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NEUROSAE 2018 ANNUAL MEETING EDITION (VOLUME 10, ISSUE 3)
QUESTION 60 OF 100
A 62 year old man presents with weakness and an increase number of falls. His medical history is significant for hypertension, diabetes, and prostate hypertrophy. His neurology examination is significant for 4/5 proximal weakness in the deltoids, biceps, and triceps and distal weakness in the finger flexors of 3/5. His hip flexion is 3/5 and knee extensors are 3/5 and flexors are 4/5 bilaterally. Distal LE strength is 5/5. Sensory examination shows a distal small fiber sensory neuropathy and his reflexes are 1+ throughout and absent at the ankle. His laboratory evaluation is significant for a CK of 335, HbA1c of 6.5, and normal thyroid function. An EMG & NCV study reveals an irritative myopathy and small fiber sensory distal neuropathy.
Results of which of the following laboratory studies is the most likely to confirm the diagnosis?
A. Anti-Jo-1 antibodies **
B. Anti-NT5C1a antibodies
C. Anti-HMG-CoA antibodies
D. Thyroid peroxidase antibodies
E. Anti-mitochondrial antibodies
** = Your answer
The salient features here are the slow, progressive clinical course, patient age and sex, and the pattern of weakness. The most likely diagnosis is an inflammatory myopathy. Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy/myositis after age 50 years and more commonly affects men. The duration of symptoms prior to diagnosis varies but typically ranges between 2 and 6 years after disease onset. The patient’s pattern of muscle involvement also is highly suggestive for this condition. In addition to proximal muscle weakness typical of myopathic conditions, patients with sIBM can have distal weakness, especially of the distal flexor muscles of the forearm that affect grip and wrist strength. These patients also may have quadriceps weakness equal to or more severe than that in the hip flexor or hamstring muscles, a finding associated with early and frequent falls. Other associated signs and symptoms include dysphagia in 40% of patients with severe disease, which necessitates peg tube placement. Up to one third of patients may have an small fiber axonal neuropathy, as well.
The diagnosis has been solely based on clinical presentation, history, and results of muscle biopsy. The classic pathology is endomysial T cell infiltration with invasion of non-necrotic muscle fibers similar to polymyositis syndromes, the presence of rimmed vacuoles containing amyloid deposits and cytochrome C oxidase deficient fibers, and positive immune staining for autophagic-associated proteins p62 and TDP-43, as well as several other proteins implicated in other neurodegenerative disorders.
Unlike polymyositis and other inflammatory muscle disorders, sIBM is not responsive to therapy. A 2013 study described the target antibody associated with sIBM, 43 kDa muscle autoantigen cytosolic 5′-nucleotidase 1a (cN1A), with a sensitivity of 70% and specificity of 92%. The presence of this antibody has become a reliable diagnostic tool in patients who present with a progressive myopathy and other suggestive clinical features.
Anti-Jo-1 is associated with autoimmune polymyositis and extramuscular syndrome involving other organ syndromes, and anti-HMG-CoA-reductase antibodies recently were identified in association with an acquired necrotizing myopathy in statin exposed (and unexposed) patients. These conditions differ from typical sIBM based on a more rapid clinical course, possibly the pattern of weakness, and muscle pathology. TPO antibodies often are associated with autoimmune thyroid disease, which can affect both central and peripheral nervous systems including muscle; however, the presence of antibodies is not necessary for diagnosis in patients with signs and symptoms of an endocrine myopathy. Anti-mitochondrial antibodies are associated with primary biliary cirrhosis, not mitochondrial disease or myopathy, and thus not applicable to this situation.
* Larman HB, Salajegheh M, Nazareno R, et al. Cytosolic 5′-nucleotidase 1A autoimmunity in sporadic inclusion body myositis. Ann Neurol. 2013 Mar;73(3):408-418.
* Goyal NA. The clinical approach to muscle disorders. AAN 2017
* Mozaffar T. Unicorns, dragons, polymyositis, and other mythological beasts: the truth about polymyositis. AAN 2017.