Inclusion Body Myositis

  • Author: Michael P Collins, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
 
Updated: May 06, 2016
 

Background

Sporadic inclusion body myositis (s-IBM) and hereditary inclusion body myopathies (h-IBM) encompass a group of disorders sharing the common pathological finding of vacuoles and filamentous inclusions. They collectively demonstrate a wide variation in clinical expression, age of onset, associated diseases, and prognosis. This article focuses on s-IBM. For discussion of h-IBM, the reader is referred to other sources.[1, 2]

The term inclusion body myositis was originally used by Yunis and Samaha in 1971 for a case of myopathy that phenotypically suggested chronic polymyositis but showed cytoplasmic vacuoles and inclusions on muscle biopsy. In the subsequent years, s-IBM has been increasingly recognized and reported, primarily because of increased awareness of the condition and improved histologic techniques. A relatively common myopathic process, s-IBM is an important diagnostic consideration in the evaluation of progressive weakness in older Caucasian males.

Expression of s-IBM is variable, but all cases eventually evolve into a syndrome of diffuse, progressive, asymmetric, proximal, and distal weakness that is generally refractory to immunosuppressive treatment.

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Pathophysiology

s-IBM has been traditionally classified as one of the idiopathic inflammatory myopathies along with dermatomyositis (DM) and polymyositis (PM). However, the pathologic findings of sporadic inclusion body myositis (s-IBM) involve both inflammatory and degenerative characteristics, and the true primary pathogenesis of the disease remains a subject of significant debate. Theoretically, the possibilities include (1) a primary T-cell mediated autoimmune response causing muscle damage, (2) a primary degenerative process involving abnormal protein processing leading to a secondary inflammatory response, and (3) separate and independent immune and degenerative processes caused by an external trigger.[3]

Inflammatory changes

s-IBM is characterized by the presence of non-necrotic myofibers invaded by mononuclear inflammatory cells, which, as a pathologic phenomenon, is significantly more common than vacuolated, congophilic, and necrotic fibers.[4, 5] It is found at all stages of the disease in both treated and untreated patients.

The endomysial infiltrates in patients with s-IBM are composed primarily of CD8+ T cells and macrophages in a 2:1 ratio.[6] Myeloid dendritic (antigen-presenting) and CD138+ plasma cells are also present in substantial numbers,[7, 8] while B cells and natural killer (NK) cells are rare. T cells, macrophages, and myeloid dendritic cells all have the potential to invade non-necrotic muscle fibers.[9] The autoinvasive CD8+ T cells surround major histocompatibility complex (MHC) class I-immunoreactive myofibers and express perforin and other markers of activation.[10, 11, 12]

Identical autoinvasive T-cell clones can persist over time, even in different muscles,[13, 14] but the amplified subfamilies sometimes change, which suggests of epitope spreading.[15] Collectively, these observations implicate an antigen-driven, MHC class I-restricted, cytotoxic T-cell–mediated process directed against myofibers. The specific antigens responsible for this reaction are unknown.

Various chemokines, cytokines, and chemokine receptors are upregulated in the inflammatory cell infiltrates, blood vessels, and myofibers in s-IBM.[16] In microarray experiments, cytokine and chemokine genes are differentially upregulated to a significantly greater degree in s-IBM and polymyositis than in dermatomyositis.[17, 18]

Humoral immunity may also play a role in the pathogenesis of s-IBM. Microarray studies have shown that many of the highest differentially expressed genes in s-IBM are immunoglobulin (Ig) genes. Indeed, Ig gene transcripts are expressed to a much greater degree in s-IBM and polymyositis than in dermatomyositis.[17, 18] Although B cells are rarely encountered in s-IBM muscle, plasma cells occur in the endomysium of patients with s-IBM in numbers 4 times higher than B cells.[7] Moreover, an analysis of antigen receptor H chain gene transcripts of B and plasma cells isolated from s-IBM muscle showed evidence of clonal expansion and variation, isotype switching, and somatic hypermutation, indicative of a local antigen-driven humoral response.[19]

Additional evidence for a primary immune etiology includes the fact that as many as 20-33% of patients with s-IBM have a concomitant systemic or neurologic autoimmune disease.[20, 21] Monoclonal gammopathies are identified with increased frequency in patients with s-IBM compared to age-related controls.[22] In addition, s-IBM is known to occur in association with chronic viral infections known to produce immune dysregulation (eg, HIV, human T-cell lymphotrophic virus I [HTLV-I], and hepatitis C).[23, 24, 25, 26]

Degenerative changes

Despite the preceding arguments in favor of an adaptive immune response in s-IBM, a purely autoimmune hypothesis for s-IBM is untenable because of the disease's resistance to most immunotherapy. Therefore, the alternate theory has arisen that s-IBM is a primarily degenerative disorder related to aging of the muscle, supported by the finding of abnormal, potentially pathogenic protein accumulations in myofibers.

Myofibers in s-IBM exhibit vacuolization, atrophy, abnormal myonuclei,[27, 28] and deposits of degeneration-associated proteins. Similar to actions in Alzheimer disease, myofibers in s-IBM accumulate amyloid-β (Aβ), phosphorylated tau (p-tau), apolipoprotein E, presenilin-1, the normal cellular isoform of prion protein (PrPc), and many other characteristic proteins.[29, 30, 31] Two major types of protein aggregates are found in s-IBM myofibers: (1) rounded, plaquelike, Aβ inclusion bodies; and (2) linear, squiggly, p-tau inclusions (paired helical filaments).[29, 30] Both are amyloidogenic.

In general, protein aggregation ensues from the binding of unfolded and misfolded polypeptides.[32] Unfolded and misfolded proteins, in turn, result from increased transcription, impaired disposal, abnormal crowding, or abnormal posttranslational modification of proteins, as might be induced by oxidative stress, various toxins, and aging. A specifically proposed mechanism involved in the formation of protein aggregates in s-IBM is inhibition of the ubiquitin-26S proteosome system, which is the primary degradation pathway for misfolded, unfolded, and other damaged proteins.[32, 33]

Of these various alien molecules, Aβ is putatively toxic.[34] Soluble Aβ oligomers are believed to be more cytotoxic than the insoluble β-pleated sheets.[35] Aβ accumulation results from increased synthesis and abnormal processing of amyloid precursor protein (APP) in s-IBM muscle.[36] Askanas and Engel have proposed that overexpression of APP and accumulation of toxic Aβ oligomers are early upstream events in the pathogenesis of s-IBM, predisposing to tau phosphorylation, oxidative stress, proteosomal inhibition, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and, hence, abnormal signal transduction and transcription.[37, 38] That said, the accumulation of Aβ in s-IBM myofibers has been challenged.[39]

Accumulation of unfolded or misfolded proteins in the ER triggers the unfolded protein response (UPR), which is a survival mechanism.[40, 41] The UPR comprises (1) the transcriptional induction of ER chaperone proteins to facilitate the folding, processing, and export of secretory proteins; (2) translational attenuation to reduce protein overload; and (3) increased retrotranslocation of misfolded proteins into the cytoplasm for ubiquitination and subsequent proteosomal degradation. In s-IBM muscle, expression of ER chaperone proteins is increased, colocalized with Aβ and APP, suggesting that the UPR is activated in s-IBM and promotes proper APP folding.[42] Another protective agent is heat shock protein (HSP) 70, which promotes refolding of Aβ and other misfolded or unfolded proteins.[30]

Several protein kinases are also involved in the s-IBM pathogenic cascade. Kinases that promote tau phosphorylation include cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase-3β (GSK-3β). Both Cdk5 and GSK-3β are strongly expressed in vacuolated myofibers, where they colocalize with p-tau and the paired helical filaments.[43, 29] Lithium inhibits GSK-3β and was shown to decrease tau phosphorylation in a transgenic mouse model of s-IBM.[44] Its clinical efficacy in s-IBM is now being investigated in a pilot study.

