Autonomic peripheral neuropathy

doi:10.1016/S0140-6736(05)74815-7

The Lancet

Volume 365, Issue 9466, 2–8 April 2005, Pages 1259-1270

https://doi.org/10.1016/S0140-6736(05)74815-7 Get rights and content

Summary

The autonomic neuropathies are a group of disorders in which the small, lightly myelinated and unmyelinated autonomic nerve fibres are selectively targeted. Autonomic features, which involve the cardiovascular, gastrointestinal, urogenital, sudomotor, and pupillomotor systems, occur in varying combination in these disorders. Diabetes is the most common cause of autonomic neuropathy in more developed countries. Autonomic neuropathies can also occur as a result of amyloid deposition, after acute infection, as part of a paraneoplastic syndrome, and after exposure to neurotoxins including therapeutic drugs. Certain antibodies (eg, anti-Hu and those directed against neuronal nicotinic acetylcholine receptor) are associated with autonomic signs and symptoms. There are several familial autonomic neuropathies with autosomal dominant, autosomal recessive, or X-linked patterns of inheritance. Autonomic dysfunction can occur in association with specific infections. The availability of sensitive and reproducible measures of autonomic function has improved physicians' ability to diagnose these disorders.

Section snippets

Diabetic autonomic neuropathy

Diabetes mellitus is the most common cause of autonomic neuropathy in more developed countries.³ The autonomic neuropathy typically presents late in the course of diabetes and is generally accompanied by other features of distal sensorimotor polyneuropathy. Diabetic cardiovascular autonomic neuropathy can manifest as an increased resting heart rate when the cardiac vagus is affected. When sympathetic and parasympathetic fibres are involved, the heart rate is fixed and there is inadequate

Amyloid neuropathy

Amyloidosis is due to the deposition of insoluble fibrillar proteins in a β-pleated sheet configuration within the extracellular space of tissues and organs. Various proteins have been associated with amyloidosis. The current classification of the systemic amyloidoses is based on the biochemistry of the precursor protein.26, 27 Although the fibril precursor proteins differ, there are strong similarities among the clinical presentations and pathology of the neuropathies associated with the

Acute and subacute autonomic neuropathies

Guillain-Barré syndrome (acute inflammatory demyelinating polyradiculoneuropathy) is a monophasic illness with an immune basis that presents as an acutely evolving sensorimotor polyneuropathy of varying severity. The syndrome is commonly accompanied by autonomic manifestations such as sinus tachycardia, sinus pauses, other tachyarrhythmias and bradyarrhythmias, blood-pressure lability, bowel and bladder dysfunction, pupillomotor disturbances, sudomotor dysfunction, and vasomotor abnormalities.⁴⁶

Immune-mediated and paraneoplastic autonomic neuropathies

Autonomic peripheral neuropathies have been associated with the presence of specific autoantibodies (panel 3). These neuropathies present subacutely in most cases, although acute and chronic presentations have been reported. Paraneoplastic autonomic neuropathy occurs frequently in association with anti-Hu antibodies. These antibodies are commonly found in patients with small-cell lung cancer, but they can also occur in non-small-cell lung cancer and malignant disorders of the gastrointestinal

Hereditary autonomic neuropathies

The hereditary autonomic neuropathies are listed in panel 4. Autonomic features are most prominent in the hereditary sensory and autonomic neuropathies and Fabry's disease.⁸⁹ Other hereditary autonomic neuropathies include the triple A (Allgrove's) syndrome,⁹⁰ Tangier disease,⁹¹ multiple endocrine neoplasia type 2b,⁹² and a sensory and autonomic neuropathy with arthropathy that is present in Navajo children.93, 94

Botulism

Binding of a neurotoxin from the anaerobic bacterium Clostridium botulinum to the presynaptic nerve terminal prevents release of synaptic vesicles containing acetylcholine and leads to this acute neuromuscular disorder (panel 5). The illness begins with gastrointestinal manifestations, followed by autonomic symptoms and a descending paralysis that spreads from the extraocular and bulbar muscles to the limbs.¹¹⁰ Autonomic symptoms result from cholinergic dysfunction; they include constipation,

Toxic neuropathies

Several industrial toxins, environmental toxins, marine toxins, and therapeutic drugs can cause autonomic dysfunction (panel 6). Autonomic-test abnormalities have been reported in individuals exposed to organic solvents,¹²⁶ industrial-use acrylamide,¹²⁷ arsenic,¹²⁸ thallium,¹²⁹ and other heavy metals.¹³⁰ Clinically important autonomic abnormalities are rarely observed with exposure to these toxins. Distal hyperhidrosis and hypohidrosis are the most common autonomic abnormalities.127, 128

Treatment of autonomic neuropathy

Although many of the autonomic neuropathies are not reversible, the symptoms of autonomic dysfunction respond to several specific interventions. This topic has been covered in detail in several recent reviews.139, 140

Search strategy and selection criteria

I searched MEDLINE from 1990 to 2004 with the search terms “peripheral autonomic nervous system diseases”, “autonomic neuropathy”, and “autonomic diseases”. Other search terms used included “diabetes”, “amyloid”, “immunology”, “infectious”, “inherited”, “genetic”, “toxic”, “investigation”, and “therapy”. I largely selected publications from the past 10 years but did not exclude commonly referenced and highly regarded older publications. I also searched the reference lists of articles

