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A case of seropositive autoimmune autonomic ganglionopathy with diffuse esophageal spasm
Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Case report
A case of seropositive autoimmune autonomic ganglionopathy with diffuse esophageal spasm Nobutoshi Morimoto a,⇑, Sakuma Takahashi b, Tomoki Inaba b, Motonori Takamiya a, Yasuhiko Kageyama a, Mizuki Morimoto a, Yoshiaki Takahashi a,e, Hirotake Nishimura c, Shunya Nakane d, Koji Abe e a
Department of Neurology, Kagawa Prefectural Central Hospital, Japan Department of Gastroenterology, Kagawa Prefectural Central Hospital, Japan Department of Pathology, Kawasaki Medical School, Japan d Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan e Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama University, Japan b c
a r t i c l e
i n f o
Article history: Received 16 November 2016 Accepted 22 January 2017 Available online xxxx Keywords: Autoimmune autonomic ganglionopathy (AAG) Diffuse esophageal spasm (DES) Anti-ganglionic acetylcholine receptor a3 antibody Intravenous immunoglobulin therapy (IVIg)
a b s t r a c t Autoimmune autonomic ganglionopathy (AAG) is an immune-mediated disorder that leads to various autonomic failures associated with anti-ganglionic acetylcholine receptor antibodies (anti-gAChR-Abs). Diffuse esophageal spasm (DES) is an uncommon esophageal motility disorder. We herein report the case of a 68-year-old woman with DES as a partial symptom of AAG. She presented with chronic esophageal transit failure, constipation, and numbness of the hands and feet, Adie’s pupil, thermal hypoalgesia, and decreased deep tendon reflexes. Right sural nerve biopsy showed significantly decreased numbers of small myelinated fibers. Barium swallowing X-ray showed repetitive simultaneous contractions indicating DES in the esophagus. Gastrointestinal endoscopy and CT image showed a dilated esophageal lumen and liquid effusion. Simultaneously, serum anti-gAChR-a3-Ab indicating AAG was detected. After pulse intravenous methylprednisolone (IVMP) and intravenous immunoglobulin therapy (IVIg), the bolus progression and liquid effusion improved, suggesting that DES is an important gastrointestinal symptom of AAG. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Autoimmune autonomic ganglionopathy (AAG) is an immunemediated disorder that leads to various autonomic failures and gastrointestinal dysmotilities including achalasia [1–3]. The disorder is associated with anti-ganglionic acetylcholine receptor antibodies (anti-gAChR-Abs) [2]. Diffuse esophageal spasm (DES) is an uncommon esophageal motility disorder characterized by uncoordinated, simultaneous contractions [4]. We here report a female patient with chronic esophageal transit failure as DES under diagnosis of AAG. 2. Case report A 40-year-old woman experienced numbness in the distal part of her right hand. At 42 years of age, she experienced photophobia in her left eye. At 55 years of age, she experienced the sensation ⇑ Corresponding author at: Department of Neurology, Kagawa Prefectural Central Hospital, 1-2-1 Asahimachi, Takamatsu 760-8557, Japan. E-mail address: [email protected] (N. Morimoto).
