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Isolated Sympathetic Failure With Autoimmune Autonomic Ganglionopathy
Isolated Sympathetic Failure With Autoimmune Autonomic Ganglionopathy Philip R. Fischer, MD*, Paola Sandroni, MD, PhD†, Sean J. Pittock, MD†, Co-burn J. Porter, MD‡, Lenora M. Lehwald, MD§, and Satish R. Raj, MD, MSCIk# A 16-year-old boy had a gradual onset of post-exercise myalgia with progressive fatigue and dizziness. He had bradycardia (37 beats/minute) with low supine and normal standing norepinephrine levels (56 and 311 pg/mL, respectively). He had absent sympathetically mediated vasoconstrictor responses during Valsalva maneuver testing. Circulating ganglionic acetylcholine receptor antibodies were identified. Response was gradual to treatment with intravenous immunoglobulin combined with aggressive symptomatic interventions (permanent pacemaker implantation and treatment with pyridostigmine, midodrine, and modafinil). After the intravenous immunoglobulin treatment, his autoantibody levels decreased and the autonomic abnormalities resolved. After a reconditioning exercise program and eventually undetectable antibody titers, he achieved complete recovery. The patient continued to do well after his pacemaker was removed and his medications were discontinued. Thus, severe isolated sympathetic nervous system failure can occur in adolescents with autoimmune autonomic ganglionopathy, and multifaceted treatment can be effective. Ó 2010 by Elsevier Inc. All rights reserved.
From the *Division of General Pediatric and Adolescent Medicine, † Department of Neurology, and ‡Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota; the §Division of Pediatric Neurology, Nationwide Children’s Hospital, Columbus, Ohio; and the Departments of k Medicine and #Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Ó 2010 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2010.05.003 0887-8994/$—see front matter
Fischer PR, Sandroni P, Pittock SJ, Porter CJ, Lehwald LM, Raj SR. Isolated sympathetic failure with autoimmune autonomic ganglionopathy. Pediatr Neurol 2010;43:287-290.
Introduction In adults, antibodies against the nicotinic ganglionic acetylcholine receptor have been associated with subacute autonomic failure [1,2]. Specifically, orthostatic hypotension and prominent cholinergic symptoms are pathophysiologically linked to the presence of these loss-of-function antibodies [3]. The autonomic ganglia are integral for normal functioning of both the sympathetic and parasympathetic nervous system, and both limbs of the autonomic nervous system are often affected in autoimmune autonomic ganglionopathy. Animal models confirm the role of acetylcholine receptor antibodies, reproducing the cardinal features of human autoimmune autonomic neuropathy including gastrointestinal dysmotility, urinary retention, and pupillary dilatation [4]. Human nicotinic ganglionic acetylcholine receptor antibodies have been linked to many features of autonomic impairment, including sudomotor dysfunction [5] and gastrointestinal dysmotility [6], but there can be a broad spectrum of autonomic findings that do not always follow a specific pattern [7]. Immunomodulating therapy can be helpful for some adult patients with autoimmune autonomic ganglionopathy [8], although the available data indicate that the response may be inconsistent. Ganglionic acetylcholine receptor antibodies have not been well studied in adolescents with autonomic dysfunction [9] and are not often identified in this population. There is an isolated report of ganglionic acetylcholine receptor antibodies in an adolescent linked to subacute onset of headache and severe postural dizziness with orthostatic hypotension and tachycardia [10]. After treatment with intravenous immunoglobulin, that patient experienced marked symptomatic improvement, with resolution of objective findings of autonomic dysfunction. Reported here is the case of a teenage boy with an acute to subacute onset of severe isolated sympathetic nervous system failure associated with ganglionic acetylcholine
Communications should be addressed to: Dr. Fischer; Department of Pediatric and Adolescent Medicine; Mayo Clinic; 200 First Street SW; Rochester, MN 55905. E-mail: [email protected] Received February 12, 2010; accepted May 3, 2010.
