Idiopathic Autonomic Neuropathy Research Articles

Quantitative gastrointestinal function and corresponding symptom profiles in autonomic neuropathy.

Peripheral neuropathies with autonomic nervous system involvement are a recognized cause of gastrointestinal dysmotility for a wide spectrum of diseases. Recent advances in wireless motility capsule testing allow improved sampling of regional and whole gut motility to aid in the diagnosis of gastrointestinal motility disorders and may provide additional insight into segment-specific enteric involvement of peripheral neuropathies affecting autonomic nervous system function. We utilized standardized autonomic nervous system (ANS) reflex assessment and wireless motility capsule testing to evaluate 20 individuals with idiopathic autonomic neuropathy and unexplained gastrointestinal symptoms. Additionally, we examined the relationship between quantifiable autonomic neuropathy and gastrointestinal dysmotility at specific neuroanatomical levels. Symptom profiles were evaluated using the 31-item Composite Autonomic Symptom Score questionnaire (COMPASS-31) and compared to wireless motility capsule data. We found that transit times were predominately abnormal (delayed) in the foregut (10 of 20; 50%), while contractility abnormalities were far more prominent in the hindgut (17 of 20; 85%), and that motility and symptom patterns, as assessed by the COMPASS-31 GI domain items, generally corresponded. Finally, we also found that there was neuroanatomical overlap in the presence of autonomic reflex abnormalities and WMC-based transit and/or contractility abnormalities. We found that transit times were predominately abnormal in the foregut and midgut, while contractility abnormalities were far more prominent in the hindgut in individuals with idiopathic autonomic neuropathy. There was a high rate of agreement in segmental wireless motility capsule data with neuroanatomically corresponding standardized ANS function measures (e.g., cardiovagal, sudomotor, adrenergic). Expanded sudomotor testing, including additional neuroanatomical segments, could provide additional indirect assessment of visceral involvement in ANS dysfunction.

Autoimmune autonomic ganglionopathy: Bench to Bedside

Autoimmune autonomic ganglionopathy (AAG) presents as severe generalized sympathetic and parasympathetic autonomic failure. This disorder is also known as acute pandysautonomia or idiopathic subacute autonomic neuropathy. Themost disablingmanifestations are orthostatic hypotension (OH) and gastrointestinal dysmotility. An autoimmune pathogenesis was suggested by the subacute onset, frequent associationwith antecedent viral illness, occasional association with cancer or other autoimmune disorders, and spontaneous recovery in some patients. Many cases have a rapid onset, but others have a chronic progressive course. Clinical and experimental observations demonstrate that AAG is an antibody-mediated disorder. (1) AAG patients have high levels of serum antibodies specific for the neuronal AChR in autonomic ganglia. This ganglionic AChR mediates fast synaptic transmission in all autonomic ganglia. Ganglionic AChR antibodies found in AAG patients are distinct from muscle AChR antibodies found in patients with MG. (2) Ganglionic AChR antibody levels correlate with severity of autonomic deficits. Patients with high antibody levels have a combination of OH, dry eyes and dry mouth, Adies pupil, gastroparesis, and neurogenic bladder. (3) Induction of ganglionic AChR antibodies in rabbits by immunization leads to experimental AAG which reproduces many of the cardinal features of the human disease. (4) Passive transfer of ganglionic AChR antibodies tomice causes transient autonomic failure. In electrophysiological studies, ganglionic AChR antibodies produce a reduction in ganglionic AChR current in cultured neuroblastoma cells and inhibit synaptic transmission in isolated autonomic ganglia. AAG is an antibody-mediated channelopathy that produces a severe, but treatable, form of autonomic failure.