Most of the rimmed vacuoles in s-IBM are autophagic and composed of lysosomes.[24, 45, 46] Accumulated Aβ and APP are specific targets of macroautophagy in this disease.[46] However, some of the vacuoles lack lysosomal features and instead contain nuclear proteins, suggesting that they result from the breakdown of myonuclei.[47, 48] Nuclear membrane remnants (lamin A/C and emerin), nuclear histones, and the nuclear transcription factor pElk-1 have been found in rimmed vacuoles.[47, 49] Thus, the formation of rimmed vacuoles in s-IBM is probably mediated by more than one mechanism.

As a likely secondary phenomenon, various mitochondrial abnormalities have been identified in s-IBM muscle, including ragged red fibers, cytochrome c oxidase-deficient fibers, and multiple mitochondrial DNA (mtDNA) mutations.[50, 51, 52] These changes might be mediated by aberrant mtDNA replication and maintenance due to oxidative stress, abnormal APP overexpression,[53] or proinflammatory cytokines.[54]

The downstream pathologic effects of the degenerative process were investigated in a recent proteomic, histochemical, and immunohistochemical study, which demonstrated preferential type 2 (fast twitch) myofiber involvement in most s-IBM muscles.[55] In particular, many fast twitch-specific structural proteins were differentially reduced. Expression of the corresponding gene transcripts was relatively preserved, suggesting that the protein loss was not caused by transcriptional failure. Four glycolytic enzymes were also decreased, especially glycogen-debranching enzyme.

Possible links between degenerative and inflammatory changes

Theoretically, the abnormal protein accumulations in s-IBM could be linked to the T-cell–mediated immune response by way of self-antigen presentation in MHC I/II-expressing myofibers. For example, immunoproteosome subunits are upregulated in s-IBM myofibers at sites of pathologic protein accumulation, sometimes colocalized with MHC I.[56] The immunoproteosome is specialized to produce antigenic peptides that can be presented by MHC class I molecules to CD8+ T cells.[57] Similarly, autophagosomes process intracellular antigens for MHC II presentation and CD4+ T cell recognition.[58] Thus, Aβ might be presented to CD4+ and CD8+ cells by degenerating myofibers in s-IBM, with an ensuing autoreactive T-cell response.

In addition, ER stress and the UPR can initiate inflammation via multiple intracellular signaling pathways.[59] However, the myofibers invaded by T cells in s-IBM are almost never vacuolated, and the vacuolated fibers are almost never surrounded by mononuclear inflammatory cells, arguing against a cytotoxic T-cell response to Aβ or any other abnormally accumulated protein in s-IBM.[4]

Alternatively, the inflammatory milieu within s-IBM muscle fibers might lead to the accumulation of misfolded MHC-related glycoproteins and trigger the overproduction of APP, Aβ, p-tau, and other such proteins, creating ER stress.[60, 3] In s-IBM, proinflammatory cytokines and chemokines correlate with the intramuscular accumulation of APP.[12] Exposure to IL-1β in particular might produce upregulation of APP with subsequent AB-associated degeneration. In a transgenic mouse model of IBM, lipopolysaccharide-induced inflammation increased steady state levels of APP and enhanced tau-phosphorylation in skeletal muscle, possibly secondary to proinflammatory cytokine (IL-1β, IL-6, and TNF-α)-mediated upregulation of the glycogen synthase kinase-3B (GSK-3B) signaling pathway.[44]

Of course, neither APP/Aβ-induced toxicity nor CD8+ T-cell–mediated cytotoxicity may be the primary event in s-IBM. In this regard, muscle biopsy specimens in patients with s-IBM harbor numerous alpha-B-crystallin-immunoreactive myofibers in the absence of any significant structural abnormality.[61] These "X fibers" are several-fold more frequent than necrotic, regenerating, vacuolated, and non-necrotic/invaded fibers and are many times more frequent than fibers with Congo red-, phosphorylated tau-, or ubiquitin-positive inclusions.

Alpha-B-crystallin is a small HSP, but the expression of other HSPs and markers of oxidative stress are not increased in X fibers, arguing against the presence of a nonspecific stress response or oxidative stress in these fibers. The implication of this finding is that increased expression of alpha-B-crystallin is an early event in the pathogenesis of s-IBM, triggered by an unidentified stressor acting upstream to the development of vacuolated, necrotic, invaded, and congophilic fibers. Engel has speculated that this stressor might be a viral infection or mutated gene.[61, 29] Muth et al demonstrated an association between alpha-B-crystallin and APP/Aβ in X-fibers, supporting an early inflammatory response, with subsequent degenerative Aβ accumulation and vacuolar changes.[62]

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Epidemiology

Frequency

United States

s-IBM is considered the most common acquired myopathy in patients older than 50 years and accounts for 16-28% of inflammatory myopathies in the United States and Canada.

International

In 2 population-based studies, a prevalence of 4.9 per million was reported in the Netherlands (which was felt to be an underestimate) and 9.3 per million in western Australia. The corresponding figures for individuals older than 50 years were 16 and 35.3 per million, respectively.[63, 64] A western Australian survey in 2006 revealed a prevalence of 39.5 per million for individuals older than 50 years (unpublished).

Mortality/Morbidity

The slow, relentless progression of muscle weakness in s-IBM leads to difficulty with ambulation, frequent falls, and eventual need for assistive-gait devices. Bone fractures and other complications may occur as a result of falls. Patients are often significantly disabled because of finger flexor weakness.

In a study of gait in 42 persons with s-IBM, muscle force values were found to be significantly lower than predicted values (P < .001). During habitual walking, gait speed and cadence were ≤83% of normal values. During fast walking, total gait cycle time was 133% of normal, while gait speed and cadence were 58% and 78%, respectively, of normal.[65]

Dysphagia due to weakness of the cricopharyngeal musculature may predispose individuals to aspiration pneumonia.

Mortality rate is difficult to assess based on current data. Affected individuals tend to be older, the disease is insidious and chronic, and patients often die of other medical problems. In a population-based study, the mean age of death of patients with s-IBM was not significantly different from that of the general population. Cause of death was disease-related (aspiration pneumonia and respiratory insufficiency) in 2 of 22 reported deaths.[63] In a 12-year follow-up study in the Netherlands, life expectancy was normal (81 years), although activities of daily living were restricted.[66] The most common cause of death was respiratory system disorders.

Race

No race predilection for s-IBM is known, but the condition has been noted to be uncommon among African Americans, Koreans, and Mesoamerican Mestizos.[67]

Sex

Reported male-to-female ratio ranges from 1.4:1 to 3:1.[68, 64, 63]

Age

Age of onset ranges from the late second to ninth decades. Mean age of onset is 56-60 years.[68, 63, 64]

While a large majority of individuals develop symptoms when older than 50 years, 17-20% present before the age of 50.[68, 69, 63]

The diagnosis of inclusion body myositis is often delayed by a mean of 5-8 years from time of symptom onset.[68, 63, 70, 69, 71]

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Contributor Information and Disclosures
Author

Michael P Collins, MD Associate Professor, Department of Neurology, Medical College of Wisconsin

Michael P Collins, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Peripheral Nerve Society, World Muscle Society

Disclosure: Nothing to disclose.

