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S3.2 Clinical syndromes of autoimmune autonomic ganglionopathy
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Abstracts / Autonomic Neuroscience: Basic and Clinical 149 (2009) 1–126
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. Several clinical and experimental observations indicate that AAG is an antibody-mediated disorder. (1) About 50% of AAG patients have high levels of serum antibodies specific for the neuronal AChR in autonomic ganglia. This ganglionic (α3-type) AChR is required for 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. Patients with low antibody levels may have mild or restricted autonomic deficits or postural tachycardia syndrome. (3) Removal of antibodies using plasmapheresis may result in dramatic clinical improvement. (4) Induction of ganglionic AChR antibodies in rabbits by immunization leads to experimental AAG which reproduces many of the cardinal features of the human disease. Experimental AAG is associated with impaired ganglionic synaptic transmission, loss of synaptic AChR in sympathetic and enteric ganglia, and preservation of ganglionic architecture. (5) Passive transfer of ganglionic AChR antibodies to mice 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 due to a reduction in the amplitude of the cholinergic excitatory postsynaptic potentials. AAG is an antibody-mediated channelopathy that produces a severe, but potentially treatable, form of autonomic failure. It is important to recognize AAG and differentiate this disorder for degenerative forms of autonomic failure and from other forms of peripheral autonomic neuropathy. doi:10.1016/j.autneu.2009.05.016
S3.2 Clinical syndromes of autoimmune autonomic ganglionopathy P.A. Low (Department of Neurology, Mayo Clinic, Rochester, MN, USA), P. Sandroni (Department of Neurology, Mayo Clinic, Rochester, MN, USA), S. Vernino (Department of Neurology, UT Southwestern Medical Center, Dallas, TX, USA) Autoimmune autonomic ganglionopathy (AAG) is an autoimmune autonomic neuropathy where the brunt of the disorder is on autonomic ganglion. There are a number of phenotypes of autonomic neuropathies associated with alpha3 (or α3) AChR antibody (ganglionic AChR antibody). The best recognized entities are: 1. AAG; 2. Pure autonomic failure (PAF); 3. Postural tachycardia syndrome (POTS); 4. Chronic idiopathic anhidrosis (CIA); 5. Gastrointestinal dysmotility syndromes; 6. distal small fiber neuropathy (DSFN); and 7. Other isolated autonomic neuropathies. AAG has the strongest association with high levels of ganglionic AChR antibody. AAG is characterized by generalized autonomic failure that typically includes orthostatic hypotension (OH), cholinergic failure with Adies pupils, widespread anhidrosis, bowel and bladder involvement and erectile dysfunction. The severity of autonomic failure regresses with ganglionic antibody levels. PAF is manifested as severe sympathetic adrenergic and sudomotor failure with more restricted parasympathetic involvement. The disorder is typically of insidious onset and progresses over the years. POTS is associated with ganglionic antibody in low titers in a minority of cases. The disorder is characterized by orthostatic intolerance and tachycardia with mild distal denervation in some cases. CIA is manifested as severe sudomotor failure and heat intolerance. Some cases have an autoimmune attack on eccrine sweat glands. Some cases of AAG are
manifested as isolated gastrointestinal dysmotility. Phenotypes include upper or lower gastrointestinal involvement. DSFN is manifested as distal sudomotor and vasomotor denervation. Some cases have associated somatic C fiber involvement. Ganglionic antibody is elevated in high levels in AAG and at low levels and lower frequency with these other syndromes. In general the natural history and response to immunotherapy is better in cases associated with high antibody titers and acute/subacute onset. The case for an etiopathogenetic role of antibody is strong for AAG and weaker for the other phenotypes. [1] Sandroni P, Low PA. Other autonomic neuropathies associated with ganglionic antibody. Auton Neurosci, in pressIodice. [2] V, Kimpinski K, Vernino S, Sandroni P, Fealey RD, Low PA. Efficacy of immunotherapy in autonomic autoimmune ganglionopathy. Neurology, in press. doi:10.1016/j.autneu.2009.05.017