Fischer et al: Autoimmune Autonomic Ganglionopathy 287
receptor antibodies and his subsequent recovery under multimodal treatments. Case Report Over 3 weeks in January 2008, a previously healthy 16-year-old highschool track athlete had a gradual onset of myalgia after running. He felt progressively tired and had a sense of ‘‘becoming slower and weaker.’’ He experienced excessive thirst, salt craving, weight loss, and cold intolerance. The onset of symptoms was not preceded by any illness or immunization. There was no associated fever, and there were no specific respiratory or gastrointestinal symptoms. He became progressively dizzy and was hospitalized. He had sinus bradycardia (37 beats per minute), an unremarkable echocardiogram, and low baseline sympathetic tone, as suggested by his low supine norepinephrine level (56 pg/mL; normal, >100 pg/mL) but a normal humoral response to standing (norepinephrine at 311 pg/mL). Autonomic testing revealed an abnormal Valsalva maneuver with an absent sympathetically mediated vasoconstrictor response in both late phase II and phase IV (Fig 1). He had a blunted response to cold pressor test, with an increase in systolic blood pressure of only 13 mmHg (normal 20-35 mmHg). Quantitative sweat testing was markedly reduced at all sites, suggesting severe postganglionic sympathetic sudomotor impairment.
Pharmacologic testing with atropine (to remove cardiovagal tone) increased his heart rate from 37 beats per minute to 100 beats per minute, suggesting intact or even vigorous parasympathetic cardiovagal tone. A cardiac metaiodobenzylguanidine scan indicated normal uptake (suggesting normal cardiac sympathetic nerve integrity). A Bruce protocol exercise test excluded chronotropic incompetence (peak heart rate, 160 beats per minute), with an appropriate blood pressure response and moderate exercise tolerance (12 minutes), although this was low for a track athlete. Ganglionic acetylcholine receptor antibodies were identified in a low titer (Fig 2), and the patient received intravenous immunoglobulin monthly in April, May, and June 2008, along with symptomatic treatment with pyridostigmine, midodrine, and modafinil to address his cognitive complaints. Because persistent symptomatic bradycardia caused lightheadedness and activity intolerance, a permanent dual-chamber pacemaker was implanted in July 2008. With the pacemaker, the patient experienced a modest improvement in energy and activity tolerance. Because of what he called ‘‘brain fog,’’ with memory and concentration problems, and presyncope on standing, he could no longer attend school and required home schooling. He felt cold ‘‘all the time’’ and sensed that he was not sweating as much as he did prior to his illness. He lost 9 kg over 9 months, due primarily to a reduced appetite. The patient had progressively decreasing antibody levels and progressive improvements in sudomotor function (Fig 2). Because of concerns
Figure 1. Improvement in Valsalva maneuver results over time. Active Valsalva maneuver is indicated in white at the bottom of each panel. September 2008 (top): Abnormal (unchanging) heart rate response to Valsalva maneuver, lack of late phase II elevation in blood pressure (wide arrow), lack of post-Valsalva phase IV blood pressure elevation (narrow arrow). June 2009 (bottom): Normal (increasing) heart rate response to Valsalva maneuver, lack of late phase II elevation in blood pressure (wide arrow), and more robust post-Valsalva phase IV blood pressure elevation (narrow arrow).
288 PEDIATRIC NEUROLOGY Vol. 43 No. 4
Figure 2. Time course of treatments and autonomic findings.
about deconditioning, he undertook a rigorous exercise reconditioning program. He improved clinically, gained weight, regained strength, and had a successful track season (65 seconds for a 400 m race). The midodrine and pyridostigmine were gradually withdrawn during June 2009. Subsequent Holter monitoring identified no pathology, and the pacemaker was explanted in August 2009. The patient’s sudomotor function normalized. He returned to regular school for his senior year of high school, successfully participated in athletic activities, and continued to be a straight ‘‘A’’ student. He reported no further autonomic symptoms during withdrawal from his medications.
