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Keywords:

  • acute autonomic and sensory neuropathy;
  • autoimmune autonomic ganglionopathy;
  • Guillain–Barré syndrome;
  • paraneoplastic syndrome;
  • Sjögren's syndrome

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary autonomic neuropathies
  5. Secondary autonomic neuropathies as a result of underlying immunological diseases
  6. Differential diagnosis
  7. Acknowledgements
  8. References

Autonomic neuropathies can occur primarily or secondarily to various underlying diseases. The clinical features of autonomic neuropathies vary with the severity and the modality of autonomic dysfunctions, the degree of somatic involvement, the presence or absence of anti-ganglionic acetylcholine receptor antibody and the extent of unmyelinated fiber loss. Primary autonomic neuropathies, which usually affect both cholinergic and adrenergic functions, are divided into autoimmune autonomic ganglionopathy, acute autonomic and sensory neuropathy, and acute autonomic sensory and motor neuropathy based on the concomitance or absence of sensory or motor dysfunctions (although the nosological relationship of acute autonomic sensory and motor neuropathy to Guillain–Barré syndrome should be carefully considered). The monophasic clinical course and frequent presence of a history of antecedent infections suggests that immune mechanisms participate in these neuropathies. The discovery of the anti-ganglionic acetylcholine receptor antibody significantly expanded the spectrum of autonomic neuropathies, especially autoimmune autonomic ganglionopathy, to include cases with chronic progression mimicking pure autonomic failure. Patients with primary autonomic neuropathies might manifest restricted forms of autonomic dysfunctions, such as cholinergic dysautonomia, postural orthostatic tachycardia syndrome, chronic intestinal pseudo-obstruction or acquired idiopathic generalized anhidrosis. Some immunological diseases, such as paraneoplastic syndrome, connective tissue diseases and celiac disease, might also cause diverse autonomic neuropathies. As many non-immunological diseases are known to cause various types of autonomic dysfunctions, excluding such diseases is important for the diagnosis of immune-mediated autonomic neuropathies.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary autonomic neuropathies
  5. Secondary autonomic neuropathies as a result of underlying immunological diseases
  6. Differential diagnosis
  7. Acknowledgements
  8. References

An autonomic neuropathy might occur as a secondary consequence of various diseases, including diabetes mellitus, chronic alcoholism, amyloidosis, porphyria, paraneoplastic syndrome and connective tissue diseases.[1-9] Patients without any obvious underlying diseases might also show a variety of autonomic dysfunctions.[8, 10-13] In these idiopathic or primary cases, at least three subgroups have been described with respect to the concomitance or absence of sensory or motor impairment: pure autonomic neuropathy, autonomic neuropathy with sensory impairment, and autonomic neuropathy with sensory and motor impairments.[8, 12, 13] Classically, most patients with primary autonomic neuropathies have been reported to show an acute or subacute progression to the disease nadir.[14, 15] This monophasic clinical course and the frequent presence of a history of antecedent infections led to the speculation that immune mechanisms similar to those involved in Guillain–Barré syndrome (GBS) contribute to primary autonomic neuropathies.[8, 12, 13] The discovery of the anti-ganglionic acetylcholine receptor (AChR) antibody has established the identity of autoimmune autonomic ganglionopathy (AAG).[16-18] The measurement of the anti-AChR antibody significantly expanded the spectrum of autonomic neuropathies, particularly that of pure autonomic neuropathy. This spectrum now includes patients with chronic progression mimicking that of pure autonomic failure (PAF).[11, 13, 19, 20] The presentation of AAG usually involves both cholinergic and adrenergic functions; in addition, patients with pure autonomic neuropathy might manifest a restricted form of autonomic dysfunction referred to as cholinergic dysautonomia, as well as postural orthostatic tachycardia syndrome (POTS), chronic intestinal pseudo-obstruction (CIP) or acquired idiopathic generalized anhidrosis (AIGA).[8, 19]

Patients with primary autonomic neuropathy with sensory impairment (commonly referred to as acute autonomic and sensory neuropathy [AASN]) usually show an acute progression to the disease nadir within 1 month.[12, 15] Studies have also reported cases of primary autonomic neuropathy with sensory and motor impairments (commonly referred to as acute autonomic sensory and motor neuropathy [AASMN]), although the question of whether AASMN is GBS with predominant autonomic dysfunctions or an isolated nosological entity is still under debate.[8]

