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Seropositive myasthenia and autoimmune autonomic ganglionopathy: Cross reactivity or subclinical disease?
Autonomic Neuroscience: Basic and Clinical 164 (2011) 87–88
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t n e u
Seropositive myasthenia and autoimmune autonomic ganglionopathy: Cross reactivity or subclinical disease? Mitchell G. Miglis ⁎, Rikki Racela, Horacio Kaufmann Dysautonomia Center, Department of Neurology, New York University School of Medicine, 530 First Avenue Suite 9Q, New York, NY, 10016, United States
a r t i c l e
i n f o
Article history: Received 15 February 2011 Received in revised form 4 May 2011 Accepted 20 June 2011 Keywords: Autoimmune autonomic ganglionopathy Myasthenia gravis Autonomic neuropathy Neuronal ganglionic nicotinic AChR Antibodies
a b s t r a c t Autoimmune autonomic ganglionopathy (AAG) and myasthenia gravis (MG) are both autoimmune channelopathies mediated by antibodies directed against nicotinic acetylcholine receptors. While both diseases target acetylcholine receptors, skeletal muscle and ganglionic receptor subtypes have key immunologic and genetic distinctions, and reports of patients with both AAG and MG are rare. We report a patient with antibody-confirmed AAG and elevated levels of ACh binding antibodies that did not meet clinical or electrodiagnostic criteria for MG. We presume that his skeletal muscle nAChR seropositivity was a false positive, perhaps due to the cross reactivity of the patient's ganglionic nAChR antibodies with skeletal nAChR subtypes. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Autoimmune autonomic ganglionopathy (AAG) is an autoimmune channelopathy mediated by antibodies directed against the neuronal ganglionic nicotinic acetylcholine receptor (nAChR). Sympathetic, parasympathetic, and enteric nervous systems are affected, and patients typically present with signs and symptoms of widespread autonomic dysfunction evolving over days to months. Symptoms of orthostatic hypotension and gastrointestinal dysmotility are most commonly reported, however patients can also develop urinary retention, anhidrosis, sicca syndrome, erectile dysfunction, and impairment of the pupillary light reflex (Vernino, 2008a). Somatic nerve fibers are typically spared. Greater than 50% of patients diagnosed with AAG have high levels (N0.2 nmol/L) of antibodies directed against the ganglionic nAChR (Vernino, 2008b). However, some patients with mild AAG may never be diagnosed, and thus the exact incidence of the disease may be difficult to ascertain. The severity of dysautonomia has been correlated with the serum level of ganglionic nAChR antibodies (Vernino et al., 2000). The majority of patients have an idiopathic form of the disease, while 15% of patients have paraneoplastic AAG associated with small cell lung cancer or thymoma (Vernino et al., 2008b). Antecedent viral infection is reported in a majority of cases. Myasthenia gravis (MG) is the most well understood autoimmune channelopathy. In contrast to AAG, MG is mediated by antibodies that target nAChRs at the neuromuscular junction. While both diseases
⁎ Corresponding author. Tel.: + 1 202 425 5934. E-mail address: [email protected] (M.G. Miglis). 1566-0702/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2011.06.005
target acetylcholine receptors, the skeletal muscle and ganglionic nAChR receptor subtypes have key immunologic and genetic distinctions, and reports of patients with both AAG and MG are rare. In addition, elevated levels of skeletal muscle nAChR antibodies have been reported in patients with a variety of other conditions without clinically or electrodiagnostically proven MG. We report a patient with autoantibody-confirmed AAG and elevated levels of ACh binding antibodies that did not meet clinical or electrodiagnostic criteria for MG.