S3.3 Treatment of autoimmune autonomic ganglionopathy R. Freeman (Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA) Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to autonomic failure. Patients present with recurrent syncope, orthostatic hypotension, bowel and bladder hypomotility, pupillary dysfunction, dry mouth and dry eyes (sicca syndrome). Some cases have rapid onset, while others present with a more indolent course that may mimic a neurodegenerative process. The symptoms of autoimmune autonomic ganglionopathy may be progressive, debilitating and substantially impair quality of life. Symptomatic therapies produce an incomplete response in many patients. For patients refractory to symptomatic treatment immunomodulatory therapy is required. The neuronal nicotinic acetylcholine receptor (AChR) of the autonomic ganglion mediates fast synaptic transmission in all peripheral autonomic ganglia. Several lines of evidence suggest that antibodies to the AChR mediate the autonomic features of the disorder: A body of evidence in recent years has identified B cells as a key factor in the pathogenesis of many autoimmune neurologic diseases. B cells contribute to the pathogenesis of immune mediated neurological disease through multiple mechanisms that include antibody production, complement activation and antibody-dependent cell mediated cytotoxicity; antigen presentation leading to clonal expansion of cytotoxic T cells; and by cytokine production, which activate and/or alter macrophages and T cell function. B-cells and autoantibodies have been implicated in diseases that encompass the entire neuraxis. Further, there is evidence from randomized controlled trials that immune modulation is efficacious in other autoimmune peripheral neuropathies and neuromuscular junction disorders. These data provide the rationale for the use of immune modulation to modify the natural history of AAG. Observational studies using IVIG, plasma exchange, mycophenolate, prednisone, azathioprine, and rituximab alone or in combination in treatment of AAG support this approach. To date, there are no randomized, placebocontrolled trials using immune modulation therapy in AAG. doi:10.1016/j.autneu.2009.05.018
S3.4 Impaired corpus cavernosum responses to cavernous nerve stimulation in diabetic rats: Effects of treatment with erythropoietin-delta N.E. Cameron, M.A. Cotter (School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland UK)
Abstracts / Autonomic Neuroscience: Basic and Clinical 149 (2009) 1–126
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. Several clinical and experimental observations indicate that AAG is an antibody-mediated disorder. (1) About 50% of AAG patients have high levels of serum antibodies specific for the neuronal AChR in autonomic ganglia. This ganglionic (α3-type) AChR is required for 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. Patients with low antibody levels may have mild or restricted autonomic deficits or postural tachycardia syndrome. (3) Removal of antibodies using plasmapheresis may result in dramatic clinical improvement. (4) Induction of ganglionic AChR antibodies in rabbits by immunization leads to experimental AAG which reproduces many of the cardinal features of the human disease. Experimental AAG is associated with impaired ganglionic synaptic transmission, loss of synaptic AChR in sympathetic and enteric ganglia, and preservation of ganglionic architecture. (5) Passive transfer of ganglionic AChR antibodies to mice 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 due to a reduction in the amplitude of the cholinergic excitatory postsynaptic potentials. AAG is an antibody-mediated channelopathy that produces a severe, but potentially treatable, form of autonomic failure. It is important to recognize AAG and differentiate this disorder for degenerative forms of autonomic failure and from other forms of peripheral autonomic neuropathy. doi:10.1016/j.autneu.2009.05.016