In addition to these primary autonomic neuropathies, autonomic neuropathies might be associated with underlying immunological diseases, such as paraneoplastic syndrome, collagen diseases and celiac disease.[8] The autonomic neuropathies associated with these diseases also show extensive variations.[6, 8]

Table 1 shows the major autonomic neuropathies for which immune mechanisms have been proposed. In the present review, we describe the major forms of these autonomic neuropathies from the viewpoint of their clinicopathological variability. Except for AAG, the precise immune mechanisms including putative autoantibodies have not yet been established in these neuropathies. Because various non-immunological diseases are known to cause autonomic dysfunctions similar to immune-mediated neuropathies,[1, 3, 4] differential diagnosis is important. The major differential diagnoses of immune-mediated neuropathies are shown in Table 2. We also briefly mention these diseases from this viewpoint.

Table 1. Major immune-mediated autonomic neuropathies and their levels of the anti-ganglionic acetylcholine receptor antibody
Types of neuropathyPositivity rate of anti-ganglionic acetylcholine receptor antibody
Primary autonomic neuropathies
Pure autonomic neuropathies
Autoimmune autonomic ganglionopathy50%
Cholinergic dysautonomia
Postural tachycardia syndrome10–25% (low titer)
Chronic intestinal pseudo-obstruction5–10% (low titer)
Acquired idiopathic generalized anhidrosis<20% (low titer)
Autonomic neuropathies with sensory impairment
Acute autonomic and sensory neuropathy
Autonomic neuropathies with sensory and motor impairment
Acute autonomic sensory and motor neuropathy (Guillain-Barré syndrome)
Secondary autonomic neuropathies (underlying diseases)
Paraneoplastic syndromes
Subacute sensory neuronopathy
Paraneoplastic autoimmune autonomic ganglionopathy10–25%
Paraneoplastic chronic intestinal pseudo-obstructionNot determined
Connective tissue diseases
Sjögren's syndromeAnecdotally reported
Systemic sclerosis
Rheumatoid arthritis
Systemic lupus erythematosus
Mixed connective tissue disease
Celiac disease
Table 2. Differential diagnosis of immune-mediated autonomic neuropathies
Neurodegenerative diseases
Pure autonomic failure
Multiple system atrophy
Amyloidosis
Familial amyloid polyneuropathy
Immunoglobulin light chain amyloidosis
Metabolic disorders
Diabetes mellitus
Hepatic porphyria
Nutritional deficiency
Chronic alcoholism
Infections
Botulism
Leprosy
Human immunodeficiency virus infection
Chagas disease
Diphtheria
Lyme disease
Drugs
Cis-platinum
Vinca alkaloids
Amiodarone
Perhexiline
Taxol
Toxins
Thallium
Arsenic
Inorganic mercury
Organic solvents
Acrylamide
Autoimmune diseases
Lambert-Eaton myasthenic syndrome

Primary autonomic neuropathies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary autonomic neuropathies
  5. Secondary autonomic neuropathies as a result of underlying immunological diseases
  6. Differential diagnosis
  7. Acknowledgements
  8. References

Autoimmune autonomic ganglionopathy

Since the measurement of the anti-ganglionic AChR antibody became available, the concept of AAG has been established in patients whose ailments had previously been referred to as pure pandysautonomia, acute pandysautonomia, acute panautonomic neuropathy, autoimmune autonomic neuropathy, idiopathic autonomic neuropathy and so on.[3, 10, 14, 21, 22] Approximately half of the AAG patients are reported to test positive for the anti-ganglionic AChR antibody.[10, 16, 19] The anti-ganglionic AChR antibody specifically recognizes the nicotinic AChR on the neurons of the autonomic ganglia.[16] The serum titer of the anti-ganglionic AChR antibody correlates with the severity of autonomic dysfunctions, and the antibody level decreases as the disease improves in AAG patients.[10, 11] Transgenic mice that are homozygous for null mutations in the gene encoding the alpha3 subunit of the ganglionic AChR have profound autonomic dysfunction.[23] The immunization of rabbits with a recombinant neuronal AChR alpha3 subunit fusion protein also induces autonomic neuropathy.[24] In addition, the passive transfer of not only rabbit immunoglobulin G containing ganglionic AChR antibody, but also immunoglobulin G from patients with AAG to mice, induced autonomic failure that mimics human AAG.[25] Because AAG is a disease entity that was established in the context of the anti-ganglionic AChR antibody, the nosological position and the spectrum of pure autonomic neuropathies without this antibody remain obscure, and should be clarified in future studies.

