Disorders of the autonomic nervous system: Part 1. Pathophysiology and clinical features

Autonomic dysfunction may result from diseases that affect primarily either the central nervous system or the peripheral autonomic nervous system. The most common pathogenesis of disturbed autonomic function in central nervous system diseases is degeneration of the intermediolateral cell columns (progressive autonomic failure) or disease or damage to descending pathways that synapse on the intermediolateral column cells (spinal cord lesions, cerebrovascular disease, brainstem tumors, multiple sclerosis). The peripheral autonomic nervous system may be damaged in isolation in the acute and subacute autonomic neuropathies or in association with a generalized peripheral neuropathy. The peripheral neuropathies most likely to cause severe autonomic disturbance are those in which small myelinated and unmyelinated fibers are damaged in the baroreflex afferents, the vagal efferents to the heart, and the sympathetic efferent pathways to the mesenteric vascular bed. Acute demyelination of the sympathetic and parasympathetic nerves in the Guillain-Barré syndrome may also cause acute autonomic dysfunction. Although autonomic disturbances may occur in other types of peripheral neuropathy, they are rarely clinically important.     

Invited review: autonomic dysfunction in peripheral nerve disease.

The autonomic nervous system is affected in most peripheral neuropathies, but only in a small number of conditions, such as diabetes, amyloidosis, Guillain-Barré syndrome, porphyria, and familiar dysautonomia, is autonomic dysfunction of clinical importance. The pathological changes in the peripheral autonomic nervous system are similar to those in the peripheral somatic nerves. Autonomic disturbances are most likely to occur when there is acute demyelination or damage to small myelinated and unmyelinated fibers. Autonomic investigations should include tests of both sympathetic and parasympathetic function. Treatment consists of management of the underlying cause of peripheral neuropathy, physical and pharmacological measures.     

Diabetic neuropathies

Diabetic neuropathies are the most common type of neuropathies seen in clinical practice. These neuropathies can range clinically from asymptomatic to manifesting symptoms caused by motor, sensory, and autonomic nerve dysfunction. These neuropathies can affect the peripheral nervous system, pain receptors, cardiovascular, urogenital, and gastrointestinal systems. This monograph presents an overview of the different types of diabetic neuropathies, their presentations, diagnostic tools, and strategies for management.     

The treatment of orthostatic hypotension with dihydroxyphenylserine

Neurogenic orthostatic hypotension is an incapacitating symptom of central and peripheral autonomic nervous system degeneration. It occurs in such clinical conditions as multiple system atrophy, pure autonomic failure, and small-fiber peripheral neuropathies. Although many treatments are available, their effects are inconsistent, unsustained, and complicated by side effects. 3,4-Dihydroxyphenylserine is a synthetic, unnatural amino acid that is an immediate norepinephrine precursor. There is theoretical and clinical evidence supporting the use of this agent in the treatment of neurogenic orthostatic hypotension in patients with peripheral and central autonomic nervous system dysfunction. We review the biochemistry, pharmacokinetics, and possible mechanisms of action and clinical utility of this agent in the treatment of neurogenic orthostatic hypotension.     

Ocular neuropathy in peripheral neuropathies

Ocular movements and coordination require complex and integrated functions of somatic and autonomic nervous systems. Neurological disorders affecting these nervous systems may cause ocular dysfunction involving extraocular muscles and pupils. In this article, the prevalence, clinical presentations, and management of ocular neuropathy related to certain peripheral neuropathies, including diabetic neuropathy, Guillain–Barré syndrome (GBS), chronic inflammatory neuropathies, human immunodeficiency virus (HIV)‐associated neuropathy, and hereditary neuropathies, are examined in detail. Muscle Nerve 46: 681–686, 2012     

Peripheral neuropathy as the presenting feature of multiple system atrophy

The authors report a case of multiple system atrophy (MSA) with an onset as a peripheral nerve involvement. Their patient, a 55-year-old man, had a 3-year history of distal weakness and atrophy in upper limbs with dysesthesia in the feet. Other identifiable causes of peripheral neuropathy were ruled out. The authors postulate that peripheral nervous system impairment can anticipate the typical appearance of MSA, and they suggest that, in peripheral neuropathies with autonomic system dysfunction, after excluding main causes of autonomic neuropathy, MSA may need to be suspected.     