Coauthor(s)

Paul E Barkhaus, MD Professor of Neurology and Physical Medicine and Rehabilitation, Department of Neurology, Medical College of Wisconsin; Section Chief, Neuromuscular and Autonomic Disorders, Department of Neurology, Director, ALS Program, Medical College of Wisconsin

Paul E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

M Isabel Periquet Collins, MD Assistant Professor, Department of Neurology, Medical College of Wisconsin

M Isabel Periquet Collins, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Helen C Lin, MD Assistant Professor of Neurology, Medical College of Wisconsin

Helen C Lin, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Phi Beta Kappa

Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, MHA, CPE Founding Editor-in-Chief, eMedicine Neurology; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc

Nicholas Lorenzo, MD, MHA, CPE is a member of the following medical societies: Alpha Omega Alpha, American Association for Physician Leadership, American Academy of Neurology

Disclosure: Nothing to disclose.

Additional Contributors

Dianna Quan, MD Professor of Neurology, Director of Electromyography Laboratory, University of Colorado School of Medicine

Dianna Quan, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Neurological Association

Disclosure: Nothing to disclose.

Acknowledgements

Dr. Barkhaus acknowledges support in part from the Department of Veterans Affairs. Disclaimer: This article does not necessarily reflect the views of the Department of Veterans Affairs or the United States Government.

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Helen C Lin, MD, to the original writing and development of this topic.

References
  1. Argov Z. Hereditary inclusion body myopathies. In: Engel AG, Franzini-Armstrong C, eds. Myology. 3rd ed. New York: McGraw Hill. 2004:1311-1320.

  2. Malicdan MC, Noguchi S, Nishino I. Recent advances in distal myopathy with rimmed vacuoles (DMRV) or hIBM: treatment perspectives. Curr Opin Neurol. 2008 Oct. 21(5):596-600. [Medline].

  3. Karpati G, O'Ferrall EK. Sporadic inclusion body myositis: pathogenic considerations. Ann Neurol. 2009 Jan. 65(1):7-11. [Medline].

  4. Pruitt JN, Showalter CJ, Engel AG. Sporadic inclusion body myositis: counts of different types of abnormal fibers. Ann Neurol. 1996 Jan. 39(1):139-43. [Medline].

  5. Greenberg SA. Pathogenesis and therapy of inclusion body myositis. Curr Opin Neurol. 2012 Oct. 25(5):630-9. [Medline].

  6. Engel AG, Arahata K. Monoclonal antibody analysis of mononuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol. 1984 Aug. 16(2):209-15. [Medline].

  7. Greenberg SA, Bradshaw EM, Pinkus JL, Pinkus GS, Burleson T, Due B. Plasma cells in muscle in inclusion body myositis and polymyositis. Neurology. 2005 Dec 13. 65(11):1782-7. [Medline].

  8. Greenberg SA, Pinkus GS, Amato AA, Pinkus JL. Myeloid dendritic cells in inclusion-body myositis and polymyositis. Muscle Nerve. 2007 Jan. 35(1):17-23. [Medline].

  9. Tateyama M, Fujihara K, Misu T, Itoyama Y. CCR7+ myeloid dendritic cells together with CCR7+ T cells and CCR7+ macrophages invade CCL19+ nonnecrotic muscle fibers in inclusion body myositis. J Neurol Sci. 2009 Apr 15. 279(1-2):47-52. [Medline].

  10. Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. V: Identification and quantitation of T8+ cytotoxic and T8+ suppressor cells. Ann Neurol. 1988 May. 23(5):493-9. [Medline].

  11. Orimo S, Koga R, Goto K, et al. Immunohistochemical analysis of perforin and granzyme A in inflammatory myopathies. Neuromuscul Disord. 1994 May. 4(3):219-26. [Medline].

  12. Schmidt J, Barthel K, Wrede A, Salajegheh M, Bähr M, Dalakas MC. Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle. Brain. 2008 May. 131(Pt 5):1228-40. [Medline]. [Full Text].

  13. Amemiya K, Granger RP, Dalakas MC. Clonal restriction of T-cell receptor expression by infiltrating lymphocytes in inclusion body myositis persists over time. Studies in repeated muscle biopsies. Brain. 2000 Oct. 123 (Pt 10):2030-9. [Medline].

  14. Muntzing K, Lindberg C, Moslemi AR, Oldfors A. Inclusion body myositis: clonal expansions of muscle-infiltrating T cells persist over time. Scand J Immunol. 2003 Aug. 58(2):195-200. [Medline].

  15. Salajegheh M, Rakocevic G, Raju R, Shatunov A, Goldfarb LG, Dalakas MC. T cell receptor profiling in muscle and blood lymphocytes in sporadic inclusion body myositis. Neurology. 2007 Oct 23. 69(17):1672-9. [Medline].

  16. De Paepe B, Creus KK, De Bleecker JL. Chemokine profile of different inflammatory myopathies reflects humoral versus cytotoxic immune responses. Ann N Y Acad Sci. 2007 Aug. 1109:441-53. [Medline].

  17. Greenberg SA, Sanoudou D, Haslett JN, et al. Molecular profiles of inflammatory myopathies. Neurology. 2002 Oct 22. 59(8):1170-82. [Medline].

  18. Raju R, Dalakas MC. Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIg and biological validation of clinically relevant genes. Brain. 2005 Aug. 128(Pt 8):1887-96. [Medline].

  19. Bradshaw EM, Orihuela A, McArdel SL, Salajegheh M, Amato AA, Hafler DA, et al. A local antigen-driven humoral response is present in the inflammatory myopathies. J Immunol. 2007 Jan 1. 178(1):547-56. [Medline].

  20. Koffman BM, Rugiero M, Dalakas MC. Immune-mediated conditions and antibodies associated with sporadic inclusion body myositis. Muscle Nerve. 1998 Jan. 21(1):115-7. [Medline].

  21. Badrising UA, Schreuder GM, Giphart MJ, et al. Associations with autoimmune disorders and HLA class I and II antigens in inclusion body myositis. Neurology. 2004 Dec 28. 63(12):2396-8. [Medline].

  22. Dalakas MC, Illa I, Gallardo E, Juarez C. Inclusion body myositis and paraproteinemia: incidence and immunopathologic correlations. Ann Neurol. 1997 Jan. 41(1):100-4. [Medline].

  23. Cupler EJ, Leon-Monzon M, Miller J, et al. Inclusion body myositis in HIV-1 and HTLV-1 infected patients. Brain. 1996 Dec. 119 (Pt 6):1887-93. [Medline].

  24. Tsuruta Y, Furuta A, Furuta K, Yamada T, Kira J, Iwaki T. Expression of the lysosome-associated membrane proteins in myopathies with rimmed vacuoles. Acta Neuropathol. 2001 Jun. 101(6):579-84. [Medline].

  25. Dalakas MC. Inflammatory, immune, and viral aspects of inclusion-body myositis. Neurology. 2006 Jan 24. 66(2 Suppl 1):S33-8. [Medline].

  26. Matsuura E, Umehara F, Nose H, Higuchi I, Matsuoka E, Izumi K. Inclusion body myositis associated with human T-lymphotropic virus-type I infection: eleven patients from an endemic area in Japan. J Neuropathol Exp Neurol. 2008 Jan. 67(1):41-9. [Medline].

  27. Carpenter S. Inclusion body myositis, a review. J Neuropathol Exp Neurol. 1996 Nov. 55(11):1105-14. [Medline].

  28. Karpati G, Pouliot Y, Carpenter S. Expression of immunoreactive major histocompatibility complex products in human skeletal muscles. Ann Neurol. 1988 Jan. 23(1):64-72. [Medline].

