AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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).

Types of HSAN

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.

CLINICAL

Section 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)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Progressive autonomic failure
Dopamine beta-hydroxylase deficiency
Aromatic L-amino acid decarboxylase deficiency
Surgical sympathectomy
Vagotomy
Autonomic dysreflexia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Although clinical diagnosis is essential for diagnosing autonomic neuropathies (Toth and Zochodne, 2003), special studies can be helpful in identifying a particular autonomic neuropathy. In most cases, the laboratory assists in identifying subclinical or subtle changes, and tests at the bedside can be used in many cases to assist in the diagnosis.
• At the bedside, orthostatic hypotension can be detected by using manual blood pressure and pulse measurements after standing.
• • Electrocardiography can be used to monitor heart rate while the examiner observes respiratory rhythm to determine if normal respiratory rhythms are present.
  • Beat-by-beat measurement of heart rate and R-R interval assessment can be performed by means of continuous electrocardiography during monitored respiratory activity as well as Valsalva maneuver testing.
  • Other bedside stimuli that can be used to assess for a rise in blood pressure during continuous blood pressure monitoring include isometric exercise (sustained hand grip for 3 min), a cold pressor test (immersion of a hand in ice water for 90 s), and mental arithmetic (with serial-7 or serial-17 subtraction), all of which stimulate sympathetic outflow and elevate blood pressure in healthy subjects.
• Evaluation of cerebrospinal fluid (CSF) via lumbar puncture can be useful in specific cases.
• • In pandysautonomia, CSF protein is elevated, as is CSF enolase, which may indicate damage to the dorsal root ganglia.
  • In HIV or AIDS, the CSF may demonstrate an elevated protein as well as pleocytosis.
  • Paraneoplastic varieties of autonomic neuropathies also tend to show an inflammatory picture in the CSF. However, abnormal CSF protein is not specific for autoimmune, inflammatory, or infectious causes of autonomic neuropathy.
• Measurement of basal plasma norepinephrine levels can be useful in specific forms of autonomic neuropathy.
• • In pandysautonomia, basal norepinephrine levels are low and do not rise on head-up tilt table testing.
  • Following an overnight supine position, low norepinephrine levels can be found in patients with POTS.

Imaging Studies

• SPECT and PET scanning may identify cardiac sympathetic dysfunction in both type I and type II diabetes mellitus.
• The pattern of sympathetic disturbances tends to be heterogeneous, with denervation affecting mainly the posterior myocardial region, whereas focal hyperinnervation can be observed of the proximal segment.

Other Tests

• Additional testing can be useful when clinical suspicion is strong for a particular syndrome.
• In Sjögren syndrome, results of the Schirmer test with a rose-Bengal eye stain, as well as lip biopsy to identify chronic sialoadenitis, can be diagnostic.
• In cases of suspected porphyria, high levels of porphobilinogen and delta-aminolevulinic acid can be found in urine during acute episodes.

Procedures

• Findings on nerve conduction studies (NCS) and electromyography (EMG) can be normal in pure autonomic neuropathies because the involved fibers are small myelinated and unmyelinated fibers, which cannot be assessed with NCS or EMG.
• • In autonomic neuropathies with concomitant sensory neuropathy, absence of sensory potentials may occur.
  • In autonomic neuropathies with concomitant sensorimotor neuropathy, marked loss of motor and sensory potentials is noted.
  • In cases of suspected neuromuscular transmission defect, such as with botulism or LEMS, a typical electrophysiologic pattern of low-amplitude compound muscle action potentials increasing with high-frequency repetitive stimulation is characteristic of a presynaptic neuromuscular defect.
• Three autonomic studies useful in diagnosis of autonomic neuropathy are typically performed as a battery.
• • Sympathetic skin responses (SSR) can be assessed with routine EMG equipment. This test can be used to identify indirect evidence of sweat production via measurement of changes in skin conductance on the palm/sole in response to an electrical stimulus. The stimulation of an afferent somatic branch with SSRs gives an assessment of potential adrenergic sweat production. Brief electrical stimuli are administered at intermittent intervals and a response is measured from the hands or the feet, representing a change in skin resistance due to sweating.
  • Quantitative sensory testing (QST) can be helpful in autonomic disorders with sensory neuropathy (Stewart, 1992). QST permits comparison of sensory thresholds by using vibration and temperature perception to assess both large and small-fiber modalities. These patients typically have impaired thresholds for heat and pain (Yarnitsky, 1994), but vibration and cool sensitivity may be normal.
  • The thermoregulatory sweat test (TST) complements the quantitative sudomotor axon reflex test (QSART) (Stewart, 1992) and is used to assess thermoregulatory pathways (Low, 1983). The QSART is used only to evaluate the postganglionic segment of the thermoregulatory pathway.