Autonomic involvement in inherited neuropathies

The inherited peripheral neuropathies constitute a large group of disorders, in some of which the causative metabolic defect has been identified whereas in the majority it is still unknown. Amongst the former, autonomic involvement is an important component in porphyric neuropathy, in the familial amyloid polyneuropathies, in Fabry's disease and in dopamine-hydroxylase deficiency. The latter group includes the hereditary sensory and autonomic neuropathies in some of which, such as the Riley-Day syndrome, autonomic disturbances are prominent, whereas in others they constitute only a minor component of the symptomatology. Autonomic dysfunction is an important component of the neurological manifestations in multiple endocrine neoplasia type IIB.     

Disease mechanisms in hereditary sensory and autonomic neuropathies

Inherited peripheral neuropathies are common monogenically inherited diseases of the peripheral nervous system. In the most common variant, i.e., the hereditary motor and sensory neuropathies, both motor and sensory nerves are affected. In contrast, sensory abnormalities predominate or are exclusively present in hereditary sensory and autonomic neuropathies (HSAN). HSAN are clinically and genetically heterogeneous and are subdivided according to mode of inheritance, age of onset and clinical evolution. In recent years, 6 disease-causing genes have been identified for autosomal dominant and recessive HSAN. However, vesicular transport and axonal trafficking seem important common pathways leading to degeneration of sensory and autonomic neurons. This review discusses the HSAN-related genes and their biological role in the disease mechanisms leading to HSAN.     

The sympathetic skin response: normal values, elucidation of afferent components and application limits

The sympathetic skin response (SSR), recorded at the hand and foot, was elicited using different classes of stimuli in 20 normal controls and 10 patients with peripheral neuropathy. We found that SSR latencies changed significantly with different recording sites, but not with different stimulation sites. Additionally, after ischemic conduction block of the arm in 3 normal controls, the previously obtainable SSR recorded at the hand became unobtainable with median nerve stimulation. Also, in one patient with subacute ganglionitis and 3 patients with demyelinating neuropathies, the SSR could not be elicited by electrical stimulation, but it could with deep inspiration. These results suggest that large diameter myelinated fibers may serve as afferents for the SSR. Furthermore, these findings imply that an unobtainable SSR by electrical stimulation may be due not only to dysfunction of the autonomic efferent nerve fibers, but also to abnormalities of the sensory afferents of the reflex. Therefore, investigations of autonomic dysfunction utilizing the SSR must be interpreted with caution in patients with peripheral neuropathies.     

Paraneoplastic peripheral neuropathies

Paraneoplastic peripheral neuropathies constitute a heterogeneous group of conditions. A link between the tumor and the neuropathy has been demonstrated in a subgroup only. Definite paraneoplastic neuropathies correspond to neuropathies associated with antibodies reacting with antigens common to the peripheral nervous system and the cancer. Neuropathies associated with anti-Hu antibodies are the most frequent and consist mainly in subacute sensory neuronopathy. Sensory or sensory-motor neuropathies with anti-CV2 antibodies are less frequent. The link between the cancer and the neuropathy is less clear in the other forms. The frequency of cancer in this group varies from 1 to 18 p.cent.These neuropathies include inflammatory demyelinating neuropathies, neuropathy and vasculitis, lower motor neurone diseases, and autonomic neuropathies. Occasionally, the neuropathy improves with treatment of the tumor. Recent data suggest that gangliosides may be the target of the immune process in neuropathies associated with melanoma.     

The Autonomic Symptom Profile: a new instrument to assess autonomic symptoms

OBJECTIVE: To develop a new specific instrument called the Autonomic Symptom Profile to measure autonomic symptoms and test its validity. BACKGROUND: Measuring symptoms is important in the evaluation of quality of life outcomes. There is no validated, self-completed questionnaire on the symptoms of patients with autonomic disorders. METHODS: The questionnaire is 169 items concerning different aspects of autonomic symptoms. The Composite Autonomic Symptom Scale (COMPASS) with item-weighting was established; higher scores indicate more or worse symptoms. Autonomic function tests were performed to generate the Composite Autonomic Scoring Scale (CASS) and to quantify autonomic deficits. We compared the results of the COMPASS with the CASS derived from the Autonomic Reflex Screen to evaluate validity. RESULTS: The instrument was tested in 41 healthy controls (mean age 46.6 years), 33 patients with nonautonomic peripheral neuropathies (mean age 59.5 years), and 39 patients with autonomic failure (mean age 61.1 years). COMPASS scores correlated well with the CASS, demonstrating an acceptable level of content and criterion validity. The mean (+/-SD) overall COMPASS score was 9.8 (+/-9) in controls, 25.9 (+/-17.9) in the patients with nonautonomic peripheral neuropathies, and 52.3 (+/-24.2) in the autonomic failure group. Scores of symptoms of orthostatic intolerance and secretomotor dysfunction best predicted the CASS on multiple stepwise regression analysis. CONCLUSIONS: We describe a questionnaire that measures autonomic symptoms and present evidence for its validity. The instrument shows promise in assessing autonomic symptoms in clinical trials and epidemiologic studies.     

