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ScienceDirect Neuromuscular Disorders 25 (2015) 70–72 www.elsevier.com/locate/nmd
Case report
Efficacy of intravenous immunoglobulin for treatment of Lambert–Eaton myasthenic syndrome without anti-presynaptic P/Q-type voltage-gated calcium channel antibodies: A case report Akinori Okada a, Haruki Koike a, Tomohiko Nakamura a, Masakatu Motomura b, Gen Sobue a,* b
a Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya 466-8550, Japan Medical Electronic Course Department of Electrical and Electronics Engineering, The Faculty of Engineering, Nagasaki Institute of Applied Science, 536 Abamachi, Nagasaki, Nagasaki Pref. 851-0193, Japan Received 8 July 2014; accepted 22 August 2014
Abstract We evaluated the efficacy of intravenous immunoglobulin (IVIg) in a patient with Lambert–Eaton myasthenic syndrome (LEMS). Comprehensive clinical and electrophysiological testing was performed on a 34-year-old woman with progressive limb weakness, before and after IVIg treatment. Neurological examination revealed muscle weakness, predominantly in the proximal parts of the limbs. Muscle weakness improved following a short period of maximum voluntary muscle contraction. A repetitive low-rate (3-Hz) nerve stimulation test of the abductor hallucis was normal, but high-rate (20-Hz) stimulation induced an incremental response. Anti-presynaptic P/Q-type voltage-gated calcium channel (P/QVGCC) antibodies were absent in the patient’s serum. Whole body computed tomography revealed no tumors. We diagnosed seronegative LEMS without tumor and treated the patient with IVIg. Both clinical and electrophysiological indices improved gradually after treatment. This case study indicates that treatment with IVIg is equally effective for LEMS that is seronegative or seropositive for P/Q-VGCC antibodies. © 2014 Elsevier B.V. All rights reserved. Keywords: LEMS; Seronegative LEMS; Intravenous immunoglobulin
1. Introduction Lambert–Eaton myasthenic syndrome (LEMS) is a disorder of neuromuscular transmission, initially recognized in association with small-cell lung cancer [1], but cases without any neoplasms have also been reported [2]. The most common symptoms of patients with LEMS are proximal muscle weakness, predominantly in the lower limbs, depressed tendon reflexes, and autonomic dysfunction [3]. The diagnosis can be confirmed by detecting autoantibodies directed against presynaptic P/Q-type voltage-gated calcium channels (P/QVGCCs) and by looking for reduced amplitudes of compound muscle action potentials, which increase by over 100% after maximum voluntary action or 20–50 Hz of nerve stimulation [4]. The pathomechanism of LEMS is characterized by
* Corresponding author. Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Tel.: +81 52 744 2385; fax: +81 52 744 2384. E-mail address: [email protected] (G. Sobue). http://dx.doi.org/10.1016/j.nmd.2014.08.006 0960-8966/© 2014 Elsevier B.V. All rights reserved.
impaired transmission across the neuromuscular junction due to autoantibodies directed against the presynaptic P/Q-VGCCs [5]. However, 15% of patients with LEMS are negative for these antibodies [6]. Paraneoplastic mechanisms are involved in the pathogenesis of LEMS with malignancy [6]. Hence, treatment of the malignancy is the mainstay of management. Excision of the primary tumor limits exacerbation, and has a favorable influence on the course of LEMS [7]. In cases without malignancy, treatment with 3,4-diaminopyridine is often effective for improving clinical symptoms [8]. The efficacy of immunomodulatory therapies, including steroids and immunosuppressants, has also been reported in patients with LEMS [9,10]. Intravenous immunoglobulin (IVIg) treatment has been shown to ameliorate the disease [11–15]. However, these previous reports have mainly focused on cases that were seropositive for P/Q-VGCC antibodies. The efficacy of IVIg treatment for seronegative LEMS has not been fully evaluated. In this report, we describe the efficacy of IVIg therapy in a patient with seronegative LEMS without tumors assessed using comprehensive clinical and electrophysiological studies.
