length of the illness and age of the patient. With cardiac vagal involvement, patients may develop resting tachycardia and failure to respond to physiological demands. Autonomic neuropathy, particularly when manifested as postural hypotension, may confer substantial morbidity and increased mortality in patients with diabetes (65). Development of techniques to characterize diabetic autonomic neuropathy may improve diagnosis and development of therapies aimed at preventing sudden cardiac death. Despite the importance of cardiac autonomic neuropathy, evidence indicates that many patients with diabetic autonomic neuropathy also have as a comorbidity ischemic cardiac disease that may be asymptomatic due to neuropathy; thus, autonomic neuropathy is likely to be only one of the factors causing the increased mortality in diabetes. The advent of techniques to directly characterize diabetic cardiac autonomic denervation may help elucidate the physiologic significance of this common complication and aid the development of therapeutic strategies for the prevention of sudden cardiac death. In addition, some studies also showed an association of cardiac autonomic neuropathies with chronic kidney disease and albuminuria, and they can be independent predictors of the decline of renal function over the follow-up period in patients with type 2 diabetes (61). Studies indicate that autonomic nerve antibodies are more commonly detected in patients with type 1 diabetes and autonomic neuropathy compared to subjects without autonomic neuropathy (32).

Uremia. This neuropathy is commonly associated with autonomic dysfunction and often improves following renal transplantation. Predominantly large myelinated fibers are injured, but impaired thermal perception is the first abnormal sign in 15% of uremic patients (57).

Nutritional deficiencies. Subacute combined degeneration and alcoholic neuropathy have occasionally been associated with orthostatic hypotension. In alcoholics, vagal parasympathetic dysfunction is prominent, whereas sympathetic function is preserved.

Hereditary sensory autonomic neuropathies. In this group of inherited neuropathies, autonomic dysfunction is present but is confined to distal vasomotor dysfunction and manifested by coldness, discoloration, and anhidrosis in most forms. Cardiovascular reflexes are rarely impaired clinically.

Hereditary sensory autonomic neuropathy type 1. This is an autosomal dominant disease with three point mutations identified (C133Y, C133W, V144D - chromosome 9q22.1-q22.3). These result in a defect of the gene (SPTLC1) coding for serine palmitoyltransferase enzyme that catalyzes pyridoxal-5'-phosphate-dependent condensation of L-serine and palmitoyl-CoA to 3-oxosphinganine and results in defects of sphingolipid biosynthesis. The point mutations may lead to accumulation of glucosyl ceramide, leading to neuronal degeneration. A novel missense mutation (G387A) within exon 13 of the same gene SPTLC1 has been discovered (63), yet it is unknown whether this mutation confers a dominant negative effect on the serine palmitoyltransferase enzyme as does the other mutations. Literature shows that hereditary sensory autonomic neuropathy type 1 mutations induce a shift in the substrate specificity of serine palmitoyltransferase, which leads to the formation of the two atypical deoxy-sphingoid bases 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine. Both metabolites lack the C(1) hydroxyl group of sphinganine and can, therefore, neither be converted to complex sphingolipids nor degraded. Consequently, they accumulate in the cell. Elevated deoxy-sphingoid base levels were also found in the plasma of patients with hereditary sensory autonomic neuropathy type 1 and confirmed in three groups of patients with hereditary sensory autonomic neuropathy type 1 and different SPTLC1 mutations. Based on this it has been concluded that hereditary sensory autonomic neuropathy type 1 is caused by a gain of function mutation, which results in the formation of two atypical and neurotoxic sphingolipid metabolites (53). Overexpression of the wild-type allele in a mouse model of hereditary sensory autonomic neuropathy type 1 has reversed the phenotype (22). This finding opens the prospect of possible treatments aimed at reducing the levels of these metabolites. The disorder usually affects young adults starting in the second decade of life and results in distal loss of sensation and sudomotor autonomic reflexes. There is characteristically loss of pain and temperature sensation, and also large fiber dysfunction. This results in foot ulcerations, foot deformities, and Charcot joints (neurogenic osteoarthropathy). Mutilation may also occur in the fingers and hands, and there may be loss of normal bone mineralization. A different phenotype in the same gene is located for the SPTLC2 gene on chromosome 14. That condition causes a later onset (over age 20 years and often later) that consists of small fiber painful neuropathy that later progresses to sensory ataxia. Autonomic findings are less of an issue in that alternative form. Additional forms of HSAN (1B-F) are now known but typically affect pain and sensory systems more than autonomic systems.