Autonomic dysfunction in peripheral nerve disease

Autonomic neuropathies are inherited or acquired neuropathies in which autonomic nerve fibers are selectively or disproportionately affected. Generally, sympathetic and parasympathetic fibers are both affected but there are exceptions. Acquired cases can be autoimmune; due to diabetes, amyloidosis, drugs, or toxins; or idiopathic. Autoimmune autonomic neuropathy is often subacute, sometimes associated with a neoplasm, and associated with high titers of antibody to ganglionic nicotinic acetylcholine receptor in about half of the severe cases. The molecular basis of inherited autonomic neuropathies is better known, including recent identification of the loci and genes of hereditary sensory and autonomic neuropathies types I, III, and IV. The inherited amyloid neuropathies are due to mutations of three proteins: transthyretin, apolipoprotein A1, and gelsolin. Non-invasive autonomic testing complements clinical and electrophysiological characterization of the autonomic neuropathies.     

Autonomic and peripheral neuropathy in endstage liver disease and following liver transplantation

Severe chronic liver disease may be associated with a peripheral somatic and an autonomic neuropathy. There are only a limited number of reports on the incidence and features of these neuropathies. In addition the effects of liver transplantation on these neuropathies have not been well studied. We examined peripheral somatic and autonomic nerve function in 42 patients with endstage liver disease prior to transplantation and also examined the effect of liver transplantation on these neuropathies in 14 patients. Peripheral somatic neuropathy (93%) and autonomic neuropathy (50%) were common in patients with endstage liver disease and were more frequent than previously reported. Abnormalities improved in some patients after liver transplantation, particularly if there was return of normal hepatic function.     

Vincristine-induced fatal neuropathy in non-Hodgkin's lymphoma

The vinca alkaloids are neurotoxic, usually causing a peripheral neuropathy, but cranial neuropathies are rare as side effects. We describe a case of vincristine-induced multiple cranial and autonomic neuropathy, and sensory-motor axonal peripheral neuropathy (pan-neuropathy), which is an extremely rare fatal complication of this drug. The patient developed fulminant cranial, peripheral and significant autonomic neuropathy.     

High prevalence of neuropathies in patients with end‐stage liver disease

Cocito D, Maule S, Paolasso I, Castelli L, Ciaramitaro P, Poglio F, Ottobrelli A, Grimaldi S. High prevalence of neuropathies in patients with end‐stage liver disease.
Acta Neurol Scand: 2010: 122: 36–40.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – Peripheral neuropathy has been reported in association with end‐stage liver disease, but there is only a limited number of reports on the incidence and features of these neuropathies. Materials and methods – In this study, 83 patients awaiting liver transplantation were evaluated for the presence of peripheral and autonomic neuropathy. Results – Sixty‐five percent of the patients had evidence of neuropathy, in agreement with peripheral NCS or cardiovascular autonomic function test. The neuropathy was more frequent in patients with advanced hepatic failure, evaluated with the MELD score. The most frequent abnormalities in nerve conduction studies were sensory‐motor neuropathies and sensory neuropathies, with a length‐dependent pattern. Conclusion – Peripheral neuropathy and autonomic neuropathy are common in patients with end‐stage liver disease with different etiology and correlate with the severity of the liver disease.     

Inherited autonomic neuropathies

Inherited autonomic neuropathies are a rare group of disorders associated with sensory dysfunction. As a group they are termed the "hereditary sensory and autonomic neuropathies" (HSAN). Classification of the various autonomic and sensory disorders is ongoing. In addition to the numerical classification of four distinct forms proposed by Dyck and Ohta (1975), additional entities have been described. The best known and most intensively studied of the HSANs are familial dysautonomia (Riley-Day syndrome or HSAN type III) and congenital insensitivity to pain with anhidrosis (HSAN type IV). Diagnosis of the HSANs depends primarily on clinical examinations and specific sensory and autonomic assessments. Pathologic examinations are helpful in confirming the diagnosis and in differentiating between the different disorders. In recent years identification of specific genetic mutations for some disorders has aided diagnosis. Replacement or definitive therapies are not available for any of the disorders so that treatment remains supportive and directed toward specific symptoms.     