According to a previous study of 18 patients with positive anti-ganglionic AChR antibody statuses, the mean age at onset was 61.4 years, and a female preponderance was present.[11] Antecedent infections have been reported irrespective of the presence or absence of the anti-ganglionic AChR antibody in AAG patients.[13, 22] Upper respiratory tract infections and gastrointestinal tract infections, which are likely attributable to viral infections, are the most common antecedent infections.[11]

The typical cases of AAG with a positive anti-ganglionic AChR antibody status tend to involve diffuse sympathetic and parasympathetic dysfunctions.[13, 22, 26] Orthostatic symptoms are the most common feature, and they can be accompanied by syncope. The digestive symptoms are mostly lower gastrointestinal tract complaints (e.g. diarrhea and constipation), although upper gastrointestinal tract complaints (e.g. anorexia, early satiety and heartburn) have also been reported. Some patients experience paralytic ileus. Urinary symptoms might also be present, with some patients experiencing flaccid bladder and requiring urethral catheterization. Photophobia as a result of mydriasis, dry eyes, dry mouth, abnormal perspiration and erectile dysfunction might also be found. A case with isolated sympathetic failure and positive ganglionic AChR antibody status has also been reported as AAG.[27] Interestingly, patients with a negative anti-ganglionic AChR antibody status tend to manifest partial, restricted forms of autonomic failure.[13]

The somatic nerves are believed to be spared.[16] However, according to a review on AAG, approximately 25% of AAG patients describe minor sensory symptoms, such as tingling, but objective sensory loss is not present.[16] Deep tendon reflexes are preserved in typical cases,[13] whereas the reduction or loss of deep tendon reflexes has also been described.[28-30] Nerve conduction studies are normal in AAG patients.[13, 16] The level of cerebrospinal fluid protein is usually normal, although a subset show elevated levels.[21, 29-33]

Coughing episodes and psychiatric changes have been reported in some patients.[33] Although the cause of the psychiatric problems has not been elucidated, a previous report suggested the involvement of the central nervous system.[34] Indeed, coexistent encephalitis has been reported in some cases of AAG, irrespective of the presence or absence of the anti-ganglionic AChR antibody.[13, 35] In addition, a recent study suggested an association between AAG and cognitive impairment.[36] The coexistence of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has also been reported.[35]

Analyses of sural nerve biopsy specimens from typical AAG cases showed a variable extent of unmyelinated fiber loss.[13, 14, 20] The loss of unmyelinated fibers is observed regardless of the patient's anti-ganglionic AChR antibody status.[13, 20] In the most severe cases, the number of unmyelinated fibers is approximately one-third of that observed in normal controls (two-thirds of the unmyelinated fibers in the sural nerve are considered to be sympathetic efferents).[13, 20] The number of unmyelinated fibers tends to be preserved despite the presence of autonomic dysfunction in cases with short disease durations.[13, 14] However, the loss of unmyelinated fibers tends to be more conspicuous in cases with longer disease durations.[13, 20] These findings suggest that antibody-mediated functional impairment occurs before irreversible neuronal cell loss.

The available beneficial immunomodulatory therapies, which can be used alone or in combination, include the administration of intravenous immunoglobulin, steroids, plasma exchange, azathioprine, rituximab and mycophenolate mofetil.[8, 13, 37-39] Complete recoveries have been reported in some patients after treatment, although some refractory cases have also been reported.[8] Multi-agent immunomodulatory therapies might be necessary in these refractory cases.[8, 38, 39] A patient who responded to immunomodulatory therapies even after a 20-year history of diffuse and severe autonomic failure has been reported.[37] Importantly, patients with negative anti-ganglionic AChR antibody status are also capable of responding to immunomodulatory therapies.[39]

Acute autonomic and sensory neuropathy

Since the initial report of a patient with an acute onset of profound dysautonomia and sensory impairment without motor dysfunction,[15] similar patients have also been reported as AASN.[12, 40-48] However, the definition of AASN still remains controversial, as the pathogenesis that includes its relationship to autoantibodies has not yet been clarified.[8] According to the previous study of 21 patients with AASN, the mean age at onset was 29.0 years and a female preponderance was present.[12] The age at onset seems to be younger than that of typical AAG patients who are positive for the anti-ganglionic AChR antibody status.[11] Approximately two-thirds of the patients experience symptoms that are indicative of an antecedent infection.[12] An upper respiratory tract infection is the most common preceding event, followed by a gastrointestinal tract infection.[12] In some patients, the neuropathy initiates 1 or 2 days after the antecedent infection;[12] this duration is shorter than the typical latency in GBS patients, whose peak incidence of antecedent infection is between 1 and 2 weeks.[49] In addition to the mechanisms mediated by autoantibodies, some non-specific immune mechanisms, such as cytokine-mediated mechanisms, might also contribute to the pathogenesis of AASN.[8] It has not yet been determined whether a chronic counterpart of AASN exists. Some of the patients with idiopathic sensory ataxic neuropathy with dorsal root ganglionitis might concomitantly manifest autonomic dysfunctions.[50]

