Autonomic Neuropathy

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Autonomic Neuropathy
Jan 8, 2007
Cody Toth
eMedicine

Background
Autonomic neuropathies are a collection of syndromes and diseases affecting the autonomic neurons, either parasympathetic or sympathetic, or both. Autonomic neuropathies can be hereditary or acquired in nature. Most often, they occur in conjunction with a somatic neuropathy, but they can also occur in isolation.

The autonomic nervous system modulates numerous body functions, and therefore, dysfunction of this system can manifest with numerous clinical phenotypes and various laboratory and electrophysiologic abnormalities. Often, a patient may present with symptoms related to a single segment of the autonomic system. The physician must be wary of other affected parts of the autonomic system.

In some forms, the degree and type of autonomic system involvement varies extensively. In some patients, the degree of autonomic dysfunction may be subclinical or clinically irrelevant, while in others symptoms may be disabling. Several clinically important features of autonomic neuropathies can be treated with either conservative or pharmacologic therapies; therefore, the physician must be alert to these features.


Pathophysiology
The pathophysiology of the autonomic neuropathy depends on the etiology of each particular type. These may range from genetic disorders with specific gene defects to metabolic disorders with accumulation of toxins and to autoimmune disorders with identifiable autoantibodies. Although it is accepted that a loss of somatic C fibers is associated with autonomic deficits, selective involvement is now known to occur for specific autonomic neuropathies. For example, diabetic neuropathies are associated with somatic and autonomic C-fiber impairment, while neuropathic postural tachycardia syndrome is associated with selective distal autonomic deficit (Singer, 2004).

Pandysautonomia

The syndrome of acute pandysautonomia includes both parasympathetic and sympathetic dysfunction (Low, 1983). An immunologic basis for acute pandysautonomia remains most likely, often with onset after a viral illness. Approximately 50% of patients may test positive for an autonomic ganglionic acetylcholine receptor antibody.

Postural orthostatic tachycardia syndrome

Postural orthostatic tachycardia syndrome (POTS) is a syndrome most common in young females with orthostatic intolerance characterized by palpitations with excessive orthostatic sinus tachycardia, sensation of lightheadedness, and near-syncope. POTS may be associated with an infectious prodrome and thus may represent the chronic sequelae of a form fruste of postviral pandysautonomia (Low, 1999). Antibodies against ganglionic receptors are found in 9% of patients with POTS (Novak, 1998).

Guillain-Barré syndrome

Guillain-Barré syndrome (GBS), or acute inflammatory demyelinating polyneuropathy (AIDP), is an acute autoimmune somatic neuropathy commonly associated with prominent autonomic dysfunction that can lead to both morbidity and mortality (Zochodne, 1994, Panagyres, 1989). As many as 50% of patients report a viral illness 1-4 weeks prior to onset.

Autoantibodies can be found against gangliosides, such as with anti-GM1 antibodies. Pathologic studies of the autonomic nervous system in GBS may demonstrate edema and inflammation of autonomic ganglia and destruction of peripheral ganglion cells. Chromatolysis, mononuclear cell infiltration, and nodules of Nageotte can be found within sympathetic ganglia (Zochodne, 1994).

Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an acquired neuromuscular transmission disorder with antibodies present against presynaptic voltage-gated P/Q-type Ca2+ channels. LEMS is frequently associated with clinical and electrophysiologic evidence of dysautonomia, which can be severe in 20% of patients with LEMS (O'Suilleabhain, 1998). In 50% of cases, LEMS is associated with a neoplasm, most commonly small cell carcinoma of the lung.

Holmes-Adie syndrome and Ross syndrome

Holmes-Adie syndrome is probably autoimmune in nature and manifests as tonic pupil or pupils associated with tendon areflexia. In rare cases, it is associated with an autonomic neuropathy with prominent orthostatic hypotension. Ross syndrome is a related condition where segmental anhidrosis occurs in conjunction with Adie pupil.

