eMedicine Specialties > Neurology > Neuromuscular Diseases

Autonomic Neuropathy

Steven D Arbogast, DO, Fellow, Neuromuscular Medicine, University Hospitals Case Medical Center, Cleveland
J Douglas Miles, MD, PhD, Clinical Instructor of Neuromuscular Medicine, Case Western Reserve University School of Medicine; Bashar Katirji, MD, FACP, Director, Neuromuscular Center and EMG Laboratory, The Neurological Institute, University Hospitals Case Medical Center; Professor of Neurology, Case Western Reserve University School of Medicine

Updated: Jun 25, 2009

Introduction

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; therefore, autonomic dysfunction may manifest with numerous clinical phenotypes and various laboratory and neurophysiologic abnormalities. Although a patient may present with symptoms related to a single portion of the autonomic system, the physician must be vigilant for 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; in others, symptoms may be disabling. Several clinically important features of autonomic neuropathies are treatable; therefore, the physician must be alert to these features.

Pathophysiology

The pathophysiology of autonomic neuropathies is variable and depends upon the underlying medical conditions. We have chosen to classify the autonomic neuropathies into hereditary and acquired. The acquired autonomic neuropathies may then be subsequently subdivided into primary or secondary.  

Inherited Autonomic Neuropathies

Table 1: Types of HSAN

Fabry disease

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.⁶

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, affected individuals present with acute polyneuropathy that may mimic Guillain-Barré syndrome. Autonomic dysfunction, particularly cardiac and vascular in nature, can be prominent.

Acquired Autonomic Neuropathies

• Pandysautonomia: The syndrome of acute pandysautonomia includes both parasympathetic and sympathetic dysfunction.⁷ An immunologic basis for acute pandysautonomia remains most likely, often with onset after a viral illness. Patients with what may have otherwise been called idiopathic autonomic neuropathy may test positive for an autonomic ganglionic acetylcholine receptor antibody supporting the autoimmune etiology of this condition.⁸
• 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.⁹
• 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.¹⁰ Ross syndrome is a related condition where segmental anhidrosis occurs in conjunction with Adie pupil.¹¹
• Chronic idiopathic anhidrosis: Chronic idiopathic anhidrosis is an acquired generalized loss of sweating without other autonomic features. The lesions may be pre- or postganglionic.¹²
• Amyloid neuropathy: Amyloid neuropathy can be inherited as noted above; however, it can also be associated with hematologic disease, such as multiple myeloma, leading to accumulation of immunoglobulins kappa or lambda light chains.¹³ Another acquired amyloidosis occurs with dialysis, with β2-microglobulin deposits in the nervous system. In syndromes of amyloidosis, the development of generalized autonomic failure significantly worsens the overall prognosis. Of all autonomic neuropathies, amyloidosis probably causes the most severe forms, with universal autonomic dysfunction common. A somatic neuropathy is often coexistent.¹⁴
• 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 forme fruste of postviral pandysautonomia.¹⁵ Antibodies against ganglionic receptors are found in 9% of patients with POTS.¹⁶

Secondary acquired autonomic neuropathies

Metabolic derangements that may have an associated autonomic neuropathy are as follows:

• Diabetes mellitus
  • Diabetes mellitus is the most common cause of autonomic neuropathy.  Neuropathy is the most common complication of diabetes mellitus and may have both somatic and autonomic features.^17,18,19 See eMedicine's article on Diabetic Neuropathy. Parasympathetic abnormalities are thought to precede sympathetic abnormalities, but this has not been verified.
  • A disorder called acute diabetic autonomic neuropathy appears as an 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.¹⁷
  • 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.²⁰
• 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.²¹
• Hepatic disease–related neuropathy: Neuropathies related to hepatic disease, such as primary biliary cirrhosis, 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 hypothesized that patients with autonomic neuropathies are more likely to develop hepatic encephalopathy due to a decreased intestinal transit time.²² 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 deficiencies, toxins, and drugs that may have an associated autonomic neuropathy are as follows:

• Vitamin deficiency and nutrition-related neuropathy: Deficiency of vitamin B₁₂ neuropathy may also be associated with autonomic dysfunction.²³
• Toxic and drug-induced autonomic neuropathy: Toxic and drug-induced autonomic neuropathies may occur with a large variety of chemotherapeutic medications such as vincristine, cisplatin, carboplatin, vinorelbine, paclitaxel, and suramin. Other therapeutic agents associated with a toxic autonomic neuropathy include acrylamide, pyridoxine, thallium, amiodarone, perhexiline, and gemcitabine.⁶
• Alcohol may be associated with an autonomic neuropathy, possibly related to directly toxic effects of alcohol, although thiamine deficiency may also play a role.²⁴