Hereditary sensory autonomic neuropathy type II. Also known as Moryan disease, this is an autosomal recessive disorder with an onset in early childhood and it affects both large and small sensory fibers. Currently, evidence points to a mutation in a gene termed “HSN2,” a single exon located within intron 8 of the PRKWNK1 gene, chromosome 12p13.33 (42). The defective protein product may affect the development of peripheral sensory neurons or their supporting cells. Hereditary sensory autonomic neuropathy type II involves mainly the impairment of distal function, impairment of pain, and formation of ulcers in the hand and foot. Autonomic function is usually normal, with the exception of abnormal sweating. Nerve conduction shows absent sensory potentials, and the quantitative sudomotor axon reflex test may be abnormal. On nerve biopsy, there is axonal degeneration affecting both sensory and unmyelinated fibers mediating pain and temperature. Several other genes are known to cause HSAN IIB-D but are also typically more sensory than autonomic in nature. Type IID is an autosomal recessive condition caused by mutations in the SCN9A gene. The inability to feel pain as well as extreme pain and erythromelalgia are caused by differing mutations. Autonomic features are typically absent or minimal though some phenotypes have flushing and pupillary abnormalities.

One Japanese study identified a novel homozygous mutation in SCN9A from two families with autosomal recessive hereditary sensory and autonomic neuropathy. The clinical phenotype is characterized by adolescent or congenital onset with loss of pain, temperature sensations, autonomic nervous dysfunction, bone dysplasia, hearing loss, hypogeusia, and hyposmia (68).

Hereditary sensory autonomic neuropathy type III. Also known as familial dysautonomia or Riley-Day syndrome, this condition is an autosomal recessive disorder associated with mutations of the gene coding inhibitor of k light polypeptide gene enhancer in B cells kinase complex-associated protein (IKBKAP - usually T to C transition in intron 20) on chromosome 9q31. This mutation results in a lack of expression of normal protein product (IKAP) in neuronal tissue. The specific role of IKAP is unknown, but current studies suggest that IKAP may be involved in the regulation and activation of stress response through the c-Jun N-terminal kinase signaling pathway, with misregulation of c-Jun N-terminal kinase leading to the inadequate development and low survival of neuronal cells (04). Abnormal migration and maturation of neural crest cells in implicated, especially those destined to be sensory and autonomic neurons. This disorder is almost exclusive in the Ashkenazi-Jewish population--carrier rate is 1 in 30. Onset is at birth and progresses to severe autonomic crises with postural hypotension, hypothermia or fever, fainting, reduced tearing, and vomiting crises. Other clinical features include insensitivity to pain and temperature stimuli but sparing visceral pain, absence of tears, and hypoactive corneal and tendon reflexes. Characteristically, the fungiform papillae on the tongue are absent, and taste may be impaired. Later, subjects develop fingernail dystrophy. Death occurs in over 50% of patients in the first 4 decades. On nerve biopsy, there is loss of unmyelinated axons, usually with sparing of large myelinated axons.

Hereditary sensory autonomic neuropathy type IV. This entity is characterized by congenital insensitivity to pain with anhidrosis. This autosomal recessive disorder is associated with several defects of the gene NTRK1 coding for the neurotrophic tyrosine kinase A/nerve growth factor receptor on chromosome 1q21-q22. There may be impaired binding of nerve growth factor binding to tyrosine kinase A receptor, and NGF-dependent small sensory and sympathetic neurons fail to survive. Clinically the disease begins in infancy with insensitivity to pain, significant joint deformities, self-mutilation, unintentional burns, fever, and absent sweating. Anhidrosis causes episodic fevers, and hyperpyrexia is usually the first sign of the disorder (05). Fingernail dystrophy, hyperkeratosis, and callusing due to the anhidrosis and mental retardation may be observed. Strength and reflexes are usually normal. Death may occur in infancy from impaired temperature regulation. Nerve conduction is usually normal. On histology, small myelinated axons are more severely reduced than large myelinated axons, small dorsal root ganglia neurons are severely reduced, and there is reduced innervation in skin. A large survey of genetic testing results in mostly international French-speaking countries identified seven patients with pathogenic NTRK1 mutations and a mean age of around 10 years (21).