Idiopathic distal small-fiber neuropathy

Idiopathic distal small-fiber neuropathy is a chronic peripheral somatic neuropathy affecting sympathetic postganglionic sudomotor fibers. Clinical features may include allodynia, sympathetic vasomotor changes, pallor and rubor, cyanosis, and even mottling (Stewart, 1992).

HIV infection

HIV infection may lead to autonomic neuropathy, particularly in late-terminal stages of disease. Often, this occurs in conjunction with a somatic neuropathy related to HIV infection or complications of AIDS.

Chagas disease

Chagas disease due to infection with Trypanosoma cruzi is occasionally associated with autonomic neuropathy during the chronic stage of infection. Parasympathetic dysfunction tends to be greater than sympathetic dysfunction.

Autoimmune destruction of the peripheral nervous system (PNS) and autonomic nervous system may occur, especially of autonomic nerves supplying the cardiovascular and gastrointestinal systems. Other infections such as leprosy, diphtheria, and Lyme disease can be associated with autonomic neuropathy rarely.

Botulism

Botulism produces neuromuscular paralysis due to prevented release of acetylcholine from the presynaptic terminus, as well as an acute cholinergic neuropathy.

Chronic idiopathic anhidrosis

Chronic idiopathic anhidrosis is an acquired generalized loss of sweating without other autonomic features.

Amyloid neuropathy

Three main forms of amyloid neuropathy exist: (1) hereditary amyloid neuropathy; (2) neuropathy associated with hematologic disease, such as multiple myeloma; and (3) acquired neuropathy. Of all autonomic neuropathies, amyloidosis probably causes the most severe forms, with universal autonomic dysfunction common. A somatic neuropathy is often coexistent.

Familial amyloid polyneuropathy

Familial amyloid polyneuropathy (FAP) is a rare and severe hereditary form of amyloidosis caused by a genetic mutation of the transthyretin gene. Mutant transthyretin, produced in the liver accumulates as amyloid deposits in the PNS and autonomic nervous system.

Rarely, a mutation in the gelsolin gene, which produces a protein important in cytoskeletal actin function, may also lead to amyloid deposition in autonomic nerves. Acquired amyloidosis with accumulation of immunoglobulins kappa or lambda light chains may be associated with the presence of multiple myeloma. Another acquired amyloidosis occurs with dialysis, with beta2-microglobulin deposits in the nervous system. In syndromes of amyloidosis, the development of generalized autonomic failure significantly worsens the overall prognosis. At present, liver transplantation, currently the most effective treatment for FAP, may not slow the development of autonomic neuropathy (Delahaye, 2006).

Diabetes mellitus

Diabetes mellitus is associated with many forms of neuropathy, and autonomic involvement is present in many (Zochodne, 1999). Parasympathetic abnormalities are thought to precede sympathetic abnormalities, but this has not been verified.

Laboratory evidence of autonomic dysfunction is frequent, perhaps as frequent as nerve conduction abnormalities in diabetic neuropathy (Zochodne, 1999).

Acute diabetic autonomic neuropathy appears as acute pandysautonomia and may be associated with ganglionic antibodies in some patients. Diabetic radiculoplexopathy is associated with prominent autonomic dysfunction, which may have an immunologic cause with destruction of both large and small nerve fibers (Zochodne, 1999).

Diabetes affects autonomic neurons differently; sympathetic neurons from the celiac/superior mesenteric ganglia develop pathological changes, while sympathetic superior cervical ganglion neurons do not. This selectivity may be related to increased sensitivity to oxidative stress (Semra, 2006).

Uremic neuropathy

Uremic neuropathy is a primarily somatic neuropathy commonly associated with coexistent autonomic neuropathy, either symptomatic or subclinical. The cause of uremic neuropathy remains unknown, although either accumulated toxins or lack of a neurotrophic factor may be responsible because renal transplantation reverses autonomic dysfunction while dialysis does not.

Celiac disease

Autonomic neuropathy may occur in approximately 50% of adults with celiac disease, leading to clinical features of presyncope and postural nausea (Gibbons, 2005). Autonomic denervation may be related to antineuronal antibodies; the condition does not appear to respond to a gluten-free diet (Tursi, 2006).