Infectious diseases that may have an associated autonomic neuropathy are as follows:

• Lyme disease: Patients with Lyme disease have shown lymphoplasmocellular infiltrates in the autonomic ganglia.²⁵
• HIV infection: HIV infection may lead to autonomic neuropathy, particularly in late-terminal stages of disease.²⁶ . Often, this occurs in conjunction with a somatic neuropathy related to HIV infection or complications of AIDS.²⁷  
• Chagas disease: Chagas disease due to infection with Trypanosoma cruzi is occasionally associated with autonomic neuropathy during the chronic stage of infection.²⁸ Parasympathetic dysfunction tends to be greater than sympathetic dysfunction.²⁹ Autoimmune destruction of the peripheral nervous system and autonomic nervous system may occur, especially of autonomic nerves supplying the cardiovascular and gastrointestinal systems.
• Botulism: Botulism produces neuromuscular paralysis by inhibiting the release of acetylcholine from the presynaptic terminus, as well as an acute cholinergic neuropathy.³⁰
• Diphtheria: Diphtheria has been associated with an autonomic neuropathy. Although the mechanism of action is not clear, the parasympathetic nervous system may be more affected than the sympathetic.³¹
• Leprosy: Leprosy causes nerve injury by direct invasion of Mycobacterium leprae into the nerve and Schwann cells.³² Leprosy has been shown to affect both the sympathetic and parasympathetic nervous system.³³

Autoimmune conditions that may have an associated autonomic neuropathy are as follows:

• Celiac disease: Autonomic neuropathy may occur in approximately 50% of adults with celiac disease, leading to clinical features of presyncope and postural nausea.³⁴ Autonomic denervation may be related to antineuronal antibodies; the neuropathy does not appear to respond to a gluten-free diet.³⁵
• 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.³⁶
• Rheumatoid arthritis, systemic lupus erythematosus, and connective tissue disorders: Abnormalities of sympathetic postganglionic function may be seen in rheumatoid arthritis, systemic lupus erythematosus, and other connective tissue disorders. Some of these patients may have autoantibodies to ganglionic acetylcholine receptors. Autoimmune thyroiditis, such as 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.⁶
• 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.^37,38 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.³⁷
• 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.³⁹ In 50% of cases, LEMS is associated with a neoplasm, most commonly small cell carcinoma of the lung.
• 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.⁴⁰
  • A variant of paraneoplastic autonomic neuropathy is an enteric neuronopathy that exists with antibodies directed against the myenteric plexus (anti-enteric neuronal antibodies).⁴¹ 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).⁴²
• Inflammatory bowel disease: Inflammatory bowel disease–related disorders may rarely have an associated autonomic neuropathy, particularly involving the pupillary nerves.⁴³

Mortality/Morbidity

Falls and loss of consciousness are significant contributors to morbidity associated with autonomic neuropathies. They may lead to injury, particularly in the elderly. Often, an autonomic neuropathy manifests with orthostatic hypotension, which has been associated with increased mortality in the middle aged and elderly.⁴⁴ As the autonomic nervous system is involved in involuntary control of almost every organ system, patients may have many other complaints that are discussed below.

Many cases of autonomic neuropathy have a gradually progressive course, leading to a poor outcome. Patients with severe dysautonomia are at risk for 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, such as with kidney failure in Fabry disease, may lead to mortality.

Race

Autonomic neuropathies may be seen in all races and ethnicities. Certain subtypes may demonstrate an increased incidence in specific ethnic groups. These subtypes are addressed individually above.

Sex

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

Age

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

Clinical

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.⁴⁵ 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 is typically the most disabling.⁶ 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 are typically the initial symptoms 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.

A thorough history and review of systems may reveal many of the following complaints.