Hereditary sensory autonomic neuropathy type V. This is an extremely rare, predominantly autosomal recessive disorder characterized by congenital insensitivity to pain with partial anhidrosis. The disease begins in infancy with selective loss of pain perception, resulting in acral ulcers and painless fractures. Response to tactile, vibratory, or thermal stimuli is normal (05). The gene of interest is still unknown, but a mutation in the coding region of nerve-growth factor beta on chromosome 1p11.2-p13.2 was associated with hereditary sensory autonomic neuropathy type V symptoms (23). A mutation of the NTRK1 gene may also be the cause of this neuropathy.

Fabry disease. This disorder is an X-linked recessive inborn error of glycosphingolipid metabolism associated with a deficiency of alpha-galactosidase that affects approximately 1:40,000 to 1:60,000 males. It is characterized clinically by development in young boys of premature vascular disease, pure small-fiber polyneuropathy occurring in hands and feet (“Fabry crises”), and hypohidrosis or anhidrosis. The neuropathy involves severely reduced cold perception and sudomotor function (47). Fabry disease has multiple systemic manifestations including renal disease, stroke, cardiac disease, and angiokeratoma of the skin.

Autonomic dysfunction is usually mild, caused by excessive lipid accumulation within the neurons of the autonomic nervous system as well as hypohidrosis and sexual dysfunction. Treatment consists of pain management and enzyme replacement therapy using agalsidase beta (19). Female carriers may have mild small fiber painful neuropathy.

Navajo sensory-autonomic neuropathy. This is characterized by loss of pain and temperature regulation, with loss of distal sweating. Affected infants may have pyrexias of unknown origin coupled with impaired sweating. Some patients may have a normal examination. Affected subjects have skin thickening on the hands and develop painless fractures and a progressive arthropathy. The EMG may be normal or show evidence of a mild neuropathy.

Infective causes of autonomic neuropathy. Although leprosy, diphtheria, and Lyme disease are associated with autonomic neuropathy, the autonomic nervous system is usually only minimally affected. In leprosy, the R-R intervals are affected in most patients (59). HIV is more commonly associated with sensory and motor neuropathy variants, but may also cause autonomic neuropathy. Many patients with peripheral axonal neuropathy are found to have abnormalities of autonomic reflexes on further testing. Symptoms and findings are similar to those observed in diabetic autonomic neuropathy. Nerve biopsy may show mild CD8-cell infiltration around epi- and endoneurial vessels and loss of myelinated fibers. The CSF protein may be high (130 mg/dL to 1340 mg/dL), with an increase in CSF cellularity.

Toxic and drug-induced autonomic neuropathies. Vincristine causes a dose-related neuropathy, with neurotoxicity observed with a cumulative dose of up to 50 mg. Both parasympathetic and sympathetic clinical features are observed but are generally less symptomatic than sensory symptoms (54). This entity and other forms of chemotherapy-induced neuropathy are discussed in the article on Chemotherapy-induced neuropathies.

Cisplatin causes a dose-dependent pandysautonomia neuropathy, observed in subjects receiving a cumulative dose of up to 825 mg/m2. Other associated features include peripheral neuropathy, ototoxicity, and retrobulbar neuritis (52). Autonomic neurons are typically paradoxically less affected than sensory ganglion neurons and axons.

Paclitaxel may cause autonomic neuropathy once the cumulative dose reaches 600 mg/m2 (range 50 mg/m2 to 750 mg/m2). Abnormalities of cardiovagal and adrenergic function are observed. Paclitaxel causes aggregation of microtubules.

Acrylamide monomer may be bound at low concentrations in the nervous system. Chronic exposure leads to a sensory neuropathy with excessive sweating due to sympathetic dysfunction. Acrylamide causes chromatolysis in sensory and autonomic ganglia and reduces slow axonal transport. However, evidence indicates that nerve terminal degeneration, rather than axonal damage, may be the primary neuropathological feature of acrylamide neurotoxicity (44). Repetitive exposure to acrylamide causes distal weakness and large fiber sensory loss. Pathologically the acrylamide causes chromatological changes in dorsal root ganglia neurons, and widespread swelling of nerve endings. Purkinje cells may also be a site of acrylamide action.