2. Case report An 80 year-old man presented to his primary care physician with complaints of dry mouth, decreased appetite, and early satiety progressive over several months. He also experienced lightheadedness upon arising from bed and dyspnea after routine physical tasks. He later developed constipation, urinary frequency, urgency, and hesitancy. He was hospitalized after having a syncopal event while walking to the bathroom and was diagnosed with sick sinus syndrome. A cardiac pacemaker was implanted and he was soon discharged, but his symptoms did not resolve. His past medical history was notable for Hashimoto's thyroiditis and vitiligo. On follow-up exam with his primary physician he was found to have orthostatic hypotension and was prescribed fludrocortisone. Soon thereafter he developed worsening urinary retention, was diagnosed with benign prostatic hypertrophy, and had a transurethral prostate resection. Post-operatively he developed severe hypotension and was admitted to the ICU. With the exception of severe orthostatic hypotension, neurologic exam at that time was normal. Basic
88
M.G. Miglis et al. / Autonomic Neuroscience: Basic and Clinical 164 (2011) 87–88
laboratory testing and CT of the chest, abdomen, and pelvis with contrast were unremarkable. He was eventually discharged from the hospital and referred to us for autonomic testing. Initial blood pressure was 171/94 supine, with a paced heart rate of 60 beats per minute. After 1 min on the 60degree head up tilt position the blood pressure fell to 113/67 mm Hg, with a paced heart rate of 60 beats per minute. After 7 min in the head up tilt position, blood pressure fell to 72/44 mm Hg, while paced heart rate remained at 60 beats per minute. Plasma norepinephrine concentration was 16 pg/ml while supine (normal 80–520 pg/ml) and 26 pg/ml after 3 min in the head up tilt position. Ganglionic nAChR antibodies were elevated at 6.89 nmol/L (radioimmunoprecipitation assay, as described in Vernino et al., 2000), confirming a diagnosis of AAG. Due to complaints of persistent generalized fatigue, antibodies for myasthenia were sent, and returned positive for AChR binding antibodies at 1.0 (normal 0–0.4, radioimmunoassay, Quest diagnostics). AChR blocking and modulating antibodies were not detected. Electrodiagnostic testing including repetitive stimulation of proximal musculature and single fiber EMG was normal. A trial of pyridostigmine was unsuccessful in alleviating fatigue or autonomic symptoms. Erythropoietin treatment was added to his regimen of fludrocortisone and midodrine. The patient was able to maintain his active walking schedule and noted that after the initial fatigue he experienced at the beginning of exercise, he was able to eventually warm up and finish his walk without difficulty. 3. Discussion Our patient tested positive for MG antibodies without electrodiagnostic or clinical evidence of MG. Autonomic dysfunction is rare in patients with MG. We found only fourteen cases of serologically confirmed MG with autonomic dysfunction in the literature (Tabbaa et al., 1986; Tan et al., 1993; Suarez et al., 1994; Anderson et al., 1996; Berger et al., 1996; Vernino et al., 2001; Rakocevic et al., 2003; Peltier et al., 2010). The prominent feature in most of these cases was gastrointestinal dysmotility and pseudo-obstruction. The skeletal muscle nAChR and the ganglionic nAChR, while structurally similar, are immunologically and genetically distinct. Each nAChR is formed by a pentameric complex of five subunits, at least two of which are α subunits containing binding sites for acetylcholine (Vernino et al., 2008b). The muscle nAChR has two α1 subunits, along with β1, δ, and γ or ε, but neuronal nAChRs contain only α (α2–α7 in human) and β (β2–β4) subunits (Vernino et al., 2008a). The extracellular α subunit domain of the ganglionic nAChR is approximately 60% identical in amino acid sequence to the α subunit domain of muscle nAChR (Anderson et al., 1996). Antibodies to muscle nAChR are present in 85% of patients with generalized MG and 50–60% of patients with purely ocular MG (Drachman, 1994). Although the assay is specific, false positives have been reported, specifically in non-myasthenic patients with thymoma (Cuenod et al., 1980), malignancy (McKeon et al., 2009), ALS (Mittag and Caroscio, 1980), patients with tardive dyskinesia who had received neuroleptic medications (Lieberman et al., 1984), patients receiving penicillamine (Martin et al., 1980), and elderly individuals and patients with Down's syndrome (Tan et al., 1993). Available assays for ganglionic nAChR antibodies are very specific but only 50% sensitive (Vernino et al., 2000). In their report on the characterization of ganglionic antibodies, Vernino et al. described a patient with clinical AAG who tested positive for both ganglionic and muscle nAChR antibodies (Vernino et al., 2008b). Similar to our patient, this patient had no clinical or electrophysiologic evidence of MG. He was the only patient out of an AAG cohort of 32 (3%) to test positive for both antibodies. Similarly, two of 74 patients with MG tested positive for both antibodies (3%). In both groups, the levels of antibodies did not correlate: the AAG patient had a high ganglionic antibody level