  29. Mikol J, Engel AG. Inclusion body myositis. In: Engel AG, Franzini-Armstrong C, eds. Myology. 3rd ed. NY: McGraw Hill. 2004: 1367-1388.

  30. Askanas V, Engel WK, Nogalska A. Inclusion body myositis: a degenerative muscle disease associated with intra-muscle fiber multi-protein aggregates, proteasome inhibition, endoplasmic reticulum stress and decreased lysosomal degradation. Brain Pathol. 2009 Jul. 19(3):493-506. [Medline].

  31. Levacic D, Peddareddygari LR, Nochlin D, Sharer LR, Grewal RP. Inclusion-body myositis associated with Alzheimer's disease. Case Rep Med. 2013. 2013:536231. [Medline]. [Full Text].

  32. Lee C, Yu MH. Protein folding and diseases. J Biochem Mol Biol. 2005 May 31. 38(3):275-80. [Medline].

  33. Ciechanover A. The ubiquitin proteolytic system: from a vague idea, through basic mechanisms, and onto human diseases and drug targeting. Neurology. 2006 Jan 24. 66(2 Suppl 1):S7-19. [Medline].

  34. Jayaraman M, Kannayiram G, Rajadas J. Amyloid toxicity in skeletal myoblasts: Implications for inclusion-body myositis. Arch Biochem Biophys. 2008 Jun 1. 474(1):15-21. [Medline].

  35. Glabe CG, Kayed R. Common structure and toxic function of amyloid oligomers implies a common mechanism of pathogenesis. Neurology. 2006 Jan 24. 66(2 Suppl 1):S74-8. [Medline].

  36. Vattemi G, Engel WK, McFerrin J, et al. BACE1 and BACE2 in pathologic and normal human muscle. Exp Neurol. 2003 Feb. 179(2):150-8. [Medline].

  37. Askanas V, Engel WK. Inclusion-body myositis: muscle-fiber molecular pathology and possible pathogenic significance of its similarity to Alzheimer''s and Parkinson''s disease brains. Acta Neuropathol. 2008 Dec. 116(6):583-95. [Medline]. [Full Text].

  38. Vattemi G, Nogalska A, King Engel W, D'Agostino C, Checler F, Askanas V. Amyloid-beta42 is preferentially accumulated in muscle fibers of patients with sporadic inclusion-body myositis. Acta Neuropathol. 2009 May. 117(5):569-74. [Medline].

  39. Greenberg SA. Comment on 'Interrelation of inflammation and APP in sIBM: IL-1beta induces accumulation of beta-amyloid in skeletal muscle'. Brain. 2009 Apr. 132(Pt 4):e106; author reply e107. [Medline].

  40. Mori K. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell. 2000 May 26. 101(5):451-4. [Medline].

  41. Zhang K, Kaufman RJ. Protein folding in the endoplasmic reticulum and the unfolded protein response. Handb Exp Pharmacol. 2006. 69-91. [Medline].

  42. Vattemi G, Engel WK, McFerrin J, Askanas V. Endoplasmic reticulum stress and unfolded protein response in inclusion body myositis muscle. Am J Pathol. 2004 Jan. 164(1):1-7. [Medline].

  43. Nakano S, Akiguchi I, Nakamura S, et al. Aberrant expression of cyclin-dependent kinase 5 in inclusion body myositis. Neurology. 1999 Nov 10. 53(8):1671-6. [Medline].

  44. Kitazawa M, Trinh DN, LaFerla FM. Inflammation induces tau pathology in inclusion body myositis model via glycogen synthase kinase-3beta. Ann Neurol. 2008 Jul. 64(1):15-24. [Medline].

  45. Kumamoto T, Ueyama H, Tsumura H, et al. Expression of lysosome-related proteins and genes in the skeletal muscles of inclusion body myositis. Acta Neuropathol (Berl). 2004 Jan. 107(1):59-65. [Medline].

  46. Lunemann JD, Schmidt J, Schmid D, Barthel K, Wrede A, Dalakas MC. Beta-amyloid is a substrate of autophagy in sporadic inclusion body myositis. Ann Neurol. 2007 May. 61(5):476-83. [Medline].

  47. Greenberg SA, Pinkus JL, Amato AA. Nuclear membrane proteins are present within rimmed vacuoles in inclusion-body myositis. Muscle Nerve. 2006 Oct. 34(4):406-16. [Medline].

  48. Nalbantoglu J, Karpati G, Carpenter S. Conspicuous accumulation of a single-stranded DNA binding protein in skeletal muscle fibers in inclusion body myositis. Am J Pathol. 1994 May. 144(5):874-82. [Medline].

  49. Nakano S, Shinde A, Fujita K, Ito H, Kusaka H. Histone H1 is released from myonuclei and present in rimmed vacuoles with DNA in inclusion body myositis. Neuromuscul Disord. 2008 Jan. 18(1):27-33. [Medline].

  50. Santorelli FM, Sciacco M, Tanji K, et al. Multiple mitochondrial DNA deletions in sporadic inclusion body myositis: a study of 56 patients. Ann Neurol. 1996 Jun. 39(6):789-95. [Medline].

  51. Horvath R, Fu K, Johns T, Genge A, Karpati G, Shoubridge EA. Characterization of the mitochondrial DNA abnormalities in the skeletal muscle of patients with inclusion body myositis. J Neuropathol Exp Neurol. 1998 May. 57(5):396-403. [Medline].

  52. Oldfors A, Moslemi AR, Jonasson L, Ohlsson M, Kollberg G, Lindberg C. Mitochondrial abnormalities in inclusion-body myositis. Neurology. 2006 Jan 24. 66(2 Suppl 1):S49-55. [Medline].

  53. Askanas V, McFerrin J, Baqué S, Alvarez RB, Sarkozi E, Engel WK. Transfer of beta-amyloid precursor protein gene using adenovirus vector causes mitochondrial abnormalities in cultured normal human muscle. Proc Natl Acad Sci U S A. 1996 Feb 6. 93(3):1314-9. [Medline]. [Full Text].

  54. Dalakas MC. Molecular immunology and genetics of inflammatory muscle diseases. Arch Neurol. 1998 Dec. 55(12):1509-12. [Medline].

  55. Parker KC, Kong SW, Walsh RJ, Salajegheh M, Moghadaszadeh B, Amato AA, et al. Fast-twitch sarcomeric and glycolytic enzyme protein loss in inclusion body myositis. Muscle Nerve. 2009 Jun. 39(6):739-53. [Medline]. [Full Text].

  56. Ferrer I, Martin B, Castano JG. Proteasomal expression, induction of immunoproteasome subunits, and local MHC class I presentation in myofibrillar myopathy and inclusion body myositis. J Neuropathol Exp Neurol. 2004 May. 63(5):484-98. [Medline].

  57. Dahlmann B. Proteasomes. Essays Biochem. 2005. 41:31-48. [Medline].

  58. Lunemann JD, Munz C. Autophagy in CD4+ T-cell immunity and tolerance. Cell Death Differ. 2009 Jan. 16(1):79-86. [Medline].

  59. Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008 Jul 24. 454(7203):455-62. [Medline]. [Full Text].

  60. Dalakas MC. Interplay between inflammation and degeneration: using inclusion body myositis to study "neuroinflammation". Ann Neurol. 2008 Jul. 64(1):1-3. [Medline].