Although the initial symptoms of neuropathy can be separated into: (i) cases of numbness or pain in the extremities or trunk; and (ii) cases related to autonomic dysfunction; the autonomic manifestations are generally widespread and severe, and affect sympathetic and parasympathetic functions from the initial phase.[12] The autonomic manifestations include disturbances of the digestive system, represented by a severe reduction in peristalsis manifesting as paralytic ileus; orthostatic hypotension, even while attempting to sit up or rise from the bed; neurogenic flaccid bladder, which requires urethral catheterization; mydriasis with the absence of light reflex; hypohidrosis or anhidrosis, spreading to most parts of the body; and erectile dysfunction.[12, 40]

The distribution of sensory deficits in AASN is variable and ranges from cases confined to distal portions of the extremities to cases spreading across the whole body.[12] The distribution of sensory deficits might include the proximal regions of the limbs, face, scalp and trunk, and tends to be asymmetrical and segmental rather than presenting as a symmetric polyneuropathy.[12, 41, 44, 46] Sensory impairment is predominant with respect to superficial sensations, such as pinprick, temperature and light touch, during the initial phase.[12] Although the sensory impairment might be restricted to the superficial sensations in some patients,[12, 41, 44-46] impairment of the deep sensations, including vibration and joint sensations, subsequently appears in other patients.[12] Sensory ataxia appears, along with the loss of proprioceptive and kinesthetic sensations.[12, 40, 42, 47] Painful sensations, which might significantly disturb a patient's quality of daily life, are also prominent in many cases.[12, 40] As the name of AASN implies, the disease typically reaches its nadir in <1 month.[12] Nerve conduction studies of AASN patients have produced findings showing that the axonal neuropathy is confined to sensory nerves.[12, 15, 47] In addition, AASN patients generally show an elevation of cerebrospinal fluid protein levels without an increase in cell count.[12]

Coughing episodes are frequently reported in AASN.[12] Because sensory impairments might spread to the oropharyngeal region and the respiratory tract in AASN, some patients suffer from aspiration pneumonia.[12] Psychiatric changes are also common and sometimes become difficult to manage.[12] In addition, a previous report described galactorrhea-amenorrhea syndrome and intractable anorexia, and suggested the involvement of the central nervous system.[41] Abnormal electroencephalographic findings, such as the slowing of basic rhythms and increased theta activity, have been reported in some AASN patients.[40, 41, 47] Sleep apnea might also be observed in severely affected patients.[12] Some AASN patients also develop SIADH.[12, 47]

Sural nerve biopsies from AASN patients show axonal neuropathy without any evidence of demyelinating changes.[12, 15, 41, 42, 44-47] Reflecting the neuropathic characteristic of a faster onset of superficial sensory impairment relative to deep sensory impairment, the small myelinated fibers tend to be reduced to a greater degree than the large myelinated fibers;[12, 41, 44, 46] the unmyelinated fibers are also reduced.[12, 41, 42, 44, 46, 47] Autopsy cases show the loss of nerve cell bodies in the thoracic sympathetic and dorsal root ganglia, as well as Auerbach's plexus, which suggests that the mainstay of the lesion is located in the autonomic and sensory ganglia.[12, 40, 42] The presence of the blood–nerve barrier in normal peripheral nerve trunks makes it difficult for humoral factors, including putative autoantibodies, to access nerve fibers.[51-55] However, the lack of the blood–nerve barrier in the autonomic and sensory ganglia might enable these factors to access neurons.[56-58] Although pathogenic autoantibodies have not yet been detected, this mechanism might play an important role in the pathogenesis of AASN.[8]

