Koji Hayashi, MD Kazuo Iwasa, MD, PhD Akiyoshi Morinaga, MD, PhD Kenjiro Ono, MD, PhD Masahito Yamada, MD, PhD Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
FIGURE 1. Median repetitive nerve stimulation (RNS). The compound muscle action potentials (CMAPs) were recorded from the abductor pollicis brevis muscle in response to 3-HZ median nerve stimulation. One year before exacerbation, there was no decremental response (A). One day after admission, the first CMAP of the RNS train was decreased compared with the previous examination (note the different calibration markings), and the decremental response was 31.9% (B). Twelve days after admission, the first CMAP recovered, and RNS showed a normal response (C).
1. O’Riordan JI, Miller DH, Mottershead JP, Hirsch NP, Howard RS. The management and outcome of patients with myasthenia gravis treated acutely in a neurological intensive care unit. Eur J Neurol 1998;5:137–142. 2. Pascuzzi RM. Prepared by the Professional and Public Information Committee Myasthenia Gravis Foundation of America: Medications and myasthenia gravis (a reference for Health Care Professionals). Available at http://www.myasthenia.org/LinkClick.aspx?fileticket5 JuFvZPPq2vg%3d. Accessed September 26, 2014. 3. Harnett MT, Chen W, Smith SM. Calcium-sensing receptor: a highaffinity presynaptic target for aminoglycoside-induced weakness. Neuropharmacology 2009;57:502–505. 4. Jones SC, Sorbello A, Boucher RM. Fluoroquinolone-associated myasthenia gravis exacerbation: evaluation of postmarketing reports from the US FDA adverse event reporting system and a literature review. Drug Saf 2011;34:839–847. 5. Lindemann L, Jacobsen H, Schuhbauer D, Knoflach F, Gatti S, Wettstein JG, et al. In vitro pharmacological selectivity profile of oseltamivir prodrug (Tamiflu) and active metabolite. Eur J Pharmacol 2010;628:6–10. 6. Muraki K, Hatano N, Suzuki H, Muraki Y, Iwajima Y, Maeda Y, et al. Oseltamivir blocks human neuronal nicotinic acetylcholine receptormediated currents. Basic Clin Pharmacol Toxicol 2015;116:87–95. 7. Kimura S, Niwa Y, Iwajima Y, Nagano Y, Yamamoto S, Ohi Y, et al. High doses of oseltamivir phosphate induce acute respiratory arrest in anaesthetized rats. Basic Clin Pharmacol Toxicol 2012;111:232– 239. 8. Marty FM, Man CY, van der Horst C, Francois B, Garot D, Manez R, et al. Safety and pharmacokinetics of intravenous zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, single-arm, phase II study. J Infect Dis 2014;209:542–550.
Published online 5 February 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24594
--------------------------------------------------------Twelve days after admission, median RNS showed no decremental response, and the initial CMAP of the RNS train had improved (Fig. 1C). On discharge at day 44, her MG-ADL score was 2. Although respiratory infection is the most common cause of MG exacerbation,1 intravenous peramivir may have induced the respiratory failure in the patient described, because it developed within 20 minutes after drug administration and the symptoms recovered rapidly, with improvement in the RNS test. Her improvement may be a result of the discontinuation of peramivir, regardless of immunotherapy. Furthermore, the safety factor for neuromuscular transmission, which decreased subclinically, may have improved because of immunotherapy. MG exacerbation has been reported with various medications.2–4 A few neuraminidase inhibitors suppress respiratory function through mechanisms including ion channel/receptor inhibition.5–8 Therefore, we speculate that peramivir may inhibit ion channels/receptors in the neuromuscular junctions, leading to respiratory failure and MC. Further studies are necessary to understand the mechanism underlying MC induction by intravenous peramivir. 936
Letters to the Editor
LAMBERT–EATON MYASTHENIC SYNDROME ASSOCIATED WITH THYMIC NEUROENDOCRINE CARCINOMA Lambert–Eaton myasthenic syndrome (LEMS) is a disorder of neuromuscular transmission secondary to primary or paraneoplastic autoimmune processes in which the most common neoplasm is small-cell lung cancer (SCLC).1,2 Only a few reported cases have described LEMS in association with thymic pathology.1,3–7 We report a patient who was diagnosed as LEMS associated with thymic carcinoma. A 60-year-old man presented with a 3-month history of fatigue, dizziness upon standing, ptosis, dry mouth, difficulty walking, and dysphagia, more pronounced in the morning. Neurological examination revealed limitation in upward/downward gaze, weak gag reflex, dysphonia, proximal muscle weakness, and bilateral hypoactive deep Additional Supporting Information may be found in the online version of this article. C 2015 Wiley Periodicals, Inc. V
MUSCLE & NERVE
June 2015
FIGURE 1. Total-body FDG-PET scan reveals a retrosternal right paramedian mediastinal mass, as indicated by the “3,” which suggests thymic carcinoma.
