She had no medical or surgical past history. Clinical and laboratory examinations (erythrocyte sedimentation rate, C-reactive protein, and complete blood count) were otherwise normal. Sonography (Philips iU22 Ultrasound system with a L12-5 50 mm linear transducer) demonstrated a hypoechoic mass of the semitendinosus muscle, which had ill-defined margins. On axial and sagittal images (Fig. 1A,B), the semitendinosus muscle was infiltrated and enlarged. Muscle fibers were thickened, but their orientation was preserved. Doppler examination showed both central and peripheral hypervascularity of the muscle lesion. There was no extension to the adjacent hamstring muscles (biceps femoris or semimembranosus). MR imaging showed focal enlargement of the semitendinosus muscle, with normal signal intensity on T1-weighted images and homogeneous hyperintensity on STIR images. Homogeneous enhancement was observed after intravenous gadolinium administration (Fig. 1C). No other lesions were noted. Swelling and pain disappeared spontaneously within 2 weeks. A follow-up examination performed 4 weeks later showed complete resolution of MR abnormalities (Fig. 1D). The patient made a complete recovery. Long-term follow-up confirmed the final diagnosis of focal myositis. Focal myositis is a rare, benign, soft tissue pseudotumor, which was first described by Heffner et al.1 Isolated cases have been published,2–5 but only 1 study described MRI features in a series of 8 patients.6 The etiology is unknown.7,8 Focal myositis may affect both children and adults. Skeletal muscles of the lower extremities are typically involved, and the most commonly affected site is the thigh.8 Other locations have been reported.7 Steroids are commonly used for treatment, but the natural history is for disappearance without treatment.3,9 Several authors have described possible recurrence or evolution to polymyositis.1,6,9,10 The typical appearance on MR imaging is an isointense or slightly hypointense signal on T1-weighted unenhanced images with homogeneous contrast enhancement. Lesions are hyperintense on STIR sequences.6 MRI may occasionally show the persistence of muscle fiber orientation.11 The sonographic features of focal myositis have not been described previously. In our patient, sonography showed hypoechoic enlargement of the muscle. Ultrasound can more readily show the thickening of muscle fibers with persistence of fiber orientation better than any other imaging modality. In this patient, there was no history of trauma. Infectious myositis is another cause of myositis, but the clinical and laboratory features were not were not consistent with infection. Other inflammatory processes could be considered, such as proliferative fasciitis, but it was excluded due to the intramuscular location of the lesion. The only other pathology that we considered was polymyositis with focal onset. Because histology cannot differentiate between focal myositis and polymyositis with focal onset, muscle biopsy was not performed. Instead, follow-up examination showed disappearance of abnormalities, and was not consistent with proliferative myositis, polymyositis, or dermatomyositis. In conclusion, we report the sonographic features of focal myositis. In the evaluation of an intramuscular Letters to the Editor

mass, the persistence of fiber orientation can be considered a valuable sign to suggest myositis and rule out a neoplasm. However, one should also consider other inflammatory processes in the differential diagnosis. Long-term follow-up is necessary given the possible evolution to polymyositis, dermatomyositis, or proliferative myositis.1,9,10 Pierre-Eloi Laurent, MD1 Maud Larribe, MD1  Guenoun, MD1,2 Daphne Pierre Champsaur, MD, PhD1,2 Thomas Le Corroller, MD, PhD1,2 1

^pital Sainte Marguerite, Marseille, Service de Radiologie, Ho France  de Me decine de Marseille, Laboratoire d’Anatomie, Faculte Marseille, France 2

