Sections

Overview

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

All forms of inherited autonomic neuropathies are rare. Familial amyloid polyneuropathy, the hereditary sensory autonomic neuropathies, Fabry disease, and the porphyrias are genetic diseases in which autonomic neuropathy is a common feature.

Familial amyloid polyneuropathy

Familial amyloid polyneuropathy (FAP) is often caused by a genetic mutation of the transthyretin gene. Mutant transthyretin produced in the liver accumulates as amyloid deposits in the peripheral nervous system 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. Liver transplantation, currently the most effective treatment for FAP, may slow the development of autonomic neuropathy, but not in all cases.^[1]

Hereditary sensory autonomic neuropathy

Currently, 5 types of hereditary sensory autonomic neuropathy (HSAN) have been defined (see Table 1). These types differ in their presentation, the portions of the autonomic nervous system affected, their associated genes, and inheritance pattern.^[2]

HSAN I has an autosomal dominant inheritance, and the disease is characterized by distal limb involvement with marked sensory loss, including loss of pain sensation, making affected individuals more susceptible to injury. HSAN I has been associated with point mutations in serine palmitoyltransferase (SPT) at chromosome arm 9q22.1-q22.3.^[3]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.^[4]

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, 2 novel missense mutations in the tyrosine kinase domain were found in a 10-year-old patient with HSAN IV.^[5]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 to those with HSAN IV. The genetic mutation has been isolated to the nerve growth factor beta gene.^[6]

Table. Types of HSAN (Open Table in a new window)

HSAN	Mode of Inheritance	Onset	Symptoms	Signs
Type I	Autosomal dominant, point mutations in SPT, 9q22.1-9q22.3	Second decade of life	Distal lower-limb involvement, ulceration of the feet, particularly the soles	Low sensory action potential amplitude
Type II, Morvan disease	Autosomal recessive	Congenital onset	Pansensory loss of upper and lower limbs, also trunk and forehead; early ulcers	Loss of myelinated and unmyelinated fibers
Type III, Riley-Day syndrome or familial dysautonomia)	Autosomal recessive, 9q31	Childhood onset, predominantly Ashkenazi Jews	Pallor in infancy, irregularities in temperature and blood pressure; Difficulties in eating and swallowing	Absence of unmyelinated fibers
Type IV	Autosomal recessive, 1q21-1q22	Congenital onset	Widespread anhidrosis, lost sense of pain, intellectual disability	Loss of myelinated and small unmyelinated fibers
Type V	Autosomal recessive	Congenital onset	Pain insensitivity in extremities	Not applicable

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.^[7]

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

The acquired autonomic neuropathies are much more prevalent than the inherited ones. Here, we subclassify the acquired autonomic neuropathies into primary and secondary disorders. Primary autonomic neuropathies are disorders that are idiopathic or that have autonomic neuropathy as a characteristic feature of the disease process itself. In the secondary autonomic neuropathies, an identifiable cause, such as a nutritional deficiency, may lead to autonomic neuropathy, but does not have autonomic neuropathy as a defining feature of the disease process. Subclassification can be somewhat artificial as the true mechanism of action is not clear in all cases, although it can be helpful when trying to develop an understanding of autonomic neuropathy.

Primary acquired autonomic neuropathies

See the list below:

Pandysautonomia: The syndrome of acute pandysautonomia includes both parasympathetic and sympathetic dysfunction.^[8]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.^[9]
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.^[10]
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.^[11]Ross syndrome is a related condition where segmental anhidrosis occurs in conjunction with Adie pupil.^[12]
Chronic idiopathic anhidrosis: Chronic idiopathic anhidrosis is an acquired generalized loss of sweating without other autonomic features. The lesions may be pre- or postganglionic.^[13]
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.^[14]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.^[15]
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.^[16]Antibodies against ganglionic receptors are found in 9% of patients with POTS.^[17]

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.^{[18, 19, 20, 21]}See Medscape Reference'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.^[18]
- 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.^[22]
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.^[23]
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.^[24]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.^[25]
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.^[7]
Alcohol may be associated with an autonomic neuropathy, possibly related to directly toxic effects of alcohol, although thiamine deficiency may also play a role.^[26]

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.^[27]
HIV infection: HIV infection may lead to autonomic neuropathy, particularly in late-terminal stages of disease.^[28]. Often, this occurs in conjunction with a somatic neuropathy related to HIV infection or complications of AIDS.^[29]
Chagas disease: Chagas disease due to infection with Trypanosoma cruzi is occasionally associated with autonomic neuropathy during the chronic stage of infection.^[30]Parasympathetic dysfunction tends to be greater than sympathetic dysfunction.^[31]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.^[32]
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.^[33]
Leprosy: Leprosy causes nerve injury by direct invasion of Mycobacterium leprae into the nerve and Schwann cells.^[34]Leprosy has been shown to affect both the sympathetic and parasympathetic nervous system.^[35]

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.^[36]Autonomic denervation may be related to antineuronal antibodies; the neuropathy does not appear to respond to a gluten-free diet.^[37]
Sj ö gren syndrome: Sj ö gren syndrome may lead to peripheral and autonomic neuropathy without characteristic systemic symptoms. A small-fiber neuropathy associated with Sj ö gren syndrome can be associated with widespread anhidrosis. Also, a sensory neuronopathy due to Sj ö gren syndrome can be associated with autonomic dysfunction. The cause of neuropathy in these patients is likely to be autoimmune, but this remains unclear.^[38]
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 Sj ö gren syndrome such as xerostomia. Patients with systemic sclerosis and mixed connective tissue disorder may have abnormalities of autonomic functioning of esophageal motor activity.^[7]
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.^{[39, 40]}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.^[39]
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.^[41]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.^[42]
- A variant of paraneoplastic autonomic neuropathy is an enteric neuronopathy that exists with antibodies directed against the myenteric plexus (anti-enteric neuronal antibodies).^[43]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).^[44]
Inflammatory bowel disease: Inflammatory bowel disease–related disorders may rarely have an associated autonomic neuropathy, particularly involving the pupillary nerves.^[45]

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.^[46]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.

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?

See the list below:

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?

See the list below:

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?

Clinical Presentation

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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, American Osteopathic Association

Disclosure: Nothing to disclose.

Coauthor(s)

J Douglas Miles, MD, PhD Assistant Professor of Neuroscience, Marshall University School of Medicine, and Clinical Instructor of Neurology, 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, Society for Neuroscience

Disclosure: Nothing to disclose.

Bashar Katirji, MD, FACP Director, Neuromuscular Center and EMG Laboratory, The Neurological Institute, University Hospitals Cleveland 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, American Neurological Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, 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, Phi Beta Kappa

Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, CPE, MHCM, FAAPL Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Former Chief Medical Officer, MeMD Inc

Nicholas Lorenzo, MD, CPE, MHCM, FAAPL is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association for Physician Leadership

Disclosure: Nothing to disclose.

Additional Contributors

Paul E Barkhaus, MD, FAAN, FAANEM Professor of Neurology and Physical Medicine and Rehabilitation, Chief, Neuromuscular and Autonomic Disorders Program, Director, ALS Program, Department of Neurology, Medical College of Wisconsin

Paul E Barkhaus, MD, FAAN, FAANEM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Neurological Association

Disclosure: Nothing to disclose.

Autonomic Neuropathy

Background

Pathophysiology