tendon reflexes. Routine biochemical tests and brain MRI were normal. Nerve conduction studies and needle electromyography findings were normal except for generalized lowamplitude compound muscle action potentials (CMAPs). The ulnar CMAP recorded from the abductor digiti minimi increased by >400% after 10 seconds of maximal voluntary exercise (refer to Fig. S1 in Supplementary Material available online). Low-frequency (2–3 HZ) repetitive nerve stimulation (RNS) of the same nerve showed an 18%–23% decrement (see Fig. S2 in Supplementary Material). RNS at 20, 30, and 50 HZ showed a >300% increment in CMAP amplitude of ulnar nerve (see Fig. S3 in Supplementary Material). The serum voltage-gated calcium channel (VGCC) antibody level was elevated significantly (728.80 pmol/L). Anti-acetylcholine receptor (antiAChR) antibody was negative. Thus, the diagnosis was confirmed as LEMS. Thoracic computed tomography (CT) showed right paratracheal, hilar, and high anterior mediastinal lymphadenopathy. A paraneoplastic panel analysis revealed anti-Ri antibodies. A total body fluorodeoxyglucose-positron emission tomography (FDGPET) scan revealed a retrosternal right paramedian mediastinal mass, suggestive of thymic carcinoma (Fig. 1). Thymectomy was performed, and pathological examination showed atrophic thymus tissue surrounding a high-grade, poorly differentiated neuroendocrine carcinoma. All symptoms improved gradually over 1 month after thymectomy, and no need for immunotherapy was apparent at last follow-up 1 year after thymectomy. The case satisfies the criteria for a diagnosis of a paraneoplastic neurological syndrome.8 The patient was diagnosed clinically with LEMS, which is a classical paraneoplastic syndrome. Furthermore, he had anti-Ri positivity, among the most well-characterized onconeural antibodies. Major benefit after removal of the tumor by thymectomy is further evidence in support of the diagnosis of a paraneoplastic syndrome. Letters to the Editor
Thymic tumors are classified into 3 groups, thymomas, thymic carcinomas, and neuroendocrine thymic tumors (the rarest), according to the World Health Organization’s 2014 classification. They exhibit discrete immunohistochemical properties and have the capacity to secrete ectopic hormones, which contribute to the pathogenesis. However, SCLCs also belong to the neuroendocrine tumor family. Therefore, our case suggests possible underlying extrapulmonary neuroendocrine carcinoma in LEMS and the importance of investigating for this possibility. Unfortunately, we could not test expression of VGCC or staining for Ri proteins on tumor cells. Thoracic CT is currently considered to be the first choice to screen for thymoma, whereas FDG-PET is helpful for distinguishing between thymic hyperplasia, thymoma, and thymic carcinoma.9 However, in our patient, thoracic CT could not distinguish between these possibilities. FDGPET was of great benefit for determining the likelihood of thymic neuroendocrine carcinoma in this patient. In LEMS, increases in anti-AChR, anti-Hu, and anti-Ri antibodies have been described.10–12 We also found anti-Ri antibodies without evidence of other neurological/nonneurological paraneoplastic syndromes. The patient described here demonstrates the association between LEMS, VGCC, and anti-Ri antibodies and thymic carcinoma. This case highlights the constellation of paraneoplastic neurological features and emphasizes the role of thymic abnormalities in LEMS. Mecbure Nalbantoglu, MD1 Leyla Kose, MD1 Nurten Uzun, MD1 Aysegul Gunduz, MD1 Metin Hallac, MD2 Meral Erdemir Kiziltan, MD1 Mehmet Ali Akalin, MD1 1
Department of Neurology, Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey Department of Nuclear Medicine Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey
2
MUSCLE & NERVE
June 2015
937