Profound bradycardia and hypotension in a normal heart

Bradycardia is a common arrhythmia that rarely can be caused by autonomic dysfunction. There are case reports of bradycardia attributed to diabetic autonomic neuropathy, 1 Horng H.C. Chen F.C. Kuo C.P. Wu C.T. Wong C.S. Bradycardia and hypotension refractory to ephedrine and atropine treatment: severe autonomic dysfunction with abnormal heart rate variability. Acta Anaesthesiologica Taiwanica. 2006; 44: 109-112 PubMed Google Scholar and Guillain-Barré syndrome. 2 Pfeiffer G. Schiller B. Kruse J. Netzer J. Indicators of dysautonomia in severe Guillain-Barre syndrome. J Neurol. 1999; 246: 1015-1022 Crossref PubMed Scopus (47) Google Scholar Autoimmune autonomic neuropathy (AAN), also known as idiopathic autonomic neuropathy or pure pandysautonomia, 3 Schondorf R. Low P.A. Idiopathic orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia?. Neurology. 1994; 43: 132-137 Crossref Google Scholar has been reported to rarely manifest with bradycardia as one of a constellation of signs. 4 Suarez G.A. Fealey R.D. Cailleri M. Low P.A. Idiopathic autonomic neuropathy: Clinical, neurophysiologic, and follow-up on 27 patients. Neurology. 1994; 44: 1675-1682 Crossref PubMed Google Scholar , 5 Klein C.M. Vernino S. Lennon V.A. et al. The spectrum of autoimmune autonomic neuropathies. Ann Neurol. 2003; 53: 752-758 Crossref PubMed Scopus (177) Google Scholar We present an unusual case of severe bradycardia in a young patient with probable autoimmune autonomic dysfunction.

Acute Idiopathic Autonomic Neuropathy with Local Autonomic Failure in a Child

Acute Idiopathic Autonomic Neuropathy with Local Autonomic Failure in a Child

S3. Autonomic neuropathies — Recent advances: S3.1 Pathogenesis of autoimmune autonomic ganglionopathy

Antibodies against nicotinic acetylcholine receptors (AChR) are implicated in myasthenia gravis as well as in autoimmune autonomic ganglionopathy (AAG). AAG typically presents as severe generalized sympathetic and parasympathetic autonomic failure. This disorder is also known as acute pandysautonomia or idiopathic subacute autonomic neuropathy. The most disabling manifestations are orthostatic hypotension (OH) and gastrointestinal dysmotility. An autoimmune pathogenesis was suggested by the subacute onset, frequent association with antecedent viral illness, occasional association with cancer or other autoimmune disorders, and spontaneous recovery in some patients.

Autoimmune autonomic neuropathy: Clinical and experimental

Autoimmune autonomic neuropathy (AAN) results in severe generalized sympathetic and parasympathetic autonomic failure. This disorder is also known as acute pandysautonomia or idiopathic subacute autonomic neuropathy. The most disabling manifestations are orthostatic hypotension (OH) and gastrointestinal dysmotility. An autoimmune pathogenesis was suggested by the subacute onset, frequent association with antecedent viral illness, occasional association with cancer or other autoimmune disorders, and spontaneous recovery in some patients.

OC7 Trigeminal neuropathy and autonomic neuropathy – a rare combination

Introduction Idiopathic trigeminal neuropathy is an uncommon orofacial symptom giving rise to paraesthesia and/or anaesthesia of one or more divisions of the trigeminal nerve in the absence of an obvious aetiology. Idiopathic autonomic neuropathy is a rare disorder giving rise to cholinergic and/or adrenergic dysfunction of the autonomic nervous system. The combination of trigeminal and autonomic neuropathy in the absence of diabetes mellitus is unusual.Signs and symptoms A 45‐year‐old male was referred to the Oral Medicine Unit of UCL Eastman Dental Institute and UCLHT Eastman Dental Hospital for assessment of possible xerostomia secondary to autonomic neuropathy. Medical history & social history. The patient had long‐standing trigeminal neuropathy, long‐standing autonomic neuropathy giving rise to dysphagia, gastrointestinal and bladder function and orthostatic hypotension. There was a previous history of Hodgkin's disease.Oral disease history Clinical examination revealed neurotrophic destruction of the nasal septum (trigeminal trophic syndrome), chronic periodontitis, but no features of long‐standing xerostomia. Resting sialometry was >0.1 ml min–1.Diagnosis Trigeminal trophic syndrome secondary to trigeminal neuropathy and partial autonomic neuropathy.Treatment The patient was referred for appropriate periodontal therapy.Conclusion This is a unique example of trigeminal sensory neuropathy and autonomic neuropathy in the absence of diabetes mellitus. Early diagnosis of both disorders is important to ensure avoidance of facial complications such as trigeminal trophic syndrome and the oral consequences of long‐standing xerostomia.