A. Okada et al. / Neuromuscular Disorders 25 (2015) 70–72
repetitive stimulation
2. Case report Before referral to our hospital, a 34-year-old non-smoking woman had been experiencing general fatigue for 3 years after contracting an upper respiratory tract infection. She also complained of upper and lower limb weakness and photophobia. At the time of referral, her height was 152 cm, body weight 39.6 kg, blood pressure 89/64 (systolic/diastolic) mmHg in the supine position, and resting heart rate 71 beats per minute. She was alert and well oriented. Examination revealed that the cranial nerves were intact. Bilateral mydriasis with sluggish light reflexes was observed. Although results of pilocarpine hydrochloride (0.05%) and pivalephrine (0.04%) drug application tests were normal, pupil diameters in the dark were 4.9 mm/5.4 mm (right/left). Manual muscle testing revealed moderate weakness in the proximal parts of the extremities and mild weakness in the distal parts. Muscle weakness improved following a short period of maximum voluntary contraction. Deep tendon reflexes were absent, and sensory multimodal examination was normal. Plantar responses were flexor on both sides, and cerebellar signs were negative. Except for abnormal pupillary responses, there were no signs of autonomic dysfunction such as dry eyes, dry mouth, orthostatic intolerance, gastrointestinal dysmotility, dysuria, or abnormal sweating. Head-up tilt test did not reveal any autonomic dysfunction. Nerve conduction studies, performed as previously described [16], revealed normal motor and sensory conduction velocities and distal motor latencies. However, small amplitudes for resting compound muscle action potentials (CMAPs) in the upper and lower limbs were evident (0.6 mV for the ulnar nerve, control value: 7.4 ± 1.8 mV; 0.2 mV for the tibial nerve, control value: 11.8 ± 3.5 mV). CMAP increased (8 times in the ulnar nerve, 10 times in the tibial nerve) following a short period of maximum voluntary muscle contraction. A low-rate (3-Hz) repetitive nerve stimulation test of the abductor hallucis was normal. By contrast, high-rate (20-Hz) stimulation induced an incremental response (Fig. 1). These results were highly suggestive of LEMS [4]. Serum autoantibodies directed against P/Q-VGCCs were negative. Other autoantibodies, including anti-acetylcholine receptor, anti-nuclear, and anti-thyroglobulin antibodies, were also negative. Levels of neuron-specific enolase, progastrinreleasing peptide, carcinoembryonic antigen, and carbohydrate antigen 19-9 (CA19-9) were normal. Whole body computed
71
a) 200μV 100ms
b) 500μV 100ms Fig. 1. Repetitive low- and high-rate nerve stimulation tests. A repetitive low-rate (3-Hz) nerve stimulation test recording at the abductor hallucis shows a normal response (A). By contrast, a repetitive high-rate (20 Hz) stimulation test induces a response increment of 400% (B). Repetitive stimulation tests reveal electrophysiological patterns of Lambert–Eaton myasthenic syndrome.
tomography, with and without contrast enhancement, revealed no tumors. Findings from brain and spinal cord magnetic resonance imaging were also normal. Based on the results of these tests, we diagnosed the patient as seronegative LEMS without tumors. She received 0.4 g/kg IVIg infusion per day over 5 days. We evaluated the patient using the Quantitative Myasthenia Gravis (QMG) Test as described previously [17] and performed a nerve conduction test before treatment, and 2 weeks, 2 months, 4 months, and 1 year posttreatment. Before IVIg, she could outstretch her arm for 164 s and her leg for 39 s (Table 1). Her handgrip strength was 15 kg. Two weeks after IVIg, she no longer complained of weakness, and her limb-outstretch times improved (arm: 223 s; leg: 55 s). Her handgrip also improved, increasing to 26 kg. CMAPs in the ulnar and tibial nerves slightly improved to 1.2 mV and 0.3 mV, respectively. She reported significant improvements in fatigability 4 months after IVIg, and a further improvement in limb-outstretch time was observed. The response to the initial IVIg treatment was sustained over 4 months, but she still showed mild weakness of the limbs. We administered a second course of
Table 1 Clinical and laboratory findings before and after intravenous immunoglobulin treatment*.
Limb outstretch time*** Arm outstretch (s) Leg outstretch (s) Hand grip (kg) Electrophysiological finding CMAPs in the ulnar nerve (mV) CMAPs in the tibial nerve (mV)
Before treatment
2 weeks after treatment
4 months after treatment
1 year after treatment
Control values**
164 39 15
223 55 26
240 76 25
240 145 25
240≦ 240≦ 30≦
0.6 0.2
1.2 0.3
1.5 0.3
CMAPs = compound muscle action potentials. * Second intravenous immunoglobulin treatment was done 5 months after the first treatment. ** Control values for CMAPs were based on a previously published report [17]. *** Limb outstretched time was assessed as described previously [18].