• Facial - Facial pallor, anhidrosis
• Ocular - Blurring then graying of vision, blacking out, tunnel vision, sensitivity to light, difficulty with focusing, reduced lacrimation, and 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, headache, chest pain, and shortness of breath (Elderly patients may complain of coat hanger or lower extremity discomfort. These symptoms may be worse after a large meal or in severe illness.)
• 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)⁴⁶ , hyposalivation, altered sense of taste⁴⁷ , presyncope with micturition, and defecation
• Renal - Nocturia, bladder urgency, bladder frequency, enuresis, incomplete bladder voiding, urinary retention, and urinary incontinence
• Sexual – Impotence, loss of ejaculation, and retrograde ejaculation in men; inability to achieve orgasm or nonspecific sexual dysfunction in both sexes
• Sweating - Anhidrosis or hypohidrosis, compensatory hyperhidrosis, and gustatory sweating⁴⁶
• Temperature regulation - Hypothermia (from loss of shivering and inability to vasoconstrict to prevent heat loss) and hyperpyrexia
• Extremities - Burning feet most commonly observed in small-fiber sensory neuropathy, pruritus, dysesthesia, allodynia, hyperalgesia, nocturnal exacerbation of symptoms, dry skin, and loss of distal leg hair, brittle nails, pallor, and cold feet
• Respiratory – Impaired control of bronchomotor tone, leading to a depressed bronchoconstrictory response to cholinergic stimuli (caused by diabetes mellitus); impaired ventilatory and heart rate response to hypoxia, but not to hypercapnia, in patients with diabetes

Physical

General techniques of the 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, and 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 and glove 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:

• Orthostatic vital signs are essential. Blood pressure and heart rate is measured after several minutes of baseline rest, 1 minute after sitting and 3 minutes after standing.
  • Orthostatic hypotension is present if systolic pressure increases more than 20 mm Hg or drops 10 mm Hg in the presence of presyncopal symptoms.
  • Postural tachycardia syndrome is present if tachycardia response is excessive (>30 bpm increase from baseline).
• 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 anhidrosis, 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.

• Skin and mucosal membrane changes and ulcerations can be observed in leprosy, Lyme disease, HSAN, and diphtheria.
• Angiokeratomas of the trunk or groin in a patient with a history of renal failure and previous strokes is suggestive of Fabry disease.
• Somatic neuropathy, systemic infections, and other HIV/AIDS systemic manifestations can suggest HIV-associated neuropathy.²⁷
• Concomitant liver, renal, and cardiac disease may suggest amyloidosis.
• 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.

Causes

The causes of autonomic neuropathy are varied. The discussion noted above in the Pathophysiology covers many of the common and uncommon causes of autonomic neuropathy.

Differential Diagnoses

Workup

Laboratory Studies

Initial laboratory evaluation should include a complete blood count, basic metabolic panel, liver function testing, and immunoelectrophoresis. More specific testing should be based on the patient’s history of other medical conditions.

Special situations

Based upon the findings after the above evaluation and clinical situation, more specific tests may be considered.

• Blood tests may be considered based upon the clinical history and findings on autonomic testing.
  • Oral glucose tolerance test to evaluate for diabetes mellitus, if an initial serum glucose level is normal or nondiagnostic.
  • Testing for SS-A and SS-B if there is concerns for Sjögren syndrome (Sicca syndrome).
  • Anti-ganglionic acetylcholine receptor (AChR) autoantibodies if the onset was acute to subacute in nature.
  • Specific genetic tests for the familial forms of dysautonomia can be ordered.
  • Specific tests for infections, inflammatory, autoimmune, and paraneoplastic causes can be ordered based upon the history and physical examination.
  • 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.
  • A history of neuropathy, mental status changes, and abdominal pain should prompt the physician to evaluate the patient for acute intermittent porphyria. In cases of suspected porphyria, high levels of porphobilinogen and delta-aminolevulinic acid can be found in urine during acute episodes.
• 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.

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.

Procedures

Autonomic testing

Autonomic testing using the following methods should be performed to assess the severity and parts of the autonomic nervous system that are involved. These tests have also recently been recommended (Level B) by the American Academy of Neurology for evaluation of patients with distal symmetric polyneuropathy.⁴⁸

• Tilt table testing to test adrenergic vasomotor function and cardiac sympathetic function.
• Cardiac response to deep breathing and R-R interval to evaluate cardiovagal functions.
• Cardiac response to Valsalva maneuvers to test parasympathetic innervation to the heart.
• Quantitative Sudomotor Axon Reflex Testing (QSART) to evaluate the postganglionic segment of the thermoregulatory pathway. Four regions are tested: forearm, proximal leg, distal leg, and dorsum of the foot. Electrical stimulation (iontophoresis) is applied to the skin, and the volume of sweat produced can be measured.

Nerve conductions studies and electromyography

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.