1. Titulaer MJ, Wirtz PW, Kuks JBM, Schelhaas HJ, van der Kooi AJ, Faber CG, et al. The Lambert–Eaton myasthenic syndrome 1988– 2008: a clinical picture in 97 patients. J Neuroimmunol 2008;201– 202:153–158. 2. O’Neill JH, Murray NM, Newsom-Davis J. The Lambert–Eaton myasthenic syndrome. A review of 50 cases. Brain 1988;111:577–596. 3. Tormoehlen LM, Pascuzzi RM. Thymoma, myasthenia gravis, and other paraneoplastic syndromes. Hematol Oncol Clin N Am 2008;22: 509–526. 4. Warren NM, Bennett M, Lai M, Forty J, Walls TJ. Lambert–Eaton myasthenic syndrome associated with thymitis. Neurology 2005;64: 168–169. 5. Pasqualoni E, Aubart F, Brihaye B, Sacr e K, Maisonobe T, Laissy J-P, et al. Lambert–Eaton myasthenic syndrome and follicular thymic hyperplasia in systemic lupus erythematosus. Lupus 2011;20:745–748. 6. Lauritzen M, Smith T, Fischer-Hansen B, Sparup J, Olesen J. Eaton– Lambert syndrome and malignant thymoma. Neurology 1980;30:634– 638. 7. Morimoto M, Osaki T, Nagara Y, Kodate M, Motomura M, Murai H. Thymoma with Lambert-Eaton myasthenic syndrome. Ann Thorac Surg 2010;89:2001–2003. 8. Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004;75:1135–1140. 9. El-Bawab H, Al-Sugair AA, Rafay M, Hajjar W, Mahdy M, Al-Kattan K. Role of flourine-18 fluorodeoxyglucose positron emission tomography in thymic pathology. Eur J Cardiothorac Surg 2007;31:731–736. 10. Lee JH, Shin HY, Kim SM, Sunwoo IN. A case of Lambert-Eaton myasthenic syndrome with small-cell lung cancer and transient increase in anti-acetylcholine-receptor-binding antibody titer. J Clin Neurol 2012;8:305–307. 11. Rozsa C, Vincent A, Aranyi Z, Kovacs GG, Komoly S, Illes Z. Paraneoplastic chronic demyelinating neuropathy and Lambert–Eaton myasthenic syndrome associated with multiple anti-neural antibodies and small-cell lung cancer. Ideggyogy Sz 2008;61:325–328. 12. Pittock SJ, Lucchinetti CF, Lennon VA. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol 2003; 53:580–587.
Published online 20 February 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24610
--------------------------------------------------------HIGH PREVALENCE OF INCREASED NERVE VASCULARIZATION IN HEALTHY INDIVIDUALS Several studies have suggested that increased nerve vascularization, as detected by color Doppler ultrasonography, is highly associated with pathology; for example, carpal tunnel syndrome,1 ulnar neuropathy,2 and chronic inflammatory demyelinating polyneuropathy (CIDP).3 We examined nerve vascularization as part of a study to collect normal values for nerve ultrasound. In 60 healthy volunteers, 30 men and 30 women, we measured bilateral cross-sectional area (CSA) and nerve vasculariza-
tion of the median nerve at the wrist and forearm, ulnar nerve at the wrist, fibular nerve in the popliteal fossa and at the fibular head, and tibial nerve at the ankle. We did not examine the ulnar nerve at the elbow because we had already collected normal CSA values in previous work.4 We recruited normal volunteers from a variety of sources. Exclusion criteria were a history of diabetes, dialysis, a known neuropathy, or symptoms indicating a neuropathy (tingling sensations, numbness, or paresis). We used an ultrasound machine (ProSound Alpha 7 Premier; Hitachi Aloka) with 4–16-MHZ linear-array transducer. CSAs were measured on transverse scans within the hyperechoic rim surrounding the nerve. Nerve vascularization was examined by standard color and power Doppler imaging in cross-sectional and longitudinal planes. Settings were optimized to detect slow velocities; gain was set as high as possible without scatter artifacts. Pulse repetition frequency was then lowered to just above the level that artifacts appeared. Wall filter was on (level 4 out of 15). Nerve vascularization was scored as either present or absent. Statistical analyses were performed on right-sided measurements only. The study was approved by the medical ethics committee of our hospital. Mean age for men was 42.5 (range 18–77) years and for women 44.5 (19–75) years. The results of the ultrasound measurements are listed in Table 1. For CSA, upper limits of normal were calculated as the 95th percentile (ULN95), because most of the measurements were not normally distributed (Shapiro–Wilk test). There were no significant differences between CSA in men and women (Mann–Whitney U-test). Nerve vascularization was very common in the median nerve at the wrist (36% of examined nerves), whereas no vascularization was seen in the forearm and in the ulnar nerve at the wrist. Vascularization was also seen in the fibular nerve in the popliteal fossa (14%) and at the fibular head (4.2%), and the tibial nerve at the ankle (4.2%). The CSA of the median nerve at the wrist was higher in nerves with vascularization than in those without (median 8 mm2 vs. 7 mm2; Mann–Whitney U-test, P 5 0.029) and the CSA ULN95 (12.4 mm2 vs. 11.1 mm2). There was no association of vascularization in left and right median nerves (Fisher exact test, P 5 0.78). There were not enough measurements to stratify for vascularization in the other nerves.