1.7 0.4
7.4 ± 1.8 11.8 ± 3.5
72
A. Okada et al. / Neuromuscular Disorders 25 (2015) 70–72
IVIg (0.4 g/kg per day, over 5 days) 5 months after the first treatment, because she complained of slightly increased fatigability. Her muscle weakness and general fatigue improved again after the second treatment. Overall, her muscle weakness and general fatigue indices improved significantly 1 year after the first IVIg treatment, although the improvement in nerve conduction indices was less significant. Additional immunomodulatory therapies were not administered. She resumed her previous social life and occupation. 3. Discussion The neurological symptoms and electrophysiological findings of patients with LEMS seronegative for P/Q-VGCC antibodies are similar to those of seropositive LEMS [6,18]. However, seronegative LEMS is characterized by juvenile-onset and less frequent concurrence of tumors compared with seropositive cases [6]. Seventy percent of seropositive patients have small-cell lung cancer, compared with only 12% of seronegative patients [6]. The prognosis for patients with seronegative LEMS is considered good compared with seropositive LEMS [19]. Specific antitumor therapy often improves LEMS symptoms in LEMS patients with tumors [20] In LEMS patients without tumors, immunotherapy often improves LEMS symptoms [9]. In 1992, the first report of clinical improvement for LEMS after IVIg was published, on a patient seropositive for P/Q-VGCC antibodies [12]. In 1996, a randomized double-blind placebocontrolled crossover trial on 9 patients with LEMS was reported [11], thus IVIg may be considered as a treatment option for LEMS [21]. However, this study focused mainly on patients seropositive for P/Q-VGCC antibodies. The efficacy of IVIg for patients with seronegative LEMS is still unknown. This is the first case report describing comprehensive clinical and electrophysiological testing before and after the IVIg treatment in a patient with LEMS without P/Q-VGCC antibodies. Our patient clearly demonstrated an improvement in clinical and electrophysiological indices, particularly the latter, after treatment. These findings indicate that immune-mediated mechanisms should also be considered in LEMS that is seronegative for P/Q-VGCC antibodies, as well seropositive cases. Some of the seronegative patients may have antibodies directed against N-type VGCCs, although the presence of these antibodies was not assessed in our case [22,23]. Further studies, including the search for corresponding antigens, are needed to elucidate the mechanisms behind the efficacy of IVIg for seronegative LEMS. Acknowledgements This work was supported by grants from the Ministry of Health, Labor and Welfare and the Ministry of Education, Culture, Sports, Science and Technology of Japan. References [1] O’Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 1988;111:577–96.
[2] Motomura M. The Lambert-Eaton myasthenic syndrome: a study of 110 Japanese cases. Rinsho Shinkeigaku 1999;39:1237–9. [3] Lang B, Newsom-Davis J, Wray D, et al. Autoimmune etiology for myasthenic (Eaton-Lambert) syndrome. Lancet 1981;2:224–6. [4] AAEM Quality Assurance Committee. American Association of Electrodiagnostic Medline. Literature review of the usefulness of repetitive nerve stimulation and single fiber EMG in the electrodiagnostic evaluation of patients with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome. Muscle Nerve 2001;24:1239–47. [5] Motomura M, Johnston I, Lang B, et al. An improved diagnostic assay for Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 1995;58:85–7. [6] Chalk CH, Murray NM, Newsom-Davis J, et al. Response of the Lambert-Eaton myasthenic syndrome to treatment of associated small-cell lung carcinoma. Neurology 1990;40:1552–6. [7] Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol 2011;10:1098–107. [8] Newsom-Davis J. A treatment algorithm for Lambert-Eaton myasthenic syndrome. Ann N Y Acad Sci 1998;841:817–22. [9] Tim RW, Massey JM, Sanders DB. Lambert-Eaton myasthenic syndrome (LEMS). Clinical and electrodiagnostic features and response to therapy in 59 patients. Ann N Y Acad Sci 1998;841:823–6. [10] Bain PG, Motomura M, Newsom-Davis J, et al. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology 1996;47:678–83. [11] Bird SJ. Clinical and electrophysiologic improvement in Lambert-Eaton syndrome with intravenous immunoglobulin therapy. Neurology 1992;42:1422–3. [12] Buchwald B, Ahangari R, Weishaupt A, et al. Presynaptic effects of immunoglobulin G from patients with Lambert-Eaton myasthenic syndrome: their neutralization by intravenous immunoglobulins. Muscle Nerve 2005;31:487–94. [13] Muchnik S, Losavio AS, Vidal A, et al. Long-term follow-up of Lambert-Eaton syndrome treated with intravenous immunoglobulin. Muscle Nerve 1997;20:674–8. [14] Peterlin BL, Flood W, Kothari MJ. Use of intravenous immunoglobulin in Lambert-Eaton myasthenic syndrome. J Am Osteopath Assoc 2002;102:682–4. [15] Motomura M, Fukuda T. Lambert-Eaton myasthenic syndrome. Brain Nerve 2011;63:745–54. [16] Nakao YK, Motomura M, Fukudome T, et al. Seronegative Lambert-Eaton myasthenic syndrome: study of 110 Japanese patients. Neurology 2002;59:1773–5. [17] Koike H, Hirayama M, Yamamoto M, et al. Age associated axonal features in HNPP with 17p11.2 deletion in Japan. J Neurol Neurosurg Psychiatry 2005;76:1109–14. [18] Richard J, Barohn MD. The Quantitative Myasthenia Gravis (QMG) Test: the manual. Myasthenia Gravis Foundation of America, Inc. 2000. [19] Oh SJ, Hatanaka Y, Claussen GC, et al. Electrophysiological differences in seropositive and seronegative Lambert-Eaton myasthenic syndrome. Muscle Nerve 2007;35:178–83. [20] Abicht A, Lochmuller H. What’s in the serum of seronegative MG and LEMS?: MuSK et al. Neurology 2002;59:1672–3. [21] Roberts A, Perera S, Lang B, et al. Paraneoplastic myasthenic syndrome IgG inhibits 45Ca2+ flux in a human small cell carcinoma line. Nature 1985;317:737–9. [22] el Far O, Marqueze B, Leveque C, et al. Antigens associated with N- and L-type calcium channels in Lambert-Eaton myasthenic syndrome. J Neurochem 1995;64:1696–702. [23] Martin-Moutot N, De Haro L, Segar M. Distinct evolution of calcium channel antibody types in Lambert-Eaton myasthenic syndrome. J Neuroimmunol 2008;197:47–53.
ScienceDirect Neuromuscular Disorders 25 (2015) 70–72 www.elsevier.com/locate/nmd
Case report
Efficacy of intravenous immunoglobulin for treatment of Lambert–Eaton myasthenic syndrome without anti-presynaptic P/Q-type voltage-gated calcium channel antibodies: A case report Akinori Okada a, Haruki Koike a, Tomohiko Nakamura a, Masakatu Motomura b, Gen Sobue a,* b
a Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya 466-8550, Japan Medical Electronic Course Department of Electrical and Electronics Engineering, The Faculty of Engineering, Nagasaki Institute of Applied Science, 536 Abamachi, Nagasaki, Nagasaki Pref. 851-0193, Japan Received 8 July 2014; accepted 22 August 2014
Abstract We evaluated the efficacy of intravenous immunoglobulin (IVIg) in a patient with Lambert–Eaton myasthenic syndrome (LEMS). Comprehensive clinical and electrophysiological testing was performed on a 34-year-old woman with progressive limb weakness, before and after IVIg treatment. Neurological examination revealed muscle weakness, predominantly in the proximal parts of the limbs. Muscle weakness improved following a short period of maximum voluntary muscle contraction. A repetitive low-rate (3-Hz) nerve stimulation test of the abductor hallucis was normal, but high-rate (20-Hz) stimulation induced an incremental response. Anti-presynaptic P/Q-type voltage-gated calcium channel (P/QVGCC) antibodies were absent in the patient’s serum. Whole body computed tomography revealed no tumors. We diagnosed seronegative LEMS without tumor and treated the patient with IVIg. Both clinical and electrophysiological indices improved gradually after treatment. This case study indicates that treatment with IVIg is equally effective for LEMS that is seronegative or seropositive for P/Q-VGCC antibodies. © 2014 Elsevier B.V. All rights reserved. Keywords: LEMS; Seronegative LEMS; Intravenous immunoglobulin
1. Introduction Lambert–Eaton myasthenic syndrome (LEMS) is a disorder of neuromuscular transmission, initially recognized in association with small-cell lung cancer [1], but cases without any neoplasms have also been reported [2]. The most common symptoms of patients with LEMS are proximal muscle weakness, predominantly in the lower limbs, depressed tendon reflexes, and autonomic dysfunction [3]. The diagnosis can be confirmed by detecting autoantibodies directed against presynaptic P/Q-type voltage-gated calcium channels (P/QVGCCs) and by looking for reduced amplitudes of compound muscle action potentials, which increase by over 100% after maximum voluntary action or 20–50 Hz of nerve stimulation [4]. The pathomechanism of LEMS is characterized by
* Corresponding author. Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Tel.: +81 52 744 2385; fax: +81 52 744 2384. E-mail address: [email protected] (G. Sobue). http://dx.doi.org/10.1016/j.nmd.2014.08.006 0960-8966/© 2014 Elsevier B.V. All rights reserved.