Discussion Many autonomic disorders can present in early childhood with feeding problems, altered pain sensation, limited sweat or lacrimal production, and respiratory difficulties. Familial dysautonomia and congenital central hypoventilation syndrome are two such autonomic disorders in children [11]. Dopamine b-hydroxylase deficiency, which results in the absence of epinephrine and norepinephrine, is rare but can present at any age. Postural orthostatic tachycardia syndrome affects up to 1% of adolescents and presents with fatigue, dizziness, nausea, and pain in various body sites [9]. However, isolated sympathetic failure, as seen in the present patient, and autoimmune autonomic ganglionopathy have only very rarely been identified in adolescence. In the present case, the patient was a previously healthy adolescent who developed sympathetic failure as demonstrated by fatigue, orthostatic intolerance, sinus bradycardia, severe sudomotor dysfunction, and altered cardiovascular responses to Valsalva maneuvers. The pres-
ence of norepinephrine in plasma catecholamine measurements excluded dopamine b-hydroxylase deficiency. He had elevated levels of ganglionic acetylcholine receptor antibodies and, as he began to recover some sudomotor function, had more distal than proximal sudomotor dysfunction in a pattern previously reported by Kimpinski et al. [5]. During his treatment with pressor medications, intravenous immunoglobulin, and a conditioning program, both the subjective and objective abnormalities resolved progressively over time (12-18 months). Notably, his autoimmune autonomic ganglionopathy distinctly involved the sympathetic noradrenergic vasomotor and sympathetic cholinergic sudomotor systems without involvement of the parasympathetic cardiovagal system, resulting in a low resting heart rate from unopposed cardiovagal tone. Furthermore, there was no history of a recognized antecedent viral illness, as has been commonly reported in other cases with autoimmune autonomic ganglionopathy [8]. There is broad heterogeneity in presentation of autoimmune autonomic ganglionopathy, and there is some evidence that antibody titers predict symptoms in some affected adults with orthostatic hypotension [12]. The present patient had a very low antibody titer, which raised questions initially about whether to treat with intravenous immunoglobulin. In retrospect, the improvement in his symptoms paralleled the reductions in his antibody titer. Although acetylcholine receptor antibodies seem to be fairly specific [13], some patients without detectable antibodies can also respond to immunomodulation [8]. This finding suggests that other,
Fischer et al: Autoimmune Autonomic Ganglionopathy 289
unidentified antibodies or mechanisms might also be active. In the interim, patients with sudomotor failure and cholinergic symptoms should be considered candidates for antibody testing and possibly for immunomodulating treatments. The present patient improved over time with a variety of treatments. The pacemaker maintained his heart rate in a range adequate to support activities of daily living. Subjectively, he felt the pyridostigmine was very effective, despite the negative chronotropic effects of this drug [14]. The mechanism might relate to an increase in ganglionic synaptic acetylcholine and, subsequently, an increase in sympathetic neurotransmission across antibody-compromised synapses. When intravenous immunoglobulin is incompletely helpful, physicians can consider other immunomodulating treatments, such as plasmapheresis [15] and glucocorticoids [8]. In the present case, deconditioning (as evidenced by exercise intolerance and a maximal oxygen uptake of less than 45 L/min per kilogram in an adolescent boy) compromised the patient’s recovery even when antibody levels were decreasing and autonomic function was improving. Deconditioning is a common comorbid problem with autonomic dysfunction in adolescents, and gradually increasing reconditioning programs can be beneficial [9]. The present patient’s symptoms persisted even beyond the resolution of objective