Hepatic disease–related neuropathy

Hepatic disease–related neuropathies, as with primary biliary cirrhosis (PBC), can be associated with autonomic neuropathy in 48% of patients. The cause of autonomic neuropathy in hepatic disease remains unclear, but it may be associated with toxic metabolite accumulation or related immune-mediated mechanisms. It may be reversible following liver transplantation. Maheshwari et al (2004) hypothesized that patients with autonomic neuropathies are more likely to develop hepatic encephalopathy due to a decreased intestinal transit time. Although this group's study did not show an independent effect of autonomic neuropathy on hepatic encephalopathy, their findings did demonstrate that patients with autonomic neuropathies were more likely to develop new-onset hepatic encephalopathy.

Vitamin deficiency and nutrition-related neuropathy

Deficiency of vitamin B-12 and alcohol- or nutrition-related neuropathy may also be associated with parasympathetic dominant autonomic dysfunction.

Toxic and drug-induced autonomic neuropathy

Toxic and drug-induced autonomic neuropathies may occur with chemotherapeutic medications such as vincristine, cisplatin, carboplatin, vinorelbine, Taxol, and suramin. Other therapeutic agents associated with a toxic autonomic neuropathy include acrylamide, pyridoxine, thallium, amiodarone, perhexiline, and gemcitabine.

Paraneoplastic autonomic neuropathy

Paraneoplastic autonomic neuropathy may occur as a component of paraneoplastic neuronopathy with anti-Hu antibodies in 23% of patients. Autonomic dysfunction appears to result from autoimmune destruction of autonomic postganglionic and myenteric neurons.

Additional antibodies against ganglionic receptors are found in 41% of patients with idiopathic or paraneoplastic autonomic neuropathy. A reversible and dose-dependent association between the level of ganglionic binding antibodies and severity of autonomic dysfunction occurs.

A variant of paraneoplastic autonomic neuropathy is an enteric neuronopathy that exists with antibodies directed against the myenteric plexus. Other paraneoplastic autonomic syndromes may have autoantibodies against neuronal cytoplasmic proteins of the collapsin response–mediator family (CRMP-5) and against Purkinje cell cytoplasm (PCA-2).

Sjögren syndrome

Sjögren syndrome may lead to peripheral and autonomic neuropathy without characteristic systemic symptoms. A small-fiber neuropathy associated with Sjögren syndrome can be associated with widespread anhidrosis. Also, a sensory neuronopathy due to Sjögren syndrome can be associated with autonomic dysfunction. The cause of neuropathy in these patients is likely to be autoimmune, but this remains unclear.

Rheumatoid arthritis, systemic lupus erythematosus, and connective tissue disorders

Rheumatoid arthritis, systemic lupus erythematosus, and other connective tissue disorders may have abnormalities of sympathetic postganglionic function. Some of these patients may have autoantibodies to ganglionic acetylcholine receptors. Autoimmune thyroiditis, as with chronic thyroiditis and Hashimoto thyroiditis, can be associated with some features of Sjögren syndrome such as xerostomia. Patients with systemic sclerosis and mixed connective tissue disorder may have abnormalities of autonomic functioning of esophageal motor activity.

Acute intermittent porphyria and variegate porphyria

Acute intermittent porphyria and variegate porphyria can both have forms of peripheral neuropathy. Attacks can be triggered by exposure to particular drugs. During episodes with acute polyneuropathy that may mimic GBS. Autonomic dysfunction, particularly cardiac and vascular in nature, can be prominent.

Hereditary sensory autonomic neuropathy

Currently, 5 types of hereditary sensory autonomic neuropathy (HSAN) have been defined. HSAN I has an autosomal dominant inheritance, and the disease is characterized by distal limb involvement with marked sensory loss and susceptibility to painless injuries.

HSAN I has been associated with point mutations in serine palmitoyltransferase (SPT) at chromosome arm 9q22.1-q22.3 (Bejaoui, 2001). SPT is the rate-limiting enzyme in synthesis of sphingolipids, including ceramide and sphingomyelin. Ceramide is necessary for regulation of programmed cell death in a number of tissues, including the differentiation of neuronal cells.