1. Heffner RR, Armbrustmacher VW, Earle KM. Focal myositis. Cancer 1977;40:301–306. 2. Moreno-Lugris C, Gonzalez-Gay MA, Sanchez-Andrade A, Blanco R, Basanta D, Ibanez D, et al. Magnetic resonance imaging: a useful technique in the diagnosis and follow up of focal myositis. Ann Rheum Dis 1996;55:856. 3. Jun J, Im S, Park JH, Yoo SH, Park G-Y. Focal myositis of unilateral leg. Ann Rehabil Med 2011;35:944–948. doi:10.5535/arm.2011.35.6.944. 4. .Kransdorf MJ, Temple HT, Sweet DE. Focal myositis. Skeletal Radiol 1998;27:283–287. 5. Binesh F, Taghipour S, Navabii H. Focal myositis of the thigh misdiagnosed radiologically as rhabdomyosarcoma. BMJ Case Rep 2011; 2011:10–12. doi:10.1136/bcr.12.2010.3574. 6. Gaeta M, Mazziotti S, Minutoli F, Genitori A, Toscano A, Rodolico C, et al. MR imaging findings of focal myositis: a pseudotumour that may mimic muscle neoplasm. Skeletal Radiol 2009;38:571–578. doi: 10.1007/s00256-009-0664-3. 7. Masson C, Hopp e E, Houitte R, Bouvard B. Myosite focale d’Heffner. Rev Rhum 2008;75:178–180. doi:10.1016/j.rhum.2007.10.616. 8. Llauger J, Bagu e S, Palmer J, Matıas-Guiu X, San Roman L, Doncel A. Focal myositis of the thigh: unusual MR pattern. Skeletal Radiol 2002;31:307–310. doi:10.1007/s00256-002-0494-z. 9. Smith AG, Urbanits S, Blaivas M, Grisold W, Russell JW. Clinical and pathologic features of focal myositis. Muscle Nerve 2000;23:1569– 1575. 10. Flaisler F, Blin D, Asencio G, Lopez FM, Combe B. Focal myositis: a localized form of polymyositis? J Rheumatol 1993;20:1414–1416. 11. Demir MK, Beser M, Akinci O. Case 118: Proliferative myositis. Radiology 2007;244:613–616. doi:10.1148/radiol.2442041504.

Published online 10 March 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24649

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MYASTHENIA GRAVIS ASSOCIATED WITH IPILIMUMAB AND NIVOLUMAB IN THE TREATMENT OF SMALL CELL LUNG CANCER T-lymphocyte–activating drugs are now used to treat solid tumors, as well as lymphoma.1–6 Nivolumab, an anti–PD-1 (programmed cell death-1 protein) monoclonal antibody, and ipilimumab, a CTLA-4 (cytotoxic Tlymphocyte–associated protein-4) inhibitor, are in clinical trials for several malignancies, including small-cell lung cancer (SCLC).1 Studies have suggested a link between susceptibility to myasthenia gravis (MG) and 4 single-nucleotide polymorphisms (SNPs) resulting from ineffective transcription of the CTLA-4 gene.7 Two case reports have linked MG with ipilimumab use for MUSCLE & NERVE

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melanoma, but there are no reports of MG occurring in association with other malignancies or with nivolumab.8,9 We present a case of a patient with SCLC who developed drug-induced MG shortly after induction with nivolumab and ipilimumab. A 70-year-old man with a 1-year history of stage 4 SCLC refractory to first-line cisplatin/etoposide chemotherapy and radiation presented with ptosis and diplopia 16 days after starting treatment with ipilimumab and nivolumab (NCT01928394).1 After developing symptoms, the agents were discontinued. MG was suspected, and repetitive nerve stimulation (RNS) demonstrated a decremental response (17%) to 3-HZ stimulation of the abductor digiti minimi. No facilitation was present to suggest Lambert–Eaton myasthenic syndrome (LEMS). Acetylcholine receptor binding antibodies were positive (1.64 nmol/L), as were modulating and striational antibodies. P/Q-type calciumchannel antibodies were absent. There was no thymoma on computed tomography imaging. He started prednisone 1 mg/kg (90 mg/day) at onset, followed by 3 sessions of plasmapheresis with improvement. He was discharged 7 days later on prednisone 90 mg/day, but was readmitted 1 day later with dyspnea and generalized weakness. He required intubation and did not improve despite a switch to intravenous methylprednisolone starting at 80 mg, and 3 additional sessions of plasmapheresis followed by 200 g (0.5 g/kg) of intravenous immunoglobulin. He had repeat RNS 9 days after his initial study, which showed a 25% decrement without post-exercise facilitation. His subsequent hospital course was complicated by complete heart block requiring pacemaker placement, sepsis, and bleeding duodenal ulcers. Medical care was withdrawn in concert with family’s wishes on hospital day 22. Ipilimumab and nivolumab monotherapy are established treatments for melanoma,3,8,9 and they are used in clinical trials for the treatment of other malignancies.1,4,6 Ipilimumab has been associated with druginduced MG and other autoimmune neurologic conditions (e.g., transverse myelitis), and the reported severity of ipilimumab-associated MG has ranged from mild fatigue to death.5,6 Given the rapid progression to respiratory failure, our patient highlights the potential risk of severe myasthenic crisis associated with ipilimumab. The severity may be explained by overstimulation of the patient’s immune system in response to his chemotherapeutic regimen and his coexisting SCLC.10,11 The exact mechanism of MG induction is unclear, but it is suspected to be due to cytotoxic T-lymphocyte activation.12 The possible role of nivolumab in causation is unclear. Neurologists should recognize ipilimumab and similar treatments as potential causes of MG. Development of MG symptoms during ipililmumab administration should result in prompt drug cessation and initiation of therapy directed at preventing myasthenic crisis. Aaron I. Loochtan, DO1 Myles S. Nickolich, MD2 Lisa D. Hobson-Webb, MD1 1 Department of Durham, North 2 Department of Durham, North