Prospective evaluation of somatic and autonomic small fibers in selected autonomic neuropathies.

There are a number of distal and generalized small-fiber neuropathies. The neuropathologic basis is poorly understood as somatic and autonomic C fibers are not usually studied in the same region of the body. To evaluate prospective somatic and autonomic C-fiber function in 11 healthy control subjects and 38 patients with different clinical patterns of neuropathy. Distal small-fiber neuropathy (DSFN), peripheral neuropathy (PN), diabetic neuropathy (DN), neuropathic postural tachycardia syndrome (POTS), and idiopathic autonomic neuropathy (IAN) were evaluated. Intraepidermal nerve fiber density was used to evaluate distal somatic C fibers. Both quantitative sudomotor axon reflex test and skin norepinephrine content were measured for the biopsy site to assess distal autonomic C-fiber function. Postganglionic sudomotor, adrenergic, and cardiovagal functions were evaluated by autonomic reflex testing and quantified using a Composite Autonomic Severity Scale. Skin norepinephrine concentration was significantly related to CASS. DN was associated with somatic and autonomic C-fiber impairment with good agreement. POTS was associated with selective distal autonomic deficit. DSFN had combined distal somatic and C-fiber impairment. IAN showed combined and selective distal and generalized autonomic C-fiber impairment. The somatic neuropathies had C-fiber impairment affecting both populations to varying degrees. Although a general agreement exists between the loss of somatic C fibers and autonomic deficits, selective involvement occurs for specific autonomic neuropathies.

Micturition disturbance in acute idiopathic autonomic neuropathy

Objective: To define the nature of micturition disturbance in patients with acute idiopathic autonomic neuropathy (AIAN). Methods: Micturitional symptoms were observed during hospital admissions and the in outpatient clinics in...

Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension

Background: Pharmacological treatment of orthostatic hypotension is often limited because of troublesome supine hypertension. Objective: To investigate a novel approach to treatment using acetylcholinesterase inhibition, based on the theory that...

Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease

Neuronal nicotinic AChRs (nAChRs) are implicated in the pathogenesis of diverse neurological disorders and in the regulation of small-cell lung carcinoma growth. Twelve subunits have been identified in vertebrates, and mutations of one are recognized in a rare form of human epilepsy. Mice with genetically manipulated neuronal nAChR subunits exhibit behavioral or autonomic phenotypes. Here, we report the first model of an acquired neuronal nAChR disorder and evidence for its pertinence to paraneoplastic neurological autoimmunity. Rabbits immunized once with recombinant α3 subunit (residues 1–205) develop profound gastrointestinal hypomotility, dilated pupils with impaired light response, and grossly distended bladders. As in patients with idiopathic and paraneoplastic autoimmune autonomic neuropathy, the severity parallels serum levels of ganglionic nAChR autoantibody. Failure of neurotransmission through abdominal sympathetic ganglia, with retention of neuronal viability, confirms that the disorder is a postsynaptic channelopathy. In addition, we found ganglionic nAChR protein in small-cell carcinoma lines, identifying this cancer as a potential initiator of ganglionic nAChR autoimmunity. The data support our hypothesis that immune responses driven by distinct neuronal nAChR subtypes expressed in small-cell carcinomas account for several lung cancer–related paraneoplastic disorders affecting cholinergic systems, including autoimmune autonomic neuropathy, seizures, dementia, and movement disorders.

Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease.