HSAN II is inherited as an autosomal recessive condition and is more severe with a congenital onset. HSAN II has a pansensory loss with early ulcers, and nerves demonstrate a marked loss of myelinated and unmyelinated fibers. HSAN III (Riley-Day syndrome) is autosomal recessive in Ashkenazi Jews, with early childhood onset of autonomic crises. The genetic defect in HSAN III is in the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) at chromosome arm 9q31. HSAN III nerve pathology shows absence of unmyelinated fibers with essentially normal myelinated fibers.

Patients with HSAN IV present with widespread anhidrosis and insensitivity to pain. The genetic defect in HSAN IV is in the tyrosine kinase receptor A or nerve growth factor receptor at chromosome arm 1q21-q22. This defect is autosomal recessive. Recently, two novel missense mutations in the tyrosine kinase domain were found in a 10-year-old patient with HSAN IV (Ohto, 2004). This finding may provide a better understanding of the neuropathophysiology of HSAN IV.

Patients with HSAN V present with pain insensitivity and preservation of other sensory modalities. Some patients with HSAN V have similar genetic abnormalities as those with HSAN IV. The genetic mutation has been isolated to the nerve growth factor beta gene (Einarsdottir, 2004

Fabry disease is an X-linked recessive disorder with mutations in the gene for alpha-galactosidase. Somatic and autonomic neuropathy is due to accumulation of glycolipids. Attacks may be triggered by changes in temperature or exercise. Nerve pathology demonstrates loss of both small myelinated and unmyelinated fibers.


Mortality/Morbidity
Most cases have a gradually progressive course. In several forms of autonomic neuropathy, development of autonomic dysfunction worsens overall prognosis. This is particularly true in amyloidosis, diabetic neuropathy, and GBS. Patients with severe dysautonomia can have sudden death secondary to cardiac dysrhythmia, as has been documented in GBS and diabetic neuropathy.



Single-photon emission CT (SPECT) and positron emission tomography (PET) have demonstrated that cardiac sympathetic dysfunction is commonly present in both type I and type II diabetes mellitus.
When associated with vascular complications, dysautonomia related to diabetic neuropathy is also associated with increased mortality.
In other disorders, other forms of systemic dysfunction may lead to mortality, such as with kidney failure in Fabry disease.

Race
One form of autonomic neuropathy, HSAN III (Riley-Day syndrome), is inherited in an autosomal recessive form in Ashkenazi Jews.

Sex
In general, no predilection for autonomic neuropathies exists with regard to sex. POTS is more common among young females. Fabry disease is inherited as an X-linked recessive disorder; therefore, it manifests in males.

Age
In general, no predilection for autonomic neuropathies exists with regard to age. Patients with most of the forms of HSAN (except HSAN I) present at birth or in childhood.



CLINICALSection 3 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References


History
Most of the primary autonomic disorders are chronic in nature, with symptoms often initiating in an insidious fashion. However, in acute autonomic neuropathies, the onset can be dramatic with presentation as a generalized dysautonomia. In general, patients present with symptoms of both sympathetic and parasympathetic dysfunction, with or without symptoms of somatic nervous system dysfunction (Suarex, 1999). Some symptoms, such as those of orthostatic intolerance, are common in autonomic neuropathies, whereas other symptoms, such as complete anhidrosis, are rare as a primary manifestation.

Orthostatic hypotension is often the first recognized symptom and typically is the most disabling (Low, 1997). However, other autonomic symptoms can occur before syncope, and these include impotence or ejaculatory dysfunction, decreased sweating, and urinary incontinence. For example, in Sjögren syndrome, dry mouth and eyes along with anhidrosis is the initial presentation in affected patients. Detailed family history may yield information about possible inherited forms of autonomic neuropathy. In some cases, involvement may be subtle in certain family members, thus escaping detection. Careful attention to use and dosage of prescription medication as well as over-the-counter nutritional and other health or dietary supplements is important.