Table 1. CSA and vascularization in the examined nerves. Vascularization N (%) Nerve, site Median nerve, wrist Median nerve, forearm Ulnar nerve, wrist Fibular nerve, popliteal fossa Fibular nerve, fibular head Tibial nerve, ankle
2
CSA ULN* (mm )
Right (N560)
Left (N560)
Bilateral (N560)
Total (N5120)
11.2 6.0 5.0 7.3 10.0 12.6
26 (43) 0 (0) 0 (0) 8 (13) 4 (6.7) 4 (6.7)
17 (28) 0 (0) 0 (0) 9 (15) 1 (1.7) 1 (1.7)
8 (13) 0 (0) 0 (0) 2 (3.3) 0 (0) 0 (0)
43 (36) 0 (0) 0 (0) 17 (14) 5 (4.2) 5 (4.2)
*Upper limit of normal, 95th percentile of the right side
938
Letters to the Editor
MUSCLE & NERVE
June 2015
FIGURE 1. Median repetitive nerve stimulation (RNS). The compound muscle action potentials (CMAPs) were recorded from the abductor pollicis brevis muscle in response to 3-HZ median nerve stimulation. One year before exacerbation, there was no decremental response (A). One day after admission, the first CMAP of the RNS train was decreased compared with the previous examination (note the different calibration markings), and the decremental response was 31.9% (B). Twelve days after admission, the first CMAP recovered, and RNS showed a normal response (C).
1. O’Riordan JI, Miller DH, Mottershead JP, Hirsch NP, Howard RS. The management and outcome of patients with myasthenia gravis treated acutely in a neurological intensive care unit. Eur J Neurol 1998;5:137–142. 2. Pascuzzi RM. Prepared by the Professional and Public Information Committee Myasthenia Gravis Foundation of America: Medications and myasthenia gravis (a reference for Health Care Professionals). Available at http://www.myasthenia.org/LinkClick.aspx?fileticket5 JuFvZPPq2vg%3d. Accessed September 26, 2014. 3. Harnett MT, Chen W, Smith SM. Calcium-sensing receptor: a highaffinity presynaptic target for aminoglycoside-induced weakness. Neuropharmacology 2009;57:502–505. 4. Jones SC, Sorbello A, Boucher RM. Fluoroquinolone-associated myasthenia gravis exacerbation: evaluation of postmarketing reports from the US FDA adverse event reporting system and a literature review. Drug Saf 2011;34:839–847. 5. Lindemann L, Jacobsen H, Schuhbauer D, Knoflach F, Gatti S, Wettstein JG, et al. In vitro pharmacological selectivity profile of oseltamivir prodrug (Tamiflu) and active metabolite. Eur J Pharmacol 2010;628:6–10. 6. Muraki K, Hatano N, Suzuki H, Muraki Y, Iwajima Y, Maeda Y, et al. Oseltamivir blocks human neuronal nicotinic acetylcholine receptormediated currents. Basic Clin Pharmacol Toxicol 2015;116:87–95. 7. Kimura S, Niwa Y, Iwajima Y, Nagano Y, Yamamoto S, Ohi Y, et al. High doses of oseltamivir phosphate induce acute respiratory arrest in anaesthetized rats. Basic Clin Pharmacol Toxicol 2012;111:232– 239. 8. Marty FM, Man CY, van der Horst C, Francois B, Garot D, Manez R, et al. Safety and pharmacokinetics of intravenous zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, single-arm, phase II study. J Infect Dis 2014;209:542–550.