    Only 4 regions are tested: forearm, proximal leg, distal leg, and dorsum of the foot.

    The patient is covered with alizarin red powder, which when moist, changes from orange to purple. The patient's temperature is then raised above core temperature, and photography is performed to map for areas of color change, revealing areas of anhidrosis/hypohidrosis where color did not change (Fealey, 1997). Electrical stimulation (iontophoresis) is applied to the skin, and the volume of sweat produced can be measured.

    QSART can be useful in small-fiber neuropathies and in POTS, where 33% of patients have abnormal distal findings (Low, 1999).

    The TST and QSART can both be useful in idiopathic anhidrosis. A lack of color changes with the TST is essentially diagnostic for postganglionic sudomotor dysfunction.

• Vascular studies are occasionally useful in assessing autonomic neuropathy.
• • Adrenergic function can be assessed by measuring skin blood flow, transcutaneous oxygenation, and skin temperature.
  • Doppler probes can be used for blood flow measurements.
  • Infrared thermometry and telethermography can be used to measure skin temperature.
  • Assessment of skin temperature can be useful in patients with small-fiber neuropathy.
• Urodynamic studies may be used to examine the lower urinary tract function (Madersbacher, 1999).
• • Measurements include urine flow rate, residual volume, cystometry during both filling and voiding, urethral pressure profile measurements, and pelvic floor neurophysiology.
  • An important measure in assessment of a neurogenic bladder is the postmicturition residual volume; this can be measured invasively by urethral catheterization after voiding, but it can also be measured noninvasively with ultrasonography.
• Videofluoroscopy is useful in assessment of swallowing in the presence of oropharyngeal dysphagia.
• • A barium swallow study, meal, and follow-through study are helpful in suspected upper gastrointestinal disorders, though endoscopic assessment provides the opportunity for biopsy in particular situations, as well as better visualization.
  • Esophageal manometry may be of value in disorders of motility and esophagogastric function.
  • Gastric motility may be assessed by using radioisotope methods and scintigraphic scanning.
  • In cases of small-bowel disorders suspected to be neurologic in nature, manometry may be of value in discriminating myopathic from neuropathic disorders. Large-bowel dysfunction can be assessed via measurement of transit time (Bharucha, 1993).
• The autonomic reflex screen (ARS) and composite autonomic scoring scale (CASS), a subset of ARS, may both be used to assess a number of autonomic functions.
• • The ARS consists of a quantitative sudomotor axon reflex test, orthostatic blood pressure and heart rate response to tilt, heart rate response to deep breathing, the Valsalva ratio, and beat-to-beat blood pressure measurements during phases II and IV of the Valsalva maneuver, tilt, and deep breathing.
  • The ARS involves a 10-point CASS of autonomic function (Low 1993): 4 points are allotted for adrenergic and 3 points each for sudomotor and cardiovagal failure.
  • Deep breathing and Valsalva ratio analysis can be used to evaluate cardiovagal functions; tilt response and Valsalva maneuver can be used to measure cardiosympathetic function; quantitative sudomotor axon reflex test is indicated for postganglionic sudomotor function; and blood pressure responses to tilt and Valsalva maneuver measures adrenergic vasomotor function.
  • Scores are normalized for age and sex. Patients with a score of <4 on the CASS have mild autonomic failure; a score of 4-6 suggests moderate autonomic failure; and a score of 7-10 implies severe failure.
  • The ARS test is reliable and useful for monitoring clinical progression with an autonomic neuropathy.
• Diagnostic and laboratory studies useful in autonomic neuropathy include bedside studies and autonomic studies
• • Bedside studies - Manual postural blood pressure and pulse measurements; electrocardiography for R-R interval assessment with Valsalva maneuver; measurement of normal respiratory rhythms, blood pressure measurement during isometric exercise, cold pressor test, and mental arithmetic; basal plasma norepinephrine levels; and NCS and EMG
  • Autonomic studies - SSR; QST; TST and QSART; Measurement of skin blood flow, transcutaneous oxygenation, and skin temperature; urodynamic studies; and videoesophagofluoroscopy
• Heart rate variability is lower in diabetes patients with chronic complications compared with those without chronic complications (Kudat, 2006).
• Esophageal manometry and gastric emptying scintigraphy can also be useful in patients with possible autonomic neuropathy and dysphagia.
• • Diabetic patients with symptoms of esophageal dysmotility have insufficient lower esophageal sphincter relaxation and a higher percentage of simultaneous waves detected, while diabetic patients with cardiovascular autonomic neuropathy have greater pathological simultaneous contractions (Ascaso, 2006)
  • Esophageal dysmotility and delayed gastric emptying may occur in up to 50% of diabetic patients. In particular, reports of abdominal fullness predicted delayed gastric emptying (Ohlsson, 2006).