S3.2 Clinical syndromes of autoimmune autonomic ganglionopathy P.A. Low (Department of Neurology, Mayo Clinic, Rochester, MN, USA), P. Sandroni (Department of Neurology, Mayo Clinic, Rochester, MN, USA), S. Vernino (Department of Neurology, UT Southwestern Medical Center, Dallas, TX, USA) Autoimmune autonomic ganglionopathy (AAG) is an autoimmune autonomic neuropathy where the brunt of the disorder is on autonomic ganglion. There are a number of phenotypes of autonomic neuropathies associated with alpha3 (or α3) AChR antibody (ganglionic AChR antibody). The best recognized entities are: 1. AAG; 2. Pure autonomic failure (PAF); 3. Postural tachycardia syndrome (POTS); 4. Chronic idiopathic anhidrosis (CIA); 5. Gastrointestinal dysmotility syndromes; 6. distal small fiber neuropathy (DSFN); and 7. Other isolated autonomic neuropathies. AAG has the strongest association with high levels of ganglionic AChR antibody. AAG is characterized by generalized autonomic failure that typically includes orthostatic hypotension (OH), cholinergic failure with Adies pupils, widespread anhidrosis, bowel and bladder involvement and erectile dysfunction. The severity of autonomic failure regresses with ganglionic antibody levels. PAF is manifested as severe sympathetic adrenergic and sudomotor failure with more restricted parasympathetic involvement. The disorder is typically of insidious onset and progresses over the years. POTS is associated with ganglionic antibody in low titers in a minority of cases. The disorder is characterized by orthostatic intolerance and tachycardia with mild distal denervation in some cases. CIA is manifested as severe sudomotor failure and heat intolerance. Some cases have an autoimmune attack on eccrine sweat glands. Some cases of AAG are
manifested as isolated gastrointestinal dysmotility. Phenotypes include upper or lower gastrointestinal involvement. DSFN is manifested as distal sudomotor and vasomotor denervation. Some cases have associated somatic C fiber involvement. Ganglionic antibody is elevated in high levels in AAG and at low levels and lower frequency with these other syndromes. In general the natural history and response to immunotherapy is better in cases associated with high antibody titers and acute/subacute onset. The case for an etiopathogenetic role of antibody is strong for AAG and weaker for the other phenotypes. [1] Sandroni P, Low PA. Other autonomic neuropathies associated with ganglionic antibody. Auton Neurosci, in pressIodice. [2] V, Kimpinski K, Vernino S, Sandroni P, Fealey RD, Low PA. Efficacy of immunotherapy in autonomic autoimmune ganglionopathy. Neurology, in press. doi:10.1016/j.autneu.2009.05.017
S3.3 Treatment of autoimmune autonomic ganglionopathy R. Freeman (Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA) Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to autonomic failure. Patients present with recurrent syncope, orthostatic hypotension, bowel and bladder hypomotility, pupillary dysfunction, dry mouth and dry eyes (sicca syndrome). Some cases have rapid onset, while others present with a more indolent course that may mimic a neurodegenerative process. The symptoms of autoimmune autonomic ganglionopathy may be progressive, debilitating and substantially impair quality of life. Symptomatic therapies produce an incomplete response in many patients. For patients refractory to symptomatic treatment immunomodulatory therapy is required. The neuronal nicotinic acetylcholine receptor (AChR) of the autonomic ganglion mediates fast synaptic transmission in all peripheral autonomic ganglia. Several lines of evidence suggest that antibodies to the AChR mediate the autonomic features of the disorder: A body of evidence in recent years has identified B cells as a key factor in the pathogenesis of many autoimmune neurologic diseases. B cells contribute to the pathogenesis of immune mediated neurological disease through multiple mechanisms that include antibody production, complement activation and antibody-dependent cell mediated cytotoxicity; antigen presentation leading to clonal expansion of cytotoxic T cells; and by cytokine production, which activate and/or alter macrophages and T cell function. B-cells and autoantibodies have been implicated in diseases that encompass the entire neuraxis. Further, there is evidence from randomized controlled trials that immune modulation is efficacious in other autoimmune peripheral neuropathies and neuromuscular junction disorders. These data provide the rationale for the use of immune modulation to modify the natural history of AAG. Observational studies using IVIG, plasma exchange, mycophenolate, prednisone, azathioprine, and rituximab alone or in combination in treatment of AAG support this approach. To date, there are no randomized, placebocontrolled trials using immune modulation therapy in AAG. doi:10.1016/j.autneu.2009.05.018
S3.4 Impaired corpus cavernosum responses to cavernous nerve stimulation in diabetic rats: Effects of treatment with erythropoietin-delta N.E. Cameron, M.A. Cotter (School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland UK)