Published online 5 February 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24594
--------------------------------------------------------Twelve days after admission, median RNS showed no decremental response, and the initial CMAP of the RNS train had improved (Fig. 1C). On discharge at day 44, her MG-ADL score was 2. Although respiratory infection is the most common cause of MG exacerbation,1 intravenous peramivir may have induced the respiratory failure in the patient described, because it developed within 20 minutes after drug administration and the symptoms recovered rapidly, with improvement in the RNS test. Her improvement may be a result of the discontinuation of peramivir, regardless of immunotherapy. Furthermore, the safety factor for neuromuscular transmission, which decreased subclinically, may have improved because of immunotherapy. MG exacerbation has been reported with various medications.2–4 A few neuraminidase inhibitors suppress respiratory function through mechanisms including ion channel/receptor inhibition.5–8 Therefore, we speculate that peramivir may inhibit ion channels/receptors in the neuromuscular junctions, leading to respiratory failure and MC. Further studies are necessary to understand the mechanism underlying MC induction by intravenous peramivir. 936
Letters to the Editor
LAMBERT–EATON MYASTHENIC SYNDROME ASSOCIATED WITH THYMIC NEUROENDOCRINE CARCINOMA Lambert–Eaton myasthenic syndrome (LEMS) is a disorder of neuromuscular transmission secondary to primary or paraneoplastic autoimmune processes in which the most common neoplasm is small-cell lung cancer (SCLC).1,2 Only a few reported cases have described LEMS in association with thymic pathology.1,3–7 We report a patient who was diagnosed as LEMS associated with thymic carcinoma. A 60-year-old man presented with a 3-month history of fatigue, dizziness upon standing, ptosis, dry mouth, difficulty walking, and dysphagia, more pronounced in the morning. Neurological examination revealed limitation in upward/downward gaze, weak gag reflex, dysphonia, proximal muscle weakness, and bilateral hypoactive deep Additional Supporting Information may be found in the online version of this article. C 2015 Wiley Periodicals, Inc. V
MUSCLE & NERVE
June 2015
FIGURE 1. Total-body FDG-PET scan reveals a retrosternal right paramedian mediastinal mass, as indicated by the “3,” which suggests thymic carcinoma.
tendon reflexes. Routine biochemical tests and brain MRI were normal. Nerve conduction studies and needle electromyography findings were normal except for generalized lowamplitude compound muscle action potentials (CMAPs). The ulnar CMAP recorded from the abductor digiti minimi increased by >400% after 10 seconds of maximal voluntary exercise (refer to Fig. S1 in Supplementary Material available online). Low-frequency (2–3 HZ) repetitive nerve stimulation (RNS) of the same nerve showed an 18%–23% decrement (see Fig. S2 in Supplementary Material). RNS at 20, 30, and 50 HZ showed a >300% increment in CMAP amplitude of ulnar nerve (see Fig. S3 in Supplementary Material). The serum voltage-gated calcium channel (VGCC) antibody level was elevated significantly (728.80 pmol/L). Anti-acetylcholine receptor (antiAChR) antibody was negative. Thus, the diagnosis was confirmed as LEMS. Thoracic computed tomography (CT) showed right paratracheal, hilar, and high anterior mediastinal lymphadenopathy. A paraneoplastic panel analysis revealed anti-Ri antibodies. A total body fluorodeoxyglucose-positron emission tomography (FDGPET) scan revealed a retrosternal right paramedian mediastinal mass, suggestive of thymic carcinoma (Fig. 1). Thymectomy was performed, and pathological examination showed atrophic thymus tissue surrounding a high-grade, poorly differentiated neuroendocrine carcinoma. All symptoms improved gradually over 1 month after thymectomy, and no need for immunotherapy was apparent at last follow-up 1 year after thymectomy. The case satisfies the criteria for a diagnosis of a paraneoplastic neurological syndrome.8 The patient was diagnosed clinically with LEMS, which is a classical paraneoplastic syndrome. Furthermore, he had anti-Ri positivity, among the most well-characterized onconeural antibodies. Major benefit after removal of the tumor by thymectomy is further evidence in support of the diagnosis of a paraneoplastic syndrome. Letters to the Editor