As for the treatment, intravenous immunoglobulin, plasma exchange or steroids (alone or in combination) have been administered.[12] However, it might be difficult to determine the efficacy of the treatment because of the monophasic nature of AASN, as the recovery might simply reflect the natural course of the disease process.[12] Sensory deficits tend to persist for a long time and compromise the activities of daily life in severely affected patients.[12, 59] Autonomic dysfunctions, however, tend to improve to some extent, although significant residual deficits remain in severely affected patients.[12, 43, 48, 59]

Acute autonomic sensory and motor neuropathy (AASMN) and Guillain–Barré syndrome

The nosological entity of AASMN should be carefully considered, because the GBS diagnostic criteria might also include AASMN.[60] Indeed, autonomic dysfunctions are common in patients with GBS,[3, 61] with the most conspicuous forms being cardiovascular dysfunctions, which might lead to sudden death.[61-63] Therefore, a better classification of AASMN might be GBS with prominent autonomic dysfunction. In fact, several previous reports have described GBS patients with prominent autonomic dysfunction.[62, 64, 65] However, some patients who present severe autonomic dysfunctions from the initial phase of the disease in addition to acute sensorimotor neuropathy have been reported as AASMN.[66-71] These patients seem to be heterogeneous from the perspective of the timing of the appearance, severity and prognosis of weakness.

Some patients diagnosed with AASN reported motor dysfunctions.[42, 44, 72] In addition, slight abnormalities of motor nerve conduction indices or neurogenic changes in electromyography have been described in some cases, despite clinically preserved motor functions in other AASN patients.[40, 41, 43] Motor dysfunctions in patients reported as AASN might occur primarily or secondarily to disuse or abnormalities of neighboring sensory nerves in the nerve trunk.[8] However, the significance and the mechanisms of motor dysfunction in cases reported as AASN have not yet been determined. Therefore, the continuum between AASN and AASMN should be more explicitly determined. Neuronal cell loss in the dorsal root ganglia was shown in an autopsy case of a patient who presented profound dysautonomia, as that initial manifestation and developed weakness several days later.[64] Therefore, cases with AASMN would be considered as the ganglionopathy that participates in the pathogenesis.[8] Because these patients require management for autonomic failure rather than for motor dysfunction, AASMN might warrant attention in the spectrum of autonomic neuropathies.[8]

Restricted forms of autonomic neuropathies

Although AAG, AASN and AASMN usually manifest widespread autonomic failure, affecting both cholinergic and adrenergic functions, some patients with primary autonomic neuropathy might manifest restricted forms of autonomic dysfunctions. Patients with a high titer of serum anti-ganglionic AChR antibody tend to manifest profound and widespread autonomic failure,[11, 22] whereas those with a low titer of antibodies tend to show various restricted forms of autonomic dysfunctions.[13, 26]

Cholinergic dysautonomia is a unique form of autonomic dysfunction that results from selective postganglionic cholinergic dysfunction; this disorder is characterized by marked parasympathetic dysfunctions, but no sympathetic symptoms except for sudomotor dysfunction.[13, 48, 73-86] To date, studies have not determined whether cholinergic dysautonomia falls on the continuum of the AAG spectrum or whether cholinergic dysautonomia is a distinct entity. Pathogenic autoantibodies, including the anti-ganglionic AChR antibody, have not been reported in typical cholinergic dysautonomia cases. Most patients with cholinergic dysautonomia are children and young adults. Females are more likely to be affected,[13, 73-75, 77-80, 84-86] and antecedent infections have been reported in some cases.[13, 74, 81, 83, 85, 86] The progression of cholinergic dysautonomia is acute to subacute. Although the symptoms are similar to AAG, they are fundamentally different: cholinergic dysautonomia does not include orthostatic hypotension. Although the clinical course is monophasic, the recovery is usually incomplete.[13, 81, 83] Cholinergic dysautonomia usually manifests as pure dysautonomia, whereas cases with sensory involvement have also been reported.[8, 84]

Postural tachycardia syndrome (POTS) is characterized by an increased heart rate without orthostatic hypotension on standing.[87, 88] The etiology and pathophysiology of POTS are heterogeneous,[19, 88, 89] and immune mechanisms have been suggested in some cases.[19] Interestingly, 10–25% of the POTS patients have a low titer of the anti-ganglionic AChR antibody.[16, 19, 90] The age at disease onset ranges from young adulthood to middle age,[89, 90] and there is a female preponderance.[90] The onset of symptoms might be acute and can occur after infection, trauma or surgery.[88, 90]