impaired transmission across the neuromuscular junction due to autoantibodies directed against the presynaptic P/Q-VGCCs [5]. However, 15% of patients with LEMS are negative for these antibodies [6]. Paraneoplastic mechanisms are involved in the pathogenesis of LEMS with malignancy [6]. Hence, treatment of the malignancy is the mainstay of management. Excision of the primary tumor limits exacerbation, and has a favorable influence on the course of LEMS [7]. In cases without malignancy, treatment with 3,4-diaminopyridine is often effective for improving clinical symptoms [8]. The efficacy of immunomodulatory therapies, including steroids and immunosuppressants, has also been reported in patients with LEMS [9,10]. Intravenous immunoglobulin (IVIg) treatment has been shown to ameliorate the disease [11–15]. However, these previous reports have mainly focused on cases that were seropositive for P/Q-VGCC antibodies. The efficacy of IVIg treatment for seronegative LEMS has not been fully evaluated. In this report, we describe the efficacy of IVIg therapy in a patient with seronegative LEMS without tumors assessed using comprehensive clinical and electrophysiological studies.
A. Okada et al. / Neuromuscular Disorders 25 (2015) 70–72
repetitive stimulation
2. Case report Before referral to our hospital, a 34-year-old non-smoking woman had been experiencing general fatigue for 3 years after contracting an upper respiratory tract infection. She also complained of upper and lower limb weakness and photophobia. At the time of referral, her height was 152 cm, body weight 39.6 kg, blood pressure 89/64 (systolic/diastolic) mmHg in the supine position, and resting heart rate 71 beats per minute. She was alert and well oriented. Examination revealed that the cranial nerves were intact. Bilateral mydriasis with sluggish light reflexes was observed. Although results of pilocarpine hydrochloride (0.05%) and pivalephrine (0.04%) drug application tests were normal, pupil diameters in the dark were 4.9 mm/5.4 mm (right/left). Manual muscle testing revealed moderate weakness in the proximal parts of the extremities and mild weakness in the distal parts. Muscle weakness improved following a short period of maximum voluntary contraction. Deep tendon reflexes were absent, and sensory multimodal examination was normal. Plantar responses were flexor on both sides, and cerebellar signs were negative. Except for abnormal pupillary responses, there were no signs of autonomic dysfunction such as dry eyes, dry mouth, orthostatic intolerance, gastrointestinal dysmotility, dysuria, or abnormal sweating. Head-up tilt test did not reveal any autonomic dysfunction. Nerve conduction studies, performed as previously described [16], revealed normal motor and sensory conduction velocities and distal motor latencies. However, small amplitudes for resting compound muscle action potentials (CMAPs) in the upper and lower limbs were evident (0.6 mV for the ulnar nerve, control value: 7.4 ± 1.8 mV; 0.2 mV for the tibial nerve, control value: 11.8 ± 3.5 mV). CMAP increased (8 times in the ulnar nerve, 10 times in the tibial nerve) following a short period of maximum voluntary muscle contraction. A low-rate (3-Hz) repetitive nerve stimulation test of the abductor hallucis was normal. By contrast, high-rate (20-Hz) stimulation induced an incremental response (Fig. 1). These results were highly suggestive of LEMS [4]. Serum autoantibodies directed against P/Q-VGCCs were negative. Other autoantibodies, including anti-acetylcholine receptor, anti-nuclear, and anti-thyroglobulin antibodies, were also negative. Levels of neuron-specific enolase, progastrinreleasing peptide, carcinoembryonic antigen, and carbohydrate antigen 19-9 (CA19-9) were normal. Whole body computed
71
a) 200μV 100ms
b) 500μV 100ms Fig. 1. Repetitive low- and high-rate nerve stimulation tests. A repetitive low-rate (3-Hz) nerve stimulation test recording at the abductor hallucis shows a normal response (A). By contrast, a repetitive high-rate (20 Hz) stimulation test induces a response increment of 400% (B). Repetitive stimulation tests reveal electrophysiological patterns of Lambert–Eaton myasthenic syndrome.