Neuronal nicotinic AChRs (nAChRs) are implicated in the pathogenesis of diverse neurological disorders and in the regulation of small-cell lung carcinoma growth. Twelve subunits have been identified in vertebrates, and mutations of one are recognized in a rare form of human epilepsy. Mice with genetically manipulated neuronal nAChR subunits exhibit behavioral or autonomic phenotypes. Here, we report the first model of an acquired neuronal nAChR disorder and evidence for its pertinence to paraneoplastic neurological autoimmunity. Rabbits immunized once with recombinant alpha3 subunit (residues 1-205) develop profound gastrointestinal hypomotility, dilated pupils with impaired light response, and grossly distended bladders. As in patients with idiopathic and paraneoplastic autoimmune autonomic neuropathy, the severity parallels serum levels of ganglionic nAChR autoantibody. Failure of neurotransmission through abdominal sympathetic ganglia, with retention of neuronal viability, confirms that the disorder is a postsynaptic channelopathy. In addition, we found ganglionic nAChR protein in small-cell carcinoma lines, identifying this cancer as a potential initiator of ganglionic nAChR autoimmunity. The data support our hypothesis that immune responses driven by distinct neuronal nAChR subtypes expressed in small-cell carcinomas account for several lung cancer-related paraneoplastic disorders affecting cholinergic systems, including autoimmune autonomic neuropathy, seizures, dementia, and movement disorders.

Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies.

Idiopathic autonomic neuropathy is a severe, subacute disorder with a presumed autoimmune basis. It is indistinguishable from the subacute autonomic neuropathy that may accompany lung cancer or other tumors. Autoantibodies specific for nicotinic acetylcholine receptors in the autonomic ganglia are potentially pathogenic and may serve as serologic markers of various forms of autoimmune autonomic neuropathy. We tested serum from 157 patients with a variety of types of dysautonomia. Immunoprecipitation assays with iodine-125-labeled epibatidine and solubilized human neuroblastoma acetylcholine receptors were used to detect autoantibodies that bound to or blocked ganglionic receptors. Ganglionic-receptor-binding antibodies were found in 19 of 46 patients with idiopathic or paraneoplastic autonomic neuropathy (41 percent), in 6 of 67 patients with postural tachycardia syndrome, idiopathic gastrointestinal dysmotility, or diabetic autonomic neuropathy (9 percent), and in none of 44 patients with other autonomic disorders. High levels of the binding antibodies correlated with more severe autonomic dysfunction (including the presence of tonic pupils). Levels of these antibodies decreased in patients who had clinical improvement. All seven patients with ganglionic-receptor-blocking antibodies had ganglionic-receptor-binding antibodies and had idiopathic or paraneoplastic autonomic neuropathy. Seropositivity for antibodies that bind to or block ganglionic acetylcholine receptors identifies patients with various forms of autoimmune autonomic neuropathy and distinguishes these disorders from other types of dysautonomia. The positive correlation between high levels of ganglionic-receptor antibodies and the severity of autonomic dysfunction suggests that the antibodies have a pathogenic role in these types of neuropathy.

Idiopathic postural orthostatic tachycardia syndrome

Stimulated by the widespread use of head-up tilt testing, transient episodes of neurocardiogenically mediated hypotension and bradycardia have become a well recognized cause of recurrent syncope and near syncope (generally referred to as neurally mediated syncope). On the other hand, a large subgroup of patients was identified, who appeared to have a less severe hypotension and orthostatic intolerance that is characterized by postural tachycardia, exercise intolerance, disabling fatigue, lightheadedness and dizziness. This form of disability has been recognized as postural orthostatic tachycardia syndrome (POTS). While the etiology of POTS is still unclear, a mild form of idiopathic peripheral autonomic neuropathy (partial dysautonomia) or beta-receptor hypersensitivity has been suggested for the pathophysiology of this disorder. A detailed history and physical examination that includes a careful neurologic examination are essential for diagnosis. Head-up tilt testing is often useful as a standardized measure of response to postural change. This review summarizes the history, current knowledge of clinical features, diagnosis and therapeutic strategies.