• 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.
• 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.
• Other uncommon 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 patients.
• 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).⁴⁹
• Skin or nerve biopsy (see histology findings) may be performed if clinically indicated.
• Specific autonomic tests that are being performed at some institutions include the following:
  • The thermoregulatory sweat test (TST) complements the quantitative sudomotor axon reflex test (QSART)⁹ and is used to assess thermoregulatory pathways.⁷ 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.⁵⁰ 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.
  • 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.⁹ 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 pain⁵¹ , but vibration and cool sensitivity may be normal.
  • Pupillometry measure changes in papillary response and is being investigated at some institutions as a potential marker for autonomic neuropathy.⁵²
  • Quantitative direct and indirect test of sudomotor function (QDIRT) involves making a silicone impression of a patient's skin while sweating is induced by acetylcholine iontophoresis. The presence of sweat droplets can be quantified in the silicone cast⁵³ , providing a marker of sudomotor function.
• 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.
• Urological studies
  • Urodynamic studies may be used to examine the lower urinary tract function.⁵⁴
  • Measurements include urine flow rate, residual volume, cystometry during 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.
• Gastrointestinal studies
  • 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.⁴⁷
  • 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.⁵⁵
    • 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.⁵⁶

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.⁵⁷ 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 reduced epidermal fiber densities.⁵⁸

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.⁵⁹ 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.⁶⁰

Immunologic findings

Patients with autoimmune autonomic neuropathy can have antiganglionic acetylcholine receptor (AChR) autoantibodies.⁶¹ 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. Higher antibody titers correlate with greater autonomic dysfunction as well as increased frequency of cholinergic dysautonomia.

Patients with POTS may also demonstrate presence of ganglionic receptors.¹⁶

In specific disorders, testing for the presence of autoantibodies can help determine a diagnosis. Antinuclear antibodies and antibodies to Sjögren syndrome antigens A and B (SSA and SSB) are seen in several connective tissue disorders. Antibodies against voltage-gated calcium channels (VGCC) are associated with LEMS. 

Staging

The combination of tilt table testing, cardiac responses to deep breathing and the Valsalva maneuver, and QSART comprise the composite autonomic scoring scale (CASS), which may be used to assess the severity of autonomic dysfunction. The CASS is reliable and useful for monitoring clinical progression with an autonomic neuropathy. The CASS is a 10-point scale; 4 points are allotted for adrenergic and 3 points each for sudomotor and cardiovagal failure. Scores are normalized for age and sex. Patients with a score of less than 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.⁶²

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

Treatment

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. 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.⁶³ 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.

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. Physical counter-maneuvers should also be attempted.⁶⁴ The maneuvers include crossing the legs, squatting, and tensing the leg muscles, abdominal muscle, buttocks, or whole body.

Compressive stockings should be used. The thigh-high moderate compression stockings give the most benefit. Although they are difficult to put on and can be uncomfortable for patients, they should be strongly encouraged to use these as much as possible.

Gentle isometric exercises to help build up muscle tone is essential for patients with orthostatic intolerance. We often time recommend water aerobics or water jogging. If a place to perform these types of exercises is not available, then patients are encouraged to start gentle aerobic exercises often times with a recumbent bicycle, to avoid putting them in a position where they may experience loss of consciousness or fall.

Conservative treatment for other symptoms may also be tried, including eating smaller frequent meals, artificial tears for dry eyes, antiperspirants for hyperhidrosis and avoidance of hot environments for patients with anhidrosis.

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 such as beta-blockers for controlling heart rate may be sufficient.⁶⁵ In more severe cases, volume expansion with fludrocortisone⁶⁶ or venoconstriction with the α 2-adrenergic agonist midodrine⁶⁷ may be necessary. Remembering that both of these medications may lead to supine hypertension is important and a balance may be difficult to strike. Pyridostigmine has been used successfully for treatment of both POTS and orthostatic hypotension.⁶⁸ In addition, selective serotonin reuptake inhibitors (SSRIs)⁶⁹ and phenobarbital⁷⁰ have been shown to benefit specific patients.

Erythropoietin therapy can be effective in treating orthostatic hypotension in some patients, particularly patients with diabetes who have anemia and orthostatic hypotension.⁷¹ 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.⁷²

If an autoimmune cause of the autonomic neuropathy is found or strongly suspected, then immunomodulatory therapy may be considered. Intravenous immunoglobulin (IVIG)⁷³ plasmapheresis⁷⁴ and oral immunosuppressant medications⁷⁵ have been used successfully.

Possible management for gastrointestinal autonomic neuropathy in patients with diabetes may include aminoguanidine, which can prevent diabetes-induced changes in nitric oxide synthase–related changes in animal models of ileum autonomic neuropathy.⁷⁶

Treatments for Specific Conditions

Surgical Care

Liver transplant should be considered for patients with FAP that is associated with a transthyretin defect. 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.^79,80

Liver transplant may also be considered in patients with other hepatic disease related neuropathies. The neuropathies may be reversible in particular cases.