Other toxic causes of chronic autonomic neuropathy include exposure to vacor, amiodarone, hexacarbons, thallium, and arsenic. Chronic use of amiodarone is associated with neuromyopathy and possibly autonomic failure with orthostatic hypotension (46).

Other conditions that may be associated with autonomic neuropathies.

Holmes-Adie syndrome. This syndrome is associated with a tonic pupil (initially presents unilaterally but may progress to bilateral), with tendon areflexia. Autonomic neuropathy and, less commonly, peripheral neuropathy have been associated with this syndrome; autonomic dysfunction occurs in 28% to 40% of patients (36). The range of autonomic disturbance includes orthostatic hypotension, impairment of cardiovascular reflexes, chronic diarrhea, and coughing. The combination of tonic pupil, areflexia, and generalized or segmental anhidrosis is also known as the Ross syndrome. Hyperhidrosis has been reported coincident with this syndrome (14). Adie pupil may be associated with different neuropathies, such as hereditary, inflammatory, paraneoplastic, diabetic, amyloid, and alcohol-related neuropathies. Adie pupil may also occur with sensory neuronopathy as part of Sjögren syndrome (48).

Postural orthostatic tachycardia syndrome. This syndrome is associated with postural presyncope, coupled with rapid tachycardia often in excess to the degree of hypotension. Manifestations include postural-induced tachycardia and palpitations that may be coupled with dyspnea, visual blurring, fatigue, exercise intolerance, abdominal cramping, and nausea. The condition may be associated with an infectious prodrome and, thus, represent the chronic sequelae of a form fruste of postviral pandysautonomia or after various viral infections, including COVID-19. The syndrome is detailed in other sections. A minority of patients have coexistent small fiber sensory and autonomic neuropathy.

Celiac disease. Celiac disease is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages. Celiac disease is associated with clinically significant autonomic neuropathy in 2.4% of cases, leading to syncope, presyncope, and postural nausea (27). Autonomic denervation may be related to an autoimmune process and, therefore, this condition does not appear to respond to a strict gluten-free diet (62). The distinction between celiac disease and the more common gluten intolerance or gluten food allergy is critical.

Prion diseases. Prion diseases are typically recognized as rapidly progressive dementing illnesses that also feature myoclonus and cerebellar ataxia. Late-onset hereditary sensory and autonomic neuropathy caused by truncation of prion protein (PrP) and associated with systemic amyloidosis have been described. The symptoms can be disabling and are comparable to familial amyloid polyneuropathy (50).

Autonomic dysfunction is long associated with Guillain-Barré syndrome. In a Mayo clinic retrospective study of 187 patients, 36% had autonomic symptoms (11). Autonomic dysfunction is not seen in chronic inflammatory demyelinating polyneuropathy. However, one case reported tonic pupil in chronic inflammatory demyelinating polyneuropathy, which was different from Aides pupil in that it did not have the light-near dissociation (25). This entity is discussed in the article on acute autonomic neuropathies.

Parkinson disease with significant autonomic insufficiency, including orthostatic hypotension, is a well-known entity that can be problematic to clinically distinguish from multiple system atrophy. Patients with Parkinson disease also have constipation and other autonomic features. Evidence of additional sensory and autonomic neuropathy and cardiac denervation are also known. There is strong evidence that patients with Parkinson disease have reduced epidermal nerve fiber density as opposed to the centrally based multiple system atrophy (29). Both conditions show phosphorylated alpha-synuclein staining in peripheral samples compared to none in controls. Previous studies have shown reduced epidermal nerve fiber density in patients with Parkinson disease supporting small fiber and autonomic neuropathy; however, these combined findings support an accurate separation of patients with Parkinson disease from those with multiple system atrophy (29).