Autonomic function and unmyelinated fibers in chronic inflammatory demyelinating polyradiculoneuropathy

Because autonomic function may be abnormal in some demyelinating peripheral neuropathies, it has been studied with a number of noninvasive and invasive tests in 14 patients with chronic inflammatory demyelinating polyradiculoneuropathy. There were abnormalities of the 30:15 ratio in 3 patients and an abnormal thermoregulatory sweat test in 5 patients. These findings are indicative of mild parasympathetic and sympathetic dysfunction. Minor pathological changes in unmyelinated fibers were demonstrated on morphometric examination of sural nerves of 10 patients.     

An update on electrophysiological studies in neuropathy

PURPOSE OF REVIEW: The review concentrates on the use of clinical neurophysiology in peripheral nerve disorders covered in the present issue. It is pertinent to distinguish different types of involvement of fibers in diabetic neuropathy, including the involvement of small and large fibers, to outline the diagnostic criteria of inflammatory neuropathies, and to describe the spectrum of peripheral nerve pathophysiology in inherited neuropathies. Painful neuropathies represent a particular challenge to clinical neurophysiology since it is mainly small fibers, which are difficult to study, that are affected. RECENT FINDINGS: Electrodiagnostic studies have relevance in distinguishing neuropathies with different etiologies in diabetes mellitus, and different strategies and methods are necessary to study patients with autonomic and small-fiber involvement. The involvement of motor or sensory fibers, or both, and primary axonal or demyelinative pathology are important questions relating to immune-mediated neuropathies studied in the context of the specificity of antibodies against various neuronal and Schwann-cell structures. In hereditary neuropathy, electrophysiological studies are also used to distinguish axonal neuropathies from demyelinating neuropathies, though overlap and 'intermediate' patterns have become well recognized. In pain syndromes, conventional electrophysiological studies may give normal results if large fibers are not involved, and the use of autonomic measures in these situations has particular relevance. SUMMARY: The usefulness of electrodiagnostic measures depends on the clinical, diagnostic, or pathophysiological question involved, and the strategy employed should reflect the advantages and limitations of these methods. If adequate consideration is paid to these properties, then such studies have a central role in the diagnosis and adequate treatment of patients with neuromuscular disorders.     

Neurophysiological studies of thin myelinated (A delta) and unmyelinated (C) fibers: application to peripheral neuropathies.

Dysfunction of small fibers may appear in isolation or associated with large fiber lesions. In some acute neuropathies, such as pandysautonomia, small-fiber impairment is relatively pure but it may also appear in disorders with prominent somatic damage, such as Guillain-Barré syndrome, in which autonomic failure worsens the prognosis. At the present time, chronic idiopathic distal small-fiber neuropathy is diagnosed more frequently, and in some prevalent disorders, such as diabetic or amyloidotic polyneuropathies, small-fiber dysfunction is very noticeable. In pure autonomic failure, a peripheral autonomic failure exists, distinguishing it from multiple-system atrophy. Complex regional pain syndrome is a severe condition in which small fibers are responsible for disabling signs and symptoms, and only instrumental recordings lead to the proper treatment. Standard neurophysiological techniques evaluate large myelinated fibers exclusively. Small-fiber polyneuropathy has been considered as a type of somatic neuropathy, but thin myelinated and unmyelinated fibers are responsible not only for temperature and pain perception but also autonomic function. For instance, full autonomic evaluation is needed in some clinical situations such as autonomic failure in the elderly or orthostatic intolerance syndrome. To evaluate small-fiber impairment we need a battery of sensitive, reproducible, specific and noninvasive tests covering somatic and autonomic systems. In this review, we describe and analyze a number of neurophysiological techniques used to diagnose and characterize small-fiber dysfunction in humans. These include cardiovascular monitoring, sudomotor testing, pupillary responses and quantitative sensory tests, and also to some extent thermography and laser evoked potentials. The use of such techniques has proven useful not only for diagnosis, but also to guide adequate therapy and optimize follow-up.