Uremic neuropathy with autonomic dysfunction has shown some reversibility with renal transplantation, whereas dialysis does not appear to improve the autonomic deficit.

Consultations

Consultations should be considered based upon the underlying pathophysiology of the autonomic neuropathy.

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 patients with orthostatic intolerance may require a high-salt diet and high fluid intake as noted above.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications. Many of the medications used to treat dysautonomia are considered off label.

Sympathomimetic agents

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

Midodrine (ProAmatine)

Prodrug metabolized to desglymidodrine, a selective alpha1-adrenoreceptor agonist. Effects via arterioconstriction and venoconstriction.

Dosing

Adult

2.5-5 mg PO bid/tid

Pediatric

Not established

Interactions

Drugs stimulating alpha-adrenergic agonists may enhance or potentiate pressor effects; cardiac glycosides may precipitate or worsen bradycardia; psychopharmacologic agents or beta-blockers may precipitate or worsen AV block or arrhythmia

Contraindications

Documented hypersensitivity; acute renal disease; severe organic heart disease; pheochromocytoma; urinary retention; persistent and excessive supine hypertension

Precautions

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

Caution in diabetes mellitus or visual complications; discontinue and reevaluate if any signs or symptoms suggesting bradycardia occur

Mineralocorticoids

These agents can be used to treat orthostatic hypotension.

Fludrocortisone (Florinef)

Promotes increased reabsorption of sodium and loss of potassium at renal distal tubules.

Dosing

Adult

0.1-0.2 mg/d PO

Pediatric

Not established

Interactions

Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects; decreases salicylate levels

Contraindications

Documented hypersensitivity; systemic fungal infections

Precautions

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

Taper dose gradually when therapy discontinued; caution in Addison disease, potassium loss, and sodium retention

Anticholinergic agents

These agents are useful in cases of difficult bladder emptying.

Oxybutynin (Ditropan)

Commonly used drug in bladder disorder. Known for anticholinergic-antispasmodic effects. Smooth muscle relaxing effect distal to cholinergic receptor site. Long-acting form available for qd dosing.

Dosing

Adult

5 mg PO tid

Pediatric

2.5 mg PO tid

Interactions

Coadministration with other anticholinergic agents may exacerbate anticholinergic adverse effects, including dry mouth, drowsiness, constipation; CNS effects increase when administered concurrently with other CNS depressants

Contraindications

Documented hypersensitivity; glaucoma; partial or complete GI obstruction; myasthenia gravis; ulcerative colitis; toxic megacolon

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in urinary tract obstruction, reflux esophagitis, heart disease

Tolterodine tartrate (Detrol)

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).

Dosing

Adult

2 mg PO bid; can be adjusted to 1 mg PO bid

Pediatric

Not established

Interactions

Patients receiving macrolide antibiotics or antifungal agents should not receive doses > 1 mg PO bid

Contraindications

Documented hypersensitivity; urinary retention; gastric retention; uncontrolled narrow-angle glaucoma

Precautions

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

Beta-adrenergic blocker

This agent can be used to treat orthostatic tachycardia in POTS patients.

Metoprolol (Lopressor, Toprol XL)

For treatment of orthostatic tachycardia. Inhibits beta-adrenergic input.

Dosing

Adult

12.5 mg PO qd /bid; titrate to patients symptoms with target dose of 50 mg of long-acting formulation daily

Pediatric

Not established

Interactions

Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels of metoprolol, possibly resulting in decreased pharmacologic effects; toxicity of metoprolol may increase with coadministration of sparfloxacin, phenothiazines, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; metoprolol may increase toxicity of digoxin, flecainide, clonidine, epinephrine, nifedipine, prazosin, verapamil, and lidocaine

Contraindications

Documented hypersensitivity; uncompensated congestive heart failure, bradycardia, asthma, cardiogenic shock, depression, and A-V conduction abnormalities

Precautions

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

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may reduce signs and symptoms of acute hypoglycemia and may decrease clinical signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; monitor patient closely and withdraw the drug slowly; during IV administration, carefully monitor blood pressure, heart rate, and ECG

Vasopressin analogues

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

Desmopressin acetate (DDAVP)

Vasopressin analogue without effect on V1 receptors responsible for vasopressin-induced vasoconstriction. Acts on V2 receptors at renal tubuli, increasing cellular permeability of collecting ducts, responsible for antidiuretic effect. Prevents nocturnal diuresis and elevated morning BP, resulting in renal water reabsorption. Nasal spray and tab (more convenient).