Prognosis and complications

Prognosis depends on the cause of chronic autonomic neuropathy. In general, serious life-threatening complications include an increased incidence of sudden cardiac death and of cerebrovascular events. Sudden cardiac death has been associated with diabetic autonomic neuropathy, although associated cardiac ischemia may equally provoke the event. As with the acute autonomic neuropathies such as Guillain-Barré syndrome, subarachnoid hemorrhage may occur in the setting of hypertension and autonomic instability. Some autonomic conditions have a good prognosis. In postural orthostatic tachycardia syndrome, there is improvement in up to 80%, and 60% return to normal. The prognosis is improved if there is a history of a viral prodrome.

Clinical vignette

A 57-year-old woman presented with burning pain in her feet and then hands for 1 year. The subject had decreased sweating in her limbs, nocturnal diarrhea, and urinary frequency. The patient reported increased bleeding of her gums when brushing her teeth, and had unintentionally lost 35 pounds in 6 months. There was no family history of neuropathy. Mother and aunt had type 2 diabetes mellitus.

On examination strength was normal. Reflexes were decreased at the knees and ankles. There was decreased pin and light touch perception in the legs up to the knee as well as in the distal fingers. Vibration and joint position sense were normal. Rectal examination showed decreased tone.

Nerve conduction studies showed absent sensory responses in the arm and leg as well as decreased motor amplitudes. The case IV vibration detection threshold in the foot was normal, the cool and heat-pain detection thresholds were insensitive (greater than 25 just noticeable difference). The R6, Valsalva, and 30:15 ratios were severely reduced for age. The quantitative sudomotor axon reflex test showed a reduced sweat volume in the forearm and proximal leg with prolonged latencies at both sites. There was no measurable sweat output in the distal leg and foot.

The serum biochemistry was normal except for the presence of an elevated IgG kappa. The nerve biopsy showed amyloid deposits affecting perineurial and endoneurial vessels, consistent with an amyloid polyneuropathy.

Biological basis

Etiology and pathogenesis

There are wide ranges of potential etiologies described for chronic autonomic neuropathies. Specific causes are discussed under the clinical manifestations section.

Epidemiology

Diabetic neuropathy has a cumulative incidence of 1% per year, and more than 50% of patients with diabetes develop neuropathy. Approximately 60% of patients with diabetes have laboratory evidence of peripheral autonomic neuropathy and 30% have clinical evidence.

Prevention

Many autonomic neuropathies have no known prevention. Avoidance of toxins and medications known to produce autonomic neuropathy can help prevent some forms. Intensive control of glucose can help reduce the risk of developing autonomic neuropathy in patients with diabetes.

Differential diagnosis

The clinician should consider autonomic disorders with central nervous system involvement in subjects who develop autonomic dysfunction. The principal differential diagnosis is between autonomic neuropathies, pure autonomic failure, and multisystem atrophy. These include:

Table 2. Distinguishing Autonomic Neuropathy From Other Causes of Autonomic Failure

Diagnostic workup

Diagnostic considerations are discussed in the article devoted to acute autonomic neuropathies. In addition to these tests, measurement of catecholamine levels may help in the diagnosis of certain autonomic conditions but require special conditions and atraumatic blood draw. In postural orthostatic tachycardia syndrome, plasma norepinephrine levels may be low at rest and elevated on standing (greater than 600 pg/mL) (46). Composite Autonomic Severity Score (CASS) is a validated instrument for laboratory quantitation of autonomic failure derived from standard autonomic reflex tests. This reflects a summation of the sudomotor (0 to 3), cardiovagal (0 to 3), and adrenergic (0 to 4) subscores (45). This scale has been utilized to quantitate autonomic disorders in conditions such as chronic inflammatory demyelinating neuropathy.

Management

Some of the autonomic neuropathies are amenable to treatment of the underlying disease. Lambert-Eaton myasthenic syndrome usually responds to treatment of the underlying malignancy but immunosuppressive agents such as prednisone alone or in combination with azathioprine as well as plasma exchange and IVIG have been successful in improving symptoms. Aminopyridines, such as 3,4-diaminopyridine (DAP), are the mainstay of treatment and are also effective in improving autonomic function; more than 85% of patients with Lambert-Eaton myasthenic syndrome demonstrate significant clinical benefit from DAP therapy (56). Firdapse® (amifampridine) form of 3,4 DAP was approved in the United States in 2018. The results of the Diabetes Control and Complications Trial study show that improvement in glycemic control can prevent, and probably reverse, progression of diabetic autonomic pathology (17). Burden and Burden described three patients who developed weight loss and symptomatic autonomic neuropathies with diabetes (09). Each of these patients had resolution of their autonomic neuropathy in association with recovery of their normal weight, suggesting that recovery from diabetic autonomic neuropathy with weight loss should be anticipated with return to premorbid weight and glycemic control. Liver transplantation has been shown to reverse autonomic neuropathy secondary to cirrhosis (49), supporting the idea that the etiology of autonomic neuropathy in these cases likely arises from metabolic dysfunction rather than structural alteration.