and a low muscle antibody level, while the two MG patients had a high muscle antibody level and a low ganglionic antibody level. Despite testing positive for skeletal muscle nAChR binding antibodies, our patient did not fit the clinical phenotype of MG, nor was his electrodiagnostic testing supportive of this diagnosis. His subacute clinical presentation was one of widespread autonomic failure, and the diagnosis of AAG was confirmed with a highly specific confirmatory test. In addition, our patient's antibody levels did not correlate, with a much higher ganglionic antibody level compared to muscle binding antibody level. We thus presume that our patient's skeletal muscle nAChR seropositivity was a false positive, perhaps due to the cross reactivity of the ganglionic antibodies with muscle nAChRs. In work by Lennon and Vernino, rabbits immunized against ganglionic α3 subunits developed antibodies against other nAChR subtypes, including skeletal muscle (Lennon et al., 2003). These animals developed prominent signs of dysautonomia, but none of them developed clear signs of motor weakness. However, in later work, Vernino et al. did report some rabbits with both muscle and ganglionic antibodies that developed muscle weakness and dysautonomia (Vernino et al., 2006, 2008b). While one should remember that MG can rarely be associated with autonomic symptoms, in these patients there are nearly always signs and symptoms of fatigable weakness, and one should always interpret the results of serologic testing in light of the patient's clinical presentation. Further study on the degree of false positive skeletal muscle nAChR antibodies in patients with AAG is warranted. Acknowledgment We thank Dr. Steven Vernino for performing the ganglionic AChR antibody testing and his insightful comments on this manuscript. References Anderson, N.E., et al., 1996. Intestinal pseudo-obstruction, myasthenia gravis, and thymoma. Neurology 47, 985–987. Berger, A.R., et al., 1996. Myasthenia gravis presenting as uncontrollable flatus and urinary/fecal incontinence. Muscle Nerve 19, 113–114. Cuenod, S., et al., 1980. Antibodies to acetylcholine receptor in patients with thymoma but without myasthenia gravis. Neurology 30, 201–202. Drachman, D., 1994. Myasthenia gravis. N. Engl. J. Med. 330, 1797–1810. Lieberman, J.A., et al., 1984. Antibodies to acetylcholine receptors in tardive dyskinesia. Lancet 1, 1066. Lennon, V., et al., 2003. Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease. J. Clin. Invest. 111, 907–913. Martin, V.M., et al., 1980. Anti-acetylcholine receptor antibodies in penicillamine treated patients without myasthenia. Lancet 2, 705. McKeon, A., et al., 2009. Ganglionic acetylcholine receptor autoantibody: oncological, neurological, and serological accompaniments. Arch. Neurol. 66, 735–741. Mittag, T.W., Caroscio, J., 1980. False positive immunoassay for acetylcholine antibody in amyotrophic lateral sclerosis. N. Engl. J. Med. 302, 868. Peltier, et al., 2010. Coexistent autoimmune autonomic ganglionopathy and myasthenia gravis associated with non-small-cell lung cancer. Muscle Nerve 41, 416–419. Rakocevic, G., et al., 2003. Myasthenia gravis, thymoma, and intestinal pseudoobstruction: a case report and review. J. Clin. Neuromuscul. Dis. 5, 93–95. Tabbaa, M.A., Leshner, R.T., Campbell, W.W., 1986. Malignant thymoma with dysautonomia and disordered neuromuscular transmission. Arch. Neurol. 43, 955–957. Tan, C.K., et al., 1993. Acute intestinal pseudo-obstruction due to malignant thymoma. Singapore Med. J. 34, 175–178. Suarez, et al., 1994. Idiopathic autonomic neuropathy: clinical, neurophysiologic, and follow-up studies on 27 patients. Neurology 44, 1675–1682. Vernino, S., 2008a. Neuronal acetycholine receptor autoimmunity. Ann. N. Y. Acad. Sci. 1132, 124–128. Vernino, et al., 2008b. Characterization of ganglionic acetylcholine receptor autoantibodies. J. Neuroimmunol. 197, 63–69. Vernino, et al., 2006. Experimental acetylcholine receptor autoimmunity: coexisting myasthenia and autonomic failure. Neuromuscul. Disord. 16 (Supp 1), S180. Vernino, et al., 2000. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N. Engl. J. Med. 343, 847–855. Vernino, et al., 2001. Myasthenia gravis with autoimmune autonomic neuropathy. Auton. Neurosci. 88, 187–192.