that food and liquid clogged her esophagus. The symptoms gradually progressed, and at was 68 years of age, she experienced frequent food and liquid clogging on her esophagus, and therefore she was admitted to our hospital. She had a past history of left ovarian cystectomy at 67 years, with no similar diseases in her family. Upon admission to our hospital, her consciousness was alert, pupils were round but anisocoric (right 2 mm/left 4 mm). Light reflex was sluggish in her left eye. There were no other cranial nerve deficits or muscle weakness. Deep tendon reflexes were decreased in bilateral upper extremities, and absent in bilateral lower extremities. Dysesthesia and thermal hypoalgesia in bilateral hands and feet were observed. Constipation and chronic esophageal transit failure were detected. Barium swallowing X-ray showed poor progression of a bolus with repetitive simultaneous contractions (Fig. 1a, dots) and contractions of prolonged duration (Fig. 1a, arrowheads) in the esophagus. Chest CT image (Fig. 1b, arrowheads) and gastrointestinal endoscopy (Fig. 1c) showed expansion of the esophageal lumen and liquid effusion. The 0.125% pilocarpine test showed significant contraction in the left pupil, with reduced size from 4.5 to 2 mm
http://dx.doi.org/10.1016/j.jocn.2017.01.027 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Morimoto N et al. A case of seropositive autoimmune autonomic ganglionopathy with diffuse esophageal spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.01.027
2
Case report / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Fig. 1. (a) Barium swallowing X-rays show repetitive simultaneous contractions (dots) and contractions of prolonged duration (arrowheads) in the esophagus. (b) Chest CT image shows expanded esophageal lumen and liquid effusion (arrowheads). (c) Gastrointestinal endoscopy shows expanded esophageal lumen and liquid effusion. (d) Infrared light imaging shows before instillation, 60 min after instillation of 0.1% pilocarpine, 90 min after 5.0% cocaine, and 45 min after 5.0% tyramine, sequentially. A significant contraction was observed by pilocarpine in the left pupil from 4.5 to 2 mm, indicating Adie’s pupil. (e) Micrographs show a transverse section of the right sural nerve stained with p-phenylenediamine to visualize myelin. The number of small myelinated fibers is significantly lost, whereas large myelinated fibers are comparatively preserved. Scale bar = 100 lm. (f) Cardiac scintigraphy with 123I-metaiodobenzylguanidine (MIBG), the heart-to-mediastinum uptake ratio (H/M) was decreased in the delayed phase (H/M = 1.90). (g) Compared to the pre-treatment (a), barium swallowing X-ray shows improvement of barium flow after treatment (g), although expansion of esophageal lumen remained unchanged. (h) Compared to the pre-treatment (b), Chest-CT shows disappearance of liquid effusion after the treatment (h).
after 60 min (Fig. 1d), indicating Adie’s pupil. Nerve conduction study showed insufficiently evoked sensory nerve action potentials (SNAP) in median and sural nerves, with well-preserved compound muscle action potentials (CMAP) and conduction velocities (CV) in median and tibial nerves. Right sural nerve biopsy was performed and showed significantly decreased numbers of small myelinated fibers (Fig. 1e). In the Schellong test, blood pressure (BP) fell from 135/84 mmHg at supine to 117/85 mmHg at standing. Cardiac scintigraphy using 123I-metaiodobenzylguanidine (MIBG) revealed a MIBG heart-to-mediastinum uptake ratio (H/M) that was slightly decreased (H/M = 1.90) (Fig. 1f). There were no particular abnormalities in a complete blood cell count, common serum biochemistry, and cerebrospinal fluid, except that serum anti-gAChRa3-Ab was detected by luciferase immunoprecipitation systems (LIPS) assay [3]. Based on chronic autonomic sensory neuropathy and serum anti-gAChRa3-Ab positivity, the patient was diagnosed with AAG. She received both pulse intravenous methylprednisolone (IVMP) and intravenous immunoglobulin therapy (IVIg), with improved bolus progression and liquid effusion, although expansion of the esophageal lumen remained unchanged (Fig. 1g and h).
3. Discussion Serum anti-gAChR-Abs are found 50% of the AAG patients, correlate with disease severity, and are pathogenic [1,2]. Furthermore, anti-gAChRa3-Ab directly causes autonomic dysfunction in immunized rabbits [5]. In the present case, serum anti-AChRa3-Ab was confirmed as the cause of AAG. DES is a one of the esophageal motility disorders which includes achalasia. In achalasia, the lower esophageal sphincter (LES) typically fails to relax. In contrast, DES is characterized by abnormal esophageal contractions [4]. It is suggested that different types of autonomic fibers are affected by each of them, because the relaxation of the esophagus smooth muscle is mainly controlled by sympathetic nerve, and the contraction by parasympathetic nerve. The present case could be diagnosed as DES based on barium swallowing X-ray resultings showing repetitive simultaneous esophageal contractions, but not achalasia which was previously reported [3]. The clinical characteristics of seropositive-AAG are summarized in Table 1. Gastrointestinal tract symptoms are found in 83–91.7% of seropositive AAG patients [1,3]. Notably, 3 achalasia cases were
Please cite this article in press as: Morimoto N et al. A case of seropositive autoimmune autonomic ganglionopathy with diffuse esophageal spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.01.027
3
Case report / Journal of Clinical Neuroscience xxx (2017) xxx–xxx Table 1 Clinical features of patients with seropositive-AAG.