  61. Banwell BL, Engel AG. AlphaB-crystallin immunolocalization yields new insights into inclusion body myositis. Neurology. 2000 Mar 14. 54(5):1033-41. [Medline].

  62. Muth IE, Barthel K, Bähr M, Dalakas MC, Schmidt J. Proinflammatory cell stress in sporadic inclusion body myositis muscle: overexpression of alphaB-crystallin is associated with amyloid precursor protein and accumulation of beta-amyloid. J Neurol Neurosurg Psychiatry. 2009 Dec. 80(12):1344-9. [Medline].

  63. Badrising UA, Maat-Schieman M, van Duinen SG, et al. Epidemiology of inclusion body myositis in the Netherlands: a nationwide study. Neurology. 2000 Nov 14. 55(9):1385-7. [Medline].

  64. Phillips BA, Zilko PJ, Mastaglia FL. Prevalence of sporadic inclusion body myositis in Western Australia. Muscle Nerve. 2000 Jun. 23(6):970-2. [Medline].

  65. Davenport TE, Benson K, Baker S, Gracey C, Rakocevic G, McElroy B, et al. Lower extremity peak force and gait kinematics in individuals with inclusion body myositis. Arthritis Care Res (Hoboken). 2014 Sep 8. [Medline].

  66. Cox FM, Titulaer MJ, Sont JK, Wintzen AR, Verschuuren JJ, Badrising UA. A 12-year follow-up in sporadic inclusion body myositis: an end stage with major disabilities. Brain. 2011 Nov. 134:3167-75. [Medline].

  67. Shamim EA, Rider LG, Pandey JP, O'Hanlon TP, Jara LJ, Samayoa EA. Differences in idiopathic inflammatory myopathy phenotypes and genotypes between Mesoamerican Mestizos and North American Caucasians: ethnogeographic influences in the genetics and clinical expression of myositis. Arthritis Rheum. 2002 Jul. 46(7):1885-93. [Medline].

  68. Lotz BP, Engel AG, Nishino H, et al. Inclusion body myositis. Observations in 40 patients. Brain. 1989 Jun. 112 (Pt 3):727-47. [Medline].

  69. Lindberg C, Persson LI, Bjorkander J, Oldfors A. Inclusion body myositis: clinical, morphological, physiological and laboratory findings in 18 cases. Acta Neurol Scand. 1994 Feb. 89(2):123-31. [Medline].

  70. Beyenburg S, Zierz S, Jerusalem F. Inclusion body myositis: clinical and histopathological features of 36 patients. Clin Investig. 1993 May. 71(5):351-61. [Medline].

  71. Sayers ME, Chou SM, Calabrese LH. Inclusion body myositis: analysis of 32 cases. J Rheumatol. 1992 Sep. 19(9):1385-9. [Medline].

  72. Badrising UA, Maat-Schieman ML, van Houwelingen JC, et al. Inclusion body myositis. Clinical features and clinical course of the disease in 64 patients. J Neurol. 2005 Dec. 252(12):1448-54. [Medline].

  73. Lotz BP, Engel AG, Nishino H, Stevens JC, Litchy WJ. Inclusion body myositis. Observations in 40 patients. Brain. 1989 Jun. 112 ( Pt 3):727-47. [Medline].

  74. Hund E, Heckl R, Goebel HH, Meinck HM. Inclusion body myositis presenting with isolated erector spinae paresis. Neurology. 1995 May. 45(5):993-4. [Medline].

  75. Kraemer P, Sagui E, Brosset C, et al. [Inclusion myositis associated with primary biliary cirrhosis of the liver]. Presse Med. 2003 Mar 15. 32(10):460. [Medline].

  76. Kanellopoulos P, Baltoyiannis C, Tzioufas AG. Primary Sjogren's syndrome associated with inclusion body myositis. Rheumatology (Oxford). 2002 Apr. 41(4):440-4. [Medline].

  77. Williams SF, Mincey BA, Calamia KT. Inclusion body myositis associated with celiac sprue and idiopathic thrombocytopenic purpura. South Med J. 2003 Jul. 96(7):721-3. [Medline].

  78. Cherin P, Menard D, Mouton P, et al. Macrophagic myofasciitis associated with inclusion body myositis: a report of three cases. Neuromuscul Disord. 2001 Jul. 11(5):452-7. [Medline].

  79. Wenzel J, Uerlich M, Gerdsen R, et al. Association of inclusion body myositis with subacute cutaneous lupus erythematosus. Rheumatol Int. 2001 Oct. 21(2):75-7. [Medline].

  80. Derk CT, Vivino FB, Kenyon L, Mandel S. Inclusion body myositis in connective tissue disorders: case report and review of the literature. Clin Rheumatol. 2003 Oct. 22(4-5):324-8. [Medline].

  81. Massawi G, Hickling P, Hilton D, Patterson C. Inclusion body myositis evolving in systemic lupus erythematosus? A case report. Rheumatology (Oxford). 2003 Aug. 42(8):1012-4. [Medline].

  82. Kovacs GG, Lindeck-Pozza E, Chimelli L, et al. Creutzfeldt-Jakob disease and inclusion body myositis: abundant disease-associated prion protein in muscle. Ann Neurol. 2004 Jan. 55(1):121-5. [Medline].

  83. Arnardottir S, Ansved T, Nennesmo I, Borg K. Report of a patient with inclusion body myositis and CD8+ chronic lymphocytic leukaemia--post-mortem analysis of muscle and brain. Acta Neurol Scand. 2001 Feb. 103(2):131-5. [Medline].

  84. Hengstman GJ, Brouwer R, Egberts WT, et al. Clinical and serological characteristics of 125 Dutch myositis patients. Myositis specific autoantibodies aid in the differential diagnosis of the idiopathic inflammatory myopathies. J Neurol. 2002 Jan. 249(1):69-75. [Medline].

  85. Sekul EA, Chow C, Dalakas MC. Magnetic resonance imaging of the forearm as a diagnostic aid in patients with sporadic inclusion body myositis. Neurology. 1997 Apr. 48(4):863-6. [Medline].

  86. Phillips BA, Cala LA, Thickbroom GW. Patterns of muscle involvement in inclusion body myositis: clinical and magnetic resonance imaging study. Muscle Nerve. 2001 Nov. 24(11):1526-34. [Medline].

  87. Arnardottir S, Svanborg E, Borg K. Inclusion body myositis--sensory dysfunction revealed with quantitative determination of somatosensory thresholds. Acta Neurol Scand. 2003 Jul. 108(1):22-7. [Medline].

  88. Rodríguez Cruz PM, Needham M, Hollingsworth P, Mastaglia FL, Hillman DR. Sleep disordered breathing and subclinical impairment of respiratory function are common in sporadic inclusion body myositis. Neuromuscul Disord. 2014 Aug 20. [Medline].

  89. Brady S, Squier W, Sewry C, Hanna M, Hilton-Jones D, Holton JL. A retrospective cohort study identifying the principal pathological features useful in the diagnosis of inclusion body myositis. BMJ Open. 2014 Apr 28. 4(4):e004552. [Medline]. [Full Text].

  90. Mendell JR, Sahenk Z, Gales T, Paul L. Amyloid filaments in inclusion body myositis. Novel findings provide insight into nature of filaments. Arch Neurol. 1991 Dec. 48(12):1229-34. [Medline].

  91. Griggs RC, Askanas V, DiMauro S, et al. Inclusion body myositis and myopathies. Ann Neurol. 1995 Nov. 38(5):705-13. [Medline].