Chronic intestinal pseudo-obstruction (CIP) is characterized by an impairment of gastrointestinal motility without any evidence of anatomical obstruction.[91, 92] The presentation of CIP might be idiopathic or associated with a variety of underlying diseases.[91, 92] Although the pathophysiology of CIP is diverse – it might have neurogenic, myogenic or mesenchymogenic origins – inflammatory neuropathy of the enteric nervous system is postulated in some patients.[93, 94] Interestingly, 5–10% of the CIP patients test positive for a low titer of the anti-ganglionic AChR antibody.[10, 16, 19] Patients with the anti-Hu antibody might also manifest CIP.[95] Young to middle-aged females are more likely to be affected when enteric inflammatory neuropathy is present.[94, 96] Although the term “chronic” is frequently used with CIP, the symptoms might develop acutely after a viral illness;[96-98] spontaneous remission might also be observed.[19, 96, 97]

Acquired idiopathic generalized anhidrosis (AIGA), also known as chronic idiopathic anhidrosis,[99] is characterized by selective sudomotor involvement without other symptoms or signs of dysautonomia.[100] Some immune mechanisms have been postulated in the pathogenesis of AIGA, because cases showing spontaneous resolution have been reported.[19] The anhidrosis is caused by defective neuroglandular transmission or degenerative changes as a result of cellular infiltration in sweat glands in most patients.[19, 100] However, a case with degenerative changes in postganglionic sudomotor axons or neurons has also been reported.[101]

Secondary autonomic neuropathies as a result of underlying immunological diseases

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary autonomic neuropathies
  5. Secondary autonomic neuropathies as a result of underlying immunological diseases
  6. Differential diagnosis
  7. Acknowledgements
  8. References

Paraneoplastic syndrome

Paraneoplastic syndrome is frequently associated with autonomic neuropathy.[6, 8] The recognition of paraneoplastic autonomic neuropathy in patients with paraneoplastic syndrome is important for prognostic reasons, because patients with autonomic dysfunction tend to have a worse prognosis.[102] Subacute sensory neuronopathy is the most typical form of paraneoplastic neuropathy, and autonomic dysfunctions are found in some of the patients with subacute sensory neuronopathy.[6, 103, 104] Subacute sensory neuronopathy is usually associated with small-cell lung cancer and anti-Hu antibodies.[6, 9] Although the classical form of subacute sensory neuronopathy is characterized by sensory ataxia, other reports have described patients with sensory symptoms that manifest as pain, painful dysesthesia or mechanical hyperalgesia without conspicuous sensory ataxia.[6, 9] Indeed, a previous report of paraneoplastic sensory neuropathy categorized the patients into two separate groups: (i) patients who had experienced ataxia; and (ii) patients who had experienced pain.[104] In the painful group, the primary complaints were severe pain and mechanical hyperalgesia, with some patients reporting impairments in deep sensation or kinesthetic sensation.[104] Furthermore, the patients in the ataxic group occasionally complained of painful sensations or painful dysesthesia. These observations suggest that these two forms of paraneoplastic neuropathy might exist over a continuous spectrum of pathophysiological events, with predominant impairment of small sensory neuro-axons or large sensory neuro-axons at the extremes of the spectrum.[6, 9, 105] In addition, various extents of autonomic dysfunction can be observed in patients with subacute sensory neuronopathy.[6, 9, 104] Autopsy cases with subacute sensory neuronopathy have shown a loss of neurons in the thoracic sympathetic ganglia in addition to that in the dorsal root ganglia, suggesting the overlap of sensory and autonomic ganglionopathies.[9, 106] In addition to subacute sensory neuronopathy, AAG and CIP are frequently associated with malignancies.[6, 9, 10, 93, 107]

Some of the well-characterized paraneoplastic autoantibodies, such as anti-Hu and anti-CV2/CRMP-5, are frequently associated with autonomic neuropathy. According to a previous large-scale study of patients with the anti-Hu antibody, 30% of the patients manifested some type of autonomic dysfunction.[95] In another study, autonomic neuropathy was reported in 31% of patients who were seropositive for the anti-CV2/CRMP-5 antibody.[108] With regard to the anti-ganglionic AChR antibody, 21% of seropositive patients manifested features suggestive of autonomic neuropathy.[109]

Connective-tissue diseases

Autonomic dysfunctions have been reported in association with Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, mixed connective-tissue disease and systemic sclerosis.[1, 3, 4, 110] Although the autonomic dysfunctions in these diseases are usually subclinical, some patients might develop clinically significant autonomic neuropathy, particularly if they have Sjögren's syndrome.[111-114] In patients who do not have Sjögren's syndrome, acute and clinically significant autonomic neuropathy has been reported in concordance with systemic lupus erythematosus.[115, 116] The previous reports presented patients with Sjögren's syndrome with anti-ganglionic AChR antibody; these patients had developed gradually progressive autonomic dysfunction.[113, 114] The relationship between Sjögren's syndrome and AAG is an open question to be clarified. The overlap might be present in a manner that is similar to paraneoplastic neuropathy, as mentioned earlier.