Orthostatic hypotension/orthostatic intolerance Anhidrosis / heat intolerance Pupil abnormality Sicca complex Attacks of coughing Gastrointestinal tract symptoms Bladder dysfunction Sensory disturbance
Nakane et. Al [3] (Japan 2015) n = 24
Klein et. Al [1] (USA 2003) N = 18
Present case
20 (83.3%) 15 (62.5%) 11 (45.8%) 14 (58.3%) 4 (16.7%) 22 (91.7%), (Achalasia n = 3) 16 (66.7%) 6 (25.0%)
8 (44%) 8 (44%) 11 (61%) 12 (66%) Not mentioned 15 (83%) 9 (50%) Not mentioned
(±) faintness ( ) Adie’s pupil ( ) (+) Diffuse esophageal spasm (DES), constipation ( ) Thermal hypoalgesia
contained in a previous report. Because both sympathetic and parasympathetic ganglia utilize nicotinic cholinergic synapses expressing gAChRs, anti-gAChR-Abs that interfere with ganglionic transmission could cause not only achalasia but also DES [3]. Several recent studies suggest that IVIg, IVMP, or plasma exchange (PE) and immunosuppressant agents are effective for AAG treatment [3,6]. In the present case, both IVMP and IVIg combined therapies were performed, and a clinical effect was observed on DES. These findings suggest that DES may be an important gastrointestinal symptom of AAG as well as achalasia. Sources of support There are no financial relationships to disclose.
References [1] Klein CM, Vernino S, Lennon VA, et al. The spectrum of autoimmune autonomic neuropathies. Ann Neurol 2003;53:752–8. [2] Vernino S, Low PA, Fealey RD, et al. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000;343:847–55. [3] Nakane S, Higuchi O, Koga M, et al. Clinical features of autoimmune autonomic ganglionopathy and the detection of subunit-specific autoantibodies to the ganglionic acetylcholine receptor in Japanese patients. PLoS One 2015;10: e0118312. [4] Richter JE, Castell DO. Diffuse esophageal spasm: a reappraisal. Ann Int Med 1984;100:242–5. [5] Vernino S, Low PA, Lennon VA. Experimental autoimmune autonomic neuropathy. J Neurophysiol 2003;90:2053–9. [6] Iodice V, Kimpinski K, Vernino S, et al. Immunotherapy for autoimmune autonomic ganglionopathy. Auton Neurosci 2009;146:22–5.
Please cite this article in press as: Morimoto N et al. A case of seropositive autoimmune autonomic ganglionopathy with diffuse esophageal spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.01.027
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Case report
A case of seropositive autoimmune autonomic ganglionopathy with diffuse esophageal spasm Nobutoshi Morimoto a,⇑, Sakuma Takahashi b, Tomoki Inaba b, Motonori Takamiya a, Yasuhiko Kageyama a, Mizuki Morimoto a, Yoshiaki Takahashi a,e, Hirotake Nishimura c, Shunya Nakane d, Koji Abe e a
Department of Neurology, Kagawa Prefectural Central Hospital, Japan Department of Gastroenterology, Kagawa Prefectural Central Hospital, Japan Department of Pathology, Kawasaki Medical School, Japan d Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan e Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama University, Japan b c
a r t i c l e
i n f o
Article history: Received 16 November 2016 Accepted 22 January 2017 Available online xxxx Keywords: Autoimmune autonomic ganglionopathy (AAG) Diffuse esophageal spasm (DES) Anti-ganglionic acetylcholine receptor a3 antibody Intravenous immunoglobulin therapy (IVIg)
a b s t r a c t Autoimmune autonomic ganglionopathy (AAG) is an immune-mediated disorder that leads to various autonomic failures associated with anti-ganglionic acetylcholine receptor antibodies (anti-gAChR-Abs). Diffuse esophageal spasm (DES) is an uncommon esophageal motility disorder. We herein report the case of a 68-year-old woman with DES as a partial symptom of AAG. She presented with chronic esophageal transit failure, constipation, and numbness of the hands and feet, Adie’s pupil, thermal hypoalgesia, and decreased deep tendon reflexes. Right sural nerve biopsy showed significantly decreased numbers of small myelinated fibers. Barium swallowing X-ray showed repetitive simultaneous contractions indicating DES in the esophagus. Gastrointestinal endoscopy and CT image showed a dilated esophageal lumen and liquid effusion. Simultaneously, serum anti-gAChR-a3-Ab indicating AAG was detected. After pulse intravenous methylprednisolone (IVMP) and intravenous immunoglobulin therapy (IVIg), the bolus progression and liquid effusion improved, suggesting that DES is an important gastrointestinal symptom of AAG. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Autoimmune autonomic ganglionopathy (AAG) is an immunemediated disorder that leads to various autonomic failures and gastrointestinal dysmotilities including achalasia [1–3]. The disorder is associated with anti-ganglionic acetylcholine receptor antibodies (anti-gAChR-Abs) [2]. Diffuse esophageal spasm (DES) is an uncommon esophageal motility disorder characterized by uncoordinated, simultaneous contractions [4]. We here report a female patient with chronic esophageal transit failure as DES under diagnosis of AAG. 2. Case report A 40-year-old woman experienced numbness in the distal part of her right hand. At 42 years of age, she experienced photophobia in her left eye. At 55 years of age, she experienced the sensation ⇑ Corresponding author at: Department of Neurology, Kagawa Prefectural Central Hospital, 1-2-1 Asahimachi, Takamatsu 760-8557, Japan. E-mail address: [email protected] (N. Morimoto).