Thymic tumors are classified into 3 groups, thymomas, thymic carcinomas, and neuroendocrine thymic tumors (the rarest), according to the World Health Organization’s 2014 classification. They exhibit discrete immunohistochemical properties and have the capacity to secrete ectopic hormones, which contribute to the pathogenesis. However, SCLCs also belong to the neuroendocrine tumor family. Therefore, our case suggests possible underlying extrapulmonary neuroendocrine carcinoma in LEMS and the importance of investigating for this possibility. Unfortunately, we could not test expression of VGCC or staining for Ri proteins on tumor cells. Thoracic CT is currently considered to be the first choice to screen for thymoma, whereas FDG-PET is helpful for distinguishing between thymic hyperplasia, thymoma, and thymic carcinoma.9 However, in our patient, thoracic CT could not distinguish between these possibilities. FDGPET was of great benefit for determining the likelihood of thymic neuroendocrine carcinoma in this patient. In LEMS, increases in anti-AChR, anti-Hu, and anti-Ri antibodies have been described.10–12 We also found anti-Ri antibodies without evidence of other neurological/nonneurological paraneoplastic syndromes. The patient described here demonstrates the association between LEMS, VGCC, and anti-Ri antibodies and thymic carcinoma. This case highlights the constellation of paraneoplastic neurological features and emphasizes the role of thymic abnormalities in LEMS. Mecbure Nalbantoglu, MD1 Leyla Kose, MD1 Nurten Uzun, MD1 Aysegul Gunduz, MD1 Metin Hallac, MD2 Meral Erdemir Kiziltan, MD1 Mehmet Ali Akalin, MD1 1
Department of Neurology, Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey Department of Nuclear Medicine Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey
2
MUSCLE & NERVE
June 2015
937
1. Titulaer MJ, Wirtz PW, Kuks JBM, Schelhaas HJ, van der Kooi AJ, Faber CG, et al. The Lambert–Eaton myasthenic syndrome 1988– 2008: a clinical picture in 97 patients. J Neuroimmunol 2008;201– 202:153–158. 2. O’Neill JH, Murray NM, Newsom-Davis J. The Lambert–Eaton myasthenic syndrome. A review of 50 cases. Brain 1988;111:577–596. 3. Tormoehlen LM, Pascuzzi RM. Thymoma, myasthenia gravis, and other paraneoplastic syndromes. Hematol Oncol Clin N Am 2008;22: 509–526. 4. Warren NM, Bennett M, Lai M, Forty J, Walls TJ. Lambert–Eaton myasthenic syndrome associated with thymitis. Neurology 2005;64: 168–169. 5. Pasqualoni E, Aubart F, Brihaye B, Sacr e K, Maisonobe T, Laissy J-P, et al. Lambert–Eaton myasthenic syndrome and follicular thymic hyperplasia in systemic lupus erythematosus. Lupus 2011;20:745–748. 6. Lauritzen M, Smith T, Fischer-Hansen B, Sparup J, Olesen J. Eaton– Lambert syndrome and malignant thymoma. Neurology 1980;30:634– 638. 7. Morimoto M, Osaki T, Nagara Y, Kodate M, Motomura M, Murai H. Thymoma with Lambert-Eaton myasthenic syndrome. Ann Thorac Surg 2010;89:2001–2003. 8. Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004;75:1135–1140. 9. El-Bawab H, Al-Sugair AA, Rafay M, Hajjar W, Mahdy M, Al-Kattan K. Role of flourine-18 fluorodeoxyglucose positron emission tomography in thymic pathology. Eur J Cardiothorac Surg 2007;31:731–736. 10. Lee JH, Shin HY, Kim SM, Sunwoo IN. A case of Lambert-Eaton myasthenic syndrome with small-cell lung cancer and transient increase in anti-acetylcholine-receptor-binding antibody titer. J Clin Neurol 2012;8:305–307. 11. Rozsa C, Vincent A, Aranyi Z, Kovacs GG, Komoly S, Illes Z. Paraneoplastic chronic demyelinating neuropathy and Lambert–Eaton myasthenic syndrome associated with multiple anti-neural antibodies and small-cell lung cancer. Ideggyogy Sz 2008;61:325–328. 12. Pittock SJ, Lucchinetti CF, Lennon VA. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol 2003; 53:580–587.
