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. 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. The immunization of rabbits with a recombinant neuronal AChR alpha3 subunit fusion protein also induces autonomic neuropathy. 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. 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. 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.
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. Interestingly, patients with a negative anti-ganglionic AChR antibody status tend to manifest partial, restricted forms of autonomic failure.
The somatic nerves are believed to be spared. 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. Deep tendon reflexes are preserved in typical cases, 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. Although the cause of the psychiatric problems has not been elucidated, a previous report suggested the involvement of the central nervous system. 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. The coexistence of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has also been reported.
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. 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. Importantly, patients with negative anti-ganglionic AChR antibody status are also capable of responding to immunomodulatory therapies.
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, 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. 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. The age at onset seems to be younger than that of typical AAG patients who are positive for the anti-ganglionic AChR antibody status. Approximately two-thirds of the patients experience symptoms that are indicative of an antecedent infection. An upper respiratory tract infection is the most common preceding event, followed by a gastrointestinal tract infection. In some patients, the neuropathy initiates 1 or 2 days after the antecedent infection; this duration is shorter than the typical latency in GBS patients, whose peak incidence of antecedent infection is between 1 and 2 weeks. 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. 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.
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. 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. 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. 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. 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. 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.
Coughing episodes are frequently reported in AASN. Because sensory impairments might spread to the oropharyngeal region and the respiratory tract in AASN, some patients suffer from aspiration pneumonia. Psychiatric changes are also common and sometimes become difficult to manage. In addition, a previous report described galactorrhea-amenorrhea syndrome and intractable anorexia, and suggested the involvement of the central nervous system. 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. 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.
As for the treatment, intravenous immunoglobulin, plasma exchange or steroids (alone or in combination) have been administered. 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. 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. 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. 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. Therefore, cases with AASMN would be considered as the ganglionopathy that participates in the pathogenesis. Because these patients require management for autonomic failure rather than for motor dysfunction, AASMN might warrant attention in the spectrum of autonomic neuropathies.
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. 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. 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. 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, is characterized by selective sudomotor involvement without other symptoms or signs of dysautonomia. Some immune mechanisms have been postulated in the pathogenesis of AIGA, because cases showing spontaneous resolution have been reported. 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.