CHRONIC FATIGUE SYNDROME

Jain SS, DeLisa JA: Chronic fatigue syndrome: a literature review from a physiatric perspective. Am J Phys Med Rehabil 1998;77:160–167 To examine the literature on chronic fatigue syndrome (CFS), especially as it relates to cognitive deficits and exercise, more than 200 articles related to CFS were selected from computer-based research as well as pertinent articles noted in the references of individual articles. All were relevant articles on CFS, although articles in a foreign language were excluded. CFS is a controversial diagnosis of exclusion, but certain subgroups do appear to exist. It may represent multiple diseases or multiple stages of the same disease. Although cognitive deficits are commonly reported, the measured impairments are relatively subtle and are in the area of complex information processing speed, or efficiency. Magnetic resonance imaging, single-photon emission computer tomography, and neuroendocrine studies present preliminary evidence suggestive of the cerebral involvement primarily in the white matter. The weakness and fatigue may be the result of alterations in the central nervous system, not in the peripheral muscles. However, it is hard to separate the documented weakness and endurance deficits from deconditioning. Autonomic symptoms such as orthostatic intolerance and a predisposition to neurally mediated syncope may be explained by cardiovascular deconditioning, a postviral idiopathic autonomic neuropathy, or both. The review points out the need for more carefully designed studies of CFS that focus on the relationship between neuropathology, psychopathology and neuropsychologic functioning. The role of exercise as a stimulus for exacerbation or in treatment needs to be further studied using clear diagnostic criteria as well as control groups that carefully match the activity level.

Does the Chronic Fatigue Syndrome Involve the Autonomic Nervous System?

Purpose: To investigate the role of the autonomic nervous system in the symptoms of patients with chronic fatigue syndrome (CFS) and delineate the pathogenesis of the orthostatic intolerance and predisposition to neurally mediated syncope reported in this patient group.Patients and Methods: Twenty-three CFS patients and controls performed a battery of autonomic function tests. The CFS patients completed questionnaires pertaining to autonomic and CFS symptoms, their level of physical activity, and premorbid and coexisting psychiatric disorders. The relationship between autonomic test results, cardiovascular deconditioning, and psychiatric disorders was examined with multivariate statistics and the evidence that autonomic changes seen in CFS might be secondary to a postviral, idiopathic autonomic neuropathy was explored.Results: The CFS subjects had a significant increase in baseline (P <0.01) and maximum heart rate (HR) on standing and tilting (both P <0.0001). Tests of parasympathetic nervous system function (the expiratory inspiratory ratio, P <0.005; maximum minus minimum HR difference, P <0.05), were significantly less in the CFS group as were measures of sympathetic nervous system function (systolic blood pressure decrease with tilting, P <0.01; diastolic blood pressure decrease with tilting, P <0.05; and the systolic blood pressure decrease during phase II of a Valsalva maneuver, P <0.05). Twenty-five percent of CFS subjects had a positive tilt table test. The physical activity index was a significant predictor of autonomic test results (resting, sitting, standing, and tilted HR, P <0.05 to P <0.009); and the blood pressure decrease in phase II of the Valvalsa maneuver, P <0.05) whereas premorbid and coexistent psychiatric conditions were not. The onset of autonomic symptoms occurred within 4 weeks of a viral infection in 46% of patients—a temporal pattern that is consistent with a postviral, idiopathic autonomic neuropathy.Conclusion: Patients with CFS show alterations in measures of sympathetic and para-sympathetic nervous system function. These results, which provide the physiological basis for the orthostatic intolerance and other symptoms of autonomic function in this patient group, may be explained by cardiovascular deconditioning, a postviral idiopathic autonomic neuropathy, or both.

Idiopathic dysautonomia treated with intravenous gammaglobulin

SummaryBackground A previously healthy 23-year-old man presented with a short history of abdominal pain and diarrhoea followed by blurred vision, severe postural hypotension, reduced sweating and unremitting fever.Methods Examination revealed fixed dilated pupils, impaired sweating and postural hypotension. Clinical and neurophysiological examination showed no motor or sensory deficit. A diagnosis of idiopathic autonomic neuropathy was made. He became gravely ill with profound life-threatening hypotension and a prolonged ileus.Findings Within 36 h of receiving intravenous gammaglobulin (IVGG) his pupillary areflexia and severe hypotension resolved. 2 weeks later the autonomic failure recurred but again responded to treatment with IVGG. IVGG is a recognised treatment for Guillain-Barré syndrome.Interpretation This case report demonstrates that IVGG is also effective in the rare pure dysautonomic variant.

