Journal of Neurology

, Volume 257, Issue 12, pp 2091–2093

Amyloid myopathy: a therapeutic trial for the rare and underdiagnosed myopathy with bortezomib


    • Department of NeurologyKyoto Prefectural University of Medicine
  • Reiko Mizutani
    • Department of NeurologyKyoto Prefectural University of Medicine
  • Reina Isayama
    • Department of NeurologyKyoto Prefectural University of Medicine
  • Chihiro Shimazaki
    • Department of HematologyKyoto Prefectural University of Medicine
  • Takahiko Tokuda
    • Department of NeurologyKyoto Prefectural University of Medicine
  • Masanori Nakagawa
    • Department of NeurologyKyoto Prefectural University of Medicine
Letter to the Editors

DOI: 10.1007/s00415-010-5642-0

Cite this article as:
Shiga, K., Mizutani, R., Isayama, R. et al. J Neurol (2010) 257: 2091. doi:10.1007/s00415-010-5642-0

Dear Sirs,

A 69-year-old woman was referred to our clinic because of a 6-month history of progressive muscle weakness. Five years previously, when she was diagnosed as having nephrotic syndrome, the renal biopsy showed deposition of AL-amyloid. Subsequent investigations revealed multiple myeloma with λ-type Bence-Jones protein at stage 3 according to the international staging system. A course of vincristine, doxorubicin and dexamethasone (VAD) and an additional course of cyclophosphamide were administered, followed by another course of melphalan (L-PAM) at age 67. The proteinuria slightly improved but persisted for 5 years, when proximal weakness developed.

Neurological examination revealed proximally dominant weakness with MRC scale 4 in the deltoid and 3 in the iliopsoas muscles and she was unable to stand up from a full squat. Serum creatine kinase (CK) elevated to 3,399 U/L. Electromyography showed a myogenic pattern with small motor unit potentials, fibrillation potentials and early recruitment pattern. Muscle biopsy revealed a variation of fiber size, little infiltration of inflammatory cells, and homogeneous accumulations beneath the muscle membrane (Fig. 1a). Congo red-positive materials were noted both in vessel walls and in muscle fibers (Fig. 1b, c, d) with fluorescence for rhodamine, consistent with amyloid deposition, the hallmark of amyloid myopathy. We were not able to identify whether the deposits were located beneath the basal lamina or the plasmalemma due to lack of electron microscopic preparation.
Fig. 1

Biopsied specimen of the left deltoid muscle. a Hematoxylin and eosin staining section revealed a small artery with thickened wall and muscle fibers with sarcoplasmic accumulations (inset). b Congo red staining section of the formalin-fixed tissue showed marked amyloid deposition in a perimysial vessel. c, d Congo red staining of the fresh frozen section was examined with rhodamine red. d Rhodamine red image overlaid on the transparent image, showing amyloid deposition in the muscle parenchyma (arrowheads) and the perimysial vessels (arrow). The figures a, c, and d are serial sections of the same part of the frozen sample. Scale bar 50 μm

Five years ago, the serum CK value was 110 U/L (Fig. 2). Two years later, when her nephrotic syndrome deteriorated, the CK elevated to 2,336 IU/L without overt weakness. Interestingly, after she received L-PAM, the CK decreased to 120 U/L just 1 month after the treatment. When girdle weakness developed 6 months ago, the CK again soared to 3,378 U/L. The fluctuation of CK and the amyloid deposition in the muscle led us to the diagnosis of amyloid myopathy due to multiple myeloma. We then administered two consecutive courses of bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11 for the first course and 1.0 mg/m2 on days 1, 4, 8, and 11 for the second course). The treatment reduced the proportion of myeloma cells from 16.8 to 1.2%. The CK started to fall a few weeks after the first course and eventually fell to 187 U/L 1 month after the second course, when she was able to rise from a sitting position more easily. However, multiple myeloma deteriorated in the following months and the CK again elevated to 694 U/L. She was not able to receive additional treatment because of her poor general status.
Fig. 2

The time course of serum creatine kinase and daily excretion of protein. Letters on top show administered medications. VAD vincristine, doxorubicin, and dexamethasone; CPA cyclophosphamide; L-PAM melphalan. The percentage on the bottom indicates the proportion of myeloma cells in bone marrow preparation. The CK value decreased in response to two different treatments, L-PAM and bortezomib. With administration of bortezomib, the daily excretion of urinary protein also decreased, another indicator of renal amyloidosis

Amyloid myopathy, a progressive myopathy in a proximally dominant fashion, is caused by a variety of primary amyloidoses, such as familial amyloidosis, AL-amyloidosis and multiple myeloma [13]. Postulated mechanisms include impaired muscle metabolism or failed electrical conduction by amyloid deposition beneath the muscle membrane [4, 5]. Therapeutic trials have included plasmapheresis, administration of corticosteroid, and high-dose chemotherapy; however, approximately 60% of these patients were non-responders [3]. Bortezomib can decrease the production of amyloid in 35% of patients with refractory multiple myeloma and AL-amyloidosis [6, 7], thus being a feasible treatment for amyloid myopathy. It is hypothesized that circulating amyloid and amyloid oligomers are in dynamic equilibrium between deposition and clearance [8]. By inhibiting production of amyloid, bortezomib can alleviate muscle injury from still undeposited amyloid or amyloid oligomers. We surmised that the decrease of CK following the administration of bortezomib in this patient reflected alleviation of muscle injury by reducing circulating amyloid. The incomplete recovery may suggest that relatively short courses of bortezomib were not sufficient or that bortezomib should have been administered earlier. We believe bortezomib remains a potential treatment for amyloid myopathy; however, a multicenter trial is mandatory.

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© Springer-Verlag 2010