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Neurology, Duke University Medical Center, Carolina, USA Medicine, Duke University Medical Center, Carolina, USA

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1. A phase 1/2, open-label study of nivolumab monotherapy or nivolumab combined with ipilimumab in subjects with advanced or metastatic solid tumors (to be published). 2. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 2015;372;311–319. 3. Gibney GT, Kudchadkar RR, DeConti RC, Thebeau MS, Czupryn MP, Tetteh LF, et al. Safety, correlative markers and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. Clin Cancer Res 2015;21:712-720. 4. Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, et al. Nivolumab for Metastatic Renal Cell Carcinoma: results of a randomized phase II trial. J Clin Oncol 2014 Dec 1. pii: JCO.2014.59.0703. 5. Ramalingam SS, Mazie`res J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Phase II study of nivolumab (anti-PD-1, BMS936558, ONO-4538) in patients with advanced, refractory squamous non-small cell lung cancer: metastatic non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2014;90:1266–1267. 6. Tomasini P, Khobta N, Greillier L, Barlesi F. Ipilimumab: its potential in non-small cell lung cancer. Ther Adv Med Oncol 2012;4:43–50. 7. Mao HT, Wang XB, Zhang L, Gu HT. Studies on the genetic pathogenesis of myasthenia gravis caused by CTLA-4 gene polymorphism. Chinese J Med Genet 2004;21:574–578. 8. Johnson DB, Saranga-Perry V, Lavin PJM, Bryan Burnette W, Clark SW, Uskavitch DR, et al. Myasthenia gravis induced by ipilimumab in patients with metastatic melanoma. J Clin Oncol 2014;32:1–3. 9. Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro Oncol 2014;16:589–593. 10. Peltier AC, Black BK, Raj SR, Donofrio P, Robertson D, Biaggioni I. Coexistent autoimmune autonomic ganglionopathy and myasthenia gravis associated with non-small-cell lung cancer. Muscle Nerve 2010; 41:416–419. 11. Sakamaki Y, Yoon HE, Oda N. Non-small-cell lung cancer associated with non-thymomatous myasthenia gravis. Jpn J Thorac Cardiovasc Surg 2006;54:207–211. 12. Blanco P, Viallard JF, Pellegrin JL, Moreau JF. Cytotoxic T lymphocytes and autoimmunity. Curr Opin Rhumatol 2005;17: 731–734.

Published online 10 March 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24648

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DISTAL MYASTHENIA GRAVIS PRESENTING AS ISOLATED DISTAL MYOPATHY We read with great interest the article by Mongiovi and colleagues.1 They discussed 4 patients with neuromuscular junction (NMJ) disorders in whom the initial clinical/electrodiagnostic impression was of a myopathy. We recently saw a 47-year-old man with myasthenia gravis (MG) who had an 8-year history of slowly progressive hand weakness and was long suspected to have a distal upper limb myopathy. The patient had predominant involvement of finger extension with milder involvement of finger flexion, wrist flexion, and wrist and finger extension (Fig. 1). He had no ocular or bulbar symptoms and denied muscle fatigability or fluctuating weakness. Electromyography (EMG) on multiple occasions showed patchy spontaneous activity with low amplitude, short duration motor unit potentials in the distal upper limbs. Sensory nerve conduction studies were normal. The overall impression was of a chronic myopathy. He had a significant response to intravenous steroids on 2 occasions, but trials of multiple steroid-sparing agents including mycophenolate (which was ineffective at a dose of 1 g twice daily for 1 year) and azathioprine and methotrexate (which were associated with skin reactions) MUSCLE & NERVE

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