that food and liquid clogged her esophagus. The symptoms gradually progressed, and at was 68 years of age, she experienced frequent food and liquid clogging on her esophagus, and therefore she was admitted to our hospital. She had a past history of left ovarian cystectomy at 67 years, with no similar diseases in her family. Upon admission to our hospital, her consciousness was alert, pupils were round but anisocoric (right 2 mm/left 4 mm). Light reflex was sluggish in her left eye. There were no other cranial nerve deficits or muscle weakness. Deep tendon reflexes were decreased in bilateral upper extremities, and absent in bilateral lower extremities. Dysesthesia and thermal hypoalgesia in bilateral hands and feet were observed. Constipation and chronic esophageal transit failure were detected. Barium swallowing X-ray showed poor progression of a bolus with repetitive simultaneous contractions (Fig. 1a, dots) and contractions of prolonged duration (Fig. 1a, arrowheads) in the esophagus. Chest CT image (Fig. 1b, arrowheads) and gastrointestinal endoscopy (Fig. 1c) showed expansion of the esophageal lumen and liquid effusion. The 0.125% pilocarpine test showed significant contraction in the left pupil, with reduced size from 4.5 to 2 mm
http://dx.doi.org/10.1016/j.jocn.2017.01.027 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Morimoto N et al. A case of seropositive autoimmune autonomic ganglionopathy with diffuse esophageal spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.01.027
2
Case report / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Fig. 1. (a) Barium swallowing X-rays show repetitive simultaneous contractions (dots) and contractions of prolonged duration (arrowheads) in the esophagus. (b) Chest CT image shows expanded esophageal lumen and liquid effusion (arrowheads). (c) Gastrointestinal endoscopy shows expanded esophageal lumen and liquid effusion. (d) Infrared light imaging shows before instillation, 60 min after instillation of 0.1% pilocarpine, 90 min after 5.0% cocaine, and 45 min after 5.0% tyramine, sequentially. A significant contraction was observed by pilocarpine in the left pupil from 4.5 to 2 mm, indicating Adie’s pupil. (e) Micrographs show a transverse section of the right sural nerve stained with p-phenylenediamine to visualize myelin. The number of small myelinated fibers is significantly lost, whereas large myelinated fibers are comparatively preserved. Scale bar = 100 lm. (f) Cardiac scintigraphy with 123I-metaiodobenzylguanidine (MIBG), the heart-to-mediastinum uptake ratio (H/M) was decreased in the delayed phase (H/M = 1.90). (g) Compared to the pre-treatment (a), barium swallowing X-ray shows improvement of barium flow after treatment (g), although expansion of esophageal lumen remained unchanged. (h) Compared to the pre-treatment (b), Chest-CT shows disappearance of liquid effusion after the treatment (h).
after 60 min (Fig. 1d), indicating Adie’s pupil. Nerve conduction study showed insufficiently evoked sensory nerve action potentials (SNAP) in median and sural nerves, with well-preserved compound muscle action potentials (CMAP) and conduction velocities (CV) in median and tibial nerves. Right sural nerve biopsy was performed and showed significantly decreased numbers of small myelinated fibers (Fig. 1e). In the Schellong test, blood pressure (BP) fell from 135/84 mmHg at supine to 117/85 mmHg at standing. Cardiac scintigraphy using 123I-metaiodobenzylguanidine (MIBG) revealed a MIBG heart-to-mediastinum uptake ratio (H/M) that was slightly decreased (H/M = 1.90) (Fig. 1f). There were no particular abnormalities in a complete blood cell count, common serum biochemistry, and cerebrospinal fluid, except that serum anti-gAChRa3-Ab was detected by luciferase immunoprecipitation systems (LIPS) assay [3]. Based on chronic autonomic sensory neuropathy and serum anti-gAChRa3-Ab positivity, the patient was diagnosed with AAG. She received both pulse intravenous methylprednisolone (IVMP) and intravenous immunoglobulin therapy (IVIg), with improved bolus progression and liquid effusion, although expansion of the esophageal lumen remained unchanged (Fig. 1g and h).