tomography, with and without contrast enhancement, revealed no tumors. Findings from brain and spinal cord magnetic resonance imaging were also normal. Based on the results of these tests, we diagnosed the patient as seronegative LEMS without tumors. She received 0.4 g/kg IVIg infusion per day over 5 days. We evaluated the patient using the Quantitative Myasthenia Gravis (QMG) Test as described previously [17] and performed a nerve conduction test before treatment, and 2 weeks, 2 months, 4 months, and 1 year posttreatment. Before IVIg, she could outstretch her arm for 164 s and her leg for 39 s (Table 1). Her handgrip strength was 15 kg. Two weeks after IVIg, she no longer complained of weakness, and her limb-outstretch times improved (arm: 223 s; leg: 55 s). Her handgrip also improved, increasing to 26 kg. CMAPs in the ulnar and tibial nerves slightly improved to 1.2 mV and 0.3 mV, respectively. She reported significant improvements in fatigability 4 months after IVIg, and a further improvement in limb-outstretch time was observed. The response to the initial IVIg treatment was sustained over 4 months, but she still showed mild weakness of the limbs. We administered a second course of
Table 1 Clinical and laboratory findings before and after intravenous immunoglobulin treatment*.
Limb outstretch time*** Arm outstretch (s) Leg outstretch (s) Hand grip (kg) Electrophysiological finding CMAPs in the ulnar nerve (mV) CMAPs in the tibial nerve (mV)
Before treatment
2 weeks after treatment
4 months after treatment
1 year after treatment
Control values**
164 39 15
223 55 26
240 76 25
240 145 25
240≦ 240≦ 30≦
0.6 0.2
1.2 0.3
1.5 0.3
CMAPs = compound muscle action potentials. * Second intravenous immunoglobulin treatment was done 5 months after the first treatment. ** Control values for CMAPs were based on a previously published report [17]. *** Limb outstretched time was assessed as described previously [18].
1.7 0.4
7.4 ± 1.8 11.8 ± 3.5
72
A. Okada et al. / Neuromuscular Disorders 25 (2015) 70–72
IVIg (0.4 g/kg per day, over 5 days) 5 months after the first treatment, because she complained of slightly increased fatigability. Her muscle weakness and general fatigue improved again after the second treatment. Overall, her muscle weakness and general fatigue indices improved significantly 1 year after the first IVIg treatment, although the improvement in nerve conduction indices was less significant. Additional immunomodulatory therapies were not administered. She resumed her previous social life and occupation. 3. Discussion The neurological symptoms and electrophysiological findings of patients with LEMS seronegative for P/Q-VGCC antibodies are similar to those of seropositive LEMS [6,18]. However, seronegative LEMS is characterized by juvenile-onset and less frequent concurrence of tumors compared with seropositive cases [6]. Seventy percent of seropositive patients have small-cell lung cancer, compared with only 12% of seronegative patients [6]. The prognosis for patients with seronegative LEMS is considered good compared with seropositive LEMS [19]. Specific antitumor therapy often improves LEMS symptoms in LEMS patients with tumors [20] In LEMS patients without tumors, immunotherapy often improves LEMS symptoms [9]. In 1992, the first report of clinical improvement for LEMS after IVIg was published, on a patient seropositive for P/Q-VGCC antibodies [12]. In 1996, a randomized double-blind placebocontrolled crossover trial on 9 patients with LEMS was reported [11], thus IVIg may be considered as a treatment option for LEMS [21]. However, this study focused mainly on patients seropositive for P/Q-VGCC antibodies. The efficacy of IVIg for patients with seronegative LEMS is still unknown. This is the first case report describing comprehensive clinical and electrophysiological testing before and after the IVIg treatment in a patient with LEMS without P/Q-VGCC antibodies. Our patient clearly demonstrated an improvement in clinical and electrophysiological indices, particularly the latter, after treatment. These findings indicate that immune-mediated mechanisms should also be considered in LEMS that is seronegative for P/Q-VGCC antibodies, as well seropositive cases. Some of the seronegative patients may have antibodies directed against N-type VGCCs, although the presence of these antibodies was not assessed in our case [22,23]. Further studies, including the search for corresponding antigens, are needed to elucidate the mechanisms behind the efficacy of IVIg for seronegative LEMS. Acknowledgements This work was supported by grants from the Ministry of Health, Labor and Welfare and the Ministry of Education, Culture, Sports, Science and Technology of Japan. References [1] O’Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 1988;111:577–96.