Dosing

Adult

2-4 mcg IM administered at 8:00 pm as single dose

Pediatric

Not established

Interactions

Coadministration with demeclocycline and lithium decreases effects; fludrocortisone and chlorpropamide increase effects

Contraindications

Documented hypersensitivity; hemophilia; von Willebrand disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Avoid hyponatremia; monitor osmolality and plasma sodium levels q6wk; minimize fluid intake in the evening before administration (not to exceed 8 oz with dinner and 8 oz after dinner; nothing 2 h prior hs); caution in coagulation disorders and predisposition to thrombus formation and in fluid and electrolyte imbalance, hypertension, or severe cardiovascular disease

Acetylcholinesterase inhibitor

This agent can be used to treat orthostatic hypotension or orthostatic tachycardia.

Pyridostigmine (Mestinon)

Increases acetylcholine neurotransmission at peripheral
autonomic ganglia, which likely increases peripheral vasoconstriction sympathetic nerve fiber transmission. May also increase vagal cardiac input in POTS patients.

Dosing

Adult

60 mg tid or 180 mg SR qd; lower initial doses may be used

Pediatric

Not established

Interactions

Pyridostigmine increases effects of depolarizing neuromuscular blockers; increases toxicity of edrophonium

Contraindications

Documented hypersensitivity; gastrointestinal or urinary obstruction

Precautions

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

Caution in bronchial asthma and those receiving a cardiac glycoside
Overdose may cause cholinergic crisis, which may be fatal; atropine IV should be readily available for treatment of cholinergic reactions

Cholinergic agents

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

Bethanechol hydrochloride (Duvoid, Urecholine)

Used for selective stimulation of the bladder to produce contraction to initiate micturition and empty bladder. Most useful in bladder hypocontractility, if sphincters functional and coordinated. Rarely used because of GI stimulation and difficulty in timing effect.

Dosing

Adult

10-50 mg PO tid/qid

Pediatric

Not established

Interactions

Concurrent ganglion-blocking compounds may critically decrease BP

Contraindications

Documented hypersensitivity; peptic ulcer disease; obstructive pulmonary disease; bradycardia; vasomotor instability; hypotension; AV conduction defects; hyperthyroidism; epilepsy; mechanical GI/GU obstruction

Precautions

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

Urinary retention secondary to possible urine reflux into kidneys

Phosphodiesterase inhibitors

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

Sildenafil (Viagra)

Selective inhibitor of PDE5 that inactivates cGMP, allowing attenuation of the vasodilatory effect of NO. Effective in men with mild-to-moderate erectile dysfunction. Take on an empty stomach about 1 h before sexual activity. Sexual stimulation is necessary to activate response. The increased sensitivity for erections may last 24 h. Available as 25-, 50-, and 100-mg tabs.

Dosing

Adult

25-100 mg PO 1 h before sexual activity

Pediatric

Not established

Interactions

Potentiates vasodilatory effect of NO, resulting in potentially fatal drop in blood pressure; coadministration with ketoconazole, erythromycin, or cimetidine increases plasma sildenafil concentrations; coadministration with rifampin decreases plasma levels of sildenafil

Contraindications

Documented hypersensitivity; concurrent or intermittent use of organic nitrates in any form

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause headaches (16%), flushing (10%), upset stomach (7%), nasal congestion (4%), blue haze at the periphery of vision (3%); adverse effects more common in men taking 100 mg; serious adverse effects may occur in severe heart disease and in those taking nitrates; rates of MI are 1.7 (drug) vs 1.4 (placebo) per 100 man-years

Neuromuscular blocker agent, toxin

Used in patients with hyperhydrosis localized to palmar or axillary region.

Botulinum toxin type A (Botox)