IVIG has been used increasingly in the treatment of autoimmune forms of dysautonomia, typically the subacute or acute forms. However, some anecdotal or retrospective studies suggest that patients with small fiber neuropathy and autonomic dysfunction treated with intravenous immunoglobulin therapy may benefit (69). However, patients develop aseptic meningitis or severe headache, more than other patient populations (58). A recent randomized placebo-controlled trial of IVIG for 20 patients with small fiber neuropathy associated with two autoantibodies, trisulfated heparin disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3), found no benefit (31). An earlier and larger randomized placebo-controlled study of 60 patients with idiopathic small fiber neuropathy without these antibodies in the Netherlands also showed no benefit (28).

Purinergic signaling has been shown to be involved in the regulation of cardiovascular function. Animal studies showed that P2Y12 receptor could mediate diabetic cardiac autonomic neuropathy (DCAN)-induced sympathetic reflexes. The study findings suggested that P2Y12 receptor in stellate ganglion could be a potential therapeutic target for the treatment of diabetic cardiac autonomic neuropathy (33).

Many of the diseases that lead to autonomic neuropathy cannot be treated directly; therefore, a symptomatic approach is used. Lifestyle changes can be remarkably helpful; these are geared toward placing as little stress on the autonomic nervous system as possible and involve behavioral techniques. Pharmacotherapy should only be considered when the patient's symptoms become severe and only after lifestyle changes have failed to produce adequate relief. The last tier of treatment involves consideration of surgical interventions.

Orthostatic hypotension can be one of the most debilitating symptoms of autonomic neuropathy (26). Patient education techniques include standing up slowly, avoiding large meals, elevating the head of the bed to help improve nocturnal diuresis, and avoiding early morning orthostatic hypotension. Thigh-high hose compression can reduce venous pooling; waist-high stockings are more effective in increasing standing blood pressure but are frequently too cumbersome for patients slowed by neurologic disease. Extra salt, water, and caffeine can also be added to the diet to reduce postprandial hypotension. In addition to the medications listed in Table 3, droxidopa, an orally active synthetic amino acid, has been approved by the FDA for short-term treatment of neurogenic orthostatic hypotension. It is converted to norepinephrine by the enzyme aromatic L-amino acid decarboxylase (39).

Table 3. Treatment of Orthostatic Hypotension in Autonomic Neuropathy

Supine hypertension can be a paradoxical and confounding problem in some patients with orthostatic hypotension due to autonomic neuropathy. Some of these patients have been shown to develop left ventricular hypertrophy, suggesting that treatment is warranted. Avoidance of the supine position during the day and the use of short-acting vasodilators such as transdermal nitroglycerin at night can successfully combat this problem (38).

Management of autonomic dysfunction of the urinary bladder such as over distension, overflow incontinence, and bladder and sphincter dyssynergia first revolves around behavioral changes with scheduled voiding every 3 to 4 hours. Intermittent self-catheterization can be started if the patient continues to have significant postvoid residuals.

Table 4. Treatment of Neurologic Dysfunction of the Bladder

Erectile dysfunction can be managed with sildenafil with mild to no side effects. It should be avoided in patients who are taking nitrates or those who have had a recent myocardial infarction or stroke or in those with marked orthostatic hypotension. Vardenafil (10 mg single dose, orally; start at 5 mg if the patient is older than 65 years of age; one dose per day maximum) and tadalafil (10 mg single dose, orally; reduce dosage if the patient is using a potent CYP3A14 inhibitor; 20 mg per 36 hours maximum) appear to be as effective as sildenafil (50 mg single dose, orally; 25 mg if the patient is older than 65 years of age or is using potent CYP3A14 inhibitor; 100 mg per dose, one dose per day maximum), but tadalafil has a longer duration of action. Alprostadil and papaverine can be tried if sildenafil is not successful (20).