Facial - Facial pallor, anhidrosis
Ocular - Blurring then graying of vision, blacking out, tunnel vision, sensitivity to light, difficulty with focusing, reduced lacrimation, loss of pupillary size over time (which is often correlated with loss of visual symptoms)
Cardiovascular - Orthostatic onset of palpitations, nausea, tremulousness, presyncope with light-headedness, visual blurring, tinnitus, and even chest pain and shortness of breath

Orthostatic hypotension may follow and is often associated with postprandial state, alcohol, exercise, or temperature-induced exacerbation of hypotension.
Supine hypertension and a loss of diurnal variation in blood pressure may occur later.
Micturition and defecation may induce presyncope.
With worsening symptoms, episodes of syncope with complete loss of consciousness after standing may occur.
In the most severe of autonomic neuropathies, orthostatic tolerance loss with inability to stand because of immediate syncope may occur.
Episodes of palpitations, angina, dyspnea, and syncope may relate to cardiac arrhythmias as well.
Gastrointestinal - Constipation, episodic diarrhea, early satiety, increased gastric motility, dysphagia, bowel atony, bowel incontinence, gastroparesis in diabetes mellitus (which may cause food stasis and subsequent vomiting) (Watkins, 1987), hyposalivation, and altered sense of taste (Bharucha, 1993).
Renal - Nocturia, bladder urgency, bladder frequency, enuresis, incomplete bladder voiding, urinary retention, and urinary incontinence
Sexual - Impotence (mainly parasympathetic) and loss of ejaculation (mainly sympathetic), retrograde ejaculation, and possibly, female sexual dysfunction
Sweating - Anhidrosis or hypohidrosis, compensatory hyperhidrosis, gustatory sweating (Watkins, 1987) (Hyperpyrexia may occur in severe anhidrosis.)
Temperature regulation - Hypothermia (from loss of shivering and inability to vasoconstrict to prevent heat loss) and hyperpyrexia (may be of concern to patients with anhidrosis who are exposed to high temperatures)
Feet - Burning feet most commonly observed in small-fiber sensory neuropathy (itching of feet may precede burning), pruritus, dysesthesia, allodynia, hyperalgesia, nocturnal exacerbation of symptoms, dry skin, loss of distal leg hair, brittle nails, pallor, and cold feet
Respiratory – Diabetes mellitus may lead to an impaired control of bronchomotor tone, leading to a depressed bronchoconstrictory response to cholinergic stimuli. An impaired ventilatory and heart rate response to hypoxia, but not to hypercapnia, has also been observed in diabetic patients. This neuroadrenergic denervation does not, however, seem to correlate with severity of poor control when glycosylated hemoglobin values are correlated (Antonelli Incalzi, 2006).

Physical
Findings on physical examination

Several physical examination findings are associated with autonomic neuropathy (Low, 1997). Certain general examination findings can be used to assist in the specific diagnosis, including the following:


Characteristic skin and mucosal membrane changes can be observed in leprosy, Lyme disease, and diphtheria.
Characteristic angiokeratoma of the trunk with renal failure and previous strokes is suggestive of Fabry disease.
The presence of somatic neuropathy, systemic infections, and other HIV/AIDS systemic manifestations can suggest HIV-associated neuropathy (Cohen, 1989).
Occurrence of liver, renal, and cardiac disease may suggest amyloidosis.
The presence of severe metabolic disease such as renal failure or hepatic failure with a somatic neuropathy suggests a metabolic neuropathy.
The presence of hepatomegaly, spider nevi, caput medusae, parotid hypertrophy, Dupuytren contracture, and other features of alcoholism may suggest a concurrent ethanol/nutritional neuropathy.
Occurrence of arthritis, rash, renal disease, pulmonary disease, xerophthalmia, and xerostomia can suggest a connective tissue disorder, such as rheumatoid arthritis, systemic lupus erythematosus, or Sjögren syndrome.
Techniques of physical examination

Detailed neurologic examination should be performed to detect a somatic peripheral neuropathy. Motor examination should concentrate on the strength and muscle bulk of distal muscles, as well as on deep tendon reflexes. Sensory examination should include assessment of painful and temperature stimuli, as well as light touch, vibration, and proprioception to distal extremities. An important finding on sensory examination is a stocking pattern of sensory loss, which suggests concurrent somatic neuropathy.