autonomic abnormalities, and it was reconditioning that provided the essential step in getting him back to school and athletic participation. The natural history of autoimmune neuropathies in adolescents remains undetermined. As with adult patients, there may be a spectrum of responses, ranging from a single episode of disease, to a relapsing-remitting course, to the development of chronic manifestations. In summary, this patient demonstrated severe, isolated sympathetic nervous system failure in association with a ganglionic acetylcholine receptor antibody. He improved over 18 months with pharmacologic treatment designed to alter the abnormal ganglionic synaptic transmission (intravenous immunoglobulin and pyridostigmine), increase his vascular tone (midodrine), and improve his cognition (modafinil). Subsequently, the patient benefitted from a rigorous reconditioning program and returned to his baseline state. Adolescents presenting with autoimmune autonomic gan-
290 PEDIATRIC NEUROLOGY Vol. 43 No. 4
glionopathy can benefit from multifaceted therapeutic interventions. References [1] Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000;343:847-55. [2] McKeon A, Lennon VA, Lachance DH, Fealey RD, Pittock SJ. Ganglionic acetylcholine receptor autoantibody: oncological, neurological, and serological accompaniments. Arch Neurol 2009;66:735-41. [3] Sandroni P, Vernino S, Klein CM, Lennon VA, Benrud-Larson L, Sletten D, et al. Idiopathic autonomic neuropathy: comparison of cases seropositive and seronegative for ganglionic acetylcholine receptor antibody. Arch Neurol 2004;61:44-8. [4] Vernino S, Ermilov LG, Sha L, Szurszewski JH, Low PA, Lennon VA. Passive transfer of autoimmune autonomic neuropathy to mice. J Neurosci 2004;24:7037-42. [5] Kimpinski K, Iodice V, Sandroni P, Fealey RD, Vernino S, Low PA. Sudomotor dysfunction in autoimmune autonomic ganglionopathy. Neurology 2009;73:1501-6. [6] Dhamija R, Tan KM, Pittock SJ, Foxx-Orenstein A, Benarroch E, Lennon VA. Serologic profiles aiding the diagnosis of autoimmune gastrointestinal dysmotility. Clin Gastroenterol Hepatol 2008;6:988-92. [7] Klein CM, Vernino S, Lennon VA, Sandroni P, Fealey RD, Benrud-Larson L, et al. The spectrum of autoimmune autonomic neuropathies. Ann Neurol 2003;53:752-8. [8] Iodice V, Kimpinski K, Vernino S, Sandroni P, Low PA. Immunotherapy for autoimmune autonomic ganglionopathy. Auton Neurosci 2009; 146:22-5. [9] Johnson JN, Mack KJ, Kuntz NL, Brands CK, Porter CJ, Fischer PR. Postural orthostatic tachycardia syndrome: a clinical review. Pediatr Neurol 2010;42:77-85. [10] Murali HR, Mack KJ, Kuntz NL. Acquired orthostatic intolerance and alpha-3 ganglionic acetylcholine antibodies in an adolescent girl [Abstract]. Clin Auton Res 2009;19:298. [11] Axelrod FB, Chelimsky GG, Weese-Mayer DE. Pediatric autonomic disorders. Pediatrics 2006;118:309-21. [12] Gibbons CH, Freeman R. Antibody titers predict clinical features of autoimmune autonomic ganglionopathy. Auton Neurosci 2009;146:8-12. [13] Vernino S, Lindstrom J, Hopkins S, Wang Z, Low PA, Muscle Study Group. Characterization of ganglionic acetylcholine receptor autoantibodies. J Neuroimmunol 2008;197:63-9. [14] Raj SR, Black BK, Biaggioni I, Harris PA, Robertson D. Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome. Circulation 2005;111:2734-40. [15] Schroeder C, Vernino S, Birkenfeld AL, Tank J, Heusser K, Lipp A, et al. Plasma exchange for primary autoimmune autonomic failure. N Engl J Med 2005;353:1585-90.
From the *Division of General Pediatric and Adolescent Medicine, † Department of Neurology, and ‡Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota; the §Division of Pediatric Neurology, Nationwide Children’s Hospital, Columbus, Ohio; and the Departments of k Medicine and #Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Ó 2010 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2010.05.003 0887-8994/$—see front matter
Fischer PR, Sandroni P, Pittock SJ, Porter CJ, Lehwald LM, Raj SR. Isolated sympathetic failure with autoimmune autonomic ganglionopathy. Pediatr Neurol 2010;43:287-290.