  92. Salajegheh M, Pinkus JL, Taylor JP, Amato AA, Nazareno R, Baloh RH, et al. Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis. Muscle Nerve. 2009 Jul. 40(1):19-31. [Medline]. [Full Text].

  93. Breithaupt M, Schmidt J. Update on treatment of inclusion body myositis. Curr Rheumatol Rep. 2013 May. 15(5):329. [Medline].

  94. Needham M, Mastaglia FL. Sporadic inclusion body myositis: A review of recent clinical advances and current approaches to diagnosis and treatment. Clin Neurophysiol. 2016 Mar. 127 (3):1764-73. [Medline].

  95. Benveniste O, Guiguet M, Freebody J, Dubourg O, Squier W, Maisonobe T, et al. Long-term observational study of sporadic inclusion body myositis. Brain. 2011 Nov. 134:3176-84. [Medline].

  96. Barohn RJ, Amato AA, Sahenk Z, et al. Inclusion body myositis: explanation for poor response to immunosuppressive therapy. Neurology. 1995 Jul. 45(7):1302-4. [Medline].

  97. Rutkove SB, Parker RA, Nardin RA, et al. A pilot randomized trial of oxandrolone in inclusion body myositis. Neurology. 2002 Apr 9. 58(7):1081-7. [Medline].

  98. Badrising UA, Maat-Schieman ML, Ferrari MD, et al. Comparison of weakness progression in inclusion body myositis during treatment with methotrexate or placebo. Ann Neurol. 2002 Mar. 51(3):369-72. [Medline].

  99. Soueidan SA, Dalakas MC. Treatment of inclusion-body myositis with high-dose intravenous immunoglobulin. Neurology. 1993 May. 43(5):876-9. [Medline].

  100. Amato AA, Barohn RJ, Jackson CE, et al. Inclusion body myositis: treatment with intravenous immunoglobulin. Neurology. 1994 Aug. 44(8):1516-8. [Medline].

  101. Walter MC, Lochmuller H, Toepfer M, et al. High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol. 2000 Jan. 247(1):22-8. [Medline].

  102. Cherin P, Pelletier S, Teixeira A, et al. Intravenous immunoglobulin for dysphagia of inclusion body myositis. Neurology. 2002 Jan 22. 58(2):326. [Medline].

  103. Dalakas MC, Somies B, Dambrosia J, et al. Treatment of inclusion-body myositis with IVIg: A double blind, placebo-controlled study. Neurology. 1997. 48:712-716. [Medline].

  104. Dalakas MC, Koffman B, Fujii M, et al. A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology. 2001 Feb 13. 56(3):323-7. [Medline].

  105. Lindberg C, Trysberg E, Tarkowski A, Oldfors A. Anti-T-lymphocyte globulin treatment in inclusion body myositis: a randomized pilot study. Neurology. 2003 Jul 22. 61(2):260-2. [Medline].

  106. Muscle Study Group. Randomized pilot trial of betaINF1a (Avonex) in patients with inclusion body myositis. Neurology. 2001 Nov 13. 57(9):1566-70. [Medline].

  107. Muscle Study Group. Randomized pilot trial of high-dose betaINF-1a in patients with inclusion body myositis. Neurology. 2004 Aug 24. 63(4):718-20. [Medline].

  108. Barohn RJ, Herbelin L, Kissel JT, King W, McVey AL, Saperstein DS. Pilot trial of etanercept in the treatment of inclusion-body myositis. Neurology. 2006 Jan 24. 66(2 Suppl 1):S123-4. [Medline].

  109. Dalakas MC, Rakocevic G, Schmidt J, Salajegheh M, McElroy B, Harris-Love MO. Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis. Brain. 2009 Jun. 132(Pt 6):1536-44. [Medline].

  110. Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle Nerve. 2009 Mar. 39(3):283-96. [Medline].

  111. Terracciano C, Nogalska A, Engel WK, Askanas V. In AbetaPP-overexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of AbetaPP751 and GSK3beta activation: effects mitigated by lithium and apparently relevant to sporadic inclusion-body myositis. J Neurochem. 2010 Jan. 112(2):389-96. [Medline]. [Full Text].

  112. Hicks J. Comprehensive rehabilitative management of patients with polymyositis and dermatomyositis. In: Dalakas M, ed. Polymyositis and Dermatomyositis. Boston, Mass: Butterworth-Heinemann; 1988. 293-318.

  113. Liu LW, Tarnopolsky M, Armstrong D. Injection of botulinum toxin A to the upper esophageal sphincter for oropharyngeal dysphagia in two patients with inclusion body myositis. Can J Gastroenterol. 2004 Jun. 18(6):397-9. [Medline].

  114. Spector SA, Lemmer JT, Koffman BM, et al. Safety and efficacy of strength training in patients with sporadic inclusion body myositis. Muscle Nerve. 1997 Oct. 20(10):1242-8. [Medline].

  115. Johnson LG, Collier KE, Edwards DJ, Philippe DL, Eastwood PR, Walters SE, et al. Improvement in aerobic capacity after an exercise program in sporadic inclusion body myositis. J Clin Neuromuscul Dis. 2009 Jun. 10(4):178-84. [Medline].

  116. Rose MR, McDermott MP, Thornton CA, et al. A prospective natural history study of inclusion body myositis: implications for clinical trials. Neurology. 2001 Aug 14. 57(3):548-50. [Medline].

  117. Peng A, Koffman BM, Malley JD, Dalakas MC. Disease progression in sporadic inclusion body myositis: observations in 78 patients. Neurology. 2000 Jul 25. 55(2):296-8. [Medline].

  118. Amato AA, Gronseth GS, Jackson CE, et al. Inclusion body myositis: clinical and pathological boundaries. Ann Neurol. 1996 Oct. 40(4):581-6. [Medline].

  119. Askanas V, Engel WK. Inclusion-body myositis: a myodegenerative conformational disorder associated with Abeta, protein misfolding, and proteasome inhibition. Neurology. 2006 Jan 24. 66(2 Suppl 1):S39-48. [Medline].

  120. Askanas V, Engel WK. New advances in the understanding of sporadic inclusion-body myositis and hereditary inclusion-body myopathies. Curr Opin Rheumatol. 1995 Nov. 7(6):486-96. [Medline].

  121. Askanas V, Engel WK, McFerrin J, et al. Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology. 2003 Jul 22. 61(2):257-60. [Medline].

  122. Barkhaus PE. The electrodiagnostic evaluation of the patient with suspected myopathy. In Kincaid JC, ed. The Young, the Old, and the Weak: A Basic Course in Electrodiagnostic Medicine. Rochester, MN: American Association of Electrodiagnostic Medicine. 1998.

  123. Barkhaus PE, Periquet MI, Nandedkar SD. Quantitative electrophysiologic studies in sporadic inclusion body myositis. Muscle Nerve. 1999 Apr. 22(4):480-7. [Medline].

  124. Barohn RJ. The therapeutic dilemma of inclusion body myositis. Neurology. 1997 Mar. 48(3):567-8. [Medline].

  125. Behrens L, Kerschensteiner M, Misgeld T, et al. Human muscle cells express a functional costimulatory molecule distinct from B7.1 (CD80) and B7.2 (CD86) in vitro and in inflammatory lesions. J Immunol. 1998 Dec 1. 161(11):5943-51. [Medline].

  126. Brannagan TH, Hays AP, Lange DJ, Trojaborg W. The role of quantitative electromyography in inclusion body myositis. J Neurol Neurosurg Psychiatry. 1997 Dec. 63(6):776-9. [Medline].

  127. Chou SM. Myxovirus-like structures in a case of human chronic polymyositis. Science. 1967 Dec 15. 158(807):1453-5. [Medline].