Histologic Findings

Biopsy findings

Sural nerve biopsy is occasionally diagnostic for types of autonomic neuropathy. In inherited autonomic neuropathies, a selective loss of particular fiber types can indicate the diagnosis. In autoimmune or infectious mediated forms of autonomic neuropathy, small perivascular infiltrates may be visible. In amyloidosis, characteristic Congo red staining indicates the presence of eosinophilic, extracellular, amorphous material surrounding perineurial and endoneurial vessels and within sympathetic ganglia and vagal nerves.

Epidermal skin biopsy can be used in the diagnosis of small-fiber neuropathies. This technique is less invasive than nerve biopsy. In autonomic neuropathies, autonomic fibers are deeper than the epidermal level; therefore, deeper biopsy is required to assess the fibers innervating sweat glands and piloerector muscles. In general, autonomic neuropathies of greater severity are associated with less epidermal fiber densities (Singer, 2004).

As distal endings are primarily involved in distal axonopathy forms of neuropathy, skin biopsy may be more sensitive than sural nerve biopsy to detect early abnormalities (Nolano, 2003). Skin biopsy is also useful in congenital causes of autonomic neuropathy, as in congenital insensitivity to pain with anhidrosis (CIPA), where a lack of nerve fibers in the epidermis and only a few hypotrophic and uninnervated sweat glands are found in the dermis (Nolano, 2000).

Immunologic findings

Patients with autoimmune autonomic neuropathy can have anti-ganglionic acetylcholine receptor (AChR) autoantibodies (Klein, 2003). Patients with high antibody values (>1.00 nmol/L) tend to have a constellation of sicca complex (marked dry eyes and dry mouth), abnormal pupillary light responses, upper gastrointestinal symptoms, and neurogenic bladder. The higher the antibody titer, the greater the autonomic dysfunction as well as greater frequency of cholinergic dysautonomia.

Patients with POTS syndrome may also demonstrate presence of ganglionic receptors (Novak, 1998).

Staging

The ARS is reliable and useful for monitoring clinical progression with an autonomic neuropathy.