Idiopathic autonomic neuropathy: clinical, neurophysiologic, and follow-up studies on 27 patients.

We evaluated the natural history, electrophysiologic characteristics, spectrum of autonomic involvement, pathology, and laboratory features in 27 patients with idiopathic autonomic neuropathy who were followed up for a mean of 32 months. The typical features of idiopathic autonomic neuropathy include the absence of an associated disease, frequent history of preceding infection, and acute or subacute onset with a monophasic course. The spectrum of autonomic involvement ranges from panautonomic to selective adrenergic or cholinergic failure. There is infrequent involvement of somatic nerve fibers as assessed by routine nerve conduction studies. Pathologic features include the presence of a small inflammatory mononuclear cell infiltrate in the epineurium. Recovery tends to be gradual and frequently incomplete. The acute onset, frequent antecedent viral infection, selectivity of involvement by fiber type and autonomic level, and presence of perivascular mononuclear cell infiltration suggest that the underlying mechanism is likely to be immune-mediated. These observations may justify plasma exchange or other immunosuppressive modalities as early therapeutic intervention in patients with progressive disability.

Effect of xamoterol in a patient with idiopathic autonomic failure

We report the effect of xamoterol on autonomic, humoral and haemodynamic function in a patient with idiopathic autonomic neuropathy. Xamoterol produced marked symptomatic improvement, slightly increased heart rates in the sitting, supine and upright tilt positions and higher blood pressures while seated and on recovery from upright tilt. There were, however, no differences in blood pressure responses following a meal or during head-up tilt. We suggest that before ascribing symptomatic benefit to xamoterol in this condition, objective haemodynamic improvement should be recorded. Further studies of treatment in idiopathic autonomic failure require to be placebo controlled.

Hemodynamic effects of octreotide in patients with autonomic neuropathy.

The somatostatin analogue, ectrootide, is being used to treat postprandial hypotension in patients with autonomic neuropathy. Although the therapeutic effect of the drug is presumably secondary to a splanchnic vasoconstrictor action, its effect on splanchnic hemodynamics has never been characterized in patients with autonomic neuropathy. Moreover, it is unknown whether octreotide acts on other vascular beds in this group of patients or whether it affects cardiac output. We, therefore, measured splanchnic, forearm, and systemic vascular resistance and cardiac output before and after administering octreotide (0.4 microgram/kg s.c.) to patients with idiopathic autonomic neuropathy and diabetic autonomic neuropathy. Splanchnic blood flow was determined from the clearance of indocyanine green in seven patients. We observed that octreotide decreased splanchnic blood flow (from 850 +/- 77 to 664 +/- 48 ml/min, p less than 0.005), increased mean blood pressure (from 97 +/- 6 to 115 +/- 3 mm Hg, p less than 0.005), and increased splanchnic vascular resistance (from 0.118 +/- 0.012 to 0.18 +/- 0.018 mm Hg/ml/min, p less than 0.005). Forearm blood flow was measured by plethysmography in 13 patients. Octreotide increased forearm vascular resistance in patients with idiopathic autonomic neuropathy (n = 8) from 19.1 +/- 1.0 to 27.2 +/- 3.8 mm Hg/ml/min/100 ml forearm volume (p less than 0.01) and from 25.2 +/- 3.9 to 41.0 +/- 6.8 mm Hg/ml/min/100 ml (p less than 0.01) in patients with diabetic autonomic neuropathy (n = 5). Cardiac output was measured by two-dimensional echocardiography. Octreotide administration increased cardiac output in five of six patients with idiopathic autonomic neuropathy (from 4.4 +/- 0.4 to 5.0 +/- 0.5 l/min, p less than 0.02) and five of five patients with diabetic autonomic neuropathy (from 3.8 +/- 0.4 to 5.1 +/- 0.4 l/min, p less than 0.02). Systemic vascular resistance increased in patients with idiopathic autonomic neuropathy from 21.2 +/- 2 to 24.9 +/- 2.6 (p less than 0.05) but did not change in patients with diabetic autonomic neuropathy. The pressor effect of octreotide in patients with autonomic neuropathy is associated with increased splanchnic and forearm vascular resistance and with increased cardiac output.