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t n e u
Seropositive myasthenia and autoimmune autonomic ganglionopathy: Cross reactivity or subclinical disease? Mitchell G. Miglis ⁎, Rikki Racela, Horacio Kaufmann Dysautonomia Center, Department of Neurology, New York University School of Medicine, 530 First Avenue Suite 9Q, New York, NY, 10016, United States
a r t i c l e
i n f o
Article history: Received 15 February 2011 Received in revised form 4 May 2011 Accepted 20 June 2011 Keywords: Autoimmune autonomic ganglionopathy Myasthenia gravis Autonomic neuropathy Neuronal ganglionic nicotinic AChR Antibodies
a b s t r a c t Autoimmune autonomic ganglionopathy (AAG) and myasthenia gravis (MG) are both autoimmune channelopathies mediated by antibodies directed against nicotinic acetylcholine receptors. While both diseases target acetylcholine receptors, skeletal muscle and ganglionic receptor subtypes have key immunologic and genetic distinctions, and reports of patients with both AAG and MG are rare. We report a patient with antibody-confirmed AAG and elevated levels of ACh binding antibodies that did not meet clinical or electrodiagnostic criteria for MG. We presume that his skeletal muscle nAChR seropositivity was a false positive, perhaps due to the cross reactivity of the patient's ganglionic nAChR antibodies with skeletal nAChR subtypes. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Autoimmune autonomic ganglionopathy (AAG) is an autoimmune channelopathy mediated by antibodies directed against the neuronal ganglionic nicotinic acetylcholine receptor (nAChR). Sympathetic, parasympathetic, and enteric nervous systems are affected, and patients typically present with signs and symptoms of widespread autonomic dysfunction evolving over days to months. Symptoms of orthostatic hypotension and gastrointestinal dysmotility are most commonly reported, however patients can also develop urinary retention, anhidrosis, sicca syndrome, erectile dysfunction, and impairment of the pupillary light reflex (Vernino, 2008a). Somatic nerve fibers are typically spared. Greater than 50% of patients diagnosed with AAG have high levels (N0.2 nmol/L) of antibodies directed against the ganglionic nAChR (Vernino, 2008b). However, some patients with mild AAG may never be diagnosed, and thus the exact incidence of the disease may be difficult to ascertain. The severity of dysautonomia has been correlated with the serum level of ganglionic nAChR antibodies (Vernino et al., 2000). The majority of patients have an idiopathic form of the disease, while 15% of patients have paraneoplastic AAG associated with small cell lung cancer or thymoma (Vernino et al., 2008b). Antecedent viral infection is reported in a majority of cases. Myasthenia gravis (MG) is the most well understood autoimmune channelopathy. In contrast to AAG, MG is mediated by antibodies that target nAChRs at the neuromuscular junction. While both diseases
⁎ Corresponding author. Tel.: + 1 202 425 5934. E-mail address: [email protected] (M.G. Miglis). 1566-0702/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2011.06.005
target acetylcholine receptors, the skeletal muscle and ganglionic nAChR receptor subtypes have key immunologic and genetic distinctions, and reports of patients with both AAG and MG are rare. In addition, elevated levels of skeletal muscle nAChR antibodies have been reported in patients with a variety of other conditions without clinically or electrodiagnostically proven MG. We report a patient with autoantibody-confirmed AAG and elevated levels of ACh binding antibodies that did not meet clinical or electrodiagnostic criteria for MG.