One of several toxins produced by clostridium botulinum. Blocks neuromuscular transmission through a 3-step process: (1) Blockade of neuromuscular transmission; botulinum toxin type A (BTA) binds to the motor nerve terminal. The binding domain of the type A molecule appears to be the heavy chain, which is selective for cholinergic nerve terminals. (2) BTA is internalized via receptor-mediated endocytosis, a process in which the plasma membrane of the nerve cell invaginates around the toxin-receptor complex, forming a toxin-containing vesicle inside the nerve terminal. After internalization, the light chain of the toxin molecule, which has been demonstrated to contain the transmission-blocking domain, is released into the cytoplasm of the nerve terminal. (3) BTA blocks acetylcholine release by cleaving SNAP-25, a cytoplasmic protein that is located on the cell membrane and that is required for the release of this transmitter. The affected terminals are inhibited from stimulating muscle contraction. Toxin does not affect synthesis or storage of acetylcholine or conduction of electrical signals along the nerve fiber. Prevents calcium-dependent release of acetylcholine and produces a state of denervation at the neuromuscular junction and postganglionic sympathetic cholinergic nerves in the sweat glands.
Typically, a 24-72 h delay between administration of toxin and onset of clinical effects exists, which terminate in 2-6 mo.
This purified neurotoxin complex is a vacuum-dried form of purified BTA, which contains 5 ng of neurotoxin complex protein per 100 U.
BTA has to be reconstituted with 2 mL of 0.9% sodium chloride diluent. With this solution, each 0.1 mL results in 5 U dose. Patient should receive 5-10 injections per visit.
Must be reconstituted from vacuum-dried toxin into 0.9% sterile saline without preservative using manufacturer's instructions to provide injection volume of 0.1 mL; must be used within 4 h of storage in refrigerator at 2-8°C.
Preconstituted dry powder must be stored in freezer at <5°C. Each injection produces an area of anhydrosis approximately 1.2 cm in diameter. Results in anhydrosis lasting 4-12 months.
Injections of botulinum toxin must be repeated at varying intervals to maintain long-term results.

Dosing

Adult

Palmar hyperhidrosis: 50 subepidermal injections of 2 U per palm (total 100 U per palm)

Pediatric

Not established

Interactions

Aminoglycosides or drugs that interfere with neuromuscular transmission may potentiate effects of botulinum toxin

Contraindications

Documented hypersensitivity; infection present at injection site

Precautions

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 exceed recommended dosages and frequencies of administration; presence of antibodies to botulinum toxin type A may reduce effects of therapy; when used for cervical dystonia, may cause dysphagia, upper respiratory infection, neck pain, or headache; ptosis may occur when used for blepharism or strabismus; weakness of hand muscles and blepharoptosis may occur when used for palmar or facial hyperhidrosis, respectively

When used cosmetically for glabellar lines may cause headache, respiratory infection, flu syndrome, blepharoptosis, or nausea

Colony-stimulating Factor

May be used in patients with orthostatic hypotension or POTS.

Epoetin alfa (Epogen, Procrit)

Purified glycoprotein produced from mammalian cells modified with gene coding for human erythropoietin (EPO). Amino acid sequence is identical to that of endogenous EPO. Biological activity mimics human urinary EPO, which stimulates division and differentiation of committed erythroid progenitor cells and induces release of reticulocytes from bone marrow into the blood stream.
Has been shown to increase the functional capacity of patients with MSA, particularly those who have the characteristic mild anemia associated with this disease. Up to 38% of patients with severe autonomic failure are anemic. Lack of sympathetic stimulation may lead to a decrease of erythropoietin production and development of anemia. Sympathetic impairment and low plasma norepinephrine levels have been found to correlate with severity of anemia. Therapy with recombinant erythropoietin, even low doses (25-50 units/kg body weight SC, 3 times a week) has successfully corrected anemia and improved upright BP.

Dosing

Adult

25-50 U/kg body weight SC weekly titrated for hematocrit of 50%

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; uncontrolled hypertension

Precautions

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

Caution in porphyria, hypertension, history of seizures; decrease dose if hematocrit increase exceeds 4 U in any 2-wk period; the multidose preserved formulation contains benzyl alcohol and may increase risk of neurologic toxicity in infants (use preservative-free formulation); treatment results depend on adequate iron supplementation

Anticholinergic agent

Used for hyperhidrosis.

Glycopyrrolate (Robinul)

Acts in smooth muscle, CNS, and secretory glands to blocks action of acetylcholine at parasympathetic sites.

Dosing

Adult

1-2 mg PO bid/tid initially, then titrate to effective dose

Pediatric

<12 years: Not recommended
>12 years: Administer as in adults

Interactions

Levodopa decreases effects of glycopyrrolate; both amantadine and cyclopropane increase glycopyrrolate toxicity

Contraindications

Documented hypersensitivity; narrow-angle glaucoma, tachycardia, ulcerative colitis, paralytic ileus, or acute hemorrhage

Precautions

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

Glycopyrrolate may increase chances of developing megacolon, hyperthyroidism, CHF, CAD, hiatal hernia, and BPH; not recommended for children <12 years and patients with down syndrome

Immune globulin

Used for autoimmune causes of autonomic neuropathy.

Immune globulin intravenous (CarimuneGammagard S/D, Gammar-P, Gamunex, Polygam S/D)

Neutralize circulating myelin antibodies through antiidiotypic antibodies; down regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).