Introduction In adults, antibodies against the nicotinic ganglionic acetylcholine receptor have been associated with subacute autonomic failure [1,2]. Specifically, orthostatic hypotension and prominent cholinergic symptoms are pathophysiologically linked to the presence of these loss-of-function antibodies [3]. The autonomic ganglia are integral for normal functioning of both the sympathetic and parasympathetic nervous system, and both limbs of the autonomic nervous system are often affected in autoimmune autonomic ganglionopathy. Animal models confirm the role of acetylcholine receptor antibodies, reproducing the cardinal features of human autoimmune autonomic neuropathy including gastrointestinal dysmotility, urinary retention, and pupillary dilatation [4]. Human nicotinic ganglionic acetylcholine receptor antibodies have been linked to many features of autonomic impairment, including sudomotor dysfunction [5] and gastrointestinal dysmotility [6], but there can be a broad spectrum of autonomic findings that do not always follow a specific pattern [7]. Immunomodulating therapy can be helpful for some adult patients with autoimmune autonomic ganglionopathy [8], although the available data indicate that the response may be inconsistent. Ganglionic acetylcholine receptor antibodies have not been well studied in adolescents with autonomic dysfunction [9] and are not often identified in this population. There is an isolated report of ganglionic acetylcholine receptor antibodies in an adolescent linked to subacute onset of headache and severe postural dizziness with orthostatic hypotension and tachycardia [10]. After treatment with intravenous immunoglobulin, that patient experienced marked symptomatic improvement, with resolution of objective findings of autonomic dysfunction. Reported here is the case of a teenage boy with an acute to subacute onset of severe isolated sympathetic nervous system failure associated with ganglionic acetylcholine
Communications should be addressed to: Dr. Fischer; Department of Pediatric and Adolescent Medicine; Mayo Clinic; 200 First Street SW; Rochester, MN 55905. E-mail: [email protected] Received February 12, 2010; accepted May 3, 2010.
Fischer et al: Autoimmune Autonomic Ganglionopathy 287
receptor antibodies and his subsequent recovery under multimodal treatments. Case Report Over 3 weeks in January 2008, a previously healthy 16-year-old highschool track athlete had a gradual onset of myalgia after running. He felt progressively tired and had a sense of ‘‘becoming slower and weaker.’’ He experienced excessive thirst, salt craving, weight loss, and cold intolerance. The onset of symptoms was not preceded by any illness or immunization. There was no associated fever, and there were no specific respiratory or gastrointestinal symptoms. He became progressively dizzy and was hospitalized. He had sinus bradycardia (37 beats per minute), an unremarkable echocardiogram, and low baseline sympathetic tone, as suggested by his low supine norepinephrine level (56 pg/mL; normal, >100 pg/mL) but a normal humoral response to standing (norepinephrine at 311 pg/mL). Autonomic testing revealed an abnormal Valsalva maneuver with an absent sympathetically mediated vasoconstrictor response in both late phase II and phase IV (Fig 1). He had a blunted response to cold pressor test, with an increase in systolic blood pressure of only 13 mmHg (normal 20-35 mmHg). Quantitative sweat testing was markedly reduced at all sites, suggesting severe postganglionic sympathetic sudomotor impairment.
Pharmacologic testing with atropine (to remove cardiovagal tone) increased his heart rate from 37 beats per minute to 100 beats per minute, suggesting intact or even vigorous parasympathetic cardiovagal tone. A cardiac metaiodobenzylguanidine scan indicated normal uptake (suggesting normal cardiac sympathetic nerve integrity). A Bruce protocol exercise test excluded chronotropic incompetence (peak heart rate, 160 beats per minute), with an appropriate blood pressure response and moderate exercise tolerance (12 minutes), although this was low for a track athlete. Ganglionic acetylcholine receptor antibodies were identified in a low titer (Fig 2), and the patient received intravenous immunoglobulin monthly in April, May, and June 2008, along with symptomatic treatment with pyridostigmine, midodrine, and modafinil to address his cognitive complaints. Because persistent symptomatic bradycardia caused lightheadedness and activity intolerance, a permanent dual-chamber pacemaker was implanted in July 2008. With the pacemaker, the patient experienced a modest improvement in energy and activity tolerance. Because of what he called ‘‘brain fog,’’ with memory and concentration problems, and presyncope on standing, he could no longer attend school and required home schooling. He felt cold ‘‘all the time’’ and sensed that he was not sweating as much as he did prior to his illness. He lost 9 kg over 9 months, due primarily to a reduced appetite. The patient had progressively decreasing antibody levels and progressive improvements in sudomotor function (Fig 2). Because of concerns
Figure 1. Improvement in Valsalva maneuver results over time. Active Valsalva maneuver is indicated in white at the bottom of each panel. September 2008 (top): Abnormal (unchanging) heart rate response to Valsalva maneuver, lack of late phase II elevation in blood pressure (wide arrow), lack of post-Valsalva phase IV blood pressure elevation (narrow arrow). June 2009 (bottom): Normal (increasing) heart rate response to Valsalva maneuver, lack of late phase II elevation in blood pressure (wide arrow), and more robust post-Valsalva phase IV blood pressure elevation (narrow arrow).