  128. Civatte M, Bartoli C, Schleinitz N, et al. Expression of the beta chemokines CCL3, CCL4, CCL5 and their receptors in idiopathic inflammatory myopathies. Neuropathol Appl Neurobiol. 2005 Feb. 31(1):70-9. [Medline].

  129. Dabby R, Lange DJ, Trojaborg W, et al. Inclusion body myositis mimicking motor neuron disease. Arch Neurol. 2001 Aug. 58(8):1253-6. [Medline].

  130. Dahlbom K, Lindberg C, Oldfors A. Inclusion body myositis: morphological clues to correct diagnosis. Neuromuscul Disord. 2002 Nov. 12(9):853-7. [Medline].

  131. Danon MJ, Friedman M. Inclusion body myositis associated with progressive dysphagia: treatment with cricopharyngeal myotomy. Can J Neurol Sci. 1989 Nov. 16(4):436-8. [Medline].

  132. De Paepe B, De Bleecker JL. Beta-chemokine receptor expression in idiopathic inflammatory myopathies. Muscle Nerve. 2005 May. 31(5):621-7. [Medline].

  133. De Paepe B, De Keyzer K, Martin JJ, De Bleecker JL. Alpha-chemokine receptors CXCR1-3 and their ligands in idiopathic inflammatory myopathies. Acta Neuropathol (Berl). 2005 Jun. 109(6):576-82. [Medline].

  134. Dion E, Cherin P, Payan C, et al. Magnetic resonance imaging criteria for distinguishing between inclusion body myositis and polymyositis. J Rheumatol. 2002 Sep. 29(9):1897-906. [Medline].

  135. Ferrer I, Carmona M, Blanco R, et al. Involvement of clusterin and the aggresome in abnormal protein deposits in myofibrillar myopathies and inclusion body myositis. Brain Pathol. 2005 Apr. 15(2):101-8. [Medline].

  136. Ferrer I, Martin B, Castano JG, et al. Proteasomal expression, induction of immunoproteasome subunits, and local MHC class I presentation in myofibrillar myopathy and inclusion body myositis. J Neuropathol Exp Neurol. 2004 May. 63(5):484-98. [Medline].

  137. Figarella-Branger D, Civatte M, Bartoli C, Pellissier JF. Cytokines, chemokines, and cell adhesion molecules in inflammatory myopathies. Muscle Nerve. 2003 Dec. 28(6):659-82. [Medline].

  138. Fratta P, Engel WK, McFerrin J, et al. Proteasome inhibition and aggresome formation in sporadic inclusion-body myositis and in amyloid-beta precursor protein-overexpressing cultured human muscle fibers. Am J Pathol. 2005 Aug. 167(2):517-26. [Medline].

  139. Fratta P, Engel WK, Van Leeuwen FW, et al. Mutant ubiquitin UBB+1 is accumulated in sporadic inclusion-body myositis muscle fibers. Neurology. 2004 Sep 28. 63(6):1114-7. [Medline].

  140. Hermanns B, Molnar M, Schroder JM. Peripheral neuropathy associated with hereditary and sporadic inclusion body myositis: confirmation by electron microscopy and morphometry. J Neurol Sci. 2000 Oct 1. 179(S 1-2):92-102. [Medline].

  141. Jaworska-Wilczynska M, Wilczynski GM, Engel WK, et al. Three lipoprotein receptors and cholesterol in inclusion-body myositis muscle. Neurology. 2002 Feb 12. 58(3):438-45. [Medline].

  142. Krivickas LS, Amato AA, Krishnan G, et al. Preservation of in vitro muscle fiber function in dermatomyositis and inclusion body myositis: a single fiber study. Neuromuscul Disord. 2005 May. 15(5):349-54. [Medline].

  143. Li M, Dalakas MC. The muscle mitogen-activated protein kinase is altered in sporadic inclusion body myositis. Neurology. 2000 Apr 25. 54(8):1665-70. [Medline].

  144. Luciano CA, Dalakas MC. Inclusion body myositis: no evidence for a neurogenic component. Neurology. 1997 Jan. 48(1):29-33. [Medline].

  145. Monsonego A, Zota V, Karni A, et al. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest. 2003 Aug. 112(3):415-22. [Medline].

  146. Nakano S, Shinde A, Kawashima S, et al. Inclusion body myositis: expression of extracellular signal-regulated kinase and its substrate. Neurology. 2001 Jan 9. 56(1):87-93. [Medline].

  147. Nishino H, Engel AG, Rima BK. Inclusion body myositis: the mumps virus hypothesis. Ann Neurol. 1989 Mar. 25(3):260-4. [Medline].

  148. Oldfors A, Larsson NG, Lindberg C, Holme E. Mitochondrial DNA deletions in inclusion body myositis. Brain. 1993 Apr. 116 (Pt 2):325-36. [Medline].

  149. Oldfors A, Lindberg C. Diagnosis, pathogenesis and treatment of inclusion body myositis. Curr Opin Neurol. 2005 Oct. 18(5):497-503. [Medline].

  150. Parissis D, Karkavelas G, Taskos N, Milonas I. Inclusion body myositis in a patient with a presumed diagnosis of post-polio syndrome. J Neurol. 2003 May. 250(5):619-21. [Medline].

  151. Price P, Santoso L, Mastaglia F, et al. Two major histocompatibility complex haplotypes influence susceptibility to sporadic inclusion body myositis: critical evaluation of an association with HLA-DR3. Tissue Antigens. 2004 Nov. 64(5):575-80. [Medline].

  152. Raju R, Vasconcelos O, Granger R, Dalakas MC. Expression of IFN-gamma-inducible chemokines in inclusion body myositis. J Neuroimmunol. 2003 Aug. 141(1-2):125-31. [Medline].

  153. Sekul EA, Dalakas MC. Inclusion body myositis: new concepts. Semin Neurol. 1993 Sep. 13(3):256-63. [Medline].

  154. Van der Muelen MF, Hoogendijk JE, Moons KG, et al. Rimmed vacuoles and the added predictive value of SM-31 staining in diagnosing sporadic inclusion body myositis. Neuromuscular Disorders. 2001. 11:447-451.

  155. Verma A, Bradley WG, Adesina AM, et al. Inclusion body myositis with cricopharyngeus muscle involvement and severe dysphagia. Muscle Nerve. 1991 May. 14(5):470-3. [Medline].

  156. Verma A, Tandan R. TDP-43: a reliable immunohistochemistry marker for inclusion body myositis?. Muscle Nerve. 2009 Jul. 40(1):8-9. [Medline].

  157. Wiendl H, Mitsdoerffer M, Schneider D, et al. Human muscle cells express a B7-related molecule, B7-H1, with strong negative immune regulatory potential: a novel mechanism of counterbalancing the immune attack in idiopathic inflammatory myopathies. FASEB J. 2003 Oct. 17(13):1892-4. [Medline].