Dosing

Adult

2 g/kg IV over 2-5 d

Pediatric

Not established

Interactions

Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 months of vaccine)

Contraindications

Documented hypersensitivity; IgA deficiency

Precautions

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

Check serum IgA before IVIG (use an IgA-depleted product if deficient, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion)
Increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; lab result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Anti-inflammatory agent

Can be used if an inflammatory cause of the autonomic neuropathy is considered to be autoimmune in nature.

Prednisone (Deltasone, Sterapred, Orasone)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocyte and antibody production.

Dosing

Adult

5-60 mg/d PO qd or divided bid/qid; taper over 2 wk, as symptoms resolve

Pediatric

4-5 mg/m²/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk, as symptoms resolve

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI bleeding or ulceration

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Follow-up

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/anhidrosis 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 dysrhythmia, 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. In specific cases, the prognosis may be improved by controlling diabetes mellitus, limiting alcohol intake, 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 resolution of the acute illness.

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 sildenafil, tadalafil, or vardenafil 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?

In most cases, autonomic neuropathy is permanent. It may become worse as the disease progresses. The goal of treatment is to relieve symptoms of the disease, or to prevent disease progression when possible.

Where can further information be obtained?

• The Dysautonomia Foundation
• The National Dysautonomia Research Foundation
• eMedicine's Brain and Nervous System Center, Kidneys and Urinary System Center, and Immune System Center.
• eMedicine's patient education articles Guillain-Barré Syndrome, Bladder Control Problems, and Chronic Fatigue Syndrome.

Miscellaneous

Medicolegal 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.

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Keywords

syndrome of acute pandysautonomia, postural orthostatic tachycardia syndrome, POTS, Guillain-Barré syndrome, GBS, acute inflammatory demyelinating polyneuropathy, AIDP, Lambert-Eaton myasthenic syndrome, LEMS, Holmes-Adie syndrome, idiopathic distal small-fiber neuropathy, human immunodeficiency virus, HIV, Chagas disease, Chagas' disease, botulism, chronic idiopathic anhidrosis, familial amyloid polyneuropathy, FAP, diabetes mellitus, uremic neuropathy, hepatic disease, vitamin B-12 deficiency, paraneoplastic autonomic neuropathy, Sjögren syndrome, acute intermittent porphyria, variegate porphyria, hereditary sensory autonomic neuropathy, HSAN, Fabry disease, autonomic dysreflexia, AD, acquired immunodeficiency syndrome, AIDS, autonomic nervous system, ANS, autonomic reflex screen, ARS, composite autonomic scoring scale, CASS, collapsin response–mediator family, CRMP-5, cerebrospinal fluid, CSF, vasopressin, DDAVP, electromyography, EMG, inhibitor of k-light polypeptide gene enhancer inB-cells, IKBKAP, mitochondrial neurogastrointestinal encephalomyopathy, MNGIE, M-phase phosphoprotein-1, MPPI, multiple system atrophy, MSA, nerve conduction studies, NCS, progressive autonomic failure, PAF, primary biliary cirrhosis, PBC, Purkinje cell cytoplasmic antibody-2, PCA-2, Parkinson disease, PD, positron emission tomography, PET, peripheral nervous system, PNS, quantitative sudomotor axon reflex test, QSART, quantitative sensory testing, QST, single-photon emission computed tomography, SPECT, serine palmitoyltransferase, SPT, sympathetic skin responses, SSR, selective serotonin reuptake inhibitor, SSRI, thermoregulatory sweat test, TST

Contributor Information and Disclosures

Author

Steven D Arbogast, DO, Fellow, Neuromuscular Medicine, University Hospitals Case Medical Center, Cleveland
Steven D Arbogast, DO is a member of the following medical societies: American Academy of Neurology and American Osteopathic Association
Disclosure: Nothing to disclose.

Coauthor(s)

J Douglas Miles, MD, PhD, Clinical Instructor of Neuromuscular Medicine, Case Western Reserve University School of Medicine
J Douglas Miles, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Medical Association, and Society for Neuroscience
Disclosure: Nothing to disclose.

Bashar Katirji, MD, FACP, Director, Neuromuscular Center and EMG Laboratory, The Neurological Institute, University Hospitals Case Medical Center; Professor of Neurology, Case Western Reserve University School of Medicine
Bashar Katirji, MD, FACP is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Physicians, and American Neurological Association
Disclosure: Nothing to disclose.

Medical Editor

Paul E Barkhaus, MD, Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center
Paul E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

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