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Mean SSR amplitudes and ESC values showed differences between HC and patients with MSA or PN (p < 0.05), but not in patients with VVS or PD. Absence of SSR was associated with abnormal ESC (p < 0.05). Patients with abnormal CV-Aut dysfunction had lower ESC (p< 0.05). Palm ESC (P-ESC) and sole ESC (S-ESC) assessment had a sensitivity of 0.91 and 0.95 to predict sudomotor dysfunction, with a specificity of 0.78 and 0.85, respectively. The area under ROC curve was 0.905 and 0.98, respectively.
ESC in palms and soles has a high diagnostic accuracy for sudomotor dysfunction as detected by absent SSR in patients with MSA and PN.
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Neuropathic pain, which affects 7–10% of the general population, is induced by the lesions or diseases of the somatosensory system including the central neurons and peripheral fibers. Numerous causes of neuropathic pain have been identified, and globally, its prevalence is rising continuously among the ever-increasing aging population, especially among those with diabetes and cancer. Most drugs approved for normal inflammatory pain (NSAIDs, etc.) are ineffective against CNS-related pain due to underlying mechanisms and pathways involved in initiating the neuropathy pain cascade. Hence, considering the multifactorial etiology of neuropathic pain, small molecule natural products (morphine onwards) and their synthetic variants have been explored against neuropathic pain, with remarkable success. However, the pharmacological liabilities (habit-forming, psychoactive, etc.) are still a major challenge with an ever-greater unmet need. The article presents a critical review of the types, manifestations, diagnosis, and different signaling pathways linked to the pharmacology of neuropathic pain and nociception. It summarizes diverse categories of natural products from medicinal plants like alkaloids, terpenoids, steroids, coumarins, glycosides, lignans and flavonoids revealing their pain attenuation abilities.
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Both peripheral neuropathy and autonomic dysfunction are known consequences of chronic and excessive alcohol consumption. The prevalence of peripheral neuropathy among chronic alcohol abusers is 46.3% (CI 35.7%–57.3%) when confirmed via nerve conduction studies. Alcohol-related peripheral neuropathy is generally described as a progressive, predominantly sensory axonal length-dependent neuropathy. Based on cardiovascular reflex tests, 16%–73% of the chronic alcohol abusers suffer from autonomic dysfunction. Erectile dysfunction is the most commonly reported feature. The most important risk factor for both conditions is total lifetime dose of ethanol. There is also evidence that other risk factors have been identified in the pathogenesis of peripheral neuropathy due to alcohol abuse including genetic factors, male gender, and type of alcohol consumed. There is limited evidence for other environmental risk factors in the pathogenesis of alcohol-induced autonomic dysfunction. Currently, there is limited evidence regarding the management for both conditions, but sparse data support abstinence to lead to a significant improvement in autonomic dysfunction and the use of B-vitamin supplementation including thiamine to be promising in the management of alcohol-induced peripheral neuropathy.
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SeminarAutonomic peripheral neuropathy

Summary

Section snippets

Diabetic autonomic neuropathy

Amyloid neuropathy

Acute and subacute autonomic neuropathies

Immune-mediated and paraneoplastic autonomic neuropathies

Hereditary autonomic neuropathies

Botulism

Toxic neuropathies

Treatment of autonomic neuropathy

Search strategy and selection criteria

Lancet

Am J Cardiol

J Urol

J Diabet Complications

Am J Gastroenterol

Mayo Clin Proc

J Neurol Sci

Am J Med

Crit Rev Oncol Hematol

Am J Med

Am J Med

Genomics

J Neurol Sci

J Auton Nerv Syst

Lancet

Mayo Clin Proc

Gastroenterology

Mayo Clin Proc

Auton Neurosci

Am J Hum Genet

Am J Hum Genet

Clin Neurophysiol

Heart rate variability: the time domain

Testing the autonomic nervous system

Semin Neurol

The peripheral nervous system and diabetes

The sympathetic nervous system in diabetic neuropathy: a clinical and pathological study

Brain

The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis

Diabetes Care

Increased intraoperative cardiovascular morbidity in diabetics with autonomic neuropathy

Anesthesiology

QT interval prolongation and mortality in type 1 diabetic patients: a 5 year cohort prospective study

Diabetes Care

Cardiac sympathetic dysinnervation in diabetes: implications for enhanced cardiovascular risk

Circulation

Treatment of diabetic cystopathy

Ann Intern Med

Association of type and duration of diabetes with erectile dysfunction in a large cohort of men

Diabetes Care

Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence

N Engl J Med

Sexual dysfunction in women with type 1 diabetes: a controlled study

Diabetes Care

Gastrointestinal transit disorders in patients with insulin-treated diabetes mellitus

Dig Dis

Predictors of delayed gastric emptying in diabetes

Diabetes Care

Natural history of diabetic gastroparesis

Diabetes Care

Relationships of upper gastrointestinal motor and sensory function with glycemic control

Diabetes Care

Gastrointestinal tract symptoms among persons with diabetes mellitus in the community

Arch Intern Med

Pathogenesis of fecal incontinence in diabetes mellitus: evidence for internal-anal-sphincter dysfunction

N Engl J Med

Gustatory sweating in diabetes mellitus

Diabet Med

The systemic amyloidoses

N Engl J Med

Hereditary and acquired amyloid neuropathies

J Neurol

Amyloidosis and neuropathy

Vascular and neural mechanisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation

J Appl Physiol

A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine

N Engl J Med

Transthyretin-associated neuropathic amyloidosis: pathogenesis and treatment

Seminar
Autonomic peripheral neuropathy