Published online 20 February 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24610
--------------------------------------------------------HIGH PREVALENCE OF INCREASED NERVE VASCULARIZATION IN HEALTHY INDIVIDUALS Several studies have suggested that increased nerve vascularization, as detected by color Doppler ultrasonography, is highly associated with pathology; for example, carpal tunnel syndrome,1 ulnar neuropathy,2 and chronic inflammatory demyelinating polyneuropathy (CIDP).3 We examined nerve vascularization as part of a study to collect normal values for nerve ultrasound. In 60 healthy volunteers, 30 men and 30 women, we measured bilateral cross-sectional area (CSA) and nerve vasculariza-
tion of the median nerve at the wrist and forearm, ulnar nerve at the wrist, fibular nerve in the popliteal fossa and at the fibular head, and tibial nerve at the ankle. We did not examine the ulnar nerve at the elbow because we had already collected normal CSA values in previous work.4 We recruited normal volunteers from a variety of sources. Exclusion criteria were a history of diabetes, dialysis, a known neuropathy, or symptoms indicating a neuropathy (tingling sensations, numbness, or paresis). We used an ultrasound machine (ProSound Alpha 7 Premier; Hitachi Aloka) with 4–16-MHZ linear-array transducer. CSAs were measured on transverse scans within the hyperechoic rim surrounding the nerve. Nerve vascularization was examined by standard color and power Doppler imaging in cross-sectional and longitudinal planes. Settings were optimized to detect slow velocities; gain was set as high as possible without scatter artifacts. Pulse repetition frequency was then lowered to just above the level that artifacts appeared. Wall filter was on (level 4 out of 15). Nerve vascularization was scored as either present or absent. Statistical analyses were performed on right-sided measurements only. The study was approved by the medical ethics committee of our hospital. Mean age for men was 42.5 (range 18–77) years and for women 44.5 (19–75) years. The results of the ultrasound measurements are listed in Table 1. For CSA, upper limits of normal were calculated as the 95th percentile (ULN95), because most of the measurements were not normally distributed (Shapiro–Wilk test). There were no significant differences between CSA in men and women (Mann–Whitney U-test). Nerve vascularization was very common in the median nerve at the wrist (36% of examined nerves), whereas no vascularization was seen in the forearm and in the ulnar nerve at the wrist. Vascularization was also seen in the fibular nerve in the popliteal fossa (14%) and at the fibular head (4.2%), and the tibial nerve at the ankle (4.2%). The CSA of the median nerve at the wrist was higher in nerves with vascularization than in those without (median 8 mm2 vs. 7 mm2; Mann–Whitney U-test, P 5 0.029) and the CSA ULN95 (12.4 mm2 vs. 11.1 mm2). There was no association of vascularization in left and right median nerves (Fisher exact test, P 5 0.78). There were not enough measurements to stratify for vascularization in the other nerves.
Table 1. CSA and vascularization in the examined nerves. Vascularization N (%) Nerve, site Median nerve, wrist Median nerve, forearm Ulnar nerve, wrist Fibular nerve, popliteal fossa Fibular nerve, fibular head Tibial nerve, ankle
2
CSA ULN* (mm )
Right (N560)
Left (N560)
Bilateral (N560)
Total (N5120)
11.2 6.0 5.0 7.3 10.0 12.6
26 (43) 0 (0) 0 (0) 8 (13) 4 (6.7) 4 (6.7)
17 (28) 0 (0) 0 (0) 9 (15) 1 (1.7) 1 (1.7)
8 (13) 0 (0) 0 (0) 2 (3.3) 0 (0) 0 (0)
43 (36) 0 (0) 0 (0) 17 (14) 5 (4.2) 5 (4.2)
*Upper limit of normal, 95th percentile of the right side
938
Letters to the Editor
MUSCLE & NERVE
June 2015