 
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Composite of 20 motor unit action potentials (MUAPs) recorded with a concentric needle electrode from the biceps brachii of a patient with s-IBM. Note the wide range in size and complexity in the MUAPs. Copyright, Paul E Barkhaus, MD, 2000, with permission.
Top - A large, complex motor unit action potential (MUAP; 5 phases, approximately 2500 microV amplitude and 3 ms duration) firing at a progressively increasing rate (ie, shifting left) at about 13 Hz in apparent isolation. In normal muscle, other motor units typically would be recruited at this threshold (calibration 500 microV/division vertical; 10 ms/division horizontal). In the bottom trace the sensitivity is increased to 100 microV/division vertical (no change in horizontal time base), showing very small motor unit action potentials (MUAPs) in the baseline on either side of the large MUAP. This phenomenon may give rise to a mistaken "neurogenic" impression of the MUAP, as these small potentials are overlooked easily or mistaken for baseline noise or fibrillation potentials. Note also that despite the large amplitude of this MUAP, the spikes include essentially no area, giving them a needle-like appearance. Copyright, Paul E Barkhaus, MD, 2000, with permission.
On the left are 3 motor unit action potentials (MUAPs) that have been "captured" from the same site and analyzed using a computer-assisted method. Note that the middle one has a satellite or "early" potential linked to it, characterized by the blackened/blurred area created by their superimposition to the left of the main portion of the MUAP. The reason for this is the increased variability in the interpotential interval on successive sweeps (ie, increased jitter). On the right, this middle MUAP is displayed in faster mode (9 sweeps). Note that on the fifth trace, the early component is absent, indicating a block. This shows the infrequent phenomenon in s-IBM of increased jitter and blocking, Copyright, Paul E Barkhaus, MD, 2000, with permission.
Interference pattern in biceps brachii. Top trace - Normal interference pattern at full effort (calibration - 500 microV/division vertical; 1 s/division horizontal). The middle trace is an interference pattern from a patient with severe s-IBM (calibration - 100 microV/division vertical; 1 s/division horizontal). This epoch of signal actually shows the patient going from minimal activation at the left (beginning of the sweep) to full effort on the far right. The "notch" just to the right of the second division mark shows a baseline shift from needle electrode movement. Overall, no amplitude change of "fullness" is seen going from minimal to full effort, and the amplitude of the signal epoch is less than half of what might be expected in normal muscle. The bottom trace is an expanded segment showing interference pattern from biceps brachii; this trace is from a patient with advanced s-IBM (calibration - 100 microV/division vertical; 10 ms/division horizontal), from the early or far left portion of the middle sweep (see "H" bar position between the middle and lower sweeps). This shows a relatively full baseline of small-amplitude, complex motor unit action potentials (MUAPs). Copyright, Paul E Barkhaus, MD, 2000, with permission.
Modified Gomori trichrome stained section showing (1) 2 muscle fibers (MFs) containing intracytoplasmic vacuoles (open arrows) and (2) mononuclear inflammatory infiltrates invading a nonnecrotic MF (solid arrow). Copyright, Isabel P Collins, MD, 2000, with permission.
Congo red-stained section showing apple green birefringent amyloid deposits within muscle fibers (MFs) (arrow). The MF on the right side of the section is focally surrounded and invaded by inflammatory cells. Courtesy of Jerry R Mendell, MD.
Electron micrograph showing characteristic 15-to18-nm tubulofilaments (arrow). Copyright, Isabel P Collins, MD, 2000, with permission.
Table 1. Clinical Differential Diagnosis of s-IBM
Disease Points of Differentiation
h-IBM Clinically and genetically heterogeneous group of diseases; positive family history; muscle biopsy features similar to s-IBM, but no inflammation
Polymyositis (PM)* Weakness usually symmetric and proximally predominant; occasional cardiac and pulmonary involvement; similar to s-IBM, biopsy shows endomysial inflammation with invasion of non-necrotic fibers by CD8+ cells, but unlike s-IBM, rimmed vacuoles and ragged red fibers are infrequent and amyloid deposits and tubulofilaments not seen (see Histologic Findings)
Dermatomyositis (DM) Weakness usually symmetric and proximally predominant; occasional cardiac and pulmonary involvement; characteristic skin lesions; characteristic biopsy findings (eg, perifascular atrophy, muscle infarcts, microvascular MAC deposits in the endomysium, focal capillary depletion, and conspicuous alterations in endothelial cells of endomysial microvasculature)
Oculopharyngeal muscular dystrophy (OPMD) Predominant involvement of oculopharyngeal musculature (no extraocular muscle involvement in s-IBM); biopsy shows vacuoles, myopathic changes, and infrequent tubulofilaments (similar to s-IBM) but no inflammation; biopsy also shows pathognomonic intranuclear filamentous inclusions having smaller diameters than s-IBM tubulofilaments in 2-9% of nuclei; genetic testing is available for OPMD (PABPN1 gene); rare, genetically distinct oculopharyngodistal variant in Japan
Late-onset distal myopathies Clinically and genetically heterogeneous group of diseases; positive family history unless sporadic case; biopsy may show rimmed vacuoles and tubulofilamentous inclusions in Welander, distal myopathy, Nonaka distal myopathy, and tibial muscular dystrophy, all of which can be classified as h-IBM. Gene testing is available for Nonaka distal myopathy (GNE) and tibial muscular dystrophy (titin).
Overlap myositis PM- or DM-like clinical and myopathological presentation but with additional systemic and serologic features diagnostic of an underlying connective tissue disease (eg, systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, scleroderma, or mixed connective tissue disease)
Myasthenia gravis Unlike s-IBM, extraocular muscles are routinely involved; weakness is usually symmetric and tends to fluctuate, increasing with repeated or sustained exertion; spontaneous remissions can occur; motor unit action potentials (MUAPs) are unstable (increased jitter), whereas jitter is typically normal in s-IBM; repetitive nerve stimulation often shows abnormal decrement (rare in s-IBM); antibodies to acetylcholine receptors or muscle-specific kinase (MuSK) absent in s-IBM
Motor neuron disease Upper motor neuron signs such as hyperreflexia and extensor plantar responses are not present in s-IBM; EMG in s-IBM may show neurogenic changes (ie, enlarged MUAPs), but these changes are relatively minor compared with predominance of smaller MUAPs, suggesting myopathy; fasciculation potentials are characteristic of motor neuron disease but rarely reported in s-IBM; recruitment is decreased in motor neuron disease and "early" in s-IBM; muscle biopsy in motor neuron disease shows denervation atrophy.
Acid maltase deficiency Weakness is typically proximal-predominant (torso included); respiratory failure seen in about one third of adults; EMG is myopathic, similar to that of s-IBM, but in acid maltase deficiency, insertional activity is prominently increased, with profuse complex repetitive and myotonic discharges, whereas myotonic discharges are not seen in s-IBM and complex repetitive discharges are uncommon; muscle biopsy shows lysosomal (acid phosphatase-positive), glycogen-laden (PAS-positive) vacuoles, foci of acid phosphatase reactivity in nonvacuolated fibers, and glycogen accumulation by electron microscopy.
Chronic inflammatory demyelinating polyradiculoneuropathy Weakness is usually both proximal and distal and mildly asymmetric, similar to s-IBM, but more often distally accentuated and lacking in the characteristic quadriceps/deep finger flexor emphasis of s-IBM; almost all patients have sensory signs and symptoms; examination shows diffuse hypo/areflexia; nerve conductions are abnormal, consistent with demyelination; EMG shows chronic reinnervational and no myopathic changes; serum creatine kinase (CK) is typically normal.
*Patients whose polymyositis does not respond to treatment and who have a clinical picture suggestive of s-IBM should be reevaluated. A repeat biopsy should be considered, as they may have s-IBM. Failure to confirm the diagnosis on initial biopsy may have been due to sampling error or insufficient processing.
Table 2. MUAP Features in Myopathy
Condition Changes in MUAP Features
Nonspecific abnormality Increased complexity (ie, phases, turns, late components)



Only amplitude reduced



Specific for myopathy Shortened duration (simple or nonpolyphasic MUAPs)



Area reduced



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