The TST can be useful in monitoring progression of idiopathic anhidrosis and Sjögren syndrome where prominent anhidrosis/hypohidrosis occurs.

• Esophageal manometry and gastric emptying scintigraphy can also be useful in patients with possible autonomic neuropathy and dysphagia.
• • Diabetic patients with symptoms of esophageal dysmotility have an insufficient lower oesophageal sphincter relaxation and a higher percentage of simultaneous waves detected, while diabetic patients with cardiovascular autonomic neuropathy have greater pathological simultaneous contractions (Ascaso 2006)
  • Esophageal dysmotility and delayed gastric emptying may occur in up to 50% of diabetic patients. In particular, complaints of abdominal fullness predicted delayed gastric emptying (Ohlsson 2006).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

General management

The first objective of management of a patient with autonomic neuropathy is to administer specific treatment for treatable conditions. For example, if an autoimmune neuropathy is present, attempted management with immunomodulatory therapies should be considered. If diabetes mellitus is the underlying cause, strict control of blood glucose to prevent further worsening is essential. However, many of the autonomic neuropathies are not treatable with specific therapy. In these cases, symptomatic therapy becomes vitally important.

In cases of orthostatic intolerance, conservative therapy should be attempted first. Maintenance of high intakes of fluid and salt, as tolerated, can be attempted. Avoidance of alcohol, which could lead to a delayed hypovolemic state, as well as a second cause of autonomic neuropathy, should be advised. Slow cautious movements between different body postures should be emphasized.

Encourage patients to sit or lie down upon the initiation of orthostatic symptoms. The head of the bed can be elevated so the patient sleeps at a 15-20° angle to stimulate nocturnal mineralocorticoid release.

Occasionally, compressive stockings can be used, although some patients do not tolerate these.

Finally, the action of simply drinking 1-2 glasses of water can have a significant effect on systolic blood pressure. In patients with severe neurogenic orthostatic hypotension, intake of this volume led to an increase in systolic blood pressure of more than 30 mm Hg (Jordan, 2000). Surprisingly, plasma norepinephrine in this patient group increased, and this vasopressor response was almost completely abolished by intravenous ganglion blockade. Therefore, simply drinking water increases blood pressure not only by increasing volume status, but also by increasing sympathetic activity.

Pharmacologic therapy

Pharmacologic therapy of orthostatic intolerance should be attempted in more difficult cases or when conservative therapy is unsuccessful.

Several medications are effective in controlling orthostatic intolerance. In less severe cases, such as in patients with POTS, medications controlling heart rate may be sufficient. In more severe cases, volume expansion with fluorocortisone or venoconstriction with the alpha2-adrenergic agonist midodrine may be necessary.

Secondary drugs that may be useful in particular patients include nonsteroidal anti-inflammatory drugs, serotonin reuptake inhibitors (SSRIs), and acetazolamide.

Erythropoietin therapy can be effective in treating orthostatic hypotension in some patients, particularly diabetic patients with anemia and orthostatic hypotension (Winkler, 2001). Erythropoietin may increase norepinephrine levels, thereby improving vasomotor tone. Also, erythropoietin promotes increased vascular sensitivity to angiotensin II, possibly through nitric oxide, and it may have direct pressor effects on vascular smooth muscle cells. DDAVP (vasopressin) produces an antidiuretic function at the renal tubuli, preventing nocturesis and elevating morning blood pressure.

Possible management for gastrointestinal autonomic neuropathy in diabetes patients may include aminoguanidine, which can prevent diabetes-induced changes in nitric oxide synthase–related changes in animal models of ileum autonomic neuropathy (Shotton, 2006).

Treatments for specific conditions

Treatment of specific conditions can be tailored to the particular disease or syndrome.

Bladder dysfunction

Bladder dysfunction should be investigated with a urodynamic study initially before therapies are introduced.