3. Discussion Serum anti-gAChR-Abs are found 50% of the AAG patients, correlate with disease severity, and are pathogenic [1,2]. Furthermore, anti-gAChRa3-Ab directly causes autonomic dysfunction in immunized rabbits [5]. In the present case, serum anti-AChRa3-Ab was confirmed as the cause of AAG. DES is a one of the esophageal motility disorders which includes achalasia. In achalasia, the lower esophageal sphincter (LES) typically fails to relax. In contrast, DES is characterized by abnormal esophageal contractions [4]. It is suggested that different types of autonomic fibers are affected by each of them, because the relaxation of the esophagus smooth muscle is mainly controlled by sympathetic nerve, and the contraction by parasympathetic nerve. The present case could be diagnosed as DES based on barium swallowing X-ray resultings showing repetitive simultaneous esophageal contractions, but not achalasia which was previously reported [3]. The clinical characteristics of seropositive-AAG are summarized in Table 1. Gastrointestinal tract symptoms are found in 83–91.7% of seropositive AAG patients [1,3]. Notably, 3 achalasia cases were
Please cite this article in press as: Morimoto N et al. A case of seropositive autoimmune autonomic ganglionopathy with diffuse esophageal spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.01.027
3
Case report / Journal of Clinical Neuroscience xxx (2017) xxx–xxx Table 1 Clinical features of patients with seropositive-AAG.
Orthostatic hypotension/orthostatic intolerance Anhidrosis / heat intolerance Pupil abnormality Sicca complex Attacks of coughing Gastrointestinal tract symptoms Bladder dysfunction Sensory disturbance
Nakane et. Al [3] (Japan 2015) n = 24
Klein et. Al [1] (USA 2003) N = 18
Present case
20 (83.3%) 15 (62.5%) 11 (45.8%) 14 (58.3%) 4 (16.7%) 22 (91.7%), (Achalasia n = 3) 16 (66.7%) 6 (25.0%)
8 (44%) 8 (44%) 11 (61%) 12 (66%) Not mentioned 15 (83%) 9 (50%) Not mentioned
(±) faintness ( ) Adie’s pupil ( ) (+) Diffuse esophageal spasm (DES), constipation ( ) Thermal hypoalgesia
contained in a previous report. Because both sympathetic and parasympathetic ganglia utilize nicotinic cholinergic synapses expressing gAChRs, anti-gAChR-Abs that interfere with ganglionic transmission could cause not only achalasia but also DES [3]. Several recent studies suggest that IVIg, IVMP, or plasma exchange (PE) and immunosuppressant agents are effective for AAG treatment [3,6]. In the present case, both IVMP and IVIg combined therapies were performed, and a clinical effect was observed on DES. These findings suggest that DES may be an important gastrointestinal symptom of AAG as well as achalasia. Sources of support There are no financial relationships to disclose.
References [1] Klein CM, Vernino S, Lennon VA, et al. The spectrum of autoimmune autonomic neuropathies. Ann Neurol 2003;53:752–8. [2] Vernino S, Low PA, Fealey RD, et al. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000;343:847–55. [3] Nakane S, Higuchi O, Koga M, et al. Clinical features of autoimmune autonomic ganglionopathy and the detection of subunit-specific autoantibodies to the ganglionic acetylcholine receptor in Japanese patients. PLoS One 2015;10: e0118312. [4] Richter JE, Castell DO. Diffuse esophageal spasm: a reappraisal. Ann Int Med 1984;100:242–5. [5] Vernino S, Low PA, Lennon VA. Experimental autoimmune autonomic neuropathy. J Neurophysiol 2003;90:2053–9. [6] Iodice V, Kimpinski K, Vernino S, et al. Immunotherapy for autoimmune autonomic ganglionopathy. Auton Neurosci 2009;146:22–5.
Please cite this article in press as: Morimoto N et al. A case of seropositive autoimmune autonomic ganglionopathy with diffuse esophageal spasm. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.01.027