The neuropathic features in patients with Sjögren's syndrome vary extensively and include the following: ataxic neuropathy, painful neuropathy, autonomic neuropathy, multiple mononeuropathy, multiple cranial neuropathy, trigeminal neuropathy and radiculoneuropathy.[112] There is a significant overlap of the ataxic and painful features in individual patients with Sjögren's syndrome-associated neuropathy. Autopsy cases with both ataxic and painful neuropathies showed findings suggestive of sensory ganglionopathy.[112, 117] In addition, various degrees of autonomic dysfunctions might be observed in patients with ataxic and painful neuropathies.[112, 117] For example, a segmental distribution of the areas of anhidrosis was reported in a patient with ataxic neuropathy.[111] The autopsies of similar patients showed autonomic ganglionopathy in addition to sensory ganglionopathy.[112, 117] The overlap of the sensory and autonomic neuropathies from the viewpoint of ganglionopathy seems to be similar to that of paraneoplastic neuropathy, as described earlier.

Celiac disease

Celiac disease is a gluten-sensitive autoimmune disorder characterized by elevated titers of antibodies to gliadin and transglutaminase, and inflammation evident in small bowel biopsy specimens.[118] It is associated with numerous neurological manifestations, including cerebellar ataxia, myelopathy, myopathy and peripheral neuropathy.[118] Patients who presented subacutely with presyncope and postural nausea as autonomic symptoms have been reported.[119] According to a previous report of skin biopsy in patients with celiac disease, the disorder involves a non-length-dependent pattern of the small fibers.[120] This finding indicates that small neurons might be preferentially affected in some patients with celiac disease, as in paraneoplastic syndrome and Sjögren's syndrome.[105]

Differential diagnosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary autonomic neuropathies
  5. Secondary autonomic neuropathies as a result of underlying immunological diseases
  6. Differential diagnosis
  7. Acknowledgements
  8. References

Neurodegenerative diseases

Since the measurement of anti-ganglionic AChR antibody has become available, some patients with chronic progressive autonomic failure that mimics that of PAF have been included in the spectrum of AAG.[11, 20] PAF has been categorized as a neurodegenerative disease and is characterized by chronic, progressive and severe autonomic failure without other neurological deficits. The pathological reports of PAF have suggested that this disease is a form of Lewy body disease.[121-123] It is generally accepted that the autonomic dysfunctions in PAF are caused by peripheral, but not central, involvement.[124, 125] Therefore, the pathological findings in such cases would be indistinguishable from those of PAF.[124]

It is important to recognize AAG as a distinct diagnosis in patients with slowly progressive autonomic dysfunctions that mimic PAF, because the correct diagnosis provides the opportunity to administer the proper treatment. For example, diarrhea is not common in patients with PAF,[125] but it might be present in AAG cases, including long-standing patients.[11, 20] In addition, urinary retention is present in both PAF and AAG,[13, 125] but severe retention requiring urethral catheterization is rare in PAF.[125] Some of the laboratory findings indicative of sympathetic dysfunctions are more profound in PAF compared with AAG.[126] These differences might help to distinguish AAG patients from those previously diagnosed with PAF.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder clinically characterized by autonomic failure, parkinsonism, cerebellar ataxia and pyramidal signs in any combination.[127-130] Patients with MSA were previously reported as having Shy–Drager syndrome, striatonigral degeneration or olivopontocerebellar atrophy, depending on which manifestation was most prominent.[130] According to a previous report of 230 patients, autonomic symptoms were initially manifested in 28% of patients.[130] These autonomic dysfunctions in MSA are considered to be mainly attributable to preganglionic involvement,[127, 129] although peripheral involvement would also be observed to some extent.[131]