288 PEDIATRIC NEUROLOGY Vol. 43 No. 4
Figure 2. Time course of treatments and autonomic findings.
about deconditioning, he undertook a rigorous exercise reconditioning program. He improved clinically, gained weight, regained strength, and had a successful track season (65 seconds for a 400 m race). The midodrine and pyridostigmine were gradually withdrawn during June 2009. Subsequent Holter monitoring identified no pathology, and the pacemaker was explanted in August 2009. The patient’s sudomotor function normalized. He returned to regular school for his senior year of high school, successfully participated in athletic activities, and continued to be a straight ‘‘A’’ student. He reported no further autonomic symptoms during withdrawal from his medications.
Discussion Many autonomic disorders can present in early childhood with feeding problems, altered pain sensation, limited sweat or lacrimal production, and respiratory difficulties. Familial dysautonomia and congenital central hypoventilation syndrome are two such autonomic disorders in children [11]. Dopamine b-hydroxylase deficiency, which results in the absence of epinephrine and norepinephrine, is rare but can present at any age. Postural orthostatic tachycardia syndrome affects up to 1% of adolescents and presents with fatigue, dizziness, nausea, and pain in various body sites [9]. However, isolated sympathetic failure, as seen in the present patient, and autoimmune autonomic ganglionopathy have only very rarely been identified in adolescence. In the present case, the patient was a previously healthy adolescent who developed sympathetic failure as demonstrated by fatigue, orthostatic intolerance, sinus bradycardia, severe sudomotor dysfunction, and altered cardiovascular responses to Valsalva maneuvers. The pres-
ence of norepinephrine in plasma catecholamine measurements excluded dopamine b-hydroxylase deficiency. He had elevated levels of ganglionic acetylcholine receptor antibodies and, as he began to recover some sudomotor function, had more distal than proximal sudomotor dysfunction in a pattern previously reported by Kimpinski et al. [5]. During his treatment with pressor medications, intravenous immunoglobulin, and a conditioning program, both the subjective and objective abnormalities resolved progressively over time (12-18 months). Notably, his autoimmune autonomic ganglionopathy distinctly involved the sympathetic noradrenergic vasomotor and sympathetic cholinergic sudomotor systems without involvement of the parasympathetic cardiovagal system, resulting in a low resting heart rate from unopposed cardiovagal tone. Furthermore, there was no history of a recognized antecedent viral illness, as has been commonly reported in other cases with autoimmune autonomic ganglionopathy [8]. There is broad heterogeneity in presentation of autoimmune autonomic ganglionopathy, and there is some evidence that antibody titers predict symptoms in some affected adults with orthostatic hypotension [12]. The present patient had a very low antibody titer, which raised questions initially about whether to treat with intravenous immunoglobulin. In retrospect, the improvement in his symptoms paralleled the reductions in his antibody titer. Although acetylcholine receptor antibodies seem to be fairly specific [13], some patients without detectable antibodies can also respond to immunomodulation [8]. This finding suggests that other,
Fischer et al: Autoimmune Autonomic Ganglionopathy 289
unidentified antibodies or mechanisms might also be active. In the interim, patients with sudomotor failure and cholinergic symptoms should be considered candidates for antibody testing and possibly for immunomodulating treatments. The present patient improved over time with a variety of treatments. The pacemaker maintained his heart rate in a range adequate to support activities of daily living. Subjectively, he felt the pyridostigmine was very effective, despite the negative chronotropic effects of this drug [14]. The mechanism might relate to an increase in ganglionic synaptic acetylcholine and, subsequently, an increase in sympathetic neurotransmission across antibody-compromised