Conservative therapy may be sufficient in mild dysfunction, such as a strict fluid schedule and bladder training. In cases of spastic bladder activity, medications such as tolterodine and oxybutynin may be useful. In cases of detrusor areflexia, cholinergic medications such as bethanechol may be helpful.

Refractory situations may require intermittent catheterization. Surgical options such as artificial sphincters may be necessary in some patients. Sexual dysfunction may require sildenafil and, less commonly, prosthetic devices or assistive devices. The efficacy and safety of sildenafil in diabetic patients with autonomic failure and orthostatic hypotension is largely unknown.

Gastrointestinal conditions

Gastrointestinal difficulties can be present in many autonomic neuropathies, though the patient or physician may not recognize it as such.

Changes in diet with increased fiber ingestion and increased fluid intake can be attempted first. In patients with Sjögren syndrome or thyroiditis, problems with hyposalivation can lead to difficulties in oral hygiene, and the patient should be reminded about regular dental checkups. Occasionally, cyproheptadine can be useful in treatment of altered sense of taste.

Pandysautonomia

The treatment of pandysautonomia is mainly supportive until spontaneous recovery can occur. In some patients, orthostatic hypotension may be relieved by fludrocortisone 0.1-0.2 mg daily or the midodrine hydrochloride at 5-15 mg daily. Erythropoietin may be helpful in some patients with orthostatic hypotension (Winkler, 2001). No definite evidence of course-modifying treatment exists, although glucocorticoid therapy, plasma exchange, and intravenous immunoglobulin therapy have all been attempted. Most patients have a good prognosis once the acute episode is over.

Postural orthostatic tachycardia syndrome

The treatment of POTS may require a high-salt diet and high fluid intake. Beta-adrenergic agonist therapy may be useful in some patients (Low, 1999).

Dysautonomia

Management of dysautonomia within cases of GBS is difficult (Zochodne, 1994, Panagyres, 1989). Primary therapy of the condition consists of supportive measures and intravenous immunoglobulin or plasma exchange therapy. Vasoactive therapy is occasionally required and should be administered in an intensive care unit with intra-arterial blood pressure monitoring. Patients with severe bradyarrhythmias can require pacemaker assessment.

Lambert-Eaton myasthenic syndrome

The treatment of LEMS involves treatment of underlying malignancy in appropriate cases. The use of immunosuppressive therapies such as prednisone, azathioprine, plasma exchange, and intravenous immunoglobulin (IVIG) has also been successful. Autonomic dysfunction in LEMS may also respond to 3,4 diaminopyridine, which may also lead to improvements in strength.

Amyloidoses

In amyloidoses associated with myeloma, treatment must be directed against the myeloma.

Sjögren syndrome

Sjögren syndrome is probably autoimmune, but responses to immunosuppression are largely unsatisfying, although a trial may be indicated in particular patients.

Episodes of porphyria can be treated by intravenous infusion of hematin, glucose, and vitamin B-6.

Surgical Care

• The most common form of FAP is associated with a transthyretin defect. This form of FAP has been treated with liver transplantation, which should be strongly considered in young patients. Transthyretin is a serum transport protein synthesized primarily in the liver, and transplantation prevents its production in the abnormal form and thus prevents its deposition (Monteiro, 1998; Tashima, 1999).
• Uremic neuropathy with autonomic dysfunction has shown some reversibility with renal transplantation, whereas dialysis does not appear to improve the autonomic deficit.
• Hepatic disease–related neuropathies may also be reversible following liver transplantation in particular cases.

Consultations

Useful consultations may be obtained depending on the type of autonomic neuropathy present.

• Infectious conditions, such as HIV infection, Chagas disease, leprosy, diphtheria, and Lyme disease may require the input of an infectious diseases expert.
• Consultations with internal medicine specialists, including endocrinologists, hepatologists, and nephrologists, are often useful in the diagnosis and management of forms of amyloidosis, porphyria, diabetes mellitus, thyroiditis, hepatic failure, and renal failure.
• A rheumatologist can be of great assistance in diagnosing and managing cases of Sjögren syndrome, rheumatoid arthritis, systemic lupus erythematosus, and other connective tissue disorders.