Dry eyes can be managed with the liberal use of artificial tears; in severe cases, surgical closure of the tear duct can be considered (20). Dry mouth can be treated with pilocarpine.

Gastroparesis can be managed either with erythromycin or metoclopramide. The most effective pharmacological treatment is cisapride, although it has restricted access in the United States and has serious side effects, which include cardiac arrhythmia, aplastic anemia, and hepatic toxicity. Intrapyloric injection of botulinum toxin was also shown to be effective in improving symptoms associated with diabetic gastroparesis resistant to conventional treatment (35). Tegaserod (6 mg two times per day, 30 to 60 minutes before meals, for 4 to 6 weeks) is useful in patients with irritable bowel syndrome. Loperamide can also be used to manage diarrhea if infectious causes have been eliminated. One pilot study showed pyridostigmine (cholinesterase inhibitor) improves colonic transit and symptoms in some patients with autonomic neuropathy and constipation (07). Studies have shown promising results of gastric electrical stimulation, which accelerates gastric emptying by delivering electrical currents to the stomach and may possibly become an alternative therapy for patients who are refractory to prokinetic agents (43).

Excessive tachycardia associated with postural orthostatic tachycardia syndrome can be treated with small doses of beta-blockers such as propranolol.

Botulinum toxin has been studied and found to be successful in treating some of the symptoms of autonomic dysfunction, including bladder symptoms and axillary hyperhidrosis (37). Palmar and plantar hyperhidrosis can be effectively treated with tap water iontophoresis. Other treatments include topical agents such as aluminum chloride hexahydrate and oral medications such as beta-blockers or benzodiazepines.

In inherited amyloid neuropathy (familial amyloid polyneuropathy), liver transplantation was previously thought to prevent progression of the disease. However, observations show that liver transplants may not always arrest the development of autonomic neuropathy (18). Tafamidis, a 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, selectively binds to TTR with negative cooperativity and kinetically stabilizes wild-type native TTR and mutant TTR. Results from two initial trials indicated that the beneficial effects of tafamidis were sustained over a 30-month period and that starting treatment early is beneficial. It was initially approved in Europe in 2011 and has since been approved in other countries for early-stage TTR-FAP (66). In August 2018, patisiran (Onpattro®), a double-stranded small interfering ribonucleic acid is approved for hereditary amyloidosis by the FDA. This is the first treatment approved for hereditary transthyretin-mediated amyloidosis (HATTR) polyneuropathy and also the first treatment approved in this class of drugs called small interfering ribonucleic acid (siRNA). This works by silencing a portion of the RNA involved in causing the disease. The efficacy of patisiran was shown in a clinical trial involving 225 patients where 148 patients were randomized and received a drug infusion or placebo every 3 weeks. Patients on patisiran had better outcomes on measures of polyneuropathy (01). Trials are ongoing to assess the benefit of patisiran for treatment of cardiomyopathy.

Special considerations

Pregnancy

Hagay and Weissman recommended pre-pregnancy autonomic screening for patients with diabetes, as moderate-to-severe autonomic dysfunction (particularly the presence of gastropathy) is felt to be a relative contraindication for pregnancy (34). The tests should be performed prior to conception, because pregnancy itself may make the tests unreliable. However, the number of pregnancies is not related to the presence of autonomic dysfunction in diabetic women (02).

Anesthesia

Several studies have found that patients with diseases known to have autonomic complications may require intraoperative blood pressure support compared to nonaffected controls (10). Preoperative screening of diabetics with noninvasive autonomic tests may be useful in identifying those patients at higher risk for cardiovascular instability or intraoperative hypothermia (41).

Patients who have familial amyloid polyneuropathy are at risk of significant intraoperative hypotension during liver transplantation due to autonomic dysfunction (64).

Patients with hereditary sensory autonomic neuropathy type IV have a high incidence of cardiovascular events, and, thus, in addition to perioperative temperature control, the risk of bradycardia and hypotension would be a primary anesthetic concern (55).