Amyloidosis

Autonomic disturbances are frequent and might become the first sign of the disease in amyloidosis.[132] Although various amyloidogenic proteins are known to cause amyloidosis,[133] the transthyretin (ATTR) type of familial amyloid polyneuropathy and acquired immunoglobulin light chain (AL) amyloidosis are the most frequently encountered forms in association with autonomic neuropathy.[132] Although familial amyloid polyneuropathy had been reported in association with endemic foci in Portugal, Japan and Sweden, the recent development of biochemical and molecular analyses has shown that this disease is more widespread and more frequent than previously thought.[134-136] Classically, a small-fiber neuropathy with predominant autonomic dysfunctions from the early phase of the disease is a characteristic feature in amyloidosis, especially in patients with familial amyloid polyneuropathy from endemic foci.[134, 137] However, autonomic dysfunctions have become evident in the later phase of the disease in those from endemic foci.[7]

Metabolic disorders

Diabetes mellitus is the most common cause of neuropathy worldwide, and autonomic dysfunctions, such as orthostatic intolerance, gastroparesis, diarrhea, urinary retention and erectile dysfunction, are the characteristic manifestations of diabetic neuropathy.[138]

The hepatic porphyrias cause widespread sympathetic and parasympathetic abnormalities, such as abdominal pain, nausea, vomiting, obstinate constipation, bladder distension and sweating abnormalities.[3] The clinical features related to the exclusion of autonomic dysfunctions include the following: somatic peripheral neuropathy, skin symptoms and central nervous system manifestations.[139]

Vitamin B1 (thiamine) and B12 (cobalamin) deficiency causes autonomic dysfunctions; these dysfunctions are frequently asymptomatic.[140-142] However, autonomic symptoms, especially gastrointestinal dysmotility, become predominant in some patients.[143, 144] Alcoholic neuropathy might be caused by the direct toxicity of ethanol or its metabolites, as well as nutritional deficiencies.[5, 145, 146] Small-fiber predominant nerve fiber loss is a characteristic feature in alcoholic neuropathy without nutritional deficiency.[145, 147] Small-fiber neuropathy is generally associated with autonomic dysfunctions; however, these dysfunctions are not the clinically predominant features in most patients with alcoholic neuropathy.[5, 147] This might be attributable to preferential involvement of parasympathetic functions, rather than sympathetic functions.[5]

Infections

Botulism is well known for causing autonomic dysfunctions similar to cholinergic dysautonomia, which might become the predominant symptoms.[3, 8] This disease is caused by the neurotoxin produced by the anaerobic bacterium Clostridium botulinum. Typically, 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.[148] Orthostatic hypotension is also present in some cases.[149] However, autonomic symptoms can occur, even in the absence of the characteristic abnormalities of motor and cranial nerves.[148, 150]

In addition, other infectious agents, such as leprosy, human immunodeficiency virus infection, Chagas disease, diphtheria and Lyme disease, can cause autonomic neuropathy.[1, 4]

Drug-induced and toxic neuropathies

Autonomic neuropathy can occur as a consequence of chemotherapy for the treatment of cancer.[151] Clinically evident dysautonomia can occur after the administration of any of the following: cis-platinum (including cisplatin), vinca alkaloids (including vinblastine, vincristine, and vindesine), amiodarone, perhexiline and taxol.[1, 3] Improvement might occur gradually after withdrawal of the drug, but some abnormalities can persist.

Several industrial toxins can also cause autonomic neuropathy. Heavy metals (such as thallium, arsenic and inorganic mercury) and organic solvents (such as n-hexane and acrylamide) have been reported to cause autonomic dysfunctions.[1, 3, 4]

Lambert–Eaton myasthenic syndrome

Lambert–Eaton myasthenic syndrome is an autoimmune presynaptic disorder of neuromuscular transmission.[152, 153] Lambert–Eaton myasthenic syndrome is characterized by the production of an antibody to presynaptic voltage-gated calcium channels.[154] This antibody impairs acetylcholine release and leads to proximal weakness, hyporeflexia and autonomic dysfunctions.[152] Roughly half of the cases have an associated neoplasm at the time of diagnosis of Lambert–Eaton myasthenic syndrome.[152] Autonomic testing has shown evidence for autonomic dysfunctions, particularly those of cholinergic functions.[153]

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary autonomic neuropathies
  5. Secondary autonomic neuropathies as a result of underlying immunological diseases
  6. Differential diagnosis
  7. Acknowledgements
  8. References

This work was supported by grants from the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Kimi Imai Memorial Foundation for research of Incurable Neuromuscular Diseases.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Primary autonomic neuropathies
  5. Secondary autonomic neuropathies as a result of underlying immunological diseases
  6. Differential diagnosis
  7. Acknowledgements
  8. References