Coordination and gait are important to assess for an ataxic component to any suspected peripheral neuropathy.

Specific abnormalities in autonomic functioning can be detected by using physical examination techniques, including the following:


Measure lying, sitting, and orthostatic blood pressures to detect a postural decrease, especially if more than 20 mm Hg of systolic pressure, or drop of 10 mm Hg in the presence of presyncopal symptoms. Pulse should be measured concurrently to examine for loss of compensatory tachycardia and the presence of excessive tachycardia response in the case of POTS.
Measure blood pressure during isometric exercise (sustained hand grip). The patient squeezes a handgrip dynamometer with one hand to maximum capability. Following this, grip is then reduced to 25-30% of maximum pressure for approximately 5 minutes. The normal response for diastolic blood pressure is an increase of >16 mm Hg in the opposite arm.
Measure postprandial blood pressures. An abnormal result would be to measure a drop in systolic blood pressure of >20 mm Hg approximately 15-20 minutes after a meal.
Measure multiple daily blood pressures to examine for diurnal fluctuation. A difference of <15 mm Hg with either systolic or diastolic blood pressure between daytime (awake) values and nighttime (sleeping) values could indicate presence of autonomic neuropathy (Foss, 2001).
Measure heart rate and blood pressure during a cold pressor test with hand immersed in ice-cold water for at least 1 minute. The contralateral arm blood pressure is measured, with a drop of >10 mm Hg in diastolic blood pressure considered to be normal (Sayinalp, 1994).
Measure blood pressure and heart rate beat by beat during monitored respiratory activity as well as with Valsalva maneuver. During quiet respiration, heart rate increases during inspiration and falls during expiration in normal conditions.
Examine for skin shriveling in response to holding the hand in water for a prolonged time.
Examine the palms, soles, and axillae for sweat.
Examine pupillary responses to light and accommodation.
Examine for presence of Horner syndrome with light palpation of both sides of the face to determine unilateral anhydrosis, assessment of pupillary size to determine miosis, and assessment for ptosis. Of note, ptosis in Horner syndrome is due to a sympathetic defect to Mueller muscle, which is found in both superior and inferior eyelids; therefore, Horner syndrome can produce a ptosis of both upper and lower eyelids.
Examine the oral cavity for excessive dental caries in xerostomia.
Examine the conjunctiva and cornea for excessive scratches or signs of trauma due to xerophthalmia.
Palpate the lower abdomen for detection of a distended bladder.
Other problems to consider

Certain findings can rule out diagnosis of autonomic neuropathy and suggest a separate disorder of the autonomic nervous system.

Progressive autonomic failure typically manifests in the fifth or sixth decade of life. The onset is insidious, with orthostatic intolerance and genitourinary symptoms as the dominant features. It differs from Shy-Drager syndrome with an absence of pyramidal and extrapyramidal involvement and absence of preganglionic involvement. Progressive autonomic failure differs from peripheral autonomic neuropathies because of the absence of somatic symptoms.

Most patients with multiple system atrophy develop the disease when older than 40 years, with subacute progression. Genitourinary dysfunction is the most frequent initial symptom in women; erectile dysfunction is the most frequent initial symptom in men. As with peripheral autonomic neuropathy, patients with multiple system atrophy can present with light-headedness, dizziness, dimming of vision, and head, neck, or shoulder pain. However, patients with multiple system atrophy demonstrate CNS involvement with pyramidal, extrapyramidal, and cerebellar system involvement.

Patients with Parkinson disease may also present with autonomic dysfunction, including constipation, urinary retention, and incontinence and orthostatic hypotension. However, unlike peripheral autonomic neuropathies, patients with Parkinson disease demonstrate features of extrapyramidal dysfunction, including tremor, rigidity, and akinesia.