synapses. When intravenous immunoglobulin is incompletely helpful, physicians can consider other immunomodulating treatments, such as plasmapheresis [15] and glucocorticoids [8]. In the present case, deconditioning (as evidenced by exercise intolerance and a maximal oxygen uptake of less than 45 L/min per kilogram in an adolescent boy) compromised the patient’s recovery even when antibody levels were decreasing and autonomic function was improving. Deconditioning is a common comorbid problem with autonomic dysfunction in adolescents, and gradually increasing reconditioning programs can be beneficial [9]. The present patient’s symptoms persisted even beyond the resolution of objective autonomic abnormalities, and it was reconditioning that provided the essential step in getting him back to school and athletic participation. The natural history of autoimmune neuropathies in adolescents remains undetermined. As with adult patients, there may be a spectrum of responses, ranging from a single episode of disease, to a relapsing-remitting course, to the development of chronic manifestations. In summary, this patient demonstrated severe, isolated sympathetic nervous system failure in association with a ganglionic acetylcholine receptor antibody. He improved over 18 months with pharmacologic treatment designed to alter the abnormal ganglionic synaptic transmission (intravenous immunoglobulin and pyridostigmine), increase his vascular tone (midodrine), and improve his cognition (modafinil). Subsequently, the patient benefitted from a rigorous reconditioning program and returned to his baseline state. Adolescents presenting with autoimmune autonomic gan-
290 PEDIATRIC NEUROLOGY Vol. 43 No. 4
glionopathy can benefit from multifaceted therapeutic interventions. References [1] Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000;343:847-55. [2] McKeon A, Lennon VA, Lachance DH, Fealey RD, Pittock SJ. Ganglionic acetylcholine receptor autoantibody: oncological, neurological, and serological accompaniments. Arch Neurol 2009;66:735-41. [3] Sandroni P, Vernino S, Klein CM, Lennon VA, Benrud-Larson L, Sletten D, et al. Idiopathic autonomic neuropathy: comparison of cases seropositive and seronegative for ganglionic acetylcholine receptor antibody. Arch Neurol 2004;61:44-8. [4] Vernino S, Ermilov LG, Sha L, Szurszewski JH, Low PA, Lennon VA. Passive transfer of autoimmune autonomic neuropathy to mice. J Neurosci 2004;24:7037-42. [5] Kimpinski K, Iodice V, Sandroni P, Fealey RD, Vernino S, Low PA. Sudomotor dysfunction in autoimmune autonomic ganglionopathy. Neurology 2009;73:1501-6. [6] Dhamija R, Tan KM, Pittock SJ, Foxx-Orenstein A, Benarroch E, Lennon VA. Serologic profiles aiding the diagnosis of autoimmune gastrointestinal dysmotility. Clin Gastroenterol Hepatol 2008;6:988-92. [7] Klein CM, Vernino S, Lennon VA, Sandroni P, Fealey RD, Benrud-Larson L, et al. The spectrum of autoimmune autonomic neuropathies. Ann Neurol 2003;53:752-8. [8] Iodice V, Kimpinski K, Vernino S, Sandroni P, Low PA. Immunotherapy for autoimmune autonomic ganglionopathy. Auton Neurosci 2009; 146:22-5. [9] Johnson JN, Mack KJ, Kuntz NL, Brands CK, Porter CJ, Fischer PR. Postural orthostatic tachycardia syndrome: a clinical review. Pediatr Neurol 2010;42:77-85. [10] Murali HR, Mack KJ, Kuntz NL. Acquired orthostatic intolerance and alpha-3 ganglionic acetylcholine antibodies in an adolescent girl [Abstract]. Clin Auton Res 2009;19:298. [11] Axelrod FB, Chelimsky GG, Weese-Mayer DE. Pediatric autonomic disorders. Pediatrics 2006;118:309-21. [12] Gibbons CH, Freeman R. Antibody titers predict clinical features of autoimmune autonomic ganglionopathy. Auton Neurosci 2009;146:8-12. [13] Vernino S, Lindstrom J, Hopkins S, Wang Z, Low PA, Muscle Study Group. Characterization of ganglionic acetylcholine receptor autoantibodies. J Neuroimmunol 2008;197:63-9. [14] Raj SR, Black BK, Biaggioni I, Harris PA, Robertson D. Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome. Circulation 2005;111:2734-40. [15] Schroeder C, Vernino S, Birkenfeld AL, Tank J, Heusser K, Lipp A, et al. Plasma exchange for primary autoimmune autonomic failure. N Engl J Med 2005;353:1585-90.