2. Case report An 80 year-old man presented to his primary care physician with complaints of dry mouth, decreased appetite, and early satiety progressive over several months. He also experienced lightheadedness upon arising from bed and dyspnea after routine physical tasks. He later developed constipation, urinary frequency, urgency, and hesitancy. He was hospitalized after having a syncopal event while walking to the bathroom and was diagnosed with sick sinus syndrome. A cardiac pacemaker was implanted and he was soon discharged, but his symptoms did not resolve. His past medical history was notable for Hashimoto's thyroiditis and vitiligo. On follow-up exam with his primary physician he was found to have orthostatic hypotension and was prescribed fludrocortisone. Soon thereafter he developed worsening urinary retention, was diagnosed with benign prostatic hypertrophy, and had a transurethral prostate resection. Post-operatively he developed severe hypotension and was admitted to the ICU. With the exception of severe orthostatic hypotension, neurologic exam at that time was normal. Basic
88
M.G. Miglis et al. / Autonomic Neuroscience: Basic and Clinical 164 (2011) 87–88
laboratory testing and CT of the chest, abdomen, and pelvis with contrast were unremarkable. He was eventually discharged from the hospital and referred to us for autonomic testing. Initial blood pressure was 171/94 supine, with a paced heart rate of 60 beats per minute. After 1 min on the 60degree head up tilt position the blood pressure fell to 113/67 mm Hg, with a paced heart rate of 60 beats per minute. After 7 min in the head up tilt position, blood pressure fell to 72/44 mm Hg, while paced heart rate remained at 60 beats per minute. Plasma norepinephrine concentration was 16 pg/ml while supine (normal 80–520 pg/ml) and 26 pg/ml after 3 min in the head up tilt position. Ganglionic nAChR antibodies were elevated at 6.89 nmol/L (radioimmunoprecipitation assay, as described in Vernino et al., 2000), confirming a diagnosis of AAG. Due to complaints of persistent generalized fatigue, antibodies for myasthenia were sent, and returned positive for AChR binding antibodies at 1.0 (normal 0–0.4, radioimmunoassay, Quest diagnostics). AChR blocking and modulating antibodies were not detected. Electrodiagnostic testing including repetitive stimulation of proximal musculature and single fiber EMG was normal. A trial of pyridostigmine was unsuccessful in alleviating fatigue or autonomic symptoms. Erythropoietin treatment was added to his regimen of fludrocortisone and midodrine. The patient was able to maintain his active walking schedule and noted that after the initial fatigue he experienced at the beginning of exercise, he was able to eventually warm up and finish his walk without difficulty. 3. Discussion Our patient tested positive for MG antibodies without electrodiagnostic or clinical evidence of MG. Autonomic dysfunction is rare in patients with MG. We found only fourteen cases of serologically confirmed MG with autonomic dysfunction in the literature (Tabbaa et al., 1986; Tan et al., 1993; Suarez et al., 1994; Anderson et al., 1996; Berger et al., 1996; Vernino et al., 2001; Rakocevic et al., 2003; Peltier et al., 2010). The prominent feature in most of these cases was gastrointestinal dysmotility and pseudo-obstruction. The skeletal muscle nAChR and the ganglionic nAChR, while structurally similar, are immunologically and genetically distinct. Each nAChR is formed by a pentameric complex of five subunits, at least two of which are α subunits containing binding sites for acetylcholine (Vernino et al., 2008b). The muscle nAChR has two α1 subunits, along with β1, δ, and γ or ε, but neuronal nAChRs contain only α (α2–α7 in human) and β (β2–β4) subunits (Vernino et al., 2008a). The extracellular α subunit domain of the ganglionic nAChR is approximately 60% identical in amino acid sequence to the α subunit domain of muscle nAChR (Anderson et al., 1996). Antibodies to muscle nAChR are present in 85% of patients with generalized MG and 50–60% of patients with purely ocular MG (Drachman, 1994). Although the assay is specific, false positives have been reported, specifically in non-myasthenic patients with thymoma (Cuenod et al., 1980), malignancy (McKeon et al., 2009), ALS (Mittag and Caroscio, 1980), patients with tardive dyskinesia who had received neuroleptic medications (Lieberman et al., 1984), patients receiving penicillamine (Martin et al., 1980), and elderly individuals and patients with Down's syndrome (Tan et al., 1993). Available assays for ganglionic nAChR antibodies are very specific but only 50% sensitive (Vernino et al., 2000). In their report on the characterization of ganglionic antibodies, Vernino et al. described a patient with clinical AAG who tested positive for both ganglionic and muscle nAChR antibodies (Vernino et al., 2008b). Similar to our patient, this patient had no clinical or electrophysiologic evidence of MG. He was the only patient out of an AAG cohort of 32 (3%) to test positive for both antibodies. Similarly, two of 74 patients with MG tested positive for both antibodies (3%). In both groups, the levels of antibodies did not correlate: the AAG patient had a high ganglionic antibody level