[2] Motomura M. The Lambert-Eaton myasthenic syndrome: a study of 110 Japanese cases. Rinsho Shinkeigaku 1999;39:1237–9. [3] Lang B, Newsom-Davis J, Wray D, et al. Autoimmune etiology for myasthenic (Eaton-Lambert) syndrome. Lancet 1981;2:224–6. [4] AAEM Quality Assurance Committee. American Association of Electrodiagnostic Medline. Literature review of the usefulness of repetitive nerve stimulation and single fiber EMG in the electrodiagnostic evaluation of patients with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome. Muscle Nerve 2001;24:1239–47. [5] Motomura M, Johnston I, Lang B, et al. An improved diagnostic assay for Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 1995;58:85–7. [6] Chalk CH, Murray NM, Newsom-Davis J, et al. Response of the Lambert-Eaton myasthenic syndrome to treatment of associated small-cell lung carcinoma. Neurology 1990;40:1552–6. [7] Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol 2011;10:1098–107. [8] Newsom-Davis J. A treatment algorithm for Lambert-Eaton myasthenic syndrome. Ann N Y Acad Sci 1998;841:817–22. [9] Tim RW, Massey JM, Sanders DB. Lambert-Eaton myasthenic syndrome (LEMS). Clinical and electrodiagnostic features and response to therapy in 59 patients. Ann N Y Acad Sci 1998;841:823–6. [10] Bain PG, Motomura M, Newsom-Davis J, et al. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology 1996;47:678–83. [11] Bird SJ. Clinical and electrophysiologic improvement in Lambert-Eaton syndrome with intravenous immunoglobulin therapy. Neurology 1992;42:1422–3. [12] Buchwald B, Ahangari R, Weishaupt A, et al. Presynaptic effects of immunoglobulin G from patients with Lambert-Eaton myasthenic syndrome: their neutralization by intravenous immunoglobulins. Muscle Nerve 2005;31:487–94. [13] Muchnik S, Losavio AS, Vidal A, et al. Long-term follow-up of Lambert-Eaton syndrome treated with intravenous immunoglobulin. Muscle Nerve 1997;20:674–8. [14] Peterlin BL, Flood W, Kothari MJ. Use of intravenous immunoglobulin in Lambert-Eaton myasthenic syndrome. J Am Osteopath Assoc 2002;102:682–4. [15] Motomura M, Fukuda T. Lambert-Eaton myasthenic syndrome. Brain Nerve 2011;63:745–54. [16] Nakao YK, Motomura M, Fukudome T, et al. Seronegative Lambert-Eaton myasthenic syndrome: study of 110 Japanese patients. Neurology 2002;59:1773–5. [17] Koike H, Hirayama M, Yamamoto M, et al. Age associated axonal features in HNPP with 17p11.2 deletion in Japan. J Neurol Neurosurg Psychiatry 2005;76:1109–14. [18] Richard J, Barohn MD. The Quantitative Myasthenia Gravis (QMG) Test: the manual. Myasthenia Gravis Foundation of America, Inc. 2000. [19] Oh SJ, Hatanaka Y, Claussen GC, et al. Electrophysiological differences in seropositive and seronegative Lambert-Eaton myasthenic syndrome. Muscle Nerve 2007;35:178–83. [20] Abicht A, Lochmuller H. What’s in the serum of seronegative MG and LEMS?: MuSK et al. Neurology 2002;59:1672–3. [21] Roberts A, Perera S, Lang B, et al. Paraneoplastic myasthenic syndrome IgG inhibits 45Ca2+ flux in a human small cell carcinoma line. Nature 1985;317:737–9. [22] el Far O, Marqueze B, Leveque C, et al. Antigens associated with N- and L-type calcium channels in Lambert-Eaton myasthenic syndrome. J Neurochem 1995;64:1696–702. [23] Martin-Moutot N, De Haro L, Segar M. Distinct evolution of calcium channel antibody types in Lambert-Eaton myasthenic syndrome. J Neuroimmunol 2008;197:47–53.