Diet

The treatment of POTS may require a high-salt diet and high fluid intake. Maintenance of high intakes of fluid and salt, as tolerated, can be also be attempted for other causes of orthostatic hypotension (Low, 1999).

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Sympathomimetic agents

These are used in orthostatic hypotension if simple measures yield no improvement.

Drug Category: Mineralocorticoids

These agents can be used to treat orthostatic hypotension.

Drug Category: Anticholinergic agents

These agents are useful in cases of difficult bladder emptying.

Drug Name	Tolterodine tartrate (Detrol)
Description	Competitive muscarinic receptor antagonist for overactive bladder, but differs from other anticholinergic types because of selectivity for urinary bladder over salivary glands. High specificity for muscarinic receptors. Minimal activity or affinity for other neurotransmitter receptors and other potential targets (eg, calcium channels).
Adult Dose	2 mg PO bid; can be adjusted to 1 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; urinary retention; gastric retention; uncontrolled narrow-angle glaucoma
Interactions	Patients receiving macrolide antibiotics or antifungal agents should not receive doses > 1 mg PO bid
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Do not administer doses > 1 mg PO bid to patients with significantly reduced hepatic function; caution in renal impairment

Drug Category: Cholinergic agents

These agents stimulate cholinergic receptors in the smooth muscle of the urinary bladder for stimulation of bladder emptying.

Drug Category: Phosphodiesterase inhibitors

These oral agents act peripherally to induce smooth muscle relaxation of the corpora cavernosa.

Drug Category: Vasopressin analogues

Oral or nasal spray agents acting to prevent nocturnal urinary production.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• Maneuvers to avoid complications of orthostatic hypotension, particularly falls in elderly patients, as described above, are important to avoid further associated morbidity.
• Bladder and gastrointestinal difficulties must be monitored to prevent anuria and bowel obstruction.
• Patients with hypohidrosis/anhydrosis must be cautious in warm climates to avoid excessive heat, preventing heat stroke.
• Foot care is essential in patients with small-fiber neuropathy and diabetic neuropathy. Patients should be instructed to test temperatures with a sensitive limb and to avoid trauma that could have ulcerative complications.
• Patients with dry mouth should be instructed to seek regular dental checkups and be instructed about proper methods of oral hygiene.
• Patients with dry eyes should be given advice regarding proper hydration of the eyes to avoid conjunctival difficulties.

Complications

• Many complications of autonomic neuropathy exist, as described above.
• The most severe are cardiac arrest, cardiac dysrhythmias, blood pressure fluctuations, and risk of cerebral and cardiac ischemia.

Prognosis

• The prognosis depends on the particular syndrome causing autonomic neuropathy.
• • In many cases, the course is gradually progressive in nature.
  • The prognosis can be improved by controlling diabetes mellitus if present, by limiting alcohol intake, by and treating correctable syndromes or diseases as applicable to prevent progression.
• In the case of acute autonomic neuropathies, such as acute pandysautonomia and GBS, the prognosis is often good after the acute illness, provided that supportive care is optimal.

Patient Education

Patient education begins in the primary care office or with the neurologist as a consultant. Discussion of the following simple questions should be encouraged:

• What is autonomic neuropathy?
• • Autonomic neuropathy is damage to nerves controlling many everyday body activities. It can be caused by a number of different diseases, each of which affects the nerves forming the autonomic nervous system.
  • Some of the functions regulated by the autonomic nervous system are control of heart rate, blood pressure, digestion, bladder function, bowel function, sweating, and even breathing. These are unconscious vital functions important to the body.
• How does it occur?
• • Different diseases may damage the nervous system, which includes the autonomic nervous system.
  • The most common of these diseases is probably diabetes mellitus, but other diseases of nerves can do this as well.
• What are the symptoms?
• • Lightheadedness and low blood pressure upon rising, which can lead to unconsciousness in severe cases
  • Heart-rate variability
  • Heart-rhythm variability with irregular beats
  • Lack of tears within the eyes
  • Lack of saliva
  • Feeling full earlier than expected with a meal
  • Nausea and vomiting
  • Problems with swallowing
  • Constipation, which if severe can result in bowel obstruction
  • Diarrhea
  • Incontinence of bladder and bowel functions
  • Urgency of bladder (rushing to the bathroom)
  • Problems with penile erection
  • Lack of sweating
• How is it treated?
• • In many cases, no specific treatment is available for autonomic neuropathy. In some cases, such as with diabetes mellitus, the best approach is to control the diabetes to prevent progression.
  • In mild cases, changes in diet, sleeping position, and nonmedicinal changes can help some patients.
  • In more severe cases, drugs can be used to maintain blood pressure to prevent fainting.
  • Medications can help with bladder function and erectile function.
• How can a patient take care of him or herself?
• • Avoid rising too quickly.
  • Drink water regularly if standing blood pressure falls too much.
  • Follow physician guidelines about how to treat specific symptoms.
  • Avoid excessive alcohol intake, which may reduce blood pressure and lead to a neuropathy, which can worsen the autonomic problems.
  • Men who have trouble having erections should talk to their health care providers. Medications such as Viagra can help a man achieve and maintain an erection. In some cases, prosthetic devices or other devices to assist in erection may be useful.
• How long will the effects last?
• • The autonomic neuropathy continues once the patient has it in most cases.
  • Worsening can occur through the course of the autonomic neuropathy.

Where can further information be obtained?

• The Dysautonomia Foundation
• The National Dysautonomia Research Foundation

For excellent patient education resources, visit eMedicine's Brain and Nervous System Center, Kidneys and Urinary System Center, and Immune System Center. Also, see eMedicine's patient education articles Guillain-Barré Syndrome, Bladder Control Problems, and Chronic Fatigue Syndrome.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Management of autonomic neuropathy should start from the initial diagnosis. The primary care physician should be responsible for educating patients about possible complications.
• Failure to diagnose autonomic neuropathy can lead to complications such as injuries from fainting, cardiac arrest, and severe bladder and bowel problems.
• Increase the medical and public awareness of the importance of seeing a neurologist with this condition, preferably one with training in peripheral neuropathy. The neurologist can make specific suggestions to the primary care physician regarding the individual patient with autonomic neuropathy.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Antonelli Incalzi R, Fuso L, Pitocco D, et al. Decline of neuroadrenergic bronchial innervation and respiratory function in type 1 diabetes mellitus: a longitudinal study. Diabetes Metab Res Rev. Oct 2 2006;[Medline].
• Ascaso JF, Herreros B, Sanchiz V, et al. Oesophageal motility disorders in type 1 diabetes mellitus and their relation to cardiovascular autonomic neuropathy. Neurogastroenterol Motil. 2006;18(9):813-822. [Medline].
• Bejaoui K, Wu C, Scheffler MD, et al. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet. Mar 2001;27(3):261-2. [Medline].
• Bharucha AE, Camilleri M, Low PA, Zinsmeister AR. Autonomic dysfunction in gastrointestinal motility disorders. Gut. Mar 1993;34(3):397-401. [Medline].
• Cohen JA, Laudenslager M. Autonomic nervous system involvement in patients with human immunodeficiency virus infection. Neurology. Aug 1989;39(8):1111-2. [Medline].
• Dawkins JL, Hulme DJ, Brahmbhatt SB, et al. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet. Mar 2001;27(3):309-12. [Medline].
• Delahaye N, Rouzet F, Sarda L, et al. Impact of liver transplantation on cardiac autonomic denervation in familial amyloid polyneuropathy. Medicine (Baltimore). 2006;85(4):229-238.