Autoimmune Autonomic Neuropathies
abstract & commentary
Source: Vernino S, et al. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000;343:847-855.
Immunoprecipitation assays with solubilized human neuroblastoma acetylcholine receptors and iodine-125-labeled epibatadine, the latter a high-affinity agonist of neuronal ganglionic receptors, were used to screen serum from 157 dysautonomia patients for ganglionic-receptor-blocking and binding antibodies, respectively. Patients diagnoses included idiopathic autonomic neuropathy (n = 28), paraneoplastic autonomic neuropathy (n = 18, 12 with small cell lung cancer), postural tachycardia syndrome (n = 15), idiopathic gastrointestinal dysmotility (n = 34), diabetic autonomic neuropathy (n = 18), pure autonomic failure (n = 24), multi-system atrophy, and nondiabetic sensorimotor and autonomic neuropathy (n = 10 each). These latter comprised Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, hereditary sensory and autonomic neuropathy, and idiopathic small fiber neuropathy. Autonomic function tests used to diagnose dysautonomia, the Composite Autonomic Severity Scale (Low PA. J Clin Neurophysiol 1993;10:14-27), encompassed the quantitative sudomotor axon reflex test (QSART), heart rate response to deep breathing and Valsalva maneuver, blood pressure response to head-up tilt and Valsalva maneuver, the thermoregulatory sweat test, and gastrointestinal motility studies including intestinal transit and endoscopic manometry. Exclusionary criteria included Lambert Eaton syndrome, lack of objective evidence of dysautonomia, and insufficient data to diagnose the type of dysautonomia. Healthy subjects (n = 133), and 13 with gastrointestinal symptoms but normal motility studies, served as controls.
None of the 146 controls demonstrated detectable antibodies. Ganglionic-receptor-binding antibodies were detected in 25 (16%) dysautonomia patients, 19 (76%) of which had either idiopathic autonomic neuropathy (14/28, 50%), or paraneoplastic autonomic neuropathy (5/18, 28%). No patient with degenerative or non-diabetic dysautonomia expressed the antibody. Idiopathic (4/28, 14%) and paraneoplastic (3/18, 17%) autonomic neuropathy patients were positive for ganglionic-receptor-blocking antibodies which, however, were never found in the absence of binding antibodies. Higher antibody levels correlated with more severe autonomic failure as assessed by the Composite Autonomic Severity Scale and changing levels correlated with clinical status. Idiopathic and paraneoplastic autonomic neuropathies are immune mediated. Ganglionic-receptor-binding and blocking antibodies are predictors of these forms of autonomic neuropathy, and appear to play a role in their pathogenesis.
Commentary
Complement-fixing sympathetic ganglia and complement-fixing vagus nerve autoantibodies are present in up to 40% and 13%, respectively, of Type 1 diabetics at diagnosis, compared to 5% and 0%, respectively, of healthy controls (Zanone MM, et al. Diabetologia 1993; 36:564-569; Diabetes Care 1997;1:1-4). Diabetics with autonomic neuropathy, diagnosed on the basis of severe diabetic diarrhea, gastroparetic vomiting, postural hypotension, and bladder paresis, are antibody positive more often than diabetics without autonomic neuropathy, 33% vs. 8%, respectively (Schsnell O, et al. Diabetologia 1996;39:970-975). Those with electrocardiographic-based cardiac autonomic neuropathy are also more likely to demonstrate complement-fixing sympathetic ganglia autoantibodies (9/22, 41%) than patients without cardiac autonomic neuropathy (3/26, 12%). Autonomic nervous tissue antibodies appear to play a role in the autonomic neuropathy of type 1 diabetes.
Autoantibodies do not appear to play a role in the pathogenesis of cardiac dysautonomia in type 2 diabetes. Among 127 type 2 diabetics, complement-fixing sympathetic and parasympathetic ganglia autoantibodies were detected in approximately 9% and 6% respectively, compared to 1% and 0% in normal controls. However, no significant difference in antibody levels was evident in diabetics with or without cardiac dysautonomia (Schnell O, et al. Exp Clin Endocrinol Diabetes 2000;108:181-186).
Significantly, in the absence of a hereditary small fiber neuropathy, dysautonomia should alert the neurologist to an acquired etiology. Only one of nine hereditary motor and sensory neuropathy type I patients (Charcot-Marie-Tooth disease, type I, HMSN I) demonstrated abnormalities on two or more autonomic function tests (pupillary reflexes, vasomotor control, baroreceptor reflexes, and sudomotor function), compared to three of three patients with Lambert Eaton syndrome and none of 33 controls. Dysautonomia is uncommon in HMSN I (Kalmijn S, et al. Electromyogr Clin Neurophysiol 1999;39:349-353). —Michael Rubin
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