Autonomic dysreflexia is a syndrome of imbalanced reflex sympathetic discharge occurring in patients with spinal cord injury above the splanchnic sympathetic outflow. A sudden increase in both systolic and diastolic blood pressures can appear, giving rise to episodes of dramatic hypertension. Patients with autonomic dysreflexia may report hyperhidrosis and flushing above the level of spinal cord injury.

Syphilis can be associated with tabes dorsalis, which causes a radiculomyelitis associated with autonomic features, but it has not been associated with an autonomic neuropathy.


Causes

Immune-mediated causes

Acute pandysautonomia (Low, 1983)
Acute cholinergic pandysautonomia (Low, 1983)
Acute autonomic and sensory neuropathy (Klein, 2003)
POTS (Low, 1999)
Guillain Barré syndrome (Panagyres, 1989)
Chronic inflammatory demyelinating neuropathy (Lyu, 2002)
Lambert-Eaton myasthenic syndrome (O'Suilleabhain, 1998)
Holmes-Adie syndrome (Lebel, 2002)
Inflammatory bowel disorder–related causes (Struab, 1997)
Paraneoplastic autonomic neuropathy (Sillevis, 2002)
Paraneoplastic sensory neuropathy (Sillevis, 2002)
Paraneoplastic syndromes with ganglionic-receptor–binding antibodies (Sillevis, 2002)
Enteric neuronopathy (Sillevis, 2002)
Anti–CRMP-5 (collapsin response mediator protein-5) antibody syndrome (Yu, 2001)
Anti–Purkinje cell antibody 2 (PCA-2) antibody syndrome (Yu, 2001)
Anti-M-phase phosphoprotein-1 (anti-MPPI) antibody syndrome (Zochodne, 2003)
Rheumatoid arthritis (Low, 1997)
Systemic lupus erythematosus (Low, 1997)
Sjögren syndrome (Gemignani, 1994)
Systemic sclerosis (Low, 1997)
Mixed connective tissue disease (Low, 1997)
Autoimmune thyroiditis (Low, 1997)
Hereditary causes

Hereditary sensory and autonomic neuropathy I (Bajaoui, 2001, Dawkins, 2001)
Hereditary sensory and autonomic neuropathy II (Low, 2003)
Hereditary sensory and autonomic neuropathy III (Riley-Day syndrome) (Low, 2003)
Hereditary sensory and autonomic neuropathy IV (Low, 2003)
Hereditary sensory and autonomic neuropathy V (Low, 2003)
Fabry disease (Low, 1997)
Tangiers disease (Low, 1997)
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) (Low, 1997)
Idiopathic causes

Idiopathic distal small-fiber neuropathy (Holland, 1998, Stewart, 1992)
Chronic idiopathic anhidrosis (Low, 1997)
Infectious causes

Chagas disease (Pentreath, 1995)
Human immunodeficiency virus (Cohen, 1989)
Leprosy (Low, 1997)
Diphtheria (Low, 1997)
Lyme disease (Low, 1997)
Causes related to systemic disease

Diabetic autonomic neuropathies (Zochodne, 2000)
Acquired amyloid neuropathies (Kyle, 1983)
Uremic neuropathy (Zochodne, 2000)
Alcoholic neuropathy (Low, 1997)
Subacute combined degeneration (Low, 1997)
Hepatic disease–related causes (Low, 1997)
Primary biliary cirrhosis–related causes (Low, 1997)
Celiac disease (Straub, 1997)
Toxic causes

Vincristine (Low, 1997)
Cisplatin (Low, 1997)
Carboplatin (Low, 1997)
Vinorelbine (Low, 1997)
Taxol (Low, 1997)
Acrylamide (Low, 1997)
Suramin (Low, 1997)
Pyridoxine intoxication (Low, 1997)
Thallium poisoning (Low, 1997)
Amiodarone (Low, 1997)
Perhexiline (Low, 1997)
Gemcitabine (Low, 1997)