and a low muscle antibody level, while the two MG patients had a high muscle antibody level and a low ganglionic antibody level. Despite testing positive for skeletal muscle nAChR binding antibodies, our patient did not fit the clinical phenotype of MG, nor was his electrodiagnostic testing supportive of this diagnosis. His subacute clinical presentation was one of widespread autonomic failure, and the diagnosis of AAG was confirmed with a highly specific confirmatory test. In addition, our patient's antibody levels did not correlate, with a much higher ganglionic antibody level compared to muscle binding antibody level. We thus presume that our patient's skeletal muscle nAChR seropositivity was a false positive, perhaps due to the cross reactivity of the ganglionic antibodies with muscle nAChRs. In work by Lennon and Vernino, rabbits immunized against ganglionic α3 subunits developed antibodies against other nAChR subtypes, including skeletal muscle (Lennon et al., 2003). These animals developed prominent signs of dysautonomia, but none of them developed clear signs of motor weakness. However, in later work, Vernino et al. did report some rabbits with both muscle and ganglionic antibodies that developed muscle weakness and dysautonomia (Vernino et al., 2006, 2008b). While one should remember that MG can rarely be associated with autonomic symptoms, in these patients there are nearly always signs and symptoms of fatigable weakness, and one should always interpret the results of serologic testing in light of the patient's clinical presentation. Further study on the degree of false positive skeletal muscle nAChR antibodies in patients with AAG is warranted. Acknowledgment We thank Dr. Steven Vernino for performing the ganglionic AChR antibody testing and his insightful comments on this manuscript. References Anderson, N.E., et al., 1996. Intestinal pseudo-obstruction, myasthenia gravis, and thymoma. Neurology 47, 985–987. Berger, A.R., et al., 1996. Myasthenia gravis presenting as uncontrollable flatus and urinary/fecal incontinence. Muscle Nerve 19, 113–114. Cuenod, S., et al., 1980. Antibodies to acetylcholine receptor in patients with thymoma but without myasthenia gravis. Neurology 30, 201–202. Drachman, D., 1994. Myasthenia gravis. N. Engl. J. Med. 330, 1797–1810. Lieberman, J.A., et al., 1984. Antibodies to acetylcholine receptors in tardive dyskinesia. Lancet 1, 1066. Lennon, V., et al., 2003. Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease. J. Clin. Invest. 111, 907–913. Martin, V.M., et al., 1980. Anti-acetylcholine receptor antibodies in penicillamine treated patients without myasthenia. Lancet 2, 705. McKeon, A., et al., 2009. Ganglionic acetylcholine receptor autoantibody: oncological, neurological, and serological accompaniments. Arch. Neurol. 66, 735–741. Mittag, T.W., Caroscio, J., 1980. False positive immunoassay for acetylcholine antibody in amyotrophic lateral sclerosis. N. Engl. J. Med. 302, 868. Peltier, et al., 2010. Coexistent autoimmune autonomic ganglionopathy and myasthenia gravis associated with non-small-cell lung cancer. Muscle Nerve 41, 416–419. Rakocevic, G., et al., 2003. Myasthenia gravis, thymoma, and intestinal pseudoobstruction: a case report and review. J. Clin. Neuromuscul. Dis. 5, 93–95. Tabbaa, M.A., Leshner, R.T., Campbell, W.W., 1986. Malignant thymoma with dysautonomia and disordered neuromuscular transmission. Arch. Neurol. 43, 955–957. Tan, C.K., et al., 1993. Acute intestinal pseudo-obstruction due to malignant thymoma. Singapore Med. J. 34, 175–178. Suarez, et al., 1994. Idiopathic autonomic neuropathy: clinical, neurophysiologic, and follow-up studies on 27 patients. Neurology 44, 1675–1682. Vernino, S., 2008a. Neuronal acetycholine receptor autoimmunity. Ann. N. Y. Acad. Sci. 1132, 124–128. Vernino, et al., 2008b. Characterization of ganglionic acetylcholine receptor autoantibodies. J. Neuroimmunol. 197, 63–69. Vernino, et al., 2006. Experimental acetylcholine receptor autoimmunity: coexisting myasthenia and autonomic failure. Neuromuscul. Disord. 16 (Supp 1), S180. Vernino, et al., 2000. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N. Engl. J. Med. 343, 847–855. Vernino, et al., 2001. Myasthenia gravis with autoimmune autonomic neuropathy. Auton. Neurosci. 88, 187–192.